Textbook of

TUBERCULOSIS AND NONTUBERCULOUS

MYCOBACTERIAL DISEASES
 Textbook of
TUBERCULOSIS AND NONTUBERCULOUS
MYCOBACTERIAL DISEASES
Third Edition

Editor
Surendra K Sharma
Former Senior Professor and Head
Department of Internal Medicine
[WHO Collaborating Centre for Research and
Training in Tuberculosis
Centre of Excellence for Extrapulmonary TB
Ministry of Health and Family Welfare, Government of India]
All India Institute of Medical Sciences
New Delhi, India
Adjunct Professor
Department of Molecular Medicine
Jamia Hamdard Institute of Molecular Medicine
Jamia Hamdard [Deemed to be University]
New Delhi, India
Adjunct Professor
Departments of General Medicine and Respiratory Medicine
Jawaharlal Nehru Medical College
Datta Meghe Institute of Medical Sciences [Deemed to be University]
Wardha, Maharashtra, India

Assistant Editor
Alladi Mohan
Chief, Division of Pulmonary and Critical Care Medicine
Professor and Head
Department of Medicine
Sri Venkateswara Institute of Medical Sciences
Tirupati, Andhra Pradesh, India

Foreword
Mario C Raviglione

JAYPEE BROTHERS MEDICAL PUBLISHERS

The Health Sciences Publisher
New Delhi | London
 Jaypee Brothers Medical Publishers (P) Ltd.

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Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases
First Edition: 2001
Second Edition: 2009
Third Edition: 2020
ISBN: 978-93-89129-21-2
 Dedicated to
Our late parents for their encouragement
Our teachers and students for their inspiration
Anju and Himabala for their moral support
Abhishek, Animesh and Vikram Chandra for their cheerful enthusiasm
 Contributors

SK Acharya VH Balasangameshwara Abha Chandra

Former Professor and Head Former Chief Medical Officer Professor and Head
Department of Gastroenterology and National Tuberculosis Institute Department of Cardiovascular and
Human Nutrition Directorate General of Health Services Thoracic surgery
All India Institute of Medical Sciences Bengaluru, Karnataka, India Sri Venkateswara Institute of Medical
New Delhi, India Sciences
D Behera Tirupati, Andhra Pradesh, India
Professor
SK Agarwal
Department of Pulmonary Medicine Rohan Chawla
Professor and Head
Postgraduate Institute of Medical Associate Professor
Department of Nephrology
Education and Research Dr Rajendra Prasad Centre for
All India Institute of Medical Sciences Chandigarh, India Ophthalmic Sciences
New Delhi, India
All India Institute of Medical Sciences
S Bhan New Delhi, India
AN Aggarwal Former Professor and Head
Professor and Head Department of Orthopaedics Vatsla Dadhwal
Department of Pulmonary Medicine All India Institute of Medical Sciences Professor
Postgraduate Institute of Medical New Delhi, India Department Obstetrics and Gynaecology
Education and Research All India Institute of Medical Sciences
Chandigarh, Punjab, India Deepali K Bhat New Delhi, India
Department of Transplant Immunology
and Immunogenetics
Gautam Ahluwalia Chandan J Das
All India Institute of Medical Sciences
Professor Associate Professor
New Delhi, India
Department of Medicine Department of Radiodiagnosis
Dayanand Medical College and Hospital All India Institute of Medical Sciences
Rajesh Bhatia
Ludhiana, Punjab, India New Delhi, India
Former Director
Department of Communicable Diseases
Vineet Ahuja WHO Regional Office for South-East Asia Prasenjit Das
Professor New Delhi, India Additional Professor
Department of Gastroenterology and Department of Pathology
Human Nutrition Vineet Bhatia All India Institute of Medical Sciences
All India Institute of Medical Sciences Medical Officer–MDR-TB New Delhi, India
New Delhi, India Department of Communicable Diseases
World Health Organization Malika Davids
Regional Office for South-East Asia Lung Infection and Immunity Unit
Jason Andrews
New Delhi, India Division of Pulmonology and
Assistant Professor
University of Cape Town Lung Institute
Department of Medicine-Infectious
Gregory Calligaro Department of Medicine
Diseases University of Cape Town
Pulmonologist
Stanford University Cape Town, South Africa
Groote Schuur Hospital
Stanford, California, USA
Researcher at Lung Infection and
Immunity Unit Rodney Dawson
Minu Bajpai Division of Pulmonology and University Professor and Head
Professor and Head of Cape Town Lung Institute UCT Lung Institute
Department of Paediatric Surgery Department of Medicine Department of Medicine
All India Institute of Medical Sciences University of Cape Town University of Cape Town
New Delhi, India Cape Town, South Africa Cape Town, South Africa
viii Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Sajal De Gaurav PS Gahlot Sanjay Gupta

Associate Professor Assistant Professor Chief Medical Officer
Department of TB and Department of Pathology Department of Tuberculosis and
Respiratory Diseases Army Hospital RR Respiratory Diseases
Mahatma Gandhi Institute of Medical New Delhi, India National Institute of Tuberculosis and
Sciences Respiratory diseases
Wardha, Maharashtra, India New Delhi, India
SP Garg
Former Professor
Surendran Deepanjali Dr Rajendra Prasad Centre for Siddhartha Datta Gupta
Associate Professor Professor
Ophthalmic Sciences
Department of Medicine Department of Pathology
All India Institute of Medical Sciences
Jawaharlal Institute of Postgraduate All India Institute of Medical Sciences
New Delhi, India
Medical Education and Research New Delhi, India
Puducherry, India
Haileyesus Getahun
Coordinator Nicola A Hanania
B Dey
TB/HIV and Community Engagement Associate Professor of Medicine
Center for Tuberculosis Research
[THC] Section of Pulmonary and Critical Care
Johns Hopkins School of Medicine
Global TB Programme [GTB] Medicine
Baltimore, MD, USA
World Health Organization [WHO] Baylor College of Medicine
Geneva, Switzerland Houston, Texas, USA
Keertan Dheda
Professor of Respiratory Medicine
Head of the Lung Infection and J Harikrishna
Marzieh Ghiasi
Immunity Unit Associate Professor
McGill International TB Centre
Division of Pulmonology and Department of Medicine
McGill University
University of Cape Town Lung Institute Sri Venkateswara Institute of
Montreal, Quebec, Canada
Department of Medicine Medical Sciences
University of Cape Town Tirupati, Andhra Pradesh, India
Cape Town, South Africa Ankur Goyal
Assistant Professor
CV Harinarayan
Department of Radiodiagnosis
Samjot S Dhillon Director
All India Institute of Medical Sciences
Associate Professor of Oncology Institute of Endocrinology, Diabetes,
New Delhi, India
Roswell Park Cancer Institute Thyroid and Osteoporosis Disorders
Assistant Professor of Medicine Sakra World Hospitals
Department of Medicine KK Guntupalli Bengaluru, Karnataka, India
Pulmonary Medicine and Thoracic Professor of Medicine
Oncology Chief, Pulmonary AK Hemal
State University of New York [SUNY] Critical Care and Sleep Former Professor
Buffalo, New York, USA Medicine Section Department of Urology
Baylor College of Medicine All India Institute of Medical Sciences
Alisgar Esmail Houston, Texas, USA New Delhi, India
Lung Infection and Immunity Unit
Division of Pulmonology and
University of Cape Town Lung Institute Arun K Gupta Md Khurshid Alam Hyder
Department of Medicine Professor and Head Public Health Administrator
University of Cape Town Department of Radiodiagnosis UN House Pulchowk
Cape Town, South Africa All India Institute of Medical Sciences Lalitpur
New Delhi, India Kathmandu, Nepal
Dennis Falzon
Medical Officer Alisha Gupta R Jain
Global TB Programme Department of Paediatric Surgery Center for Tuberculosis Research
World Health Organization All India Institute of Medical Sciences Johns Hopkins School of Medicine
Geneva, Switzerland New Delhi, India Baltimore, Maryland, USA
 Contributors ix

Manisha Jana DR Karnad Amitabh Kumar

Associate Professor Professor and Chief Chest Specialist
Department of Radiodiagnosis Medical-Neuro Intensive Care Unit New Delhi Municipal Corporation
All India Institute of Medical Sciences Department of Medicine [NDMC] Charak Palika Hospital
New Delhi, India Seth GS Medical College and New Delhi, India
KEM Hospital
Mumbai, Maharashtra, India Arvind Kumar
Babban Jee Former Professor
Scientist C Department of Surgical Disciplines
Department of Health Research VM Katoch All India Institute of Medical Sciences
Ministry of Health and Family Welfare Former Secretary New Delhi, India
Government of India Department of Health Research [DHR]
New Delhi, India Ministry of Health and Family Welfare Rajeev Kumar
Government of India Professor
Former Director General Department of Urology
SK Jindal
Indian Council of Medical Research All India Institute of Medical Sciences
Former Professor and Head
New Delhi, India New Delhi, India
Department of Pulmonary Medicine
Postgraduate Institute of Medical NASI—ICMR Chair
Shaji Kumar
Education and Research Public Health Research
Professor
Chandigarh, India Rajasthan University of Health Sciences
Division of Hematology
Jaipur, Rajasthan, India
Mayo Clinic
Thomas Joseph Rochester, Minnesota, USA
Global TB programme Sunil D Khaparde
World Health Organization Former Deputy Director General- Sunesh Kumar
Geneva, Switzerland Tuberculosis Professor
Central TB Division Department of Obstetrics and
Ministry of Health and Family Welfare Gynaecology
Shalini Joshi All India Institute of Medical Sciences
Government of India
Consultant New Delhi, India
New Delhi, India
Department of Internal Medicine
Fortis Hospitals and Health Care T Mohan Kumar
Bengaluru, Karnataka, India Saurav Khatiwada Head of the Department and Chief
Department of Endocrinology and Consultant
Metabolism Institute of Pulmonary Medicine and
SK Kabra
All India Institute of Medical Sciences Research
Professor
New Delhi, India Sri Ramakrishnan Hospital
Department of Paediatrics
Coimbatore, Tamil Nadu, India
All India Institute of Medical Sciences
New Delhi, India
MPS Kohli Jason Limberis
National Consultant Lung Infection and Immunity Unit
Tamilarasu Kadhiravan Public Private Mix [Union SEA Office] Division of Pulmonology and
Additional Professor Central TB Division University of Cape Town Lung Institute
Department of Medicine Directorate General of Health Services Department of Medicine
Jawaharlal Institute of Postgraduate Ministry of Health and Family Welfare University of Cape Town
Medical Education and Research Government of India Cape Town, South Africa
Puducherry, India New Delhi, India
Rakesh Lodha
Professor
Arvind Kumar Kairo SS Kothari Division of Pulmonology, Intensive Care
Assistant Professor Professor and Tuberculosis
Department of ENT and Neck Surgery Department of Cardiology Department of Paediatrics
All India Institute of Medical Sciences All India Institute of Medical Sciences All India Institute of Medical Sciences
New Delhi, India New Delhi, India New Delhi, India
 x Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Knut Lönnroth SP Munigoti John Porter

Professor of Social Medicine Consultant Professor
Karolinska Institutet Department of Endocrinology and London School of Hygiene and Tropical
Senior Consultant Metabolism Medicine
Centre for Epidemiology and Fortis Hospitals and Health Care London, UK
Community Health Bengaluru, Karnataka, India
Stockholm County Council Jagdish Prasad
Department of Public Health Sciences Former Director General of Health
Social Medicin Y Mutheeswaraiah
Services
Stockholm, Sweden Professor and Head
Ministry of Health and Family Welfare
Department of General Surgery
Government of India
Sri Venkateswara Institute of Medical
New Delhi
Govind K Makharia Sciences
Head of Cardiothoracic and
Professor Tirupati, Andra Pradesh, India
Vascular Surgery Department
Department of Gastroenterology and
Safdarjung Hospital
Human Nutrition
HL Nag New Delhi, India
All India Institute of Medical Sciences
New Delhi, India Professor
Department of Orthopaedics Kurupath Radhakrishnan
All India Institute of Medical Sciences Former Senior Professor
NK Mehra New Delhi, India Department of Neurology and Director
Dr CG Pandit National Chair Sree Chitra Tirunal Institute for Medical
Former Dean [Research] Sciences and Technology
Former Professor and Head Sreenivas Achutan Nair Thiruvananthapuram, Kerala, India
Department of Transplant Immunology Stop TB Partnership
Senior Consultant
and Immunogenetics Geneva, Switzerland
Avitis Institute of Medical Sciences
All India Institute of Medical Sciences Palakkad, Kerala, India
New Delhi, India
Jai P Narain
Former Director AK Rai
DK Mitra Department of Communicable Diseases Assistant Professor
Professor and Head WHO Regional Office for South-East Asia Department of Biotechnology
Department of Transplant Immunology New Delhi, India Motilal Nehru National Institute of
and Immunogenetics Technology
All India Institute of Medical Sciences Allahabad, Uttar Pradesh, India
New Delhi, India
Madhukar Pai
Director
M Ramam
McGill Global Health Programs
Professor
Alladi Mohan Associate Director
Department of Dermatology and
Chief, Division of Pulmonary and McGill International TB Centre
Venereology
Critical Care Medicine Professor of Epidemiology All India Institute of Medical Sciences
Professor and Head McGill University New Delhi, India
Department of Medicine Montreal, Quebec, Canada
Sri Venkateswara Institute of Medical
Mario C Raviglione
Sciences
CN Paramasivan Professor
Tirupati, Andhra Pradesh, India
Senior Scientific Advisor Department of Biomedical Sciences for
FIND, India Health
Prasanta Raghab Mohapatra University of Milan
Professor and Head Milan, Italy
Department of Pulmonary Medicine and Tania Di Pietrantonio Former Director
Critical Care McGill University Health Center Global TB Programme
All India Institute of Medical Sciences McGill University World Health Organization
Bhubaneswar, Odisha, India Montreal, Quebec, Canada Geneva, Switzerland
 Contributors xi

Ruma Ray Erwin Schurr K Aparna Sharma

Professor Leader Associate Professor
Department of Pathology Infectious Diseases and Immunity in Department of Obstetrics and
All India Institute of Medical Sciences Global Health Gynaecology
New Delhi, India McGill University Health Centre All India Institute of Medical Sciences
McGill University New Delhi, India
Montreal, Quebec, Canada
Divya Reddy
Pulmonary Division
Aparna Singh Shah Kusum Sharma
Albert Einstein College of Medicine/
Regional Advisor Professor
Montefiore Medical Center
Blood Safety and Laboratory Technology Medical Microbiology
Bronx, New York, USA WHO Regional Office for South-East Asia Postgraduate Institute of Medical
New Delhi, India Education and Research
BB Rewari Chandigarh, India
Scientist–HIV/STI/HEP N Sarita Shah
World Health Organization Regional Associate Chief
Office for South-East Asia Science International Research and SC Sharma
New Delhi, India Programs Branch Professor and Head
Division of Tuberculosis Elimination Department of ENT and Neck Surgery
National Center for HIV, Viral Hepatitis, All India Institute of Medical Sciences
A Roy STD and TB Prevention New Delhi, India
Professor Centers for Disease Control and
Department of Cardiology Prevention
All India Institute of Medical Sciences Atlanta, Georgia, USA Surendra K Sharma
New Delhi, India Former Senior Professor and Head
Aman Sharma Department of Internal Medicine
KS Sachdeva Professor [WHO Collaborating Centre for Research
Deputy Director General–TB Rheumatology Services and Training in Tuberculosis
Central TB Division Department of Internal Medicine Centre of Excellence for Extrapulmonary
Postgraduate Institute of Medical TB, Ministry of Health and Family Welfare,
Directorate General of Health Services
Education and Research Government of India]
Ministry of Health and Family Welfare
Chandigarh, India All India Institute of Medical Sciences
Government of India
New Delhi, India
New Delhi, India
Amit Sharma Adjunct Professor
Chest Specialist
Department of Molecular Medicine
Pournamy Sarathchandran Department of Tuberculosis and
Jamia Hamdard Institute of Molecular
Former Assistant Professor Respiratory Diseases
Medicine
Department of Neurology National Institute of Tuberculosis and
Jamia Hamdard [Deemed to be University]
Sree Chitra Tirunal Institute for Medical Respiratory Diseases
New Delhi, India
Sciences and Technology New Delhi, India
Thiruvananthapuram, Kerala, India Adjunct Professor
Gaurav Sharma Departments of General Medicine and
Scientist I Respiratory Medicine
Kavitha Saravu
Department of Transplant Immunology Jawaharlal Nehru Medical College
Additional Professor
and Immunogenetics Datta Meghe Institute of Medical
Department of Medicine
All India Institute of Medical Sciences Sciences [Deemed to be University]
Kasturba Medical College
New Delhi, India Wardha, Maharashtra, India
Manipal, Karnataka, India

JB Sharma
Jussi Saukkonen Professor Amar Singh
Director Department of Obstetrics and Department of Transplant Immunology
Medical Intensive Care Unit Gynaecology and Immunogenetics
VA Boston Healthcare System All India Institute of Medical Sciences All India Institute of Medical Sciences
West Roxbury, MA, USA New Delhi, India New Delhi, India
 xii Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Divya Singh Srikanth Tripathy Andrew Vernon

Department of Radiodiagnosis Scientist G and Director-in-charge Chief
All India Institute of Medical Sciences National Institute for Research in Clinical Research Branch
New Delhi, India Tuberculosis Division of Tuberculosis Elimination
Chennai, Tamil Nadu, India National Center for HIV, Viral Hepatitis,
Rupak Singla STD and TB Prevention
Head Centers for Disease Control and
Department of Tuberculosis and AK Tyagi Prevention
Respiratory Diseases Vice-Chancellor Atlanta, Georgia, USA
National Institute of Tuberculosis and Guru Gobind Singh [GGS]
Respiratory Diseases Indraprastha University Late VK Vijayan
New Delhi, India Sector 16-C, Dwarka, New Delhi, India Former Advisor
Professor ICMR Bhopal Memorial Hospital and
Ramnath Subbaraman Department of Biochemistry Research Centre
Assistant Professor National Institute for Research in
University of Delhi [South Campus]
Department of Public Health and Environmental Health
New Delhi, India
Community Medicine Former Director
Tufts University School of Medicine Vallabhbhai Patel Chest Institute
Boston, MA, USA University of Delhi
Mukund Uplekar
Former Senior Medical Officer Delhi, India
Grant Theron Policy, Strategy and Innovations Unit
Lung Infection and Immunity Unit
Global TB Programme Kamini Walia
Division of Pulmonology and University
World Health Organization Scientist F
of Cape Town Lung Institute
Geneva, Switzerland Indian Council of Medical Research
Department of Medicine
Hon. Professor New Delhi, India
University of Cape Town
Cape Town, South Africa Interdisciplinary School of
Health Sciences Diana Weil
Deanna Tollefson Pune University Coordinator
Epidemiologist Pune, Maharashtra, India TB Policy, Strategy and Innovations [PSI]
International Research and Programs Global TB Programme [GTB]
Branch World Health Organization [WHO]
Division of Tuberculosis Elimination Pradeep Venkatesh Geneva, Switzerland
National Center for HIV, Viral Hepatitis, Professor
STD and TB Prevention Dr Rajendra Prasad Centre for Ting-Heng Yu
Centers for Disease Control and Ophthalmic Sciences McGill University Health Center
Prevention All India Institute of Medical Sciences McGill University
Atlanta, Georgia, USA New Delhi, India Montreal, Quebec, Canada
 Foreword

“Rarely has any epidemic tormented the humankind with the tenacity and destructive impact of tuberculosis [TB]…TB
still constitutes a social, economic and political threat set to impede development of entire populations…”. This is what
I said in my foreword to the previous edition of this book in 2009. It is hardly surprising that the statements remain true
nine years later. On the occasion of the publication of the new edition that will explore in-depth from all angles this ancient
disease, I feel honoured to have been asked by Professor Surendra K Sharma, for a second time in a row, to write a foreword
of his Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases—3rd edition, a book that is a true state-of-the-art
manual on the disease. In the Global TB Report of the World Health Organization [WHO], published in October 2017 when
I was still director of the Global TB Programme, we highlighted several important facts. First, thanks to recent intensive
efforts to improve the collection and reporting of data through special surveys and surveillance, WHO now estimates that
there may be over a million more cases of TB than previously believed. This translated into 10.4 million people developing
TB in 2016 and 1.7 million dying of it. Second, the report stresses that, despite the rise in absolute numbers, the mortality
rate from TB continues falling at about 3% per year. As a result of control efforts, an estimated 53 million lives have been
saved since 2000. This is encouraging; however, the TB incidence rate is declining very slowly at an average of 1.5% a year.
With such an enormous toll in terms of number of deaths, TB, remains the biggest killer from a single infectious agent.
Thirdly, over 4 million people who develop TB are still being ‘missed’ by health systems each year: a large number of
them are not diagnosed due to poor access to services or lack of capacity; and an even larger number is probably diagnosed
and treated somehow outside the public sector but not notified. Fourth, the global multidrug-resistant TB [MDR-TB] crisis
continues, with an estimated 600,000 new MDR-TB and rifampicin-resistant cases in 2016. A trend analysis revealed that
the estimated percentage of new TB cases with MDR-TB globally remains roughly unchanged at 4%. However, severe
epidemics still ravage some regions, particularly Eastern Europe and Central Asia. Extensively drug-resistant TB
[XDR-TB], which is more expensive and difficult to treat than MDR-TB, has now been reported in most countries that are
capable of detecting it. Unfortunately, the progress in the MDR-TB response has been far too slow: while there has been
an increase of cases being diagnosed thanks to more laboratories rolling out rapid tests, only less than a quarter of the
estimated cases are being detected and treated. In 2019, at the time of publication of the 3rd edition of this book, therefore,
several major challenges remain to be faced. The first one is to ensure that all the cases are diagnosed, managed successfully
and notified; the second is to respond effectively to the MDR-TB crisis; the third is to consolidate achievements in the
response to HIV-associated TB; the fourth is to ensure research efforts are urgently intensified so that innovations emerge
within years instead of decades; and the fifth is to ensure all financial gaps in both control and research efforts are filled.
In May 2014, the World Health Assembly of WHO approved—through an historical resolution—a set of new and ambitious
targets for 2030 and 2035 to be reached through a new global TB strategy. This new End TB Strategy, based on three pillars
and four fundamental principles, incorporates all possible elements that are essential for a recipe towards TB elimination.
The TB-specific interventions are included in the first pillar of the new strategy: it consists of a modern version of DOTS
[1994-2005] and the Stop TB Strategy [2006-2015], which incorporates all technological innovations from early diagnosis
of TB and universal drug susceptibility testing using rapid molecular tests to treatment of all types of TB and management
of latent infection among people with a higher risk of getting TB. The second pillar consists of those broad health system
policies that are essential to render any disease control effort successful: these include regulatory approaches such as
mandatory case notifications and rational drug use, as well as essential far-reaching measures like universal health coverage
and social protection to ensure that the poorest among the poor can access care. The third pillar emphasises the role of
research and rapid intake and adaptation of all innovations in all countries world-wide. It is in this context that the
publication of the 3rd edition of this book by Professor Surendra K Sharma is particularly important. Indeed, this edition
represents a major advance over the previous ones as it is based on the feedback received from different categories of
students and health professionals and adapted to the needs of such different audiences. As a result of a “client survey”,
the editor decided to develop a set of two different textbooks: an elaborate version for postgraduates and more advanced
readers and a compact one providing the essentials for undergraduate students. The larger version, similar to the
2nd edition, although slimmer and more user-friendly, is a comprehensive and well-referenced textbook. It will contain
chapters focused on clinical aspects—a true reference for clinicians managing patients with any variety of TB. It will also
present the very basics of TB, from epidemiology to bacteriology, from genetics to immunology, and from diagnosis to
treatment. In some cases, the old chapters have been merged to make them more easily accessible. For some new areas,
xiv Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

such as the place of TB in the post Millennium Development Goal [MDG] agenda or the engagement of communities in
TB care, new chapters have been added. Continuing its laudable trend, the inclusion of many chapters devoted to public
health and control aspects in this edition makes this textbook an international reference in a broader sense. Above all,
there are chapters that examine the delicate interface between public services and the private and non-state sector, an issue
that must be faced with an innovative spirit given its challenging nature, and the fundamental infection control measures
often neglected in many countries. Importantly, for every clinical and public health practitioner, the book contains a
description of the WHO’s new global strategy—the End TB Strategy 2016-2035—and the International Standards of TB
Care including their adaptation in the Indian context. These chapters provide the most modern and innovative thinking
about the way the TB epidemic must be addressed at the bedside, in the clinics, and in the health centres supervised by
TB control programmes. The second compact version of the book is a practical “handbook” for young undergraduates to
carry in the pockets of a coat. This will contain the essential information with additional sections made available “on-line”.
It is intended as a rapid reference to help quick learning and action. Naturally, to cover all needs and provide the best
possible information to readers, a remarkable panel of authors has been put together by Professor Sharma; it includes both
experts from India and international authorities. In conclusion, the two versions of this prestigious textbook, devoted
to a major disease that has affected humanity since its beginning, have all the characteristics to consolidate the
previous edition’s reputation of an authoritative and international reference for all readers. The fact that it is conceived
and produced in India, the country which not only has the highest TB burden in the world, but has also contributed to
many of the major advances in TB care and control over the past decades, is symbolic. And the fact that it is published in
the historical year during which TB will be the subject of a high-level meeting of leaders at the United Nations General
Assembly adds value to a book that expresses the latest scientific knowledges about the crucial topic of TB. It is my hope
that this modern and up-to-date textbook becomes a fundamental companion for all junior and senior practitioners tackling
TB prevention, care and control in India, elsewhere in Asia, and world-wide so that our global fight against this ancient
disease can be better informed and more effective.

Mario C Raviglione FRCP [UK] FERS Hon RSP [RF]

Professor
Department of Biomedical Sciences for Health
University of Milan
Milan, Italy
Former Director
Global TB Programme
World Health Organization
Geneva, Switzerland
 Preface to the Third Edition

The first edition of Tuberculosis book in 2001 was widely acclaimed not only in India and South-East Asia, but also in several
other parts of the world. Subsequently, the second edition of Tuberculosis was published in 2009 which was well received
and established itself as a standard textbook on tuberculosis [TB]. The last decade has witnessed phenomenal changes in
our understanding of TB and there have been overwhelming requests for updating this textbook. Further, major advances
have also occurred in nontuberculous mycobacterial [NTM] diseases in the recent years. This prompted us to bring out the
third edition of the book which is now titled Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases with an aim
to provide a well referenced standard textbook on TB and NTM diseases that will chronicle the rich and vast experience
of clinicians and researchers from across the globe.
This edition has several new contributors, all of them are leading authorities, from various parts of the world. All the
chapters have been thoroughly re-written and updated, many of them are by new but renowned contributors. Several
new high quality clinical, radiographic images, gross pathology specimen photographs, and photomicrographs have been
included in this edition for the readers’ convenience. This edition documents the rapid advances that have occurred at a
blistering pace in TB diagnosis, universal drug-susceptibility testing [DST] and treatment of dug-susceptible and drug-
resistant TB, including multidrug-resistant and extensively drug-resistant TB [M/XDR-TB], programmatic management of
drug-resistant TB, public-private mix, the ENGAGE-TB approach, and END TB strategy, among others. The present edition
includes recent classification of drugs and drug combinations including recent generation quinolones, bedaquiline and
linezolid used in treating M/XDR-TB and a chapter detailing the latest developments in the field of laboratory diagnosis
and management of NTM diseases.
We sincerely believe that the third edition will help undergraduate and postgraduate medical students and medical
college faculty members in updating their knowledge. We hope that it will continue to be a valuable source of reference
to researchers and enhance the understanding of practising physicians and contribute to patient management. The third
edition is also envisaged to be a practical guide for health care workers, nurses, and other paramedical staff.
This effort would not have been possible but for the kind co-operation and magnanimity of our contributors who spared
their valuable time and patiently went through endless series of revisions and constant updating. We would like to thank
Shri Jitendar P Vij [Group Chairman], Mr Ankit Vij [Managing Director], Ms Chetna Malhotra Vohra [Associate Director–
Content Strategy] of M/s Jaypee Brothers Medical Publishers [P] Ltd, New Delhi, India, for their encouragement and
support, and excellent technical assistance. Our families have stood by us through these turbulent times and without their
unstinting support and constant encouragement, this third edition would not have materialised.

Surendra K Sharma
Alladi Mohan
 Preface to the First Edition

Tuberculosis is an ancient disease which continues to haunt us even as we step into the next millennium. Tuberculosis is
the most common cause of death world over due to a single infectious agent in adults and accounts for over a quarter of all
avoidable deaths globally. One-third of India’s population is infected with Mycobacterium tuberculosis, there are 12 million
active tuberculosis cases in India. One person dies of tuberculosis every minute in India. The deadly synergy between
Mycobacterium tuberculosis and the human immunodeficiency virus [HIV] has resulted in a resurgence of tuberculosis
world over. The impact of this “cursed duet” on human suffering has been enormous. With HIV making rapid inroads in
India, the spectre of dual infection with HIV and tuberculosis is going to be a daunting prospect. In spite of this gloomy
scenario, the treatment of tuberculosis is one of the most cost-effective methods of cure. Research work carried out in India
has had a tremendous impact on tuberculosis control. The observations from the well-known, randomized controlled trial
“The Madras Study” carried out at the Tuberculosis Research Centre [TRC], Chennai, Tamil Nadu, India, established
the efficacy of the domiciliary treatment and has paved the way for the National Tuberculosis Programme in India and
several other countries. Pioneering contributions from eminent clinicians, bacteriologists and epidemiologists from the
TRC, Chennai; National Tuberculosis Institute, Bangalore; Sanatoria at Madanapalle, Kasauli, Dharampur, Bhowali,
have greatly enhanced our understanding of tuberculosis.
The changing clinical presentation of tuberculosis, advances in laboratory and imaging diagnostic modalities and
therapeutic measures such as directly observed treatment, short-course [DOTS] all suggest a pressing need to have a
recent textbook of tuberculosis. Furthermore, while every doctor working in India encounters the disease in one or other
form, very little has been documented regarding the Indian perspective of tuberculosis. Often, the medical students,
postgraduates and researchers returning empty handed from libraries expressed their desire for a book which documents
the Indian experience. Paucity of a well referenced, standard textbook of tuberculosis, which chronicles the rich and vast
clinical experience of clinicians from India prompted us to undertake this venture. We have attempted to present a picture
of tuberculosis as it is seen in India with contributions from experts who have vast experience in managing tuberculosis
in the Indian setting. Our book contains chapters on History, Pathology, Epidemiology, Clinical Presentation, Diagnosis,
Treatment, Prevention and Control of tuberculosis highlighting the Indian perspective of tuberculosis. We have also
provided guidelines published by the authorities concerned with tuberculosis control, and other statements as useful
appendices. Though we have made an effort to maintain a uniform style and format, we have been careful to preserve
the views expressed by the contributors in their original form. As we step into the new millennium, it is obvious that the
crusade against this ancient foe of mankind is still going on. Contrary to the wishful thinking in the 1980s, tuberculosis still
remain to be a research priority of paramount importance and is an important component of curricula of medical schools.
Keeping in mind the need of the hour, we have attempted to highlight the rationale behind DOTS and its importance in
tuberculosis control. We believe that our book will help undergraduate and postgraduate medical students to update their
knowledge. It will also be a source of reference to researchers and better the understanding of practising physicians and
help in patient management. We also hope that the book can serve as a practical guide on the management of tuberculosis
to health care workers, nurses and other paramedical staff.
A book of this magnitude would not have been possible but for the magnanimity and kindness of our contributors
who took time off their busy schedule to prepare their manuscripts. We would like to thank Mr Jitendar P Vij,
Chairman and Managing Director and Mr RK Yadav, Publishing Director, M/s Jaypee Brothers Medical Publishers Pvt
Ltd., for their support, co-operation and technical excellence. Without the unstinting support, constant encouragement and
help from our families this endeavour would not have been possible.

S.K. Sharma
A. Mohan
 Acknowledgements

We would like to especially thank the M/s Jaypee Brothers Medical Publishers [P] Ltd, New Delhi, India, who have granted
permissions to reproduce various items from their published work and these have duly acknowledged in the respective
chapters. An invaluable help of the World Health Organization [WHO], Geneva, Switzerland for liberally granting
permission to reproduce figures and tables from several publications is gratefully acknowledged.
We express our sincere gratitude to the following Drs Mario Raviglione, Dennis Falzon, Mukund Uplekar, Knut Lonnroth,
Deanna Tollefson, N Sarita Shah, Andrew Vernon, Haileyesus Getahun, Mr Thomas Joseph, Drs Sreenivas A Nair,
Md Khurshid Alam Hyder, Vineet Bhatia, Diana Weil, Divya Reddy, Jussi Saukkonen, Keertan Dheda, Erwin Schurr,
Madhukar Pai and John Porter, for their excellent contributions. Special thanks are also due to Dr PC Hopewell, University
of California, San Francisco, USA for his suggestions on the International Standards for Tuberculosis Care [ISTC].
We especially thank Dr Jai P Narain, Former Director, Department of Communicable Diseases, WHO Regional Office for
South-East Asia, New Delhi, Dr Jagdish Prasad, Former Director General of Health Services [DGHS], Ministry of Health and
Family Welfare, Government of India [MoH & FW, GoI], Dr LS Chauhan, Former Deputy Director General [Tuberculosis],
Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India,
for their valuable contributions, critical comments, stimulating discussions, constant support and encouragement. We
would like to thank Dr VM Katoch, Former Secretary, Department of Health Research [DHR], MoH & FW, GoI, and
Former Director General, Indian Council of Medical Research [ICMR], New Delhi, and Dr CN Paramasivan, Foundation
for Innovative New Diagnostics [FIND], India, for their constant encouragement.
We thank Dr KS Sachdeva, Deputy Director General [Tuberculosis], Central TB Division, Directorate General of Health
Services, MoH & FW, GoI, for his constant support and encouragement. We also wish to thank Directors of National Institute
of Tuberculosis and Respiratory Diseases [NITRD], New Delhi; ICMR-National Institute for Research in Tuberculosis [NIRT],
Chennai and National Tuberculosis Institute [NTI], Bengaluru, Karnataka, the administration of Arogyavaram Medical
Centre, Madanapalle, Andhra Pradesh, and TB Sanatorium at Bhowali, Uttarakhand for permitting us to reproduce the
images of these well known institutions.
We are grateful to the Departments of Pathology, All India Institute of Medical Sciences [AIIMS], New Delhi;
Sri Venkateswara Institute of Medical Sciences [SVIMS], Tirupati, Andhra Pradesh; and Postgraduate Institute of Medical
Education and Research [PGIMER], Chandigarh for providing gross pathology specimen figures and histopatho­
logy photomicrographs. We wish to thank the Departments of Radio­d iagnosis, AIIMS, New Delhi and SVIMS,
Tirupati for providing classic radiographic imaging figures. We sincerely thank Dr Ajay Garg, Department of Neuroradio­
logy, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi for providing radio­graphic images,
Dr C Narasimhan, CARE Hospitals, Hyderabad, Telangana, India, Dr Tara Roshini Paul, Professor, Department of Pathology,
Nizam’s Institute of Medical Sciences, Hyderabad, for providing echocardiographic images, photomicrographs respectively.
We also wish to thank faculty members of AIIMS, New Delhi; SVIMS, Tirupati; and other medical colleges across
India and several other parts of the world, several generations of undergraduate and postgraduate students, for their
constructive criticism and useful suggestions during our discussions. These inputs were indeed useful for the Third Edition
of the book.
Invaluable help rendered by Dr Krishna Srihasam, Boston, USA; and Dr Srinivas Bollineni, Dallas, USA, in getting full
text references is also thankfully acknowledged. We also wish to thank Mr Alladi V Srikumar’s timely help with broadband
connectivity.
 Contents

1. History............................................................................................................................ 1
Alladi Mohan, Surendra K Sharma

2. Epidemiology of Tuberculosis: Global Perspective.......................................................................13

Dennis Falzon, Knut Lönnroth, Mario C Raviglione

3. Pathology of Tuberculosis....................................................................................................25
Siddhartha Datta Gupta, Prasenjit Das, Gaurav PS Gahlot, Ruma Ray

4. The Mycobacteria..............................................................................................................52
Aparna Singh Shah, Rajesh Bhatia

5. Immunology of Tuberculosis.................................................................................................59
DK Mitra, AK Rai, Amar Singh

6. Genetic Susceptibility Parameters in Tuberculosis......................................................................73

NK Mehra, Gaurav Sharma, Deepali K Bhat

7. Genetics of Susceptibility to Tuberculosis.................................................................................92

Ting-Heng Yu, Tania Di Pietrantonio, Erwin Schurr

8. Laboratory Diagnosis of Tuberculosis: Best Practices and Current Policies....................................... 106

Madhukar Pai, Marzieh Ghiasi, Kavitha Saravu

9. Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis............................. 113

Chandan J Das, Ankur Goyal, Divya Singh

10. Pulmonary Tuberculosis.................................................................................................... 146

VK Vijayan, Sajal De

11. Lower Lung Field Tuberculosis............................................................................................ 155

Gautam Ahluwalia, Surendra K Sharma

12. Endobronchial Tuberculosis................................................................................................ 160

Samjot S Dhillon, Nicola A Hanania

13. Tuberculosis Pleural Effusion.............................................................................................. 175

AN Aggarwal

14. Silicotuberculosis............................................................................................................ 200

Prasanta Raghab Mohapatra
xxii Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

15. Abdominal Tuberculosis.................................................................................................... 208

Govind K Makharia

16. Granulomatous Hepatitis................................................................................................... 222

Vineet Ahuja, SK Acharya

17. Neurological Tuberculosis.................................................................................................. 230

Pournamy Sarathchandran, Kurupath Radhakrishnan

18. Tuberculosis and Heart..................................................................................................... 253

SS Kothari, A Roy

19. Skeletal Tuberculosis....................................................................................................... 267

S Bhan, HL Nag

20. Musculoskeletal Manifestations of Tuberculosis....................................................................... 294

Aman Sharma, Kusum Sharma

21. Cutaneous Tuberculosis.................................................................................................... 302

M Ramam

22. Lymph Node Tuberculosis.................................................................................................. 313

Saurav Khatiwada, Arvind Kumar

23. Tuberculosis in Head and Neck............................................................................................ 326

Arvind Kumar Kairo, SC Sharma

24. Ocular Tuberculosis......................................................................................................... 335

Pradeep Venkatesh, Rohan Chawla, SP Garg

25. Tuberculosis in Pregnancy ................................................................................................. 346

Sunesh Kumar, Vatsla Dadhwal, K Aparna Sharma

26. Female Genital Tuberculosis .............................................................................................. 354

Sunesh Kumar, JB Sharma

27. Genitourinary Tuberculosis ................................................................................................ 368

Rajeev Kumar, AK Hemal

28. Tuberculosis in Chronic Kidney Disease................................................................................. 379

SK Agarwal

29. Disseminated/Miliary Tuberculosis....................................................................................... 391

Surendra K Sharma, Alladi Mohan

30. Tuberculosis at Uncommon Body Sites................................................................................... 411

Y Mutheeswaraiah, J Harikrishna
 Contents xxiii

31. Complications of Pulmonary Tuberculosis............................................................................... 419

D Behera

32. Tuberculosis and Acute Respiratory Distress Syndrome.............................................................. 432

DR Karnad, KK Guntupalli

33. Haematological Manifestations of Tuberculosis ....................................................................... 442

Shaji Kumar

34. Endocrine Implications of Tuberculosis.................................................................................. 453

CV Harinarayan, Shalini Joshi, SP Munigoti

35. Tuberculosis and Human Immunodeficiency Virus Infection.......................................................... 466

BB Rewari, Amitabh Kumar, Srikanth Tripathy, Jai P Narain

36. Tuberculosis in Children ................................................................................................... 483

SK Kabra, Rakesh Lodha

37. Surgical Aspects of Childhood Tuberculosis............................................................................. 495

Minu Bajpai, Alisha Gupta, Manisha Jana, Arun K Gupta

38. Tuberculosis in the Elderly................................................................................................. 506

Surendran Deepanjali, Tamilarasu Kadhiravan

39. Tuberculosis in Health Care Workers..................................................................................... 520

SK Jindal

40. Nutrition and Tuberculosis................................................................................................. 529

Ramnath Subbaraman, Jason Andrews

41. Nontuberculous Mycobacterial Infections................................................................................ 540

VM Katoch, T Mohan Kumar, Babban Jee

42. Drug-resistant Tuberculosis................................................................................................ 579

Keertan Dheda, Grant Theron, Gregory Calligaro, Jason Limberis, Malika Davids, Alisgar Esmail, Rodney Dawson

43. Antituberculosis Drug Resistance Surveillance......................................................................... 609

CN Paramasivan, VH Balasangameshwara

44. Treatment of Tuberculosis.................................................................................................. 621

Rupak Singla, Sanjay Gupta, Amit Sharma

45. Hepatotoxicity Associated with Anti-tuberculosis Treatment......................................................... 637

Divya Reddy, Jussi Saukkonen

46. Surgery for Pleuropulmonary Tuberculosis.............................................................................. 644

Abha Chandra
 xxiv Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

47. Stopping TB: The Role of DOTS in Global Tuberculosis Control...................................................... 654
Deanna Tollefson, N Sarita Shah, Andrew Vernon

48. The Role of Medical Colleges in Tuberculosis Control................................................................. 668

D Behera, MPS Kohli, Jai P Narain

49. Public-Private Mix for TB Care............................................................................................. 676

Mukund Uplekar, Sreenivas Achutan Nair

50. Building Partnerships for Tuberculosis Control......................................................................... 684

Vineet Bhatia, Md Khurshid Alam Hyder

51. Integrating Community-based Tuberculosis Activities into the Work of Non-governmental and
other Civil Society Organisations [The ENGAGE-TB Approach]....................................................... 697
Haileyesus Getahun, Thomas Joseph

52. WHO’s New End TB Strategy............................................................................................... 704

Mukund Uplekar, Diana Weil

53. The Revised National Tuberculosis Control Programme.............................................................. 712

Jagdish Prasad, Sunil D Khaparde, KS Sachdeva

54. Tuberculosis Vaccine Development: A Current Perspective........................................................... 727

AK Tyagi, B Dey, R Jain

55. Ethical and Legal Issues in Tuberculosis Control....................................................................... 746

John Porter

56. Airborne Tuberculosis Transmission and Infection Control Strategies.............................................. 759

Kamini Walia, Jai P Narain

57. Standards for TB Care in India............................................................................................. 768

58. International Standards for Tuberculosis Care.......................................................................... 797

59. Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India]..................................... 886

Index......................................................................................................................................................................961
 1
History
Alladi Mohan, Surendra K Sharma

INTRODUCTION TUBERCULOSIS IN ANCIENT TIMES

As a destroyer of mankind, tuberculosis has no equal... It is thought that TB probably existed in cattle before its
VA Moore (1) advent in man.
Tuberculosis [TB] has been a major cause of suffering muncami tva havisa jivanayakam
and death since times immemorial. Thought to be one of agnatayaksmad uta rajayakshma...
the oldest human diseases, the history of TB is at least as [I deliver you by means of oblation so that you may live from
old as the mankind. Over the years, not only the medical the unknown disease and from the “rajayakshma”]
implications but also the social and economic impact of TB [RV, X,161,1]
has been enormous.
There have been references to this ancient scourge in the In the Krishna Yajurveda Samhita, there is reference
Vedas [vide infra] and it was called “rajayakshma” [meaning to how, Soma [Moon] had been affected by “yakshma”.
“wasting disease”]. Hippocrates [460-377 B.C.] called the Since “Soma”, who was the “King and Ruler” was affected
disease “pthisis”, a Greek word which meant “to consume”, by “yakshma”, it came to be known as “rajayakshma”
“to spit” and “to waste away“ (2,3). The word “consumption” [Figure 1.1].
[derived from the Latin word “consumere”] has also been In Sanskrit, the disease has been called “rajayakshma”,
used to describe TB in English literature. The Hebrew word “ksayah”, and “sosa”.
“schachepheth” [meaning “waste away”] has been used in
Rajayakshma ksayah soso rogarad iti cha smritah
the Bible. J.L. Schonlein, Professor of Medicine at Zurich,
naksatranam, dvijanam cha rajno bhud yad aym pura
is credited to have named the disease “tuberculosis” (1).
yach cha raja cha yakshma cha rajayakshma tato matah
The word “tuberculosis” is a derivative of the Latin word
[Vagabhatta, Ast-s and Ast-hrd, Nidana V, 1-2]
“tubercula” which means “a small lump” (2,4,5). Several
names have been used to refer to TB in the years gone by. Krodho yakshma jvaro roga eko ‘rtho dukhasamjnitah
Acute progressive TB has been referred to as “galloping yasmat sa rajnah prag asid rajayakshma tatomatah
consumption”. Pulmonary TB has been referred to as “tabes [Charaka Samhita, Chikitsasthanam VIII, 11]
pulmonali”. Tuberculosis cervical lymphadenitis has been
called as “scrofula”, “King’s Evil”, “stroma”. Abdominal Changes resembling those caused by TB have been
TB has been called as “tabes mesenterica”. Cutaneous TB described in the skeletal remains of neolithic man (7).
has been called “lupus vulgaris”. Vertebral TB has been Terms such as “lung cough” and “lung fever” have been
called as “Pott’s disease”. Oliver Wendell Holmes referred used in ancient Chinese literature to describe a disease
to the disease as “white plague” (6). While scores of other which might have been TB (8). There have been references
diseases like smallpox and plague killed millions of people, to what could have been TB in the Code of Hammurabi
their reign has been relatively short-lived. Tuberculosis has of the Babylonian era (6). Evidences of TB lesions of bone
been ever present and is resurging with a vengeance. have also been found in Egyptian mummies dating back
 2 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 1.1: Krishna Yajurveda Samhita, II kanda, III prasna, V anuvaka, 25th stanza, where the legend of “Soma” being afflicted with “rajayakshma”
is described

to 3400 B.C. (7). Mycobacterium tuberculosis has been Cappodocian [50 B.C.], in his book The causes and symptoms
demonstrated microscopically in the mummy of a child of of chronic diseases gave a very accurate description of TB and
five years (8). mentioned that fever, sweating, fatigue and lassitude were
There are several references to conditions resembling symptoms of the TB. He suggested testing the sputum with
TB in Greek literature by Homer [800 B.C.], Hippocrates, fire or water was of diagnostic value (7). Galen described
Aristotle [384-322 B.C.] and Plato [430-347 B.C.], that patients with “consumption” manifest cough, sputum,
Galen [129-199], Vegetius [420] were also familiar with wasting, chest pain and fever and considered haemoptysis
consumption. Arabic physicians Al Razi [850-953], Ibn Sina to be pathognomonic of the disease (6).
[980-1037] correlated lung cavities with skin ulceration. Following the pioneering efforts by Andreas Vesalius
During the middle ages, there are records of healing [1514-1564] post-mortem examination was performed
touch of monarchs was being used to treat “scrofula” frequently. This method of study facilitated understanding
[King’s Evil]. King Charles II bestowed the royal touch on of pathological findings, such as, lung cavities, empyema
an astounding 92,102 patients with “scrofula” (9). By around among others. Franciscus de Boe [1614-1672] [also known
1629, death certificates in London specified the disease as as Sylvius] for the first time associated small hard nodules
“consumption” which was a leading cause of death. By discovered in various tissues at autopsy with symptoms of
this time the contagious nature of TB was strongly believed “consumption” which the patients suffered during their life-
though there were people who contested this opinion. time though his explanation for the same was not correct (7).
The Republic of Lucca is credited to have passed the first John Jacob Manget in 1700 gave the description of classical
legislative action aimed at controlling TB in the world (4,9). miliary TB (10). The clinical presentation of consumption was
This was followed by similar measures in several Italian described in detail by Thomas Willis [1621-1675]. Richard
cities and Spain. Morton [1637-1698] had described several pathological
appearances of “pthisis” in his treatise Pthisiologica (4-6,7).
DIAGNOSIS Meaningful clinical examination became possible with
the description of the technique of percussion by Leopold
Why, when one comes near consumptives... does one Auenbrugger [1722-1809]. However, Auenbrugger’s
contract their disease, while one does not contract work was virtually ignored until the time of Jean Nicolas
dropsy, apoplexy, fever, or many other ills?.... Covisart [1775-1821], who rediscovered and propagated the
Aristotle technique. Gaspard Bayle [1774-1816] accurately described
In the early days, diagnosis of TB was based on symptoms many of the pathological changes of TB, but unfortunately
and signs. In Charaka Samhita [Nidanasthana, VI, 14], succumbed to the disease which he probably contracted
heaviness in the head, coughing, dyspnoea, hoarseness of while performing autopsy studies (11). The technique of
voice, vomiting of phlegm, spitting of blood, pain in the sides physical examination of the lung was further refined by
of the chest, grinding pain in the shoulder, fever, diarrhoea the invention of stethoscope by Rene Theophile Hyacinthe
and anorexia have been described as the eleven symptoms Laënnec [1781-1826], who was a student of Corvisart and a
of TB. Furthermore, a physician who is well versed in the friend of Bayle. Sadly, Laennec, his younger brother, mother
aetiology, clinical presentation and premonitory symptoms and two uncles all succumbed to TB (6).
of “consumption” was considered to be a “Royal Physician” Fracastorius [1443-1553] is credited to have originated the
[Charaka Samhita, Nidanasthana, VI, 17]. “germ theory” and believed that TB was contagious. He also
The earliest classical descriptions of TB in Greek literature mentioned about antiseptics in his chapter on the treatment
date back to the writings by Hippocrates. Aretaeus the of TB. In 1720, the English physician Benjamin Marten
 History 3

conjectured, in his publication A new theory of consumption,

that TB could be caused by “certain species of animalcula
or wonderfully minute living creatures”, which, once they
had gained a foothold in the body, could generate the lesions
and symptoms of the disease. He also stated that
“it may be therefore very likely that by an habitual lying in
the same bed with a consumptive patient, constantly eating
and drinking with him, or by very frequently conversing so
nearly as to draw in part of the breath he emits from the lungs,
consumption may be caught by a sound person...I imagine that
slightly conversing with consumptive patients is seldom or
never sufficient to catch the disease” (12)
For unknown reason the work of Marten went into
oblivion for a long time. The likely reason could be that he
was thinking very much ahead of his time. Jean Antoine
Villemin [1827-1892] in a series of experiments provided
conclusive evidence that TB was indeed a contagious disease
though some workers of that era did not accept these results.
He presented his results to the Academie de Medcine on
December 5, 1865 and stated that TB was a specific infection
caused by an inoculable agent (3,6).
“During my wandering through medicine, I encountered sites
where gold was lying around. It needs a lot of serendipity
to distinguish gold from ignobility; this, however, is not a
Figure 1.2: Robert Koch: the discoverer of Mycobacterium tuberculosis
particular achievement.” Reproduced with permission from “Rubin SA. Tuberculosis. The
 Robert Koch (13) captain of all these men of death. Radiol Clin North Am 1995;33:619-
Robert Heinrich Herman Koch [Figure 1.2], son of 39 (reference 6)”
a mining engineer, was born on December 11, 1843 in
Clausthal village in the Harz mountains (3,6,14,15). Koch Table 1.1: World TB Day themes
pursued medical studies at the Gottingen University in
Year World TB Day theme
1862 and qualified maxima cum laude in 1866 with his M.D.
thesis on succinic acid. On March 24, 1882 Koch announced 1997 Use DOTS more widely
1998 DOTS success stories
the discovery of the tubercle bacillus during the monthly
1999 Stop TB, use DOTS
evening meeting of the Berlin Physiological Society. In 1884, 2000 Forging new partnerships to stop TB
he published a more comprehensive paper Die aetiologic der 2001 DOTS: TB cure for all
tuberculose in the second volume of the Reports of the Imperial 2002 Stop TB, fight poverty
Health Office. In 1905, he was awarded the Nobel Prize for 2003 DOTS cured me–It will cure you too!
his contributions in the field of TB research (3,5,6). In 1982, 2004 Every breath counts–stop TB now
2005 Frontline TB care providers: Heroes in the fight against TB
a century after Dr Koch’s announcement, the World Health 2006 Actions for life–Towards a world free of TB
Organization [WHO] and the International Union Against 2007 TB anywhere is TB everywhere
Tuberculosis and Lung Disease [IUATLD], now called The 2008 I am stopping TB
Union proposed the 24th March as the “World TB Day” as a 2009 I am stopping TB
part of a year-long centennial effort under the theme “Defeat 2010 On the move against TB: Innovate towards action
TB: Now and Forever.” Thereafter, since 1996, 24th March is 2011 On the move against TB: Transforming the fight towards
elimination
celebrated as “World TB Day” every year (16,17). The event 2012 Call for a world free of TB
was intended to educate the public about the devastating 2013 Stop TB in my lifetime
health and economic consequences of TB, and its continued 2014 Reach the three million–A TB test, treatment and cure for all
tragic impact on the global health. Each “World TB Day” 2015 Gear up to end TB
addresses a different theme [Table 1.1]. Robert Koch died 2016 United to end TB
2017 Let’s unite to end TB
on May 27, 1910, aged 66 years.
2018 Wanted: Leaders for a TB-free world
It was Robert Koch who finally demystified the secret of
TB = tuberculosis; DOTS = directly observed treatment, short-course
the cause of TB and after thousands of years, the organism
finally revealed itself to humans. Though, Robert Koch was
wrong in his belief that tuberculin would cure TB, tuberculin With the advent of Wilhelm Conrad Roentgen [1845-1923],
became an invaluable tool for the diagnosis of latent TB the technique of radiological imaging became available.
infection (18). Francis Williams in Boston, L. Bouchard and A. Beclere
4 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

in France, John MacIntyre and David Lawson in Britain ‘Tis called the evil:
were pioneers in the use of radiography in the study A most miraculous work in this good king;
of TB (3,6). By this time, the deep mystery that was TB Which often since my here-remain in England
became demystified to some extent in that basic concepts of I have seen him do. How he solicits heaven,
the agent, the pathology as a result of it and its detection Himself best knows; but strangely visited people,
became established ushering in the era of definitive diagnosis All swollen and ulcerous, pitiful to the eye,
of TB. The mere despair of surgery, he cures,
Hanging a golden stamp about their necks,
TREATMENT Put on with holy prayers; and ’tis spoken,
To the succeeding royalty he leaves
In the Yajurveda, there are references to Soma performing The healing benediction
a “yagna” [sacred offering] seeking cure from TB. Since William Shakespeare
ancient times amulets, invocations, charms, Royal touch Macbeth, IV, iii, 146
and prayers have been used to treat TB. Chemicals such
as arsenic, sulphur, calcium, several vegetable, plant and There have been references to TB in several works of fiction.
animal products including excreta of humans and animals, There are references to TB in William Shakespeare’s plays
blood letting have been used over the centuries in the fond such as the “consumptive lover” of Much Ado About Nothing
hope of curing TB. Robert Koch, soon after his discovery of and “scrofula” in Macbeth. Charles Dickens describes the
the tubercle bacillus, ambitiously introduced the treatment sufferings of Little Blossom in David Copperfield. Thomas
using “Koch’s lymph” with disastrous results. It was later Mann’s The Magic Mountain contains one of the most
known that the substance was a glycerin extract of the well-known descriptions of TB sanatorium. Little Eva of
tubercle bacillus and was named as “tuberculin” (3,6). Harriet Beecher Stowe’s Uncle Tom’s Cabin, Milly Theale
During the 19th century, bed rest and change in in Henry James’ The Wings of the Dove, Marguerite Gautier
environment emerged as important forms of treatment of in Alexander Dumas’ La Dame aux Cameilas also suffered
TB. Hermann Brehmer, Peter Dettweiler, George Bodington, from TB.
Edward Livingston Trudeau, were all pioneers of the TB does not respect anybody. Several important
sanatorium movement. Hermann Brehmer, a Botany student personali­ties, statesmen, writers, poets, performing artists
suffering from TB, was instructed by his physician to seek have been consumed by TB [Table 1.2]. John Keats and
out a healthier climate. He travelled to the Himalayan Percy Bysshe Shelley symbolised the era of the “romantic
mountains where he could pursue his botanical studies consumptive youths of the 19th century” (3). The image of
while trying to rid himself of the disease. He returned home John Keats conveyed by the writings of contemporaries of
cured and began to study medicine. In 1854, he presented his era is that of a fragile poet who fell victim to TB because
his doctoral dissertation bearing the title, “Tuberculosis is his sensitive nature had been unable to withstand contact
a curable disease”. In the same year, he built an institution with a crude world (3). In a well-known anecdote, when his
in GÖrbersdorf where, in the midst of fir trees, and with friend John Brown discovers a drop of blood on the sheet
good nutrition, patients were exposed on their balconies while examining him, Keats says:
to continuous fresh air. This set up became the blueprint “I know the colour of that blood. It’s ‘arterial blood’...
for the subsequent development of sanatoria (12). During That blood is my death warrant, I must die ... (3)
this period, surgery was extensively used for the treatment Shelley, a fellow poet also suffered from TB pleurisy but
of TB. The reader is referred to the chapter “Surgery for did not succumb to the disease. On hearing the passing of
pleuropulmonary tuberculosis” [Chapter 46] for the details. Keats, Shelley wrote:
Efforts by Albert Calmette and his assistant Camille
From the contagion of the world’s slow stain
Guérin resulted in the introduction of bacille Calmette-
He is secure, and now can never mourn
Guérin [BCG] vaccine (19). Pioneering work of Selman
A heart grown cold, a head grown gray in vain;
Waksman led to the introduction of streptomycin as an
Nor, when spirit’s self has ceased to burn,
effective anti-TB drug. Jorgen Lehman was instrumental
With sparkless ashes load an unlamented urn...
in the discovery of para-amino salicylic acid [PAS]. With
the availability of these drugs and isoniazid, the era of The Bronte family included six children all of whom
modern predictably effective treatment ushered in. With the succumbed to TB. Maria and Elizabeth died at a very young
introduction of rifampicin, the treatment duration could be age. The son died of consumption, alcohol and opium. Emily
further shortened to the present-day six-month short-course [Wuthering Heights] and Charlotte [Jane Eyre] died aged 29
chemotherapy. and 39 respectively. It was thought that, their father Rev.
Patrick Bronte was the source of infection. The families of
TUBERCULOSIS IN ARTS AND LITERATURE Ralph Waldo Emerson and Henry David Thoreau were also
wiped out by consumption (3,6).
Youth grows pale, and spectre thin, and dies Several famous Indians had also succumbed to TB. The
John Keats list includes the famous mathematician Srinivasa Ramanujan,
Ode to a Nightingale writer Munshi Prem Chand, Kamala Nehru, among others.
 History 5

Table 1.2: Well-known victims of tuberculosis DRUG-RESISTANT TUBERCULOSIS

Mathematician With the introduction of anti-TB drugs in the mid-1940s, the
Srinivasa Ramanujan era of cure for TB became a reality. Within a short period
Doctors of about a half-century, the menace of drug-resistant TB
Rene Theophile Hyacinthe Laënnec
Edward Livingston Trudeau
[DR-TB] became a serious threat to TB control. The 1990s
Writers and Poets witnessed mutlidrug-resistant TB [MDR-TB], then the early
Alexander Pope years of the new millennium have witnessed the menace
Samuel Johnson of extensively drug-resistant TB [XDR-TB]. The impact of
Jean-Jacques Rousseau X/MDR-TB on TB control is covered in “Drug-resistant
Johann Wolfgang von Goethe
tuberculosis” [Chapter 42].
Sir Walter Scott
Percy Bysshe Shelley
John Keats INDIA AND TUBERCULOSIS CONTROL
Leigh Hunt
Elizabeth Barrett Browning Research carried out in India has had a tremendous impact
Charlotte Brontë on TB and this experience has been of immense value in the
Emily Brontë control of TB worldwide. The first sanatorium in India was
Anne Brontë started in 1906 in Tilonia, Rajasthan. Subsequently, other
Fyodor Dostoevsky sanatoria were set-up in Almora in 1908 and Pendra Road,
Robert Louis Stevenson
Anton Chekhov
Central Provinces in Madhya Pradesh, at about the same
Franz Kafka time. The first sanatorium outside the patronage of Christian
Katherine Mansfield missionary organisations, called Hardinge Sanatorium was
George Orwell established at Dharampur, near Shimla in 1909 with the
Munshi Prem Chand help of donations from some Mumbai-based philanthropists,
Statesmen/Stateswomen
mainly Parsis, under the banner of the Consumptives’
Kamala Nehru
Eleanor Roosevelt Homes Society. The first Government-run sanatorium [King
Mohammed Ali Jinnah Edward Sanatorium] was started at Bhowali in Uttarakhand
Nelson Mandela [Figure 1.3]. The Union Mission Tuberculosis Sanatorium
Musicians [UMTS] was established in Arogyavaram, Madanapalle,
Frederic Francois Chopin Chittoor district, Andhra Pradesh in 1915 [Figure 1.4A].
Niccolo Paganini
With the advent of the National Tuberculosis Programme
Carl Maria von Weber
Performing Artists [NTP] in 1962, the UMTS was converted to a general hospital
Vivien Leigh called the Arogyavaram Medical Centre [Figure 1.4B] which
Elisa Rachel Felix is continuing to function even today. Till the mid-1950s,
Amitabh Bachchan important TB research activity in India was pioneered by
researchers [Figure 1.4C] at the UMTS sanatorium (26,27).
India became a member of the International Union
RISK FACTORS Against Tuberculosis in 1929. From the funds generated in
response to the appeal made on behalf of the government
Historically, several genetic, social, environmental and
by the then Vicereine Lady Linithgow, and the King George
biological determinants of health have been identified as
V Thanksgiving [Anti-Tuberculosis] Fund, the Tuberculosis
risk factors for TB. Role of genetic factors in the causation
Association of India [TAI] was formed in February, 1939.
of TB has been covered in the chapters “Genetic susceptibility
In 1940, the TAI and Government of India jointly set-up
parameters in tuberculosis” [Chapter 6] and “Genetics of
the New Delhi Tuberculosis Centre as a model clinic. In
susceptibility to tuberculosis” [Chapter 7]. No account of the
1951, the clinic was upgraded as first TB Training and
history of TB would be complete without a reference to
Demonstration Centre in the country. In 1941, the Lady
this modern foe. The impact of the twin disaster of human
Linlithgow sanatorium was setup at Kasauli (26-29). The
immunodeficiency virus [HIV] infection and TB on human
subsequent years saw the establishment of the Tuberculosis
suffering has been covered in the chapter “Tuberculosis
Chemotherapy Centre [TCC] at Chennai [then called
and human immunodeficiency virus infection” [Chapter 35].
Madras] and the National Tuberculosis Institute [NTI] at
The deadly interaction between diabetes mellitus [DM]
Bengaluru [then called Bangalore].
and TB is being increasingly recognised world over and
has lead to the institution of bi-directional screening for TB
National Institute for Research in Tuberculosis,
and DM (20-22). Evidence has become available suggesting
that use of immunomodulator drugs [biologicals] has been
Chennai
associated with the development of fatal TB in rheumatoid In October 1955, on the request of the Government of India,
arthritis (22,23). Data are also emerging suggesting that the WHO sponsored the visit to India of three representatives
tobacco smokers have about three-fold higher risk of TB than of the British Medical Research Council [BMRC] to advise
non-smokers; even after adjustment for other factors (24,25). on studies designed to provide information on the mass
 6 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B

C D E F
Figure 1.3: King Edward Sanatorium at Bhowali, Nainital, Uttarakhand state [A,B]. Late Dr Tarachand, originally a physician, who became a
famous thoracic surgeon and his wife Dr Shanti Tarachand [expert in anaesthesiology] are well-known names at this Sanatorium. The museum in
the sanatorium houses many of the surgically resected gross pathology specimens [C to F]

Figure 1.4B: The Union Mission Tuberculosis Sanatorium, at Arogya­

varam, Madanapalle, Chittoor district, Andhra Pradesh, that later
became the Arogyavaram Medical Centre

Figure 1.4A: Lord Pentland, Governor of the then Madras State of beds available for their admission at that time. It was
opened the Union Mission Tuberculosis Sanatorium at Madanapalle feared that outpatient treatment might prove inadequate for
on July 19, 1915, seen along with Dr Christian Frimodt-Moller, the first the treatment of the disease, and that a high proportion of
Medical Superintendent and members of the Governing Body patients so treated might become chronic excretors of drug-
[Kind courtesy: Dr B Wesley, Director, Arogyavaram Medical Centre, resistant organisms and might pose a serious public health
Madanapalle]
risk if use of domiciliary chemotherapy was widespread.
With the knowledge then available, it was agreed that it
domiciliary appli­cation of chemotherapy in the treatment would be premature to begin mass domiciliary application of
of pulmonary TB (30). This was particularly relevant as the chemotherapy, even in a limited area. It was finally decided
number of patients with TB far outnumbered the number to undertake a controlled comparative study of the treatment
 History 7

of patients at home and in a sanatorium initially, and to auspices of the Indian Council of Medical Research [ICMR],
follow up the family contacts. Patients were to be admitted the Government of Tamil Nadu, the WHO and the BMRC.
to study from among those routinely diagnosed by the chest This Centre started its activities with eight international staff
clinic service of a large city. In order to implement these members belonging to the WHO and a team of national staff
decisions, the TCC was established at Madras [Chennai] members drawn from the ICMR and the Government of
in 1956 [Figure 1.5A] as a five-year project, under the joint Tamil Nadu under the dynamic leadership of Dr Wallace Fox
of the BMRC. The Centre was housed in two main blocks,
in a one-and-a-quarter hectare campus on Spur Tank Road,
Chetput, in the heart of Chennai city. The Centre, which
had an initial lease of life of only five years and had faced
the threat of closure in 1961, has evolved further. In keeping
with the wide sphere of activities of the Centre, the ICMR
in 1978 renamed the TCC as the “Tuberculosis Research
Centre” [TRC] (30) [Figure 1.5B]. The TRC was renamed
on August 1, 2011 as National Institute for Research in
Tuberculosis [NIRT] [Figure 1.5C]. Presently, a permanent
institute under the ICMR, the NIRT is an internationally
Figure 1.4C: Pioneers of research at Union Mission Tuberculosis recognized institution for TB research. It is a Supranational
Sanatorium, Arogyavaram, Madanapalle: Dr PV Benjamin [left panel],
Reference Laboratory and a WHO Collaborating Centre
Dr Johannes Frimodt-Moller [middle panel], and Dr KT Jesudian [right
panel] for TB Research and Training [Figure 1.5D]. Recently, an
[Kind courtesy: Dr B Wesley, Director, Arogyavaram Medical Centre, International Centre for Excellence in Research [ICER], in
Madanapalle] collaboration with NIH, was established at the Centre.

A B

C D
Figure 1.5: Tuberculosis Chemotherapy Centre, Madras [Chennai] [A]; Tuberculosis Research Centre, Madras [Chennai] [B]; renaming of
Tuberculosis Research Centre as National Institute for Research in Tuberculosis [C,D]
[Kind courtesy: National Institute for Research in Tuberculosis]
 8 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

for medical and paramedical personnel, in policies and

procedures consistent with the WHO recommended DOTS
strategy. Other functions of the NTI include monitoring
and supervising TB control programme in the country, to
plan, co-ordinate and execute research in TB epidemiology
in India.
Figure 1.6: Pioneers of research at Tuberculosis Chemotherapy
Centre, Madras [Chennai]: Dr Wallace Fox [left panel]; Professor D.A. National Institute of Tuberculosis and
Mitchison [middle panel]; and Dr Hugh Stott [right panel]
[Kind courtesy: National Institute for Research in Tuberculosis, Chennai] Respiratory Diseases
The Lala Ram Sarup [LRS] TB hospital was established
The Madras Experiment by TAI in 1952. It was upgraded into an autonomous
institute, the LRS Institute of Tuberculosis and Respiratory
Pioneering researchers who worked at TCC, TRC, NIRT are Diseases under the Ministry of Health and Family Welfare
shown in Figure 1.6. The findings of the “Home-Sanatorium in 1991 by the Government of India. The institute has
study” conducted by the TRC, Madras [Chennai], have recently been renamed in 2012 as National Institute of
found their way into several journals and textbooks on Tuberculosis and Respiratory Diseases [NITRD] (32). The
TB. The finding that TB patients can be effectively treated LRS TB hospital functions in the NITRD. The WHO and the
as outpatients and continue to live in their homes without Global Laboratory Initiative [GLI] have recently recognised
added risk to their family contacts has revolutionised Microbiology Laboratory at NITRD as a National Centre
the whole concept of the management of TB (30). These of Excellence in 2014 for the WHO/GLI TB Supranational
pioneering studies also form the conceptual basis for the
Reference Laboratory Network. The NITRD [Figure 1.8]
modern-day “DOTS”.
has been designated by the WHO as a WHO Collaborating
Centre [WHO CC] in TB Training [WHOCC No. IND-128]
National Tuberculosis Institute on November 6, 2014. The NITRD-WHO CC was opened
In order to formulate an effective strategy to control TB in on World TB Day 2015. The NITRD is a key player in TB
India, the NTI was established under Directorate General control in India.
of Health Services, Ministry of Health and Family Welfare,
Government of India, at Bengaluru [then, called Bangalore] National JALMA Institute for Leprosy and Other
in 1959, and was formally inaugurated on September 16, Mycobacterial Diseases
1960 by Pandit Jawaharlal Nehru, the first Prime Minister
of India (31). The NTI is located in the northern part of The India Centre of Japanese Leprosy Mission for Asia
the Bengaluru near Rajamahal Guttahally on a sprawling [JALMA] was established in Agra by the Japanese in 1963
field of 23 acres of land [Figure 1.7A]. The main central and was managed by a Tokyo based voluntary organisation
old building of oriental architecture called “Avalon”, was JALMA (33). On April 1, 1976 the India Centre of JALMA
a palace belonging the erstwhile Maharaja of Mysore was officially handed over to the Government of India
[Figure 1.7B]. The NTI has grown rapidly and has been and subsequently to the ICMR. This was named as Central
designated as the WHO Collaborating Centre for TB JALMA Institute for Leprosy in 1976 and has been renamed
research and training since June 1985. The NTI plays an as “National JALMA Institute for Leprosy and other
important role in organising training activities in TB control Mycobacterial Diseases [NJILOMD]” in 2005 [Figure 1.9].

A B
Figure 1.7: National Tuberculosis Institute, Bengaluru: Entrance [A]; Avalon building [B]
 History 9

Figure 1.8: National Institute of Tuberculosis and Respiratory Diseases Figure 1.9: National JALMA Institute for Leprosy and other
[NITRD], Lala Ram Sarup [LRS] TB hospital, New Delhi Mycobacterial Diseases, Agra. Inset: Main gate

The NJILOMD is equipped with the state-of-the art facilities National Antituberculosis Drug-resistance Survey
such as well-equipped laboratories, modern hospital and
The RNTCP, in collaboration with the NTI, Bengaluru; U.S.
well-set Field Programmes at Model Rural Health Research
Centers for Disease Control and Prevention and the WHO;
Unit [MRHRU] at Ghatampur and a satellite centre at Banda,
has initiated the first national anti-TB drug-resistance survey
serves as a National Reference Laboratory [NRL] for TB for
(36,37). In this survey covering 120 TB units in 24 states,
4 states [Assam, Himachal Pradesh, Uttarakhand and Eastern
13 drugs including all first-line and most of second-line
Uttar Pradesh] and repository centre for mycobacterial
anti-TB drugs were tested. The survey was conducted in
strains. The institute has a major thrust on research in TB
a representative sample of both newly diagnosed sputum
and other mycobacterial diseases (33).
smear-positive pulmonary TB cases [Category I] and
The history of TB and time line of various TB diagnostic
previously treated sputum smear-positive pulmonary TB
tests are shown in Figures 1.10 and 1.11 respectively.
cases [Category II] (36,37).
Revised National Tuberculosis Control
Other New Innovations
Programme
Since the beginning, the RNTCP had provided thrice-
Considered to be one of the most spectacular cost-
weekly intermittent treatment (38-41). With more recent
effective health interventions ever conceived, the Revised
evidence accumulating, the programme has introduced
National Tuberculosis Control Programme [RNTCP] of the
daily treatment from 2016 and the entire country is being
Government of India, which began in 1997, now covers the
covered in a phased manner. The RNTCP is also scaling up
whole country. The RNTCP has been the fastest expanding
the newer diagnostic modalities, namely, cartridge-based
programme, and the largest in the world in terms of
nucleic acid amplification tests [CBNAAT], such as, Xpert
patients initiated on treatment. The reader is referred to the
MTB/RIF and line probe assay [LPA] for early diagnosis
chapter “The revised national tuberculosis control programme”
of TB and molecular detection of drug susceptibility. The
[Chapter 53] for details on this topic.
evidence-based Indian Extrapulmonary TB [INDEX TB]
guidelines have been published in 2017 (42). Active case
Involvement of Medical Colleges in finding in vulnerable populations under the RNTCP is also
Tuberculosis Control being studied (43,44). Introduction of newer anti-TB drugs,
The RNTCP has the unique distinction of involving medical such as bedaquiline and delamanid under conditional access
colleges in TB control (34). This topic is covered in detail in program, under RNTCP is underway (45).
the chapter “The role of medical colleges in tuberculosis control”
[Chapter 48]. CHANGING GLOBAL FACE OF TUBERCULOSIS
CONTROL
Tuberculosis Notification
The recent paradigm shift in efforts directed at TB control
In order to have complete information of all TB cases, globally is highlighted in the chapters “Building partnerships
the Government of India declared TB to be a notifiable for tuberculosis control” [Chapter 50], Integrating Community-
disease on May 7, 2012 (35). Accordingly, all health care based Tuberculosis Activities into the Work of Non-governmental
providers including government, private, non-governmental and Other Civil Society Organisations [The ENGAGE-TB
organisations, individual practitioners are expected to notify Approach]” [Chapter 51] and “WHO’s new end TB strategy”
TB cases. [Chapter 52].
 10 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 1.10: A brief history of TB

TB = tuberculosis; BCG = bacille Calmette-Guérin; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome;
MDR-TB = multidrug-resistant tuberculosis; XDR-TB = extensively drug-resistant tuberculosis; CBNAAT = cartridge-based nucleic acid
amplification tests; RNTCP = Revised National Tuberculosis Control Programme; FL-LPA = first-line line probe assay; DST = drug-susceptibility
testing; DR-TB = drug-resistant tuberculosis; SL-LPA = second-line line probe assay

EPILOGUE twin disaster of HIV and TB and X/MDR-TB seem to be

on the verge of threatening to ruin the mankind. While it
A look at the history of TB [Figure 1.10] and time line of is heatedly debated that TB is “resurging”, this may hold
various TB diagnostic tests [Figure 1.11] reveals that it true for the industrialised countries. But in the third-world
took several thousands of years for humans to identify the countries like India, TB never seems to have “disappeared”
causative organism, another 60 years to arrive at effective to “resurge” later. TB has always been with us, only
treatment. Towards the end of the twentieth century, the revealing itself every now and then and making us wiser.
 History 11

Figure 1.11: Time-line of various TB diagnostic tests

TB = tuberculosis; LED = light emitting diode; DST = drug-susceptibility testing; PCR = polymerase chain reaction; FL-LPA = first-line line probe
assay; SL-LPA = second-line line probe assay; DRT = drug-resistance testing

ACKNOWLEDGEMENTS 11. Duffin JM. Sick doctors: Bayle and Laennec on their own pthisis.
J Hist Med Allied Sci 1988;43:165-82.
The authors wish to acknowledge the help rendered by Vedic 12. History of tuberculosis. Available from URL: http://globaltb.
scholars K Gopala Ghanapatigal, Vedaparayandar, Tirumala njms.rutgers.edu/abouttb/historyoftb.html. Accessed on July 15,
Tirupati Devasthanams, Tirupati, and V Swaminatha Iyer, 2018.
Retired Principal, Kendriya Vidyapeetha, Guruvayoor, 13. Kaufmann SHE. Robert Koch the Nobel Prize, and the ongoing
Kerala, India, for their invaluable help in tracing the threat of tuberculosis. N Engl J Med 2005;353:2423-6.
references to TB in the Vedas. 14. Sakula A. Robert Koch: centenary of the discovery of the tubercle
bacillus, 1882. Thorax 1982;37:246-51.
15. Akkermans R. Robert Heinrich Herman Koch. Lancet Respir
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24. Bates M, Marais BJ, Zumla A. Tuberculosis comorbidity with survey. Available at URL: http://www.searo.who.int/india/
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25. Dheda K, Barry CE 3rd, Maartens G. Tuberculosis. Lancet 37. National Drug Resistance Survey. Available at URL: http://
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26. Leaves from history-12. Anti-tuberculosis movement in India. 38. Sharma SK, Solanki R, Mohan A, Jain NK, Chauhan LS; Pleural
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27. Leaves from history-15. The Union Mission Tuberculosis in immunocompetent patients with tuberculosis pleural effusion.
Sanatorium, Arogyavaram, Madanapalle. Indian J Tuberc 2003; Int J Tuberc Lung Dis 2012;16:1505-9.
50:70. 39. Jindal SK, Aggarwal AN, Gupta D, Ahmed Z, Gupta KB,
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 2
Epidemiology of Tuberculosis:
Global Perspective
Dennis Falzon, Knut Lönnroth, Mario C Raviglione

INTRODUCTION and surveillance data reported by the national authorities

responsible for TB control in their respective countries.
No country in the world today, rich or poor, can claim to be
The burden of disease is expressed as the TB incidence
free of tuberculosis [TB]. In some high income countries, the
and prevalence; the burden of death as TB mortality.
rates of TB have been brought down to very low levels, but
The background data are collected online in aggregated
the demographic realities of aging and migration, shifts in
format by the Global TB Programme of WHO on an annual
host vulnerability, as well as the evolution of the organism
basis and are also supplemented periodically with data
itself, constantly threaten a comeback. The burden of TB
from special surveys [e.g., drug-resistance and disease
morbidity and mortality in the world as a whole impinges
prevalence]. Following collection, data undergo checks
most heavily on the people of developing countries, and
for internal consistency and are then consolidated into a
disproportionately on the poor and other dis­advantaged
central database. Modelled estimates are used when data
subpopulations of better resourced countries. In 2014,
are missing; the methodology employed to derive these
9.6 million new TB cases were estimated by the World
estimates has been described elsewhere (1,4). The updated
Health Organization [WHO] to have occurred globally,
information is published each year in the annual Global
with 4 million in the South-East Asian Region [SEAR] of
Tuberculosis Reports that WHO has issued uninterruptedly
WHO and 2.2 million in India alone (1). Apart from posing
since 1997 (5,6). The information is updated each year and
a formidable burden of disease worldwide, TB ranks as the
the raw data can be downloaded free-of-charge or via
10th leading cause of global deaths and 13th in terms of years
interactive query tools [e.g., country profiles]. Mortality data
of healthy life lost worldwide (2). It competes with human
are also collected by WHO through a separate mechanism
immunodeficiency virus [HIV] as the leading cause of death
from the one described above and estimates are also used to
from an infectious disease. These staggering statistics jar with
replace missing data in the countries where vital registration
the fact that the large majority of TB patients could be cured
is not functional (7). The definitions and indicators in use
and many TB deaths avoided with 6 months of treatment,
in this Chapter have been revised and standardised over
which is generally well-tolerated, accessible and affordable
a number of years, and their latest update was released in
in most settings. This chapter traces the historical imprint of
2013 (8). The countries included in the regional groupings
TB upon humankind and looks at the major determinants
in this Chapter are as defined by WHO (1).
of TB in the world today and the evolution of the epidemic
in recent decades in different geographical regions.
HISTORICAL PERSPECTIVE
In conclusion, we outline the actions that need to be taken
in future to consign TB to history, as the perspective for Deoxyribonucleic acid [DNA] studies of archaeological
global health and development policy shifts beyond the material show that TB has afflicted mankind since the
2015 horizon of the United Nations Millennium Development Neolithic period (9). However, it is also likely that this host-
Goals [MDG] (3). pathogen relationship dates back much further than nine
This Chapter uses findings from several published millennia (10). Hippocrates [c.460-c.377 BCE], the Father of
sources. In addition to those referenced throughout the text Western Medicine, described the public health importance of
we use estimates derived by WHO based on notification what was referred to as phthisis at his time. Over the years,
 14 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

the disease acquired evocative names such as “galloping countries to very low levels. Even if this decline was
consumption”, “the white plague” and “captain of all these temporarily halted or even reversed in a number of
men of death”, all attesting to its tragic legacy (11,12). At the industrialised countries from the late 1980s (20,21), rates
height of the epidemic in western Europe around the end of have since continued to fall bringing the TB incidence lower
the 18th and start of the 19th centuries, TB was likely to be than 10/100,000 in many of them today [Figure 2.1]. In
killing an astounding 1% of the population each year (13). western countries, the TB burden has now become largely
Around this time, TB was the cause of one-fourth of deaths concentrated in two broad age-bands in the population:
in London and of between one-third and one-sixth elsewhere [i] the elderly native patient with reactivation of TB infection
in England and Wales (14). TB mortality declined during the contracted at a time when TB was rife and [ii] younger adults
19th century in western Europe, albeit it remained a major who have a higher risk of recent infection [e.g., homeless
killer even at the end of the century (15). This decrease is persons, migrants from high prevalence settings] or of
commonly ascribed to improvements in socioeconomic progression [e.g., people living with HIV].
conditions (16), although it has been argued that the However, the TB caseload in the world today concentrates
isolation of cases in sanatoria and possibly the evolution of to a large extent in poorer countries where the disease
natural immunity may have contributed to this trend (17). remains an important public health threat. There is much
The decline in TB was disturbed during the period of the two less documentation about trends of TB in the developing
World Wars in the 20th century but resumed immediately world. In many low and lower-middle income countries the
after their end. In countries like France, Great Britain, impact of control efforts on annual risk of TB infection has
the Netherlands, and Norway, the annual risk of TB been less dramatic than in the richer ones (22).
infection fell at the fastest rates ever documented in the
decades after 1950 (18,19). Continued improvements in NATURAL HISTORY, RISK AND DETERMINANTS
the economic situation, nutrition, and living conditions, OF TUBERCULOSIS
effective preventive measures, and expanded curative
services equipped with the newly introduced anti-TB In humans, the natural course of TB from infection to disease
medicines brought the burden of disease in European shares some characteristics with other infectious conditions

Figure 2.1: Estimated TB incidence rates by country, 2014

Reproduced with permission from “World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.22. Geneva: World Health
Organization; 2015 (1)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/
 Epidemiology of Tuberculosis: Global Perspective 15

caused by directly transmissible organisms. Exposure to infected with HIV are on average less infectious, albeit the
the viable organisms, usually through respiratory droplets overall transmission of TB is increased within a community
expelled during coughing, but also possible through where HIV prevalence is elevated.
infected milk can lead to implantation in the lung or other In contrast to infection, the risk of progression to disease
tissues. This normally results in asymptomatic [latent is largely determined by predisposing factors in the host.
or persistent] infection. Progression to disease with the Many conditions which modulate the immune response can
clinical manifestations may then ensue rapidly in the first thus increase the likelihood of disease in a person infected
12-18 months post-exposure or after many decades. In up to with Mtb. HIV stands out as the most potent risk factor,
half of cases, pulmonary forms of the disease develop which increasing the relative risk for TB by more than 20, but others
are infectious to their contacts; other individuals contract such as under-nutrition, silicosis, tobacco smoking, diabetes,
less infectious pulmonary or non-infectious extrapulmonary harmful alcohol use, and immunomodulatory drugs such
forms. The disease, if left untreated, results in death in as anti-tumour necrosis factor agents also play a role. Age
over two-thirds of pulmonary sputum-smear positive cases is also an important factor and risk appears higher in late
within 10 years [without HIV infection], as was documented adolescence and young adulthood. Finally, besides these
in the pre-antibiotic era (23). Alternatively, it may resolve risks, the likelihood that a person is cured or dies of TB is
spontaneously in a minority of cases or evolve towards a influenced also by an array of other factors, including the
chronic form of disease that may last for years. Successful form of disease, for e.g., higher mortality in miliary TB and
resolution of the disease does not confer a lasting immunity TB meningitis (29-31) and whether effective chemotherapy
and the disease may later reactivate. Patients with chronic for TB is provided (32,33). If treated with combined,
disease may survive for several years and be infectious until first-line anti-TB chemotherapy, the chances of cure may
death or, rarely, spontaneous resolution. The propensity of exceed 90% among patients with drug-susceptible bacilli.
TB to chronicity and to recurrence makes it different from Patients treated for multidrug-resistant TB [MDR-TB],
many other infectious conditions. defined as isolates of Mtb resistant to rifampicin and
Spontaneous mutations create strains of Mycobacterium isoniazid, with or without resistance to other anti-TB drugs,
tuberculosis [Mtb] which are resistant to different drugs however, are less likely to have a successful outcome
used in their treatment (24). These events are rare, and than those without, and success is less likely if additional
have been estimated to occur at average rates of 2.56 × 108 resistance is present (34,35). The provision of anti-retroviral
and 2.25 × 1010 per bacterium per generation for isoniazid treatment [ART] to TB/HIV patients has been shown
and rifampicin respectively (25). However, exposure to to significantly decrease the chances of unsuccessful
individual anti-TB medicines favours the selection and outcomes (36-38).
replication of drug-resistant strains within an affected The impact that different risks factors for TB infection,
individual. TB patients who acquire drug-resistance from disease progression and unfavourable outcome have on TB
treatment may transmit these strains to their contacts epidemiology varies substantially across the world. The
[primary drug-resistant infection]. sum effect of the interplay of these risks on a population is
A number of factors influence the natural history of TB a function of the potency of these factors at the individual
at its different stages in an individual. Exposure to infection patient level and their prevalence in the population.
is more likely when the number of infectious cases is high For instance, the overall population level effect of HIV is
in a particular setting, when the period of transmissibility is very pronounced in southern African countries, where
long, and when opportunities for effective contact between infection is highly prevalent in contrast to countries of the
infectious and susceptible persons are high. In situations Indian subcontinent, where less potent risk factors which
where population density is high such as during rapid occur more frequently are more important. The use of
urbanization and the expansion of slum settlements, the population attributable fractions [PAF] is useful to analyse
risk of exposure may also increase, as crowded and poorly this interaction in individual countries (39,40). There are
ventilated settings are conducive to an intense exposure sharp differences among the 22 highest TB burden countries
to the infectious agent. Once exposed, not all individuals which concentrate about 80% of TB incidence in the world
have the same risk of infection and other factors come in the relative contribution of each of these determinants
into play: these determinants are largely external to the to their TB incidence. For instance, in all countries except
host and include those related to the infecting inoculum Thailand and those in Africa, the PAF for adult TB associated
[critical size of droplets, concentration of bacilli in sputum], with smoking was higher than for HIV while in 14 of the
environmental conditions which promote the persistence 22 countries the total PAF related to under-nutrition was the
of infectious nuclei in the air, and virulence of the strain. highest. Problems of alcohol use and diabetes are important
Certain genotypes of the Beijing lineage of Mtb have been in certain countries but if their prevalence increases in
associated with rapid worldwide spread and an association the world, they may become more prominent in future.
with disease clustering, suggesting increased virulence These risk factors for TB are eminently modifiable and,
even when drug-resistance is acquired by these strains, an therefore, amenable to public health interventions; in
added concern (26-28). It has been estimated in the past that, contrast, other risk factors like age and genetic predisposition
if left untreated, each person with active TB may infect on could serve to profile individuals and risk groups where
average between 10 and 15 people every year. TB patients action could be more meaningfully targeted.
 16 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

THE GLOBAL BURDEN OF TUBERCULOSIS declining [Figure 2.3] achieving this MDG target far ahead
of the 2015 deadline. The MDG target has also been met in
Incidence all six WHO regions and in 16 of the 22 HBCs (1).
In 2014, there were an estimated 9.6 million [range 9.1-10
million] incident cases of TB in the world, equivalent overall
Table 2.1: TB incidence and case detection, South-
to 133 cases per 100,000 population but with very extreme
East Asia Region of WHO, by country, 2014
geographical variations [Figure 2.1] (1). One million incident
cases were children and 3.2 million [range, 3.0-3.4 million] Incidence
[in thousands;
occurred among women. Fifty-eight percent of incident TB Country including HIV] Case detection (%)
cases occurred in Asia and 28% in the African Region. India
Bangladesh 360 [320-410] 53 [47-60]
[23%], Indonesia and China [10% each] accounted for two-
fifths of global cases in 2014. Over one third of the world’s Bhutan 1.3 [1.1-1.4] 85 [77-94])
caseload was concentrated in the 11 countries of the South- DPR Korea 110 [100-120]) 93 [87-100]
East Asia Region, where the rate, at 211/100,000 population, India 2200 [2000-2300] 74 [70-80]
was much higher than the global value [Table 2.1] (1). Indonesia 1000 [700-1400] 32 [23-46]
In South Africa and Swaziland, about 1% of the
Maldives 0.15 [0.130-0.170] 89 [78-100]
population is estimated to develop TB each year, while
many countries in western Europe, the US, Australia and Myanmar 200 [180-220] 70 [64-78]
New Zealand have rates about a 100 times lower than this. Nepal 44 [39-50] 79 [71-90]
In 2014, 1.2 million [13%] of the 9.6 million new TB cases Sri Lanka 13 [12-15] 69 [62-79]
were HIV-seropositive globally, and 74% of TB cases among Thailand 120 [61-190] 59 [36-110]
people living with HIV worldwide were in the African Timor-Leste 5.8 [4.8-6.9] 63 [53-77]
Region [Figure 2.2] (1). In parts of southern Africa, more
All S-E Asia Region 4000 [3700-4400] 62 [56-68]
than 50% of TB cases were co-infected with HIV. Globally,
the estimated TB incidence rate was relatively stable from TB = tuberculosis; WHO = World Health Organization; HIV = human
immunodeficiency virus; S-E = South-East
1990 until around 2000, since when it has been slowly

Figure 2.2: Estimated HIV prevalence in new and relapse TB cases, 2014
Reproduced with permission from “World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.22. Geneva: World Health
Organization; 2015 (reference 1)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/
 Epidemiology of Tuberculosis: Global Perspective 17

Figure 2.3: Global trends in estimated rates of TB incidence [1990-2014], and prevalence and mortality rates [1990-2015]. Left: estimated
incidence rate including HIV-positive TB [green] and estimated incidence rate of HIV-positive TB [red]. Centre and right: The horizontal dashed
lines represent the Stop TB Partnership targets of a 50% reduction in prevalence and mortality rates by 2015 compared with 1990. Shaded areas
represent uncertainty bands. Mortality excludes TB deaths among HIV-positive people.
HIV = human immunodeficiency virus
Reproduced with permission from “World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.22. Geneva: World Health
Organization; 2015 (reference 1)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/

Prevalence drug-susceptible disease (34,41,42). Representative data from

surveys performed at least once or on routine surveillance
There were an estimated 13 million prevalent cases
of diagnostic drug susceptibility testing of TB patients is
[range, 11-14 million] of TB in 2014, equivalent to a rate of
now available from 144 countries worldwide.
174 cases per 100,000 population. TB prevalence rates are
Based on these data, it is estimated that in 2014 there
declining in all six WHO regions and by the end of 2015
were 480,000 [360,000-600,000] newly emerging MDR-TB
and are estimated to have fallen by 42% globally since 1990
cases in the world, and 190,000 [120,000-260,000] MDR-TB
missing the international target of halving TB prevalence
deaths. Globally, 3.3% {95% confidence intervals [CI] 2.2%
by 2015, compared with the baseline in 1990. However, the
to 4.4%} of new [previously untreated] TB cases and 20%
target has already been met by the Region of the Americas
[95% CI 14% to 27%] of previously treated cases are
and the Western Pacific Region and SEAR (1).
estimated to have MDR-TB. These proportions, however,
differ markedly between countries, showing low levels
Deaths in the SEAR 2.2% [95% CI 1.9% to 2.6%] in new and 16%
There were an estimated 1.5 million total TB deaths in [14% to 18%] in previously treated patients and very high
2014 or about 16 deaths per 100,000 population in the levels in eastern Europe and central Asia compared with the
world. About 390,000 of these deaths were among people rest of the world [Figure 2.5]. Among new cases in Belarus
living with HIV. Approximately 90% of total TB deaths MDR-TB is present in 34%, and in 23%-26% in Kazakhstan,
occurred in the African Region and SEAR, with India and Kyrgyzstan, the Republic of Moldova, and Uzbekistan;
Nigeria accounting for about one-third of the global TB between 55% and 62% of previously treated patients in these
deaths in 2014. TB mortality rate [excluding deaths among countries had MDR-TB. Levels vary across the vast expanse
HIV-positive people] has fallen by 47% between 1990 of the Russian Federation but some regions have the highest
and 2015 narrowly missing the target of a 50% reduction proportions ever reported worldwide. The time trends in drug
[Figure 2.4]. Mortality rates are declining in all six WHO resistance levels vary substantially between countries (43),
regions but at a different pace (1). although comparable data from serial measurements over
time are not available for many countries. Extensively
drug-resistant TB [XDR-TB] or MDR-TB with additional
Drug-resistant TB
resistance to both the fluoroquinolones and the second-line
The prospect of an increase in the number of drug-resistant injectable drugs, the two most important classes of medicines
cases among the TB burden remains a matter of concern, in the treatment of MDR-TB, has now been reported by
even if the overall number of TB patients is on the decline. 105 countries globally, including all countries of the WHO
Cases with drug-resistant TB need more resources and SEAR except Sri Lanka and Timor-Leste. In countries with
support to treat appropriately with regimens that are representative data, globally 9.7% [95% CI 7.4% to 12%] of
longer, more toxic and costly than those in general use for MDR-TB cases have XDR-TB.
 18 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 2.4: Estimated TB mortality rates [excluding TB deaths among HIV-positive people], 2014
Reproduced with permission from “World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.22. Geneva: World Health
Organization; 2015 (reference 1)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/

Figure 2.5: Percentage of MDR among new [previously untreated] TB cases. Figures are based on the most recent year for which data have been
reported, which vary among countries. Data reported before the year 2000 are not shown.
Reproduced with permission from “World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.22. Geneva: World Health
Organization; 2015 (reference 1)”
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/
 Epidemiology of Tuberculosis: Global Perspective 19

A GLOBAL RESPONSE These differences may reflect geographical variations

in TB epidemiology as well as diagnostic and reporting
In the early 1990s, after more than a decade of neglect, WHO
practices. The 5.7 million new and relapse cases notified in
published new estimates showing that millions of people
2013 represent about 64% [range: 61-66%] of the estimated
were affected with TB and died from it (44). As a result, in
incidence that year. Case detection ratio [CDR] was highest
1993, WHO declared TB to be a global health emergency (45).
in 2014 in the Region of the Americas [77%; range 75%-81%],
It was realised back then that many countries were ill- the Western Pacific Region [85%; range 81%-90%] and the
prepared to counter the challenge that TB posed for the European Region [79%; range 75-83%]. All regions have
future. Political commitment was lacking, surveillance was improved their estimated CDRs since 1995, when the global
neglected, and treatment regimens and diagnostic services estimate was 39% [range 38%-41%] and when DOTS started
varied greatly in effectiveness. In 1994, WHO proposed a to be expanded in the world. However, in 2014, there still
basic package of interventions to address the emergency, remained a gap of approximately 3.6 million people with TB
which eventually acquired the term DOTS [originally an who were “missed” [Table 2.1]. The gap between estimated
acronym for “directly-observed treatment, short course”] (46). TB incidence and notified cases is a result of either under-
In 2006, DOTS evolved into a more comprehensive reporting of TB cases to the national surveillance systems
framework—the Stop TB Strategy—with activities covering of under-detection or both. Under-reporting of diagnosed
a larger set of dimensions important for TB care and TB cases may occur when the private sector providers fail
prevention (47,48). to notify cases to the national TB programme or else when
In 2000, an ambitious Global Plan to Stop TB was reporting from diagnostic facilities and laboratories within
launched by WHO and the Stop TB Partnership with the national TB programmes is dysfunctional. Under-
the long-term vision of eliminating TB as a public health diagnosis of patients with TB may occur because of lack of
problem (49). The planning became more elaborate over awareness of TB among communities, poor access to the
the following years and in its latest update, in 2010, it was health care services to appropriate diagnostics for people
estimated that US$ 47 billion would be required to be spent who do present to health facilities seeking care or a low
between 2011 and 2015 in order to achieve the targets set index of suspicion of TB among health professionals.
for 2015 (50). The detection and treatment of patients with rifampicin-
More than two decades after the WHO emergency resistant disease and MDR-TB, conditions requiring longer,
announce­ment, TB remains one of the principal public health more toxic and expensive treatment regimens, has also
concerns due to an infectious condition in all countries in the increased; in 2014, the number of new enrollments on
world. But despite the plight of the millions of patients who MDR-TB treatment reached about one third of estimated
have fallen ill with TB and died since 1993, much important cases that could potentially be detected among the
progress has been registered. National programmes have pulmonary TB cases notified by the countries.
been strengthened and learnt to adapt to the changes in The World Health Assembly [WHA] in a resolution in
the epidemic such as the challenges of HIV-associated TB 2009 urged countries to work towards providing universal
and of drug-resistant strains as well as the environment access to care for drug-resistant TB patients (51). Drug-
around them, including the impact of migration, health resistant strains have been detected in an increasing number
sector reforms, financial crises and perennial pressure to of countries over the last two decades, and the widespread
integrate TB services in primary health care. As a result, introduction and use of new, rapid molecular assays are
about 43 million lives have been saved between 2000 and destined to snowball this trend. The response of countries
2014 through effective diagnosis and treatment (1). The has varied but some of the countries with the highest burden
efforts of treatment programmes have thus had a profound are on track to achieve universal access to treatment for their
impact on sustaining the substantial decline in TB incidence population if they sustain the efforts put in place in the last
and mortality over the last decade in all regions of the world. few years (52).
TB/HIV interventions have progressed and by 2014, 51% of As a result of the worldwide expansion of effective care,
TB patients worldwide knew their HIV status [79% in the treat­ment success in new TB cases has reached 86% among
African Region where the TB/HIV burden is the highest]. patients placed on treatment in 2013 globally, a substantial
Among known TB/HIV patients coverage of therapy with increase from 2000 when it was 69%. The target of 85%
anti-retroviral drugs reached 77% in 2014, up from 49% in success has thus been reached and sustained. Success rates
2011. However, only 23% of countries globally reported are lower among retreatment patients [65%] and among
provision of isoniazid preventive therapy [IPT] to people MDR-TB patients [48%] attesting to the worse prognosis
living with HIV in 2014. when the effectiveness of first line drugs is diminished
In 2014, countries notified a total of 6.3 million TB [Figure 2.6]. Treatment of XDR-TB and forms of TB with
cases, just over 6 million newly diagnosed and 261,000 on additional resistance is fraught with difficulties and
treatment [Table 2.2]. About 15% of newly emerging cases outcomes are generally poorer than in MDR-TB (35,53,54);
reported globally were extrapulmonary; the proportion of patients with infectious forms of TB bearing such advanced
these cases varied substantially from 7% in the Western patterns of resistance present a challenge to infection
Pacific Region to 23% in the Eastern Mediterranean Region. control.
20 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 2.2: TB case notifications in the 22 high TB burden countries, WHO Regions and globally, 2014
New or previous treatment history
Percentage
unknown Relapse
of pulmonary
Retreat- Pulmonary Pulmonary cases
ment bacterio- Pulmonary bacterio- Pulmonary Extra- bacteriol-
Total New and excluding logically clinically Extra- logically clinically pulmo- ogically
notified relapse relapse confirmed diagnosed pulmonary confirmed diagnosed nary confirmed
Afghanistan 32,712 31,746 966 14,737 8,573 7,227 1,209 65
Bangladesh 196,797 191,166 5,631 106,767 42,832 37,406 2,989 863 309 72
Brazil 81,512 73,970 7,542 41,120 17,801 9,479 3,602 1,488 480 70
Cambodia 43,738 43,059 679 12,168 11,286 18,310 445 709 141 51
China 826,155 819,283 6.872 235,704 526,106 32,348 25,125 33
DR Congo 116,894 115,795 1,099 75,631 13,494 19,566 4,298 1,892 914 84

Ethiopia 119,592 119,592 40,087 41,575 37,930 49

India 1,683,915 1,609,547 74,368 754,268 343,032 275,502 124,679 112,066 66
Indonesia 324,539 322,806 1,733 193,321 101,991 19,653 6,449 1,391 1 66
Kenya 89,294 88,025 1,269 34,997 30,872 14,640 3,569 2,947 1,000 53
Mozambique 58,270 57,773 497 24,430 23,455 6,276 1,542 2,070 50
Myanmar 141,957 138,352 3,605 42,608 70,305 16,108 5,276 3,650 405 39
Nigeria 91,354 86,464 4,890 49,825 29,460 4,764 2,415 0 64
Pakistan 316,577 308,417 8,160 122,537 120,350 57,463 7,420 426 221 52
Philippines 267,436 243,379 24,057 92,991 139,950 4,161 6,277 41
Russian 136,168 102,340 33,828 37,296 40,894 8,763 7,982 6,753 652 49
Federation
South Africa 318,193 306,166 12,027 155,473 106,482 33,522 7,430 2,693 566 60
Thailand 71,618 67,722 3,896 34,394 21,115 10,244 1,969 0 0 63
Uganda 46,171 44,187 1,984 26,079 11,854 4,180 1,499 468 107 69
UR Tanzania 63,151 61,571 1,580 23,583 23,380 13,600 1,008 51
Viet Nam 102,087 100,349 1,738 49,938 25,179 18 118 7,114 69
Zimbabwe 32,016 29,653 2,363 11,224 13,151 3,909 1,369 49
High-burden 5,160,146 4,961,362 198,784 2,179,178 1,763,137 653,169 223,666 137,416 4,796 56
countries
AFR 1,342,400 1,300,852 41,548 635,560 399,155 212,057 39,782 11,217 3,081 62
AMR 228,476 215,243 13,233 127,864 40,746 32,501 10,193 2,918 1,021 76
EMR 465,677 453,393 12,284 183,630 151,696 103,959 12,368 866 874 56
EUR 321,421 266,058 55,363 112,416 76,759 39,175 23,935 11,483 2,290 61
SEAR 2,580,605 2,482,074 98,531 1,188,654 632,418 389,819 152,498 117,970 715 64
WPR 1,375,572 1,335,816 39,756 449,845 734,179 103,085 44,354 3,037 1,316 40
Global 6,314,151 6,053,436 260,715 2,697,969 2,034,953 880,596 283,130 147,491 9,297 58
TB = tuberculosis; WHO = World Health Organization; AFR = African; AMR = American region; EMR = Eastern Mediterranean region; EUR = European
region; SEAR = South-East Asia region; WPR = Western Pacific region
Reproduced with permission from “World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.22. Geneva: World Health
Organization; 2015 (reference 1)”

THE FUTURE OF TB: A LONG-TERM of TB in the world. However, these gains have not benefited
PERSPECTIVE the whole of humanity in an equitable manner and huge
disparities have emerged within the globalised economies
The last 150 years have seen significant improvement in the of today’s world. TB remains a barometer of poverty,
social conditions of large swathes of the world’s population. insecurity, malnutrition and low basic health coverage,
They have also been characterised by significant scientific risk factors that abound in poor and rich countries alike.
discoveries and the broad scale application of interventions The HIV-epidemic has influenced the TB dynamic in
based on this knowledge. These two phenomena have many countries in Africa and elsewhere over the last three
contributed hugely to the gradual decline in global burden decades.
 Epidemiology of Tuberculosis: Global Perspective 21

Figure 2.6: Treatment outcomes for patients diagnosed with MDR-TB by WHO Region, 2007-2012 cohorts. The total number of cases with
outcome data is shown beside each bar
Reproduced with permission from “World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.22. Geneva: World Health
Organization; 2015 (reference 1)”
MDR-TB = multidrug-resistant tuberculosis; WHO = World Health Organization
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/

For a disease that is largely curable, the fact that reduction in the importance of TB as a public health priority
millions of people still develop it each year and that about worldwide, bringing down its burden to levels which have
4,000 TB patients die each day is a sordid reminder of only been achieved by industrialized countries to date.
the sad inequities of today’s world and the ability of the Three key targets are aimed for by 2035, namely: [i] a 95%
TB bacillus to elude modern medicine and public health reduction of TB mortality [in comparison with 2015 levels];
measures. Nonetheless, recent advances in diagnostics, [ii] a 90% reduction of TB incidence [down to <10 cases per
vaccine science and therapeutics bring fresh optimism 100,000 population]; and [iii] the elimination of catastrophic
to the future perspective of the TB pandemic. For the costs due to TB for all families affected by the disease. The
first time in four decades, new TB drugs are starting to reader is referred to the chapter “WHO’S New end TB strategy
become available with an express indication for TB (55,56). [Chapter 52]” for further details.
In addition, new compounds are being tested in clinical The activities encompassed by the new strategy will
trials and other medicines are being repurposed for use in build upon the successes achieved up until now but will also
TB. About 10 vaccine candidates have now entered clinical embark upon new ones within territories that lie beyond the
trials (57), albeit the prospect of having an effective vaccine traditional confines of TB care programs. The activities are
for the prevention of TB in adults in the near future remains grouped under three pillars: [i] integrated, patient-centred
uncertain. care and prevention; [ii] bold policies and supportive
For new technologies to make a difference to TB care and systems; and [iii] intensified research and innovation.
control they need to be effectively implemented in the target Components within all of the three pillars concern the
settings using, where possible, innovative methods. One practice of surveillance and epidemiology in one way or
illustrative example was the broad scale adoption of Xpert® another. For instance, the drive to rapidly find and treat the
MTB/RIF, a rapid, reliable molecular diagnostic method 3.6 million TB patients who escape detection or reporting
that the WHO endorsed in December 2010 (58,59). By will involve a number of articulated actions to improve the
September 2014, more than 3,500 machines and 8.8 million coverage of reliable diagnostics, implement early diagnostic
test cartridges had been procured by 110 low- or middle- strategies, increase the awareness about TB of the public and
income countries [http://www.who.int/tb/areas-of-work/ health care workers, mandate the obligatory notification of
laboratory/mtbrifrollout/en/]. This rapid, unprecedented TB, and ensure that this is matched by means to facilitate the
transfer of techno­logy and expanded adoption of a new test reporting of cases and the capture of data from laboratories
was made possible in these countries through a lowering of and diagnostic centers [e.g., wider use of information and
the price for the equipment and the con­sumables following communication technology], provide universal health
negotiations with the manufacturers by its co-developer, coverage and build links with the private health care sector.
Foundation for Innovative and New Diagnostics [FIND] Broad-scale interventions aimed at active and earlier case
[www.finddiagnostics.org], and the financial support of the finding, increasing contact tracing and treatment of latently-
US Government, the Bill and Melinda Gates Foundation infected persons (61), will require close measurement of
[www.gatesfoundation.org] and UNITAID [www.unitaid.eu]. the response. Health workers who are monitoring patients
A new vision beyond 2015 has now been endorsed by on treatment would likewise need to exploit better the
the WHA (60). This strategy [End TB Strategy] envisages a communication technologies which are available even in
22 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

low resource settings, particularly mobile phones and data process, as well as national TB programmes and technical
services; more evidence is required on the interventions partners [a detailed list of individuals involved in recent
which are most effective in this promising field and how years is available at pages v to viii in reference 1]. We are
they can be best adopted by programmes (62). Drug-safety especially indebted to Dr Philippe Glaziou of the Global TB
monitoring in the context of the early introduction of Programme at WHO/HQ for his help in the development
new medicines will be important to fully understand the of this chapter.
potential toxicity of these agents (63). Many countries will
need to invest on more effective vital registration systems to REFERENCES
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 3
Pathology of Tuberculosis
Siddhartha Datta Gupta, Prasenjit Das, Gaurav PS Gahlot, Ruma Ray

‘’He becomes the true discoverer who establishes the truth; and to a million. Once infected, further progression of disease
the sign of truth is the general acceptance. In science, credit goes depends upon immunity level of the individual. In healthy
to the man who convinces the world, not to the man to whom the individuals, 90% will not progress disease and only 10%
idea first comes’’. will develop active disease [50% of these within 2 years and
other 50% later on in life] (3). Therefore, pulmonary TB (80%)
Dubos RJ. The germ theory of tuberculosis.
is the predominant form of disease. The lung is indeed the
In: The White Plague: tuberculosis, man and society (1)
primary site of infection in most instances. Extra-pulmonary
TB [EPTB] is commonly a consequence or accom­paniment
INTRODUCTION of pulmonary TB. However, TB affects almost every organ
Tuberculosis [TB] has been known to mankind since ancient in the body. It would be beyond the scope of this chapter
times (1,2). The aetiology, pathogenesis, clinical features and to deal with the pathology of TB with reference to each and
the treatment of TB have been the subject of controversy and every organ in detail. Readers are, therefore, referred to the
myths for centuries. However, there was agreement on one respective chapters concerned with different organ systems
score, that the disease was associated with poor prognosis. that supplement this chapter.
Robert Koch discovered the infectious agent of TB, on
March 24, 1882. It was hoped that the discovery of TB bacilli CLASSIFICATION
will mark the end of the scourge, phthisis, struma, phyma,
hectic fever, consumption, white death, the ‘white plague’, TB is classified into different clinic-pathological types
or the ‘Captain of all these men of death’, as remarked by the depending on various factors [Table 3.1]. Though there
evangelist John Bunyon. Unfortunately that did not happen. may be some link in the relationship of age to the exposure
The human immunodeficiency virus [HIV] mediated and type of TB, terminology related to age such as
acquired immunodeficiency syndrome [AIDS] pandemic “childhood TB” and “adulthood TB” should not be used.
has also had a devastating effect on demography of TB. The natural history of TB is described in detail in the
The pathology of TB is essentially similar to most other chapter “Pulmonary tuberculosis [Chapter 10].” Certain key
infectious diseases, that is the consequence of interplay aspects of the natural history of TB are described here
between the bacillus and host immunity. The relationship briefly. Primary TB occurs in persons who have been
between the two can be varied, complex and can last life- exposed to Mycobacterium tuberculosis [Mtb] for the first time.
long. The host can win over the bacillus or the bacillus In areas of the world where TB is highly endemic,
can overwhelm the host. At times, the battle may stop for primary TB usually occurs in children. Primary TB can
years, only to resume later on. All this is reflected in the also occur when acquired immunity to TB is lost due to
gross and microscopic appearances of the different organs. senescence or immunedeficiency diseases. As pointed out
The infectious agent is in the form of 1-5 micron diameter by Rich, “resistance is a notoriously fluctuating condition
airborne particles [droplet nuclei], that contain 1-5 bacilli; and even though resistance may have been previously
the infectious dose being 1-10 bacilli. One bout of cough acquired, it may be overcome by new invasion of tubercle
can produce 3,000 droplet nuclei and a sneeze produces up bacillus” (4). Progressive primary TB arises when there is
26 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 3.1: Classification of tuberculosis mechanism have a prominent lymphocyte component

[Figure 3.1]. There is an almost sequential change due to
Based on sequence of events following the first exposure
Primary TB
interplay amongst the causative agent [identifiable or non-
identifiable], macrophage activity, T-cell responses, B-cell
Disease caused by Mtb in a person with no previous exposure
overactivity and circulating immune complexes of biological
Progressive primary TB mediators resulting in a granulomatous inflammation.
Primary disease which is generally self-limiting may progress to Granuloma is not a mere collection of inflammatory
give rise to larger lesions cells but an active site production of numerous enzymes
Post-primary TB and cytokines, which are involved in the very serious
Disease which is the result of endogenous reactivaton business of trapping and removing the causative agent (7).
[in a person previously exposed to Mtb] or exogenous reinfection Morphologically, granulomas invariably show some degree
Based on location of organisation. Macrophages are the essential constituent of
Localised disease most granulomas. These macrophages are usually activated,
Pulmonary TB with abundant, pale to eosinophilic or foamy cytoplasm.
Extrapulmonary TB The margins become indistinct so that adjacent macrophages
seem to form a continuous sheet, akin to the surface
Disseminated TB
squamous epithelium, hence they are called epithelioid
TB disease process involving more than two non-contiguous sites. histiocytes and these granulomas are termed as epithelioid
Disseminated TB can occur in primary [early generalised TB] and
post-primary [late generalised TB] forms of the disease. When the
cell granulomas. Not all granulomas are, however, of the
lesions are uniform and are of the size of a millet seed, the term epithelioid cell type. Epithelioid cells may fuse to form
miliary TB is used multinucleated giant cells. Generally, two types of giant cells
TB = tuberculosis; Mtb = Mycobacterium tuberculosis are identifiable in TB. In one type, the nuclei are arranged
along the periphery, almost forming a rosette around the
central cytoplasmic area. This is called the Langhans’ type
of giant cell after Theodore Langhans [1868] who critically
inadequate immunity. It is most commonly seen in infants, evaluated granulomas in TB [Figure 3.1B, arrow] (4). In the
adolescents and elderly. foreign-body type of giant cells, the nuclei do not show
Post-primary TB, is generally a disease of the adults due such a regular arrangement and are oriented haphazardly
to endo­genous reactivation or exogenous reinfection in a [Figure 3.1C, arrow]. The offending foreign-body may or
previously sensitised patient, who has retained some degree may not be identified within this giant cell. In some lesions
of acquired immunity. Haematogenous spread of the disease associated with multiple discrete granulomas, it appears as
throughout the lungs and to multiple organs [miliary TB] though each granuloma has a single giant cell. The foreign
may occur in both the primary and post-primary forms of body type of giant cells though are the most common giant
the disease. cells noted in TB granulomas, the Langhans’ type of giant
cells are pathognomic of this disease. Surrounding the
HISTOPATHOLOGICAL APPEARANCE macrophages is a variable cuff of lymphocytes which may
be relatively more prominent in immunologically induced
The histopathological hallmark of TB is a granuloma. In
granulomas [Figure 3.1A, black arrow]. Other types of
fact, TB is cited as the classical example of a granulomatous
inflammatory cells such as eosinophils may also form a part
inflammation. It is, therefore, necessary to briefly discuss the
of the granuloma. Older granulomas that are healing show
features of a granuloma here.
fibrosis. Ultimately, the entire granuloma may undergo
fibrosis, hyalinisation, calcification and even ossification.
Histology of Granuloma The presence of a central area of necrosis distinguishes a
The term granuloma [derived from the diminutive of the necro­tis­ing granuloma from a non-necrotising granuloma.
Latin term for a grain, granulum] was used by Rudolph The histopathological lesion of TB is the prototype of a
Virchow [1818], to describe tumours that may ulcerate and necrotising epithelioid cell granuloma [Figure 3.1A, yellow
give rise to granu­lation tissue (5,6). However, the present arrow] while that of sarcoidosis is a classic example of a
connotation is different. Granuloma can be defined as a non-necrotising epithelioid cell granuloma. Therefore, it
focal, compact collection of inflammatory cells in which is not uncommon to refer to TB type and sarcoid type of
mononuclear cells predominate. Granulomas are the granulomas, based on presence or absence of necrosis.
result of a persistent non-degradable Mtb, or the result of The causes of granulomatous infection are numerous and
hypersensitivity to its antigen or both. Therefore, granulomas are provided in Table 3.2 (8). Often the TB granulomas
may be formed as a consequence of an immunological are reticulin poor, that means, sparse reticulin fibres can
mechanism or otherwise. Granulomas which are due to a be identified around and inside the granulomas; while in
non-immunological mechanism generally do not reveal a sarcoidosis reticulin condensation can be noted around
peripheral lymphocyte response [e.g., some of the foreign and inside the granulomas, with silver reticulin stain.
body granulomas], whereas those due to an immunological However, practical utility of this feature is often debated.
 Pathology of Tuberculosis 27

A B

C D
Figure 3.1: Histomorphology of an epitheloid cell granuloma with central granular necrosis [yellow arrow], an organized rim of epithelioid histiocytes
[green arrow] and peripheral lymphocyte cuffing [black arrow] [A] [Haematoxylin and eosin × 100]. Langhans’ giant cells [arrow] show peripheral
nuclear garlanding [B] [Haematoxylin and eosin × 100], on the other hand foreign body giant cells show irregular nuclear arrangement [arrow] [C]
[Haematoxylin and eosin × 100]. Ziehl-Neelsen stain shows multiple beaded curved magenta coloured tubercle bacilli [D] [Ziehl-Neelsen × 200].

Sometimes independent granulomas [if such a term can Granulomatous Inflammation in Tuberculosis
be used] appear to coalesce to form confluent granulomas.
Presence of confluent granulomas, especially in intestinal As described, confluent necrotising granulomas characterise
biopsy, is a very useful histological feature to differentiate TB, though this feature is not always present (9). Broadly,
intestinal TB from Crohn’s disease (9). the microanatomical lesions in TB are classified into
The diagnosis of the aetiology of granulomas, on exudative and proliferative lesions. Exudative lesions are
histopatho­logical grounds, can vary from “accurate” to less well-demarcated, comprise of neutrophils, lymphocytes,
“presumptive” to “impossible”. If the cause is apparent, macrophages and epithelioid histiocytes arranged in a
as in the case of a foreign body or a parasite or fungus or loose collection with little fibroblastic proliferation. These
acid-fast bacilli [AFB], then the diagnosis can be made with lesions are also described as soft granulomas and are likely
reasonable certainty [Figure 3.1D, arrows]. Newer, sensitive to contain AFB. Proliferative lesions are well circumscribed
molecular biological techniques may help resolve the issue, with a lymphocyte cuff surrounding well-aggregated
though, their specificity is variable. In other instances, the epithelioid histiocytes. Plasma cells may be found but
diagnosis is at the best presumptive or compatible with a neutrophils are scant. Surrounding fibroblastic profileration
clinical suspicion. In many cases, the cause of granulomatous is also more marked [hard granuloma]. Acid-fast bacilli are
inflammation may not be evident on histo­p athological less readily demonstrated. Langhans giant cells are seen in
examination. both types but are more common in the proliferative type.
28 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 3.2: Aetiology of some granulomatous infections necrosis is a structureless necrosis. It not only implies
permanent tissue destruction, but is also a mechanism for
Well-recognised agents
destruction of Mtb. Within the caseum low oxygen tension,
Mycobacteria Tuberculosis, leprosy, Buruli ulcer, low pH and local accumulation of fatty acids inhibit
swimming pool [fish tank] granuloma
bacillary replication. The caseum can become inspissated
Bacteria Brucellosis, melioidosis, actinomycosis, and encapsulated by fibrous tissue [fibrocaseous granuloma].
nocardiosis, granuloma inguinale,
The caseous focus can become completely organised and
listeriosis, tularemia
converted to fibrous scar that is often calcified or ossified.
Chlamydiae Lymphogranuloma venereum, trachoma
It may undergo liquefaction and cavitation. Liquefaction
Rickettsiae Q-fever [Coxiella burnetii infection], probably involves proteolytic enzymes derived from
Spirochetes: syphilis, pinta, yaws neutrophils and macrophages which are present within or
Fungi: cryptococcosis, candidiasis,
sporotrichosis, histoplasma, aspergillosis,
around the caseous focus. Unlike caseous debri, liquefied
blastomycosis, coccidioidomycosis, material is usually teeming with bacilli. Cavitation occurs
chromoblastomycosis, mycetoma when the liquefied area ruptures into an airway and is
Protozoa Leishmaniasis, toxoplasmosis evacuated by coughing. Dissemination of bacilli in this
manner contributes to the development of TB pneumonia.
Nematodes Visceral larva migrans [toxocariasis]
The caseous areas can become completely organised and
Trematodes Schistosomiasis, paragonimiasis,
converted to fibrous scar over a period of weeks. These
fascioliasis, clonorchiasis
areas may become calcified over several months. After
Viruses Infectious mononucleosis,
several years, the foci may even be ossified. The presence of
cytomegalovirus, measles, mumps
caseation necrosis generally implies that the lesion is active.
Foreign body Talc, silica, zirconium However, it may be mentioned that tubercle bacilli may lie
Recently recognised dormant for many years even in calcified lesions.
Bacterium Cat-scratch disease [Bartonella henselae] Of interest is the recent observation that instead of the
Actinomyces Whipple’s disease [Tropheryma whipplei] usual reaction referred to, mycobacterium can give rise
Idiopathic or suspected
to a spindle cell-lesion. These pseudotumours are often
but not established loaded with bacilli (10). The typical lesions described
above are responsible for the tiny tubercles that may be
Measles virus Crohn’s disease
visible to the unaided eye. Galen noted tubercles in various
Mycobacterium Primary biliary cirrhosis
animals [tubercle, Latin tuberculum meaning a diminutive
Viral Kikuchi’s disease of tuber, small swelling e.g., tuberosity] in the condition
? Sarcoidosis called hydrops thoracis. Sylvius noted that phthisis was
? Chronic granulomatous disease of accompanied by tubercles. Francisus Delaboe Sylvius in his
childhood, orofacial granulomatosis Opera Medica in 1679 also made a description of tubercles.
[Melkersson-Rosenthal syndrome] The name TB was derived for this disease because in 1839,
JN Schonlein, Professor of Medicine at Zurich, suggested that
TB be used as a generic term for all the manifestations of
These two types of granuloma are not specific to a particular phthisis In 1869, Richard Morton in his book [Phthisiologica]
type of TB and both can coexist. The number, size and extent named these lesions tubercles (1) and thus, this term has
of these granulomas depend upon the number of infecting been in use ever since.
bacilli, mode of spread and amount of tuberculo-protein
discharged into the developing lesion. It may be mentioned
DIFFERENTIAL DIAGNOSIS
that exudative lesions, sometime with a predominance of
neutrophils, are seen more often in TB of serous surfaces, The histopathological diagnosis of TB lies essentially in
such as on the meninges, pleura and peritoneum. Sometimes, the demonstration of the characteristic granulomatous
neutrophils may predominate in TB lesions in organs with inflammation and the causative organism. A presumptive
a loose texture [e.g., TB bronchopneumonia] giving the diagnosis of TB can be made if a necrotising, confluent
appearance of a non-mycobacterial infection. It is in such epithelioid cell granuloma is demonstrated. Unfortunately,
instances that TB may be mistaken for an acute inflammation not all TB granulomas are necro­tising. Similarly in the list of
and the diagnosis can be missed if Ziehl-Neelsen [ZN] granulomatous diseases [Table 3.2] there are conditions that
staining is not performed. Eosinophils are conspicuous by reveal granulomas identical to TB. Comparison between TB
their absence in TB except in the gastrointestinal tract lesions. and sarcoidosis granulomas is provided in Table 3.3.
Mathew Ballie in 1709 and subsequently, Alois Rudolph It must be emphasised that there is no single appearance
Vetter in 1803, compared some of the lesions in phthisis to or combination of features that can distinguish TB and
cheese. This “cheese-like” necrosis, on gross examination sarcoidosis histopathologically. Schaumann and Asteroid
of TB lesions is called the caseous necrosis. This term has bodies within giant cells may be found in TB. Necrotising
been extended to microscopy also. Caseating granulomas are sarcoid granulomas are found especially in cutaneous
characteristically but not exclusively found in TB. Caseation sarcoidosis and are reported even in pulmonary lesions (11).
 Pathology of Tuberculosis 29

Table 3.3: Comparison between tuberculosis and other organisms, including a few fungal species can also
sarcoidosis granulomas show positivity. Less frequently used methods include
fluorescence with Auramine-Rhodamine [AR] staining,
Feature Tuberculosis Sarcoidosis
Dieterle stain (12) and immunohistochemistry (13).
Epithelioid cells Present Present All these methods are more sensitive than the conventional
Necrosis Usual Not common ZN staining and are applicable to paraffin sections and
Confluent granulomas Usual Discrete archival blocks. The former requires a fluorescence
Giant cells in granulomas Multiple Few microscope for visualisation. Use of light emitting diodes for
fluorescent microcopy, as an alternative to power consuming
Reticulin within Usually lost Usually preserved
granulomas light microscopic examination in low resource setting may
further popularize the use of AR stain in near future (14).
Acid-fast bacilli May be present Absent
The Dieterle stain is less specific due to morphologic
similarities of organisms with Nocardia and those of cat-
scratch disease (12). Immunohistochemical staining though
Table 3.4: Methods of demonstration of mycobacteria
is sensitive and specific, it lacks the simplicity of routine
in tissues
stains and is more expensive. Perhaps it would take some
Culture more time before this method gains as much popularity
Modified Ziehl-Neelsen staining
Dieterle staining
and acceptance for the demonstration of organisms as in
Auramine-Rhodamine staining diagnosis of tumours.
Immunohistochemistry Direct detection of Mtb, rapidly, is perhaps one of the
Nucleic acid amplification tests most significant landmarks in medicine. Molecular methods
like use of cartridge-based nucleic acid amplification tests
[CB-NAAT], line probe assay [LPA] (15,16) have made
The preservation of reticulin in sarcoidosis can be attributed detection of Mtb and drug-susceptibility testing more
to the lack of necrosis and early fibrosis and is a useful rapid and specific. The reader is referred to the chapter
distinguishing feature. Both reticulin-rich and reticulin-poor “Laboratory diagnosis” [Chapter 8] for further details on this
granulomas may be found in TB, there is nothing more topic. In the authors’ institution, due to high prevalence
rewarding than the demonstration of Mtb. Table 3.4 lists of cases of TB [and belief in the dictum: diagnose a rare
some of the possible methods of demonstrating Mtb in tissue disease and you will be rarely right!], in suspected cases,
samples. the demonstration of caseating epithelioid cell granulomas
Appropriate precautions are to be taken and protocols is considered sufficient evidence to strongly suggest TB even
are to be followed for the collection and transport of tissue if AFB are not demonstrated. Therefore, it is not unusual
samples. It is always necessary to contact the laboratory for to start appropriate therapy following a biopsy report
this purpose. Often invaluable information is lost because “granulomatous lymphadenitis compatible with TB”.
of improper collection and transport of samples. The most
frequently employed method is the modified ZN staining.
In May 1882, Paul Ehrlich published a paper indicating that PATHOGENESIS OF TUBERCULOSIS
tubercle bacilli are not decolourised by nitric acid following The lung is the predominant primary site of TB infection in
staining by a mixture of gentian violet and aniline oil. postnatal life. Mtb is the most frequent pathogen. In the past
Hence, the expression “acid-fast” bacilli. Koch accepted Mycobacterium bovis was a significant pathogen but with the
this method. Franz Ziehl recommended that carbolic acid pasteurisation of milk and relative control over bovine TB,
be used instead of aniline. Freidrich Neelsen recommended infection by Mycobacterium bovis is now rare. A variety of
fuchsin and sulphuric acid instead of gentian violet and conditions are reported to render individuals susceptible or
nitric acid. This is the ZN stain [1892] which is widely are associated with an increased risk of TB. Many of these
employed worldwide. Ironically, Paul Ehrlich diagnosed result in decreased immunity. Some of these include silicosis,
that he had TB by staining his own sputum sample. He pulmonary alveolar proteinosis, malignant neoplasm (17)
spent a year resting in Egypt and returned to Germany and immunodeficiency disorders among others [Table 3.5].
in good health (1). The ZN staining is relatively simple, The key aspects related to the pathogenesis of TB are
is applicable to paraffin sections and has been in use for covered in the chapters “Pulmonary tuberculosis” [Chapter 10],
many years throughout the world. However, with ZN stain, “Tuberculosis in children” [Chapter 36], “Immunology of
AFB are not always demonstrable and the species of the tuberculosis” [Chapter 5], “Genetic susceptibility parameters
bacillus cannot be identified. In histopathological sections, in tuberculosis” [Chapter 6], and “Genetics of susceptibility to
to our experience, AFB can be demonstrated by ZN stain in tuberculosis” [Chapter 7].
30%-40% cases; while in cytology smears, the positivity rate is
up to 60%-70%. The typical AFB appreas as curved, beaded, PRIMARY TUBERCULOSIS
purplish-red bacilli [Figure 3.1D], which may be confused
with false positive staining of the Nocardia, Legionella and The following discussion focuses on the pathogenesis and
M. leprae with ZN stain. Hair shaft, dust particles and pathology of primary TB in general. Primary pulmonary
30 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 3.5: Conditions predisposing to the by a nodular, often subpleural, area of necrosis surrounded
development of tuberculosis by fibrosis. Hyalinisation and eventual calcification of this
nodule is the routine. Microscopic calcification can occur as
Immunodeficiency disorders affecting CMI including HIV infection
and AIDS
early as two months but radiologically visible calcification
takes a year or longer. Calcification does not imply a sterile
Immunosuppressive therapy
lesion. The most important aspect of primary TB is that the
Malignant neoplasm [carcinomas of the head and neck, stomach, organisms remain dormant for a variable length of time.
intestines and lungs; Hodgkin’s disease, non-Hodgkin’s lymphoma,
Resorption of calcium from the lung and lymph node lesions
acute lymphocytic and myelogenous leukaemia]
occurs subsequently in about one-third of children with
Silicosis
primary complex [see below] over a period of years (22).
High dose, long-term corticosteroid treatment Although, the above account of the sequence of events briefly
Poorly controlled diabetes mellitus describes primary TB in the lungs, the description in other
Chronic kidney disease, haemodialysis organs is essentially similar.
Connective tissue disorders
Organ transplantation
Primary Complex
Intravenous drug abuse, heroin addiction It can be appreciated that in primary TB there is usually a
Tobacco smoking unit comprising the focus of primary TB and the infected
draining lymph nodes. This is known as the primary complex
CMI = cell-mediated immunity; HIV = human immunodeficiency virus;
AIDS = acquired immunodeficiency syndrome of Ranke. Invariably the intervening lymphatics between the
lesion and the lymph nodes are included as a constituent of
the primary complex. The term primary complex as such is
used in reference to TB and has the advantage that it can
TB will be discussed a little later under “pulmonary TB.” be used as a general term implying primary TB without any
The earliest foundation of primary TB was actually laid reference to a particular organ. A similar primary complex
by Marie-Jules Parrot [1829-1883] in 1876. At a time when has been described in the case of cryptococcosis (23).
the understanding of TB was based on several conjectures, Over the years, the terms primary complex in the lung
primary TB in children was explained on the basis of what and Ghon’s complex [named after Anton Ghon] are used
is known as the Parrot’s Law which stated that: “pulmonary synonymously. The focus of primary infection in the lung is
TB does not exist in the child without involvement of the usually subpleural, in the middle portion [upper region of the
tracheobronchial gland”. In other words, this observation lower lobe or the lower portion of the middle lobe when on
implies that primary TB includes a prominent lymph nodal the right side] and is known as the Ghon’s focus. Therefore,
involvement. The significance of this was not clear even after the unit of Ghon’s focus and the draining tracheobronchial
the discovery of the tubercle bacillus. In 1896, George Kuss lymph nodes [with the intervening lymphatics, included
[1867-1936] brought out a monograph on the pathology of by some] is the Ghon’s complex. The term Ghon’s complex
TB due to aerogenous infections which included what is should not be used to denote primary complex in organs
understood as primary TB. Once again his ideas did not other than the lung. More details regarding Ghon’s complex
receive much attention. Eugene Albrecht [1872-1908] in will be discussed in the section on pulmonary TB.
1907 extended the concept of primary TB in childhood In keeping with Koch’s observations in guinea pigs, the
to adult TB and Hans Albrecht in 1909 confirmed the lesion in primary TB is small, often not discernible; whereas
observations of Kuss and elaborated on Parrot’s law (18). the draining lymph nodes are appreciably enlarged. This is
These studies formed the basis of the observations of reflected in Parrot’s Law mentioned earlier. This is opposite
Anton Ghon [1866-1936] (19). to what is seen in post-primary TB. Therefore, the presence
The infection is carried along the lymphatics to the of an enlarged lymph node with a correspondingly smaller
draining tracheobronchial lymph nodes that enlarge. The parenchymal lesion is suggestive of primary TB and serves
regional nodes are invariably involved and may be more as a general guideline to distinguish primary and post-
prominent than the parenchymal lesion especially so in primary TB. In post-primary TB the parenchymal lesion
children. Spread of infection to the draining lymph nodes as usually overshadows the lesion in the draining lymph
well as vascular involvement, mentioned earlier, may lead nodes. The importance of the lung being a common site of
to dissemination of bacilli from primary complex to almost primary TB has already been mentioned. The mucosa of
all tissues through blood and lympha­tics. A bacillaemia is, the gastrointestinal tract is another site of entry of tubercle
therefore, common at this stage (20,21). The initial infection bacilli. However, there are other routes of infection that are
is typically unrecognised though the tubercle bacilli less common and less easily recognized (24).
disseminate throughout the body. Most primary TB infections
heal spontaneously, with calcification in some of the cases.
Congenital and Perinatal Tuberculosis
Repair begins with the resorption of caseous material,
followed by fibrosis and dystrophic calcification. A typical The youngest possible contact of TB is the foetus of a mother
primary parenchymal focus of TB in the lung is characterised with active TB. Fortunately, the foetus is less susceptible to
 Pathology of Tuberculosis 31

A B
Figure 3.2: A heart-lung complex from an autopsy with congenital tuberculosis showing multiple millet-like tubercles [white arrows] in both lungs.
In addition, one hilar necrotising lymph node is evident [blue arrow].

TB in utero in contrast to the vulnerability of the newborn the face, scalp, knees, legs, feet, hands and forearm. Persons
infant. Although the cause for this is not apparent, a relative with occupations which involve contact with potentially
anoxia of foetal tissues may be a reason. Rarely, infection infective material, such as, pathologists, microbiologists,
may occur in utero or at birth. There are over three hundred laboratory workers, necropsy attendants, butchers, slaughter
cases of congenital TB reported in the literature (25-28). house workers, cattle handlers and milkers are all at special
The route of infection in congenital TB could be aspiration risk. Due to its similarity to primary syphilis, cutaneous TB
of the amniotic fluid in perinatal period [due to TB of the is also known as “tuberculosis chancre”. Regional lymph
endometrium, genital tract] or placenta [late in pregnancy] node enlargement occurs as in the case of primary complex
or haematogenous spread. When the route of infection is at other body sites (29). Primary cutaneous TB has been
haematogenous, the bacilli reach the foetus through the described in a doctor eight weeks after he administered
placenta along the umbilical vein so that a primary complex mouth to mouth respiration to a comatose TB patient (30).
forms in the liver and accompanying portal lymph nodes. TB has also been described following subcutaneous or
The bacilli may sometimes bypass the liver and may be intramuscular injection. Contaminated syringe, needle or
conveyed via the ductus venosus to the lungs. Widespread fluid or exhaled tubercle bacilli by the medical attendant
involve­­ment of the lungs, hilar and mediastinal lymph nodes may be the sources of inoculation of bacilli into the patients’
with­­out an associated hepatic lesion indicates aspiration skin. A primary syringe-transmitted infection of a muscle
of the infected amniotic fluid (25), inhalation of tubercle should be distinguished from secondary infection of a
bacilli from the genital tract or from the room air during muscular haematoma by TB bacilli, in a patient, who is
or just after birth (26). Congenital TB is characterised by already infected. There is a report of one hundred and two
a non-immune, non-reactive response. Multiple primary children developing primary TB at the site of typhoid and
foci or miliary distribution are common (27,28), and paratyphoid A and B [TAB] vaccination, transmitted by a
regional lymph node involvement occurs with emphasis school vaccinator who was found to have active TB (31).
on caseation and a large number of bacilli [Figure 3.2]. Primary cutaneous TB has also been reported following
Microscopically, polymorphonuclear leucocytes predominate venipuncture (32). Despite, a clear clinical information, it
but lymphocytes, epithelioid cells and Langhans’ giant cells may be difficult to differentiate primary TB of the skin from
are rare. The reader is referred to the chapter “Tuber­culosis a secondary one (33). The histopathological spectrum can
in children” [Chapter 36] for more details on this topic. vary from a sequence of non-necrotising epithelioid cell
granulomas with no AFB [high-immune], to the necrotising
Skin epitheloid granulomas with some AFB, to the necrotising
lesions with abundant AFB [low-immune]. Lupus vulgaris
The skin when intact is the best form of protection from stands at the high immune pole, whereas TB cutis orificiales
infections. Unfortunately, even a small breach in this and acute miliary TB form the low immune pole (34,35).
seemingly impenetrable barrier exposes the individual It would not be out of place to mention that bacille Calmette-
to infections. Thus, the skin may provide a site of entry Guérin [BCG] inoculation is in essence an iatrogenic primary
for tubercle bacilli. Usually there is a history of trauma at infection (36). Primary inoculation TB has been reported
the site of infection ranging from a dog’s scratch to a major following BCG vaccination as a form of immunotherapy for
road accident. Common sites include exposed areas such as malignant melanoma (37). Therefore, it appears that in many
32 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

countries where BCG vaccination is given to the newborn, Primary TB of the liver is invariably congenital. This
the most common primary TB is cutaneous, and with the has already been discussed in the description of congenital
draining lymph nodes [axillary in most instances] accounts and perinatal primary TB. Cases of primary hepatic TB are
for a frequent primary complex in such cases (38). reported from time to time (55,56). It must be emphasised
that in adults, the lack of evidence for a focus of TB
Gastrointestinal Tract and Liver elsewhere does not necessarily indicate that the lesion in the
liver is primary TB.
The gastrointestinal tract is one of the sites of primary contact
between the tubercle bacilli and the host. With a significant
Head and Neck
reduction in the number of cases due to contaminated milk,
it is unlikely that the gastrointestinal tract would be a Cervical lymph nodes are frequently affected by TB. A
relatively frequent site for primary TB. It should be noted proportion of these may reflect a constituent of a primary
that the lack of evidence or inability to demonstrate another complex. The likely route of infection in the case of cervical
site of infection often results in a mistaken labelling a site of lymph node is considered to be the tonsil (57). However, in
TB as “primary”. Almost every organ in the gastrointestinal most cases, the focus in the tonsil is microscopic and difficult
tract is reported to as a likely site of primary TB. An to identify. Exceptionally, the tonsillar lesion may be readily
associated enlargement of regional lymph nodes may or may apparent and ulcerated [Figure 3.3], and the mucosa over
not have been observed. the lymphoid tissue at the pharyngeal entrance may be the
Primary TB has also been described in the buccal site of primary infection (58). Similarly, the uvula (59) the
mucosa (39). It may follow dental extraction and result pharynx (60) and the larynx (61,62) have been reported to be
in infection of the tooth socket (40). The primary focus is the sites of primary TB. In these instances the infection may
usually small or not easily recognizable, whereas the lymph follow the common mode of entry, that is through inhalation.
node enlargement, mainly submandibular, is prominent. It is, therefore, not surprising that the nose (63,64) and the
The tongue is rarely the site of primary infection (41-43). nasopharynx have been infected primarily (65,66). This forms
Secondary TB of the tongue is more frequent and invariably the basis of the Calmette test, where tuberculin was used to
follows TB of the respiratory tract. be dropped into the conjunctiva (4).
Isolated reports of primary TB of the oesophagus (44,45), Primary TB can involve the middle ear (67-69). The bacilli
stomach (46-48), duodenum (49), ileum (50), and the colon (51) are thought to enter the Eustachian tube by swallowing and
are available. Primary TB of the vermiform appendix and regurgitation of the infected amniotic fluid by the foetus.
stomach is rare. Most of the cases of TB of the appendix In the Lubeck disaster, some of the victims developed middle
are secondary to TB of the ileocaecal region. Nevertheless, ear infection probably by aspiration of vomited vaccine into
there are cases of apparently primary infection of the the Eustachian tube (7).
vermiform appendix reported in literature (24,52,53). An Primary TB of the salivary glands is uncommon and
interesting report describes multiple sites of primary TB of source of infection may be transoral spread with retrograde
the gastrointestinal tract (54). extension along the salivary ducts from oral mucosa or
It may be mentioned that earlier observations indicate
that primary TB of the gastrointestinal tract due to bovine
TB infrequently involves the lungs. The classical evidence
of primary infection of the gastrointestinal tract by TB is
provided by obser­vations following the tragedy at Lubeck,
in Germany. During the period of this disaster, a virulent
TB bacillus of the bovine strain [BCG] was employed for
immunisation by mouth.
Unfortunately, a contamination of the cultures led to
the accidental administration of virulent human strain
of TB bacillus to 251 newborn infants. The bacilli were
administered orally on three separate occasions during the
first 10 days of life. A total of 72 infants died of primary
and fatal TB while 175 were reported to be alive with
arrested lesions at the end of four years. An autopsy study
revealed that the alimentary tract was involved in all the
cases. The small intestine was most frequently affected
[98.3%],while the upper alimentary tract and the cervical
lymph nodes were affected in 78.3% of cases. Interestingly,
pulmo­nary lesions were found in 15% of the autopsies. In Figure 3.3: Photomicrograph showing tonsillar tissue covered by
all probability, these lesions were secondary to aspiration partially ulcerated stratified squamous epithelium with underlying
because simultaneous lesions were demonstrated in the evidences of confluent necrotising granulomas. A Langhans’ giant cell
mouth, pharynx or the intestine (4). is also noted [arrow] [Haematoxylin and eosin × 40]
 Pathology of Tuberculosis 33

haematogenous from primary site or lymphatic spread from Table 3.6: List of some reported sites of primary
infected tonsils. The parotid gland is thought to be involved, tuberculosis
due to infection of the buccal mucosa at the site of the third
Common
molar tooth (70,71). Primary TB involving adenolymphoma
Lung
[Warthin’s tumour] of the parotid (4,24) has been described.
BCG vaccination [when vaccination is successful in infancy]
Less common
Genitourinary Tract Tonsil
The skin of the penis is another rare site of primary Adenoids
TB (72-74). In some cases the infection is transmitted Probably uncommon
following circumcision (73) by operators suffering from TB. Ileum [common in era when bovine type of infection was frequent]
An interesting report (24), penile TB was described in Rare
72 Jewish infants following ritual circumcision. As a part Colon, pharynx, duodenum, stomach, uvula, skin, liver [in con­
of haemostasis, the circumcised organ was sucked and genital infection], buccal mucosa, oesophagus, larynx, parotid
in this manner the infection was supposedly transmitted gland, nasopharynx, tongue, nose, penile skin, conjunctiva, vulva,
from an infected rabbit to the infants. Some cases may middle ear, injection site, lacrimal gland, retina
occur following sexual transmission. Similarly an infected BCG = bacille Calmette-Guérin
male may transmit the disease to the female partner (24).
In general, it appears that the vagina is less often the site of
primary TB than the penile skin. Infection of the vulva has to tuberculin skin test [TST]. There are two more aspects that
also been reported. need to be mentioned. Primary TB is invariably associated
with haematogenous dissemination or generalisation.
Eye Subsequently, either disseminated/miliary TB may result
or seeding of various organs may not be associated with
Ocular TB can be classified into primary when there are no
concurrent disease. Later, depending on the relationship
systemic manifestations, and secondary, when there is either
between the host immunity and the mycobacteria that may
haematogenous spread or direct invasion from adjacent
lie dormant for years, TB may manifest in one or more of
tissue (75). Primary TB of the conjunctiva (76-79) and the
these organs. In a small proportion of cases the primary
lachrymal sac without the involvement of the conjunctiva
infection may not heal but progress.
have also been described. Most of the patients with
conjunctival TB present with unilateral, chronic conjunctivitis
GENERALISED [DISSEMINATED] TUBERCULOSIS
without any systemic mani­festations. Morphologically
conjunctival lesions can be divided into four groups, as: Generalised TB is the occurrence of wide spread visceral
[i] localised ulceration associated with lymphadenopathy; tubercles due to haematogenous dissemination [Figure 3.2]
[ii] nodular-localised area of conjunctivitis containing of virulent TB bacilli from an active caseous source of
multiple nodules that later ulcerate; [iii] hypertrophic infection (81-83). The reader is referred to the chapter
granulomatous-massive flattened granulations commonly “Disseminated/miliary tuberculosis” [Chapter 29] for further
associated with lymphadenopathy [most common]; and details.
[iv] pedunculated mass without lymphadenopathy (76). The characteristic findings of miliary TB include small,
Lesions probably occur after some minor injury or abrasion. discrete nodules, grey to reddish on cut surface, 1-2 mm in
Enlarged regional lymph nodes [preauricular or submandi­ diameter, distributed evenly throughout the affected organ.
bular] complete the primary complex (24). It may be Older lesions, that may be caseous, tend to be yellowish in
mentioned that phlyctenular keratoconjunctivitis may appear colour. The lung, liver, spleen [Figures 3.2A and 3.4] and
as a consequence of hypersensitivity to proteins to which the bone marrow are most frequently affected. Even in these
individual has been previously exposed. Thus, phlyctenules organs, tubercles tend to be larger in the lung and spleen than
may appear if droplets of coughed sputum containing bacilli in the liver and marrow. Miliary tubercles at the apical lobes
or tuberculo-protein are deposited on the conjunctiva of such of the lungs may be larger and more numerous especially in
individuals. A rare instance of primary TB of the retina has adults. Pleural and pericardial involvement is common with
been reported (80). bilateral pleural effusions frequently associated with miliary
Whether it is necessary to catalogue and compile a list of TB. Miliary tubercles may be found studding other organs,
sites of primary TB [Table 3.6] is open to debate. However, such as, the kidney, intestine, fallopian tube, epididymis,
this gives an insight into the variety of possible locations prostate, adrenals, bone, meninges, brain, skin, eye and
through which the Mtb can enter the human body. It must lymph nodes. Mediastinal lymph node enlargement occurs
be emphasised that the lung is perhaps the most frequent in a high percentage of infants. Patients may present with
site of primary TB. The course of primary TB is generally features that point to the involvement of only one organ,
benign especially with the advent of effective chemo­ such as, meningitis, despite having disseminated disease.
therapy. In a majority no ill-effect is felt and infection is All tubercles resulting from acute generalised dis­
recognised by delayed type hypersensitivity [DTH] reaction semination are approximately of the same size and in the
 34 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B C

D E F
Figure 3.4: A specimen of spleen showing multiple yellowish white coalescent nodules on its cut surface [arrows] in a patient with miliary TB [A].
A lung specimen from a TB patient showing features of bronchiectasis [arrows] [B]. An excised small intestine specimen showing many trans­
verse ulcers [arrows], in case of intestinal TB [C]. A nephrectomy specimen showing features of calyceal necrosis, cavity formation and a
necrotic shaggy inner surface showing tubercles [arrows] [D]. A specimen of TB epididymo-orchitis showing multiple cohesive necrotic nodules
[arrows] [E]. TB salpingitis with markedly thickened walls. The lumen is dilated and shows TB ulcer with shaggy base [arrow] [F]
TB = tuberculosis

same stage of histological spectrum. However, repeated primary forms of TB. Miliary TB invariably affects both
showers of bacillemia may yield tubercles of different lungs symmetrically. Further, pulmonary TB is a major
sizes. Histologically, miliary tubercles typically consist of source of infection. The following account of the pathology
a Langhans’ giant cell with surrounding epithelioid cells. of pulmonary TB may include certain features that have
Depending on the compactness of the arrangement of been described earlier. Although the intention is not to
epithelioid cells and necrosis, miliary tubercles are of two repeat, some aspects of primary TB are included with special
types: cellular and caseating. The cellular form consists of reference to the lung as an organ and also to provide a basis
compact epithelioid and giant cells with very little or no for understanding further course of pulmonary TB.
caseation and are known as “hard” tubercles [ordinary The pathology of pulmonary TB has been elucidated by
miliary tubercles]. The caseating type consists of loosely a number of studies that included a careful and detailed
formed tubercles with caseation necrosis. These are known examination of lungs obtained at autopsies. In addition to
as “soft” tubercles [acute caseating miliary tubercles]. AFB the elegant studies of Rich (4) and Medlar (84), who studied
are more likely to be found in soft tubercles. It is not clear nearly 1332 unexpected deaths in New York, with further
whether one type of granuloma is the precursor of the other. evaluation of 17000 necropsy records with reference to
Patients who survive for weeks may show a central area pulmonary TB, Nayak and co-workers at New Delhi studied
of caseation surrounded by satellite granulomas. Eventually around 1680 autopsies (85,86).
healing takes place and the granulomas undergo progressive
hyalinisation and calcification. This may give a fine mottling Primary Pulmonary Tuberculosis
on chest radio­graphs. Some immunosuppressed patients
with generalised [disseminated] TB may show granulomas Primary TB has already been dealt with in detail earlier. Only
that are softer than the soft tubercles. Giant cells are not certain relevant aspects shall be highlighted here. Classical
found. The epithelioid cells are not well developed and features of a primary complex in the lung [Ghon Complex]
are dispersed. On the other hand, there is prominent are a small [usually < 1 cm] often inapparent paren­
necrosis with numerous bacilli. This is also referred to as chymal lesion [Ghon lesion or Ghon focus] coupled with
non-reactive TB. enlarged, ipsilateral hilar and less commonly paratracheal
nodes [Figure 3.2B]. The lymph nodes are generally much
larger than the parenchymal focus. As has been repeatedly
PULMONARY TUBERCULOSIS
indicated, the location of the parenchymal lesion is usually
Pulmonary TB is the most frequent organ TB worldwide. towards the middle of the lung [upper part of the lower lobe
Lungs account for a majority of both primary and post- or the lower region of the middle or upper lobe depending
 Pathology of Tuberculosis 35

on the side]. Certain sites such as the apical and posterior The spread of infection from the primary lesion is by a
segments of the upper lobe, apical segment of the lower variety of ways, such as, direct extension into adjacent tissue
lobe or upper portion of right middle lobe are described as or by endobronchial, lymphatic or vascular pathways for
likely sites of primary infection, however, no part of the lung a disseminated spread. Endobronchial spread of liquefied
is exempt (84). A single Ghon’s complex was identified in caseous material is a cause of ipsilateral or contralateral
58% and multiple in 16% of cases studied by Medlar [84]. acinar pneumonia. Implantation of mycobacterium in the
In one case, five foci were identified, one in each different mucosa of the upper airway can result in laryngotracheal,
lobe. In 26% cases, the complex was incomplete because oral or middle ear TB. Swallowing infective sputum can also
either a parenchymal or lymph nodal component was not lead to TB and ulceration of the intestinal mucosa. Ipsilateral
demonstrated. A typical primary or Ghon’s focus is single, hilar lymph node spread is especially prominent in primary
2 mm or more in size and located within 1 cm of the pleura infections. Perforation of a bronchus by an enlarged caseous
of the collapsed lung. Lesions within the lung are relatively lymph node followed by endobronchial spread can result
uncommon. A majority of the primary foci calcify and a in massive segmental or lobular pneumonia. From regional
minority show caseous necrosis [85% and 15% respectively]. lymph nodes, bacilli can disseminate through lymphatics
Lymph node enlargement is easily identified in a large to the pleura, spine and other viscera. Haematogenous
majority [87%]. In order to demonstrate the tubercle, it may dissemination can occur through the thoracic duct after
be necessary to make serial slices in about three-fourths of lymph node involvement or by direct extension of the lesion
the cases whereas in the remaining, the lesions are readily into branches of the pulmonary vein.
apparent. Bilateral adenopathy is uncommon except with
left-sided primary foci (87). Massive lymphadenopathy is Healing
reported (88) especially in the poorly nourished subjects.
Healing of the primary lesions is the rule. The caseous focus
Progression of Tuberculosis is gradually replaced by reticulin and collagen deposition.
Event­ually, hyalinisation, and calcification are common [up
The natural history of TB in the human host is influenced to 85%]. Subsequent demonstration of these lesions may be
by age, sex, mycobacterial virulence, infecting dose, natural difficult. However, a minority of patients may demonstrate
and acquired resistance, certain host factors resulting in a radiologically a residual hyalinised scar or calcification at the
tendency of the disease to follow a pattern of progression site of the primary [Ghon] lesion, in the lung parenchyma
according to Wallgren’s timetable (89). Interplay of these and in the hilar or paratracheal lymph nodes—a combination
factors and the likely mode of spread of the bacillus result referred to as the healed primary [Ghon] complex.
in different manifestations.
Early in the course of disease, tuberculin conversion after Early Generalisation
primary infection may result in mild illness. In the first few
years, there is an increased susceptibility to miliary spread Early generalisation or dissemination is an invariable
and meningitis. Miliary disease and meningitis follow accompani­ment of primary pulmonary TB [detailed above].
within two to nine months in 10% of children under two The primary infection is accompanied by early lympho-
years of age although these forms can be seen at any age. haematogenous spread within hours or days from the site of
Segmental large lesion [epituberculosis] is an early sequel initial implantation (90). It is felt that occult mycobacteraemia
of primary TB in infants and in a minority of adolescents is probably common before acquired immunity, and thus,
and young adults, generally within two to nine months may seed many sites in the body especially where the
of primary infection. Though these lesions were large bacillus is favoured to remain viable (20). While the sites
on chest radiograph, these used to disappear gradually of these seedings have already been mentioned, one
over time. Pleural effusion, which follows primary TB, aspect needs to be highlighted here. Huebschmann [1928]
is also seen as a sequel of the post-primary pulmonary observed a group of nodular lesions in one or both apices
disease. Progression to post-primary TB is more likely if of the lung that occasionally follow primary TB in children.
primary infection is acquired in the later years of young These foci are so small that special techniques may be
adulthood than in childhood. In childhood infection, necessary to demonstrate them. These Huebschmann
the post-primary disease is delayed until adolescence. foci heal and cause no further disease. It is likely that
Extrapulmonary organ TB is variable. Cervical lymphadenitis Simon foci, which are larger, single or multiple apical
may be early but, skeletal and renal TB usually present very caseous nodules with a tendency to calcify, are exaggerated
late. This progression is only a broad direction and not form of these smaller foci. The importance of Simon
absolute. foci lies in the pathogenesis of post-primary TB (4). In a
minority of cases haematogenous dissemination results in
Further Changes of the Primary Complex miliary TB.
The primary complex may heal or progress further.
Liquefaction and Progressive Primary Tuberculosis
Progression occurs in a small proportion of cases. Early
dissemination is common but may not necessarily result in Liquefaction of solid caseous foci is thought to be related
concurrent illness. to the onset of delayed hypersensitivity with the release
36 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

of hydrolytic enzymes by macrophages (91). Liquefaction lobar or seg­men­tal bronchus by the enlarged lymph nodes
may result in a caseous mass that may include the enlarged or primary pulmo­nary lesion resulting in accumulation of
lymph nodes. Within the liquefied area there are multiplying mucus, distal to the obstructed bronchus in the form of
tubercle bacilli and, therefore, there is a risk of transmission pulmonary infiltrate without any systemic manifestations.
of disease. Due to the lique­factive necrosis there is extensive Epituberculosis is a rare but more frequent in infants and
parenchymal destruction and cavitation, which is generally children than in adults. It is a benign lesion appearing as a
a little less than the size of the original caseous mass. The dense homogeneous shadow on chest radiographs, typically
cavity may communicate with an airway, and thus, promote wedge shaped, extending from the hilum to the pleura.
bronchial spread to other parts of the lung, larynx and the The lesion is frequently large rather sharply defined and
alimentary tract. An acute fatal bronchopneumonia may has the appearance of an area of consolidation. Clinical
result. In some of these cases the inflammatory reaction is symptoms are few and the shadow generally clears
neutrophilic, like in the case of bacterial pneumonia, but AFB after several months. Residual changes are infrequent
are demonstrable. Due to such a reaction, the diagnosis may and radiographs may show slight abnormal marking or
be missed. Discharge of the liquefied material through the calcifications. The radiographic appearance is relatively
adjacent pleura results in pleural effusion, pneumothorax or dramatic and sinister, in contradiction to clinical symptoms
empyema. Caseous lymph nodes may similarly discharge and the outcome. It has been suggested that this is a
liquefied contents into the bronchus [Figure 3.5]. non-specific pneumonic consolidation that occurs in TB.
Progressive primary TB directly follows the primary The shape of the shadow is highly suggestive of involve­
lesion. There occurs an extended primary focus or TB ment of a portion of lung tissue supplied by a bronchus.
bronchopneumonia. Cavitation may ensue. Cavitation and Rich (4) studied several of such cases and found that a
progressive primary disease are more likely in infancy, caseous lymph node had perforated the bronchial wall,
at puberty and in the elderly. There is a tendency for discharged its contents and resulted in aspiration of the
progressive primary TB to involve lesions that are apical. material. It is understandable, that the caseous material is
This location is similar to that of post-primary TB. poor in bacilli, otherwise the lesion would be a progressive
bronchopneumonia. The resulting consolidation could be
Lobar and Segmental Lesions partly due to a “hypersensitive” reaction to the contents of
the lymph node [a positive “pulmonary tuberculin test”,
As a consequence of spread along the submucosal lymphatics if such a term is acceptable]. The alveoli in such cases
of bronchi, tubercle formation with ulceration of bronchial would resemble pneumonia with epithelioid cells and few
mucosa at times, is followed by complete necrosis of or no AFB. There is also sufficient evidence to suggest the
the bronchus. Within the bronchus a cold abscess may atelectasis theory and relief of atelectasis by interventional
develop and can be seen on the radiograph as a rounded bronchoscopy (93). A combination of aspiration and
or elongated shadow. Bronchial lesions are rare but may obstruction by lymph nodal compression may occur. With
result in narrowing of the lumen. Extrinsic com­pres­sion continued treatment, the TB lymph nodes heal, obstruction
from enlarged lymph nodes is a relatively more likely cause is relieved, drainage is re-established, and resolution of the
of bronchial obstruction. The lobe or segment subtended by pulmonary infiltrate occurs. Often these lesions disappear
the obstruction may be the seat of obstructive hyperinflation, on their own.
atelectasis, secondary [non-TB] pneumonia, TB pneumonia,
and disseminated intra-alveolar epithelioid cell granulomas.
Primary Tuberculosis in Adults
Atelectasis most commonly affects the anterior segments of
the upper lobes and the right middle lobe. Endobronchial The radiological and other features of adult primary TB
TB is a complication of primary TB in children (92). Residual are essentially similar to childhood primary disease (94,95).
bronchostenosis and bronchiectasis [Figure 3.4B] may occur Prominent hilar and mediastinal glands and caseation are
as late complications. less frequent in adults except in patients with AIDS. Also,
Hilar and mediastinal lymph nodes may very rarely bronchial obstruction and dissemination are less common.
cause impaired venous return, severe enough to cause As in children, endobronchial TB can complicate post-
superior media­stinal syndrome. Such lymph nodes may primary TB in adults. With increasing primary adult TB,
result in tracheal obstruction at the thoracic inlet, rupture endobronchial TB may occur as a sequelae of adjacent
into the mediastinum and pointing abscess into the parenchymal disease from which submucosal lymphatic
supraclavicular fossa, erosion of blood vessel, invasion of spread leads to mucosal ulceration, hyper-plastic polyp
pericardium, compression of or erosion into the oesophagus formation or fibrostenosis with atelectasis of the subtended
and the formation of various fistulae. lobe (96).

Epituberculosis Post-Primary Pulmonary Tuberculosis

The term “Epituberculosis” was first coined by Eliasberg In contrast, to primary TB, the localisation of post-primary
and Newland’ in 1921 as a nontuberculous consolidation pulmonary TB is apical or sub-apical. This area has been
of TB lung (4). It is defined as the obstruction of adjacent referred to as the ‘vulnerable region’ by Medlar (84). This site
 Pathology of Tuberculosis 37

probably relates to the relatively higher oxygen tension in the Table 3.7: Lesions in post-primary pulmonary TB
region resulting from the effect of gravity on the ventilation-
Pulmonary lesions
perfusion ratio in the upright lung. Presently, evidence
suggests that this is possibly because of better survival of Lobular pneumonia
the bacillus at this region as the higher oxygen tension has Nodular TB
an unfavourable effect on the macrophage and thereby Small nodule
permits intracellular growth (97). This may also influence Large nodule
progressive primary disease that is more frequent in the Healed nodules
apical and posterior segments of the upper lobe. Higher Fibrocaseous TB
vascularity and consequently increased oxygen tension may With cavity
determine the preferential multiplication of bacilli at other Without cavity
sites also, such as ends of long bones, vertebrae and the renal Tuberculosis bronchopneumonia
cortex. Similarly, mitral stenosis, which results in higher Bronchial lesions
pulmo­nary arterial pressure and increased apical blood flow,
Bronchial inflammation
confers a protective effect. The reverse is true for pulmonary Endobronchial TB
stenosis (98). Lowered blood flow may also be associated Bronchiectasis
with lower lymph flow, and thus, lesser antigen clearance. Whole lung TB
The great majority of these cases represent recrudescence
Miliary tuberculosis
of dormant tubercle bacilli occurring several years after the
primary infection or even decades after primary infection. Complications
As has been mentioned earlier, there is a haematogenous Haemoptysis
seeding of the apical and sub-apical regions of the lungs— Aspergilloma
Amyloidosis
following primary infection. This is the endogenous
Carcinoma
pathway resulting in reactivation TB (99). However, there Oral cavity and upper respiratory tract TB
is evidence to suggest that a bronchial spread from an index
Pleural lesions
case may be the route of infection. This is the exogenous
TB = tuberculosis
pathway resulting in reinfection TB. The organisms may
reach by either pathways (4). Infection with other related Based on references 85,86
species of mycobacteria may also have the same result. The
pathological lesions seen in post-primary pulmonary TB are
enumerated in Table 3.7 (84,85).
by epithelioid cells and giant cells and are encapsulated by
a fibrous wall. Large nodules are similar but show more
Early Lesions
caseation and less encapsulation [Figures 3.5A and 3.5B].
The earliest lesion is probably an apical or subapical lobular Healed nodules are of the size of small nodules and are
pneumonia (85). These lesions are not well-documented fibrosed or hyalinised or calcified. Anthracotic pigment may
because it is believed that the pneumonia gives way to be identified in any nodule (85).
a granuloma rapidly. An outline of the alveolar reticulin Active nodules, especially of the small size are predo­
framework in the centre of some of these granulomas may minantly located in the apical and sub-apical regions and
suggest such a transition (85). It may be mentioned that in may be single or multiple. The reverse is true for healed
1925, Assmann drew attention to the fact that the earliest nodules. It appears that small nodules give rise to larger ones
lesion clearly visible in clinical TB consists of infiltrates and nodular TB may expand to form fibrocaseous lesions.
not at the apex, but at the sub-apical and infraclavicular It may be mentioned that these nodules are not related to
region. These infiltrates [Fruhinfiltrat] are known as Assmann Ghon’s focus. The location and the absence of accompanying
infiltrates or foci (4). The histological counterpart of these enlarged lymph nodes should provide a clue. AFB could
lesions is not known. be demonstrated in 7% of small nodules and 29% of large
nodules [85].
Nodular Lesions
Fibrocaseous Tuberculosis
Nodular lesions [coin lesions, tuberculomas] are localised,
well-defined areas of TB wherein the adjacent pulmonary Fibrocaseous TB includes lesions that reveal well-known
parenchyma is usually normal or may show some scarring. features of TB such as caseation, consolidation, liquefaction
A small nodule is less than a centimeter in diameter, whereas and fibrosis. Grossly, various patterns are seen. The apical
the large nodule is larger than a centimeter in diameter. and posterior segments of the upper lobes are predominantly
Grossly, nodules are white to yellow in colour and may involved (100-102). Lymph node involvement is slight in
vary in consistency from soft lesions that are largely necrotic comparison to primary TB. Retraction of lung parenchyma
to firm or hard lesions that are fibrosed or calcified. Small is associated often with pleural thickening. In some cases
nodules have a central area of caseation, are surrounded the lung may have an appearance of bronchopneumonia
 38 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B

C D

E F
Figure 3.5: Lung biopsies showing confluent necrotising epithelioid cells granulomas [arrows]. Central necrosis and peripheral rim of lymphocytes
are seen [A and B] [Haematoxylin and eosin × 100]. Extensive necrosis of lymph node with peripheral epithelioid cell granulomas [arrow] are noted
[C] [Haematoxylin and eosin × 40]. Colonic biopsies showing submucosal large confluent necrotising epithelioid cell granulomas [arrows] [D],
[Haematoxylin and eosin × 40]; [E] [Haematoxylin and eosin × 100]. Peritoneal biopsy showing necrotising epithelioid cell granulomas. Adjacent
fat is marked with an arrow [F] [Haematoxylin and eosin × 100]
 Pathology of Tuberculosis 39

due to consolidation. At times, the caseous areas stand out granuloma, small pseudopolyps and eventual healing by
amidst the black background of anthracotic pigmentation. fibrosis. Bronchostenosis may give rise to post-stenotic
The most striking feature is the presence of one or more dilatation of the bronchus. This should not be confused
cavities. Cavities may assume-varying sizes and may be so with bronchiectasis. The reader is referred to the chapter
large as to result in a severe loss of lung parenchyma. The “Endobronchial tuberculosis” [Chapter 12] for further details.
wall of the cavity may be lined by TB granulation issue or Bronchiectasis directly attributable to pulmonary TB
show varying fibrosis. Often the thick walls of cavities seen is rare [Figure 3.4B] (84). In those instances when this is
on radiographs are found to be accounted for by a rim of found, it usually occurs in the upper lobe and is relatively
consolidation of the adjacent lung. Communication may asymptomatic. Along with bronchostenosis it predisposes to
or may not have been established with a bronchus. These secondary infection, haemo­ptysis and atelectasis. Extension
findings have implications on auscultation of the chest. of TB to the pleura is common. Pericardial TB may follow
Traversing the wall or the lumen along fibrous bands, are pleuritis or by lymphatic spread from a pulmonary focus.
bronchi and branches of pulmonary artery. Fortunately in
most instances the chronic process allows the arteries to Whole Lung Tuberculosis
obliterate. The caseous material may soften the wall of the
Rarely TB can affect the whole lung. This condition has
arteries giving rise to Rasmussen’s aneurysms. These may
a high mortality and results due to diffuse bronchogenic
give rise to haemoptysis that may be fatal.
spread or haemato­genous dissemination (104).
Microscopically variable caseous necrosis, extensive
fibrosis, numerous palisades of epithelioid cells and
fibroblasts together with Langhans’ giant cells are seen Complications
[Figure 3.5A]. Areas of consoli­dation may show caseous The reader is referred to the chapter “Complications of
pneumonia or even a neutro­philic response. Microscopic pulmonary tuberculosis [Chapter 31] for details.
cavities may be identified in such pneumonic foci. Cavities
are lined by necrotic TB granulation tissue and show fibrosis. PLEURAL TUBERCULOSIS
Occasional cavities may be lined in part by columnar or
squamous epithelium. AFB can be demonstrated more Pleural effusion is a more frequent sequel to primary TB
frequently in fibrocaseous lesions than in nodular TB. in adolescents and adults than in younger children. It can
Thus, in cavitary lesions AFB were found in 88% compared occur many years after primary infection as an extension of
with 77% in non-cavitary lesions (4). Smaller cavities may post-primary TB or as an isolated effusion. Pleural effusion
heal. Healing in general results in fibrosis and cicatrisation may complicate any TB pathology of lung or rib cage where
extending between the upper pole of the hilum and the the pleura is an involved bystander.
apex, thus elevating the hilum on that side. This causes Primary effusion usually occurs on the same side as
volume loss on the ipsilateral side. Simultaneously the upper the primary complex, and hence is a result of contiguous
mediastinum would be pulled towards the side of the lesion affliction. Bilateral pleural effusions or those on the side
distorting the trachea and giving a characteristic radiological opposite to the primary complex should suggest miliary
or disseminated TB. Pleural and subpleural granulomas,
appearance. Modern treatment, however, allows rapid
usually seen on both visceral and parietal surfaces, tend to
closure of cavities, which leaves little evidence of disease
follow the lymphatics on the visceral surface and may be
on chest radio­graphs. Serious complications resulting from
discrete. Diffuse or focal fibrosis may follow.
pulmonary TB are uncommon now except when the disease
Large caseous or cavitary lesions rupture into the pleural
has been neglected and becomes chronic and progressive.
space more commonly in post-primary TB and cause
bronchopleural fistula with empyema. Empyema may heal
Other Lesions with a fibrothorax and sometimes as a calcified pleural
The TB bronchopneumonia and miliary TB are a consequence plaque resulting in a trapped lung. These patients may
of a large dose of virulent organisms disseminating through present with functional disability. Histological diagnosis is
the bronchus or the blood stream respectively. It is obvious based on the identification of granulomas [Figure 3.5A].
that the host immunity may be compromised. The lesions The volume and cellular nature of the exudate are dictated
have been described earlier. by the cell-mediated immunity. The fluid is exudative,
serofibrinous and occasionally purulent. Predominant cell
Bronchial Lesions type is lymphocyte with a few mesothelial cells. Rarely,
histiocyte clusters may be seen which strongly suggest TB
Despite being closely associated with the lung parenchyma, pleural effusion. A neutrophilic response does not rule out
bronchi do not appear to be frequently affected in pulmonary TB, though it is necessary to demonstrate the organism
TB (84). In a majority of cases, the inflammation is non- unequivocally in such cases. Direct microscopy and culture
specific and typical granulomas may not be seen. In some studies often do not reveal tubercle bacilli. Primary pleural
cases endobronchial TB, as discussed under primary TB usually resolves without anti-microbial therapy but when
pulmonary TB, may follow post-primary lesions (103), and it develops in adolescence and young adulthood, it may
this is characterised by bronchial inflammation, ulceration, carry the risk of post-primary TB, usually pulmonary within
40 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

five to ten years. Therefore, treatment of pleural effusion hypertrophic [10%] and ulcero-hypertrophic [30%]. Ulcera­
with antituberculosis drugs is fully justified. tive lesions indicate a highly virulent process (109-111). The
intestine is indurated with an increase in mesenteric fat.
ABDOMINAL TUBERCULOSIS Ulcers are generally transverse to the long axis [Figure 3.4C].
Circumferential or annular ulcers are usually less than 3 cm
The term abdominal TB generally includes TB of the in length (112,113). The ulcers are superficial and may
gastrointestinal tract and the peritoneum. It is customary to have undermined edges. Apparently the disposition of the
exclude TB of organs like the kidneys and adrenals from this ulcers is a reflection of the direction of lymphatics around
list. Isolated TB of organs such as the liver is uncommon. the intestine and vascular supply from the mesentery to the
The TB of the intestines accounts for a majority of such intestinal wall (114-116). The base of the ulcer is covered
cases [65%-78%]. Disseminated abdominal TB has also been by necrotic sloughs. On the serosa small tubercles may be
observed (105,106). present, predominantly, seen over the areas of mucosal
involvement. Authors feel that it is necessary to document
Intestinal Tuberculosis these lesions in the serosa since in essence these are lesions
The primary form of gastrointestinal TB is extremely rare of TB peritonitis. However, these are localised lesions and do
and has been discussed earlier. Intestinal TB usually involves not result in the usual manifestations of peritonitis that are
the ileum, ileocaecal region and the adjacent caecum. discussed below. Perforation of the intestine when present
Although this disease is chronic and invariably presents with is usually proximal to a stricture. The ‘hypertrophic type’
symptoms suggestive of an abdominal disorder. Recurrent is characterised by scarring of the bowel loops and often
intestinal obstruction is an important presentation. Around mimics a carcinoma. The ulcero-hypertrophic type has
one-third to a quarter of the patients present with acute features of the two types described earlier. Cobblestoning
abdomen (107,108). Most cases of intestinal TB are due to of mucosa and pseudopolypi may be seen due to mucosal
post-primary TB. fissuring ulcers. The ileocaecal region is distorted and the
normal angle as seen on barium films becomes obtuse. It
is important to note that in TB, both sides of the ileocaecal
Gross and Microscopic Pathology
valve are involved leading to its incompetence. This is unlike
The credit to the description of intestinal TB goes to F. the features seen in Crohn’s disease (112,113). However, in
Koenig, whose masterly description in 1892 resulted in the practice, it is often not easy to differentiate ileal TB from
disease being called “Koenig’s syndrome” (108). Grossly, Crohn’s disease based on gross or endoscopic findings
intestinal TB is classified into three types: ulcerative [60%], [Table 3.8]. Lymph nodes may be enlarged, but as in other

Table 3.8: Differentiating features between intestinal tuberculosis and Crohn’s disease
Features Tuberculosis Crohn’s Disease
Macroscopic
Anal involvement Rare Relatively common
Serosal tubercles Usually present Not seen
Length of strictures Short [< 3 cm] Long
Internal fistulae Rare Common
Perforation Uncommon Rare
Ulcers Circumferential/transverse Along mesenteric border/longitudinal serpiginous
Microscopic
Granuloma in intestine/lymph node Present in majority Absent in a quarter
Lymph node granulomas May be only site Absent
Type of granuloma Large, confluent Small, discrete
Caseation Present Absent
Cuff of inflammatory cells Common Usually absent
Fibrosis/hyalinisation Can be seen Rare
Fissures beyond submucosa Absent Present
Transmural lymphoid aggregates Not seen Present
Submucosal widening Absent Present
Fibrosis of muscularis propria May be present Not seen
Pyloric gland metaplasia May be seen Absent
Adapted from reference 114
 Pathology of Tuberculosis 41

cases of post-primary TB, these may not be prominent. a spread from an abdominal organ, usually a ruptured
Rarely lymph nodes may assume a large size, giving rise TB lymph node. The lesions in peritoneal TB can be
to the condition called tabes mesenterica. We have seen cases classified into two types: exudative or moist type, clinically
that have very little resemblance to the description provided characterised by ascites and the plastic or dry type that is
above. Surely, if the abdomen is a magic box to the surgeon, responsible for the typical doughy abdomen. Cirrhosis may
intestinal TB has all the ingredients for a very successful be associated in a small proportion [6%] of patients with
show. peritoneal TB (119).
Microscopic appearance of intestinal TB is similar to that On gross examination, multiple, white tubercles are
of TB elsewhere. Necrotising and non-caseating granulomas generally seen. With laparoscopic examination such lesions
[Figures 3.5B, 3.5C and 3.5D] are the hallmark of intestinal may resemble a metastatic carcinoma. In some cases
TB. In addition, the intestinal mucosa shows features of numerous peritoneal adhesions are identified. Microscopic
chronic inflammation in the form of crypt architectural examination reveals typical granulomas [Figure 3.5F]. Ascitic
distortion, branching pyloric metaplasia, etc. Features of fluid cytology shows a predominance of lymphocytes.
activity, in form of ulcer, cryptitis and crypt abscess may It must be pointed out that on some occasions the reaction
be noted. The granulomas in TB are mostly confluent, large, may be neutrophilic mimicking an acute bacterial peritonitis.
necrotising, with lymphocyte cuffing and Langhans’ giant
cells. While early lesions show granulomas in the mucosa Tuberculosis of Liver
and Peyer’s patches, in later lesions these are mostly seen
Hepatic involvement by TB is not rare and is usually
in the submucosa [Figures 3.5D and 3.5E]. Sometimes the
associated in generalised TB spread. In a study of paediatric
granulomas may be elusive and certain specimens may TB, only 12% of cases showed granulomas in the liver
not reveal any granuloma (117). In fact in some studies, (120). This low incidence can be attributed to the inherent
granulomas have been demonstrated in only 40% of the drawback of needle biopsy as it samples a very small portion
resected intestinal specimens. Identification of granulomas of the liver. Examination of serial sections may yield better
in the mesenteric lymph nodes is a strong pointer of TB, results with the presence of TB hepatic granulomas in 30%
however, the same may also be noted in Crohn’s disease, up of cases with TB (121). The liver in TB can have specific
to 20%-25% cases (117). Demonstration of AFB in histological and non-specific histopathological changes. Korn et al (122)
sections is very rare [10%-20% cases] (113). Hence, the have emphasised the occurrence of focal hyperplasia of
pathologists must rely on overall histological appearance Kupffer cells in TB. This refers to localised areas of Kupffer
to convey a specific diagnosis. However, at times, based cell proliferation with dilated sinusoids. Although such
on mucosal pinch biopsies, a specific diagnosis is often lesions may be the forerunners of microgranulomas, they
not possible. In such scenarios, if the ancillary tests, such differ from microgranulomas in that these are composed
as, microbiological and molecular methods, also remain of typical Kupffer cells, have a stellate rather than rounded
elusive, a therapeutic trial of anti-TB drugs are given. Clinical configuration and lack characteristic epithelioid cells. On
and radiological improvement confirms the diagnosis; if the other hand, microgranulomas are small aggregates of
no improvement is seen, the diagnosis is reconsidered as epithelioid cells, usually centrilobular in location and lack
Crohn’s disease, and a repeat biopsy is obtained. Myco­ giant cells and caseation (122). In fatal cases of TB, actual
bacterial culture of the biopsy material may increase the involvement by granulomatous process is common; whereas
yield ten-fold. In the case of the colon, histopathological and in localised form, the non-specific changes predominate.
bacterio­logical examinations can provide diagnosis in 60% The rarer forms of hepatic TB lesions include TB cholangitis,
of cases (118). tuberculoma and TB of the lymph nodes at the porta
hepatis. In TB, most of the hepatic granulomas are lobular,
Complications though, portal tract granulomas can be seen. Confluence
of granulomas, Langhans’ giant cells, lymphocyte cuffing,
Haemorrhage, perforation, obstruction, fistula formation and
necrosis and poor reticulin fibers around the granulomas, if
malabsorption due to obstruction and blind-loop syndrome
present, are indicators of possible TB aetiology [Figures 3.6A,
and massive enlargement of mesenteric lymph nodes
3.6B and 3.6C]. However, hepatic granulomas can be seen
[tabes mesen­terica] can occur in intestinal TB.
in sarcoidosis [portal tract predominant] [Figures 3.6D
and 3.6E], parasitic infestation, fungal infections, steatosis
Differential Diagnosis associated granulomas [Figure 3.6F] or granulomas asso­
Apart from Crohn’s disease, ischaemic enteritis, Yersinia ciated with hepatotrophic viral infections. Hence, the biopsy
entero­colitica, amoebiasis and carcinoma caecum (113,115). findings need to be correlated with clinical scenario and
Syphilis and lymphogranuloma venereum are curiosities of should be further investigated with ancillary techniques
historical interest. and special stains.

Peritoneal Tuberculosis Genitourinary Tuberculosis

Peritoneal TB is post-primary and is the result of either Genitourinary TB [GUTB] usually occurs in the reproduc­
haemato­genous spread from a focus elsewhere or due to tive age group with a considerable lag period of up to
 42 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B

C D

E F

Figure 3.6: Photomicrograph showing confluent necrotising lobular epithelioid cell granulomas [arrows] [A and B] [Haematoxylin and eosin × 100].
Reticulin staining shows poor reticulin fibers around and inside the granuloma, suggesting TB [arrow] [C] [Reticulin × 200]. Portal based sarcoid
granulomas with foreign body giant cells [arrows] [D] [Haematoxylin and eosin × 100]. Reticulin staining shows perigranuloma reticulin fibre
condensation. Fibres are also seen inside the granuloma [arrows] [E] [Reticulin × 200]. A lobular fat granuloma in a case of nonalcoholic
steatohepatitis. Fat droplets are noted inside the granuloma [arrows] [F] [Haematoxylin and eosin × 100]
TB = tuberculosis
 Pathology of Tuberculosis 43

two years in 90%-95% cases following the occurrence of lesions can persist as localised tuberculomas or discharge
primary TB (123). The disease involves the urinary tract into the draining calyx. Sloughing of the necrotic contents
and the genital tract either singly or in combination. Due to into the calyx leads to cavity formation. Such cavities have
anatomical considerations, infection of the urinary tract and shaggy necrotic walls with fibrosis of the adjacent renal
the male genital tract in combination is common. parenchyma (125), or resulting in defunct, destroyed calcified
kidney [autonephrectomy] [Figure 3.4D] (126). TB may result
Urinary Tract in changes of pyonephrosis with dilatation of calyces known
Initially, renal TB granulomas are located in the cortex, as “putty” or “cement” or “chalk” kidney, which spreads
which has a high perfusion rate. Cortical granulomas may down to affect ureters, bladder or urethera leading to ureteric
remain dormant and if the host resistance is favourable, then strictures and segmental dilatation and obstruction (124).
fibrosis ensues. Highly virulent organisms or low resistance TB interstitial nephritis can only be diagnosed by presence
can cause progression of the lesion and the necrotic debri of granuloma in interstitium, as kidney will be of normal
may lodge in the proximal tubule and loop of Henle. These size and smooth contour with sterile urine. Severe lesions
produce medullary lesions which can enlarge, coalesce may destroy the parenchyma fairly extensively [Figures 3.7A
and produce papillary necrosis (124). The larger medullary and 3.7B] (127).

A B

C D
Figure 3.7: Renal biopsy showing confluent epithelioid cell granulomas. Glomerulus is noted [arrow] [A] [Haematoxylin and eosin × 100]. Urethral
TB shows necrotising epithelioid cell granulomas with ulceration of urothelial lining [arrow] [B] [Haematoxylin and eosin × 100]. Fallopian tube
section shows mucosal confluent granulomas [C] [Haematoxylin and eosin × 100]. Endometrial biopsy showing epithelioid cell granuloma in a
proliferative endometrium [arrow] [D] [Haematoxylin and eosin × 100]
TB = tuberculosis
44 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Some observers believe that kidneys can be involved Female Genital Tuberculosis
by ascending infection from the bladder through the
Female genital TB is usually secondary to a pulmonary
ureteral route. While such ascending infection is not very
TB. Modes of spread include haematogenous (90%), direct
common, communication of the caseating granuloma with
descending or lymphatic routes. It may be a component of
the collecting system is usually responsible for the spread
generalised miliary TB. Transmission by sputum, used as
of infection into the distal urinary system like pelvis, ureter
a lubricant by an infected partner, has been reported (133).
and urinary bladder. Additionally, lymphatic spread can
Sexual transport through semen in male patients with GUTB
occur to contiguous structures. TB ureteritis initially appears
has been noticed in 3.9% cases (131).
as dilated and ragged irregular urothelium [“beaded”
Pathologically, the fallopian tube [95%-100%] is the most
or “corkscrew” ureter]. Gradually it can lead to stricture
common site of involvement [Figures 3.4F and 3.7C] (134,135).
formation leading to ureteral shortening and fibrous contrac­
The tubes are usually involved bilaterally. These get seeded
tion that appears as “golf hole” orifice in the bladder. This
during the primary infection. The lesions get reactivated
can lead to obstruction, which in advanced cases, may
or clinically manifested usually after a long latent period.
result in TB pyonephrosis. There may be focal or diffuse Endometrial TB (50%-60%), myometrial TB (2.5%) are related
calcification of the renal parenchyma. to spread from the fallopian tubes (136). Less commonly,
Renal amyloidosis can occur in patients with pulmonary cervix [5%-15%] and vulva, vagina are involved, as an
TB of long duration. Apart from specific TB process, kidney extension from the endometrial lesion. Ovarian infection
can show several non-specific changes in pulmonary TB. [20%-30%] can also occur from the tubal source (137). Rarely
Shah et al (128) examined renal needle biopsy specimens sexual transmission can cause vulvar ulcers and inguinal
from 30 patients with pulmonary TB. Of these, 70% had lymphadenopathy in females (138). Frequently, more than
abnormal renal histopathology in the form of cloudy one organ may be involved (127).
swelling of the tubular epithelial cells, focal lymphocytic Gross lesions can be miliary, ulcerative, proliferative
aggregates, membranous glomerulonephritis, interstitial or a combination of these. Fistula formation has also been
fibrosis and amyloidosis (128). reported. Granulomas are identified usually in the mucosa
The initial lesions in the urinary bladder in TB are seen of the affected organ. Histopathological confirmation by
around the urethral orifices. Progressively, in advanced endometrial curettage with staining for AFB and culture are
lesion the whole bladder wall may be involved. There necessary for diagnosis. Curettage should ideally be done
is granulomatous inflammation and ulceration of the in the late menstrual cycle. However, it is not necessary
mucosa. Later on, fibrosis may lead to urethral stricture to believe that granulomas are identi­fied only in secretory
formation and and the bladder becomes small, contracted endometrium. Granulomas can be found in any phase of the
and calcified, finally resulting in nonfunctional bladder menstrual cycle and also in hyperplasia of the endometrium
[autocystectomy] (129). [Figure 3.7D]. Cervical biopsy is also useful. Identification
It may be mentioned that treatment of transitional cell of necrotising epithelioid cell granulomas with or without
carci­noma of the urinary bladder often involves instillation demonstration of AFB establishes the diagnosis in a
of BCG into the bladder. This may give rise to BCG considerable number of cases. Caseation has been reported
granulomas, histologically indistinguishable from TB. to be more frequent in the elderly. Unfortunately, AFB are
hardly identifiable in most instances (127).
Male Genital Tract
If the infection proceeds from the urinary bladder, involve­ NEUROTUBERCULOSIS
ment of seminal vesicle, vas deferens and epididymis can Neurotuberculosis includes TB of the meninges, the brain,
occur (130). Isolated testicular TB is rare. All such cases spinal cord and the nerves. TB meningitis [TBM] is the most
are accompanied by epididymal infection through infected common form of neurotuberculosis and generally develops
urine, lymphatics or haematogenous routes, resulting in TB from the breakdown of a small initial focus in the superficial
epididymo-orchitis [Figure 3.4E]. TB epididymitis can lead cortex or leptomeninges. This focus discharges caseous
to thickening of the vas by the granulomatous process and material into the cerebrospinal fluid [CSF] (139). Such a
bilateral involvement has been noticed in 34% cases (131). focus can destabilize following years of quiescence due to
Rarely cold abscess can also form near the epididymis (129). advanced age, trauma, malnutrition, chronic debilitation
TB of the prostate can mimic a nodular or benign hyperplasia and immune suppression. TBM can also result from
clinically. Involvement of multiple sites in the male genital miliary spread of the disease. The miliary tubercles in the
tract is not uncommon, as reported in an autopsy series (124). leptomeninges are most frequently seen on the lateral aspect
As concurrent or previous renal TB is seen in many cases (132), of parietal and temporal lobes on either side of the Sylvian
genital TB is usually sequelae to a descending infection from fissure and along the blood vessels at these sites.
the kidney (127). There are six main parenchymal changes in neuro­
Penile TB is very rare. As a form of skin TB, it can be tuberculosis. These are ventriculitis, border zone encephalitis,
acquired from sexual contact. It can also be a manifestation infarction, internal hydrocephalus, diffuse oedema and
of either local or haematogenous spread. tuberculoma. Ventriculitis is less frequently encountered
 Pathology of Tuberculosis 45

than meningitis. In this condition, the ependymal lining of meningeal plaque which is often masked macroscopically
the ventricles and choroid plexus show tubercles. Border by the surrounding meningitis; and [iii] macroscopic
zone encephalitis is caused by impingement of the meningeal visualisation of caseous nodules is often difficult.
exudate on the underlying brain parenchyma. Frequently, Parenchymal tuberculoma is less frequently seen than
there is only a glial reaction. Occasionally the changes may TBM. This may be due to the difference in their pathogenesis.
be of inflammatory nature. Infarction is caused by vasculitis Usually small tubercles are found in association with TBM.
due to inflammation of the vessels in the meningeal exudate. While TBM is a typical leptomeningeal reaction to tubercle
The vessels commonly involved are branches of the middle bacilli, tuberculoma is the manifestation of hypersensitivity
cerebral artery, especially the perforating vessels to the basal to tuberculoproteins in the susceptible individual (141).
ganglia (140). The vascular changes occur in the form of Generally tuberculomas [Figure 3.8B] favour infratentorial
periarteritis, endarteritis, panarteritis, necrosis and throm­ location, the most frequent site being the cerebellum. The
bosis. Narrowing or total occlusion of the vessels results in physical continuity between a tuberculoma and meningeal
infarction of the zone supplied by the artery. exudate is usually not evident, although this has been
In TBM, hydrocephalus evolves due to the following occasionally observed (142).
reasons: [i] blockage of the basal cisterns and medullocere­
bellar angles and obstruction to the flow of the CSF by the Microscopic Features
basal exudate; and [ii] interference in the absorption of CSF
by arachnoid granulations. Large areas of caseous necrosis feature the leptomeningeal
reaction with a cellular infiltrate consisting predominantly
of lymphocytes and plasma cells. There may be focal
Macroscopic Features
epithelioid granulomas with giant cell reaction [Figure 3.9A].
In TBM, the brain is heavier in weight due to cerebral Ependymal lining of the ventricles reveals ependymitis
oedema. The leptomeninges in the basilar area appear which resembles the inflammatory reaction of meningitis.
opaque as the underlying thick exudate fills up the cisterns Choroid plexitis may also be evident. In some cases
[Figure 3.8A]. Sometimes, the exudate is found on the surface the inflammatory reaction may be polymorphic giving
of the brain mimicking pyogenic meningitis. The gyri appear the appearance of a pyogenic meningitis. However, in these
flattened with obliteration of sulci. Superficial blood vessels cases, numerous AFB are demonstrable.
look congested. Serial slicing reveals ventriculitis with Immediately beneath the meningeal exudate, the brain
matted appearance of the choroid plexus. There may be shows oedema, perivascular inflammatory infiltrate and
ventricular dilatation and areas of infarction in the middle microglial reaction [Figure 3.9B]. In longstanding cases
cerebral artery territory. Finding the parenchymal tubercles gliosis ensues. If the inflammation is caused by fewer
giving rise to TBM is difficult task because: [i] the tubercles bacilli, complete resolution of the exudate is possible
are frequently of small size [commonly 3-5 mm in diameter]. with treatment. Residual well-circumscribed, small caseous
Thus if the slices are thicker than 3 mm, the lesions may foci may remain following treatment if the bacilli are
be missed; [ii] the site of origin is frequently a caseous abundant.

A B
Figure 3.8: Gross specimen photograph of a brain base, showing thick exudate in TB meningoencephalitis [arrows] [A]. Cut-surface shows
tubercles around the basal ganglia and corpus callosum [arrows] [B]
TB = tuberculosis
 46 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 3.9: Photomicrographs showing perivascular epithelioid cell granulomas in TB encephalitis [Haematoxylin and eosin × 100] [A].
Cortical gliosis [arrows] is also noted [Haematoxylin and eosin × 200] [B]
TB = tuberculosis

Histopathologically, tuberculomas show epithelioid

granulo­matous response with chronic inflammatory cells
and Langhans giant cells. There are areas of caseous necrosis.
An occasional case shows focal calcification.
The TB abscess consists of pus-filled cavities containing
tubercle bacilli. The wall of TB abscess shows granulation
tissue with inflammatory cells. There is usually a paucity
of epithelioid cells or giant cells and the lesion may be
misdiagnosed clinically as pyogenic abscess. The content of
the cavity usually shows numerous AFB.
Intracranial TBM often extends into the spinal meninges.
Only in a few cases the inflammation starts in the sub­
arachnoid space from a small subpial tubercle [Rich focus]
or TB vertebral osteomyelitis. Rarely there can be spinal
intramedullary tuberculomas similar to intracranial lesions.

MUSCULOSKELETAL TUBERCULOSIS
Figure 3.10: Gross specimen photograph of a long bone with evidences
Bone and joint TB usually follows a primary pulmonary
of TB osteomyelitis
infection. Less commonly there can be contiguous spread TB = tuberculosis
from pleura, periaortic lymph nodes or haematogenous
dissemination (143). The most frequently involved site is
the vertebral body and this form of spinal TB is known as Histopathologically, the presence of a granulomatous
spondylitis, i.e., “Pott’s disease”. In this disease, the classical inflam­ma­tion with necrosis is compatible with the diagnosis
involvement is of two consecutive vertebrae with destruction of TB. Histopathological evidence of mycobacterial
of the intervertebral discs. The lower thoracic and upper infection has been documented in 94% of synovial biopsy
lumbar areas are common sites of disease (144,145). It samples (147). In general, mycobacterium load is 107-109
clinically presents as local pain, which increases in severity and less than 105 in pulmonary and osteoarticular lesions,
over weeks to months and the differential diagnoses include respectively. In the case of the bone, the best material for
degenerative disc, spondyloarthropathy, facet joint disease, microbiological assessment is centrifuged residue from large
vertebral body collapse due to osteoporosis, osteopenia, quantity of abscess, curettings from wall of cold abscess
subacute/chronic Staphylococcus aureus spinal infections, prior to secondary infections or curettings from the base of
osteomyelitis and malignancies. Any other bone or joint can sinus tract lining. Direct smear examination of tuberculous
be involved by TB, but weight bearing ones like knee and material obtained during operation or obtained by aspiration
hip joints are more prone to be affected (146). The next of the infected synovium [from joints, bursae and tendon
common form of skeletal TB is TB arthritis [Figure 3.10]. sheaths] or involved lymph nodes or the tuberculous osseous
 Pathology of Tuberculosis 47

cavities may yield a positive result for tubercle bacilli. been observed in up to about 26%-40% cases. Immune
Special stains can demonstrate AFB in some cases (148,149). anergy with loss of tuberculin reactivity is common.
Mycobacterial culture positivity varies from 30.4%-87% of The progressive loss of tuberculin reactivity appears to
cases (150). coincide with a CD4+ T-lymphocyte count below 300-400
per cubic millimeter, although very low counts may be
TUBERCULOSIS IN THE IMMUNOCOMPROMISED associated with a significant tuberculin reaction at a level
TB is often the sentinel disease warning of HIV infection of 5 mm or greater particularly after boosting by a second
and the development of AIDS. When active TB occurs in test (152-154). In the terminal stages, when the immune
patients with AIDS, pulmonary TB is almost always present defect is severe, there may be aggregates of macrophages
and in up to 70% of the cases extrapulmonary disease is with numerous intracellular organisms, but no granuloma
associated. The source of infection could be recrudescence formation. Dissemi­nated, non-reactive TB with necrosis,
of latent infection [the most common source], or accelerated much nuclear debris, many extracellular stainable AFB and
progression of newly acquired disease or superinfection of minimal cellular reaction are also seen. Surrounded by a
those previously infected. few histiocytes and lymphocytes areas of naked necrosis
Impaired cell mediated immunity [CMI] due to the can be seen. The mechanisms of necrosis in the absence of
reduced number of T-cells, specifically, the CD4+ subset significant numbers of inflammatory cells is unclear and so
is considered to be the reason for the higher incidence is the mechanism by which the cell response is excluded.
of TB in AIDS. Macrophage and peripheral monocyte
function is reduced and consequently there is reduced NONTUBERCULOUS MYCOBACTERIAL
activation of lymphokines. The cellular arm of immunity INFECTIONS OF LUNG
is, thus, seriously impaired and the body’s defences against The focus of this section is on the pathogenesis and
intracellular pathogens such as mycobacteria and other pathology of the infections caused by ubiquitously present
organisms such as Pneumocystis jiroveci become defective. [slow > rapid growing] nontuberculous mycobacteria [NTM].
TB bacilli itself may also cause immunosuppression (151). Pulmonary involvement is most common [94%], other
Until a late stage has been reached in the immune impairment, being lymphatics [3%] and skin/soft tissue/disseminated
TB presents the usual clinical and pathological patterns sites [3%]. Microbiological classification, characterisation
observed in immunocompetent persons. Post-primary TB and other details regarding NTM are dealt with elsewhere.
is most often encountered. Only when the immune defect The reader is referred to the chapters titled “The mycobacteria”
has become severe the presentation becomes atypical and [Chapter 4] and “Nontuberculous mycobacterial infections”
resembles more the pattern of primary disease (152-154). [Chapter 41] for details.
Hilar and mediastinal lymphadenopathy [often bilateral]
can occur in up to 60% of adult TB cases co-infected with
Pathology
AIDS, while this is observed only in 3% patients without
AIDS. Middle and lower zone involvement is more often The gross and microanatomical knowledge regarding NTM
observed than the usual upper lobe involvement. Diffuse disease is incomplete as the number of cases studied that
infiltrates or a miliary pattern is apparent in 15% cases and have not been modified by previous treatment, are rare. Also
distant haematogenous dissemination to unusual sites is many cases have not been studied, as they have been passed
common. Pleurisy commonly occurs. The disease, thus, off as resistant TB or a nodular infiltrative disease. NTM
resembles primary or progressive primary TB. Cavitation disease differs from TB in not causing a defined sequence of
is less frequent. Therefore sputum is less frequently primary and post-primary disease (155,156). Haematological
positive for AFB. Surprisingly even in the late stages of dissemination occurs only in the immunosuppressed.
immunosuppression, typical compact or ‘hard’ tuberculoid Radiological patterns of M. avium-intracellulare complex
granulomas with minimal necrosis and few bacilli, [MAIC], M. kansasii disease and M. xenopi resemble post-
epithelioid cells and Langhans’ giant cells can be seen. There primary TB. In M. kansasii, the cavities are thin walled.
is, however, the eventual tendency for the cell aggregates In NTM disease, the anterior segments of the upper lobes
to become smaller. They are more loosely formed and the are more frequently affected. Spread to contiguous pleura
lymphocyte collar may not be evident. AFB are often found, and pericardium is rare and spread to the lymph nodes is
giant cells are rare and karyorrhexis [nuclear fragmentation] uncommon. M. genavense is a new atypical agent in HIV
is often seen (152-154). patients. Study of an HIV-negative elderly female without
Chest radiograph may be confusing. In a few cases, other lung disease showed a wide distribution of the lesions,
the chest radiograph may be normal even in patients frequent bronchiectasis, patchy air-space disease, nodules
with bacteriologically proven parenchymal TB. This is and relative infrequency of cavities (157).
especially so in infections caused by Mycobacterium avium- The histopathology of the lung in NTM infections can
intracellulare complex [MAIC]. Diffuse interstitial pattern be summed up as a spectrum ranging from a collection
on chest radiographs can be caused by Pneumocystis jiroveci of lympho­cytes through aggregations of epithelioid cells
infection in patients with AIDS and is easily confused and typical sarcoid-like tubercles to characteristic caseating
with other diseases. A positive blood culture for Mtb has granulomas (115,158). The nodular pattern seen on computed
48 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

tomography [CT] consists of discrete peribronchial 4. Rich AR. The pathogenesis of tuberculosis. 2nd edition. Illinois:
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6. Wain H. The story behind the word. Illinois: Charles C. Thomas;
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aggregation of polymorphs and areas of acute inflammation Microbiol 2007;5:39-47.
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may sometimes be identified. Well-formed epithelioid classification. Clin Infect Dis 1996;23:146-58.
granulomas are uncommon and caseous necrosis is not 9. Rook GAW, al Attiyah R. Cytokines and Koch phenomenon.
Tubercle 1991;72:13-20.
a feature. Disseminated disease from rapid growers is
10. Morrison A, Gyure KA, Stone J, Wong K, Mc Evoty, Koeller K,
uncommon. et al. Mycobacterial spindle cell pseudotumor of the brain: a case
With more effective treatment of Pneumocystis jiroveci, report and review of the literature. Am J Surg Pathol 1999;23:
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Detection of mycobacterial infections using the Dieterle stain.
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Radiological findings are frequently negative even 13. Gutierrez-Cancela MM, Garcia Marin JF. Comparison of Ziehl-
when tissue evidence of pulmonary infection by MAIC Neelsen staining and immunohistochemistry for detection of
is present (161,162). Macroscopically the organs are often Mycobacterium bovis in bovine and caprine tuberculous lesions.
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 4
The Mycobacteria
Aparna Singh Shah, Rajesh Bhatia

INTRODUCTION Table 4.1: Classification of mycobacteria

The generic name Mycobacterium was introduced by Group 1
Lehmann and Neumann in 1896. The organisms were named Obligate pathogens
so because of the mold like [myco: fungus; bacterium: Mycobacterium tuberculosis
bacteria] pellicular growth of these organisms in liquid Mycobacterium leprae
medium (1). The true bacterial nature of these organisms Mycobacterium bovis
was, however, soon established. The genus Mycobacterium Group 2
is the only genus in the family Mycobacteriaceae and Skin pathogens
order Actinomycetales. The complete genome sequence of
Mycobacterium marinum
Mycobacterium tuberculosis [Mtb] comprises 4043 genes, 50 of Mycobacterium ulcerans
which are responsible for encoding ribonucleic acids [RNAs] Group 3
while remaining genes encode 3993 proteins. The guanine
Opportunistic pathogens
+ cytosine [G+C] ratio in the deoxyribonucleic acid [DNA]
of mycobacteria is 62-70 mol% and similar to that observed Mycobacterium kansasii
Mycobacterium avium-intracellulare
in Nocardia (2). High G+C ratio indicates strong aerobic
requirements of organisms. Group 4
An important character of the Mtb is their ability Non- or rarely pathogenic
to resist decolourisation by a weak mineral acid after Mycobacterium gordonae
staining with one of the aryl-methane dyes. This property Mycobacterium smegmatis
of acid fastness is, however, not unique to mycobacteria Group 5
because Nocardia, Rhodococcus, Legionella micdadei, bacterial Animal pathogens
spores and the protozoa Isospora and Cryptosporidium Mycobacterium paratuberculosis
are also acid-fast. The genus is better defined on the Mycobacterium lepraemurium
chemical structure of the mycolic acids and its antigenic
structure.
of ways. A clinical classification is more practical and is
CLASSIFICATION described in Table 4.1.
Mycobacteria other than human or bovine tubercle
The genus Mycobacterium comprises of more than 197 species, bacilli that cause human disease resembling tuberculosis
of which several are non-pathogenic environmental bacteria. [TB] are called nontuberculous mycobacteria [NTM]. These
The different species of the Mtb complex show a 95%-100% are also known as anonymous, unclassified, tuberculoid,
DNA relatedness based on studies of DNA homology, paratubercle, atypical mycobacteria, mycobacteria other than
and the sequence of the 16S rRNA gene are same for all tuberculosis [MOTT]. These have been classified by Runyon
the species. Mycobacteria has been classified in a variety (2,3) in several groups [Table 4.2].
 The Mycobacteria 53

Table 4.2: Runyon classification of nontuberculous mycobacteria

Runyon group Species Disease in man
I. Photochromogens Mycobacterium kansasii Pulmonary disease
Mycobacterium marinum Swimming pool granuloma
Mycobacterium simiae
Mycobacterium asiaticum
II. Scotochromogens Mycobacterium scrofulaceum Lymphadenitis in children
Mycobacterium gordonae
Mycobacterium szulgai
Mycobacterium flavescens
III. Nonphotochromogens Mycobacterium avium Pulmonary disease in immunocompromised hosts
Mycobacterium intracellulare
Mycobacterium xenopi
Mycobacterium ulcerans
Mycobacterium terrae
Mycobacterium haemophilum
IV. Rapid growers Mycobacterium chelonae Superficial and systemic diseases
Mycobacterium fortuitum
Mycobacterium abscessus
Source: reference 3

MYCOBACTERIUM TUBERCULOSIS Gram-positive bacteria (4). It has high lipid content which
accounts for about 60% of the cell wall weight. Mtb has a
Morphology tough cell wall that prevents passage of nutrients into and
The tubercle bacilli are slender, straight or slightly curved excreted from the cell, therefore giving it the characteristic
rod-shaped organisms measuring 2-4 μm in length and of slow growth rate. The cell wall has several distinct layers.
0.2-0.8 μm in breadth occurring singly, in pairs or in small The inner layer, overlying the cell membrane is composed
groups. The size depends on conditions of growth and of peptidoglycan [murein]. External to the murein is a layer
long, filamentous, club shaped and branching forms may of arabinogalactan, which is covalently linked to a group
sometimes be seen. M. bovis is usually straighter, stouter of long chain fatty acids termed mycolic acid. The Mtb cell
and shorter. However, no distinction between M. bovis and wall contains three classes of mycolic acids: alpha-, keto-
Mtb can be made based on morphology. The bacilli are non- and methoxy­mycolates. The cell wall also contains lipid
sporing, non-motile and non-capsulated. In suitable liquid complexes including acyl glycolipids and other complex,
culture media, virulent human and bovine tubercle bacilli such as, free lipids and sulfolipids. There are porins in the
form characteristic long, tight, serpentine cords in which membrane to facilitate trans-port (5). This complex structure
organisms are aligned in parallel. Cord factor [trehalose confers low permeability to the cell wall, thus, reducing the
6, 6’ dimycolate] is a glycolipid found in the cell walls of effectiveness of antimicrobial agents. Lipoarabinomannan
mycobacteria, which causes the cells to grow in serpentine [LAM] present in the cell wall facilitates the survival of
cords. It is primarily associated with virulent strains of Mtb. mycobacteria within macrophages. Diagnostic efficacy of
It is known to be toxic to mammalian cells. Though its exact detection of LAM is being studied especially for extra-
role in virulence is unclear, although it has been shown to pulmonary TB [EPTB] (6).
induce granulomatous reactions identical to those seen in TB. The unusually impermeable cell wall of mycobacteria
The bacilli are Gram positive though these do not take is believed to be advantageous in stressful conditions of
the stain readily. These organisms resist decolourisation by osmotic shock or desiccation. In addition, mycobacteria use
25% sulphuric acid and absolute alcohol for 10 minutes and other survival strategies including efflux pumps, response
hence these are called acid and alcohol fast. Acid-fastness regulators, antibiotic-modifying or degrading enzymes such
is based on the integrity of the cell wall. Beaded or barred as β-lactamase, target-modifying enzymes, and decoys that
forms are frequently seen in Mtb while M. bovis stains more mimic the drug target (7).
uniformly. In younger cultures non acid-fast rods and
granules have been reported. Culture Characters
Growth Requirements
Mycobacterial Cell Wall
Mycobacteria are obligate aerobes and derive energy from
The mycobacterial cell wall is complex in nature. It essentially oxida­tion of many simple carbon compounds. Biochemical
distinguishes mycobacteria from other prokaryotes. activities are not characteristic and growth rate is much
Mycobacteria in general give a weakly positive response to slower than that of most bacteria. The generation time
Gram stain but are phylogenetically more closely related to in vitro is about 18 hours. At the earliest, the growth
54 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

appears in about two weeks but may be delayed up to concentration of clinical samples and partial elimination
six to eight weeks. Optimum temperature for growth is of contaminating organisms. These organisms can survive
37 °C and growth does not occur below 25 °C and above exposure to 5% phenol, 15% sulphuric acid, 3% nitric acid,
40 °C. Optimum pH for growth is 6.4-7.0. Increased carbon 5% oxalic acid and 4% sodium hydroxide. Tincture iodine
dioxide [CO2] tension [5%-10%] enhances growth. Human destroys it in five minutes while 80% ethanol does so in
strains grow more luxuriantly in culture [eugonic] than do two to ten minutes. Thus, 80% ethanol is recommended as a
bovine strains [dysgonic]. The addition of a low percentage disinfectant for skin, rubber gloves, and other such materials.
of glycerol to the medium encourages the growth of human The cultures of tubercle bacilli can be killed by exposure to
strains but not that of bovine strains, which may infact be direct sunlight for three hours while in sputum they can
inhibited. survive for 20-30 hours. In droplets these may survive for
eight to ten days. Cultures can be stored for two years in a
Culture Media deep freezer at –20°C. The organisms are resistant to drying
and can survive for long periods in dried sputum. Ordinary
The reader is referred to the chapter “Laboratory diagnosis”
day-light even passing through glass has a lethal effect on
[Chapter 8] for details on various types of media (8) that are
bacteria.
commonly used for cultivation of mycobacteria.
Antigenic Structure
Colony Characters
Mycobacteria being complex unicellular organisms, contain
On solid media human type of tubercle bacilli give rise to
many antigenic proteins, lipids and polysaccharides. The
discrete, raised, irregular, dry, wrinkled colonies which are
exact number of antigenic determinants is unknown. The
creamy white to begin with and then develop buff colour.
mycobacterial antigens have been broadly classified as:
By contrast the bovine type grows as flat, white, smooth,
[i] soluble [cytoplasmic] and insoluble [cell wall lipid
moist colonies which “break up” more readily when touched.
bound]; and [ii] carbohydrates or proteins. Antigens have
Tubercle bacilli will grow on top of liquid medium as a
been extensively used to classify, identify and type the
wrinkled pellicle if the inoculum is carefully floated on the
mycobacteria.
surface and flask left undisturbed, otherwise these will grow
as floccules throughout the medium. However, a diffuse
growth can be obtained by adding a wetting agent, such
Soluble Antigens
as, Tween 80. Virulent strains tend to form long serpentine Up to 90 soluble antigens are demonstrated by sensitive
cords in the liquid media while a virulent strains grow in a techni­ques. Soluble antigens are divisible into four major
more dispersed fashion. groups designa­ted as group I to IV [Table 4.3].

Virulence in Animals Polysaccharide Antigens

Under natural conditions Mtb infects man, monkeys, Polysaccharide antigens are responsible for the group
cows, buffalo, pigs, dogs and occasionally parrots. Under specificity while type specificity is due to protein
experimental conditions, it is virulent to guinea pigs antigen. Following infection by tubercle bacilli, delayed
and mice and less virulent in rabbits and avirulent in hypersensitivity develops to the protein [tuberculin].
chicken. Mice are most commonly used for reasons of cost, Tuberculins from Mtb, M. bovis and M. microti appear to be
convenience, their amenability to genetic manipulations (9). indistinguishable.
Guinea pigs exhibit many pathological features similar to
those seen in humans, but unlike humans these are exqui­ Biochemical Properties
sitely sensitive to a progressive pulmonary infection (10).
Rabbits display pathogenicity more characteristic of human Mtb has distinctive biochemical properties, some of which
disease, ranging from spontaneous healing to caseous and are utilised for identification of various species. The reader
cavitary pulmonary lesions (11).

Susceptibility to Physical and Chemical Agents Table 4.3: Soluble antigen sharing in mycobacteria
Group Present in Shared with
The best method to inactivate tubercle bacilli is by heat and
chemical methods are all relative to it. The thermal death Group I All mycobacteria Nocardia
Corynebacterium
time at 60°C is 15-20 minutes. These are more resistant Listeria
to chemical agents than other bacteria because of the
Group II Slow growing -
hydrophobic nature of the cell surface and their clumped mycobacteria
growth. Dyes, such as, malachite green or antibiotics such as
Group III Rapid growing Nocardia
penicillins can be incorporated into media without inhibiting
mycobacteria
the growth of tubercle bacilli. Acids and alkalies permit the
Group IV Individual species None, unique
survival of some exposed tubercle bacilli and are used for
 The Mycobacteria 55

is referred to the chapter “Laboratory diagnosis” [Chapter 8] Bacteriocins

for further details.
There is limited evidence that some strains of mycobacteria
liberate substances that inhibit the growth of other species.
Pathogenesis
Mtb is divisible into 11 types by means of bacteriocins
The first event in the pathogenesis of TB, whether inapparent produced by rapidly growing mycobacteria.
or overt, is the implantation of bacilli in tissues. The Bacteriocins are being considered as new wave of
most frequent portal of entry is lungs, resulting from potential therapeutic compounds, in particular type 1
the inhalation of airborne droplets containing a few bacteriocins known as lantibiotics. The gene encoded nature
bacilli which are expectorated by an open case of TB. Less of these peptides facilitates their genetic manipulation and
frequently the bacilli may be ingested and lodged, in the consequent activities as anti-microbial agents (13).
tonsil or in the wall of the intestine, which may follow
consumption of raw contaminated milk. Finally, third but a Molecular Typing
rare mode of infection is direct implantation of bacilli into
the skin, such as, in workers working with infected materials Molecular biological techniques provide valuable information
or handling cultures of tubercle bacilli. The reader is referred for sub-classification or typing of Mycobacterium species–
to the chapter “Pathology” [Chapter 3], for further details on both Mtb and NTM. In past two decades several of
this topic. these techniques have facilitated evaluation of relapse
Mycobacteria produce no recognised toxins. The various or reactivation of disease, reinfection with a different
components of the bacillus have been shown to possess strain, epidemiological tracing or spread of infection,
different biological activities which may influence patho­ understanding dynamics of development of drug resistance
genesis, allergy and immunity in the disease [Table 4.4]. and identification of different variants of myco­bacteria that
The production and development of lesions and their may predominantly infect high-risk populations.
healing or progression are determined chiefly by the number A good typing method has to be robust, reproducible,
of mycobacteria in the inoculum and their subsequent capable of discriminating between strains of two different
multiplication and resistance and hypersensitivity of and based upon stable genetic structure. Strain specific
the host. The essential pathology of TB consists of the pattern of DNA fragments can be demonstrated by
production, in infected tissues of a characteristic lesion, splitting DNA strands into diffe­r ent fragments using
the tubercle. restriction enzymes. The pattern of sliced fragments [genetic
fingerprint] is strain specific and can be visualised using
Mycobacteriophages gel electrophoresis. A combination of this techni­que with
hybridisation technology [Southern blot] has been applied to
Mycobacteriophages have been used for subdivision of the analysis of the restriction fragment length polymor­phism
some species of mycobacteria. Mtb has been divided into
[RFLP]. The resolution of RFLP has been increased with the
four phage types-A, B, C and I [I stands for intermediate
use of insertion sequences [IS] in construction of probes (14).
between A and B].
Mycobacteria have relatively large amount of repetitive
Mycobacteriophages have provided key tools for TB
DNA elements. These can be in the form of short sequences.
genetics. The advances in mycobacteriophage recom­binants
A category of these are mobile genetic elements and called
will facilitate postgenomic explorations into mycobacterio­
as insertion sequences. Multiple copies of these IS may be
phage biology. More than 70 complete genome sequences
present within a strain. Most studied is IS6110 which may
are now available to facilitate better studies on mycobacterial
have one copy in M. bovis but multiple copies in different
genome (12).
locations in Mtb, thus making it a reliable molecular
marker for genotyping (15). IS6110-based typing is one of
Table 4.4: Mycobacterial components as determinants the most widely applied genotyping methods in molecular
of pathogenicity epidemiology of TB.
Cell component Pathogenic effect With the availability of polymerase chain reaction [PCR]
Cell wall Induces resistance to infection technology which is economical, easy to perform and
Causes delayed hypersensitivity extensive automation, IS6110-based PCR fingerprinting has
Can replace whole cell in Freund’s adjuvant become popular. Major drawback is weak discriminatory
Tuberculoprotein Elicits tuberculin reaction power in strains with low copy numbers of IS6110 (16).
Induces delayed hypersensitivity PCR technology is employed for spacer oligonucleotide
Induces formation of epitheloid and giant cells
typing, or spoligotyping. It is a rapid method for genotyping.
Polysaccharides Induce immediate hypersensitivity Spoligotyping data can be represented in absolute terms
Causes exudation of neutrophils from blood
[digitally], and the results can be readily shared among
vessels
laboratories, thereby enabling the creation of large inter­
Lipids Cause accumulation of macrophages and
national databases. The method is highly reproducible,
neutrophils
sensitive and cost-effective (17,18). Spoligotyping is fast,
Phosphatides Induce formation of tubercles
simple and robust method, but at times is less discriminatory.
56 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Strain differences can be better determined by subjecting Although, the conventional tuberculin skin test [TST]
clusters obtained by spoligotyping to RFLP based on and relatively advanced versions of interferon-γ release
IS6110 (19,20). Encouraged by the potential of these assays [IGRAs] are currently available for detection of latent
techniques, Ahmed and Hasnain (21) have advocated a TB infection [LTBI] detection, however, in the absence of
systems biology approach. gold standard neither of tests precisely identifies those
Apart from IS genetic elements, mycobacteria may also infected (23). The accumulated evidence suggests either of
have tandem repeats [TR] of genetic material, some of these the two tests alone or two step approach for LTBI detection
are called as variable number of tandem repeats [VNTR]. in high-income countries, whereas, the low cost, simple
Genotyping based on VNTR is also useful. A specific class technique based TST is the most preferred method in
of these VNTR is mycobacterial interspersed repetitive low-income countries (23,24).
units [MIRUs]. A 24 MIRU-VNTR loci based typing system
or IS6110-RFLP are considered as the gold standard in Laboratory Diagnosis
molecular typing of Mtb complex (22).
Commercial systems for the genotyping methods utilising Before TB can be treated, a diagnosis needs to be made in
PCR technology for repetitive DNA elements broadly an efficient and timely manner. The laboratory diagnosis is
called as repetitive sequence-based PCR are now becoming based on demonstration and isolation of tubercle bacilli. The
available, thus, enhancing access to this technology. essential steps for diagnosis are: [i] collection of specimens;
[ii] demonstration of organism; [iii] culture on suitable
media; [iv] identification by various tests; [v] guinea pig
Immunity and Hypersensitivity
inoculation; [vi] antibiotic sensitivity testing [wherever
Infection with Mtb induces delayed hypersensitivity [allergy] possible]; and [vii] nucleic acid amplification tests [NAATs].
and resistance to infection [immunity]. Unless a host dies Microscopy and culture are done in peripheral and
during the first infection with tubercle bacilli, there is an intermediate laboratories, whereas identification of Mtb and
increased capacity to localise tubercle bacilli, retard their antibiotic sensitivity testing are done in selected referral
multiplication, limit their spread and reduce lymphatic places. The reader is referred to the chapter “Laboratory
dissemination. This can be attributed to the development of diagnosis” [Chapter 8] for further details.
cellular immunity during the initial infection. Global efforts are being made to develop an efficient and
In the course of primary infection the host also acquires affordable point of care [PoC] test. PoC implies the ability
hyper­sensitivity to the tubercle bacilli. This is made evident to make a diagnosis at the point where patient consultation
by the development of a positive tuberculin reaction. The and presentation occurs. Nucleic acid amplification tests
reader is referred to the chapter “Immunology of tuberculosis” [NAATs] can rapidly detect small quantities of DNA through
[Chapter 5] for further details. several different amplification methods, including the PCR.
With their improved simplification and automation in recent
Koch’s Phenomenon years, NAAT is becoming increasingly attractive candidate
for use at the PoC [24].
The contrast between primary infection and reinfection
is shown experimentally in Koch’s phenomenon. When a
Sensitivity Testing
guinea pig is injected subcutaneously with virulent tubercle
bacilli, the puncture wound heals quickly, but a nodule forms With the emergence of multidrug-resistance in mycobacteria,
at the site of injection in two weeks. This nodule ulcerates it is essential to perform sensitivity test on the tubercle bacilli
and the ulcer does not heal. The regional lymph nodes isolates as an aid and guide to treatment. Drug-resistant
develop tubercles and extensive caseation. When the same mutants conti­nuously arise at a low rate in any mycobacterial
animal is later injected with tubercle bacilli in another part of population. The purpose of sensitivity testing is to determine
the body, the sequence of events is quite different. There is whether the great majority of the bacilli in the culture are
a rapid necrosis of the skin and tissue at the site of injection, sensitive to the anti-TB drugs currently in use. The sensitivity
but the ulcer heals rapidly. Regional lymph nodes either do testing may be direct [performed on the original specimen]
not become infected at all or do so only after a delay. These or indirect [performed on a subculture].
differences are attributed to immunity and hypersensitivity Four methods of drug-susceptibility testing [DST] have
induced by the primary infection. The Koch’s phenomenon been standardised. These are: [i] the absolute concentration
has three components: [i] a local reaction; [ii] a focal response method; [ii] the resistance ratio method; [iii] the proportion
in which there occurs an acute congestion around the TB method; and [iv] the BACTEC-460 radiometric method.
foci in tissues; and [iii] a “systemic” response of fever which However, the use of the BACTEC 460 radiometric method
may at times be fatal. is phasing out due to the concerns of the radioactive waste
This effect is not caused exclusively by living tubercle disposal. This system is being replaced by the nonradiometric
bacilli, but also by killed ones, no matter whether they are BACTEC MGIT 960 system (25).
killed by low temperatures or prolonged periods, or by In December 2010 WHO endorsed a new technology
boiling or by certain chemicals. [cartridge-based NAAT, Xpert MTB/RIF] and recommended
 The Mycobacteria 57

that this technology should be used as the initial diagnosis its diagnosis. Mycobacterial cultures are less sensitive for
test in individuals suspected of having multidrug-resistant diagnosis, although positive cultures are more commonly
TB [MDR-TB], or human immunodeficiency virus [HIV] obtained from tissue biopsy than swab specimens (31).
associated TB. They also suggested that it could be used The disease is progressive for about three years but then
as a follow-on test to microscopy in settings where MDR- an effective immune response develops. Eventually the
TB and/or HIV is of lesser concern, especially in smear- lesion heals but often with extensive fibrosis and contractures
negative specimens, because of the lack of accuracy of leading to crippling deformities. In general, chemotherapy
smear microscopy. This test does not eliminate the need has not proved very successful in treatment. Simple excision
for conventional microscopy culture and DST, as these are of the lesion early in the disease is curative. Physiotherapy
still required to monitor treatment progress and to detect is required to prevent deformities.
resistance to drugs other than rifampicin (26). The reader is
referred to the chapter “Drug-resistant tuberculosis” [Chapter Mycobacterium marinum
42] for details on this topic.
M. marinum is a natural pathogen of cold-blooded animals.
NONTUBERCULOUS MYCOBACTERIA The skin disease produced is known as “swimming-pool
granuloma” or “fish tank granuloma” or “fish fancier’s
The NTM mycobacteria were initially grouped according to finger”. The organism was initially named as M. balnei but
speed of growth at various temperatures and production of it was later found to be identical to the fish tubercle bacillus
pig­ments (27). More recently individual species or complexes and was named as M. marinum. Lesions occur at sites of
are defined by additional laboratory characteristics, e.g. injury, which are usually the knees and elbows of swimming
nitrate reduction, production of urease, catalase and certain pool users and the hands of the fish fanciers.
antigenic features (28,29). NTM have been classified in four The lesion commences as a solitary raised watery lesion,
groups by Runyon (2,3) based on production of pigment but secondary lesions develop along the draining lymphatics.
and rate of growth. The reader is referred to the chapter Occasionally tenosynovitis may develop at back. Human
“Nontuberculous mycobacterial infections” [Chapter 41] for infection may occur in epidemic form. Infection with M.
further details. marinum causes a low-grade tuberculin reaction. The reader
is also referred to the chapter “Cutaneous tuberculosis”
MYCOBACTERIA PRODUCING SKIN ULCERS [Chapter 21] for further details.
Two conditions where skin ulceration occurs are M. ulcerans
infection causing what is known as Buruli ulcer and infection SAPROPHYTIC MYCOBACTERIA
with M. marinum which causes swimming pool granuloma. Saprophytic mycobacteria are non-pathogenic acid-fast
In addition to these two, there are some other inoculation- bacilli found in milk, butter, water, manure, grass and
associated infections. smegma of human beings and animals. Important features
of these mycobacteria are: [i] inability to set up a progressive
Mycobacterium ulcerans infection in mammals or birds; [ii] profuse growth at room
This was first described in Australia and the organism was temperature, giving rise to growth in two to three days;
named as M. ulcerans in year 1948. Later, a similar disease [iii] optimum temperature is in the vicinity of 37 °C but
was seen in the Buruli county of Uganda, and hence, the growth at room temperature is also very good; and [iv]
name Buruli ulcer was given. Epidemiological investigations extracts and purified protein derivative [PPD] prepared
suggest that the organism is inoculated into the skin by from many of these mycobacteria may cross-react with
thorny vegetation. The disease has an enormous socio- PPD-S from Mtb, resulting in positive TST in persons who
economic impact and is an important public health issue (30). are tuberculin negative. High proportion of population
The earliest sign is a discrete firm nodule fixed to the becomes hypersensitive to mycobacteria acquired from the
skin but mobile over deep tissues. It is painless but very environment.
itching. If it does not resolve at this stage it progresses to M. smegmatis is present in smegma and contaminates
the ulcerative stage which is full of bacilli. With further urine sample. It needs to be differentiated from tubercle
progress of the disease the overlying skin becomes anoxic bacilli. Smegma bacillus is acid-fast but not alcohol-fast. M.
and necrotic. Ulceration then occurs with escape of liquefied smegmatis with the esx-3 genes deleted has the potential to
necrotic tissue and the formation of a deeply undermined function as a novel vaccine vector with an enhanced innate
ulcer. The lesions which may be single or multiple are more immune-activating property. This vector, when engineered
common on exposed parts of the body, especially, limbs. to express Mtb esx-3, may become a potent TB vaccine
The PCR is highly sensitive for diagnosis on both swab capable of a level of protection superior to that of BCG (32).
and biopsy samples of lesions due to M. ulcerans. The M. paratuberculosis [Johne’s bacillus] causes chronic
PCR approaches 100% specificity and 96% sensitivity for disease in cattle, characterised by massive infiltration of the
lesion swabs, and is considered as the test of choice for intestinal tract.
58 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

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2. Runyon EH. Anonymous mycobacterial in pulmonary disease. pulmonary tuberculosis in Mumbai, India. Res Microbiol
Med Clin North Am 1959;43:273-90. 2005;156:588-96.
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Mair NS, Sharpe ME, Holt JG, editors. Bergey’s manual of Upadhyay P, et al. Determination of drug susceptibility patterns
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1989.p.1435-57. Kanpur district, North India. Infect Genet Evol 2011;11:469-75.
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5. Thomas ST, VanderVen, BC, Sherman DR, Russell DG, 22. Oelemann MC, Diel R, Vatin V, Haas W, Rüsch-Gerdes S,
Sampson NS. Pathway profiling in Mycobacterium tuberculosis: Locht C, et al. Assessment of an optimized mycobacterial inter­
elucidation of cholesterol-derived catabolite and enzymes that spersed repe­ titive–unit-variable-number tandem-repeat typing
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8. Petran EI, Vera HD. Media for selective isolation of mycobacteria. 2013;18:217-32.
Health Lab Sci 1971;8:225-30. 25. Siddiqi S, Ahmed A, Asif S, Behera D, Javaid M, Jani J, et al. Direct
9. Orme IM, Collins FM. Mouse model of tuberculosis. In: Bloom drug susceptibility testing of Mycobacterium tuberculosis for
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 5
Immunology of Tuberculosis
DK Mitra, AK Rai, Amar Singh

INTRODUCTION CHRONOLOGY OF IMMUNOPATHOGENESIS OF

Protective immunity and varied clinical manifestations of TUBERCULOSIS
infection with Mycobacterium tuberculosis [Mtb] represent Pathogenesis of pulmonary tuberculosis [TB] following
a delicate balance between the bacillus and magnitude infection with Mtb can be understood in four distinct phases
and type of the host immune response. The latter is a [Figure 5.1]. Each phase is determined by homeostasis
broad term reflecting complex interactions among various between bacillary factors and host’s innate and adaptive
arms of the immunity involving numerous cell types and immunity (1,2).
molecules. This confers a homeostatic balance either in
favour of the host, leading to containment of the infection, INITIAL ENCOUNTER AND INNATE IMMUNITY
disease or in parasite’s favour resulting in failure to contain
infection. Immunity against Mtb needs to be understood
Mycobacterium-Macrophage Interactions
not only in terms of sterilising immunity that eliminates Pathogenesis of TB starts with phagocytosis of bacilli by
Mtb infection at the initial exposure, but also with respect mono­nuclear cells including alveolar macrophages and
to immunity favouring granuloma formation that maintains dendritic cells [DCs] which play a crucial role during their
the steady state control over the bacillary spread and initial encounter with Mtb by their intrinsic or innate defence
prevents establishment of clinical disease. Both innate as mechanism[s]. A probable role of DC-specific intercellular
well as adaptive immunity are involved at various levels adhesion molecule-3 [ICAM-3] grabbing no integrin
following Mtb infection. In this chapter, first the innate and [DC-SIGN], has been implicated in DC mediated dis­
then the adaptive immunity will be discussed. It should be semination of Mtb (3). Uptake of opsonised bacilli [coated
understood that this compartmentalised approach is only for with preformed humoral elements like antibodies or comple­
the sake of better understanding of the complex cross-talk ment split products] is greatly facilitated by complement
among diverse cell subsets and bio-molecules. However, receptors [CR] expressed on macrophages, such as CR1, CR2,
in vivo, the innate and various components of adaptive CR3 and CR4; and other cell surface receptor molecules (4).
immunity work synergistically in concert. Non-opsonised bacilli are engulfed by macrophages
In this chapter, current understanding of the host immune through mannose receptors [MRs] recognising the terminal
response, various aspects of macrophage-mycobacterium mannose moieties of mycobacteria. The interaction between
inter­a ctions, with special emphasis on expansion and MRs and mycobacteria seems to be mediated through the
suppressive functions of CD4+ CD25+ Forkhead box P3 mycobacterial surface glycoprotein lipoarabinomannan
[FoxP3+] regulatory T-cells [Treg]. Role of effector T-cells and [LAM] (4,5). Additionally, non-opsonised Mtb can be taken
the cytokine/chemokine mediated recruitment of accessory up by the macrophages through binding to scavenger
immune cells for local inflam­matory response providing receptor type A as blocking CRs and MRs was not able
protective immunity is also discussed. Further, the ability of to completely abrogate the bacillary uptake. Cluster of
the organism to manipulate programmed cell death protein differentiation 14 [CD14] receptor (6) and the scavenger
1 [PD-1] pathway to establish chronic infection will also be receptors also play important role in mediating bacterial
discussed. binding. Several other groups of molecules like collections
 60 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 5.1: Events during TB infection. Broadly, TB infection is divided into four phases. The first phase includes an initial establishment of Mtb
infection in the resident alveolar macrophages. This is followed by influx of PMNs, which prevents Mtb to escape from the innate immune factors.
Subsequently, monocytes are recruited to the site of infection/ pathological site [second phase]. The third phase includes granuloma formation.
Core of granuloma is made up of multi-nucleated giant cells and elongated epithelioid cells surrounded by T-cells. This is aimed at restricting the
bacilli from spreading. The fourth and terminal phase includes dissemination of bacilli. Defective granuloma formation promotes release of bacilli
from control of immune system. Organs/loci targeted by bacilli after dissemination are listed here
DC = dendritic cells; M = macrophages; PMNs = polymorphonuclear leucocytes; TB = tuberculosis; Mtb = Mycobacterium tuberculosis

of the innate immune system may also facilitate binding and lipo­protein and LAM. In context of CD14, TLR2 binds to
uptake of Mtb. Surfactant protein A enhances the uptake LAM, a hetero­dimer of TLR2 and TLR6 binds to CD19 kDa
while surfactant D blocks it. Fibronectins also facilitate lipoprotein (10). TLR4 binds to yet undefined heat labile cell
uptake of Mtb by alveolar epithelial cells through binding asso­ciated factor and TLR9 binds to mycobacterial DNA
to antigenic proteins (7). Thus, multiple mechanisms are motifs. Engagement of TLRs by mycobacterial antigens leads
operational in the uptake of Mtb by mononuclear phago­ to coupling of MyD88 and interleukin-1 receptor-associated
cytes giving cells chance to kill the bacilli. However, all kinase [IRAK] signalling molecules resulting in multiple
these mechanisms only help in their uptake but fail to elicit signalling events that ultimately translocate transcription
optimal immune recognition leading to macrophage activation. factor nuclear factor kappa-light-chain-enhancer of activated
B cells [NFkB] from cytosol to nucleus to induce the
Recognition by Toll-like Receptors production of various cytokines required for innate as well
as adaptive immune events (11).
Both the innate and adaptive response to Mtb infection
depends to a large degree, on recognition of Mtb as a
Phagolysosome Fusion
pathogen by the pat­tern recognition receptors. Toll-like
receptors [TLRs] and myeloid differentiation primary This highly regulated event during intracellular infection
response gene 88 [MyD88] path­way play a critical role in leads to degradation of phagocytosed microorganisms
immune recognition of Mtb on the surface of macrophages by intralysosomal acidic hydrolases (12,13). Prevention
and elicitation of an effective innate immune response of phagolysosomal fusion is hypothesised to be the
and shaping the eventual T-cell responses. They are mechanism by which Mtb survives inside macrophages (14).
transmembrane proteins with leucine-rich repeat motifs in Multiacylated trehalose 2-sulphate, a derivative of myco­
extracellular domain (8,9). Of the several TLRs discovered bacterial sulphatides (15,16) and copious amount of ammonia
till date TLR2, TLR4, TLR3 and TLR9 appear to elicit cellular generated during in vitro Mtb culture is thought to be
response to mycobacterial antigens including the 19-kDa responsible for the inhibitory effect (17).
 Immunology of Tuberculosis 61

IMMUNE EFFECTOR MECHANISMS AGAINST phagocytes (19). In vitro infection of macrophages with Mtb
MYCOBACTERIUM TUBERCULOSIS leads to upregulation and excessive production of inducible
nitric oxide synthase [iNOS2], which is required for the
Free Radical-based Antimycobacterial Effector production of nitric oxide (20). Cytokines also play an
Functions of Macrophages important role in anti-mycobacterial effects of macrophages
Macrophages are key player of host immune response against and interferon-gamma [IFN-γ] is key endogenous activating
Mtb infection [Figure 5.2]. Phagocytosed microorganisms agent that triggers the anti-mycobacterial effects. Tumour
are subjected to degradation by intralysosomal acidic necrosis factor-alpha [TNF-α], synergizes with IFN-γ
hydrolases upon phagolysosome fusion. This highly induced anti-mycobacterial effects of murine macrophages
regulated event consti­tutes a significant antimicrobial in vitro (21). Together, they induce the production of nitric
mechanism of phagocytes. Upon activation, macrophages oxide and related reactive nitrogen intermediates [RNI] by
exhibit various degrees of anti-mycobacterial activity (18). macrophages via the action of the inducible form of nitric
Hydrogen peroxide [H 2O2], one of the reactive oxygen oxide synthase [NOS2] (22). Another potential mechanism
intermediates [ROI] generated by macrophages via the involved in macrophage defence against Mtb is apoptosis
oxidative burst, was the first identified effector molecule or programmed cell death. Various research groups have
that mediated mycobacteriocidal effects of mononuclear demonstrated that (23,24) macrophage apoptosis results in

Figure 5.2: Key concepts in the immunopathogenesis of TB. In most individuals, inhaled bacilli are engulfed by alveolar macrophages and
are contained by efficient microbicidal mechanisms [generation of ROI/RNI]. TLRs on the surface of macrophages recognise PAMPs and may
elicit a robust innate immune response leading to bacillary elimination. Infected macrophages simultaneously process and present antigens
to various T-cell subsets including polarised Th1/Th2 cells [CD4+ and MHC class II restricted], cytolytic [MHC class I restricted] T-cells, NKT
[CD1 restricted], and CD4+CD25+FoxP3 regulatory T [Treg] cells. Processed peptides, together with IL-12 secreted by the infected macrophage,
trigger Th1 cells to secrete IL-2, IFN, and tumour necrosis factor to further activate the macrophages. Th1 cell activation, which is central to
protective immunity, is under the control of other T-cell subsets. Effective generation of Th1 cytokine and appropriate recruitment of CCR5+,
CXCR3+ T-cells particularly in local milieu leads to ensuing effective granuloma formation and containment of diseases. On the other side
immune responses skewed towards Th2 [recruitment of CCR3+, CCR4+ T-cells] cross-inhibit protective responses, such as, granuloma formation
and fails to limit the infection leading to miliary TB
TB = tuberculosis; ROI = reactive oxygen intermediates; RNI = reactive nitrogen intermediates; TLRs= toll-like receptors; PAMPs = pathogen-
associated molecular patterns; IL = interleukin; IFN = interferon; NKT = natural killer T-cells
62 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

reduced viability of mycobacteria. In conclusion, it appears treated with anti-TNF-α treatment. However, it is thought
that macrophages play an important role both in early to be a “double-edged sword” causing bystander damage
recognition of bacilli, thus shaping the effector immune of the host tissue and cavity formation, particularly when
response and mediating the terminal lytic events under the present in relative excess in the milieu. Recently, it has been
strong influence of orchestrated T-cells response. established that discrimination between latent infection
versus active TB may be possible on the basis of preferential
MACROPHAGE T-CELL INTERACTION increase in the number of TNF-α + Mtb-specific CD4+
T-cells (27).
Engulfed mycobacteria are transported to the draining
lymph node via DCs/macrophages, where they get detected. Interleukin-1β and Interleukin-6
DCs/macrophages are currently considered to be the most
efficient inducers of activation in naïve T-cells. This efficiency Interleukin-1β is another proinflammatory cytokine secreted
stems from the fact that they provide not only the antigen- by the Mtb infected macrophages and DCs and is found
specific stimulus but also secondary and tertiary signals, via in excess at the pathologic site[s] of TB. An increased
accessory molecules on macrophages, therefore, promoting mycobacterial growth and a defective granuloma formation
efficient development of effector T-cells. Once bacteria arrive are observed in IL-1β knock out mice (28). IL-6, on the other
within the draining lymph node, naïve T-cells get activated, hand, may serve as both pro- and anti-inflammatory cytokine
undergo proliferation, and differentiation into effector cells and is increased in TB patients (29). Various reports suggest
[CD4+ and CD8+ T-cells]. Activation of naïve T-cells occurs that it may antagonise either TNF-α or IFN-γ, both of which
in the presence of live bacteria, and effector cells develop are believed to be critical for protective immune response
with expected kinetics and their phenotype depends on the against TB.
availability of specific cytokines and types of co-stimulation
provided by macrophages infected with bacilli (25). These Interleukin-2
effector cells eventually migrate to the lungs by chemokine
Interleukin-2 [IL-2] secretion by the protective CD4+ Th1
driven process in response to inflammation and mediate
cells has a pivotal role in generating an immune response
protection by activating infected phagocytes, leading to
by inducing an expansion of pool of lymphocytes specific
granuloma formation (26).
for an antigen. Several studies have demonstrated that IL-2
can influence the course of mycobacterial infections; either
ROLE OF CYTOKINES alone or in combination with other cytokines (30). Recent
Recognition of Mtb by phagocytic cells leads to cell activation report suggests that IL-2 deprivation induces apoptosis of the
and production of variety of cytokines, which in turn, effector T-cells. Treg cells are critically dependent on IL-2 for
induces further activation and cytokine production in a their survival, and therefore, strongly compete with effector
complex process of regulation and cross-regulation. Several T-cells for IL-2 available in the milieu. This may be one of the
cytokines are released, some of which take part in non- prominent mechanisms by which Treg cells inhibit effector
specific inflammation, and others, regulate the functional T-cell response (31).
bias of the relevant T-cells. A brief account of the important
cytokines produced by Mtb-infected macrophages is given Interleukin-12 and Interleukin-18
in [Figure 5.2]. These cytokines induce further activation Interleukin-12 is the most potent Th1 driving regulatory
of immune cells and lead to a complex process of immune cytokine produced by infected or stimulated macrophages
regulation. Among the pro-inflammatory cytokines TNF-α, and DCs and thus, plays a crucial role in the development
interleukin-1β [IL-1β], interleukin-6 [IL-6], interleukin-12 of protective Th1 type immunity in TB. In TB, IL-12 has been
[IL-12], interleukin-15 [IL-15] and interleukin-18 [IL-18] detected in disease sites like lung infiltrates, pleurisy and
are important. Each one plays a distinctive role in immune granulomas (32). Its receptor is also over-expressed in these
response against TB. sites. IL-18, another pro-inflammatory cytokine, is important
for IFN-γ axis of the T-cell response. High susceptibility of
Tumour Necrosis Factor-α IL-18 knockout mice to Mtb, bacille Calmette-Guérin [BCG]
and M. leprae strongly suggests a protective role of this
This prototype pro-inflammatory cytokine is produced by
cytokine in TB (33). A close parallelism has been noted
macro­phages, DCs and Th1 like cells upon infection and
between the concentration of IL-18 and IFN-γ among patients
stimulation with Mtb. It plays key roles in macrophage
suffering from TB pleural effusion. Protective effect of IL-18
activation, immuno-regulation and particularly granuloma
may be mediated by enhanced production of IFN-γ.
formation by induction of appropriate chemokine receptors
on the effector T-cells and thus recruiting them at disease
Interferon-γ
site (26). In mice, it has been shown to be involved in
maintaining latency of TB infection and is found at disease The protective role of IFN-γ in TB is well recognized. But, it
site[s]. Its role in humans is best evidenced by increased must be remembered that it is not the only terminal effector
incidence of TB among rheumatoid arthritis patients when cytokine to confer protection in TB. Mycobacterial antigen
 Immunology of Tuberculosis 63

specific in vitro production of IFN-γ by T-cells from patients better bacillary growth. Also in humans, IL-10 production
represents a surrogate marker of immunity against TB. is significantly higher patients who are purified protein
However, there exists a great deal of divergence of opinion derivative [PPD] anergic and in those with severe form
in this respect among the researchers and clinicians. In TB, of TB. Macrophages (40) and regulatory T-cells (41) from
physiologically relevant sources of IFN-γ are natural killer TB patients are suppressive for T-cell proliferation in vitro,
[NK] cells, antigen specific T-cells [helper and cytotoxic], and inhibition of IL-10 partially reversed this suppression.
macrophages themselves, and other relatively rare fine IL-10 directly inhibits CD4+ T-cell responses, and also
T-cell subsets, such as, gamma-delta [γδ] T-cells and CD1d inhibits antigen-presenting cell [APC] function of cells
restricted NK T-cells (34,35). The IFN-γ is a potent activator infected with mycobacteria (42). IL-10 is well-known for its
of infected macrophages resulting in potentiation of lytic ability to suppress IFN-γ, TNF-α and IL-12, all of which are
mechanism[s] responsible for killing of intracellular Mtb critical for eliciting a desired Th1 type immune response
and enhancement of human leucocyte antigen [HLA] and in host’s favour. Recent work on drug-resistant visceral
co-stimulatory molecules which result in efficient presentation leishmaniasis indicates IL-10 mediated upregulation of drug
of macrophage processed mycobacterial antigens and resistance genes in macrophages and parasites. Similar role
elicitation of strong T-cell responses. In addition to the of IL-10 may be a critical factor in the emergence of drug
above proinflammatory cytokines, certain anti-inflammatory resistance due to biased host immune response (43).
cytokines like IL-4, IL-10 and transforming growth factor-β
[TGF-β] are produced as well in TB (36). Transforming Growth Factor-β
Transforming growth factor-β appears to inhibit protective
Interleukin-4
immunity against Mtb and aggravates TB pathology.
The deleterious influence of IL-4 in TB is well-known and TGF-β is also produced in abundance by TB patients and
is attributed to its suppressive effect on IFN-γ production. its expression is observed at the pathologic site[s] (44). The
Mtb infected mice with progressive form of disease shows TGF-β is a well-known inhibitor of T-cell prolife­ration,
a significantly higher production of IL-4 (37). Disseminated IFN-γ production, macrophage activation and antigen
form of TB, such as, miliary TB [MTB] is associated with presentation. Moreover, it is also known for its potent host
a very high production of IL-4 by T-cells derived from tissue damaging effect and fibrosis (45). TGF-β along with
peripheral blood and bronchoalveolar lavage [BAL] fluid IL-10 potently suppresses the Th1 function during TB
following in vitro stimulation (38). It is widely believed that infection and is thought to contribute to the pathogenesis
IL-4 production is responsible for suppression of Th1 type of TB.
immune responses against TB, and thus, the host fails to
contain the disease, leading to development of severe and ADAPTIVE IMMUNITY AND ROLE OF
disseminated forms of TB. In some recent elegant studies,
EFFECTOR T-CELLS
a splice variant of IL-4 gene called IL-4δ has been detected.
The IL-4δ gives rise to protein isoform, which inhibits Cell-mediated adaptive immunity is critical in conferring
the immunosuppressive Th2 like function of native IL-4. protection against Mtb because antibodies fail to contain
Expression of IL-4δ messenger ribonucleic acid [mRNA] was the infection due to its intracellular habitat. Upon initial
very minimal in the peripheral blood mononuclear cells of exposure and recognition of immune dominant epitopes,
the healthy subjects while its expression was significantly naïve T-cells are primed and converted into effector and
higher in the thymocytes and BAL fluid in TB patients (39). memory T-cells. Effector T-cells contain the initial infectious
Tissue specific expression of this splice variant and tight load. However, dormant foci of Mtb within macrophages
correlation with the disease severity suggests a potential persist and reactivation of the bacillary foci occurs in the
immunoregulatory role in the pathogenesis of TB. Plausibly, event[s] of perturbation of a delicate balance of T-cell
IL-4δ functionally inhibits Th2 skewing of the host immunity that contained the foci so far (46). Additionally, a
immune response by antagonising the effect of native IL-4, fresh exogenous infection may also take place. Whatever is
and thus, shifting the cytokine production profile towards the case, on these subsequent exposures, the memory T-cells
Th1 response. Ratio of IL-4/IL-4δ may be useful in generated during the primary infection elicit a strong Th1
monitoring the cytokine polarised immune response among response and migrate to the site of the pathogen. Several
TB patients. lines of evidences demonstrating that mice and human who
lack T-cells, succumb to disease have elucidated the critical
Interleukin-10 role of T-lymphocytes for protection against Mtb (47-49).
Interleukin-10 is produced by the macrophages after phago­ These migrated T-cells are further activated by the processed
cytosis of Mtb and also by the Th2 cells following recognition antigens presented by the local infected macrophages and
of duly processed mycobacterial antigens. Mononuclear cells secrete key effector cytokines, such as, IFN-γ and TNF-α
from TB patients, particularly suffering from disseminated which help in activation as well as terminal differentiation
disease produce copious IL-10 in vitro in response to of the macrophages into the giant cells and development of
mycobacterial antigens (40). IL-10 transgenic mice supports granuloma which is hallmark of TB.
64 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

CYTOKINE POLARISED TH1/TH2 EFFECTOR with human immunodeficiency virus [HIV] and Mtb (57).
T-CELLS IN TUBERCULOSIS Furthermore, various studies have demonstrated that CD4+
T-cells are required for activation and maintenance of
Two broad categories of effector T-cells have been described: CD8+ T-cells under many immunological conditions (58).
Th1 type and Th2 type, based on distinctively biased pattern Indeed, an abundant literature exists to support the
of cytokines production.Th1-like response is critical for
important role of CD4+ T-cells in host defence against
containment of Mtb infection, its robustness and balance
primary TB infection. The role of CD8+ T-cells in immunity
between Th1 and Th2 type of response play an important
against TB has drawn a relatively less attention from
role to dictate whether the disease will have limited extent,
the investigators in the field. However, with recent
such as, pulmonary TB or dissemination to give rise to
studies demonstrating susceptibility of mice lacking major
severe forms of disease such as MTB, multidrug-resistant
histocompatibility complex class I [MHC class I] expression
TB [MDR-TB] [Figure 5.2] (38,50). Th1 cells secrete IL-2,
to mycobacterial infection (59), alteration of CD4+/CD8+
IFN-γ and play protective role in intracellular infections.
ratio among TB patients, antigen specific in vitro proliferation
Th2 type cells secrete IL-4, IL-5 and IL-10 and are either
indicate a definitive role of CD8+ T-cells in TB. Production
irrelevant and/or exert a negative influence on the immune
of IFN-γ and TNF-α in response to mycobacterial antigens
response. The balance between these two types of response
like early secretory antigenic target 6-kDa [ESAT-6] by the
determines host immune response against the pathogen.
The differentiation of Th1 and Th2 from precursor unbiased CD8+ T-cells derived from pleural fluid of patients with TB
Th0 cells may be under the control of cytokines, such as, pleural effusion have substantiated the role of CD8 T-cells
IL-12. It has been reported that peripheral blood mononuclear in the immunity of TB (60). CD8+ T-cells most probably
cells [PBMCs] from TB patients, when stimulated in vitro with play an important role in killing the Mtb infected target
PPD, release lower levels of IFN-γ and IL-2, as compared to cells by initially [i] TNF receptor superfamily, member 6
tuberculin-positive healthy subjects (51). Other studies have [FAS] independent granule exocytosis pathway releasing
also reported reduced IFN-γ (52), increased IL-4 secretion or lytic molecules, such as, granulysin (61); and then followed
increased number of IL-4 secreting cells (53). To address the by [ii] FAS-FAS ligand dependent apoptosis of the infected
issue of Th1/Th2 paradigm in TB, investigators focussed target cells (62). In addition to the activation of macrophages
attention to the cells producing the cytokines particularly by secreted cytokines, particularly IFN-γ, recent evidences
the T-cells derived from the disease site. Cytokine profile of indicate that CD8+ T-cells can kill the mycobacteria directly
the pleural fluid revealed excess levels of IFN-γ and IL-12 through the cytotoxic T-lymphocyte [CTL] activity (63).
relative to their levels in the peripheral blood compartment Therefore, a direct role of CTL in host immunity against TB,
(28,54). Several investigators have demonstrated a Th1 biased in addition to their macrophage activating property is well-
response in the pleural compartment representing the site of established. However, their precise function still remains to
a strong T-cell response of the local TB pathology. Study of be elucidated.
T-cells from patients with MTB provided strong indication
that extent and dissemination of TB tightly correlate with a Cytokines, Chemokines and Granulomas Formation
strong Th2 bias demonstrated by the T-cells derived from
The granulomas formation is pathologic hallmark of TB
BAL fluid representing the pathologic site of disseminated
characte­rised by organised aggregation of mononuclear
TB (38). Interestingly, IFN-γ production by the T-cells
inflammatory cells or collection of modified macrophages,
from the BAL fluid could be restored by supplementation
usually surrounded by a rim of lymphocytes and often
with IL-12. These elegant recent studies with the patients
containing multinucleated giant cells (64). TB granulomas
diagnosed on stringent criteria and specimens from both
form a focus that isolates the Mtb and promotes the
peripheral as well as the local compartments representing
development of protective immunity by allowing cross-
the immune response at the local pathologic site[s] provide
talk between T lymphocytes and macrophages. These
important insights in understanding the dynamics of
cells are generated through priming of resting memory
Th1/Th2 paradigm in human TB.
T-cells by captured antigens presented on the surface of
APCs in the draining lymphoid tissues and then released
CD4+ AND CD8+ T-CELLS IN TUBERCULOSIS into the peripheral compartment. Subsequently, homing
Existence of both CD4+ and CD8+ T-cells inside the of effector and various other T-cell subsets is mediated by
granuloma and their participation in the host defence active process of well-orchestrated trafficking of T-cells
to contain the infec­tion signifies the importance of these mediated by the groups of molecules, such as, selectins,
T-cells subsets (55,56). Mycobacteria-specific CD4+ T-cells adhesion molecules and chemokines. Chemokines are
are believed to be the primary cellular element involved largely responsible for such well-organised recruitment of
in the pathogenesis of TB and are of Th1 like functional T-cells involved in granuloma formation (65). A number of
phenotype, as they produce IFN-γ and activate macrophages chemokines have been reported in TB. Interleukin-8 [IL-8]
(25). Importance of CD4+ helper T-cells is best demonstrated was found to be produced by macrophages infected with
by significantly higher incidence and occurrence of severe Mtb (66) and this could be blocked by neutralising antibodies
and disseminated forms of TB among patients co-infected against TNF-α and IL-1β, suggesting that IL-8 production
 Immunology of Tuberculosis 65

was under the control of these cyto­kines and is produced γδ T-cells

during early course in TB patho-genesis (67). Another critical
The γδ T-cells are fine T-cell subsets. Their functional TCRs
chemokine in TB and granulomas formation is monocyte
is made of heterodimer of γ-δ chains. They are usually
chemoattractant protein-1 [MCP-1] which is produced
represented in the peripheral blood, less than 10% of total
by monocyte/macrophage and attracts the same (68).
circulating T-cell population. Mice with severe combined
In murine models, deficiency of macrophage inflam­
immunodeficiency fail to form granuloma in response to
matory protein 1-alpha [MIP1-α] inhibited the granuloma
challenge with BCG and succumb to death; they can survive
formation (69). Moreover, MIP1-α level was noted to be
such challenge when engrafted with syngeneic lymph node
significantly elevated in the serum, BAL and pleural fluids
cells depleted of αβ T-cells, suggesting an important role
in patients with TB. Expression of regulated on activation,
for Tγδ cells (74). Recent data in patients also substantiate
normal T-cell expressed and secreted [RANTES], an
a possible role of Tγδ cells in TB. Mtb reactive Tγδ cells are
important chemokine responsible for recruitment of T-cells
increased in the peripheral blood of tuberculin positive
particularly the Th1 like cells, is also increased in serum and
healthy contacts (75,76). A 20%-30% increase in the Tγδ
pleural fluid of TB patients. Apart from these several other
cells was noted in the peripheral blood of patients with a
chemokines such as MIP1-α and MIP1-β, monokine induced
strong immune reactivity compared to the patients with
by gamma interferon [MIG], IFN-g-induced protein-10
disseminated forms of TB such as extensive pulmonary TB
[IP-10] and interferon-inducible T-cell alpha chemo­
or MTB. Depletion of Tγδ cells results in less well-formed
attractant [ITAC] are reported to be elevated in TB patients,
granulomas and increased infiltration of neutrophils. This
particularly at the local disease site[s], such as, pleural
indicates that Tγδ cells are recruited quite early in the
effusion (50). Recent investigation in TB pleural effusion
infection with Mtb and direct granuloma formation.
patients demonstrated that some of the chemokine receptors
and/or chemokines can play a definitive hierarchical role in
selective recruitment of Th1 cells at the disease site[s] and Natural Killer T-cells
delineating such interaction is critical in designing molecular NK T-cells are non-conventional in the sense that they bear
immunotherapeutic strategies. It was found that chemokine cell surface markers distinctive of NK cells in addition to
receptor chemokine [C-X-C motif] receptor 3 [CXCR3]-ITAC functional TCRs. They represent a subset of T-cells with a
interaction was dominant in selective recruitment of IFN-γ distinct lineage and not restricted by MHC. They recognise
producing Th1 cells in addition to regulated on activation, lipid antigens in context of MHC like but relatively less
normal T-cell expressed and secreted RANTES-chemokine polymorphic CD1 molecules (77). CD1 molecules are sub-
[C-C motif] receptor 5 [genep/pseudogene] [CCR5] and grouped into group I consisting of CD1a, b and c whereas
CD11a–ICAM interaction. All these observations indicate CD1d is the only member of group II so far known. CD1d
an important role of these chemokines in human TB (70). restricted NK T-cells are heterogeneous in terms of their
expression of CD4+/CD8+ markers and an important
ROLE OF B-LYMPHOCYTES subset of NK T-cells uses restricted set of TCR chain pairs,
Role of B-lymphocytes in the pathogenesis of TB has not namely Vα.24/Vβ.11. These are called invariant chain
been critically evaluated. Existence of B220+ cells, which are NK T-cells [iNKT]. The NK T-cells are one of the earliest
likely B-cells in the lung granulomas, hints towards their T-cells to be triggered an immune response through several
important role in the pathogenesis of TB (71). Furthermore, immunoregulatory cytokines [IFN-γ, IL-4, IL-10, and TGF-β
the important role played by B-cells was highlighted by a etc.] and exert a strong regulatory effect on the effector T-cell
study demonstrating that when B–cell deficient mice are response (78). The first reported non-protein mycobacterial
challenged intravenously with a large dose of the bacilli, antigen was mycolic acid. Several other lipid antigens of
they are more susceptible to disease (72). Similarly, these mycobacteria, such as, LAM, phosphatidyl inositol manoside
findings were supported by recent elucidation that B-cells [PIM], glucose monomycolate and isoprenoid glycolipids
play an important role in immunity against the disease upon have been found to be recognised by NK T-cells when
higher dose of aerosol infection (73). presented by CD1d molecules. Heterogeneity of NK T-cells
in terms of release of either Th1 driving IFN-γ or Th2 driving
IL-4 or immunosuppressive IL-10 and TGF-β determines the
FINE T-CELL SUBSETS WITH AN
influence that NKT cell subsets may impose on the bulk
IMMUNOREGULATORY ROLE
T-cell responses. Selective expansion and/or activation of
These are regarded as non-classical T-cells in the sense that NK T-cell subset[s] may dictate their immunoregulatory
they either bear non-conventional T-cell receptors [TCRs] role. Expansion and preferential homing of iNKT have
or do not recognise the antigens in context of classical been documented in granuloma formation. In addition to
MHC gene products. MHC non-restricted and exert an their prompt cytokine release, NK T-cells exhibit a potent
immunoregulatory influence on the rest of the T-cells cytolytic activity both by perforin/granzyme and FAS-FAS
including the effector T-cells. Important among them and ligand dependent mechanisms. Cytotoxic NK T-cells may
worth mentioning are γδ T-cells [Tγδ cells], NK T-cells and be relevant in immunity against intracellular microorganism
the Treg cells. including Mtb (77,78).
66 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

REGULATORY T-CELLS infection. Even during the phase of latency, the bacilli
use various immune evasion strategies to circumvent the
These cells initially recognised as suppressor T-cells (79),
effective host immune response that generally contains
were subsequently identified as regulatory T-cells (80). Treg
the infection but fails to eradicate them. Clearly such
cells are initially defined on the basis of expression of CD25,
containing immune mechanism[s] is/are effective as any
the α-chain of the IL-2 receptor; they also share common
disruption in it results in reactivation of the persistent
markers with conventional, activated CD4+ T lymphocytes.
dormant infection, for example, in HIV infection. The ability
T reg cells are also characterised by some phenotypic
markers like CTLA-4, gluco­corticoids-induced TNF receptor of Mtb to survive the immune response clearly indicates
[GITR], CD103 and glyco­protein A repetitions predominant existence of series of immune evasion mechanism[s].
[GARP] (80) etc. FoxP3 is most widely accepted as the Mycobacteria are cap­a ble of producing ammonia and
definitive marker of Treg cells (81). Treg cells repor­tedly sulphatides which inhibit the fusion between phagosomes
suppress the Teff cells by release of suppressive cytokines with lysosomes. Inefficient phagolysosomes fail to process
[IL-10, TGF-β] or by a contact-dependent manner, or both the antigens of mycobacteria and present to the cognate
(82-84). Treg cells also express TLR2 (85,86) and TLR4 (87) T-cells. This, in turn, fails to stimulate repertoire of T-cells
which can bind to diverse mycobacterial pattern recognition optimally leading to weakening of immunity against the
molecules like lipids. Recent reports suggest that TLR2 pathogen. Interestingly, cholesterol mediates the phagosomal
engagement with mycobacterial component[s] may eliminate association of tryptophan aspartate containing coat
Treg g cells thereby stimulating a Th1 response, while TLR4 protein [TACO] and prevents their fusion with lysosomes.
engagement results in persistent expansion and activation Also, by retaining TACO and intercepting the phagolysosomal
of T reg cells, thus, causing immunosuppression (87). fusion mycobacteria trigger their evasion mechanisms (100).
Treg cells express a distinct set of chemokine receptors, such Mtb-infected macrophages are relatively ineffective at
as chemokine [C-C motif] receptor 4 [CCR4] and chemokine optimally triggering the T-cell proliferation and cytokine
[C-C motif] receptor 8 [CCR8] (88,89), which recruit these production due to down-regulation of human leucocyte
to the patho­logical site[s] to interact and down regulate the antigen [HLA] class II expression (101). Infected macro­
function of Teff. Involvement of Treg cells in host defence phages are also known to secrete immunosuppressive
against intracellular infections is well documented (83). cytokines, such as, IL-10 and TGF-β (102). Experimental
Several recent studies on mice and human indicate Treg cell evidences suggest that Mtb- infected macrophages are
expansion during TB (90-96) and viral infections (97,98). relatively refractory to the effects of IFN-γ, which is a key
Expansion of Tregcells in peripheral blood lymphocytes [PBL] mediator in macrophage activation. Recent studies suggest
as well as disease site[s] among patients with TB-pleural that recognition of mycobacterial antigens by TLR2 and
effusion and ascitic fluid has been reported (90). During TLR4 differentially regulates either pro- or anti-inflammatory
active TB, suppression of Mtb specific T-cell response is cytokine production by macrophages and through these
evidenced by over production of suppressive cytokines cytokines can suppress the immune recognition. Moreover,
such as IL-10 and TGF-β and decreased production of the mycobacterial interaction with TLR2 and TLR4 can
cytokines such as IL-2 and IFN-γ. It has been reported that differentially expand or eliminate the Treg cells which
Foxp3+ regulatory T-cells are over-represented in TB and suppress the effector T cells (103). All these mechanism[s]
suppress the host effector T-cell response against Mtb (41,99). help the ingested bacilli either to silence or to evade the
The higher ratio of Treg/Teff among these patients suggests immune effector function of the host and help the pathogen
the relative dominance of Treg cells. These enriched Treg survival.
cells were tightly associated with high bacillary load and A number of microorganisms that cause chronic infection
that inversely correlated with the pathogen specific IFN-γ appear to exploit the PD-1-PD-ligand[s] [PD-1-PD-L]
skewed effector T-cell response as measured by ratio of
pathway to evade the immune responses and establish
IFN-γ/IL-4. Higher frequency of Treg cells among patients
persistent infection (104). PD-1 and its ligand[s] have
with higher bacillary load strongly hints towards the antigen
important roles in regulating immune defences against
induced Treg cells generation among patients [Figure 5.3].
microbes that cause acute and chronic infec­tions. Previously,
A significantly higher fraction of proliferating Tregcells was
observed ex vivo, suggesting their expansion during TB it has been reported that PD-1-PD-L pathway inhibits T-cell
pathogenesis. This is further supported by markedly higher effector functions during human TB (105). In addition, same
antigen induced in vitro proliferation of Treg cells. These Treg group described the importance of PD-1-PD-L1 pathways
cells were preferentially expressing immune exhaustion during innate immunity against Mtb (106). Live infection
marker PD-1 on their surface (99), which is involved in of monocytes/macrophages with Mtb H37Rv upregulates
suppression of host immunity in addition to IL-10. PD-L1 expression on them and the PD-1 pathways
actively involved in suppressing cytokine production,
IMMUNE EVASION BY MYCOBACTERIUM proliferation, CTL activity and in the apoptotic regulation of
IFN-γ producing effector T-cells during active TB (107)
TUBERCULOSIS
[Figure 5.4]. These observations suggest that PD-1-PD-L
Mtb can evade and subvert various immune mechanisms pathway has been utilised by Mtb to dampen the host
adopted by the host to either eradicate or eliminate the immune responses.
 Immunology of Tuberculosis 67

Figure 5.3: Tuberculosis: an immunologic spectrum. Model depicting the immunological spectrum in the pathogenesis of human TB. Host
attempts to generate and recruit polarised immunity directed against the pathogen []. Elicitation of efficient immune response confers protection
and abrogates progression of the disease []. Reactivation of the infection due to weak/inadequate host immunity facilitates the disease
progression and its clinical manifestations []. Proportional imbalance of Teff:Treg ratio towards selective enrichment of Treg cells may lead to the
suppression of effector immune response at the pathologic site and thereby influences []. Clinical manifestations of human TB as observed in
the development of disseminated form of TB [MTB] []. Patient receiving successful anti-TB treatment are rescued from the adverse effects of
the disease and observed to have improvement in their immunological and clinical status with commitment decline in the frequency of Treg cells
TB = tuberculosis; Treg = regulatory T-cells; PTB = pulmonary tuberculosis; MTB = miliary tuberculosis

IMMUNOMODULATORS IN TUBERCULOSIS Several agents have provoked interest as candidate

adjuvant therapeutic elements. Heat killed preparation of
Several newer approaches to block certain key molecules
M. vaccae (110) and M. indicus pranii [previously known as
respon­sible for tissue destruction are gaining attention
Mycobacterium w] have been co-administered with standard
for molecular therapy. Proinflammatory cytokines like
chemotherapy to enhance the immune response. It has
TNF-α may be a target for healing of cavitary TB, while
been proposed that immunopotentiation by such adjuvant
TGF-β is thought to be a good candidate for prevention
therapeutic vaccination may promote Th1 immunity while
of fibrosis, as it helps development of fibrotic lesions.
acting simultaneously with the drugs. Thalidomide and
Role of various other cytokines in the pathogenesis of TB
pentoxyfylline have been found to rescue the patients
makes them potential targets for intervention. Recent data
from excessive effect of TNF-α (111). Other agents like
support the role of aerosolised IFN-γ in disease resolution
levamisole, inhibitors of IL-12, IFN-α have also been used
among patients with multidrug-resistant TB [MDR-TB]. in TB. However, further studies are definitely required to
Granulocyte, monocyte-colony stimulating factor [GM-CSF] confirm their role.
has also been used simultaneously with IFN-γ (108). Daily
low dose administration of recombinant IL-2 has been found
HOST BIOMARKERS FOR TUBERCULOSIS
to activate the immune system and may enhance the effect of
the drugs in patients suffering from MDR-TB (109). Molecular Identification of clinically relevant biomarkers is required for
strategies to modulate the immune response by means of better diagnosis, treatment and prevention of TB. Emerging
changing the balance of cytokines and chemokines involved resis­tance to current TB drugs necessitates development of
in TB are new fields and require further investigation. newer and better drugs. Hence, “biomarkers” indicating
 68 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 5.4: Exploitation of PD-1 and PDL-1/PDL-2 pathways by Mtb to dampen the host immune responses during TB. Model depicting mani­
pulation of PD-1-PD-L1 pathway by Mtb during pathogenesis of human TB. During initial phase of infection APCs and T-cells have low expression
of PD-L1 and PD-1 respectively and stimulate the proliferation, cytokine production and cytotoxic activity of antigen-specific naïve T-cells. During
chronic infection or in the presence of persisting antigen, T-cells become ‘exhausted’ and lose the ability to proliferate. Exhausted T-cells have
high expression of PD-1 and receive a strong co-inhibitory signal when engaging PD-L-expressing APCs. Blockade of interactions between
PD-1 and its ligands can ‘restore’ T-cells to expand their populations and regain effector functions, including cytokine production, proliferation
and cytolysis. Successful anti-tubercular therapy also leads to down-regulation of this inhibitory PD-1 receptor, and hence, restoring the T-cells
functions
Mtb = Mycobacterium tuberculosis; T = T-lymphocytes; PD-1 = programmed cell death protein-1; IFN-γ = interferon-gamma; IL-2 = interleukin-2;
CTL = cytotoxic T-lymphocyte; APCs = antigen presenting cells; PD-L1 = programmed cell death ligand 1

disease status would boost development of better drugs, protection. Recently, therapy-induced decline of FoxP3+ Treg
vaccines and diagnostics (112,113). Research on transcriptomic cells was reported to parallel with decline of Mtb-specific IL-
and proteomic analysis in TB has picked up in recent years, 10 along with elevation of IFN-γ production, and IFN-γ/IL-4
leading to identification of several potential biomarkers for ratio. Interestingly, persistence of Treg cells tightly correlated
TB diagnosis, vaccine and drug development. Biomarker with MDR-TB (99). This finding further substantiates the
research in TB has been very effectively highlighted by quite utility of Treg cell monitoring as an important predictive
a few research articles recently (113-116). Several potential biomarker for MDR-TB and response to chemotherapy.
host biomarkers in blood or blood cells in TB were identified Recently, it was observed that PD-1 expressing T-cells were
in recent years and include IP-10, IL-6, IL-10, IL-4, FoxP3, increased during active TB, and steadily declined in the
PD-1, PD-L1 and IL-12. Similarly, IFN-γ, TNF-α, IL-2, IP-10, PBL of PTB patients during successful anti-tuberculosis
IFN-γ/TNF-α, IFN-γ/IL-2 and IL-13 were identified as strong therapy. A tight correlation between the bacillary load and
candidate biomarkers [Table 5.1] that were upregulated frequency of PD-1+ T-cells, and decrease of PD-1+ T-cell
in latent TB compared to healthy uninfected controls in frequency was associated with increase in the Mtb specific
stimulated blood samples (116-119). These biomarkers would IFN-γ/IL-4 among PTB patients (107). Thus, a potential role
again find an application in diagnosis of a latent TB infection. of PD-1+ T-cells as useful biomarker to monitor treatment
IL-6, IL-10, IP-10 and TNF-α are the most promising markers outcomes during therapy and/or vaccine trial for TB patients
for active TB while FoxP3, IL-4 and IL-12 are identified as the can be considered. These biomarkers are important for two
most promising biomarkers for immunological correlates of reasons: [i] discriminating TB disease and infection; and
 Immunology of Tuberculosis 69

Table 5.1: Potential biomarker candidates for TB

            Marker
Denominator Down-regulated Up-regulated
Active TB versus healthy controls Interferon-g/Interleukin-4 Interferon-g-inducible protein 10
Interleukin-4δ2/Interleukin-4 Interleukin-2
Interleukin-4
Interleukin-6
Interleukin-8
Interleukin-10
Tumour necrosis factor-α
Monocyte chemoattractant protein-2
Transforming growth factor-β1
Interferon-g
Foxp3
Programmed cell death protein 1
Programmed cell death ligand 1
T-cell immunoglobulin and mucin domain-containing molecule 3
Active TB versus latent TB infection Interleukin-4δ2 Foxp3
Interferon-γ Tumour necrosis factor-α
Interleukin-12 Interleukin-4
Interleukin-12α, interleukin-12β
Programmed cell death ligand 1
TB = tuberculosis
Based on references 116-120

[ii] identifying correlates of protective immunity. These 10. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE,
protective immunological correlates would, in turn, be useful Eissa NT. Toll-like receptor 4 is a sensor for autophagy associated
for vaccine studies. Validation of these biomarkers in large with innate immunity. Immunity 2007;27:135-44.
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immunity” (120,121). 12. Desjardins M, Huber LA, Parton RG, Griffiths G. Biogenesis
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101. Hmama Z, Gabathuler R, Jefferies WA, Dejong G, Reiner NE. MD, et al. Biomarkers and diagnostics for tuberculosis: progress,
Altenuation of HLA-DR expression by mononuclear phago­ needs, and translation into practice. Lancet 2010;375:1920-37.
cytes infected with Mycobacterium tuberculosis is related to 115. Walzl G, Ronacher K, Hanekom W, Scriba TJ, Zumla A. Immuno­
intracellular sequestration of immature class II heterodimers. logical biomarkers of tuberculosis. Nat Rev Immunol 2011;11:
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102. Hirsch CS, Hussain R, Toossi Z, Dawood G, Shahid F, Ellner JJ. 116. Petrucci R, Abu Amer N, Gurgel RQ, Sherchand JB, Doria L,
Cross-modulation by transforming growth factor beta in human Lama C, et al. Interferon gamma, interferon-gamma-induced-
tuberculosis: suppression of antigen-driven blastogenesis and protein 10, and tuberculin responses of children at high risk of
interferon gamma production. Proc Natl Acad Sci 1996;93:3193-8. tuberculosis infection. Pediatr Infect Dis J 2008;27:1073-7.
103. Chang J, Huggett JF, Dheda K, Kim LU, Zumla A, Rook GA. 117. Babu S, Bhat SQ, Kumar NP, Kumaraswami V, Nutman TB.
Myco­bacterium tuberculosis induces selective upregulation Regula­tory T cells modulate Th17 responses in patients with
of TLRs in the mononuclear leukocytes of patients with active positive tuberculin skin test results. J Infect Dis 2010;201:20-31.
pulmonary tuberculosis. J Immunol 2006;176:3010-8. 118. Nemeth J, Winkler HM, Karlhofer F, Selenko-Gebauer N,
104. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function Graninger W, Winkler S. T-cells co-producing Mycobacterium
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105. Jurado JO, Alvarez IB, Pasquinelli V, Martínez GJ, Quiroga MF, 119. Sutherland JS, de Jong BC, Jeffries DJ, Adetifa IM, Ota MO.
Abbate E, et al. Programmed death [PD]-1:PD-ligand 1/PD- Production of TNF-alpha, IL-12[p40] and IL-17 can discriminate
ligand 2 pathway inhibits T cell effector functions during human between active TB disease and latent infection in a West African
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106. Alvarez IB, Pasquinelli V, Jurado JO, Abbate E, Musella RM, 120. Wallis RS, Maeurer M, Mwaba P, Chakaya J, Rustomjee R,
de la Barrera SS, et al. Role played by the programmed death- Migliori GB, et al. Tuberculosis-advances in development of
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 6
Genetic Susceptibility
Parameters in Tuberculosis
NK Mehra, Gaurav Sharma, Deepali K Bhat

INTRODUCTION two ways: [i] first, candidate gene studies can be carried out
on genes of known function that have a possible biological
Most people exposed to tuberculosis [TB] develop effective
role in the control of infec­tion or disease; and [ii] the second
immunity against the invading bacillus and do not develop
approach utilises a non-targeted genome-wide linkage
disease. A strong host genetic influence has been proposed
analysis, in which increased sharing of chromosomal regions
to be an important factor for the development of disease in
by affected individuals leads to identification of positional
a limited percentage of the population in a hyperendemic
candidates. Recently, development of high throughput
area (1,2). Evidence supporting the role of genetic factors
genotyping technologies and identification of thousands of
influencing suscep­tibility/resistance to TB includes differ­
polymorphic microsatellite markers as well as genome-wide
ences in the development of infection and disease among
association studies [GWAS] has led to the identification of
various human racial groups (3,4) and animal strains (5),
genes [candidate] not previously associated with the disease.
concordance of the disease in monozygotic twins (6) and
A better understanding of the disease mechanisms and of
familial occurrence of the disease. Clinical manifestations
the host-pathogen interplay could help to identify people
of pulmonary TB are due to delayed type hypersensitivity
at high or low risk of infection and provide a basis for
[DTH] reaction against Mycobacterium tuberculosis [Mtb]
early diagnosis and pre-emptive treatment of susceptible
rather than direct damage caused by the bacillus. Thus, final
individuals. In this chapter, the role of genetic factors in
outcome of the disease is the result of interaction between
influencing susceptibility to TB per se has been discussed.
the bacillus and host genes that govern immune response.
Available evidence indicate that susceptibility to TB
GENETIC SUSCEPTIBILITY TO TUBERCULOSIS
is multifactorial. Host genetic factors explain, partly why
some people are resistant and others susceptible to infection. Exposure to Mtb in a hyperendemic area does not always
Rare gene disruptions cause fatal vulnerability to certain result in disease in all individuals. Though environmental
pathogens, but more subtle differences are common and and socio-economic factors are primarily related, numerous
arise from minor variations in many genes. To predict how studies have emphasised the importance of host resistance
much our genetic make-up determines the different ways and hereditary susceptibility. Although about one-third of
in which we respond to some infectious agents is a difficult the world’s population is infected with the bacillus, only
task. This is especially because of the many contributory around 10% of those who get infected will ever develop
factors, such as, previous health status, acquired immunity clinical disease. Even in families with similar socio-economic
and variability in the pathogen. Many immunogenetic loci and nutritional conditions, the disease develops only in a
influence susceptibility to several infectious agents. A genetic few children indicating the existence of host genetic factors
basis for inter-individual variation in susceptibility to human regulating disease expression or resistance. Racial differences
infectious disease is also explained through segregation in susceptibility, family segregation analyses, immune
analysis of human leucocyte antigen [HLA] linked genes as response linked gene association studies, candidate gene
well as candidate gene studies (7-10). studies and genome scan studies have all implicated host
The goal of identification of host genetic factors genetics as the major contributing factor in determining
that underlie susceptibility to TB can be approached by susceptibility and/or resistance to infectious diseases.
74 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Racial Differences MOLECULAR GENETICS AND ORGANISATION

Racial differences influence the degree of resistance to myco­ OF HUMAN MHC GENES
bacte­rial diseases. For example, the African Americans (11) Human MHC gene cluster spans a region of about 4000 kb
and certain African tribes have been reported to be parti­ length [4 × 106 nucleotides] on the short arm of chromosome
cularly more susceptible to pulmonary TB as compared 6 in the distal portion of the 6p 21.3 band. Studies on the
to Jews, who are relatively immune. Similarly it has been structural organisation of MHC molecules have helped in
reported that the non-White patients in the age group of understanding the functional role of MHC gene products
1–20 years had higher deaths rates from pulmonary TB as in the host immune response. In the MHC region, a total of
compared to the White children of the same age group (12). 224 genes have been identified, of which 128 are assumed
Also the disease prevalence in Gurkhas of Nepal has been to be functional while the remaining 96 are pseudo genes.
found to be appreciably higher than in other ethnic groups It is remarkable that greater than 40% of these genes have
residing in the same geographical area (4). one or more assigned immune functions. The genes are
arranged in three distinct sets of molecules, each comprising
Twin Studies a cluster of Ir genes [Figure 6.1] (18). The most centromeric
Pulmonary TB has been reported to occur more commonly in segment is the class II region that spans around 1100 kb
twins even when they are living separately and in disparate and contains HLA-DP, DQ and DR loci, which are found
environ­mental conditions (6). It has been suggested that as pairs, encoding the α- and β-chains. These chains encode
the disease expression rate of TB is significantly higher in the heterodimer class II protein molecules expressed at
monozygotic twins [3.3%] than dizygotic twins [15.7%] (13). the cell surface of antigen presenting cells [macrophages,
Among household contacts, the disease is more likely to dendritic cells, Kupffer cells, Langerhans cells, B-cells,
occur in siblings than in the spouse despite closer physical activated T-cells]. The class I region on the other hand, lies
contact in the latter. at the telomeric end and contains the classical HLA-A, B and
C and related loci, spread over a region of approximately
ABO and Rh Blood Groups 2 Mb. The HLA class I molecules are expressed ubiquitously
on almost all nucleated cells.
There are reports indicating that Rh-negative persons are more The HLA genes that are involved in immune regulation
susceptible to TB than their Rh-positive counterparts (14), are mainly in the class I and class II region, which are
although others failed to confirm this observation (15). Inci­ structurally and functionally different. On the other hand,
dentally, Chinese with blood group ‘O’ have been found to
Class III genes, also referred to as the ‘central genes’ are
be more resistant to develop pulmonary TB than those with
placed between class I and class II regions and comprise of
other blood groups (16). A significant increase of pulmonary
genes involved in the complement system, tumour necrosis
TB in persons with blood groups ‘O’ and ‘AB’ has also been
factor [TNF], heat shock proteins [HSP] and a few others
reported in sputum positive Danish patients as compared to
with non-immune functions, not directly related to antigen
those with group ‘A’ or ‘B’ (17).
presentation.
IMMUNE RESPONSE GENES
Major Histocompatibility Complex Class I Genes
Genes within and associated with the major histocompatibility
The class I region is the most telomeric part of the MHC
complex [MHC] have been shown to play a crucial role in
governing susceptibility to intracellular mycobacterial complex. Although 36 genes have been defined so far
infections. It is now recognized that MHC gene products in this region, HLA-A, B and C are the most important
play a crucial role in the immune response by not only since their products have been well defined as ‘classical
providing a context for the recognition of foreign antigens transplantation antigens’. They are characterised by the high
by T-lymphocytes but also by controlling the immune degree of polymorphism both in humans as well as most
regulatory processes and final elimination of the cell bound vertebrate species. Other human class I genes that show
antigen. Some MHC gene products promote efficient T-cell sequence homology to classical loci include HLA-E, F, G,
function, whereas, others elicit a poor T-cell response or no H, and a set of 5 MHC class I chain related [MIC] genes,
response at all. These include immune response [Ir] genes MIC A–E. These have reduced expression, restricted to
and/or immune suppressive [Is] genes. In pulmonary certain tissues, such as, thymus, liver, intestine or placenta,
TB, the host immune response to Mtb is responsible for and have low polymorphism. Of the five MIC genes, only
clinical expression of the disease rather than damage by the MIC-A and MIC-B, situated between the TNF and HLA-B
mycobacteria. Therefore, an in depth study of MHC linked locus, are expressed. Closely related to these genes lies the
genes is essential for understanding mechanisms underlying hemochromatosis disease candidate gene [HFE].
disease susceptibility. A detailed description of the human HLA-A, B and C molecules are heterodimer glycoproteins
HLA system, its gene organization, biological function consisting of a MHC-encoded α or the heavy chain of about
of its various gene products and association studies with 45 kDa and a non-MHC-encoded light chain, β2-microglobulin
pulmonary TB as well as involvement of various non-HLA of 12 kDa molecular weight [Figure 6.2] (18). The α chain
genes is given here. is some 350 amino acid residues long and can be divided
 Genetic Susceptibility Parameters in Tuberculosis 75

Figure 6.1: Chromosomal location and gene map showing multiple genes within the MHC region on the short arm of chromosome 6 [6p21.3]
of man. Classical transplantation loci include HLA-A, B and C in class I and HLA-DR/DQ in the class II region [encircled]. These are highly
polymorphic loci in the HLA system with hundreds of alleles already identified in each of them.
MHC = major histocompatibility complex; HLA = human leucocyte antigen
Reproduced with permission from “Mehra NK, Kaur G, editors. The HLA complex in biology and medicine; a resource book. New Delhi: Jaypee
Brothers Medical Publishers; 2010 (reference 18)”

Figure 6.2: Schematic view of HLA class II and class I molecular structures showing the peptide-binding cleft formed between α1 and β1 domains
in class II and α1 and α2 domains in class I molecules respectively. The membrane proximal domains [α2, b2 of class II and β2 microglobulin and
α3 of class I] are conserved and nonpolymorphic
HLA = human leucocyte antigen
Reproduced with permission from “Mehra NK, Kaur G, editors. The HLA complex in biology and medicine; a resource book. New Delhi: Jaypee
Brothers Medical Publishers; 2010 (reference 18)”

into three functional regions: external, transmembrane and take part in antigen binding [antigen-binding and presenting
intracytoplasmic. The extracellular portion of the heavy domains], the α3 domain is essentially conserved. It contains
chain is folded into three globular domains, α1, α2 and binding sites for the α chain of the CD8 glycoprotein,
α3, each of which contains stretches of about 90 amino which is important for the recognition of antigens by
acids encoded by separate exons. While the α1 and α2 domains cytotoxic T-cells. The outermost domains [α1 and α2]
76 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

comprise of two long α helices separated by a cleft with a Three-dimensional structural analysis has demonstrated
floor composed of a plane of eight antiparallel β-pleated that peptides bind to HLA class II molecules in an extended
sheets. The dimension of this cleft [2.5 × 1.0 × 1.1 nm] are confor­mation. By contrast to class I bound peptides, the
suited to accommodate nonamers, but peptides ranging N- and C-termini of class II bound peptides often extend
from 10–15 amino acids in length, can also bind, depending beyond the binding groove. Three asparagine residues
on how they fold. [α62Asn, α69Asn and β82Asn], β81His and β61Trp are
The amino acid side chains of the peptides are accom­ conserved in all class II molecules and positioned to make
modated in a series of pockets named from A to F. These hydrogen bonds with the peptide main chain. The α1 and
peptide positions are critical for binding to specific pockets β1 helical regions of most class II molecules are joined by
of a particular HLA class I molecule, hence termed anchors. a salt bridge formed between α76Arg and β57sp that
Pockets A and F lie at the two ends of the peptide-binding stabilises the αβ dimer. Peptides bound by the class II
groove, are highly conserved among various HLA class groove twist along the length, progressing approximately
I molecules and accommodate the amino and carboxyl three residues for each turn. Successive side chains project
terminal residues respectively. Interaction of the peptide from the class II bound peptide at regular intervals, many of
with conserved residues in A and F pockets, therefore, which are directed towards the class II molecule. The groove
anchors it in the binding groove and the process is critical in is lined by a series of pockets [P1-P9] that align the peptide
stabilising the MHC-peptide complex. Although the peptide to be read as a single unique determinant by the TCR.
residues P2 and P9 serve as primary anchors, the residues The size of the hydrophobic P1 pocket is controlled
P1, 3, 6 and 7 act as secondary anchors, and the P4, 5 and by the Gly/Val dimorphism at position 86 on the beta chain.
8 interact with the T-cell receptor [TCR]. The deepest and the most commonly used binding pockets
are P1 and P9 followed by P4 and P6.
Major Histocompatibility Complex Class II Genes In addition to the above, two other groups of non-HLA
genes exist in the MHC class II region. The first group is ABC
The MHC class II region extends over 1000 to 1200 kb with transporter genes called transporter associated with antigen
at least six sub-regions, termed DR, DQ, DP, DO, DN and processing or transporter of antigen peptides 1 and 2 [TAP1
DM. Structurally, the class II molecules are similar to class and TAP2] genes. TAP1 and TAP2 gene products associate
I molecules and are expressed as heterodimers on the cell as a heterodimer that is involved in the transport of antigen
surface with one heavy α chain [molecular weight 34 kDa] fragments produced in the cytoplasm, into the lumen of
and one β chain [molecular weight 29 kDa] of integral the endoplasmic reticulum. The second group is the set of
membrane glycoproteins [Figure 6.2] (18). Three-dimensional proteasome-related genes that includes low molecular mass
structural differences between the two include an altered polypeptide or large multi-functional protease 2 and 7 [LMP2
position of the immunoglobulin-like 2 domain relative to and LMP7] genes. The products of LMP2 and LMP7 genes
that of the α3 domain of class I HLA, and considerable are large cytoplasmic proteolytic complex molecules that
changes in the peptide-binding site. The α- and β-chains contain multiple catalytic sites. LMP complex is involved in
assemble non-covalently to create an antigen-binding cleft the production of multiple peptides simultaneously from the
located above a conserved membrane proximal structure, same substrate to produce peptides better suited for MHC
which can interact with the CD4 molecule on T-cells. Found class I binding.
mainly on cells of the immune system, including B-cells,
macrophages, dendritic cells [DCs] and thymic epithelium, Major Histocompatibility Complex
class II molecules display a more limited distribution. Class III or Central Genes
The DR region contains multiple, highly polymorphic
The central region of MHC has no structural or functional
β genes and only one invariant α gene. The conventional
correla­tion with the class I or class II region. Presently,
serologically defined DR molecules [DR1 to DR18] are
at least 39 genes have been located in a 680-kb stretch
coded for by the DRB1 gene, whereas the DR52 and DR53
of deoxyribonucleic acid [DNA] within this region. This
specificities are encoded by the DRB3 and DRB4 genes includes genes encoding proteins involved in the immune
respectively. DRB2, DRB6, DRB7, DRB8 and DRB9 are system: the complement genes C4, C2 and factor B [Bf],
pseudogenes without a first domain exon. The DQ sub- the TNF-α and TNF-β [lymphotoxin] genes and the HSP70
region contains five genes, DQA1, DQA2, DQB1, DQB2 and genes. Further, genes with no obvious association with the
DQB3, of which DQA2, DQB2 and DQB3 are not known immune system have also been identified in this region.
to be expressed. In contrast, both DQA1 and DQB1 are These include the valyl transfer ribonucleic acid synthetase
functional and polymorphic, expressing four different types [G7] gene. Further, two B-cell associated transcript genes,
of DQ molecules by different ‘cis’ and ‘trans’ combinatorial BAT2 [G2] and BAT3 [G3] are novel genes in the class III
events. The DP sub-region contains two α and two β genes, region that encode large proline rich proteins with molecular
with DPA2 and DPB2 being pseudogenes. DPB1 shows masses of 228 and 110k Da, respectively, while the RD gene
extensive polymorphism, while DPA1 displays limited encodes a 42-kDa intracellular protein.
polymorphism. DO, DM and DN lie between the DQ and Apart from the complement components, this region con­
DP loci, and have very limited polymorphism, if any. tains two genes coding for synthesis of the steroid hormone,
 Genetic Susceptibility Parameters in Tuberculosis 77

21-hydroxylase [CYP21] genes that associate very closely have now opened up a whole new dimension of studying
with the C4A and C4B genes. Of these, the CYP21B gene is single nucleotide polymorphisms [SNPs]. Using these
more functional, and deficiency of this leads to congenital procedures, an appreciable number of ‘novel alleles’ and
adrenal hyperplasia or salt-wasting disease. The CYP21A ‘unique HLA haplotypes’ have been discovered in the
gene on the other hand, is most often deleted in certain Indian population (20,21).
specific HLA haplotypes, particularly the extended
haplotype HLA-A1, B8, DR3, SCO1 in Western Caucasians. HLA and Disease Associations
Such a haplotype is known to be associated with several
autoimmune diseases including type 1 diabetes mellitus in Ever since the first successful demonstration in 1973 of a
these populations. strong association between the presence of HLA-B27 and
ankylosing spondylitis, a large number of diseases have
been shown to be associated with variable HLA alleles.
BIOLOGICAL FUNCTIONS OF THE HLA GENES
The strongest of these associations have been those
Determination of the crystal structure of the human MHC involving HLA class II region genes with autoimmune
class I and class II molecules and the identification of the and infectious diseases with definitive population based
putative peptide binding cleft firmly established that MHC differences [Table 6.1] (22-32). A number of hypotheses have
molecules are the principal antigen binding and presenting been put forward to explain these observed associations.
molecules to the T-cells. Thus, peptide antigens alter the HLA Class-I [A, B, C] and Class-II [DR, DQ and DP]
HLA molecule by occupying the cleft to be scrutinised
by the T-cell. Zinkernagel and Doherty (19) who were
awarded the Nobel Prize for Medicine in 1996 for their
epoch making discovery of the anti-viral T-cell recognition Table 6.1: Some of the prominent HLA associations
first put this concept forward. The fundamental difference with diseases
in the above process is that whereas class I MHC molecules Disease HLA allele
bind ‘endogenous’ peptides and eliminate them through the Ankylosing spondylitis B*27:01 B*27:04 B*27:05
process of cytotoxic T-cell killing [inside out mechanism], the
Addison’s disease DRB1*03:01–DQB1*02 and
class II molecules, on the other hand, bind peptides derived DRB1*04–DQB1*03:02
from ‘external’ sources [exogenous] and present them to
Behçet’s disease B*51, B*5701
CD4+ helper T-cells [outside in mechanism].
The processing pathway in both situations utilises highly Celiac disease DQA1*05:01 – DQB1*02:01
DQA1*02:01 – DQB1*02:02
specialised cell machinery that works most effectively. The DQA1*03 – DQB1*03:02
endogenous proteins in the cytoplasm of the cell are digested
Crohn’s disease DRB1*07, DRB1*01:03, DRB1*15:02
into nine to ten amino acid peptides by the LMP complex, a
distinct subset of the cellular pool of proteasome. Peptides in Graves disease DRB1*03:01 – DQA1*05:01 – QB1*02:01
the cytoplasm may gain access to the TAP transporter on the and DRB1*04:01–DQA1*03:01 –
DQB1*03:02
membrane of the endoplasmic reticulum [ER] via a specific
transporter. Peptides transported into the ER lumen bind to HIV disease progression HLA-B*27, B*57 [slow], B*35[Px] [fast]
class I molecules, inducing a conformational change that may Type 1 diabetes mellitus DRB1*03:01, DQA1*05:01, DQB1*02:0
facilitate their export to the cell surface. The CD8+ cytotoxic or DRB1*04:01, DQA1*03:01,
DQB1*03:02
T lymphocytes see this MHC-peptide complex through the
TCR and other co-receptors, subsequently causing killing of Multiple sclerosis HLA – DRB1*15:01, DQA1*01:02,
DQB1*06:02
the target cell.
In the class II pathway, the proteolytic enzymes in Narcolepsy DQB1*06:02, DRB1*15:01 –
the endo­somal compartment help digest antigens taken DQA1*01:02-DQB1*06:02
from outside the cell into small peptide fragments by Psoriasis vulgaris C*06
endocytosis. The MHC class II molecule with its α and Rheumatoid arthritis DRB1*01:01, DRB1*01:02,
β chains assembles in the ER with the invariant chain to DRB1*04:01, DRB1*04:04,
form a stable trimolecular complex which inhibits binding of DRB1*04:05, DRB1*04:08,
DRB1*10:01, DRB1*13:03, DRB1*14:02
the endogenous or self-peptides in the ER. The trimolecular
and DRB1*14:06
complex is efficiently transported out of the ER and is
targeted to a post-Golgi compartment in the peripheral Scleroderma DRB1*11:04, DQB1*03:01, DRB1*15:02
DQB1*06:01, DQB1*05:01
cytoplasm. The invariant chain is subsequently cleaved in
endosomes, opening up the cleft for peptide occupancy. Sjögren’s syndrome DRB1*03 – DQB1*02 – DQA1*05:01;
DRB1*15 – DQB1*06 – DQA1*01:02
The developments of accurate and reproducible
high-resolution DNA-based HLA typing methods have Systemic lupus DRB1*03:01, DQB1*02:01,
erythematosus DRB1*15:01, DQB1*06:02
significantly improved our ability to define HLA alleles at a
single nucleotide difference. Further advanced technologies HLA = human leucocyte antigen; HIV = human immunodeficiency
virus
based on sequencing, mass spectroscopy and DNA chips
78 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

alleles could act directly as disease susceptibility agents of pulmonary TB appears to be due to a detrimental cell-
by means of antigenic crossreactivity or mimicry between mediated immune response to Mtb. Several investigators
infec­tious agents and the particular HLA molecule have searched for an association of the disease with either
[“molecular mimicry”] or by acting directly as receptors HLA class I [HLA-A, -B, -C] or class II [HLA-DR, DQ]
for microorganisms. Also, they can direct the immune molecules, both of which might play crucial roles in host
response by acting as Ir genes since the latter are known susceptibility to pulmonary TB. Table 6.2 summarises the
to regulate immune response to the pathogen. The specific prominent immunogenetic association studies related to
HLA gene may be physically very close to the chromosomal HLA and pulmonary TB (7-9,22-32). Majority of these studies
region that might carry a gene conferring susceptibility point towards the influence of HLA class II region genes in
or resistance to a particular disease. This hypothesis may governing susceptibility to the disease, suggesting a strong
explain the lack of complete association, and geographical influence of HLA-DR or DQ linked genes in modulation of
variation in the association accounting for the possible the immune response to Mtb infection, largely via the cell-
linkage disequilibrium. Further, genetic susceptibility may mediated immunity (33).
largely or in part may be due to the involvement of non-HLA Although only a few studies have addressed the
genes. Though classical genetic studies in humans and question of the impact of HLA class I polymorphism on
experimental models have clearly documented the primary TB development, some HLA class I alleles have been
contribution of the MHC genes, information on the reported to be associated with the disease per se. These
involvement of non-HLA genes in conferring susceptibility include HLA-A1, HLA-B51, HLA-Cw6 and HLA-Cw7 in
or resistance to various diseases is insufficient. Indians (9,23) and HLA-B*1802 and HLA-B*4001 in
Indonesians (22). Further analysis revealed that of the various
IMMUNOGENETICS OF TUBERCULOSIS HLA class I loci, alleles in the HLA-B locus play the most
dominant role in pulmonary TB development as compared to
The demonstration that MHC acts as the T-cell restriction A or C alleles. HLA-B is the most polymorphic locus within
element with its linked Ir and/or Is genes has encouraged the human MHC and the fundamental genetic variation
scientists to look for an association of HLA genes with occurs within exons 2 and 3, known by its determinant
various diseases at the population level. Several workers function during the presentation of antigenic peptides.
have demonstrated an association of HLA alleles [or their Using the interferon-γ [IFN-γ] enzyme linked immunospot
extended haplotypes] with diseases caused by known [ELISPOT] assay system and following stimulation of T-cell
infectious agents. These include hepatitis B virus infection, clones with specific Mtb synthetic peptide arrays, it has
infectious mononucleosis, viral capsid antigen in Epstein- been demonstrated that the immunodominant TB antigen
Barr virus infection, human T-cell lympho­tropic virus III presentation to the CD8+ T-cells is preferentially restricted
[HTLV III] infection and development of Kaposi’s sarcoma by HLA-B molecules suggesting that majority of the
in patients with acquired immunodeficiency syndrome epitope-specific CD8+ T-cells are HLA-B allele restricted in
[AIDS], poliomyelitis, typhoid fever, congenital rubella, etc. patients with pulmonary TB (34).
In most cases, however, a clear relationship between HLA Studies conducted by our group on the population
antigens and susceptibility to infectious diseases has not living around Delhi area revealed a significantly increased
been established. Several explanations can be put forward to frequency of HLA-A2 and B44 in pulmonary TB patients
explain this lack of association. One of these relates to as compared to healthy controls (10). Similar association
the complexity of Ir gene effects due to heterozygosity of of HLA-A2 with pulmonary TB has earlier been reported
the MHC gene products. Another contributing factor could in Egyptian patients. Other studies have suggested an
be the ‘disease heterogeneity’ because of the multiplicity association between pulmonary TB and HLA-B15 in
of epitope specific antigenic determinants on the infectious North American Blacks and Southern Chinese, HLA-B35
agents, which preclude the detection of the effects of HLA in Northern Chinese, HLA-B5 in Egyptians, HLA-B8 in
encoded factors as risk factors for infection. This antigenic Canadians and multiple HLA-A and HLA-B specificities
complexity of the invading pathogen leads to an almost in the Russian populations. However, no association of
incomplete recognition of the relevant products of the HLA class I antigens with pulmonary TB was reported in
HLA system, particularly those in the HLA class II region, Mexican Americans, European Caucasians and Japanese
which harbours majority of the genes relevant to antigen subjects. Such a heterogeneity in HLA class I association in
recognition and T-cell interaction. different populations may be due to the ethnic variability
of the population groups tested, small number of study
Population-based Studies groups, poor documentation of their diagnosis. Further,
batch variations in HLA antisera used in these studies
Among the major infectious diseases, leprosy and TB may also account for the observed heterogeneity. It is also
have emerged as good examples of the role of HLA on possible that the putative disease susceptibility gene lies
susceptibility to infection. Like in leprosy, TB too follows a in the HLA-class II region [DR/DQ locus] rather than the
disease spectrum with the localised disease having limited class I.
lung involvement at one end of the spectrum and a more The study reported by Balamurugan et al (9) in the
diffuse, disseminated infection at the other. The pathogenesis North Indian population is an attempt to delineate HLA
 Genetic Susceptibility Parameters in Tuberculosis 79

Table 6.2: Genetic association of important MHC gene variants with susceptibility and/or resistance to
tuberculosis and with disease recurrence: summary of selected studies
Study [year] (reference) HLA allele Type of association Population studied Odds ratio p-value
Balamurugan et al [2004] (9) A1 Negative Indian ND <0.001
Yuliwulandri et al [2010] (22) B*1802 Disease recurrence Indonesian ND <0.013
Yuliwulandri et al [2010] (22) B*4001 Disease recurrence Indonesian ND <0.015
Vijaya Lakshmi et al [2006] (23) B51 Positive Indian 18.5 <0.001
Vijaya Lakshmi et al [2006] (23) B52 Negative Indian 0 <0.003
Balamurugan et al [2004] (9) Cw6 Negative Indian ND <0.001
Balamurugan et al [2004] (9) Cw7 Positive Indian ND <0.001
Singh et al [1983] (7,8) DR2 Positive Indian ND <0.05
Brahmajothi et al [1991] (24) DR2 Positive Indian 0.29 0.01
Ravi Kumar et al [1999] (25) DRB1*1501 Positive Indian 2.68 0.013
Shi et al [2011] (26) DRB1*15 Positive Chinese 3.79 0.001
Dubaniewicz et al [2000] (27) DRB1*16 Positive Polish 9.7 <0.01
Lombard et al [2006] (28) DQB1*0301-*0304 Positive South Africa 2.58 0.001
Harfouch-Hammoud and Daher DRB1*04 Positive Syrian 1.77 0.01
[2008] (29)
Harfouch-Hammoud and Daher DRB1*11 Negative Syrian 0.51 0.003
[2008] (29)
Yuliwulandari et al [2010] (22) DRB1*1101 Disease recurrence Indonesian ND 0.008
Yuliwulandari et al [2010] (22) DRB1*1202 Disease recurrence Indonesian 0.32 0.0008
Dubaniewicz et al [2000] (27) DRB1*13 Negative Polish 0.04 <0.001
Lombard et al [2006] (28) DRB1*1302 Positive South Africa 5.05 <0.001
Amirzargar et al [2004] (30) DRB1*07 Positive Iranian 2.7 0.025
Kim et al [2005] (31) DRB1*0803 Disease recurrence Korean 5.31 0.00009
Amirzargar et al [2004] (30) DQA1*0301 Negative Iranian 0.25 0.033
Vejbaesya et al [2002] (32) DQA1*0601 Negative Thai ND 0.02
Vejbaesya et al [2002] (32) DQB1*0301 Negative Thai ND 0.01
Vejbaesya et al [2002] (32) DQB1*0502 Positive Thai 2.06 0.01
Ravi Kumar et al [1999] (25) DQB1*0601 Positive Indian 2.32 0.008
Kim et al [2005] (31) DRB1*0601 Disease recurrence Korean 5.45 0.00003
MHC = major histocompatibility complex; ND = not described

class I association in TB on the basis of a shared ‘sequence the amino acid sequences that constitute the peptide binding
motif’ in peptide-binding pockets of the HLA molecules. pockets as described by the crystallographic studies. In the
The rationale of such an analysis is that although HLA is Indian study (9), the class I supertypes were evaluated for
highly polymorphic, small degree of genetic polymorphism their possible association with TB by comparing the data
may or may not affect peptide presentation and molecular with a set of healthy controls belonging to the same ethnic
function. Accordingly among the genetically related alleles, background and socio-economic status. The data revealed a
each HLA molecule could preferentially bind peptides with strong positive association of ‘HLA-A3 like’ and a negative
certain anchor residues and present the same to the CD8+ association of ‘HLA-A1 like’ supertypes particularly in
T-cells. However, within these allelic groups, there could patients with more severe forms of the disease such as
be shared peptide epitopes and a considerable overlap in miliary, disseminated and/or multidrug-resistant TB
the peptide binding capacity. Therefore, there is a need [MDR-TB].
to analyze functional differences in the variable peptide
presenting HLA class I molecules. Based on the similarities HLA Class II Association Studies
of peptide binding pockets [B and F] and the preference of
identical peptide motifs, nine different supertypes covering Beginning with studies representing a strong association
most if not all HLA class I alleles have been reported (35). of HLA-DR2 with pulmonary TB in the North Indian
The specificities of the anchor residues are determined by population (7,8), several workers have tried to search for
80 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

similar association in other populations. The first such report HLA-DRB1*16 but not HLA-DRB1*15 is observed more
came from north India (7) where a moderate increase of frequently in Brazilian leprosy patients than in the controls
HLA-DR2 was demonstrated in sporadic patients with group [9.0% vs 1.8%; p = 0.0016; odds ratio = 5.81; 95%
pulmonary TB. The same investigators while confirming these confidence intervals = 2.05 to 15.45], underlying a difference
results using multiplex family studies further suggested an in the impact of MHC polymorphism which may be related
HLA-DR2 linked control of susceptibility to the disease (8). to the specificity of each pathology (44).
This association was later confirmed in several other Almost all published studies on HLA association with
populations, including south Indians and Chinese (24,36), TB have been performed in patients with pulmonary form
Indonesians (37) and Russians (38). However, others of the disease, while no substantial data are available
could not confirm this association in studies carried out regarding the extrapulmonary disease. The authors’ group
on Egyptians (39), North American Blacks (40), Mexican had investigated HLA association with various clinical
Americans (41), as well as in a study on South Indian subgroups including pulmonary TB, MDR-TB, miliary,
patients (42). Except for the latter study, all other studies disseminated TB as well as lymph node TB. High resolution
up until then were based on serological testing of expressed molecular subtyping of polymorphic DRB1 alleles revealed
HLA antigens on the surface of lymphocytes. It may be that in addition to the increased occurrence of *1501/*02
mentioned that there is up to 25% discrepancy in DR typing subtypes of HLA-DR2, a positive association was also
results by serology when compared with the more sensitive observed with specific HLA-DR6 subtypes, in particular
molecular techniques of polymerase chain reaction-sequence DRB1*1301 in patients with pulmonary TB and MDR-TB and
specific oligonucleotide probe [PCR-SSOP] hybridisation. DRB1* 1302 in extrapulmonary TB [miliary, disseminated TB
Besides being sensitive, these techniques allow definition and lymph node TB]. Although the DR2 associated haplotype
of molecular subtypes of several serologically defined HLA- association has been reported earlier also in pulmonary
DR specificities, differing even at a single nucleotide level. TB (45), the existence of additional DR6 associated haplotypes
Hence, HLA and disease association studies using molecular [both DRB1*13 and DRB1*14] in other clinical forms of
techniques provide the most relevant information on the TB indicates that alleles with similar ‘sequence motif’ in
critical amino acid residues in the peptide-binding groove the peptide binding groove may influence susceptibility
of the MHC, rather than only an associated allele. to Mtb infection and subsequent develop­ment of severe
Studies in other populations revealed variable HLA clinical disease.
allelic association with TB, for example HLA-DRB1*04 in the Data on the clinical and immunogenetic association for
Syrian population (29), HLA-DRB1*07 and HLA-DQA1*0101 the development of MDR-TB suggest that, in addition to poor
in Iranians (30), HLA-DRB1*11 in Indonesians (22), and past compliance to treatment and presence of higher number
HLA-DRB1*1302 in South Africans (28). Similarly, HLA- of cavities in the chest radiographs, presence of HLA-
DRB1*0803 and HLA- DQB1*0601 were reported to be DRB1*14 allele in patients with pulmonary TB acts as an
associated with pulmonary TB disease advancement in independent predictor for the development of MDR-TB (46).
Koreans while a strong association with resistance to Also, the development of hepatotoxicity during anti-TB
recurrent pulmonary TB was observed with HLA-DRB1*12 treatment was found to be asso-ciated with alleles in the DQ
in Indonesians (22,31). A summary analysis of all these locus, namely DQA1*0102 and DQB1*020 (47).
studies point towards HLA-DR2 or its major molecular
subtypes, *1501 or *1502 as the main allelic variants that Family Studies and Haplotypic Association
show a positive association with pulmonary TB in most
populations. Taken together, HLA and TB association data The observed variability of the associated HLA alleles in
suggests that amino acids present in the DRB1*15 molecule different ethnic groups indicates that genes controlling host
[but absent in DRB1*16 which is the other major subtype response to mycobacteria may be ‘linked’ but not situated
of HLA-DR2] could play an important role in disease around the HLA class I and II molecules, and hence, reveal
development. Nevertheless, this data does not exclude the different linkage disequilibria in different populations. In
involvement of other immune associated or linked genes, order to understand the mode of inheritance or HLA-linked
either within or outside of the human MHC. The nucleotide control of disease susceptibility, family studies particularly
sequence of peptides presented by DRB1*15 alleles are very those with at least two affected sibs are most informative.
different from those presented by DRB1*16 alleles. From the Such studies conducted by us provided the first conclusive
mechanistic point of view, the former set of peptides may be evidence for an important role of HLA-linked genes in
recognised by CD4+ T-lymphocytes in an inadequate form governing susceptibility to pulmonary TB (7,8). Combined
and consequently this situation could disturb the effective data from other populations also support an HLA-linked
immune associated anti-TB response. At the more functional control of susceptibility to pulmonary TB with a dominant
level, it has been suggested that both HLA-DRB1*1501 and rather than a recessive mode of inheritance. This is in
*1502 may be associated with down-regulation of perforin contrast to the situation in tuberculoid leprosy, where the
positive cytotoxic cells [T-lymphocytes and natural killer] data favours recessive mode of inheritance (48).
in pulmonary TB, supporting the potential role of theses In a meta-analysis [1988 patients and 2897 controls], a
alleles in the TB susceptibility (43). On the other hand, lower risk of thoracic TB was found in carriers of HLA-B13,
 Genetic Susceptibility Parameters in Tuberculosis 81

DR3, and DR7 antigens, while patients positive for HLA-DR8 Sequence analysis of the DRB1 first domain residues has
were at higher risk (33). The risk of thoracic TB tended to disclosed that only one amino acid variation can discriminate
be higher in carriers of HLA-DR2 and its major molecular the products of DRB1*1501 from DRB1*1502 and DRB1*1601
subtypes, although the results were not consistent between from DRB1*1602. Particularly DRB1*1501 carries valine at
studies. amino acid position 86 while it is substituted with glycine in
In the Saharia tribal population in central India, a DRB1*1502. Similarly, DRB1*1601 subtype has the aromatic
significantly higher occurrence of pulmonary TB is evident amino acid phenylalanine at position 67 which is substituted
compared with other tribal population in the same region. by aliphatic leucine in DRB1*1602. Studies on pulmonary
A three locus haplotype analysis of HLA-A, B and DR alleles TB did not favor a preferential involvement of any of these
in the Saharia tribal population revealed a significantly common subtypes of DR2 suggesting that the whole DR2
increased frequency of A24*-B40*-DRB1*15 haplotype and molecule or its closely linked gene[s] may be involved
a significantly reduced frequency of A*02-B*40-DRB1*16 in governing susceptibility to pulmonary TB and the
and A*02-B*40-DRB1*03 haplotype among TB patients expression of its various clinical forms. However, analysis
compared to control subjects (49). Another two locus of DR2 subtypes and the differences in radiographic severity
haplotype study involving HLA-MICA revealed a negative based on the extent of lung lesions unilateral limited [UL],
association of haplotype HLA-B*18-MICA*018 with the unilateral extensive [UE], bilateral limited [BL] and bilateral
disease (50). extensive [BE] revealed an increased trend in the frequency
The mechanisms by which anti-TB drug resistance of DRB1*1501 as the pulmonary severity increased from UL
emerges is not completely understood. In vitro studies have to BE lung lesions.
identified several determinants of resistance to the main anti- It has also been observed that the distribution of
TB drugs, but whole-genome analyses suggest that response DR2 subtypes in TB based on the valine/glycine [V/G]
to drug exposure might be much more complex than initially dimorphism at codon β86 revealed an inverse association
thought and involves a set of strategies developed by with V86 and G86 as the pulmonary severity increased from
mycobacteria to enhance their ability to adapt and evolve. UL to BE lung lesions. Similar, inverse relationship of
Recent research suggests that bacterial fitness might play a V86/G86 has also been observed in leprosy as the disease
pivotal role in the spread of antibiotic-resistant Mtb. In vitro, severity progressed from paucibacillary to the borderline
bacterial fitness is determined by the interplay of numerous lepromatous [BL]/lepromatous [LL] multibacillary leprosy.
factors including the growth deficits incurred by resistance Knowledge on the three dimensional crystallography
muta­tions, strain genetic background, and compensatory structure of the human class II HLA molecule has revealed
evolution. The involvement of HLA in TB drug-resistance that residues at position 67 and 86 of the α-helix of the
has been evalu­ated in a study from Kazakhstan evaluating β-chain are actively involved in the binding of a foreign
the HLA genes by sequence-based typing [SBT]. It was peptide. Accordingly, the peptide binding and subsequent
observed that HLA-DQA1*03:02 HLA-DRB1*08:01 and immune triggering capability of the host depends critically
DRB1*08:03 occurred more frequently in patients with on these single amino acid variants. It is possible that
drug-resistant TB than in controls (51). The growing threat DRB1*1501 and 1502 alleles may be selectively implicated
of MDR-TB and extensively drug resistant-TB [XDR-TB] in the presentation of pathogenic mycobacterial peptides
highlights the need for a better understanding of the leading to development of pulmonary TB.
complexity of drug resistance following Mtb infection and The amino acid sequence analysis of the associated
the host susceptibility index determined by HLA genes. This HLA-DRB1 genes in tuberculoid leprosy has yielded crucial
shall allow the development of enhanced diagnostic tests to information on critical sites in the peptide-binding groove
identify resistant strains, HLA-susceptible individuals and of the DR molecule that affects peptide binding and/or
strategies to curb Mtb spread, and also help in the design of T-cell interaction in immune response against mycobacteria.
more potent anti-TB drugs. A large majority of patients [87%] carry specific alleles of
DRB1characterised by positive charged residues Arg13 or
High Resolution Analysis of Molecular Subtypes Arg70 or Arg71 as compared to 43% controls conferring a
of HLA-DR2 in Mycobacterial Diseases relative risk of 8.8. Thus, susceptibility to tuberculoid leprosy
involves three critical amino acid positions of the β-chain,
The frequency of HLA alleles in the North Indian population the side chains of which when modelled on the DR1 crystal
has revealed that two alleles, namely DRB1*1501 and structure, line ‘pocket 4’ accommodating the side chain of
DRB1*1502 constitute greater than 90% of the DR2 alleles a bound peptide. Characteristically, ‘pocket 4’ is formed by
in this population. Other alleles such as DRB1*1506 and the side chains of amino acids α9, β13, β70, β71, β74 and β78.
DRB1*1602 are represented at much decreased frequencies. Substitutions of any of these can affect the local charge. For
For example, DRB1*1601 occurs in only 4% of the DR2+ example, presence of positively charged Arg at position 13
healthy individuals in this population. Studies carried and/or at position 70 or 71 will probably bind negatively
out both in north as well as south India have indicated a charged residue of the same foreign peptide and stimulate
population association of DRB1*1501 [rather than other particular T-cell clones leading to a detrimental immune
subtypes of DR2] in patients with TB. response as seen in tuberculoid leprosy. Hence, identification
82 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

of peptide motifs that bind disease asso­ciated HLA alleles and south Indian (75) populations. Another inflammatory
would contribute significantly to the search for mycobacterial cytokine, IL-1 showed an association of IL-1B +3953 C
antigenic determinants. Similarly, sequence analysis of HLA to T transition with resistance to TB in Colombians (78).
class II alleles in TB could help identify critical amino acid In addition, an intronic variant rs 4252019 T allele and a
residues for binding of Mtb derived pathogenic peptide[s] microsatellite polymorphism in IL-1RA gene were found
responsible for the detrimental/protective immune response. to influence susceptibility to TB in North Indian (80) and
This has potential implications in immune interventions Ghana (79) populations respectively. In North Indians, risk
therapies in pulmonary TB. conferring association of T allele of rs2070874 [C/T] variant
of IL-4 [drives Th2 response], IL1-12 variants rs3212220
NON-HLA GENES IN TUBERCULOSIS [G/T, T allele] and rs 2853694 [A/C, A allele] with pulmo­
nary TB was also observed. Another commonly studied
Most of the classical genetic association studies in TB have variant is IL-12B +1188A/C [rs3212227] that showed a
targeted the HLA-associated immune response genes. Using positive association in the Chinese (84) but not in African-
the candidate gene-based approach; several risk, protection Americans, Caucasians (83) and South Indians (81,82).
conferring non-HLA immune related genes have also been
implicated with TB susceptibility in recent years. These
Toll-like Receptors
include toll-like receptors [TLRs], vitamin D receptor [VDR],
dendritic cell-specific intercellular adhesion molecule-3- Toll-like receptors are a family of pathogen recognition
grabbing non-integrin [DC-SIGN], solute carrier family 11 receptors [PRRs] consisting of 12 members in mammals.
[proton-coupled divalent metal ion transporters], member 1 They are expressed on the surface of cell membrane or
[SLC11A], formerly known as natural resistance associated on the membrane of endocytic vesicles of mainly immune
macrophage protein 1 [NRAMP1] and others. A large cells including macrophages and DCs. Although interaction
number of variants in these genes show an association with of Mtb with TLRs leads to phagocytic activation, the
susceptibility to TB infection with population specific genetic interaction itself does not cause immediate ingestion of the
differences highlighted in various studies. Here, we have mycobacteria. Following interaction of specific mycobac­terial
attempted to summarise some of these common associations structures with TLRs, signalling pathways are triggered in
with a brief description on each of them [Table 6.3] (52-102). which adaptor molecule, myeloid differentiation primary
response protein 88 [MyD88] plays an important role.
Chemokines and Cytokines Subsequently, IL-1 receptor-associated kinases [IRAK], TNF
Chemokines play an important role in the recruitment of receptor-associated factor 6 [TRAF6], transforming growth
immune cells to the site of infection and the description of factor-beta [TGF-β] activated protein kinase1 [TAK1] and
these immune regulatory molecules is beyond the scope of mitogen-activated protein [MAP] kinase are recruited
this chapter. The monocyte chemoattractant protein-1 which in a signaling cascade leading to activation and nuclear
is encoded by the C-C chemokine ligand 2 gene [CCL2] is translocation of transcription factors such as nuclear factor-
known to be involved in granuloma formation, and thereby, κB [NF-κB]. This leads to transcription of genes involved
containment of Mtb infection in the lungs. Transition from in the activation of the innate host defense, mainly the
adenine to guanine at position -2518 is known to increase production of proinflammatory cytokines, such as, TNF,
the expression levels of this chemokine and the G allele IL1β, and IL-12 and nitric oxide.
has been shown to be associated with TB susceptibility in The TLRs known to be involved in the recognition
Mexicans and Koreans (53) but not in South African (54) of Mtb including TLR2, TLR4, TLR9, and possibly TLR8.
and Brazilians (103). On the other hand, a protective effect Several investigators have reported an association of various
of the -2518 G allele along with another allelic variant -362 TLR variants with the TB infection and disease severity.
C with resistance to TB has been reported in the population Description of only some of these is discussed here. An
of Ghana (52). Similarly, chemokine [C-X-C motif] ligand association of the T allele of TLR2 variant Arg677Trp
10 [CXCL10] and its -135 A allele has been shown to be [2029 C/T, rs5743706] with TB infection in the Tunisian
associated with protection against TB infection (62). population (68) and of allele A of TLR2 Arg753Gln
Among cytokines, IFN-γ variant, +874A allele with [rs5743708G/A] variant in the Turkish population with
reduced expression is associated with TB infection or severity disease susceptibility (69) has been reported. Similarly an
in various studies (93). The regulatory cytokine interleukin association of the short [≤16 GT] repeats of the microsatellite
[IL]-10 that suppresses the Th1 responses and its variant in intron II of the TLR2 gene with TB infection has been
-1082 is associated with TB in the Turkish (72) and Colombian reported in the Koreans (70). In North Indians, the TLR4
populations (89) but not in South Indians (82), Pakistanis (88) variant 896A/G [Asp299Gly] revealed strong association
and Ghanians (104). TNF-α leads to inflammation in TB with TB susceptibility (105). Further extensive genotyping
and a SNP at position -308 with G to A transition was of different TLRs revealed that the ins/ins genotype
found to be associated with resistance to TB infection of ins/del variant -196 to -174 of TLR2 was protective
in Colombians (77). However, no such association was against TB infection in the US Caucasian and West
observed in the Turkish (72), Thai (74), Cambodian (76) African TB cohorts but not in the African Americans (71).
Table 6.3: Summary of candidate gene studies of non-HLA immunogenetic variants and their associations with TB
Population
Gene [Loci] Function Genetic variant studied Association Study [year] (reference)
CCL2 Encodes monocyte chemoattractant –2518 A/G Ghanaians G allele associated with resistance to PTB Thye et al [2009] (52)
[17q12] protein involved in recruitment of [rs 1024611] Mexican G allele associated with TB susceptibility Flores Villanueva et al [2005]
immune cells and granuloma formation (53)
Korean G allele associated with TB susceptibility
Russian No association
South African No association Moller et al [2009] (54)
–362 G/C Ghanaian C allele associated with resistance to PTB Thye et al [2009] (52)
rs2857656
CD209 Encodes DC-SIGN, a cell surface –871 A/G South African G allele associated with resistance to PTB Barreiro et al [2006] (55)
[19p13] receptors for mycobacteria on Tunisian No association with TB Ben-Ali et al [2007] (56)
dendritic cells
–336 A/G Gambian G allele protective in Gambian but variable outcome Vannberg et al [2008] (57)
[rs 4804803] in other African populations. GG homozygosity
asso­ciated with decreased risk of lung cavitatory
TB
South Indian No association with TB Selvaraj et al [2009] (58)
South African A allele associated with resistance to PTB Barreiro et al [2006] (55)
Tunisian No association with TB Ben Ali et al [2007] (56)
Colombian No association with TB Gomez et al [2006] (59)
CD14 CD14 plays a role in recognition of –159 C/T Mexican TT homozygosity associated with higher risk of TB Rosas-Taraco et al [2007] (60)
[5q31] bacterial cell wall components and [rs 2569190] Colombian No association with PTB Pacheco et al [2004] (61)
lipopolysaccharides by macrophages
CXCL10 CXCL10 plays an important role –1447 A/G Chinese No association with TB Tang et al [2009] (62)
[4q21] in early immune response against [rs4508917]
respiratory tract pathogens –872 G/A Chinese No association with TB
[rs4256246]
–135 G/A Chinese A allele associated with protection against TB
Genetic Susceptibility Parameters in Tuberculosis

Gc Group specific component variants of Gc variants UK [Gujarati] Gc2/Gc2 genotype associated with TB Martineau et al [2010] (63)
[4q13] vitamin D binding protein are involved susceptibility
in antimycobacterial immunity Brazil No association with TB
South Africa No association with TB
PTPN22 PTPN22 gene encodes 788 G/A Morocco A allele associated with susceptibility to PTB Lamsyah et al [2009] (64)
[1p13] immunoregulatory molecule [rs 33996649]
intracellular lymphoid specific 1858 C/T Morocco T allele associated with resistance to PTB
phosphatase [Lyp] [rs 2476601]
VDR VDR is the receptor for active form of Taq1 T/C Gambians TT homozygosity associated with protection Bellamy et al [1999] (65)
[12q13] vitamin D and has immunomodulatory [rs 731236] against TB
effects
Contd...
83
Contd...
84
Population
Gene [Loci] Function Genetic variant studied Association Study [year] (reference)
Taq1 Meta-analysis No association Gao et al [2010] (66)
[Asia]
BsmI Meta-analysis bb genotype associated with protection against TB
[Asia]
Meta-analysis No association
[Africa]
FokI Meta-analysis If genotype associated with susceptibility to TB
[Asia]
Meta-analysis No association
[Africa]
Cdx-2 G/A South Indian G allele and GG homozygosity associated with Selvaraj et al [2008] (67)
protection against TB
TLR2 TLR2 is involved in recognition of Arg677Trp [2029 Tunisian T allele associated with TB infection Ben-Ali et al [2004] (68)
[4q32] mycobacteria by APCs C/T]
[rs 5743706]
Arg753Gln [G/A] Turkish A allele associated with TB infection Ogus et al [2004] (69)
[rs 5743708]
Intron II [GT]n Korean Association of shorter repeats with ≤16 GT with Yim et al [2006] (70)
microsatellite TB disease
Ins/del USA Insertion/Insertion genotype associated with Velez et al [2010] (71)
[–196 to –174] [Caucasians] protection against PTB
USA [African- No association
Americans]
Guinea-Bissau Insertion/Insertion genotype associated with
protection against PTB
TLR9 TLR9 regulates Th1 responses and rs 352143 [G/A] USA [African- AA genotype associated with resistance to PTB Velez et al [2010] (71)
[3p21] cooperates with TLR2 in mediating Americans]
resistance against TB USA AA genotype associated with resistance to PTB
[Caucasians]
Guinea-Bissau No association
rs 5743836 [C/T] USA [African- TT genotype associated with resistance to PTB
Americans]
Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

USA TT genotype associated with resistance to PTB

[Caucasians]
Guinea-Bissau No association
TNF-α TNF-α leads to inflammation in TB –308 G/A Turkish No association with TB Ates et al [2008] (72)
[6p21] [rs 1800629] Korean No association with TB Oh et al [2007] (73)
Thai No association with TB Vejbaesya et al [2007] (74)
South Indian No association with TB Selvaraj et al [2001] (75)

Contd...
Contd...

Population
Gene [Loci] Function Genetic variant studied Association Study [year] (reference)
Cambodian No association with PTB Delgado et al [2002] (76)
Colombian G allele associated with TB Correa et al [2005] (77)
–238 G/A Colombian A allele associated with susceptibility to TB
[rs 361525] Colombian Protective effect of haplotype TNF–308A –238G
IL-1 IL-1 mediates fever and inflammation IL-1B +3953 Colombian T allele associated with protection Gomez et al [2006] (78)
[2q14] in TB C/T
[rs 1143634]
IL-1 RA IL-1 RA is a receptor antagonist Microsatellite Gambian Microsatellite alleles influence TB Bellamy et al [1998] (79)
[2q14] which bind nonproductively to IL-1
receptor Intronic variant North Indians T allele associated with higher risk of PTB Abhimanyu et al [2012] (80)
rs 4252019 C/T
IL-2 IL-2 is a mediator of the immune –330 G/T South Indians TT homozygosity associated with protection from Selvaraj et al [2008] (81)
[4q27] activation [rs2069762] PTB
IL-4 Drives and mediate Th2 response rs 2070874 [C/T] North Indians T allele associated with higher risk of PTB Abhimanyu et al [2012] (80)
[5q31]
IL-12 IL-12 drives a Th1 response IL-12B +1188 South Indian No association with PTB Prabhu Anand et al [2007] (82),
[5q33] A/C Selvaraj et al [2008] (81)
[rs 3212227] African- No association with TB Ma et al [2003] (83)
American and
Caucasians
Chinese Associated with TB Tso et al [2004] (84)
rs 3212220 [G/T] North Indians T allele associated with PTB Abhimanyu et al [2012] (80)
rs 2853694 [A/C] North Indians A allele associated with PTB
IL-12 RB1 IL-12 RB1 encodes a receptor chain –2 C/T Moroccan T allele associated with TB Remus et al [2004] (85)
[19p13] for IL-12 Indonesian No association with TB Sahiratmadja et al [2007] (86)
Genetic Susceptibility Parameters in Tuberculosis

+641 A/G , Japanese +641, +1094 and +1132 associated with TB Kusuhara et al [2007] (87)
+1094 T/C and susceptibility and severity
+1132 G/C
IL-10 Suppress TNF and Th1 [IFN-γ] –1082 A/G Turkish G allele associated with TB in Turkish population, Ates et al [2008] (72)
[1q32] responses [rs 1800896] no effects of –819 C/T and –592 C/A
South Indian No association with PTB Prabhu Anand et al [2007] (82)
Pakistan No association with PTB Ansari et al [2009] (88)
Colombian AA homozygosity associated with pleural TB Henao et al [2006] (89)
IFN-γ Activates monocytes to kill engulfed +874 T/A Spanish A allele associated with TB susceptibility Lopez-Maderuelo et al [2003]
[12q15] mycobacteria [mediates Th1 [rs 2430561] (90)
responses] Pakistan Associated with PTB Ansari et al [2009] (88)

Contd...
85
Contd...
86
Population
Gene [Loci] Function Genetic variant studied Association Study [year] (reference)
Chinese AA homozygosity associated with TB susceptibility Ding et al [2008] (91)
AA homozygosity associated with TB susceptibility Tso et al [2005] (92)
Associated with protection against TB in meta- Pacheco et al [2008] (93)
analysis of different ethnicities
Colombian T allele associated with pleural TB Henao et al [2006] (89)
Intronic SNP North Indian A allele associated with higher risk of PTB Abhimanyu et al [2012] (80)
rs1861493 [A/G]
Intronic SNP North Indian T allele associated with higher risk of PTB Abhimanyu et al [2012] (80)
rs1861494 [C/T]
–1616 G/A West Africans GG homozygosity associated with TB susceptibility Cooke et al [2006] (94)
+3234 T/C TT homozygosity associated with TB susceptibility
IFNγR1 IFNγR1 –56 T/C CC homozygosity associated with TB susceptibility
[6q23] encodes ligand binding chain [alpha] [CA]n Homozygosity of [CA] 12 allele associated Sahiratmadja et al [2007] (86)
of IFN-γ microsatellite protection
SLC11A1 SLC11A1 gene encodes a divalent Intron 7 –81C/T USA Associated with TB infection Velez et al [2009] (95)
[2q35] cation transporter which is recruited rs 3731863 [Caucasians]
to the phagolysomal membrane on Intron 4 +14G/C USA [African Associated with TB infection
activation of macrophages rs 3731865 Americans]
G249G USA Associated with TB infection
rs 17221959 [Caucasians]
D543N [G/A] Chinese Associated with susceptibility to PTB Leung et al [2007] (96)
rs 17235409 Heterozygosity associated with severe forms of PTB Zhang et al [2005] (97)
Gambian Associated with susceptibility to PTB Bellamy et al [1998] (98)
Japanese Associated with susceptibility to PTB Gao et al [2000] (99)
Cambodian Associated with susceptibility to PTB Delgado et al [2002] (76)
3’UTR TGTG+/ Korean Associated with TB pleurisy Kim et al [2003] (100)
del rs 17235416 Danish No association with TB Soborg et al [2002] (101)
NOS2A NOS2A gene encodes iNOS Int G/T USA No association with TB Velez et al [2009] (102)
[17q11] rs 2274894 [Caucasians]
Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

USA [African- Associated with susceptibility to TB

Americans]
3’UTR C/T USA No association with TB
rs 7215373 [Caucasians]
USA [African- Associated with susceptibility to TB
Americans]
HLA = human leucocyte antigen; TB = tuberculosis; CCL2 = C-C chemokine ligand 2; PTB = pulmonary tuberculosis; DC-SIGN = dendritic cell-specific intercellular adhesion molecule-
3-grabbing non-integrin; CXCL10 = chemokine [C-X-C motif] ligand 10; PTPN22 = protein tyrosine phosphatase non-receptor type 22; VDR = vitamin D receptor; TLR = toll-like
receptor; APCs = antigen presenting cells; TNF-α = tumour necrosis factor-alpha; IL = interleukin; IFN-γ = interferon-gamma; SLC11A1 = solute carrier family 11 [proton-coupled
divalent metal ion transporters], member 1; NOS2 = nitric oxide synthase 2; iNOS = inducible nitric oxide synthase
 Genetic Susceptibility Parameters in Tuberculosis 87

Further, homozygosity for AA and TT in the TLR9 variants In a study from South India, the GG homozygosity of Cdx-
rs352143 [G/A] and rs 5743836 [C/T] respectively were 2G/A variant was found to be associated with resistance to
found to be associated with resistance to infection in African- the TB infection (67).
Americans and US Caucasians but not West Africans.
Solute Carrier Family 11 Member 1
Nitric Oxide Synthase 2 Gene
SLC11A1 [formerly known as natural resistance associated
Nitric oxide synthase 2 gene [NOS2A] gene encodes macro­­phage protein 1, NRAMP1] gene encodes a divalent
inducible nitric oxide synthase [iNOS], a cytoplasmic protein cation trans­porter which is recruited to the phagolysosomal
which is produced in response to cytokines and infection membrane on activation of macrophages. Genetic studies
(106). Nitric oxide [NO] is a gaseous signalling molecule suggest that this transporter is associated with susceptibility
that plays an important role in host defense against TB and to TB in humans (98). Genotyping of the various NRAMP1
other infections. In South Africans, a haplotype consisting polymorphisms revealed an association of at least one
of rs9282799 and rs8078340 was found to be associated SNP in African Americans and of two in Caucasians with
with TB (54). Others reported an association of rs2274894 susceptibility to TB (95). In the Chinese population, variant
and rs7215373 with TB in African Americans but not with D543N G/A showed an association with susceptibility
Caucasians (102). to pulmonary TB and its presence in heterozygous state
associated with severe forms of the disease (96,97). In another
CD209 [DC-SIGN] SNP study of the same gene conducted on the Gambians,
Japanese and the Cambodian cohorts, patients carrying the
The CD209 gene encodes the C type lectin DC-SIGN which
SNP allele 2 were found to be susceptible for pulmonary
is the Mtb receptor on dendritic cells. An association of
TB (76,98,99). Similarly, an association of 3’UTR TGTG
two promoter SNPs [-871G and -336A] with resistance to
ins/del variant [rs17235416] with tuberculous pleurisy was
pulmonary TB was reported in South Africans (55). On the
observed in Koreans (100) while no such association was
other hand, a -336G SNP was associated with protection in
the Gambian population (57) while studies carried out in the observed in the Danish population (101).
Indian (58), Colombian (59) and Tunisian (56) populations
showed no association of these variants with the disease. Genome-wide Association Studies
The GWAS involve unbiased [hypothesis free] analysis of
Protein Tyrosine Phosphatase Non-receptor thousands of genetic markers across the human genome for
Type 22 identification of disease association markers, and therefore,
can identify new susceptibility loci for infectious diseases.
The protein tyrosine phosphatase non receptor type 22
Though evidence from twin studies suggests a strong genetic
[PTPN22] gene encodes for an intracellular lymphoid specific
component to TB resistance; so far only a few statistically
phosphatase [Lyp] that regulates activation of T and B
important loci have been identified in GWAS on TB. Thye
cells. The genetic variations influencing expression of this
and coworkers (107) combined two TB GWAS [from the
phosphatase affects the TB infection and the polymorphism
Gambia and Ghana] with subsequent replication in a total
1858 T was found to be associated with resistance to TB in
of 11,425 individuals. In a gene-poor region on chromosome
Morocco (64).
18q11.2, a variant rs4331426 was found associated with
disease {combined P = 6.8 × 10[-9], odds ratio = 1.19, 95%
Vitamin D Receptor CI = 1.13-1.27} (107). Most of the genome-wide linkage
Previous studies have found an association between and association studies have been performed in African
vitamin D deficiency and susceptibility to active TB. The populations. Recently, in an attempt to identify population
1,25 dihydroxy vitamin D3 suppresses the growth of Mtb specific novel targets, a multi-stage GWAS conducted in a
in vitro and its supple­mentation may enhance antimicrobial cohort of the Indonesian [South-East Asia] population, 8
activity. A group specific component vitamin D binding independent loci showed an evidence of association and
protein [DBP] gene, called GC, encodes the DBP. This serum these were located within or near the following signalling
glycoprotein is involved in the transport of vitamin D and its genes of the immune system: gene encoding protein-jagged
metabolites to various tissues. On the basis of two SNPs in 1 [JAG1], dynein, light chain, roadblock-type 2 [DYNLRB2],
GC, three electrophoretic variants have been defined which early B-Cell factor 1 [EBF1], transmembrane protein with
differ in their binding affinity for active form of vitamin D. EGF-Like and two follistatin-like domains 2 [TMEFF2],
The GC2/GC2 genotype was reported to be associated with chemokine [C-C motif] ligand 17 [CCL17], HAUS Augmin-
the susceptibility to TB in the Gujarati Asians but not in Like Complex, Subunit 6 [HAUS6], proenkephalin [PENK]
Brazilians and south Africans (63). Further, the VDR as a and thioredoxin domain-containing protein 4 [TXNDC4]
receptor for the vitamin D [active metabolite form] is known (108). In another study, a resistance locus was identified
to have several immune regulatory effects. An association downstream of the gene encoding Wilms tumour 1 [WT1] on
between Bsm1 and Fok1 genotypes in VDR and TB was chromosome 11p13. Data from the 1000 Genomes Project was
observed in Asians but not in Africans or South Americans (66). imputed into a genome-wide dataset of Ghanaian TB patients
88 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and healthy controls. One SNP, rs2057178 was found to be 6. Comstock GW. Tuberculosis in twins: a re-analysis of the Prophit
strongly associated and replication in Indonesian, Gambian survey. Am Rev Respir Dis 1978;117:621-4.
and Russian case-control study cohorts also showed the same 7. Singh SP, Mehra NK, Dingley HB, Pande JN, Vaidya MC. HLA-
DR associated genetic control of pulmonary tuberculosis in north
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India. Indian J Chest Dis Allied Sci 1983;25:252-8.
coloured population confirmed the WT1 chr11 susceptibility 8. Singh SP, Mehra NK, Dingley HB, Pande JN, Vaidya MC. Human
locus [rs2057178] but did not show the earlier identified leukocyte antigen [HLA]-linked control of susceptibility to
variants in the locus 18q11.2 and TLR8 gene (110). pulmonary tuberculosis and association with HLA-DR types. J
Infect Dis 1983;148:676-81.
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79. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC. with tuberculosis in Chinese: a case control study. BMC Infect
Assessment of the interleukin 1 gene cluster and other candidate Dis 2007;7:19.
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80. Abhimanyu, Bose M, Jha P; Indian Genome Variation [NRAMP1] are associated with severe forms of pulmonary
Consortium. Footprints of genetic susceptibility to pulmonary tuberculosis. Clin Infect Dis 2005;40:1232-6.
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81. Selvaraj P, Alagarasu K, Harishankar M, Vidyarani M, Nisha tuberculosis in West Africans. N Engl J Med 1998;338:640-4.
Rajeshwari D, Narayanan PR. Cytokine gene polymorphisms 99. Gao PS, Fujishima S, Mao XQ, Remus N, Kanda M, Enomoto T,
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Narayanan PR. Interleukin 12 B and interleukin 10 gene 100. Kim JH, Lee SY, Lee SH, Sin C, Shim JJ, In KH, et al. NRAMP1
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101. Soborg C, Andersen AB, Madsen HO, Kok-Jensen A, Skinhoj P, in the Asian Indian population. Tissue Antigens 2010;76:
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 7
Genetics of Susceptibility to Tuberculosis
Ting-Heng Yu, Tania Di Pietrantonio, Erwin Schurr

INTRODUCTION infectious agent (9,10). For instance, host genetic susceptibility

could involve a polymorphism impacting the function of a
The importance of host genetic factors in susceptibility to
gene relevant in immunity to infection or progression from
tuber­culosis [TB] is supported by historical evidence. The
infection to clinical disease. Non-genetic factors might
variable pattern of TB incidence is thought to reflect, at least
involve advanced age, human immunodeficiency virus [HIV]
in part, the population history of exposure to Mycobacterium
infection, acquired immunodeficiency syndrome [AIDS],
tuberculosis [Mtb], the causative agent of TB. Like other
alcohol abuse, diabetes mellitus, use of immunosuppressive
infectious diseases entailing a high morbidity and mortality
drugs [e.g., corticosteroids], nutritional status or co-infection
in early life, TB is expected to select for genetic variants that
with other pathogens (11). Consequently, susceptibility to TB
confer resistance/protection. Therefore, populations with a
is dependent on the genetic background of the host and the
long history of exposure to Mtb [e.g., Europeans] display
tubercle bacilli, as well as epigenetic and ecological factors.
greater resistance than those who became only recently exposed
[e.g., American natives and sub-Saharan Africans] (1-3).
Generally, stronger genetic effects will be detected in younger,
Host-Pathogen Interplay
or early onset patients (3). For TB, numerous common Several studies have presented differences on how geneti­
genetic variants contributing moderately to susceptibility cally heterogeneous Mtb strains interact with the host (12-15).
have been identified but their functional relevance and A study investigating the impact of strain genetic diversity
impact at the population level remain elusive (4-7). on the course of disease in a mouse model showed a
Since the pathogenesis of TB is only partly understood and noticeable difference in immunopathological events ranging
clinical disease presents a complex disease syndrome rather from limited disease and 100% survival with Canetti
than a single well-defined disease state, it is possible that strains to extensive disease and significant earlier mortality
different genes control different aspects of clinical disease. with Beijing strains (16). Another study showed that the
Hence, the genetic dissection of TB susceptibility will depend overexpression of a lipid species produced by strains
on additional careful investigation of disease pathogenesis belonging to the W-Beijing family inhibited the release of
in both animal and human models (8). the pro-inflammatory cytokines like tumour necrosis factor
[TNF], interleukin-6 [IL-6], and IL-12 in murine monocyte-
PATHOGENESIS AND GENETIC STUDIES derived macrophages (9). Interestingly, there is a significant
The natural history of TB is described in the chapter joint effect of strain and host genetic variation on extent of
“Pulmonary tuberculosis” [Chapter 10]. Differentiating between IL-12 and interferon-gamma [IFN-γ] production (17). The
infection and disease progression is crucial to dissect the importance of strain-host interaction effects is further shown
genetic basis of TB (8). Exposure to mycobacteria usually by the differences in the host genetic control of the closely
does not lead to clinical disease. The outcome of exposure related bacille Calmette–Guérin [BCG] Russia and BCG
depends on a complex interaction between both host genetic Pasteur strains of mycobacteria (18).
and non-genetic factors, and environmental factors including An analysis of TB patients from the cosmopolitan
the virulence, genetic make-up and mode of exposure to the urban centre of San Francisco, California, showed stable
 Genetics of Susceptibility to Tuberculosis 93

associations between genetically distinct strains of Mtb and genetic studies. Genome-wide association studies [GWAS]
human host populations stratified by birthplace (19). The are a more powerful approach than linkage analysis to
association was detected for both reactivation disease and pinpoint common modest-risk genetic factors in complex
recent transmissions occurring in San Francisco. It is likely diseases (29,38,39). Novel technologies such as next-
that the important factors maintaining the association are generation sequencing [NGS] (40) will likely further improve
biological and social (19). A subsequent study demonstrated our understanding of TB pathogenesis (41). For example,
that Mtb lineages tend to spread in patient populations whole-exome sequencing [WES] has been employed to
originating from the same geographic area (14). Likewise, discover inherited ISG15 ubiquitin-like modifier [ISG15]
strains of the Beijing sublineage of Mtb preferentially asso­ deficiency in patients suffering from Mendelian suscepti­
ciated with populations of a defined geographical setting (20). bility to mycobacterial disease [MSMD] and lead to the
A more systematic analysis of the spread of Beijing strains realization that ISG15 is a critical inducer of interferon-
suggested that virulence mutations under strong positive gamma [IFN-γ] (42).
selection favoured the global spread of Beijing strains (21). In addition, epigenetic and transcriptomic studies
In addition, results based on the comparative sequence have contri­buted to a better understanding of TB genetics.
analysis of a large number of geographically dispersed Epigenetic mechanisms are critical for functioning of
Mtb strains detected strong evidence for a co-expansion the immune system (43), and related studies such as
of the bacilli and their human hosts during the Neolithic genome-wide analyses of methylation (44) may offer new
period. This long co-evolutionary history may underlie the insights into the genetic basis of TB (45). Interestingly,
adaptation of different strains of Mtb to different ethnic host and/or environmental factors such as diet or aging
groups (22,23). These broad population-based findings are may affect epigenetic factors (46). As for transcriptomic
further supported by the occurrence of distinct genetic lesions studies, expression quantitative trait loci [eQTL] are critical
in immunity-related guanosine triphosphatase family, M [IRGM], genetic modifiers of the expression of genes and/or micro
arachidonate 5-lipoxygenase [ALOX5], and mannose-binding ribonucleic acids [microRNAs] in cell- or tissue-specific
lectin [protein C] 2 [MBL2] for different strains of Mtb (24-26). studies (47,48). Recently an interferon-inducible neutrophil-
driven blood transcriptional signature was observed in
METHODS IN THE GENETIC DISSECTION OF TB, and the transcriptional profile in TB patients was
COMPLEX INFECTIOUS DISEASES significantly reduced after successful treatment (49-51).
Likewise, transcriptional profiling offers promise for the
Different approaches have been employed to identify diagnosis of paediatric TB (52).
the genetic control elements of infectious diseases. In
the forward genetics approach [phenotype-to-genotype] GENETIC STUDIES IN MICE
Mendelian or complex inheri­tance in humans is a dissected
using hypothesis-driven or -generating method both leading Studies involving mouse models have played a key role for
to candidate genes. Candidate genes can be identified, for our under­standing of susceptibility to TB. Although Mtb is
example, by comparison with human hereditary disorders not a natural mouse pathogen, infection of mice with Mtb
with a related clinical phenotype (11) or from linkage gives rise to well-defined and reproducible phenotypes that
hits in whole-genome scans (27,28). Whole-genome scans reflect the genetic susceptibility of the host. Susceptible mice
using linkage analysis are most successful in pinpointing develop progressive lung disease, support rapid bacterial
genes with strong effects on disease susceptibility. Linkage replication and succumb quickly to disease. Resistant mice
analyses search within families for regions of the genome restrict bacterial growth and limit tissue injury, although
that segregate preferentially with the phenotype of they eventually succumb to infection. At the time of death,
interest (29). Whole genome scans have been used to lung pathology differs considerably between susceptible
identify susceptibility loci in various human infectious and resistant strains. Pulmonary lesions in resistant mice
diseases, including TB (30-32), schistosomiasis (33), visceral display large lymphocytic aggregates that penetrate the
leishmaniasis and leprosy (5,34,35). Similarly, animal models granuloma. Lesions in susceptible mice contain large foamy
[e.g., mice, zebra fish] have been successfully employed to macrophages, degenerating neutrophils, and a few dispersed
generate candidate genes for study in human patients (36,37). lymphocytes and are often necrotic (53-57).
Subsequently candidate genes are examined by asso­ciation Similar to human studies, two major genetic approaches
tests using population- or family-based case-control designs. have been applied in the mouse to identify the genetic
Candidate genes are further analysed by mutation detec­ factors that affect the host response to Mtb infection. In the
tion and functional studies to determine the impact of the reverse genetics approach, genetically engineered mice with
polymorphism on gene function and on the phenotype of targeted mutations [gene knock-out or knock-in] are infected
interest (11). to determine if absence or presence of the corresponding
Single nucleotide polymorphisms [SNPs] have become the gene alters susceptibility (58). The forward genetics approach
preferred markers for genetic studies. With the emergence of applies quantitative trait locus [QTL] analysis on infected
affordable high-density SNP arrays, the genome-wide study informative F2 or backcross progeny resulting from crosses
of common genetic variants [minor allele frequency > 5%] between inbred, recombinant, congenic or mutant strains.
in complex human diseases has become popular in human QTL analysis determines if genes impacting on phenotype
94 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

expression are linked to the location of polymorphic markers, IFN-γ- and IL‑12p40-deficient mice would lead to increased
such as microsatellites and SNPs, distributed throughout Th2 cell activation and IL-4 production. In both IFN-γ- and
the genome. Candidate genes or chromosomal regions IL‑12p40 mutant strains, however, a lack of mycobacterial-
identified through these studies can then be validated using specific Th1 immunity did not trigger a Th2 response and
genetically engineered or congenic mice (59). Congenic IL-4 levels were not increased (64,69), suggesting that
mice are produced by transferring a defined chromosomal the increased susceptibility of these mice was caused by
segment from a donor strain onto a recipient background a defective Th1 response and not by an increased Th2
through marker-assisted backcrossing (60,61). response.
Tumour necrosis factor [TNF] is essential for macrophage
Reverse Genetic Studies of Mtb Infection activation and for the formation and maintenance of
granulomas. Mice devoid of TNF or TNF receptor-I
Gene-targeted mice have been used extensively to study [TNFRI] are highly susceptible to Mtb infection. Absence of
the involvement of different molecules and cell types TNF following a low aerosolised dose of Mtb caused
during Mtb infection. Activation of CD4+ T-cells by major mortality within 35 days (70). There were 105-fold more
histocompatibility complex [MHC] class II molecules is bacteria detected in TNF−/− mutant mice compared to wild-
essential for the control of Mtb infection. Mice deficient in type controls. Mice lacking the TNFRI had a mean survival
CD4 or MHC class II molecules had severely depleted levels time of 20 days following an intravenous dose of Mtb
of IFN-γ early in infection, which caused premature death [5 × 105 bacteria] and had 50- to 100-fold more bacilli than
of both types of mutant strains (62). Mice devoid of class wild type mice (71). Mice devoid of both the TNF receptor-II
II MHC molecules displayed a greater susceptibility to TB [TNFRII] and TNFRI also succumbed within 28 days of
than mice lacking class I MHC molecules, demonstrating that aerosol infection and had larger bacterial burdens compared
CD4+ T-cell responses are dominant to CD8+ T-cell mediated to control mice (72). The granulomatous response following
immunity in the control of infection (63). Mtb infection was also defective in both TNF and TNFRI-
The rapid progression and death of mice lacking IFN-γ deficient mice. Although a few activated macrophages
has provided indirect evidence that Th1-polarised CD4+ were present, lymphocyte co-localisation with the macro­
cells are more important than Th2 effector cells. Bacterial phages was impaired, resulting in disorganised granuloma
replication is essentially unrestricted in Ifng gene-deleted formation (70,71). Chemokine induction was also delayed in
mice, and although granulomas develop, they become TNF-deficient mice, outlining a role for TNF in the regulation
quickly necrotic (64). Macrophage activation is defective in of chemokine expression (73).
IFN‑γ-deficient mice and expression of nitric oxide synthase 2
[Nos2] is low (64,65), such that these mice cannot produce the
Forward Genetic Studies of Mtb Infection
reactive nitrogen intermediates necessary for the destruction
of intracellular bacteria. However, the susceptibility of In the 1960s, Lynch and colleagues (74) speculated that
inducible nitric oxide synthase [iNOS] deficient mice is the “gradation” across mouse strains in their susceptibility
less severe than mice lacking IFN-γ, IFN‑γ type I receptor to TB argued for “existence of a number of genes, with
[IFN‑γR1], or the IFN-responsive, signal transducer and different combinations or frequencies characterizing the
activator of transcription 1 [STAT-1] molecule, suggesting different strains”. They demonstrated, through interbreeding
that there are iNOS-independent mechanisms of protection. and backcrossing experiments between Swiss and C57BL
A proposed alternative pathway involves LRG‑47, a strains, that genetic factors influenced the response of mice
phagosomal protein involved in autophagy. A deficiency to infection with Mtb (74). F1 hybrids between the two
in LRG‑47 caused early mortality similar to that of IFN‑γR1 strains exhibited over dominance, with F1 mice surviving
knockout mice, outlining a role for LRG-47 in the defense longer than either parent strain. Informative backcross
against Mtb infection (66). [F1 × C57BL] progeny resolved into two populations,
Evidence for Th1-cell mediated protection against Mtb resistant or susceptible, suggesting a major gene effect
also arose from studies involving interleukin-12 [IL-12] segregating in this cross. Thus, the authors concluded that
knockout mice. Mouse strains with a double disruption of susceptibility to TB in the mouse was a complex trait under
IL‑12p35 and IL-12p40 [IL‑12p70-deficient] were susceptible multigenic control.
to a low dose aerosol Mtb infection and succumbed within Modern genetic studies have confirmed that susceptibility
10 weeks. IL‑12p70-deficient mice did not mount Th1 and to TB is under complex genetic control in the mouse. The first
cytotoxic T cell responses, resulting in severe lung pathology. of these studies utilised the I/St and A/Sn mouse strains. The
These mutant mice exhibited greater susceptibility to Mtb I/St mouse strain is particularly susceptible to Mtb infection
compared to mice lacking only one of the two subunits (67). compared to A/Sn mice with regard to survival time,
Mice lacking the IL-12p40 subunit were more susceptible bacterial load, lung pathology and body weight loss (75).
than IL‑12p35−/− mutant mice, as evidenced by increased The genetic basis for the differential susceptibility of I/St
bacterial burden, reduced IFN‑γ production, and decreased and A/Sn was investigated by whole genome scanning
survival time (68,69). using weight loss as a proxy for TB susceptibility. Initial
Given that Th1 cells antagonize Th2 cell functions, it was mapping studies in an informative [A/Sn × I/St] × I/St
proposed that the absence or reduction of Th1 immunity in backcross indicated that weight loss induced by intravenous
 Genetics of Susceptibility to Tuberculosis 95

Mtb H37Rv infection was controlled by two major loci with resistance at each locus (82). A second genome scan
on chromosomes 3 and 9 and two suggestive loci on analysed pulmonary replication in [C57BL/6J × DBA/2J]
chromosomes 8 and 17 in female mice (76). Suggestive F2 mice 90 days following low dose aerosol infection.
loci in male mice were localised to chromosomes 5 and Strong linkage was detected on chromosome 19 designated
10. A limited genome scan using weight loss and survival TB resistance locus-4 [Trl-4] and suggestive linkages were
time as quantitative phenotypes in [A/Sn × I/St] F2 localized to the Trl-3 region as well as chromosomes 5 and
mice confirmed the loci that mapped to chromosome 3 10. A strong additive effect was detected between Trl-3 and
[designated TB severity 1, tbs1], chromosome 9 [tbs2] and Trl-4 such that F2 mice homozygous for one parental allele
chromosome 17 in proximity to the H‑2 complex (77). at both loci had lung bacillary loads comparable to that
The effect of the H-2 locus has been attributed to a coding parental strain (83). The genetic effect of Trl-3 and Trl-4
mutation in the Tnfa gene of the susceptible I/St strain. This was further investigated using congenic strains. Transfer
polymorphism results in a larger secretion of TNF, which
of a C57BL/6J-derived, Trl-3 chromosome 7 segment onto
is speculated to contribute to the susceptibility of I/St mice
a DBA/2J genetic background [D2.B6-Chr7] increased
by increasing lung pathology (78). The genes responsible for
resistance to Mtb infection as evidenced by the decreased
the tbs1 and tbs2 loci remain unknown.
The C3HeB/FeJ strain is exquisitely susceptible to Mtb. pulmonary load and longer survival time. In contrast, D2.B6-
Premature death in C3HeB/FeJ mice is associated with Chr19 congenic mice harboring a C57BL/6J-derived, Trl-4
progressive lung disease characterised by increased chromosome 19 segment did not have an altered resistance
bacterial loads, extensive pneumonitis, and necrotic lesions. to Mtb infection relative to DBA/2J mice (84). This finding
Classical linkage studies in [C3HeB/FeJ C57BL/6J] F2 mice suggests that the effect of Trl-4 involves genetic interactions
intravenously infected with Mtb Erdman identified a major with other unknown loci, further illustrating the genetic
locus on chromosome 1 designated locus for susceptibility to complexity of susceptibility to TB.
TB 1 [sst1] (79). Congenic C3HeB/FeJ mice bearing a resistant
C57BL/6J-derived allele of sst1 [C3H.B6-sst1] survived GENETIC STUDIES IN HUMAN POPULATIONS
two times longer and had a 50–100-fold lower pulmonary
bacterial burden compared to the parental C3HeB/FeJ Mendelian Susceptibility to Mycobacterial Disease
strain. Explanted bone-marrow derived macrophages from [OMIM 209950]
C3H.B6-sst1 mice had an enhanced ability to restrict intra­ Mendelian susceptibility to mycobacterial disease is a rare
cellular replication of Mtb and induced apoptosis following
inherited condition represented by selective susceptibility
infection, whereas phagocytes from C3HeB/FeJ died by
to clinical disease caused by poorly virulent mycobacteria,
necrosis. A positional cloning strategy identified intracellular
such as BCG vaccines and nontuberculous mycobacteria
pathogen resistance 1 [Ipr1] as a strong candidate for sst1.
[NTM], in otherwise healthy patients without obvious
The Ipr1 encodes the interferon-induced protein 75 [Ifi75],
a putative transcriptional regulator. Mtb infection induced defects (85,86). The patients are also vulnerable to the more
expression of Ipr1 in the lungs of C3H. B6-sst1 mice and virulent Mtb (87,88) and approximately half also suffer from
other C3H strains but not in susceptible C3HeB/FeJ mice. clinical disease caused by Salmonella (89,90).
Restoration of a full-length Ipr1 in C3HeB/FeJ mice limited Seven autosomal genes have been found to be mutated
Mtb replication in the lungs of mice and in macrophages in patients with the syndrome: IFN-γ-receptor 1 [IFNGR1]
infected in vitro, confirming that Ipr1 was the gene and IFN-γ-receptor 2 [IFNGR2], which encodes the accessory
underlying sst1 (80). However, resistance and susceptibility chain of IFN-γ-receptor [IFN-γR]; STAT1, encoding signal
alleles of sst1 are not sufficient to confer full protection or transducer and activator of transcription 1; IL12B, encoding
susceptibility in congenic mice, indicating that genes outside the p40 subunit of IL-12 and IL-23; IL12RB1, encoding the β1
of sst1 also contribute to the phenotype of the C3HeB/FeJ chain common to the receptors for IL-12 and IL-23; interferon
and C57BL/6J parental strains. Indeed, a genome-wide regulatory factor 8 [IRF8], a transcription factor inducible
scan in sst1-adjusted crosses [C3H.B6-sst1 × C57BL/6J F2 by IFN-γ, from the interferon regulatory factor [IRF] family;
hybrids] identified four loci which mapped to chromosomes and ISG15, an IFN-γ-inducing molecule that acts in synergy
7, 12, 15 and 17, which overlaps the H-2 complex (81). The with IL-12. Also, two X-linked genes, NEMO, encoding
molecular identities of the loci on chromosomes 7, 12 and the nuclear factor-kappa B [NF-κB] essential modulator,
15 are currently unknown. which mediates signalling in the NF-κB pathway, and
A genetic study of TB susceptibility/resistance was also cytochrome B-245, beta polypeptide [CYBB], encoding the
performed using susceptible DBA/2J and resistant C57BL/6J major component of the phagocyte nicotinamide adenine
mouse strains. A genome-wide scan for loci affecting dinucleotide phosphate [NADPH] oxidase [PHOX] complex
survival time following intravenous Mtb H37Rv infection are MSMD genes (91). Interestingly, all nine MSMD-causing
was conducted in [C57BL/6J × DBA/2J] F2 hybrids. Two genes participate in IFN-γ-mediated immunity, controlling
significant loci were detected on chromosomes 1 and 7, response to [IFNGR1, IFNGR2, STAT1, IRF8, CYBB],
designated TB resistance locus-1 [Trl-1] and TB resistance or the production of [IL12B, IL12RB1, IRF8, ISG15, NEMO]
locus-3 [Trl-3], respectively. A third suggestive locus TB IFN-γ (91).
resistance locus-2 [Trl-2] was identified on chromosome 3. The extent to which cases with rare Mendelian mutations
Homozygosity for C57BL/6J-derived alleles was associated contribute to TB in areas of endemicity is unknown (92,93).
96 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

However, three children with loss of function mutation in IFNGR1

IL12RB1 were found to suffer from severe forms of TB (94).
No associations were found in a Gambian population
Moreover, sequencing of IL12RB1 in 50 children with severe
between IFNGR1 polymorphisms, including one variant
TB led to the discovery of two cases with IL12RB1 loss of
previously found associated in a Croatian population (103),
functional alleles. This result supports the suggestion that
and adult pulmonary TB (104). Two SNPs in the IFNGR1
possibly a substantial proportion of severe childhood TB
promoter region [G611A, T56C] influence expression
may arise from monogenic defects (94). Indeed, TB as only
but were not associated with increased susceptibility to
infectious disease has been described for 4 of the 9 MSMD
pulmonary or disseminated NTM infection (93). By contrast,
loci (95).
homozygosity at the -56 SNP [rs2234711] for the C-allele
was a risk factor for TB in West Africa (105). This finding
CANDIDATE GENES
was replicated in an independent sample from Kampala,
Interleukin-12/Interleukin-23/Interferon-γ Uganda (106). In Uganda, the same SNP was associated
[IL-12/IL-23-IFN-γ] Pathway with Mtb culture filtrate triggered production of TNF (106).
In a meta-analysis, no significant association between
While the phenotype-genotype relationship for IFN- the IFNGR1 -56C/T polymorphism and TB susceptibility
γ-mediated immunity against mycobacterial disease is was detected (107). However, IFNGR1 -56C/T is possibly
relatively well-defined, the significance of genetic variation associated with increased TB risk in Africans, but not in
in the IL-12/IL-23-IFN-γ pathway at the population level is Asians or Caucasians (107).
less well understood.
Interferon-γ
IL12RB1
The IFN-γ is a major TB susceptibility candidate gene
Numerous sequence polymorphisms have been described considering the importance of IFN-γ-mediated immunity in
for IL12RB1 (96). The two most common haplotypes of MSMD and in animal models of TB. Two genetic variations
the IL12RB1 gene found in many populations are: ‘QMG’ are known to affect expression of IFNG: The first [rs3138557] is
and ‘RTR’, which are derived from the amino acids a polymorphic CA repeat, where allele #2 [12 repeats] drives
substitutions p.Q214R, p.M365T and p.G378R (96,97). The high IFN-γ production when cells are stimulated (108-110).
QMG haplotype is a better responder to IL-12 than RTR (97). The T-allele of the second SNP in intron 1 [rs2430561,
Several IL12RB1 polymorphisms were reported to be +874T/A] is in strong linkage disequilibrium [LD] with allele
associated with increased susceptibility to TB disease. In two #2 of the CA repeat (111). The +874T/A SNP is located in an
small samples of Japanese TB patients the frequencies of the NF-κB binding site. The T-allele promotes while the A-allele
QMG and RTR haplotypes were analysed, and carriage of reduces NF-κB binding and thus prevents IFN-γ expression
the homozygous RTR haplotype was found to increase the in response to stimuli (111). The rs2430561 SNP is associated
risk of TB (98,99). Nine common polymorphisms, including with various diseases like hepatitis (112-114), leprosy (115)
two polymorphisms of the QMG/RTR haplotypes, were and TB (6,109,110,116-120). In contrast, no association was
analysed in a Morrocan family-based study. A modest identified between IFNG and TB in TB patients from the
association with pulmonary TB was detected in two variants Karonga district of northern Malawi (121), Texas (122),
in the 5′ untranslated region of the gene (92). However, this Brazil (123) and Croatia (124).
association has not been replicated in two ethnically distinct
populations (92,98,99). Solute Carrier Family 11, Member 1
Solute carrier family 11A, member 1, [SLC11A1], earlier
IL12B called natural resistance-associated macrophage protein 1
A strong association between an IL12B intron 2 genetic [NRAMP1] is the human homologue of the mouse Nramp1
variant and TB susceptibility was identified in a case-control gene, which serves as a divalent cation pump across
study of Hong Kong Chinese TB patients. Homozygous phagosomal membranes (125,126). Nramp1-altered cation
carriers of the [ATT] 8 repeat variant had a 2.14-fold fluxes are thought to abrogate pathogen-induced blockage
increased risk of developing TB (100). The effect of IL12B of phagosome maturation (127-129). Initially Slc11a1
polymorphisms on TB susceptibility may strongly depend [Nramp1] was identified in mice as a regulator of resistance
on the ethnic background of the study population. When to intracellular pathogens, and absence of mature Nramp1
studying samples of African and European ethnicity multiple protein resulting from the G169D polymorphism causes
association signals were characteristic for samples of African increased susceptibility to several intracellular macrophage
ancestry (101). By contrast, in a recent meta-analysis, pathogens, including BCG, Salmonella typhimurium, and
no significant associations were observed for the IL12B Leishmania donovani (130,131).
promoter variant [rs17860508] and the 3’ UTR A/C variant Polymorphisms within the human SLC11A1 gene have
[rs3212227] (102). However, the C allele of the IL12B 3’ UTR been associated with TB in numerous studies (121,132-146).
may be a TB risk factor in Caucasians but not in Asians or However, other studies failed to detect an SLC11A1-
Africans (102). TB association (147-150) providing strong evidence for
 Genetics of Susceptibility to Tuberculosis 97

genetic heterogeneity in TB susceptibility. Because of this Since vitamin D exerts its effects via the VDR and
heterogeneity it has been suggested that SLC11A1 accounts the recep­tor is present on monocytes and lymphocytes a
for only a small proportion of the total genetic contribution to possible role of VDR genetic variants in TB susceptibility has
TB susceptibility (5,151). An alternative explanation has been been studied (160). Of the 22 SNPs in the VDR gene, those
provided by a genetic study of TB susceptibility in a native associated with TB susceptibility are the polymorphisms
Canadian community (152). A potent genetic effect [relative at the restriction sites Fok1, Apa1, Taq1, and Bsm1 (7,161).
risk of 10] of the SLC11A1 region on TB was only detected Of these, the 3′ UTR region SNPs Apa I, Bsm I and Taq I
when gene-environment interactions were included into are assumed to affect messenger RNA [mRNA] stability,
the analysis (152). Since the subjects in the Canadian study thus yielding variation in VDR activity (162,163). The
suffered from primary TB, a successful replication study minor alleles for Fok1, Apa1 and Bsm1 and the major
was conducted in a pediatric TB sample from Texas (142). allele for Taq1 have been implicated in diminished VDR
A major conclusion from this study was that NRAMP1 is not function associated with TB (161). TaqI SNP [rs731236]
a TB per se susceptibility gene but rather increases the speed in exon 9 is the best known polymorphism of the VDR
of progression from infection to clinical disease. gene (164). This SNP affects transcription and reduced VDR
Several studies aimed to establish a causal relationship function (165). A number of studies across various ethnic
between SLC11A1 variants and increased TB susceptibility. populations have investigated the relationship between
The first study investigated the 5’ [CA] repeat allele that is TaqI polymorphism and TB risk but yielded inconsistent
associated with increased TB risk. Employing a whole blood results (7,39,133,137,166-182). A possible explanation for
assay the risk allele also directed higher lipopolysaccharide these inconsistencies is that the genetic effect of VDR
[LPS]-induced production of the anti-inflammatory cytokine polymorphisms is dependent on serum vitamin D levels (7).
IL-10 (153). Since mouse Slc11a1 is expressed at the
macrophage phagosomal membrane and its activity can be Human Leucocyte Antigen
assayed by the relative acquisition of mannose 6-phosphate Since the 1970s (183), classical HLA loci have been recognized
receptor [M6PR] in Salmonella-containing vacuoles (127), as leading candidates for infectious disease susceptibility.
it was reasoned that recruitment of M6PR could be used to The extreme variability at the HLA loci was proposed
gauge the functional activity of NRAMP1 in human cells. to result from infectious diseases as the major selective
Indeed, M6PR acquisition was significantly higher in human force (184-186). Various attempts have been made to
U-937 monocytic cell lines expressing SLC11A1 as compared establish the association between HLA and TB susceptibility.
to non-expressing cells. Employing MDMs from paediatric Two genome-wide linkage scans of pulmonary TB in
TB patients, a significantly lower SLC11A1 activity was Africa (30,31) failed to detect a significant linkage signal at
detected in MDMs from individuals homozygous for the HLA, while weak association [p = 0.0017] with the HLA-DQ
SLC11A1 274C/T [rs2276631] high-risk allele in comparison region was detected in a large GWAS for TB (187). There
to heterozygous individuals (154). are more targeted studies investigating a possible role of
Class II as compared to Class I alleles (188). Association of
Vitamin D Receptor HLA-DR and HLA-DQ alleles was reported in samples from
Vitamin D3 is a major mediator of macrophage activity India (189), Korea (190), South Africa (172), Indonesia (191),
in response to pathogens such as Mtb (47). Prior to the China (192) and Cambodia (193). However, the specific alleles
discovery of antibiotics, vitamin D-rich cod liver oil was implicated were inconsistent and varied among populations.
used as therapy for TB patients (155). TLR-1/2 stimulation For example, a number of studies reported asso­ciations
of human macrophages by Mtb induces the expression of HLA-DR2 alleles (194-196), HLA-DQB1* 0501 (196),
of vitamin D receptor [VDR] and the enzyme CYP27B1, and HLA-DQB1*0503 alleles (197) with TB, while others
which catalyses the conversion of 1,25 [OH] vitamin D3 to failed to detect those associations (198,199). More detailed
functional studies led to the conclusion that specific alleles
1,25[OH]2 vitamin D3, which is the biologically active form.
at the HLA_DRB1 and HLA_DQB1 genes modulate the
1,25[OH]2D3 is an essential immunoregulatory molecule
human immune response to TB (193,200).
that participates in various immune processes: activating
monocytes and cell-mediated immunity, controlling the Th1-
Th2 host immune response, phagocytosis, and suppressing Mannose-binding Lectin
lymphocyte proliferation, immunoglobulin production and Secreted by the liver, mannose-binding lectin [MBL] is
cytokine synthesis. In vitro, 1,25[OH]2D3 limits the growth an acute-phase protein that is instrumental in innate
of Mtb in human macro-phages (156,157). Additionally, immunity. MBL recognises microbial surface carbohydrates,
data from epidemiologic studies indicate a link between a particularly mannose- and N-acetylglucosamine-terminated
higher risk of TB and vitamin D defi-ciency (31,158). This is glycoproteins. Intracellular pathogens, such as Mtb, partially
supported by reports of lower vitamin D serum levels and exploit the complement system to invade and replicate
seasonal variation of TB incidence in untreated TB patients within host cells. By binding to the mannose residues in
comparing to higher incidence of TB in individuals with the LAM covering Mtb (201,202). MBL acts as an opsonin,
relatively low serum vitamin D levels (7,159). augments both complement-dependent and -independent
98 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

phagocytosis, and promotes inflammation with the release Genome-wide Association Scans
of cytokines (203,204). The impact of MBL2 alleles on TB
So far 4 GWAS in TB have been conducted. A first GWAS
susceptibility is inconsistent. Studies in South African,
Gabonese, Danish, Italian, Indian, Turkish, Brazilian, Chinese on pulmo­n ary TB was conducted on two case control
and African-American populations showed significant asso­ samples from Ghana and Gambia (187). Of the 17 SNPs
ciations between MBL2 genetic variants encoding low serum associated with P less than 5 × 10-5 only rs4331426 located
MBL levels and protection against active TB (131,205-212). in gene desert on chromosome region 18q11.2 reached
However, these results could not be replicated in studies in genome-wide significance after genotyping in additional
Caucasian American, Tanzanian, Malawi, and the Polish TB samples from Ghana and Malawi. The chromosome 18 locus
patients (121,138,207,213,214). was replicated in sample of Han Chinese TB patients (221).
Following imputation of a large number of additional SNPs
Genome-wide Linkage Studies in the Ghanaian discovery sample, a TB protective locus
was identified on chromosome region 11p13. The signal
Similar to candidate gene studies, results across genome-wide comprised three highly correlated SNPs located 45 kb
linkage studies have been inconsistent. In 2000, a study (31) downstream of the Wilms’ tumour 1 [WT1] gene of which
was performed in sib-pairs with TB from Gambia and South one was located in a transcription factor binding site. The
Africa. The authors conducted a two-stage genome-wide main protective SNP allele replicated well in the Gambian
linkage study to search for regions of the human genome sample, but displayed borderline evidence for association
containing TB-susceptibility genes. Suggestive evidence in independent samples from Indonesia and Russia (222).
of linkage was found in chromosomes 15q and Xq (31). A GWAS in Thai and Japanese samples detected a TB
However, the genes causing the linkage peak could not be
risk locus on chromosome region 20q12 after stratification by
identified. A genome scan for TB in a Brazilian population
age (223). Replication in additional samples is outstanding.
identified four regions with suggestive evidence for linkage:
A low marker density SNP was conducted in a sample
10q26.13, 11q12.3, 17q11-q21, 20p12.1 (32,215) without
from Indonesia (224). The results suggested the possible
resulting in the identification of a susceptibility gene.
contribution of SNPs in the vicinity of several immune
Using a combined genome-wide and positional mapping
signalling genes but need to be replicated in a larger study.
approach, the melanocortin 3 receptor [MC3R] and cathepsin
Z [CTSZ] genes were identified as TB susceptibility candidate A fourth GWAS was conducted in the admixed South
genes (216). A genome-wide linkage study conducted in African coloured population residing in the Western Cape
Moroccan multiplex families with pulmonary TB detected region (225). While the study failed to detect any markers
a susceptibility locus on chromosome 8q12-q13 (30). with genome-wide significance, the chromosome 11 TB
Association scanning of the linkage peak identified SNPs in protective locus previously identified in the West African
the promoter region of the thymocyte selection-associated samples was con­firmed (222). The study (222) demonstrated
high mobility group box [TOX] gene as susceptibility factor the value of genetic studies in admixed populations and
for early onset pulmonary TB (27). established the locus on chromo­some 11 as universal TB
Two studies used resistance to infection by Mtb as protective factor in African populations.
phenotype. Resistance to infection was defined as persistently Genetic studies have contributed to the discovery of
negative tuberculin skin test [PTST]. In a genome scan of Mtb specific genes and immune pathways involved in anti-TB
infection and disease in Ugandans (217), suggestive linkage immunity. However, it is clear that a large proportion of
was observed on chromosome regions 2q21-2q24 and 5p13- the genes involved in genetic susceptibility remain to be
5q22 for PTST (217). Nominal evidence for linkage of PTST discovered. This will require carefully planned studies
was also observed at the SLC11A1 [alias NRAMP1] gene. with well-defined disease phenotypes (226). Furthermore,
A second genome-wide linkage analysis identified two the contribution of rare genetic variants and epigenetic
loci relating to TST reactivity in 128 families from South factors to TB risk deserves attention and replicated genetic
Africa (218). The locus on chromosome region 11p14, associations with TB phenotypes need to be followed-up
termed TST1, controls TST = 0 mm versus TST greater than for their functional relevance. Only by linking genetic risk
0 mm, while a second locus on chromosome region 5p15, factors to biological functions will it be possible to fully
termed TST2, impacts on extent of TST reactivity. The exploit genetic results for improved tools of patient care and
most parsimonious explanation for individuals remaining disease control.
TST negative despite documented exposure is that they
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DQB1 alleles and haplotype frequency in Iranian patients with Mugerwa RD, et al. Genome scan of M. tuberculosis infection
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 Genetics of Susceptibility to Tuberculosis 105

218. Cobat A, Gallant CJ, Simkin L, Black GF, Stanley K, Hughes J, 222. Thye T, Owusu-Dabo E, Vannberg FO, van Crevel R, Curtis J,
et al. Two loci control tuberculin skin test reactivity in an Sahiratmadja E, et al. Common variants at 11p13 are associated
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219. Cobat A, Poirier C, Hoal E, Boland-Auge A, de La Rocque F, Wattanapokayakit S, Phromjai J, et al. Genome-wide association
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 8
Laboratory Diagnosis of Tuberculosis:
Best Practices and Current Policies
Madhukar Pai, Marzieh Ghiasi, Kavitha Saravu

INTRODUCTION Role of Immunological Tests

Despite the progress made in tuberculosis [TB] control, Figure 8.1 shows the available immune-based tests for
the World Health Organization [WHO] estimated that TB and their recommended use. The following tests are
10 million people developed TB in 2017, and 1.3 million not recommended for active TB diagnosis: serological,
died (1). In 2014 [updated data as per WHO 2015], over antibody-based tests, such as enzyme-linked immune
3.6 million cases were considered ‘missing,’ either because sorbent assay [ELISA] or rapid immunoglobulin G [IgG],
they were not diagnosed, or not notified to any national TB immunoglobulin M [IgM] tests, and inter­feron-gamma
programme. India accounts for 1 of the 3 million missing release assays [IGRAs] such as QuantiFERON TB Gold and
cases, and accounts for 25% of the global incident cases. TB Platinum. Serological antibody tests are discoura­ged
A recent systematic review has shown that a TB patient in by the WHO, and banned by the Government of India. As
India, on an average, faces a delay of nearly two months with the tuberculin skin test [TST], IGRAs are meant for
and visits to three healthcare providers before a diagnosis is LTBI detection, and are not recommended for active TB
made (2). Thus, diagnostic delays are common in the Indian diagnosis (7).
context. Furthermore, a majority of Indian TB patients do not
get tested for drug-resistance. Early and accurate diagnosis Role of Chest Radiology
followed by rapid treatment is critical to break the cycle of
Chest radiographs are an invaluable adjunct in the diagnosis
transmission. The purpose of this chapter is to provide a
and follow-up of TB. The sensitivity of the chest radiograph
summary of the best practices for diagnosis of active TB,
is high, but non-TB conditions may look like TB. Thus, chest
drug-resistance, and latent TB infection [LTBI].
radiographs do not have high specificity, and so remain a
supplement to microbiological tests, such as, microscopy,
DIAGNOSIS OF ACTIVE TUBERCULOSIS polymerase chain reaction [PCR] and culture. Treatment of
TB purely on the basis of radiological findings can result in
Active TB is a microbiological diagnosis, and every attempt
significant over-treatment with adverse consequences and
should be made to get a bacteriological confirmation using
additional costs for patients. Therefore, all persons with chest
a correct clinical specimen. According to the International
radiographic findings suggestive of TB, should have sputum
Standards for TB Care [ISTC], all persons with cough lasting
specimens submitted for microbiological examination.
two weeks or more, or with abnormal chest radiographs
should be evaluated for TB (3). All persons with previous
Sample Collection Methods
history of TB treatment or with treatment failure must
undergo drug-susceptibility testing [DST]. There are three Quality of samples can affect test results, and every effort
methods that are recommended for the microbiological should be made to ensure quality in specimen collection,
diagnosis of active TB disease [Table 8.1] (4-6). These are: transport and processing. Table 8.2 provides a summary of
[i] smear microscopy; [ii] nucleic acid amplification tests the samples required for the diagnosis of various types of
[NAAT]; and [iii] liquid cultures. TB (8). For pulmonary TB, sputum is the most important
 Laboratory Diagnosis of Tuberculosis: Best Practices and Current Policies 107

Table 8.1: Methods recommended for diagnosis of active TB

WHO policy
Technology WHO-endorsed tests Advantages Limitations recommendations
Smear microscopy: LED fluorescence Rapid, inexpensive Sensitivity is modest At least two sputum
visualisation of acid-fast microscopy and widely available [50%-70%], specificity is samples, stained with
bacilli under microscope technology; can rapidly very high [>98%]; cannot a fluorescence stain,
identify infectious cases detect drug-resistance, and read by a trained
and cannot distinguish microscopist using
between Mtb and NTM LED microscopy, in a
laboratory participating in
EQA (4)

NAAT: molecular tests that Xpert MTB/RIF, based on Rapid, 2-hour test. Used Cost and limited Xpert MTB/RIF may
amplify DNA/RNA targets the GeneXpert technology for detection as well as availability at be used rather than
specific to Mtb [Cepheid Inc, USA] DST. Has a sensitivity decentralised or conventional microscopy
88% and specificity peripheral labs. NAAT and culture as the initial
98% when compared cannot be used to monitor diagnostic test in all adults
to culture; sensitivity of treatment response and children presumed
68% in smear-negative to have TB. If this is not
cases. Can detect possible because of
rifampicin resistance with resource constraints,
a sensitivity of 95% and Xpert should be used
specificity of 98% rather than conventional
microscopy, culture
and DST as the initial
diagnostic test in adults
and children presumed to
have MDR-TB or HIV-
associated TB (5)
Liquid cultures: detects BACTEC MGIT® 960 Used for detection as well Reliability of second-line Liquid culture and DST
growing colonies of Mtb in [Becton Dickinson, USA], as DST. Gold standard DST is limited. High cost is a key part of the
liquid media and BacT/ALERT 3D for active TB diagnosis and limited availability are diagnostic algorithm and
[bioMerieux, France] [highest sensitivity]. Can other limitations should be routinely used
provide results within in all patients with history
10-14 days, and MGIT of previous TB treatment
can provide phenotypic or treatment failure. Liquid
DST results for first-line culture is also of help in
and select second-line paucibacillary TB cases
drugs [EPTB, smear-negative
TB, and childhood TB] (6)
TB = tuberculosis; WHO = World Health Organization; LED = light-emitting diode; EQA = external quality assurance; NAAT = nucleic acid
amplification tests; DNA = deoxyribonucleic acid; RNA = ribonucleic acid; DST = drug-susceptibility testing; MDR-TB = multidrug-resistant TB;
HIV = human immunodeficiency virus; Mtb = Mycobacterium tuberculosis; NTM = nontuberculous mycobacteria; MGIT = mycobacteria growth
indicator tube; EPTB = extra-pulmonary tuberculosis

sample for laboratory testing. Although peripheral venous Diagnosis of Extra-pulmonary TB

blood is a popular sample in the Indian private sector, there
is no accurate blood test for active TB. For extra-pulmonary The ISTC emphasises the importance of seeking micro­
TB [EPTB], it is important to obtain specimens from the biological and histopathological diagnosis of EPTB, and
site of disease, and this usually includes collection of tissue emphasises the need for collecting appropriate samples.
[biopsy] and/or body cavity fluids from the suspected ISTC recommends that all patients, including children, who
disease site. For childhood TB diagnosis, sputum can usually are suspected of having EPTB, should have appropriate
be collected from older children. In younger children, fasting specimens obtained from the suspected sites of involvement
gastric aspirates can be collected. In all the above situations, for microbiological and histological examination. In clinical
clear instructions on specimen collec­tion should be provided practice, this will mean collection of samples such as body
to patients as well as to laboratories and clinics. fluids [cerebrospinal, pleural, ascitic fluid], lymph node
 108 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 8.1: Immune-based TB tests and recommendations on their use

Ig = immunoglobulin; TB = tuberculosis; ELISA = enzyme-linked immunosorbent assay; PPD = purified protein derivative; WHO = World Health
Organization; LTBI = latent tuberculosis infection

and other tissues [e.g., endometrial tissue], and aspirates very least, all patients with history of previous TB treatment,
[e.g., gastric aspirate]. Since no single test has high accuracy, treatment failure or recurrence must undergo DST.
it is important to perform microbiological [e.g., NAAT or DST can be done using two methods: genotypic and
cultures] as well as histo­pathological investigations. pheno­typic. Genotypic methods are based on molecular
Several recent studies and the WHO have endorsed the tests that detect mutations that confer drug-resistance.
use of Xpert MTB/RIF® for TB meningitis, lymphadenitis, For example, mutations in the rpoB gene of Mtb are
and pediatric TB [gastric aspirates] (5,9,10). In 2016, Xpert strongly associated with rifampicin resistance. Examples
MTB/RIF® should be considered a central test in the work- of genotypic tests include Xpert MTB/RIF, and Hain
up of EPTB, and should be used along with existing tools, Genotype MTBDRplus {commercial line probe assay
such as, microscopy, liquid cul­tures which are the most [LPA]}. Phenotypic methods are based on detection of
sensitive technologies for detection of Mycobacterium culture growth with and without TB drugs added to the
tuberculosis [Mtb], and histopathology [biopsy] to arrive at the culture media. Phenotypic methods include solid and liquid
final diagnosis (11). Table 8.3 shows the data on accuracy of cultures. While solid cultures can take up to two months,
Xpert MTB/RIF® for EPTB, and the WHO recommendations liquid cultures can produce useful results within two weeks.
on how it should be used (12). It is important to note that According to ISTC, DST should be performed at the start
Xpert MTB/RIF® does not have high sensitivity for pleural of therapy for all previously treated patients (3). Patients
samples. So, pleural biopsy and cultures are important tools who remain sputum smear-positive at completion of the
for TB pleuritis. intensive phase of treatment and patients in whom treatment
In addition to Xpert MTB/RIF, there is a role for non- has failed, have been lost to follow-up, or relapsed following
specific biomarkers such as adenosine deaminase [ADA] one or more courses of treatment should always be assessed
and unstimulated [free] interferon-gamma [IFN-γ] in sterile for drug resistance. For patients in whom drug resistance is
fluids such as pleural, peritoneal and ascitic fluid (13). These considered to be likely, an Xpert MTB/RIF® test should be
biomarkers can be used in combination with microbiological the initial diagnostic test, as per the WHO policy. LPA or
and histopathological investigations. liquid culture and DST to at least isoniazid and rifampicin
should be performed promptly if rifampicin resistance is
detected. If multidrug-resistant TB [MDR-TB] is detected,
Drug Susceptibility Testing
DST to second-line anti-TB drugs especially fluoroquinolones
The WHO recently announced the post-2015 “End TB and injectable drugs is required for correct management.
Strategy” (14). A key component of this strategy is the push For DST, both the WHO and ISTC recommend Xpert
towards ‘univer­sal DST’ which means that all TB patients MTB/RIF® test as the initial diagnostic test because it can
should get a DST done at the time of their diagnosis. At the rapidly detect rifampicin resistance within 90 minutes with
 Laboratory Diagnosis of Tuberculosis: Best Practices and Current Policies 109

Table 8.2: Samples for TB detection

Site, purpose, or patient population Specimen of choice Comments
Active, pulmonary TB Sputum [spontaneous or induced] Sputum must be produced deep from within the lungs
Saliva is not acceptable
At least two sputum samples must be collected
Blood is not acceptable as a sample for active, pulmonary TB
Rarely, BAL fluid is used to collect lung secretions—this requires
expertise and hospital care
Active, extra-pulmonary TB Lymph node aspirate or biopsy Requires needle aspiration and/or excision biopsy
TB lymphadenitis Samples are then sent for smears for AFB, liquid culture,
molecular [PCR] tests, and histopathological examination
Histopathology and liquid culture are the most important tests;
PCR may help, if positive
TB pleural effusion Pleural fluid and pleural biopsy Requires pleural tap and/or biopsy
Samples are then sent for pleural fluid analysis, smears for
AFB, liquid culture, molecular [PCR] tests, and histopathological
examination; pleural fluid ADA or interferon-gamma is often helpful
Histopathology and liquid culture are the most important tests;
PCR may help, if positive
Peritoneal TB Ascitic fluid and peritoneal biopsy Requires ascitic tap and/or biopsy
Samples are then sent for smears for AFB, ascitic fluid analysis,
liquid culture, molecular [PCR] tests, and histopathological
examination; ascitic fluid ADA or interferon-gamma is often helpful
Histopathology and liquid culture are the most important tests;
PCR may help, if positive
TB meningitis CSF Requires spinal tap for CSF collection
Samples are then sent for smears for AFB, CSF analysis, liquid
culture, molecular [PCR] tests; CSF fluid ADA or interferon-gamma
may be helpful
Liquid culture of CSF along with CSF analysis is most important;
PCR may help, if positive
Bone and joint TB Bone/synovial tissue via biopsy Histopathology and liquid culture are the most important tests;
PCR may help, if positive
Urinary tract and kidneys Urine and tissue via biopsy First voided morning urine sample; histopathology and liquid
culture are the most important tests; PCR may help, if positive
Genitourinary tract Tissue via biopsy [e.g., Menstrual blood is not ideal; it is important to collect endometrial
endometrial tissue in women] tissue
Histopathology and liquid culture are the most important tests;
PCR may help, if positive
Disseminated TB Additional samples like bone Histopathology and liquid culture are the most important tests;
marrow/ liver biopsy and blood PCR may help, if positive
cultures
Childhood TB Sputum in older children; in Induced sputum may also be an option in older children
younger children, gastric aspirates
Latent TB infection TST or whole blood for IGRAs IGRAs are only meant for latent TB infection—they cannot
separate latent infection from active disease
TST must be correctly performed and read
TB = tuberculosis; BAL = bronchoalveolar lavage; AFB = acid-fast bacilli; PCR = polymerase chain reaction; CSF = cerebrospinal fluid;
ADA = adenosine deaminase; IGRA = interferon-gamma release assay; TST = tuberculin skin test
Adapted from reference 8

high accuracy, and allow clinicians to initiate empiric MDR- Mycobacterial culture [solid/liquid] remains the gold
TB therapy, pending confirmation with cultures (3,5). LPA standard for the diagnosis of TB. In addition, for EPTB, a
[e.g., Hain Genotype MTBDRplus] or liquid culture and DST composite reference standard [CRS] is used for diagnosis.
should then be performed promptly if rifampicin resistance The CRS includes parameters like smear for acid-fast bacilli,
is detected using Xpert MTB/RIF®. Once culture and DST myco­bacterial culture, histopathology and cytology reports
results are obtained, MDR-TB therapy can be customised to [for biopsy samples and aspirates, respectively], organ
the patient’s drug-susceptibility profile, and must include a system specific ancilliary diagnostic tests and response to
combination of at least 5 drugs to which the TB bacilli are treatment during follow-up visits. For DST, solid culture
still sensitive. The algorithm for DST is shown in Figure 8.2. and phenotypic testing remains the gold standard.
 110 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 8.3: Accuracy of Xpert for EPTB samples and the WHO recommendations on how Xpert MTB/RIF should
be used in each sample type
Sensitivity Specificity
[compared to [compared to
Sample culture] [%] culture] [%] 2013 WHO recommendations on the use of Xpert MTB/RIF (5)
Cerebrospinal fluid 81 98 Xpert is recommended as an initial diagnostic test in cerebrospinal fluid specimens
for TB meningitis [strong recommendation given the urgency of rapid diagnosis]
Lymph nodes 83 94 Xpert is recommended as a replacement test for usual practice in specific non-
respiratory specimens [lymph nodes and other tissues] for EPTB [conditional
recommendation]
Pleural fluid 46 99 Pleural fluid is a suboptimal sample and pleural biopsy is preferred. While a
positive Xpert result in pleural fluid can be treated as TB, a negative result should
be followed by other tests
Gastric lavage and 84 98 Xpert is recommended as a replacement test for usual practice in specific non-
gastric aspirate respiratory specimens [including gastric specimens] for EPTB [conditional
recommendation]
EPTB = extra-pulmonary tuberculosis; WHO = World Health Organization
Adapted from reference 11; sensitivity and specificity estimates are derived from reference 12

Figure 8.2: Algorithm for DST, based on International Standards for TB Care. Drug resistance must be suspected in all patients with history of
TB treatment in the past. In addition, patients who remain smear-positive at completion of the intensive phase of treatment and patients in whom
treatment has failed have been lost to follow-up or relapsed following one or more courses of treatment should always be assessed for drug-
resistance
RIF = rifampicin; DST = drug-susceptibility testing; MDR-TB = multidrug-resistant tuberculosis; TB = tuberculosis
Source: reference 3

Diagnosis of Latent TB Infection

Most individuals, after exposure to Mtb, contain the infection
using adaptive immune mechanisms, and the infection
remains ‘latent’. LTBI may progress to active TB disease in
about 10% of those with infection, over a lifetime. Rate of
progression to active disease is highest among patients who
are also co-infected with human immunodeficiency virus
[HIV]. Treatment of LTBI [earlier called preventive therapy,
prophylactic treatment] can reduce the risk of progression
to active disease by about 60%. For preventive therapy,
treatment options include 6-9 months of isoniazid, 3-month
regimen of weekly rifapentine plus isoniazid, or 3-4 months
isoniazid plus rifampicin, or 3-4 months rifampicin alone.
Detection of LTBI, followed by treatment, is a useful Figure 8.3: The WHO algorithm for latent TB infection testing and
strategy in specific high-risk groups. According to the management
TST = tuberculin skin test; IGRA = interferon-gamma release assay;
WHO, the following groups should be prioritised for LTBI TB = tuberculosis; LTBI = latent tuberculosis infection; WHO = World
screening: people living with HIV, adult and child contacts Health Organization
of pulmonary TB cases, patients who are to be initiated on Adapted from reference 14
 Laboratory Diagnosis of Tuberculosis: Best Practices and Current Policies 111

anti-tumour necrosis factor [TNF] treatment, patients on income and upper middle-income countries with estimated
dialysis, potential recipients of solid organ or haematologic TB incidence less than 100 per 100,000. The IGRA should
transplantation, and patients with silicosis (15). not replace TST in low-income and other middle-income
The algorithm for the management of LTBI as per the countries (16).
2014 WHO guidelines is shown in Figure 8.3 (14). The It is important to note that there is no diagnostic gold
WHO recom­mends that individuals should be asked about standard for LTBI. Two tests are available currently: the
symptoms of TB before being tested for LTBI. Individuals TST performed using Mantoux technique and the IGRA
with TB symptoms should be investigated further for active [Table 8.4] (16,17). Evidence suggests that both TST
TB using microbiological tests. If TB symptoms are absent, and IGRA are acceptable but imperfect tests (18). These
either TST or an IGRA can be used to test for LTBI in high- represent indirect immunological markers of Mtb exposure

Table 8.4: Comparison of TST with IGRAs

Characteristic TST IGRAs
Potential advantages or Simple, low-tech test IGRAs require fewer visits than TST for test completion
benefits Can be done without a laboratory [follow-up visits will be needed for both tests for initiation
No equipment necessary of LTBI treatment]
Can be done by a trained health worker even in Potential for boosting test response eliminated with IGRA
remote locations IGRA interpretation is objective whereas TST interpre­
Effect of BCG on TST results is minimal if vaccination tation is affected by inter- and intra-reader variation
is given at birth and not repeated IGRA results can be available within 24-48 hours [but are
Longitudinal studies have demonstrated its predictive likely to take longer if done in batches]
value and systematic reviews of randomised trials IGRA does not have cross-reactivity with BCG
show that treatment of LTBI is highly effective in those IGRA has less cross-reactivity than TST with NTM, though
who are TST-positive data are limited in low- and middle-income countries
Risks or undesired effects TST may give false-negative reactions due to IGRA requires a blood draw [which may be challenging in
infections, live virus vaccines, and other factors some populations, including young children]
TST may give false positive results because of BCG Risk of exposure to blood-borne pathogens
vaccination and NTM Risk of adverse events with IGRA may be reduced
Requires an intra-dermal injection compared to TST
Can rarely cause adverse reactions [acute reactions, Interpretation of serial IGRA is complicated by frequent
skin blistering and ulceration] conversions and reversions, and lack of consensus on
Interpretation of serial TST is complicated by boosting, optimum thresholds for conversions and reversions
conversions and reversions Reproducibility of IGRAs is modest and influenced by
TST interpretation is affected by inter- and intra- several pre-analytical and analytical factors
reader variation
TST requires 48-72 hours for a valid result
Values and preferences Patients may prefer to avoid visible reaction to TST Patients may prefer to avoid blood being drawn [for
Patients may prefer not to come back for repeat visit cultural or technical reasons]
for reading the test result Patients with prior BCG may not trust TST results and
Patients with prior BCG may not trust TST results and prefer IGRA
may be reluctant to accept IPT
Patients may self-read their TST results erroneously
Resource implications Less expensive than IGRAs [reagent cost is substan­ Need to establish well-equipped laboratory with
tially less than IGRA kit costs], but personnel time electricity, that can perform ELISA or ELISPOT
costs will have to be factored, along with time and cost Need to procure equipment and supplies for IGRA
for two patient visits performance and quality assurance [IGRA reagents cost
No laboratory required higher than TST reagents]
Need to establish a programme with trained staff to Need for staff training, including blood-borne pathogen
administer and read TST results training
Staff training is needed to minimise reading errors and Need for cold chain for transport of kits and reagents and
variability [under reading, within and between reader for storing them
variability, digit preference, etc.] Need for careful handling [e.g., tube shaking] and
PPD must be stored at optimal temperatures processing of blood samples [sample volume, time to
Only standardised PPD must be used incubation, etc.] to ensure reproducibility
Availability of well-trained staff or staff to be trained
TST = tuberculin skin test; IGRA = interferon-gamma release assay; LTBI = latent tuberculosis infection; BCG = bacille Calmette-Guerin;
NTM = nontuberculous mycobacteria; IPT = isoniazid preventive treatment; ELISA = enzyme-linked immunosorbent assay; ELISPOT = enzyme-
linked immunospot assay; PPD = purified protein derivative
Source: references 20,21
112 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

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2011. Available at URL: http://whqlibdoc.who.int/publications/ 20. Cattamanchi A, Smith R, Steingart KR, Metcalfe JZ, Date A,
2011/ 9789241501613_eng.pdf. Accessed on December 28, 2017. Coleman C, et al. Interferon-gamma release assays for the
5. World Health Organization. Policy update: automated real-time diagnosis of latent tuberculosis infection in HIV-infected
nucleic acid amplification technology for rapid and simultaneous individuals - a systematic review and meta-analysis. J Acquir
detection of tuberculosis and rifampicin resistance: Xpert MTB/ Immune Defic Syndr 2011;56:230-8.
RIF system for the diagnosis of pulmonary and extrapulmonary 21. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D,
TB in adults and children 2013. Available at URL: http://www. Mwansa-Kambafwile J, et al. Predictive value of interferon-
stoptb.org/wg/gli/assets/documents/WHO%20Policy%20 gamma release assays for incident active tuberculosis: a systematic
Statement%20on%20Xpert%20MTB-RIF%202013%20pre%20 review and meta-analysis. Lancet Infect Dis 2012;12:45-55.
publication%2022102013.pdf. Accessed on December 28, 2017. 22. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL,
6. World Health Organization. Use of liquid TB culture and drug Desmond E, et al. Official American Thoracic Society/Infectious
susceptibility testing [DST] in low and medium income settings. Diseases Society of America/Centers for Disease Control and
Summary report of the Expert Group meeting on the use of Prevention Clinical Practice Guidelines: diagnosis of tuberculosis
liquid culture media, Geneva 26 March, 2007. Available at URL: in adults and children. Clin Infect Dis 2017;64:e1-e33.
 9
Roentgenographic Manifestations of
Pulmonary and Extra-pulmonary Tuberculosis
Chandan J Das, Ankur Goyal, Divya Singh

INTRODUCTION the PA view and better visualisation of certain ‘hidden

areas’ [retrosternal, retrocardiac]. Apicogram facilitates
Tuberculosis [TB] continues to afflict large number of people
visualisation of the lung apices that are partially obscured
in the developing countries (1). Human immunodeficiency
in PA view due to bony superimposition. Dual-energy
virus [HIV] infection and acquired immunodeficiency
subtraction radiography can also be employed to remove
syndrome [AIDS] have added fuel to the fire. TB affects all
the overlapping bony shadows. A normal chest radiograph
organ systems; however, lungs are most commonly affected
has a high negative predictive value for active TB. The
and often are the first site of involvement. Imaging plays
frequency of false negative examination is approximately
a pivotal role in screening, diagnosis as well as follow-up
1% in the adult immunocompetent population (2,3) and
during treatment of pulmonary TB.
increases to 7%-15% in HIV-seropositive individuals (4-6).
IMAGING MODALITIES Computed Tomography
While a wide range of imaging modalities are available
Computed tomography [CT] generates multi-dimensional
[Table 9.1], chest radiograph is the first imaging technique
high resolution images and can detect small lesions which
to be sought in patients suspected to have pulmonary TB.
may be missed on radiograph. Miliary nodules in the lungs
can be seen on CT even when the radiograph is normal.
Chest Radiograph The pulmonary lesions are better characterised and disease
Postero-anterior [PA] radiograph of the chest is used as activity is more accurately assessed. In a study from Korea (7),
the initial imaging tool in patients suspected to have TB. it was found that CT gave additional information in
It is an inexpensive, easily-available modality which is 37% cases which had a significant bear­i ng on patient
often sufficient for initial diagnosis and subsequent follow- management. The mediastinum and hila are well visualised.
up. Lateral view may be done to confirm the findings of The size and nature of lymphadenopathy [homogeneous,

Table 9.1: Advantages and disadvantages of various types of imaging modalities

Modality Advantage Disadvantage
Radiography Inexpensive, easily available Radiation exposure, low sensitivity and specificity
Ultrasonography Radiation free, portable, guide pleural sampling Limited field of view [superficial structures]
Computed tomography Excellent resolution, high sensitivity, guide Radiation, iodinated contrast, relatively expensive
sampling
Magnetic resonance imaging Radiation free, accurate for lymphadenitis and Expensive, contraindications, less accurate for
associated spinal disease parenchymal lesions
PET or PET-CT High sensitivity Low specificity, radiation exposure
PET = positron emission tomography; PET-CT = positron emission tomography-computed tomography
114 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

necrotic or calcified] is defined clearly. The trachea and PRIMARY TUBERCULOSIS

bronchi can be evaluated for stenosis [site and extent].
Primary TB is seen more commonly in children, however, it
Extraluminal causes of airway narrowing, e.g., lymph
is being seen with increasing frequency in adults (10). Up to
nodes [LNs] can be determined. Pleural pathology [effusion,
60% of children with pulmonary TB are asymptomatic and
empyema, thickening and calcification] and underlying
found solely through contact investigation (11). Difficulty
chest wall involvement are well delineated. The pulmonary in obtaining a sputum sample further compounds the
and bronchial vasculature is accurately evaluated with problem. Hence, diagnosis in such cases is based on presence
CT, thus providing a road-map for planning endovascular of positive tuberculin skin test [TST] or radiographic
interventions. abnormalities.
The structures involved in primary TB are, lymph nodes,
Ultrasonography pulmonary parenchyma, pleura and tracheobronchial
Ultrasonography is an inexpensive, radiation free, portable tree. Table 9.2 enlists the various radiographic features of
primary pulmonary TB.
imaging modality. It can assess pleural disease and facilitate
diagnostic pleural fluid sampling and therapeutic drainage
procedures. Ultrasonographic assessment of the abdomen Table 9.2: Radiologic features of primary pulmonary TB
can detect concomi­t ant organomegaly and abdominal Lymphadenopathy
lymphadenopathy. Parenchymal consolidation
Tuberculoma
Magnetic Resonance Imaging
Miliary TB
Magnetic resonance imaging [MRI] is a radiation free, but Pleural effusion
costly technique which can accurately assess mediastinal
Airway involvement
and hilar lymphadenopathy. Pulmonary parenchyma can
also be evaluated, though to a lesser extent than CT. It can TB = tuberculosis
assess concomitant spinal involvement with high accuracy.
Lymphadenopathy
Positron Emission Tomography-Computed
Lymphadenopathy is the hallmark of primary TB.
Tomography Lymph node enlargement is seen in 83%-96% of paediatric
The role of positron emission tomography-computed cases (7,12,13). The frequency of lymphadenopathy ranges
tomography [PET-CT] in TB is not clearly defined. However, from 10%-43% in adults (14,15). The most common lymph
due to increasing number of referrals for PET-CT in patients node sites involved are right paratracheal and hilar
with pyrexia of unknown origin [PUO], many cases are being region [Figure 9.1]. It is postulated that this right-sided
detected by PET-CT. Also, tubercular lymphadenopathy and preponderance is due to predominance of right-sided
parenchymal nodules may show intense 18-fluorodeoxy­ parenchymal lesions owing to higher probability of air-
glucose [FDG] uptake which can mimic malignancy (3,4). borne infection reaching the right lung through its shorter
and wider bronchus and also because the right sided nodes
drain the entire right lung along with the left lower lobe.
IMAGING IN PULMONARY TUBERCULOSIS Drainage of systemic lymph nodes to the right lymph duct
The disease which develops after initial exposure to the and to the superior vena cava via thoracic duct also favour
pathogen is known as primary TB, whereas, the disease right side presentation. In a study (16) it was observed that
that develops as a result of reactivation of a previous the most frequently involved location was subcarinal [90%],
endogenous focus of infection or less commonly, exogenous followed by the hilar [85%], anterior mediastinum [79%],
reinfection is known as post-primary TB. These two forms precarinal [64%] and right paratracheal [63%]. Nodes
at all the sites simultaneously were present in 35% of
of TB differ in terms of the site of involvement, nature of
patients. Bilateral lymphadenopathy is seen in 31% of
involvement, presence of lymphadenopathy and pleural
cases (17,18). There is an age-related decline in the prevalence
effusion. However, there may be variable degree of overlap
of lymphadeno­pathy. In a study (13), lymphadenopathy
in the radiologic manifestations. A recent study based on was seen in 100% cases between 0 and 3 years of age and
genotyping of Mycobacterium tuberculosis [Mtb] isolates has in 88% of children between 4 and 15 years (13).
suggested that the radiographic features are often similar in CT has a higher sensitivity than chest radiograph in
patients who have a primary disease and those who have a detection of lymphadenopathy. Lymph nodes greater than
reactivation TB. It has been proposed that, rather than the 1 centimetre in short axis diameter [SAD] are considered
time lag from acquisition of infection to the development enlarged. The lymph nodes show various patterns of
of clinical disease, it is the integrity of the host’s immune enhancement [Figure 9.2] which can be characterised
system that predicts the radiographic appearance of TB (8,9). according to appearance on contrast-enhanced CT [CECT]
However, this result is preliminary and requires further [Table 9.3]. The CT appearance of lymph nodes reveals
validation. their pathologic appearance and correlates with clinical
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 115

A B
Figure 9.1: Chest radiograph [postero-anterior view] [A] and CECT chest [B] showing right parahilar consolidation [black arrow] with enlarged
ipsilateral hilar and paratracheal lymph nodes [white arrows]
CECT = contrast-enhanced computed tomography

A B C
Figure 9.2: CECT chest of three different patients showing necrotic right paratracheal and prevascular nodes [arrows] [A], necrotic right hilar
and subcarinal nodes with rim enhancement [arrow] [B] and homogeneously enhancing pretracheal nodes [arrow] [C]
CECT = contrast-enhanced computed tomography

Table 9.3: Characterisation of lymph nodes according to appearance in CECT

Appearance of TB lymphadenopathy on CECT Pathology
Homogeneous enhancement Lymphoid hyperplasia with TB granulomas without caseous necrosis
Heterogeneous enhancement with a small central non-enhancing TB granulomas, some caseous necrosis in the center and a complete
area capsule
Peripheral irregular thick wall enhancement with a central non- TB granulomas, caseous necrosis in the center and a complete
enhancing area and clear surrounding fat plane capsule
Peripheral thin rim enhancement with no central enhancement and Few TB granulomas with a large amount of caseous necrosis in the
clear surrounding fat plane centre
No obvious enhancement Caseous necrosis with little tubercular granulomas
Peripheral irregular enhancement with central non-enhancement TB granulomas and caseous necrosis ruptured from the capsule
which obliterates surrounding fat plane
Peripheral irregular rim enhancement with central separate Lymph nodes with liquefaction of caseous necrosis are adherent, the
enhancement and an obliterated surrounding fat plane rim and separation are formed by TB granulomas
TB = tuberculosis; CECT = contrast-enhanced computed tomography

symptoms (19). Pathologically, intrathoracic TB lymphadenitis periadenitis without adhesions is seen. In stage 4 liquefaction
passes through four stages. Stage 1 is characterised by followed by destruction of the capsules adhesion and
lymphoid hyperplasia with formation of granulomas without confluence of multiple lymph nodes is observed. The lymph
caseous necrosis. In stage 2 caseous necrosis is evident in nodes in stage 1 show homogeneous enhancement. These
affected lymph nodes with complete capsule. In stage 3, patients often do not have clinical symptoms. Heterogeneous
 116 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

enhancement with a small central necrotic area is seen less than six months of age (16,24). Central low attenuation
in early stage 2. Peripheral irregular thick enhancing and peripheral enhancement suggest active disease whereas
wall with a central non-enhancing area and almost clear homogeneous calcified nodes indicate inactive disease (25).
surrounding fat plane is seen in mid stage 2. Peripheral thin In a study from New Delhi (26) in paediatric population,
rim enhancement with no central enhancement and a clear it was found that nodal enlargement, conglomeration and
surrounding fat plane is evident in late stage 2. In this stage, obscuration of perinodal fat were the major determinants of
patients manifest clinical symptoms. Peripheral irregular active disease (26).
enhancement with central non-enhancement which extends Mediastinal sonography can be an inexpensive tool
outside the lymph node capsule and obliterates surrounding for moni­t oring response to treatment in children. In a
fat plane is observed in stage 3. The irregular enhancement retrospective study of 21 children with a positive TST,
comprises of TB granulomas and caseous necrosis that mediastinal sonography was performed through suprasternal
have ruptured from the capsule. Peripheral irregular rim and left parasternal approach (27). A comparison of pre-
enhancement with central separate enhancement and an treatment mediastinal sonograms with those obtained
obliterated surrounding fat plane is observed in stage 4. after three months of anti-TB treatment showed a marked
The patients in stages 3 and 4 frequently manifest clinical reduction of lymph node involvement in 17 [80.9%] patients.
symptoms. Peripheral rim enhancement with or without MRI can also be used to accurately assess mediastinal
central low attenuation is the most common pattern and is and hilar lymphadenopathy [Figure 9.4]. Necrotic nodes
considered fairly specific for TB in the appropriate clinical appear bright on T2-weighted images. Three patterns of TB
setting (20). However, microbiological, pathological or lymphadenitis have been described [Table 9.4]. Of these,
molecular confirmation of diagnosis is imperative as similar the most common pattern is type 2, that is, inhomogeneous
appearance has also been described in atypical mycobacterial nodes with marked hyperintensity on T2-weighted images
infection (21), treated lymphoma (20), metastasis from and peripheral enhancement in post-contrast images. This
testicular malignancy (22) and benign conditions like appearance is mostly seen in severely symptomatic patients
Whipple’s and Crohn’s disease (23). and is due to caseation necrosis of the TB lymph nodes (28).
Calcification is uncommon in primary disease [Figure 9.3].
It is seen in 10%-21% children with TB and never in infants
Table 9.4: MRI appearances of TB lymphadenopathy
Type 1 Homogeneous enhancement
Type 2 Inhomogeneous with a strong peripheral enhancement
Type 3 No contrast enhancement
MRI = magnetic resonance imaging; TB = tuberculosis

Parenchymal Lesions
Infection occurs when a susceptible person inhales droplet
nuclei that contain Mtb. Ghon’s focus refers to the initial
site of lung parenchymal involvement at the time of first
infection. The draining lymphatics and the involved lymph
nodes together with Ghon’s focus are referred to as the
Ghon’s complex [primary complex]. The Ghon’s complex further
evolves into the Ranke complex which is the combination of a
Ghon’s focus and enlarged or calcified lymph nodes. Simon’s
Figure 9.3: CECT chest showing calcification in subcarinal node foci are apical nodules that are often calcified and result from
[arrow] haematogenous seeding at the time of initial infection (29).

A B C
Figure 9.4: CECT chest [A] and MRI of thorax showing necrotic right hilar and subcarinal lymph nodes [asterisk] which are iso to hyperintense
on T1 [B] and hyperintense on T2 weighted images [C]
CECT = contrast-enhanced computed tomography
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 117

Consolidation CT has a higher sensitivity than radiographs in detecting

Consolidation is the most common pattern of parenchymal the parenchymal changes. Consolidation is seen as a
involve­­­ment in pulmonary TB. On radiographs, it is seen homogeneous soft tissue density lesion with air bronchogram
as single homogeneous opacity with ill-defined margins or break down within it. Low-attenuation areas within the
[Figure 9.5]. There can be a mass-like consolidation which consolidation, repre­sent­ing caseating necrosis can be seen
can involve an entire lobe with absent air-bronchogram. in 25% cases (7). CT is better than MRI in demonstration of
Consolidation abutting a fissure can have sharp margins. parenchymal changes. In a series of 2677 patients visiting
The radiographic picture of TB can often resemble that of the paediatric TB Clinic from New Delhi, primary complex
bacterial pneumonia. However, lack of systemic toxaemia was seen in 50% cases of paediatric pulmonary TB. Of these,
and non-responsiveness to standard antibiotic treatment can 32% had lymphadenopathy only, 29% had parenchymal and
suggest the possibility of TB. lymph node involvement and 39% had only parenchymal
There is no predilection for a particular region of the lesions (32).
lung, but a right-sided predominance has been noted (30). In
adults with primary TB, the lesion is often seen in the lower Tuberculoma
lobe. Cavitation of the parenchymal lesion is rare in children A tuberculoma is a round or oval opacity which is seen in
but can be seen in 7%-29% adults with primary TB (15,31). both primary and post-primary TB [Figure 9.6] in 7%-9% of
Endobronchial spread is rare since cavitation is uncommon. patients. It can range in size from 0.5 cm-4 cm in diameter.
Histologically, the central part of the tuberculoma consists of
caseous material and the periphery, of epithelioid histiocytes
and multinucleated giant cells with variable amount of
collagen. It is commonly seen in the upper lobes, more often
on right side. Cavitation can be seen in 10%-50% of the
lesions (30). Small discrete nodules can be seen in the vicinity
of the main lesion [“satellite lesions”] in 80% cases (33).
Majority of tuberculomas remain stable over time. On CT,
tuberculomas are seen as well-circumscribed soft tissue
density nodules with smooth margin. Calcification is
seen in the dominant nodule or the satellite lesions in
20%-30% cases. Tuberculomas can show ring-like and central
curvilinear enhancement.

Miliary Tuberculosis
Haematogenous dissemination of the bacilli results in miliary
TB in lungs and other organs (34). It is primarily a feature of
primary TB although it may be seen in post primary disease.
Figure 9.5: Chest radiograph [postero-anterior view] showing an ill- It is characterised by the presence of innumerable, 2 mm
defined area of consolidation [arrow] in the left lower lobe in a patient or less, non-calcified nodules scattered throughout both
with primary tuberculosis the lungs, with mild basilar predominance [Figure 9.7].

A B
Figure 9.6: Chest radiograph [postero-anterior view] [A] and CECT chest [B], showing well-defined, single, oval lesion in right upper lobe [arrow]
suggestive of a tuberculoma
CECT = contrast-enhanced computed tomography
 118 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 9.7: Chest radiograph [postero-anterior view] [A] and HRCT chest [B] showing bilateral, diffuse, tiny, discrete, pinpoint opacities, suggestive
of miliary tuberculosis
HRCT = high resolution computed tomography

This basal predilection is attributed to the gravity dependent Although usually observed in association with parenchymal
increase in blood flow to the lung bases. The chest radio­ and/or nodal abnor­malities, pleural effusion is the only
graph can be normal in the early stages of disease in radiographic finding in primary TB in approximately 5%
25%-40% of persons (35-37). Typical miliary lesions are of adult cases.
visible on radiographs after a latency of 3-6 weeks after Pleural effusion is most commonly non-loculated and
haematogenous dissemination (38). Initially, the lesions are moderate to large in quantity [Figure 9.8]. The effusion can
1 mm in diameter. If left untreated, the nodules increase some­times be subpulmonary in location and cause elevation
in size to 3-5 mm and coalesce to give a ‘snow-storm’ of ipsilateral hemidiaphragm. A lateral decubitus film can
appearance. Uniform distribution of nodules is seen in provide confirmation by showing the fluid shift along
85% cases while 15% show asymmetric distribution (38). lateral chest wall. The effusion can become loculated when
Associated lymphadenopathy is seen more commonly it demonstrates a convex medial margin towards the lung.
in children [95%] as compared to adults [11%]. The right Complications include empyema, bronchopleural fistula,
paratracheal lymph nodes are involved most commonly. empyema necessitans or bone erosion.
Associated parenchymal consolidation is also more common Ultrasonography is a useful modality for assessment
in children (12). In a study (32) miliary and broncho­ and follow-up of pleural pathology [Figure 9.9]. The
pneumonic forms of TB were seen in 3% patients. Rarely, pleural effusion can be quantified, evaluated for septations,
a diffuse alveolar pattern is observed in patients with asso­ sampled and drained by ultrasonography. As little as 10 ml
ciated acute respiratory distress syndrome [ARDS] (39,40). of fluid can be detected on ultrasonography when the chest
High resolution computed tomography [HRCT] is radiograph is normal.
highly sensitive for detecting miliary nodules (41). It can CT with its multi-dimensional capability helps in
reveal randomly distributed, miliary nodules in the lung evaluating pleural involvement by delineating the site,
along with lymphadeno­pathy even if the radiograph is extent of disease, presence of loculations, status of under­
normal. Thickening of interlobular and intralobular septa lying ribs and chest wall involvement. It helps in planning
is frequently evident. In the appro­priate clinical setting further management. Empyema is visualised as fluid
where the clinical suspicion of miliary TB is high, if the collection with diffuse enhancement of visceral and parietal
chest radiograph is normal, it is advisable to obtain CT of pleura [‘split pleura sign’] and extra-pleural fat proliferation
the thorax. [Figure 9.10]. Healing can result in residual pleural
thickening and calcification [Figure 9.11].
Pleural Involvement
Airway Involvement
Pleural effusion is an uncommon manifestation of primary
TB. Pleural effusion usually develops on the same side as Airway involvement may be extrinsic, due to compression
the site of initial TB infection and is typically unilateral (42). by enlarged lymph nodes or intrinsic, due to endobronchial
Bilateral effusions occur in 12%-18% of cases (18,33). spread. Lymph node compression can lead to atelectasis
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 119

A B
Figure 9.8: Chest radiograph [postero-anterior view] of two different patients showing moderate right-sided free pleural effusion [arrow] showing
Ellis curve [A] and left-sided loculated pleural effusion [arrow] with a convex medial margin towards lung [B]

Figure 9.9: Ultrasonography of chest showing right sided pleural effusion with multiple septations [asterisk]

A B
Figure 9.10: Chest radiograph [postero-anterior view] [A] showing an ill-defined opacity along the lateral chest wall [arrows] with loss of volume
of right hemithorax. CECT chest of the same patient [B] showing loss of lung volume with thick enhancing pleura and proliferation of extra-pleural
fat [arrows]
 120 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 9.11: Chest radiograph [postero-anterior view] [A] and CECT chest [B] showing loss of volume, dense and thick, peripheral left pleural
thickening with calcification [arrow] suggestive of chronic empyema

or hyperinflation. This is frequently seen in primary TB two years in all cases, 18% had parenchymal scarring, 11%
in children below two years of age and is less common had parenchymal calcification and nodal calcification
in older children [9%] and adults [18%]. This is because was seen in 6% cases (13). Resolution of parenchymal
of the larger calibre of airways and lower prevalence of abnormalities occurs within six months to two years
lymphadenopathy in the older population. The involvement on radiographs (13) and up to 15 months on CT (48).
is right-sided with obstruction occurring at the level of the Lymphadenopathy may persist for several years after
lobar bronchus or bronchus intermedius. Thus, atelectasis is treatment (13).
commonly seen involving the anterior segment of upper
lobe or the medial segment of the middle lobe. In adults, POST-PRIMARY TUBERCULOSIS
it can mimic bronchogenic carcinoma (43).
CT is the modality of choice for delineating the site, Post-primary TB most often occurs due to reactivation
extent and the cause of airway involvement. CT can provide of endo­g enous focus of infection acquired previously
excellent reconstructions in any plane and endoscopic views or exogenous reinfection. There are several patterns of
to give a complete perspective of the tracheobronchial tree. involvement seen in post-primary TB [Table 9.5] which may
Active airway disease is seen as long segment of circum­ be seen in isolation or in various combinations.
ferential wall thickening and irregularity causing luminal The radiographic features of post-primary TB which
compromise. It can involve both main bronchi with equal differ­entiate it from primary TB are: [i] predilection for apical
frequency (44). and posterior segments of the upper lobes and the superior
segment of the lower lobes; [ii] presence of cavitation; and
[iii] rarity of lymphadenopathy.
Follow-up of Primary Tuberculosis
Imaging is the main stay in the follow-up of patients
with negative pre-treatment sputum examination results.
It is of utmost value in children in whom bacteriological Table 9.5: Radiographic features of post-primary TB
confirmation is not possible. Regression of radiographic Cavitation
abnormalities in pulmonary TB is a slow process. In the Local exudative lesion
first three months of treatment, there may be worsening
Local fibroproductive lesion
of radiographic findings in the form of progression of
parenchymal involve­m ent and enlargement of existing Tuberculoma
lymph­adenopathy despite appropriate treatment (13,45-47). Bronchogenic spread
This occurs as a conse­q uence of the hypersensitivity Miliary TB
reaction that normally occurs two to ten weeks after initial Bronchostenosis
infection (13). The parenchymal and nodal abnormalities
Pleural disease
usually regress in parallel. In a series of 252 paediatric
TB = tuberculosis
patients with TB, consolidation resolved completely within
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 121

Parenchymal Disease Fibroproductive or Fibroproliferative Lesion

Exudative Lesion Healing occurs by replacement of TB granulation tissue
by fibrous tissue resulting in loss of volume. The fluffy
The most common radiographic manifestation of reactivation
ill-defined opacities of exudative lesions give way to
TB is focal or patchy heterogeneous consolidation involving
well-defined reticular and nodular opacities [Figures 9.14
the apical and posterior segments of the upper lobes and
and 9.15]. Volume loss manifests as ipsilateral tracheo-
superior segments of the lower lobes (25,47). Another
mediastinal shift, elevation of diaphragm and retraction of
common finding is the presence of poorly defined nodules
hilum. In 41% cases, an apical opacity or apical cap results
and linear opacities, which are seen in approximately 25%
from pleural thickening, subpleural atelectasis and extra-
of patients. Involvement of more than one segment is
pleural fat deposition. Mixed exudative and fibroproductive
fairly common, seen in 88% cases [Figures 9.12 and 9.13].
lesion is the most common finding seen in 79% cases. Pure
Bilateral upper lobe involvement is seen in 32%-64% cases.
exudative or fibroproductive lesions are uncommon (31).
Cavitation occurs in about 45% cases (31). If the disease is
left untreated, additional opacities develop, that coalesce
leading to lobar and total lung consolidation which can be
associated with distortion of adjacent bronchovascular and
mediastinal structures. In 3%-6% cases, tuberculomas are the
predominant parenchymal manifestation. Lymphadenopathy
is very uncommon and is seen in 5% cases (31).

Figure 9.14: Chest radiograph [postero-anterior view] showing coarse,

sharply defined opacities mainly in left upper lobe suggestive of
parenchymal fibroproliferative lesion [asterisk]

Figure 9.12: Chest radiograph [postero-anterior view] showing exten­

sive consolidation in left lung

Figure 9.15: Chest radiograph [postero-anterior view] showing volume

Figure 9.13: HRCT chest showing right upper lobe consolidation loss of left lung, extensive fibrosis both upper lobes, residual cavity
[asterisk] [white asterisk] and bronchiectatic changes in both lungs [black
HRCT = high resolution computed tomography asterisk].
 122 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Cavitation keep the cavity empty (50). TB cavity may be complicated by

intracavitary fungal ball [“mycetoma”]. The cavities may not
Cavitation occurs when an area of caseous necrosis liquefies
be discernible on radiographs in the setting of dense fibrosis,
and communicates with the bronchial tree. The sputum of
consolidation, or architectural distortion. In such cases, CT
such patients is teeming with tubercle bacilli and cavity is
is extremely helpful in detecting a cavity and intracavitary
an important sign of active disease. Cavities can be single
fungal ball.
or multiple. They may be evident radiographically in
40%-45% of patients with post-primary TB (31,48). Cavitation
Tuberculosis Bronchopneumonia
in an area of consolidation is a distinct feature of post-
primary TB and indicates likely active disease. It involves Bronchogenic spread of infection can be identified in 95%
the apical and/or posterior segments of the upper lobes in of cases with post-primary TB (51,52). This can occur due to
83%-85% and the superior segments of the lower lobes in communi­cation of a TB cavity with the bronchial tree. Similar
11%-14% patients (49). The walls of cavities can vary from spread can occur due to intrabronchial rupture of caseous
thin and smooth to thick and nodular [Figures 9.16 and 9.17]. material of a lymph node. Endobronchial spread is evident
The healing of cavitary lesions causes more cicatrisation than in 19%-58% cases (3); with the use of HRCT this may be seen
areas without cavitation (46). in up to 98% cases (43). The most common HRCT findings
Air-fluid levels are uncommon in TB cavities due to include 2-4 mm well-marginated centrilobular nodules and
effective drainage and are evident in 9%-21% cases (33,50). linear branching opacities (51). On pathologic correlation,
The basal position of the entering bronchus, its downward these have been found to represent caseous necrosis
course and its free communication with the cavity tend to within and around terminal and respiratory bronchioles.

A B
Figure 9.16: Chest radiograph [A] and HRCT [B] showing a large thick walled cavity [asterisk] in right apex with left upper zone consolidation
[arrow] in a patient with post-primary tuberculosis

A B
Figure 9.17: Chest radiograph [postero-anterior view] [A] showing a thick walled cavity [arrow] in the right upper lobe with surrounding
fibroproliferative lesion. HRCT chest [B] showing another cavity [arrow] in left upper lobe with nodules in the vicinity
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 123

The pattern of distribution of nodules showing multiple Two patterns of TB have been identified in adults recently
branching linear structures of similar calibre that originate using PET-CT. These include the “lung pattern” and the
from a single stalk is known as “tree-in-bud” appearance “lymphatic pattern”. The lung pattern is seen in 67% patients
[Figure 9.18]. These lesions result as a consequence of with predominantly pulmonary symptoms. In these cases,
extensive endobronchial dissemination and are an important mediastinal and hilar lymph nodes are slightly enlarged with
marker of disease activity. However, this appearance is non- moderate FDG uptake with a median maximum standardised
specific and has been described in several other conditions uptake value [SUVmax] of 3.9 [range 2.5-13.3]. On the other
[Table 9.6] in which there is plugging of small airways with hand, in the lymphatic pattern [Figure 9.20], patients have
fluid or exudates (53). predominantly systemic symptoms with extra-thoracic
Another radiographic feature is the presence of multiple involvement. The lymph nodes were larger in size and with
fluffy nodules approximately 5 mm in diameter, known as higher FDG uptake [median SUVmax 6.8, range 5.7-16.8] (55).
acinar nodules [Figure 9.19]. It is proposed that in most
cases of acinonodose TB, small peribronchiolar nodules grow Airway Involvement [Bronchostenosis]
and coalesce into a larger nodule, by direct extension of
inflammation through the pores of Kohn (54). The presence Airway involvement can occur by direct extension from
of a cavity and centrilobular nodules with or without tree- adjacent parenchymal infection due to cavitation, lymph
in-bud pattern can suggest the diagnosis of TB in such cases. node erosion, haematogenous spread, and extension to the
While 70% cases of these lesions resolve completely, 30% peribronchial region via lymphatic drainage. The lesions
can result in sequelae in the form of parenchymal scarring, evolve from submucosal sites of infection associated with
residual nodules and calcification (33). ulceration to hyperplastic inflammatory polyps that heal

A B C
Figure 9.18: HRCT chest showing the typical “tree-in bud” nodules [arrow] [A] in a bronchovascular distribution [arrow] with bronchiectasis [B].
Line diagram [C] illustrating the “tree-in-bud” pattern

Table 9.6: Causes of “tree-in-bud” appearance

Peripheral airway disease
Infection
  Bacterial
    Mycobacterium tuberculosis, Mycobacterium avium-
intracellulare complex, Staphylococcus aureus
  Fungal
   Aspergillus
  Viral
    Cytomegalovirus, respiratory syncytial virus
  Congenital disorders
    Cystic fibrosis, Kartagener’s syndrome
  Aspiration
    Gastric contents, hydrocarbons, toxic fumes and gases
  Immunologic disorders
    Allergic bronchopulmonary aspergillosis
   Connective tissue disorders
   Rheumatoid arthritis, Sjögren’s syndrome, peripheral
pulmonary vascular disease
  Neoplasms
Figure 9.19: Chest radiograph [postero-anterior view] showing
    Ewing’s sarcoma, gastric, breast and renal cancer extensive bilateral bronchopneumonic tuberculosis
 124 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 9.20: PET-CT images [A] in a case with breast carcinoma showing FDG uptake [arrow] in the right breast without any nodal uptake of
FDG. Repeat PET-CT image [B] after completion of chemotherapy showing no uptake in the right breast lesion representing complete remission
of the primary lesion. Multiple enlarged lymph nodes are seen in the neck and mediastinum showing FDG uptake which on FNAC showed multiple
acid-fast bacilli suggestive of TB lymphadenitis
TB = tuberculosis; FDG = fluorodeoxyglucose; PET-CT = positron emission tomography-computed tomography; FNAC = fine needle aspiration
cytology
Kind courtesy: Dr Rakesh Kumar, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi

respectively (56,58). On CT, endobronchial TB manifests as

irregular [in active disease] or smooth [in fibrotic disease]
circumfer­ential bronchial narrowing associated with mural
thickening [Figure 9.21].

Pleural Effusion
Tuberculous pleural effusion is usually regarded as a
manifestation of primary disease. However, it may occur in
association with post-primary disease in up to 19% cases (59).
It is typically unilateral in distribution and often loculated.
Residual pleural thickening or calcification may occur.
Persistence of fluid in a calcified fibrothorax should raise
concern regarding active disease, chronic TB empyema (60).

Evaluation of Activity of Tuberculosis on Imaging

The knowledge of imaging features of disease activity helps
in evaluating response to treatment and detecting disease
reacti­vation. Architectural distortion due to fibrosis and
Figure 9.21: Coronal reformatted CT image showing smooth narrowing calcification are found in both active and healed disease.
of the trachea and left main bronchus [arrows] in a patient with post- Also, small nodules and cavities may not be seen on
primary tuberculosis radiographs. The exudative lesion may remain unchanged
CT = computed tomography on serial radiographs despite adequate therapy and patient
having negative sputum mycobacterial culture. Therefore,
by fibrosis resulting in circumferential stenosis (56-60). comment on disease status based on a single radiograph is
Bronchostenosis occurs in 10%-40% patients. The main, unreli­able. Radiographic stability for at least six months and
upper, and lower lobe bronchi account for three-quarters repeated negative sputum cultures are the best indicators of
of the involved sites (60). Segmental or lobar atelectasis is disease inactivity. It is suggested that the cases should be
seen radiographically in 65%-75% and 18%-25% of cases, termed as “radiographically stable” instead of “inactive” (31).
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 125

The HRCT has a significant role in determining activity of SEQUELAE AND COMPLICATIONS OF
parenchymal lesions. It is particularly helpful in the detection TUBERCULOSIS
of small foci of cavitation in areas of dense nodularity and
A variety of sequelae and complications can occur due to
scarring. In a series (61) 80% of patients with active disease
pulmo­nary TB [Table 9.8]. The imaging features of some of
and 89% of those with inactive disease were correctly these are described further.
differentiated on HRCT (61). Table 9.7 lists the CT features
of active TB. Of these, presence of centrilobular nodules
without fibrosis and broncho­vascular distortion are the most Table 9.8: Complications and sequelae of pulmonary TB
common finding in active TB. Thin walled cavities, fibrotic Parenchymal complications
bands and well-defined nodules are seen in inactive disease Acute respiratory distress syndrome
[Figure 9.22]. Sometimes, the CT picture may be equivocal. Aspergilloma
Extensive lung destruction and cicatrization
Hence, clinical correlation is a must. Multiple cystic lung lesions
Presence of necrosis is considered a pointer of active
Airway complications
TB lymphadenitis. Since enhancement pattern of TB lymph
Bronchiectasis
nodes shows marked variation, evaluation of disease activity
Bronchiolitis obliterans
based on enhancement patterns has limited reliability. In Bronchostenosis
pleural disease, presence of fluid in the presence of diffuse Broncholithiasis
pleural thickening or enhancement suggests activity. Pleural complications
In a study (62) that assessed the role of PET-CT in patients Bronchopleural fistula
with TB, all patients underwent PET-CT before and after Empyema
one month of starting anti-TB treatment. The second PET- Fibrothorax
CT showed reduced radiotracer uptake intensity in 19 of Hydropneumothorax, pneumothorax
21 patients, with a median percentage decrease of SUVmax Vascular complications
of 31% [range 2-84] (62). Thus, PET-CT can detect early Bronchial and pulmonary arteritis and thrombosis
response to therapy by quantification of reduction in FDG Bronchial artery pseudoaneurysm
avidity of the lesions. Pulmonary artery pseudoaneurysm [Rasmussen’s aneurysm]
Pulmonary artery hypertension
Mediastinal complications
Table 9.7: Features of active TB on CT Constrictive pericarditis
Oesophagobronchial fistula
Centrilobular nodules; “tree-in-bud” appearance Oesophagomediastinal fistula
Lobular consolidation Fibrosing mediastinitis
Cavitation Chest wall complications
Bronchial wall thickening Chondritis
Empyema necessitatis
Necrotic mediastinal and hilar lymphadenopathy Osteomyelitis
Pleural effusion Spondylitis
TB = tuberculosis; CT = computed tomography TB = tuberculosis

A B
Figure 9.22: Chest radiograph [postero-anterior view] [A] and HRCT chest [B] showing extensive destruction of left lung with fibro-bullous
changes [arrow] and contralateral hyperinflation [asterisk]
HRCT = high-resolution computed tomography
 126 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Parenchymal Complications retraction and irrever­sible bronchial dilatation or due to

bronchostenosis leading to obstructive pneumonitis and
Parenchymal complications include acute respiratory
distal bronchiectasis [Figures 9.24 and 9.25]. Bronchiectasis
distress syndrome [ARDS], thin-walled cavities, fibrotic
is seen in 71%-86% patients on HRCT. Bronchostenosis
bands, extensive lung destruction and aspergilloma. ARDS
can result in persistent segmental or lobar collapse, lobar
manifests radiologically as extensive bilateral areas of
hyperinflation or obstructive pneumonitis. Broncholithiasis
ground-glass opacity or consolidation superimposed on
is an uncommon complication of pulmonary TB. It is
findings of miliary or endobronchial spread of TB. Thin-
characterised by calcified peribronchial nodes that erode
walled cavities can occur as a consequence of cicatrisa­tion
into or cause distortion of an adjacent bronchus. Right-sided
of previously active TB cavities after therapy or as sequelae
predominance has been observed (64). Other radiologic
of ARDS, in which case they are seen in the anterior portion
findings include segmental or lobar atelectasis, obstructive
of the lung. Residual fibrosis is characterised by calcification,
pneumonitis, branching opacities in a ‘V’ or ‘Y’ configuration
architec­t ural distortion and retraction of adjacent lung
[obstructive bronchocele] and focal hyperinflation (64,65).
parenchyma. These changes when extensive can result in
complete lung destruction making it defunct. An ectatic
Pleural Complications
bronchus or, more commonly, a residual tuberculous cavity
may be colonised by Aspergillus species. Haemoptysis is a The pleural complications are pleurisy, empyema,
life-threatening complication of aspergilloma and occurs fibrothorax, pneumothorax and bronchopleural fistula
in 50%-70% of affected patients (63). Radiographically, [Figure 9.26]. Fibrothorax shows diffuse pleural thickening
aspergilloma appears as a spherical nodule or mass and calcification with volume loss of the hemithorax.
separated by a crescent shaped area of decreased opacity Pnuemothorax can occur due to rupture of a cavity into the
from the adjacent cavity wall. The characteristic CT features pleural space.
consist of a mobile intracavitary nodule or mass that is
usually surrounded by air but may completely fill the cavity Vascular Complications
[Figure 9.23]. On prone and supine CT images, the
aspergilloma will gravitate to the dependent position. These include pulmonary and bronchial arteritis and
thrombosis, bronchial artery dilatation [Figure 9.27] and
pulmonary artery [Rasmussen’s aneurysm]. These can
Airway Complications
result in massive haemoptysis. The ongoing inflammation in
These include bronchiectasis, tracheobronchial stenosis and areas of active disease can cause vasculitis and thrombosis.
broncholithiasis. Bronchiectasis as a sequel of pulmonary Arteries in the vicinity of old cavities can show endarteritis
TB typically involves the upper lobes [Figure 9.22]. Since obliterans. Rasmussen’s aneurysm is a pseudoaneurysm
bronchial drainage is adequate from these sites, symptoms that results from weakening of the pulmonary artery
are usually minimal [bronchiectasis sicca]. It occurs due to wall by adjacent cavitary TB [Figure 9.28]. It may form
destruction and fibrosis of lung parenchyma, resulting in months to years after formation of the cavity and is seen

A B
Figure 9.23: Mycetoma in TB cavity: Chest radiograph [postero-anterior view] [A] showing loss of volume of right upper lobe with a cavity having
a fungal ball [asterisk] illustrating the ‘air crescent’ sign. CT chest [B] of another patient, showing soft tissue mass inside a cavity in left upper lobe
caused by a fungus ball [arrow]
TB = tuberculosis; CT = computed tomography
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 127

in 4%-5% autopsy cases (33). It may produce an ‘air- crescent’

on radiographs, thereby, mimicking a mycetoma. CT
angiography can confirm the diagnosis. Arterial embolisation
has been demonstrated as an effective method to achieve
primary control of bleeding associated with chronic TB
cavities.

Mediastinal Complications
These include oesophagomediastinal and oesophago­
bronchial fistula, fibrosing mediastinitis and constrictive
pericarditis. The mediastinal lymph nodes [especially
subcarinal lymph nodes] can caseate to form fistula with
the mid thoracic oesophagus. Fibrosis with formation of
traction diverticula in the oesophagus may also develop.
Fibrosing mediastinitis is seen as soft tissue in the media­
stinum encasing the major vessels and airway, causing
luminal compromise [Figure 9.29]. Involvement of the
Figure 9.24: Chest radiograph [postero-anterior view] showing right pericardium can cause diffuse pericardial thickening and
upper lobe collapse with elevated minor fissure [arrow] calcification leading to constrictive pericarditis.

A B
Figure 9.25: Chest radiograph [postero-anterior view] [A] showing volume loss of right upper lobe [asterisk]. HRCT chest of the same patient [B],
revealing encasement of the right upper lobe bronchus [arrow] by soft tissue causing luminal narrowing
HRCT = high-resolution computed tomography

A B
Figure 9.26: CECT chest [A] showing communication between the right main bronchus and pleural cavity suggestive of broncho-pleural fistula
[arrow] with a thick-walled pleural collection having an air-fluid level [asterisk]. Multiple nodules are seen in left lung [B]
CECT = contrast-enhanced computed tomography
 128 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 9.27: CT chest [A] showing consolidation in the right upper lobe [asterisk] with a hypertrophied intercosto-bronchial artery supplying the
region [arrow]. Selective bronchial artery angiogram [B] illustrating the hypertrophied vessel [arrow]
CT = computed tomography
Kind courtesy: Dr Ashu Seith Bhalla, Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi

Chest Wall Complications

There can be involvement of the ribs, costal cartilage and dorsal
vertebra. Also, the pleural collection can track exteriorly
through the chest wall presenting as a subcutaneous lump.
This is known as empyema necessitans.

TUBERCULOSIS AND HUMAN

IMMUNODEFICIENCY VIRUS INFECTION
By suppressing cell-mediated immunity, HIV infection
predisposes to development of progressive primary disease
or reactivation of latent infection. HIV-TB co-infection is a
common problem encountered by clinicians (66).
The radiographic manifestations of pulmonary TB
Figure 9.28: Rasmussen’s aneurysm in tuberculous cavity: Thoracic in HIV-seropositive individuals depends on the level of
CT angiogram showing fibro-cavitary changes in left upper lobe with immuno­s uppression. HIV-seropositive patients with a
a pseudoaneurysm [arrow] arising from pulmonary artery branch CD4+ T-lymphocyte count less than 200/mm3 have a higher
projecting in one of the cavities prevalence of mediastinal or hilar lymphadenopathy, a
CT = computed tomography lower prevalence of cavitation, and often extrapulmonary
involvement (4). Miliary or disseminated disease is also
associated with severe immunosuppression. Unusual or
atypical manifestations of pulmonary TB are common in
patients with very low CD4+ T-lymphocyte counts who
are severely immunosuppressed. The reader is referred to
the chapter ‘Tuberculosis and human immunodeficiency virus
infection” [Chapter 35] for details.

Radiologic Manifestations of Multidrug-resistant

Tuberculosis
Drug resistance is a major public health problem that
threatens the success of global TB control. Bilateral
involvement, multiple cavities and nodules and bronchial
dilatation are more common in patients with multidrug-
Figure 9.29: Fibrosing mediastinitis: CECT chest showing mediastinal
soft tissue [asterisk] causing extrinsic compression and narrowing of resistant TB [MDR-TB] (67). A correlation has been observed
right pulmonary artery between the radiologic features of MDR-TB and the mode of
CECT = contrast-enhanced computed tomography acquisition of drug-resistance (68,69). In new patients with
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 129

MDR-TB, presentation with non-cavitary consolidation, conditions including lymphoma, leukaemia, metastases,
pleural effusion, and a primary TB pattern of disease is sarcoidosis, histoplasmosis, and pyogenic infections.
seen (70). On the other hand, in previously treated patients Radiographs, ultrasonography, cross-sectional imaging
with MDR-TB, cavitary consolidation and a reactivation with multidetector CT and MRI, all play an important role
pattern of the disease is evident. The CT findings in in the diagnosis and post-treatment follow-up of these
extensively drug-resistant TB [XDR-TB] are similar to MDR- patients.
TB. XDR-TB manifests as an advanced pattern of primary TB
[extensive consolidation with or without lymphadenopathy] LYMPH NODE TUBERCULOSIS
in AIDS patients or an advanced pattern of MDR-TB
[multiple cavitary lesions in consolidative or nodular lesions] In India and other developing countries, lymph node TB is the
in non-AIDS patients. most common form of EPTB. Nontuberculous mycobacteria
[NTM] are the most common cause of lymphadenopathy
in the developed world (91,92). Peripheral lymph nodes
FAMILY SURVEY
are usually affected, of which cervical and supraclavicular
It is important to survey the family members who stay in nodes are most commonly involved, followed by axillary
close contact with a patient with pulmonary TB. All contacts and inguinal nodes (93,94). On ultrasound these nodes
should have a chest radiograph taken and children below depict central hypoechoic areas corresponding to necrosis.
12 years of age should undergo TST to detect asymptomatic CT demonstrates peripheral enhancement with low
contacts with latent TB infection [LTBI]. In a study (32) attenuation centres.
conducted at New Delhi, with 2677 children with pulmonary
TB, a positive family history of TB was evident in 30% ABDOMINAL TUBERCULOSIS
patients. Radiographic screening of 300 adult contacts of
Abdominal TB encompasses TB of the gastrointestinal [GI]
children with primary pulmonary complex showed active
tract, peritoneum, omentum, mesentery, abdominal lymph
pulmonary lesions in 4%-5% of those screened (32). The
nodes, and solid visceral organs such as liver, spleen and
reader is referred to the chapter “Tuberculosis in children”
pancreas. Only 15% of patients with abdominal TB have
[Chapter 36] for further details on this topic.
evidence of pulmonary involvement and chest radiograph
may be normal in 50%-65% of these patients (95).
RADIOGRAPHIC FOLLOW-UP SCHEDULE
The American Thoracic Society [ATS] and Centers for Gastrointestinal Tract Tuberculosis
Disease Control [CDC] (71) recommend the following
Any segment of the GI tract may be involved and ileocaecal
radiographic schedule. In patients with a negative sputum
region is most commonly affected, seen in 80%-90% of
mycobacterial culture, a repeat chest radiograph is indicated
patients with abdominal TB (96).
at two months of treatment; another chest radiograph is
considered as desirable at the end of treatment. In patients
Oesophageal Tuberculosis
with a positive sputum mycobacterial culture, repeat chest
radiographs at two months and at the end of treatment are This is rare and usually secondary to advanced mediastinal
considered desirable [but not essential] (72). or pulmonary disease. Barium swallow studies may show
extrinsic compression by enlarged mediastinal nodes,
EXTRA-PULMONARY TB strictures, ulceration, mucosal irregularity and traction
diverticula. Sinus tracts and fistulous communications may
With the increasing prevalence of TB worldwide, there has
develop with the mediastinum or tracheobronchial tree.
been a similar rise in its extra-pulmonary TB [EPTB] mani­
CT can reliably demonstrate full extent of extramucosal
festations as well (73). In the era before the HIV pandemic,
disease but endoscopic biopsy is required for confirming
EPTB constituted 15%-20% of all cases of TB (74-79).
the diagnosis.
In HIV-seropositive individuals, EPTB accounts for more
than 50% of all cases (80-85). The most common extrapulmo­
Tuberculosis of Stomach and Duodenum
nary site of TB in HIV-seropositive individuals is lymph
node TB. However, genitourinary, neurological, pleural, TB of stomach and duodenum can be ulcerative [most
pericardial, abdominal and musculoskeletal involvement common], hypertrophic, or in the form of multiple or solitary
has been described and virtually every organ system in the tuberculomas, TB pyloric stenosis and TB lymphadenitis.
body can be affected. In studies (86,87) from India, EPTB Imaging features are non-specific, may mimic benign ulcers
constituted 45%-56% of all TB cases in AIDS patients. in ulcerative form and malignancy in hypertrophic form.
Confirmation of diagnosis of EPTB is usually difficult. Adenocarcinoma and lymphoma are important differential
Positive findings on chest radiograph or a positive TST may diagnosis (89,97). Duodenal involvement can be intrinsic
support the diagnosis, but negative results do not exclude or extrinsic. Intrinsic involvement can be ulcerative or
the possibility of EPTB (88-90). Systemic manifestations of hyperplastic while external lymphadenopathy may lead to
TB can mimic a variety of neoplastic and non-neoplastic duodenal C-loop widening.
 130 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

TB Enteritis
TB is a common cause of small bowel obstruction in India.
Ulcerative form is more common, the ulcers having stellate
or linear shape. In addition, bowel loops can be matted and
fixed by adhesions and fibrosis. In case of acute obstruction,
plain radiograph of the abdomen shows dilated bowel
loops with multiple air-fluid levels. Enteroliths, calcified
lymph nodes and hepatosplenomegaly may be evident.
There may be evidence of perforation, ascites or intus­
susception. In case of subacute bowel obstruction, barium-
meal follow through or small bowel enterography study can
be done. Per-oral pneumocolon can be employed for optimal
distension of caecum and ileocaecal region in equivocal
cases. Ultrasonography exhibits segments of circumferential
bowel wall thickening, increased peristalsis proximal
to obstruction and ascites. Latter may become loculated
with multiple septations within. Imaging features of
intestinal TB [Table 9.9] correlate with pathological stage of
disease (98,99). Figure 9.30: Barium-meal follow through study showing ileocaecal
TB. Narrowing and mucosal irregularity of the terminal ileum [arrow]
with thin stream of barium in its lumen is seen. Caecum is contracted,
Ileocaecal TB shrunken [asterisk] and pulled out of right iliac fossa. The normal acute
Ileocaecal region can be affected in a variety of ways [Figure 9.30]: angle of ileocaecal junction is distorted
TB = tuberculosis
[i] hyperplastic with long segments of narrowing, rigidity
and loss of distensibility [pipe-stem colon]; [ii] ulcerative;
[iii] ulcero­hyperplastic; and [iv] carcinoma type, with short with rapid emptying of the diseased segment through a
annular stenosis and overhanging edges. In the early stages, gaping ileocaecal valve into a shortened, rigid, obliterated
barium studies demonstrate spasm, hypermotility and caecum [Stierlin sign] are considered characteristic (89). In
thickening [oedema] of the ileocaecal valve. Focal or diffuse advanced cases, symmetric annular napkin-ring stenosis
aphthous ulcers also occur in the early stages. These ulcers and obstruction associated with shortening, retraction,
are larger than those seen in Crohn’s disease and follow and pouch formation may be seen. Caecum characteristi­
the orientation of lymphoid follicles [i.e., longitudinal in cally becomes conical, shrunken, and retracted out of
terminal ileum and transverse in colon]. A widely gaping the iliac fossa due to fibrosis within the mesocolon, and
ileocaecal valve with narrowing of terminal ileum [Fleischner the ileocaecal valve becomes fixed, irregular, gaping,
sign, inverted umbrella sign] or a narrowed terminal ileum and incompetent (96,100,101). There is loss of the normal
ileocaecal angle [which becomes obtuse] and the dilated
terminal ileum appears suspended from a retracted
Table 9.9: Imaging features of intestinal TB amputated caecum [goose-neck deformity]. Localised partial
Stage 1 [superficial mucosal invasion] stenosis opposite the ileocaecal valve with a rounded-off
smooth caecum and a dilated terminal ileum resemble a
  Accelerated intestinal transit
  Precipitation, flocculation or dilution of the barium suspension
‘purse-string stenosis’. Persistent narrow stream of barium
due to abnormal secretion indicates bowel stenosis and is called the ‘string sign’.
  Hypersegmentation of the barium column [chicken intestine] Terminal ileum may be fixed and narrowed due to stricture
because of abnormal tone and peristalsis while the ileocaecal valve becomes fixed, irregular and
   Mucosal pattern changes: fold irregularity and thickening incompetent. Stierlin sign and string sign are not specific
   Irregular crenated intestinal contour
for TB and may be seen in Crohn’s disease also.
Stage 2 [ulceration] Ultrasonography shows wall thickening of caecum and
  Stellate ulcers are characterised by barium speck with terminal ileum, regional lymph nodes enlargement and
converging mucosal folds mesenteric thickening. CT may show circumferential wall
  Linear ulcers are transversely oriented, resulting in spasm and thickening of the caecum and terminal ileum with adjacent
circumferential strictures
mesenteric lymphadenopathy. Asymmetric thickening of
Stage 3 [sclerosis, hypertrophy, stenosis and strictures] the ileocaecal valve, thickening of the medial caecal wall,
  Strictures are usually multiple and short with segmental dilation exophytic extension and engulfment of the terminal ileum,
of bowel loops and massive lymphadenopathy with central necrosis are
   Hour-glass stenosis: short stricture with smooth stiff contours
more suggestive of TB. CT enteroclysis has greater sensitivity
   Fixity of bowel loops, matting and speculation
and specificity for detection of bowel wall abnormalities (102).
TB = tuberculosis
TB wall thickening may show hyperintensity on T2-weighted
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 131

Table 9.10: Differentiating imaging features of ileocaecal involvement in TB and Crohn’s disease
Imaging feature TB Crohn’s disease
Wall thickening Irregular asymmetric, especially medial Circumferential, more on mesenteric
caecal wall border
Omental and peritoneal thickening Yes No
Creeping fat [abnormal quantity of mesenteric fat] No Yes
Lymph node enlargement Necrotic centres, calcification Homogeneous
Pseudosacculations No Present on anti-mesenteric border
Positive findings on chest radiograph Yes No
Barium studies Fleischner’s sign Cobblestone appearance
Enteroliths Common No
Perforations, fistulae Less common More common
TB = tuberculosis

MRI images and heterogeneous enhancement on post- attenuation at CT due to its high protein and cellular
gadolinium images. content. CT may also demonstrate tethering of bowel
The differential diagnoses for ileocaecal TB include loops and mesenteric infiltration. Peritoneal thickening
Crohn’s disease, amoebiasis and primary caecal malignancy. and nodules may be appreciated on ultrasonography or
Differentiating imaging features of ileocaecal involvement in CT especially in the presence of ascites. Similarly, there
TB and Crohn’s disease are listed in Table 9.10. Amputation can be omental thickening or caking along with thickening,
of the caecum may be seen in amoebiasis, but small bowel increased vascularity and nodularity of mesentery. Fixed
is rarely involved. Caecal malignancy is always limited by loops of bowel, standing out as spokes radiating out from
the ileocaecal valve. thickened mesenteric root are described as ‘stellate sign’.
‘Club sandwich sign’ or the ‘sliced bread’ appearance is
Appendiceal TB due to alternating layers of echogenic bowel and anechoic
inter-bowel loop fluid.
Isolated involvement does not occur, rather it is usually
The radiographic differential diagnosis includes
affected in patients with active ileocaecal TB and clinically
carcinomatosis, malignant mesothelioma, and non-TB
presents as chronic appendicitis.
peritonitis. Peritoneal mesothelioma manifests as multifocal
peritoneal thickening, omental or mesenteric soft tissue
Colonic and Anorectal TB masses, thick rigid peritoneal septae, fixed bowel loops
Colonic involvement can be segmental or diffuse and may and disproportionately small amount of ascites. Features
manifest as ulcerations, rigidity, spasms, spiculations, suggestive of TB include smooth mild perito­neal thickening
perforations and pericolic abscesses. Ulcerating proctitis is [< 5 mm], enhancement and multiple fine, mobile septae (97).
another uncommon manifestation. Fistulae, strictures and TB has also been implicated in the aetiology of sclerosing
chronic ischiorectal abscesses may occur. Anal TB, seen in encapsulated peritonitis [abdominal cocoon] [Figure 9.31].
paediatric patients, may present as ulcer, fissure, fistula, Ultrasonography and CT show clustered bowel loops,
abscess. Differentials in colon include Crohn’s disease, loculated ascites and adhesions encapsulated within a thick
ulcerative colitis, ischaemic colitis and malignancy while membrane-like sac. Barium study may show concertina-
those in anorectal region include Crohn’s, malignancy, like configuration of dilated small bowel loops in a fixed
lymphogranuloma venereum and actinomycosis. U-shaped cluster or “cauliflower sign” (105).

Peritoneal, Omental and Mesenteric TB Abdominal Lymph Node TB

Classically three forms of peritoneal TB are described Lymph node enlargement is common in abdominal TB
(89,103,104): [i] wet ascitic type [90% cases] characterised and may occur without any other evidence of abdominal
by a large amount of free or loculated viscous fluid; involvement. The common lymph nodes involved are
[ii] fibrotic-fixed type characterised by mesenteric and mesenteric, periportal, retroperitoneal and in omental
omental thickening, matted bowel loops; and [iii] dry or regions [Figures 9.32 and 9.33]. There may be lymph node
plastic type-fibrous peritoneal reaction, dense adhesions enlargement, increased number of normal-sized lymph nodes
and caseous nodules. or conglomeration with matting resulting from adhesions
Ultrasonography can detect even minimal amount of due to periadenitis. On sonography, these nodes show
ascites. It may reveal multiple fibrin strands, septations central hypoechoic area in contrast to the homogeneous
and internal debris. The ascitic fluid demonstrates high nodes seen in lymphoma [Figure 9.32]. Focal areas of
 132 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The micro­nodular form occurs in association with miliary

pulmonary TB. On CT, multiple tiny, low-attenuating lesions
may be seen. More frequently, these miliary nodules are
not apparent, but the liver or spleen appear heterogeneous
and enlarged (97). In the less common macronodular form,
multiple hypo-attenuating lesions 1-3 cm in diameter or a
single mass is seen in a diffusely enlarged liver or spleen
[Figures 9.34 and 9.35] (89). These lesions may show
heterogeneous enhancement and foci of calcification. These
lesions are usually hypoechoic on ultrasound, hypointense
on T1-weighted images, hyperintense on T2-weighted
images with a less intense rim relative to the surrounding
liver. The differential diagnosis of the miliary form includes
metastases, fungal infection, sarcoidosis, and lymphoma. The
macronodular form can be mistaken for metastases, primary
malignant tumour, or pyogenic abscess.
Pancreatic TB is rare, may present as acute or chronic
A pancreatitis or may mimic malignancy (108,109). Lesions are
commonly located in the head of pancreas, may have calci­
fication and may be associated with peripancreatic lymph
node enlargement. Multiple visceral abscesses have also been
described in patients with HIV infections (109). TB can also
affect the wall of abdominal vessels, resulting in formation
of mycotic pseudoaneurysms.

GENITOURINARY TB
Genitourinary system is a common site of EPTB and
kidneys are the most commonly involved organ [Table 9.11].
The kidneys, prostate and seminal vesicles are involved
following hematogenous dissemination from the lungs. All
other genital organs, including the epididymis and bladder,
become involved by ascent or descent of mycobacteria. The
B testicle may become involved by direct extension from an
Figure 9.31: Sclerosing encapsulated peritonitis. Here is diffuse uniform epididymal infection.
peritoneal thickening [arrow] and ascites on coronal CECT image [A].
Axial CECT image shows that peritoneal thickening is forming a sac- Renal TB
like membrane around the ascites. Small bowel loops are arranged in
concertina-like configuration [abdominal cocoon] [asterisk] [B] Early findings are best detected on intravenous urography
CECT = contrast-enhanced computed tomography [IVU] while ultrasonography, CT and MRI depict the
full extent of chronic changes. The earliest urographic
calcification may also be evident on sonography or CT. Four abnormality is loss of definition of a minor calyx with
different patterns of enhancement can be seen on CECT (106). indistinct feathery outline [“moth-eaten” calyx] due to
Most frequent is peripheral rim enhancement with hypo­ erosion and irregularity of calyces or papillae. This is
dense centre [Figure 9.33A]. This pattern seen in young frequently followed by papillary necrosis, ulceration, wall
patients reflects central liquefactive or caseous necrosis. thickening, and fibrosis of the collecting system. Pelvicalyceal
Inhomogeneous enhancement is next common manifestation system may get dilated due to a stricture of the ureteropelvic
indicative of relatively less necrosis. Homogeneous enhance­ junction, or an infundibular stricture may cause localised
ment and non-enhancement are less common patterns that hydrocalycosis. Cavitation within the renal parenchyma
may occasionally be seen. Lymphadenopathy, hypointense
may be detected as irregular pools of contrast material on
on T1-weighted [Figure 9.33B], hyperintense on T2-weighted
delayed phase images and may be seen to communicate
images [Figure 9.33C], with perinodal hyperintensity, and
with a deformed calyx. Cicatricial contractures of fibrotic
predominant peripheral rim-like enhancement may suggest
parenchyma may lead to calyceal or renal pelvic traction.
the diagnosis of TB (107).
Infundibular stenosis may lead to incomplete opacification
of the calyx [phantom calyx] due to failure of contrast
Visceral TB excretion (110). Tiny infundibular stump may be seen in
Hepatic and splenic involvement manifests in a micro­ such cases [amputated calyx]. ‘Hiked up pelvis’ is the
nodular [miliary] or macronodular [tuberculoma] form (36). term used for cephalic retraction of the renal pelvis due to
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 133

A B

C D
Figure 9.32: TB abdominal lymphadenopathy on ultrasonography. Multiple enlarged hypoechoic lymph nodes are seen in peripancreatic and
periportal locations [A]. Large precaval lymph node and small retrocaval nodes [B], mesenteric [C] and retroperitoneal nodes in pre-aortic and left
para-aortic locations [D] can also be seen.
TB = tuberculosis

A B C
Figure 9.33: Axial CECT image showing multiple enlarged ring enhancing lymph nodes in periportal, peripancreatic and aortocaval locations
with central necrosis within [asterisk]. [A] Axial T1-weighted [B] and T2-weighted [C] image showing multiple retroperitoneal lymph nodes around
the aorta and IVC and in the renal hilum region [arrows]. The nodes are hypointenseon T1 [B] and hyperintense on T2 [C] with central necrosis
[arrow] within appearing more hyperintense on T2-weighted image [C]
CECT = contrast-enhanced computed tomography
 134 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

involvement of the inferior margin. ‘Kerr’s kink’ refers to

sharply angulated pelvic kink pointing in the direction of
the involved calyx, strictured infundibulum. Calculi may
be present within the renal collecting system. Characteristic
calcifications in a lobar distribution are often seen in end-
stage TB [putty kidney]. The calcifications may also be
amorphous, granular or curvilinear, and may be seen on
radiographs and CT. End-stage disease manifests as fibrosis
and obstructive uropathy, produces autonephrectomy which
may be of two types: [i] caseo-cavernous type characterised
by an enlarged sac filled with caseous material; and
[ii] calcified shrunken non-functioning kidney (110,111).
Various patterns of hydronephrosis may be seen depend­
ing on the site of the stricture and include focal caliectasis,
caliectasis without pelvic dilatation, and generalised
hydronephrosis (112). Other common findings include
parenchymal scarring, low-attenuation parenchymal lesions
Figure 9.34: Macronodular splenic TB. Spleen is enlarged with multiple and abscesses. CT is also useful in depicting the extension
well-defined 1-3 cm hypoechoic nodules on ulrasonography of disease into the extra-renal space. Ultrasonography
TB = tuberculosis findings of renal TB include hypoechoic parenchymal

A B

C D
Figure 9.35: Ultrasonography showing well-defined solid hypoechoic mass lesion in the perihilar region of the spleen [A] with internal vascularity
on colour Doppler [B]. Axial CECT images [C and D] show mild heterogeneous contrast enhancement in the lesion [asterisk]. Ultrasonography-
guided FNAC revealed epithelioid granulomas with necrosis and stain for acid-fast bacilli was positive
CECT = contrast-enhanced computed tomography; FNAC = fine needle aspiration cytology
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 135

Table 9.11: Imaging features of TB of the urinary tract of cases and asymmetric soft tissue masses are usually
seen (108). The appearance overlaps that of metastases,
Intravenous urography
haemorrhage and pri­mary neoplasms. Bilateral involve­
Renal calcifications [amorphous, granular, or curvilinear
ment, preserved contour and peripheral rim-enhancement
calcifications and putty kidney]
Mesenteric lymph node and adrenal calcifications favour TB rather than malignancy (115). The adrenal gland
Fuzziness of minor calyces [“moth-eaten” calyces] - early finding may undergo atrophy and calcification in the end stage of
Irregularity of the tips of medullary pyramids disease and show low signal on all MRI sequences.
Infundibular stenosis and strictures
Localised caliectasis or incomplete opacification of the calix
[phantom calyx]
TB of the Ureter
Small parenchymal cavities communicating with PCS Ureter involvement [Figure 9.36] is almost always secondary
Generalised hydronephrosis or caliectasis without pelvic dilatation
to renal TB due to bacilluria. Dilatation and a ragged
Kerr’s kink and hiked-up renal pelvis
Dilatation, strictures and wall irregularity of ureter [saw-tooth irregular appearance of the urothelium are the initial
ureter] features, best appreciated on urography. In advanced
Rigid shortened ureter [pipe-stem ureter] disease, ureteral shortening, filling defects, strictures or
Reduced bladder capacity [thimble bladder] with vesico-ureteric wall calcifications may be seen (89,112). The sites of normal
reflux anatomic narrowing like pelviureteric junction, across the
Ultrasonography pelvic brim, and at the vesicoureteric junction are prone
Hydronephrosis with debris within to develop strictures (104). A “beaded” or “cork-screw”
Non-uniform caliectasis with filling defects appearance of the ureter has also been reported. Severe
Wall thickening of PCS [urothelial thickening]
thickening of the wall produces a rigid shortened ureter with
Hypoechoic parenchymal lesions
narrow lumen termed pipe stem appearance. Renal damage
CECT + CT urography
secondary to ureteral strictures may be more severe than the
Renal, ureteric and nodal calcifications
effect of the direct parenchymal involvement (116).
Hydronephrosis, irregular caliectasis, infundibular stricture,
deformed renal pelvis
Hypodense parenchymal lesions [ill-defined round or peripheral Urinary Bladder TB
wedge-shaped]
Urothelial thickening of PCS and/or ureter and/or bladder with The most common finding in TB cystitis is reduced bladder
strictures capacity which along with wall thickening and irregular
Parenchymal cavities, communicating with PCS, showing contrast contractures gives the appearance of ‘thimble bladder’.
pooling on delayed phase Large tuberculomas in bladder wall can manifest as filling
Parenchymal thinning, scarring, perinephric/periureteric fat defects simulating malignancy. In advanced disease, the
stranding
Thimble bladder
bladder is small, irregular, and calcified (89,112). Fibrosis
Necrotic lymph nodes in the region of the trigone produces gaping vesico-
MRI + MR urography
ureteric junction with free reflux. Calcified TB cystitis
must be differentiated from schistosomiasis, cystitis due to
Similar to CT, except for calcifications
MR urogram gives excellent overview without administration of cyclophosphamide, radiation-induced changes, and calcified
contrast bladder carcinoma.
Diffusion-weighted MRI can demonstrate focal pyelonephritis and
evolving abscesses Female Genital TB
TB = tuberculosis; PCS = pelvicalyceal system; CECT = contrast-
enchanced computed tomography; CT = computed tomography; Fallopian tubes are most commonly affected in female genital
MRI = magnetic resonance imaging; MR = magnetic resonance TB [in up to 94%] followed by the uterus. Salpingitis is often
bilateral and results in infertility (89). Hysterosalpingography
[HSG] is the mainstay for evaluating fallopian tube
masses, dilated irregular calyces and hydronephrosis with patency. HSG findings include tubal occlusion, strictures,
debris (113). CT and MR urography demonstrate abnormal hydrosalpinx, rigid pipe-stem tubes, endometritis with
urothelial thickening and enhancement, uneven caliectasis, adhesions [causing Asherman syndrome] with obliteration
infundibular strictures and hydronephrosis [Figure 9.36]. and T-shaped distortion of the endometrial cavity (117).
The radiographic differential diagnosis for renal TB includes Ultrasonography and CT allow for adnexal evaluation, and
other causes of papillary necrosis, transitional cell carcinoma, may show tubo-ovarian abscesses, chronic calcifications and
acute focal bacterial nephritis and xanthogranulomatous calcified lymph nodes in the adnexal region (89). Changes,
pyelonephritis. such, as uterine adhesions, hydrosalpinx and tubo-ovarian
abscess are better evident on MRI.
TB of the Adrenal Glands
Male Genital TB
TB of the adrenal glands is the most common cause of
chronic adrenal insufficiency in developing countries where The most common finding in TB prostatitis is multiple
TB is highly endemic (114). Involvement is bilateral in 90% hypoechoic areas in the peripheral zone of prostate on
 136 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 9.36: Renal TB. Axial CECT images [A and B] showing pelvi-calyectasis with urothelial wall thickening and ureteric dilatation with ureteric
wall thickening on the left side. There is perinephric fascial thickening and multiple enlarged renal hilar and retroperitoneal lymph nodes
TB = tuberculosis; CECT = contrast-enhanced computed tomography

transrectal ultrasound. CECT may reveal hypoattenuating involvement is seen as linear enhancement along the
prostatic lesions, which likely represent foci of caseous ventricular margins. Communicating hydrocephalus is the
necrosis and inflammation. At MRI, a prostatic abscess most common complication of cranial TB meningitis and
demonstrates peripheral enhancement. This finding helps has a poor prognosis. Also, ischaemic infarcts can be seen
differentiate an abscess from prostatic malignancy. In as complication of cranial tuberculous meningitis and are
addition, MRI shows diffuse, radiating, streaks of low commonly bilateral. Majority are located in the basal ganglia
signal intensity in the prostate [watermelon skin sign] on and internal capsule, resulting from vascular compression
T2-weighted images (118). TB epididymo-orchitis usually and occlusion of middle cerebral artery and its branches
manifests as focal or diffuse areas of decreased echogenicity especially small perforating vessels (120-122). Cranial nerves
in testis and heterogeneous hypoechoic, enlarged, nodular may also be involved.
epididymis at ultrasound (119). Urethral involvement leads The MRI features of spinal TB meningitis include
to strictures, fistulas and periurethral abscesses. cerebrospinal fluid [CSF] loculations and obliteration of
the spinal subarachnoid space. There is loss of outline of
NEUROLOGICAL TB the spinal cord especially in the cervico-thoracic spine and
matting of the nerve roots in the lumbar region. Contrast-
Haematogenous dissemination leads to subependymal or
enhanced MRI reveals nodular, thick, linear intradural
subpial focus of TB [Rich focus] which may be located in
enhancement (122,123). Syringomyelia can occur as a
the meninges, brain, or spinal cord. Central nervous system
complication of arachnoiditis, is seen as cord cavitation that
TB may take a variety of forms, including meningitis,
demonstrates fluid signal intensity and does not show any
tuberculomas, abscess, cerebritis, ventriculitis and miliary
enhancement (122).
involvement. TB meningitis is believed to be caused by
rupture of a Rich focus into the cerebrospinal fluid [CSF].
However, tuberculoma may be secondary to haematogenous Cerebral Parenchymal TB
spread of systemic disease or evolve from extension of CSF Cerebral parenchymal disease [Figures 9.37 and 9.38] can
infection into the adjacent parenchyma (120,121). Post- occur with or without meningitis and usually manifests
gadolinium MRI is superior to CECT for demonstration of as tuberculomas while abscess and cerebritis are relatively
meningeal disease as well as parenchymal abnormalities. rare (120). Multiple tuberculomas are usually evident. The
frontal and parietal lobes are the most commonly affected
TB Meningitis regions with corticomedullary junction and periventricular
Meningeal involvement, the most common presentation of location being the predisposed sites. On CT, tuberculomas
CNS TB, is seen more commonly in children and young appear as rounded or lobulated masses demonstrating
adults [Figures 9.37 and 9.38]. On both CT and MRI, there homogeneous or ring enhancement and have irregular walls
is abnormal meningeal enhancement [corresponding to of varying thickness. The MRI features of a tuberculoma
gelatinous exudates], typically more pronounced in the depend upon whether it is caseating or not. Non-caseating
basal cisterns and sylvian fissures along with plaque tuberculomas are often hyperintense on T2-weighted images
like dural thickening. Even on non-contrast computed with homogeneous [nodular] enhancement. Caseating solid
tomography [NCCT], there is obliteration of the basal granulomas are isointense to markedly hypointense on
cisterns by isodense-hyperdense exudates. Ependymal T2-weighted images and exhibit rim enhancement (120-122).
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 137

A B

Figure 9.37: Axial contrast-enhanced MR image in patient of TB menin­

gitis showing abnormal meningeal enhancement in bilateral [more
prominent in left] sylvian fissure regions [A]. Axial contrast-enhanced
MR image shows thick-walled ring enhancing lesion in the right high
parietal lobe with significant amount of hypointense perilesional
oedema [B]. MR spectroscopy shows lipid peak at 1.3 ppm, favouring
the diagnosis of TB [C]
C MR = magnetic resonance; TB = tuberculosis

A B
Figure 9.38: Axial contrast-enhanced MR image showing abnormal meningeal enhancement in the basal cisterns corresponding to basal
exudates. Ring-enhancing tuberculomas are also seen in the left mid-brain region [A]. Sagittal contrast-enhanced MR image showing abnormal
thick enhancement along the surface of spinal cord and also lining the CSF loculations anterior to the cord [B]
MR = magnetic resonance; CSF = cerebrospinal fluid
138 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 9.12: Characteristic imaging features of neurological infections including TB

TB Neurocysticercosis Toxoplasmosis Lymphoma
Lesions are larger than NCC Individual lesion usually less than Basal ganglia and gray-while Hyperdense on non-contrast CT
2 cm matter junction are favoured sites
Thick irregular walls Periphery is smooth and thin T2 intermediate signal intensity
Perilesional oedema more than Clustering of lesions more Asymmetric nodular ring Marked diffusion restriction
NCC common enhancement
T2 hypointense central core Eccentric scolex visible as Elevated lipid-lactate with Periventricular predominance
favours TB hyperdensity or calcification on diminished levels of all other
CT and T2 hypointensity on MR metabolites on MR spectroscopy
Associated TB meningitis may Elevated choline on MR
be seen spectroscopy
Lipid peak on MR spectroscopy Central core is hyperintense on Haemorrhage may be detected Elevated relative cerebral blood
T2-weighted images [exception: on MR volume on MR perfusion
calcification]
Central core may show diffusion No diffusion restriction Haemorrhage is rare
restriction
TB = tuberculosis; NCC = neurocysticercosis; CT = computed tomography; MR = magnetic resonance

Granulomas with central liquefaction appear centrally of a focal mass. The laryngeal framework usually remains
hyper­intense on T2-weighted images with rim enhancement intact. Sinonasal cavity, thyroid gland, pharynx and skull
and surrounding oedema. Miliary tubercles appear as base can also be rarely involved.
numerous round, homogeneously enhancing lesions less
than 2 mm in diameter (122,124). Magnetic resonance [MR] MUSCULOSKELETAL TUBERCULOSIS
spectroscopy shows prominent lipid peaks in tuberculomas.
On imaging, TB abscess may be indistinguishable from Skeletal involvement occurs in approximately 1%–3% of
pyogenic abscess. Thin smooth wall, large size [> 3 cm], patients with TB. Evidence of concurrent active intrathoracic
presence of loculations and relatively less oedema favour TB. TB is present in less than 50% of these patients (127).
The differential diagnosis for cranial and spinal TB
includes other infectious or non-infectious inflammatory TB Spondylitis
diseases [e.g., sarcoidosis, lymphoma, toxoplasmosis, neuro­ The spine is the most common site of osseous involvement
cysticercosis, pyogenic and fungal infections], multicentric [in up to 50% of cases] (128). The most common location
primary neo­p lasms [e.g., hemangioblastoma, gliomas], is upper lumbar and lower thoracic spine. Usually two
and metastases [Table 9.12] (122). Features favouring consecutive vertebrae are involved but several vertebrae
tuberculomas over neuro­cysticercosis include larger size may be affected; skip lesions and single-level involvement
[> 20 mm], thick irregular walls, central T2 hypo­intensity, may also occur. The disease process usually begins in the
lipid peak on MR spectroscopy, concomitant meningitis anterior part of the vertebral body adjacent to the end
and relatively more perilesional oedema. In contrast, plate. The disk space may then become involved via several
presence of eccentric scolex and clustering of lesions favour routes. Extension may occur along the anterior or posterior
cysticercosis. longitudinal ligament or directly through the end plate.
Disk involvement manifests as collapse of intervertebral
EXTRACRANIAL, EXTRANODAL HEAD AND disk space (129). However, disk space involvement occurs
NECK TB late and is less marked compared with pyogenic infection.
Less often, posterior elements of the spine may get involved.
In TB otomastoiditis, CT demonstrates soft-tissue opacifi­
Collapse of a vertebral body, particularly the anterior
cation of the tympanic cavity and destruction of middle
segment, may result in TB kyphosis. Depending upon the site
ear structures in the later stages. Associated retro­auricular
of infection, four types of involvement can occur: paradiskal,
or epidural abscess can be seen. The differential diagnoses
anterior subperiosteal, central and appendiceal.
include pyogenic or fungal infections, sarcoidosis, cholestea­
toma, and Wegener’s granulomatosis.
Paradiskal
Chorioretinitis and uveitis are the most common mani­
festations of ocular TB (125,126). On CT or MRI, ocular Paradiskal involvement is the most common type wherein
TB usually manifests as a unilateral choroidal mass with disease process begins in the anterior part of the vertebral
melanoma, metastasis, hemangioma, sarcoidosis, and fungal body adjacent to the end plate. Two adjacent vertebral bodies
infection being the main differential diagnoses. Laryngeal are usually involved. There is demineralisation and loss of
TB manifests as soft-tissue thickening and infiltration of the definition of their end plates. Reactive sclerosis or periosteal
pre-epiglottic and paraglottic spaces, without the presence reaction in the adjoining vertebral bodies is typically
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 139

absent. With spread of infection, there is narrowing of the pleura line is displaced laterally by the paravertebral abscess
intervertebral disk space. With disease progression, there producing a fusiform ‘bird’s nest’ appearance [Figure 9.39].
is anterior wedging leading to varying degrees of kyphosis CT and MR imaging are of great value in demons­trating
and gibbus formation. a small focus of bone infection, complete extent of the
disease and treatment response [Figure 9.40]. However, the
Central diagnosis of TB is favoured if a large, calcified paravertebral
mass and absence of sclerosis or new bone formation is
In the central type, a lytic region devoid of normal trabecular seen. Conversely, intervertebral disk destruction is more
pattern is seen in the centre of vertebral body away from characteristic of a pyogenic infection.
the disk margins. This gradually enlarges and the vertebral
body may expand like a tumour. In late stages, concentric
TB Osteomyelitis
collapse occurs, just like vertebra plana.
Isolated TB osteomyelitis in the absence of associated TB
Anterior Subperiosteal arthritis is relatively rare. When it does occur, however,
femur, tibia and small bones of the hands and feet are most
In the anterior subperiosteal type, the infection begins at commonly involved. Typically, the metaphyses are affected.
the anterior vertebral margin underneath the periosteum Radiographic findings [Figure 9.41] include osteopenia,
and spreads beneath the anterior longitudinal ligament osteolytic foci with ill-defined edges, and varying amounts
producing anterior erosions of multiple vertebrae. of sclerosis (130). Sequestrum formation is more common
in children. One specific type of TB osteomyelitis is cystic
Appendiceal or Neural Arch
Isolated involvement of the neural arch is rare; usually
it occurs in contiguity with vertebral body involvement.
Unilateral pedicle involvement is the most common
manifestation. Pedicular and laminar involvement favours
TB whereas pyogenic spondylitis has a predilection for
facet joints.
Paravertebral abscesses form early and are seen in the
thoracic region as posterior mediastinal mass and in the
cervical region as widening of prevertebral soft tissues.
Paraspinal infection can also involve the psoas muscle,
resulting in psoas abscess, which can extend into the groin
and thigh. Calcification within the abscess is considered patho­
gnomic of TB (130). In the dorsal spine, the posteromedial
A

B
Figure 9.40: Axial [A] and coronal [B] CECT images showing presence
Figure 9.39: Chest radiograph [postero-anterior view] showing of prevertebral and paravertebral abscess with adjacent bone erosion.
fusiform ‘bird nest’ paravertebral abscess in lower thoracic region with Note is made of mild pericardial effusion as well. Following anti-TB
involvement of D9 and D10 vertebrae and intervening intervertebral treatment, there was near-complete resolution of these findings
disk space CECT = contrast-enhanced computed tomography; TB = tuberculosis
 140 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B

C D
Figure 9.41: Shoulder radiograph [antero-posterior view] [A] showing ill-defined lytic lesion involving left proximal metaphysis with solid periosteal
reaction and large soft tissue opacity lateral to it. Joint space is relatively preserved. No definite erosions are seen. Coronal [B], axial [C] and
sagittal [D] contrast-enhanced MR images showing intra-osseous and large extra-osseous peripheral rim-enhancing TB abscesses involving
proximal humerus, also extending into the gleno-humeral joint space; left axillary lymphadenopathy is also evident
MR = magnetic resonance; TB = tuberculosis

TB which affects diaphysis in children and young adults.

On radiographs, the lesions are oval to round, radiolucent,
well defined, and show variable amounts of sclerosis.
The radiographic features of cystic TB resemble those of
eosinophilic granuloma, sarcoidosis, cystic angiomatosis,
multiple myeloma, chordoma, fungal infections, and
metastases (130). TB involvement of short tubular bones of
the hands and feet is termed TB dactylitis and is common
in children. Fusiform soft-tissue swelling, bony expansion
and periostitis are the most common radiographic findings.
As underlying bone is destroyed, a cyst-like cavity forms
and the remaining bone appears to be ballooned out. This
appearance is termed spina ventosa [“wind-filled sail”] (130).
A useful feature in distinguishing TB from pyogenic infection
in immature skeleton is presence of trans-physeal spread;
however, fungal infections can also extend across the physis.
Other diseases, such as sarcoidosis, haemoglobinopathies, Figure 9.42: Pericardial TB. Coronal CECT image showing pericardial
hyperparathyroidism, and leukaemia may produce changes effusion and uniform, regular pericardial thickening
similar to those of TB dactylitis (130). TB = tuberculosis; CECT = contrast-enhanced computed tomography
 Roentgenographic Manifestations of Pulmonary and Extra-pulmonary Tuberculosis 141

A B

C D

E F
Figure 9.43: PET axial images [A, C, E] showing focal FDG uptake [arrow] in mediastinum [A] in abdomen, retroperitoneum [C], and mesentery
[E]. Corresponding PET-CT fusion images aptly localising FDG uptake [arrow] in prevascular space of thorax [B], retroperitoneum [D] and
mesentery [F]
PET = positron emission tomography; FDG = fluorodeoxyglucose; PET-CT = positron emission tomography-computed tomography
Kind courtesy: Dr Rakesh Kumar, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi
 142 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

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findings in adult pulmonary tuberculosis. AJR Am J Roentgenol
TB of the joints is characteristically a mono-articular 1980;134:1015-8.
disease with knees and hips being most frequently affected 4. Leung AN, Brauner MW, Gamsu G, Mlika-Cabanne N, Ben
[Figure 9.41]. The triad of juxta-articular osteoporosis, peri­ Romdhane H, Carette MF, et al. Pulmonary tuberculosis: com­
pherally located osseous erosions, and gradual narrowing of parison of CT findings in HIV-seropositive and HIV-seronegative
patients. Radiology 1996;198:687-91.
the joint space is called the Phemister triad and is characteristic
5. Greenberg SD, Frager D, Suster B, Walker S, Stavropoulos C,
of TB arthritis. However, these features can also be observed Rothpearl A. Active pulmonary tuberculosis in patients with
in rheumatoid arthritis [RA] (130). Relative preservation AIDS: spectrum of radiographic findings [including a normal
of the joint space is highly suggestive of TB arthritis; early appearance]. Radiology 1994;193:115-9.
loss of articular space is more typical of RA . MRI may be 6. Long R, Maycher B, Scalcini M, Manfreda J. The chest roentgeno­
helpful in differentiating between RA and TB arthritis (131). gram in pulmonary tuberculosis patients seropositive for human
immunodeficiency virus type 1. Chest 1991;99:123-7.
Uniform synovial thickening, large size of bone erosions,
7. Kim WS, Moon WK, Kim IO, Lee HJ, Im JG, Yeon KM, et al.
rim enhancement at site of bone erosion, and extra-articular Pulmonary tuberculosis in children: evaluation with CT. Am J
cystic masses favour TB arthritis (131). The eventual result Roentgenol 1997;168:1005-9.
in tuberculous arthritis is usually fibrous ankylosis of the 8. Jones BE, Ryu R, Yang Z, Cave MD, Pogoda JM, Otaya M, et
joint whereas bony ankylosis favours pyogenic arthritis. al. Chest radiographic findings in patients with tuberculosis
Moreover, periostitis and osseous proliferation are generally with recent or remote infection. Am J Respir Crit Care Med
more frequent and extensive in pyogenic arthritis than in 1997;156:1270-3.
9. Geng E, Kreiswirth B, Burzynski J, Schluger NW. Clinical and
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radiographic correlates of primary and reactivation tuberculosis:
of necrosis [kissing sequestra] may be present on both sides a molecular epidemiology study. JAMA 2005;293:2740-5.
of the affected joint. Necrosed cartilage and fibrinous material 10. Lee KS, Song KS, Lim TH, Kim PN, Kim IY, Lee BH. Adult-onset
form rice bodies in synovial joints, tendon sheaths and bursae. pulmonary tuberculosis: findings on chest radiographs and CT
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UNCOMMON BODY SITES 11. Pineda PR, Leung A, Müller NL, Allen EA, Black WA, FitzGerald
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[Figure 9.42]. Myocardial involvement is even rarer and spectrum of primary tuberculosis in adults. Confusion with
reinfection in the pathogenesis of chronic tuberculosis. Ann
detected on post-mortem studies.
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15. Choyke PL, Sostman HD, Curtis AM, Ravin CE, Chen JT,
POSITRON EMISSION TOMOGRAPHY-COMPUTED Godwin JD, et al. Adult-onset pulmonary tuberculosis. Radiology
TOMOGRAPHY 1983;148:357-62.
16. Andronikou S, Joseph E, Lucas S, Brachmeyer S, Du Toit G,
FDG-PET holds particular promise for monitoring response Zar H, et al. CT scanning for the detection of tuberculous
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18. Lee JY, Lee KS, Jung KJ, Han J, Kwon OJ, Kim J, et al. Pulmonary
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 10
Pulmonary Tuberculosis
VK Vijayan, Sajal De

INTRODUCTION sunlight quickly kills these bacilli. Of the several factors,

determining an individual’s risk of exposure, two factors
Pulmonary tuberculosis [TB] is a chronic infectious disease
are important. These include the concentration of droplet
of lung caused by Mycobacterium tuberculosis [Mtb] (1).
nuclei in contaminated air and the length of time that air is
Nontuberculous mycobacteria [NTM] exist in environ­
breathed. The risk of transmission of infection from a person
ment as saphrophyte and some can cause human disease
with sputum smear-negative pulmonary TB and miliary TB
especially in immunocompromised individuals (2). Pulmo­
is low and with extra-pulmonary TB [EPTB] is even lower.
nary TB patients who have cavitary lesions in their lung
are an important source of infection. These patients are
NATURAL HISTORY OF TUBERCULOSIS
usually sputum smear-positive. Coughing, sneezing or
talking produces tiny infectious droplets. One bout of The cardinal event in the pathogenesis of TB, whether
cough produces 3000 droplet nuclei and these can remain inapparent or overt is the implantation of Mtb in the tissues.
suspended in the air for a long period of time. Effective Lung is the most frequent portal of entry [Figures 10.1A and
ventilation can dilute these infectious nuclei. Mtb can 10.1B]. The organism enters the lung from the inhalation
survive in the dark for several hours. Direct exposure to of air-borne droplets, which have been coughed out by

Figure 10.1A: Chest radiograph [postero-anterior view] showing a Figure 10.1B: Chest radiograph [postero-anterior view] of the same
cavity in left upper zone [arrow]. Sputum culture was positive for Myco­ patient at 24 months of follow-up. The patient had received six months
bacterium tuberculosis short-course chemotherapy. The left upper zone cavity has disappeared
 Pulmonary Tuberculosis 147

‘open’ [sputum-positive] pulmonary TB patients who have obstruction becomes atelectatic [epituberculosis] (3). If the
received no treatment, or have not been treated fully. The obstruction is incomplete, it may act as a “ball-valve” and
initial contact with the organism results in few or no clinical results in obstructive emphysema. The inflammed caseous
symptoms or signs. The tubercle bacillus sets up a localised lymph nodes may erode through the walls of the bronchus
infection in the periphery of the lung. Four-to-six weeks and result in bronchogenic dissemination. Bronchial mucosal
later, tuberculin hypersensitivity along with mild fever and involvement may result in TB bronchitis. In a patient with
malaise develops. In the majority of patients, the process is overwhelming infection, large number of Mtb may gain
contained by local and systemic defenses. Rupture of the access to the circulation and result in miliary and meningeal
sub-pleural primary pulmonary focus into the pleural cavity TB. In majority of the patients, the initial focus of infection
may result in the development of TB pleurisy with effusion. subsides. Cicatrisation, scar formation and often calcification
Less commonly, tubercle bacilli may be ingested and develop. Repeated episodes of extension of infection
lodged in the tonsil or in the wall of the intestine. This form followed by healing and fibrosis may result in the formation
of TB occurs following the ingestion of contaminated milk of “onion skin” or “coin lesion” (2).
or milk products. Rarely, TB can occur as a result of direct
implantation of the organisms into the skin through cuts and Post-primary Tuberculosis
abrasions. This form of TB is a health hazard faced by health
care workers and laboratory staff who handle materials Rarely, the primary lesion may progress directly to the
infected with Mtb. These lesions were termed “prosector’s post-primary form characterised by extensive caseation
warts” (2). Unfortunately, Laennec, the inventor of the necrosis and cavitation. More commonly, the primary lesion
stethoscope, acquired TB in this fashion which eventually remains quiescent, and may remain so for decades or for
led to his death (2). the remainder of the individual’s life time. The precise
mechanism[s] underlying this phenomenon has not yet been
clarified as yet. However, reactivation or reinfection TB may
Primary Tuberculosis
occur due to old age, malnutrition, malignant disease, HIV
From the implantation site, the organisms disseminate via infection and acquired immunodeficiency syndrome [AIDS],
the lymphatics to the regional lymph nodes. The lesion at use of immunosuppressive drugs and intercurrent infections.
the primary site of involvement, draining lymphatics and While reactivation can occur at any site, post-primary
the inflammed regional lymph node constitutes the primary TB classically involves the apical posterior segments of the
complex. When the primary site of implantation is in the lung, upper lobes, or, the superior segment of the lower lobes in
it is called Ghon’s focus. The draining lymphatics and the more than 95% of the cases. Balasubramanian et al (4) have
involved lymph nodes together with Ghon’s focus constitute critically reviewed the pathway to the apical localisation in
the primary complex [Ghon complex]. In children, the lymph TB and proposed the integrated model for the pathogenesis
node component may be much larger than the Ghon’s focus. of TB.
Having secured entry, tubercle bacilli then disseminate Post-primary lesions are different from primary lesions
via the haematogenous route to other parts of the lung and in that, local progression and central caseation necrosis are
many organs of the body. Thus, TB widely disseminated much more marked in post-primary TB as compared to
during primary infection. Most of these metastatic foci primary TB. TB cavities are abundant sites for the growth
heal at their own. However, some of these metastatic foci of Mtb as the temperature in them is optimal, there is
may remain dormant and may reactivate at a later date abundance of oxygen and various nutrients derived from
when the host resistance decreases. The subsequent course the cell wall are readily available. The bacilli in the wall
of the events varies considerably. In most of the patients, of the cavity gain free access into the sputum and are
the primary complex resolves without becoming clinically expectorated. Such patients are said to have “open TB” and
apparent. This occurs when the immune status of the host are infectious to the community. If these bacilli are aspirated
is good, and healing occurs by fibrosis and calcification. from the cavity to other parts of the lung via the bronchi,
In a minority of patients, progressive primary TB due to many secondary pulmonary lesions develop. Early in the
the extension of the inflammatory process at the site of the illness, TB cavities are moderately thick walled, usually
primary focus can occur. In the lung, this can present as have a smooth inner surface, lack an air-fluid level and are
an area of consolidation [TB pneumonia]. This form of the surrounded by an area of consolidation. Later, in the chronic
disease was often encountered in the pre-chemotherapeutic phase of the disease, the wall may become thin, and the
era and was termed “galloping consumption” or “pneumonia cavities may appear spherical.
alba” [white pneumonia]. This form is encountered in the
present era in patients with human immuno­deficiency virus
SYMPTOMS
[HIV] infection. Caseation necrosis at the Ghon’s focus may
lead to liquefaction. Expectoration of the liquefied material Pulmonary TB is a disease of protean manifestations and
can leave a cavity with shaggy margins in the pulmonary can mimic many diseases. Previous accounts referred to
parenchyma which may be apparent on the chest radiograph. the development of erythema nodosum, phlyctenular con­
Mediastinal and tracheobronchial lymphadenopathy junctivitis and fever at the time of tuberculin conversion (2).
may produce compression of the adjacent bronchus. If this However, this presentation is uncommonly seen today. The
obstruction is complete, the lung distal to the site of bronchial patient may develop symptoms insidiously and some may
148 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

remain asymptomatic. Usually patients with pulmonary TB may be observed in severe cases. Tachycardia can occur and
present with constitutional and respiratory symptoms (3). is usually proportional to the fever. Digital clubbing occurs
Constitutional symptoms include tiredness, headache, rarely in advanced cases and with superadded suppuration.
weight loss, fever, night sweats and loss of appetite. Fever There can be an increase in the respiratory rate. EPTB foci
in TB usually appears in the late afternoon or evening, and such as cold abscess, enlarged cervical and mesenteric
is low-grade at the onset and becomes high-grade with the lymph nodes, deformity or localised immobility of the spine,
progression of disease. Some patients may remain afebrile. epididymitis, etc., can be discovered on general physical
Weight loss may precede the other symptoms. The classic examination. In addition, general physical examination may
symptoms and signs of TB are observed more frequently also reveal phlyctenular conjunctivitis or keratitis. Further,
among younger group than elderly: fever [62% versus 31%], signs of meningeal irritation and focal neurological signs
weight loss [76% versus 34%], night sweats [48% versus 6%], may be apparent in patients with extrapulmonary focus
sputum production [76% versus 48%], and haemoptysis in the nervous system. Associated signs of protein-energy
[40% versus 17%] (5). Associated laryngeal TB can result malnutrition such as anasarca, change in hair colour and
in hoarseness of the voice. Amenorrhoea can occur in leuconychia may occur. Adult patients with chronic disease
severe diseases. The most common respiratory symptom of can present with lower body mass index [BMI; kg/m2].
pulmonary TB is cough which lasts for two or more weeks. Respiratory system examination may reveal displacement
Cough may be dry or productive. It is nearly impossible of the trachea and the heart depending on the underlying
to differentiate cough due to pulmonary TB from cough patho­logy. Asymmetrical abnormalities of the chest wall
due to other respiratory diseases including smoking and such as retraction, fibrosis or collapse and prominence in
it is often passed off as a smoker’s cough. Sputum may be pleural effusion, emphysema or pneumothorax may be
mucoid, muco-purulent, purulent or blood-tinged and is observed. Undue prominence of the clavicular head of the
usually scanty. Haemoptysis, although observed in many sternocleidomastoid muscle [Trail’s sign] on one side may be
diseases, is an important and often the presenting symptom indicative of apical fibrosis due to TB. Mobility of any part
of pulmonary TB. Furthermore, TB is the most common of the chest wall may be restricted on the affected side. A
cause of haemoptysis in India. Severity of haemoptysis dull percussion note can occur as a result of consolidation,
in pulmonary TB varies from blood-stained sputum to collapse of the lung, or thickened pleura or extensive
massive haemoptysis. Massive haemoptysis usually results infiltration of the lung due to TB. A stony dull note can be
from rupture of a bronchial artery (1). Chest pain may be elicited over a pleural effusion or empyema. Hyperresonance
dull aching in character. Acute chest pain can occur in TB on percussion is encountered in pneumothorax. Cracked-
pleurisy or in pneumothorax; with severe pain occurring at pot sound may be elicited in cases where percussion is
the height of inspiration. In diaphragmatic pleurisy, pain is practiced over a cavity which communicates with bronchus
referred to the ipsilateral shoulder when central part of the of moderate size and is most distinct when the mouth is
diaphragm is involved. Occasionally chest pain can occur open. It results due to a sudden expulsion of air through
from fracture of ribs due to violent coughing. Breathlessness a constricted orifice. It has a hissing character, combined
results from extensive disease or if complications such as with a clinking sound like that produced by shaking coins
bronchial obstruction, pneumothorax or pleural effusion together. It is a rare finding. Cracked-pot sound is often
occur. Localised wheeze can occur due to endobronchial produced in healthy children when percussion is performed
TB or because compression of the bronchus by enlarged during crying. Myotactic irritability/myoedema can occur
lymph nodes. due to hyperirritability of malnourished muscles in front of
In addition to classical symptoms of cough and/or fever, the thorax. A light tap over the sternum produces fibrillary
paediatric patients may present with loss of body weight contractions, at some distance off, in the pectoral muscles.
[defined as a loss of >5% of the highest weight recorded High-pitched [tubular] bronchial breathing can be heard
in the past three months]. Symptoms of pulmonary TB in patients with TB pneumonia. Bronchial breathing can be
among immunocompromised host produces symptoms of low-pitched [cavernous] if there is an underlying cavity in
combination of two diseases and symptoms of one disease the lung or an open pneumothorax. A special type of high-
often mimic the other. Clinical manifestations of TB in pitched bronchial breathing with an “echo-like” quality
HIV-infected patients vary and generally depend upon [amphoric breathing] is indicative of a large cavity with
the severity of immunosuppression. In early stages of HIV
smooth walls or of a pneumothorax communicating with
disease, clinical presentation of TB tends to simulate that
a bronchus. It resembles the sound produced by blowing
observed in persons without immunodeficiency. Weight loss
across the mouth of a bottle and consists of one or more
and fever are the most frequent symptoms seen in patients
low-pitched fundamental tones and a number of high-
co-infected with HIV and TB (6). The reader is referred to
pitched overtones. Vocal fremitus is increased when lung is
the chapter “Tuberculosis and human immunodeficiency virus
consolidated or contains a large cavity near the surface. Vocal
infection” [Chapter 35] for further details.
fremitus is diminished when the corresponding bronchus is
obstructed and is absent when there is pleural effusion or
PHYSICAL SIGNS thickening. The presence of fine crepitations, especially post-
A thorough general physical examination should be done tussive crepitations, is an important sign of TB infiltration.
in all patients with pulmonary TB. Anaemia and cachexia A pleural rub is characteristic of pleurisy.
 Pulmonary Tuberculosis 149

Hippocratic succussion is the splashing sound which can Tuberculin Skin Test, Interferon-Gamma
be heard when a patient who has both air and fluid in the Release Assays
pleural cavity is shaken or moved suddenly. Post-tussive
suction, a sucking noise resembling that produced by an The reader is referred to the chapter “Laboratory diagnosis
India-rubber ball that is spring­ing open again, can be heard of tuberculosis: Best practices and current policies” [Chapter 8]
after a coughing, over a cavity in the lung when its walls for details on these topics.
are not too rigid. It occurs due to re-entry of air.
Imaging
DIAGNOSIS Imaging remains one of the important diagnostic modalities
The definitive diagnosis of pulmonary TB [primary and for diagnosing pulmonary TB. Sputum negativity does not
post-primary forms of the disease] involves detection exclude pulmonary TB especially when clinical symptoms
and isolation of Mtb. In addition, identification of the and radiographic features are suggestive of TB. Standard
mycobacterial species and drug-susceptibility testing may posterior-anterior view of chest should be obtained in
be required for the management. patients who have signs and symptoms suggestive of
pulmonary TB. Initial radiological manifestations include
parenchymal infiltration with ipsilateral lymph node
Haematology
enlargement. Hilar or mediastinal lymph node enlargement
Haematological abnormalities in pulmonary TB include in TB is usually unilateral and this lymph nodal enlargement
anaemia, leucocytosis, leucopaenia, purpura, leukaemoid persists longer than the parenchymal lesions. Calcification
reaction and polycythaemia vera. The erythrocyte sedi­ of the lymph nodes and the lung lesions could occur
mentation rate [ESR] is often [but not always] raised in TB several years after infection. In adults, the lesions may be
and is commonly used as a surrogate marker of active TB patchy or nodular infiltrates and may occur in any segment.
by clinicians. However, due to wide range of normal value, Dense and homogeneous lesions with lobar, segmental or
raised ESR value should not be used as a diagnostic test for subsegmental distributions are also encountered frequently
TB even among children (7). [Figures 9.5, 9.12, 9.13, 10.1A, 10.1B, 10.2, 10.3A, 10.3B and
10.4]. Cavitation, often multiple, occurs in immunocompetent
Diagnostic Mycobacteriology individuals, but is rare in immunocompromised individuals
[Figures 9.16 and 9.17]. The radiographic features of
The definitive diagnosis of pulmonary TB is made by the pulmonary TB in HIV-positive patients are frequently
isolation and identification of the Mtb. All patients presenting atypical, particularly, in the late stage of HIV infection, with
with cough and sputum for more than two weeks must have non-cavitary disease, lower lobe infiltrates, hilar lymph-
their sputum examined for Mtb. In addition, Mtb can be adenopathy and pleural effusion. More typical post-primary
isolated from bronchial washings, bronchoalveolar lavage TB with upper lobe infiltrates and cavitation is seen in the
[BAL] fluid, pleural fluid, gastric aspirate, pus, cerebrospinal earlier stages of HIV infection.
fluid [CSF], urine, blood, bone marrow biopsy and other
tissue biopsy specimens. All diagnostic specimens should
be collected before the patient is given anti-TB treatment.
Sputum microscopy is the earliest and quickest procedure
for the preliminary diagnosis of pulmonary TB. Patients
should be instructed that the material brought out from
the lungs after a productive cough, not the nasopharyngeal
discharge or saliva. The patient should rinse his/her
mouth with water before specimen collection to remove
materials that interfere with interpretation. Sputum collec­
tion should be done in an isolated, well-ventilated area.
Sputum specimen should be collected in a wide-mouth,
rigid container with tight-fitting screw tops. If the patient
cannot produce sputum, deep coughing may be induced
by inhalation of an aerosol of warm hypertonic [3% to 15%]
saline or gastric lavage especially in children can be collected.
The bacilli can be stained with basic fuchsin dyes [Ziehl-
Neelsen or Kinyoun method] or with a fluoro-chrome
[auramine-rhodamine] staining. The positive predictive
value of a properly performed smear is more than 90%
Figure 10.2: Chest radiograph [postero-anterior view] showing
for pulmonary TB. In areas with low prevalence of NTM extensive parenchymal lesions in the left lung. Few scattered lesions
fluoresceindiacetate [FDA] vital staining of sputum can help are also seen in the right lung. The sputum smear and culture were
in early diagnosis of rifampicin resistance (8). positive for Mycobacterium tuberculosis
 150 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 10.3A: Chest radiograph [postero-anterior view] showing Figure 10.4: Chest radiograph [postero-anterior view] of a patient with
extensive parenchymal infiltrates in the right lung. Few scattered sputum smear-negative and culture-positive pulmonary tuberculosis
infiltrates are also seen in the left lung. The patient had multidrug-
resistant pulmonary tuberculosis
appearance [Figure 9.18]. Cavitations usually occur at the
centrilobular area and may progress to a larger coalescent
cavity. The CT scan can document miliary disease even when
chest radiograph is normal. CT findings of early miliary
dissemination commonly include ground-glass opacification
with barely discernible nodules. On HRCT, miliary TB
typically shows fine, nodular or reticulonodualr pattern
with nodules involving both intralobular interstitium,
interlobular septa and subpleural, and perivascular regions.
Nodules are evenly distributed throughout the lung. CT
more accurately defines the group of lymph nodes involved,
their extent and size. The lymph nodes with central low
attenuation and peripheral rim enhancement especially
with contrast strongly suggest a diagnosis of mycobacterial
infection. Complications of TB like post-TB bronchiectasis,
aspergilloma etc., are better diagnosed with the help of a CT.
Other radiographic findings in pulmonary TB include
atelectasis and fibrotic scarring with retraction of the hila
and deviation of the trachea. Unilateral pleural effusion may
be the only radiographic abnormality in pleural TB. Rarely,
Figure 10.3B: Chest radiograph [postero-anterior view] of the same chest radiographs may be normal especially in patients
patient taken a year later showing pneumothorax on the right side and with endobronchial TB and HIV infection. It is important
a large cavity in the left lung. The patient did not respond to treatment to compare the current chest radiographs with the previous
and died radiographs done months or years earlier so that subtle
changes can be detected. Progression of lesions on serial
Computed tomography [CT] is more sensitive than chest chest radiographs indicates active disease.
radiograph in detecting subtle parenchymal changes and Apical-lordotic or oblique view of chest may aid in
mediastinal involvement. Primary TB typically appears visualisation of lesions obscured by bony structures or the
as air-space consolidation with hilar or mediastinal heart. Contrast-enhanced computed tomography [CECT]
lymphadenitis. Post-primary TB most commonly appears and magnetic resonance imaging [MRI] of the chest may
as nodular and linear opacities at the lung apex. High- be useful in defining intrathoracic lymph nodes, nodules,
resolution computed tomography [HRCT] findings of early cavities, cysts, calcification and vascular details in the lung
bronchogenic spread of post-primary TB are centrilobular parenchyma. Bronchial stenosis or bronchiectasis can be
2 to 4 mm nodules or branching linear structures and poorly defined by bronchography and CT of the chest. Fluoroscopy
defined nodules on CT scan correspond to caseous materials may be useful in the detection of the mobility of thoracic
filling the bronchioles and this is referred as “tree-in-bud” structures.
 Pulmonary Tuberculosis 151

Bronchoscopy Point-of-Care Diagnostic Tests

Microbiologic confirmation of TB among sputum smear- Numbers of novel techniques are currently available as
negative patients is important, especially in immuno­ point-of-care diagnostic tests for TB. These tests are simple
compromised hosts. Fibreoptic bronchoscopy is useful to enough to be performed without the help of a specialized
collect various types of specimens [aspirate, brush, lavage laboratory and the results are immediately available.
fluid and biopsy] for diagnosis of TB among sputum These tests—will be useful as adjunctive diagnostic tests in
smear-negative patients. An early diagnosis of TB is difficult-to-diagnose TB especially persons infected with HIV
possible in nearly one-third of sputum smear-negative and children, who are often smear-negative and also most
pulmonary TB, if different bronchoscopic procedures adversely affected by delays in TB diagnosis. The reader is
are employed instead of a single procedure alone (9-12). referred to the chapter “Laboratory diagnosis of tuberculosis:
The overall yield of bronchoscopic sample is greater Best practices and current policies” [Chapter 8] for details.
than 90% especially when cultures were included in the
Serological Tests
analysis (13). Smear exami­nation and mycobacterial culture
of post-bronchoscopy sputum had also high diagnostic Several commercial serological tests using different antigen
yield [93%] (14). Lidocaine, the topical anaesthetic agent, that and antibody are available for diagnosis of TB. However,
is used during bronchoscopy had inhibi­tory effect on myco­ critical review of published evidence suggests that these
bacteria and, therefore, should be used carefully. Broncho­ tests are inaccurate, imprecise and lack of reproducibility.
scopic examination in pulmonary TB may show normal The use of serological tests in the diagnosis of TB has been
bronchial mucosa to ulcerative lesions, granulomatous discouraged by the World Health Organization [WHO], and
lesions, and ulcerative-granulomatous, tumour-like lesions banned by the Government of India (20).
and residual fibrotic stenosis. Because of high mortality in
Nucleic Acid Amplification Tests and
miliary TB, it is imperative that the diagnosis is confirmed as
Other Molecular Methods
quickly as possible. In miliary TB, bronchoscopy is diagnostic
in 73%-83% of cases (15). The yield of bronchoscopy for The reader is referred to the chapter “Laboratory diagnosis
diagnosis of pulmonary TB in HIV-infected patients is similar of tuberculosis: Best practices and current policies” [Chapter 8]
to that in patients without HIV infection and transbronchial for details.
biopsy provides incremental diagnostic information (8). In
paediatric patients, gastric lavage is superior to BAL for Breath Test
bacteriologic confirmation of pulmonary TB. The overall Detection of volatile organic compounds [electronic nose]
bacteriologic yield was 34% while gastric lavage alone was and measurement of urease activity of exhaled air may
positive in 32% of the cases (16). be promising test to diagnose active pulmonary TB and
Bronchoscopy is useful to diagnose endobronchial currently they are under field evaluation (21,22).
TB. The reader is referred to the chapter “Endobronchial
tuberculosis” [Chapter 12] for details. In addition to different DIFFERENTIAL DIAGNOSIS
endobronchial lesions, black pigmentation of bronchial TB can practically involve all organs of the body and can
mucosa with scarring [anthracofibrosis] or without scaring simulate most of the diseases. Diseases which are to be
[anthracosis] can be seen (17). Indications for bronchoscopy differentiated from pulmonary TB are listed in Table 10.1.
as a diagnostic tool for pulmonary TB include: [i] patients However, by no means, this list is exhaustive.
suspected of having pulmonary TB with negative sputum
smears and in whom treatment must be started due to Table 10.1: Differential diagnosis of pulmonary TB
clinical status; [ii] suspicion of cancer; [iii] selected patients Infections
with negative cultures; [iv] lack of material being obtained   Bacterial pneumonia
by simpler methods. However, it has been demonstrated   Lung abscess
that sputum induction is a safe procedure with a high    Fungal and miscellaneous bacterial infections
diagnostic yield and high agreement with the results of Bronchogenic carcinoma
fibreoptic bronchoscopy for the diagnosis of pulmonary TB Bronchiectasis
in both HIV-seronegative and HIV-seropositive patients. Bronchial asthma
Sputum induction was well tolerated, involved low-cost, and Sarcoidosis
provided the same, if not better, diagnostic yield compared Pneumoconiosis
with bronchoscopy in the diagnosis of smear-negative Paragonimiasis
pulmonary TB (18,19). In a decision analysis model to assess
Congenital diseases
the overall utility of BAL in clinically suspected sputum
Other causes
smear-negative pulmonary TB, it has been suggested that,
   Hyperthyroidism, diabetes mellitus
in a region of high TB prevalence, empirical treatment is the
TB = tuberculosis
best course of action (12).
152 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Bacterial Pneumonia staining the specimens with India ink and demonstration of
doubly refractile cell wall, the presence of budding and the
Bacterial pneumonia, especially occurring in the upper part
clean capsule. Viable organisms in macrophages can be seen
of the lung, may mimic TB. In acute pneumonia, symptoms
in histoplasmosis. Candidiasis can occur in the pulmonary
occur suddenly and a raised white blood cell count may
TB patients with immunodeficiency.
point to the diagnosis. If sputum is negative for Mtb,
antibiotics which have no effect on Mtb can be administered
for seven-to-ten days. The patient may be re-evaluated after
Bronchogenic Carcinoma
a course of antibiotics with a chest radiograph, which may A solid round tumour in the chest radiography may pose
show clearance of the lesions in acute pneumonia. However, difficulty in distinguishing from a well-circumscribed TB
it should be noted that shadows may look smaller after the lesion. Both bronchogenic carcinoma and pulmonary TB
antibiotic course if there is collapse of the part of the lung cause loss of weight, cough, blood-streaked sputum and fever.
or pneumonia due to obstruction of a bronchus. Pneumonia Bronchogenic carcinoma may also cavitate. Bronchogenic
due to Pneumocystis jiroveci is common in patients with AIDS. carcinoma can produce post-obstructive pneumonitis and
If the sputum examination is non-contributory, BAL fluid lung abscess. The patient with bronchogenic carcinoma
examination for Mtb and Pneumocystis jiroveci is indicated (23). is usually a chronic smoker and sputum will be negative
for Mtb. Confirmation of diagnosis requires bronchoscopic
Lung Abscess biopsy in these patients.
Patients with lung abscess often produce foul-smelling
purulent sputum. Clubbing of fingers is a prominent feature
Bronchiectasis
in these patients. Peripheral blood examination reveals Patients with bronchiectasis have long history of purulent
neutrophilic leucocytosis. Ziehl-Neelsen staining of sputum sputum production. Clubbing of fingers is a prominent
is negative for Mtb. sign and coarse bubbling crepitations can be heard on
auscultation. Sputum examination is negative for Mtb. The
Fungal and Miscellaneous Bacterial Infections middle and lower lobes [or lingula on the left side] are
commonly involved in bronchiectasis. The HRCT scan of
The important fungal diseases of the lung that may
the chest will confirm the diagnosis.
mimic pulmonary TB include aspergillosis, blastomycosis,
coccidioidomycosis, cryptococcosis, and histoplasmosis.
Other miscellaneous bacterial infections can also simulate Bronchial Asthma
pulmonary TB and these include nocardiosis and Bronchial asthma patients often present with complaints of
actinomycosis. Nocardia are common bacterial inhabitants wheezing. They often give history of allergy to inhalants or
of soil. Examination of sputum or pus reveals crooked, ingestants. However, localised wheeze can occur in TB if
branching, beaded, Gram-positive filaments. Most nocardia a bronchus is obstructed by an enlarged lymph node or if
are weakly acid-fast. In TB endemic areas, fragments of there is TB bronchitis. Bronchial asthma can be diagnosed
nocardia can be mistaken as mycobcateria (24). Actinomycosis by demonstrating obstructive lung function and reversibility
is an indolent, slowly progressive bacterial infection caused after inhalation of bronchodilator.
by a variety of Gram-positive, non-spore forming anaerobic
or microaerophilic rods. The most characteristic feature of Sarcoidosis
actinomycosis is the demon­stration of “sulphur granules” in
sputum, pus or tissue specimens. These are usually yellow Sarcoidosis usually presents with bilateral hilar lymphadeno­
and consist of aggregated microorganisms. Aspergillus is pathy and pulmonary infiltration. It can also present with
responsible for four types of pulmonary mani­festations, pulmonary infiltrates or nodular lesions without mediastinal
viz: allergic broncho-pulmonary aspergillosis [ABPA], lymphadenopathy. In these situations, it is difficult to
differentiate these lesions from pulmonary TB, especially
aspergilloma, chronic necrotising pulmonary aspergillosis
miliary TB. These patients have negative tuberculin skin
and invasive aspergillosis. ABPA is characterised by asthma-
test [TST] and the sputum is negative for Mtb (25). Almost
like symptoms, eosinophilia, fleeting pulmonary infiltrates,
every organ of the body can be involved in sarcoidosis
a positive immediate skin test response to aspergillin,
and the tissue biopsy reveals non-caseating epithelioid cell
elevated serum IgE and anti-aspergillus IgG antibodies.
granulomas.
Aspergilloma occurs in patients with pre-existing TB or
other cavities and these patients can have high serum IgG
antibody titres of aspergillus. Invasive aspergillosis usually Pneumoconiosis
occurs in immunocompromised patients. Blastomycosis can Occupational exposure to silicon dioxide, asbestos, coal dust,
be diagnosed by demonstration of yeast-like organisms with beryllium, ferrous oxide etc., and hypersensitivity reactions
a highly refractile cell wall and multiple nuclei in sputum to organic inhalants can cause pulmonary infiltration that
samples. Patients with coccidioidomycosis can be diagnosed may mimic pulmonary TB. Conglomerate masses and even
by showing spherules in the sputum stained with Gomori’s cavitation can occur in silicosis. Sometimes TB develops
or Papanicolaou’s stains. Cryptococcosis can be identified by in a patient with silicosis [silico-tuberculosis]. Coal miners
 Pulmonary Tuberculosis 153

suffering from rheumatoid arthritis can develop round dilemma. The following criteria would indicate active
shadows in the lung resembling TB. Some patients with pulmonary TB: [i] clinical signs of infection and features
pneumoconiosis develop progressive massive fibrosis. of TB toxaemia [fever with evening rise, night sweats,
A carefully elicited occupational history and absence of Mtb malaise, weight loss etc.]; [ii] progressive radiographic
in the sputum help in the diagnosis. changes; [iii] microbiological, molecular, histopathological,
cytopathological evidence of TB; and [iv] response
Paragonimiasis to therapeutic trial with anti-TB treatment. Of these,
microbiological, molecular evidence is conclusive and the
Paragonimiasis is a food-borne parasitic infection caused remaining are suggestive.
by the lung fluke, most commonly, Paragonimus westermani.
Humans are infected by ingestion of metacercariae present TREATMENT
in undercooked crustaceans, contaminated water, among
others. This disease is commonly seen in North-East region The reader is referred to the chapter “Treatment of tuberculosis”
of India, South and South-East Asia, the Pacific Islands and [Chapter 44] for details.
West Africa. Initially, patients have low-grade fever and
dry cough. Subsequently, viscous brown expectoration with REFERENCES
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 11
Lower Lung Field Tuberculosis
Gautam Ahluwalia, Surendra K Sharma

INTRODUCTION below an imaginary horizontal line traced across the hilum

and includes the parahilar regions. A standard PA chest
Post-primary pulmonary tuberculosis [TB] classically affects
radiograph is ordinarily sufficient for the diagnosis of
predominantly the upper lobes. Since Laennec’s era, lower
pulmonary TB. Since lateral films of the chest are available
lung field TB was considered a rarity (1). Throughout the
very infrequently, it is difficult to identify the exact
nineteenth century, most of the researchers were of the
topographic location of the lesion i.e., whether the disease
view that involvement of the lower lung field with TB was
is confined to the lower lobe only or is present in the middle
not an important issue (2,3). However, there was a school
lobe and lingula as well. Therefore, the term ‘lower lung field
of thought holding a divergent view. In 1886, Kidd stated
TB’ has come into vogue. In a PA radiograph of the chest,
that “the apex of lower lobe is very prone to TB disease
lower lung field includes the middle lobe on right side and
and may be attacked before the apex of the upper lobe” (4).
lingula on left side in addition to the lower lobes.
Subsequently, two years later, Fowler stated that “the upper
and posterior part of the lower lobe is a spot only second
in point of vulnerability to the apex itself” (5). Except these PREVALENCE
two early documentations, the literature is silent over the The prevalence of lower lung field TB has ranged from
occurrence of lower lung field TB till the first quarter of 0.003%-18.3% [Table 11.1] (7,8,12,19-29). The reason for the
twentieth century. Subsequently, many authors concluded wide variation in the prevalence is probably due to confusion
that lower lung field may be the site of pulmonary TB in the terminology used [basal, parahilar, lower lobe, lower
in specific situations encountered rather frequently by lung field] and selection bias [hospitalised or ambulatory
clinicians (6-11). Therefore, a high index of suspicion is key patients].
to the diagnosis of lower lung field TB. In earlier medical literature, the prevalence of lower lung
field TB in studies reported from India has been observed to
TERMINOLOGY OF LOWER LUNG FIELD be higher than that reported in western studies [Table 11.1].
TUBERCULOSIS This may be due to the fact that majority of Indians tie
It is important to understand the meaning of the term ‘lower their clothes [women their sari and men their loin cloth]
lung field TB’. In the earlier reports (4-11), the term ‘basal tightly around the upper abdomen and this results in
TB’ was frequently used. However, with the advent of lateral impaired movement of diaphragm. This theory has been
radio­graphs of the chest, the term ‘lower lobe TB’ had been substantiated by Viswanathan (21) in the second quarter of
used by various authors (12-16). In view of the proximity the 20th century, who studied the diaphragmatic movements
of the lesion to hilum, the term ‘hilar and perihilar TB’ was on the radiographic screen in subjects accustomed to tight
also used by few authors (17,18). However, Ostrum and lacing around their waists. It has been suggested that the
Saber (16) suggested that various terms used by different resultant impaired movement of diaphragm leads to costal
authors were in fact referring to the same entity. type of breathing [as in females], which leads to decreased
The lower lung field is defined as the area on the ventilation, retarded blood circulation and lymphatic flow in
postero-anterior [PA] chest radiograph, which extends lower lung fields, thus making them more vulnerable to TB.
156 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 11.1: Prevalence of lower lung field TB mortality (36-38). It has also been observed that worsening
glycosylated haemoglobin levels reflecting poor glycaemic
Prevalence
No. of of lower
control increase the relative risk of developing lower lung
Year of pulmonary lung field field TB (39). Furthermore, diabetic patients have a higher
Study (reference) publication TB cases TB [%] prevalence of positive acid-fast bacilli [AFB] sputum
Colton (7) 1928 2335 0.003 smears as compared to non-diabetic patients (36). With
the increasing prevalence of diabetes in resource-limited
Ross (19) 1930 60 18.3
countries like India, this may have implications for the TB
Du Fault (8) 1932 365 0.27
control programme as diabetes-TB co-morbidity will add to
Reisner (20) 1935 4494 0.68 the infectious burden of TB in the community.
Hamilton and Freed (12) 1935 349 2.9
Viswanathan (21) 1936 638 6.4 Symptoms
Romendick et al (22) 1944 2354 2.7 The duration of symptoms may be less than two weeks,
Segarra et al (23) 1963 10962 0.85 although the mean duration is 12 weeks (28). In most of
Parmar (24) 1967 1455 3.4 the studies symptom duration of less than six months has
Tripathy and Nanda (25) 1970 707 5.1 been documented (23,27,28). Tripathy and Nanda (25) have
observed that about 20% of patients reported within two
Mathur et al (26) 1974 5072 0.63
weeks and 70% of patients within six months in their series
Berger and Granada (27) 1974 386 7.0 of 36 cases.
Chang et al (28) 1987 1276 5.1 Cough with variable amounts of expectoration is
Wang et al (29) 2006 520 15.8 the most frequent symptom (21,23,25). Mathur et al (26)
TB = tuberculosis reported cough in 100% cases. Many authors have noted
haemoptysis as an important symptom (8,11,12,20,21,23,24).
Tripathy and Nanda (25) noted haemoptysis in nearly
PATHOGENESIS two-thirds of the cases and Romendick et al (22) noted it in
75% of cases.
Besides that above cited plausible mechanism (20,21), the
The general toxaemic manifestations of TB infection,
other common pathogenetic mechanism of lower lung field
such as, fever, chills, malaise, weakness and anorexia are
TB is the ulceration of a bronchus by a lymph node affected
also frequently present. Segarra et al (23) reported these
by TB with spillage of TB material into the bronchus. Lower
symptoms in about 40% of their cases, whereas Tripathy and
lung field TB occurs as a continuum of primary TB or soon
Nanda (25) reported them in 86% of their cases. However,
after in the post-primary phase (23,24).
a recent study from east Asia has revealed that lack of fever
more than 38 °C in lower lung field TB is an important
CLINICAL FEATURES discriminating symptom as compared to lower lung field
In various studies (9,19,23,30,31), female preponderance bacterial pneumonia.
and predilection for patients under 40 years of age has been
reported. Segarra et al (23) reported that 89% of patients Signs
with lower lung field TB were less than 40 years old and
The physical signs vary with the extent and character of the
Parmar (24) reported that 46% of the patients were less than
lesions. Patients with extensive involvement of the lungs
20 years of age. However, Tripathy and Nanda (25) did
have pronounced signs of the underlying lesion. However,
not find a similar distribution in their study. In subsequent
patients who have involvement of a relatively small area,
studies, it has been observed that lower lung field TB is no
especially those in whom the lesion is limited to the apical
longer a disease of the young and afflicts the elderly more
segment of lower lobe, physical signs may be scanty or even
commonly (28,29,32).
absent. However, physical signs are encountered more often
in patients with lower lung field TB than in those with the
Associated Conditions classical upper lobe pulmonary TB (27).
Lower lung field TB appears to be more common in
patients receiving corticosteroid treatment, patients with INVESTIGATIONS
hepatic or renal disease, diabetes mellitus, pregnancy,
Sputum Examination
silicosis kyphoscoliosis and human immunodeficiency virus
[HIV] (23,27,28,33-35). Although sputum examination is the simplest way to
In fact, studies from Asia including India have revealed diagnose lower lung field TB, isolation of Mycobacterium
that in diabetic patients with TB not only lower lung field tuberculosis [Mtb] is difficult on sputum smear or myco­
TB occurs more commonly at presentation, but diabetes bacterial culture (27,28). However, the diagnostic yield
also results in poor treatment outcome (36). Moreover, of sputum examination is better in patients with cavitary
diabetic patients with TB are elderly and have a higher lesions (22).
 Lower Lung Field Tuberculosis 157

Chest Radiograph been suggested that absence of air bronchogram in a chest

radiograph is more common in patients with lower lung field
More than half of the cases of lower lung field TB have
TB as compared to lower lung field bacterial pneumonia (40).
right lung involvement, whereas one-third cases have left
Other radiographic features include evidence of atelectasis
lung involvement. Bilateral lesions are reported in 10% of
or solitary mass with intrathoracic lymphadenopathy.
cases (24,25,30,33).
The radiographic features also have a prognostic value.
The radiographic findings in lower lung field TB differ
The outcome is unfavourable in patients with lower lung
signi­ficantly from those found in upper lobe disease (20).
field TB who have lung collapse or pulmonary consolidation
The most frequent radiographic finding is consolidation,
in the chest radiograph (31,35).
which is more confluent and extensive than that found in
upper lobe TB (22,30) [Figure 11.1]. Cavitary lesions are
Bronchoscopy
also frequently seen, which may be single or multiple and
may lie within an area of consoli­dation (27,28) [Figure 11.2]. The early diagnosis of lower lung field TB is important for
Cavities may be large [3-4 cm in diameter]. The presence of prevention of severe sequelae. Fibreoptic bronchoscopy
tension cavities [thin-walled with fluid] is also a radiological [FOB] is the preferred diagnostic modality for the diagnosis
feature of lower lung field TB (22,23,25,41). Recently, it has of lower lung field TB. Abnormal bronchoscopic findings
in lower lung field TB include ulcerative granuloma,
mucosal erythema, submucosal infiltration and fibrostenosis
[Figure 11.3].
FOB provides a higher diagnostic yield than sputum
exami­n ation, especially in patients who present with
radiographic findings of pulmonary consolidation, lung
collapse or solitary mass (22,42). FOB is also important in
assessing the severity of endobronchial lesions in lower lung
field TB. The outcome is unfavorable in patients with lower
lung field TB when FOB reveals fibrostenosis or ulcerative
granuloma. If severe fibrostenosis is present, early surgical
intervention should be considered to prevent damage of the
lung distal to the obstruction (28,42).

Endobronchial Ultrasonography—
Transbronchial Needle Aspiration
The role of endobronchial ultrasound [EBUS] in complement
with FOB is also being evaluated to increase the diagnostic
Figure 11.1: Chest radiograph [posteroanterior view] showing accuracy, especially in smear-negative TB suspects per se.
consolidation in the right lower zone

Figure 11.3: Mucosal erythema and submucosal infiltration observed

during fibreoptic bronchoscopy in a patient with right lower lung
Figure 11.2: Chest radiograph [postero-anterior view] showing cavitary field tuberculosis. Bronchoalveolar lavage revealed Mycobacterium
lesion in the right lower zone tuberculosis
158 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Additionally, combining EBUS with transbronchial needle Revised National Tuberculosis Programme [RNTCP] of
aspiration [TBNA] of lymph nodes is another exciting Government of India. The reader is referred to the chapter
development under evaluation. In resource-limited countries “The Revised National Tuberculosis Control Programme”
like India, these newer modalities will need to be validated [Chapter 53] for more details.
for TB diagnosis as well as their cost effectiveness by Tracheobronchial stenosis is an important complication
indigenous operational research. of lower lung field TB leading to permanent damage of
In a study (43) from China, it has been demonstrated that lung distal to the obstruction. Since the outcome is poor
combining FOB with EBUS resulted in higher diagnostic in patients with lower lung field TB, when FOB findings
accuracy of AFB smear in bronchoalveolar lavage [BAL] fluid show fibrostenosis or ulcerative granuloma, these patients
[31.5% versus 12.5%, p = 0.018], Mycobacterium tuberculosis should be followed-up closely. The non-invasive methods
culture in BAL fluid [67.1% versus 47.9%, p = 0.024] and such as chest radiograph and flow-volume loops on
histopathology confirmation of TB in transbronchial lung pulmonary function testing are insensitive for detecting or
biopsy [TBLB] specimens [32.9% versus 4.2%, p < 0.0001] as monitoring tracheo­bronchial stenosis. In these patients, close
compared to FOB alone. Moreover, it was also observed that follow-up with FOB is necessary if chest radiograph shows
overall diagnostic accuracy for TB by using bronchoscopic no significant improvement or clinical features suggest
procedures [smear and culture of BAL fluid and TBLB] with progression of endobronchial lesions after anti-TB treatment
EBUS was higher than for FOB alone [80.8% versus 8.3%, for a few months. Surgical intervention is indicated if re-
p = 0.035]. The utility of EBUS in increasing the sensitivity of examination with FOB shows no significant improvement
cartridge-based nucleic acid amplification tests for diagnosis or worsening of endobron­chial involvement. However, if
of TB has also been demonstrated when compared to FOB severe fibrostenosis is present, early surgical intervention in
alone (44). the form of sleeve operation is indicated before permanent
Lymphadenopathy underlying a bronchus plays an sequelae, such as, damage of lung distal to the obstruction
important role in the pathogenesis of lower lung field TB. and respiratory failure occur (28,29,42).
Combination of EBUS-TBNA as compared to conventional
FOB is also being studied in patients of TB. The combination REFERENCES
of EBUS-TBNA indicates that EBUS-TBNA results in higher
1. Laennec RT. Treatise on the diagnosis and treatment of the
diagnostic yield in pulmonary TB suspect patients with diseases of the chest. New York: Haffner Publishing; 1962.
lymphadenopathy (45). 2. Landis HRM, Norris GW. Diseases of the chest. Second edition.
Philadelphia: WB Saunders Company; 1921.
MANAGEMENT 3. Fishberg M. Pulmonary tuberculosis. 3rd edition. Philadelphia:
Lea and Febiger; 1922.
Lower lung field TB presents a definite problem in diagnosis 4. Kidd P. Basic tuberculous phthisis. Lancet 1886;2:616.
because of its location and radiographic findings. Moreover, 5. Fowler JK. The localization of lesions of phthisis. London: J and A
when TB is confined to lower lung field, it often masquerades Churchill; 1888.
6. Busby JF. Basal tuberculosis. Am Rev Tuber 1939;40:692-703.
as pneumonia, lung cancer, bronchiectasis or lung abscess,
7. Colton WA. Basal lesions in pulmonary tuberculosis with report
thereby, delaying the correct diagnosis. The shift in age- of seven cases. US Vet Bureau Med Bull 1928;4:503.
distribution from the young to the aged and non-specific 8. Du Fault P. Basal pulmonary lesions. Am Rev Tuber 1932;25:
clinical features adds another challenge in the diagnosis 17-23.
of lower lung field TB (30,31,43). Therefore, TB should be 9. Dunham K, Norton W. Basal tuberculosis. JAMA 1927;89:1573-5.
considered a diagnostic possibility in patients with lower 10. Lander F. Selective thoracoplasty for persistent basal tuberculosis
lung field lesions who have the following conditions: cavities. J Thorac Surg 1938;7:455.
11. Gordon BL, Charr R, Sokoloff MJ. Basal pulmonary tuberculosis.
diabetes mellitus, advanced age, glucocorticoid treatment,
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renal or hepatic illness, malignancy or lesions with poor 12. Hamilton CE, Freed H. Lower lobe tuberculosis-a review. JAMA
response to adequate antibiotic therapy (31,46). FOB should 1935;105:427-30.
be performed early to ascertain the diagnosis of TB and 13. Jacob M. Lower lobe pulmonary tuberculosis. Med J Record 1929;
assess the severity of the endobronchial lesions. 129:32.
The patients with lower lung field TB show a favorable 14. Middleton WS. Lower lobe pulmonary tuberculosis. Am Rev
Tuber 1923;7:307.
response to conventional anti-TB therapy. Delayed diagnosis
15. Ossen EZ. Tuberculosis of the lower lobe. N Engl J Med 1944;
affects the outcome in these patients (31,46). Significant 230:693-8.
resolution of chest radiograph findings and/or sputum 16. Ostrum HW, Saber W. Early recognition of lower lobe
negativity was observed with anti-TB treatment, if the tuberculosis. Radiology 1949;53:42-8.
diagnosis to treatment time was less than three months (43). 17. Bernard M, Lelong M, Renard G. La localisation perihilare de la
Treatment of lower lung field TB is similar to the tuberculose pulmonaire chronique de la adultae. Ann de Med
treatment elsewhere in the body. The reader is referred 1927; 21:366.
18. Faber K. Perihilar pulmonary tuberculosis in adults. Acta Med
to the chapter “Treatment of tuberculosis” [Chapter 44] for Scand 1931;75:403.
details. Long-term follow-up is recommended to diagnose 19. Ross EL. Tuberculosis in nurses-a study of the disease in 60
possible relapse after the completion of treatment. In India, nurses admitted to Manitoba sanatorium. Can Med Assoc J 1930;
patients with lower lung field TB receive DOTS under the 22:347-54.
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20. Reisner D. Pulmonary tuberculosis of the lower lobe. Arch Intern treatment outcome of pulmonary tuberculosis. Epidemiol Infect
Med 1935;56:258-80. 2009;137:203-10.
21. Viswanathan R. Tuberculosis of the lower lobe. Br Med J 1936;2: 37. Carreira S, Costeira J, Gomes C, André JM, Diogo N. Impact of
1300-2. diabetes on the presenting features of tuberculosis in hospitalized
22. Romendick SS, Freidman B, Schwartz HF. Lower lung field patients. Rev Port Pneumol 2012;18:239-43.
tuberculosis. Dis Chest 1944;10:481-8. 38. Rawat J, Sindhwani G, Biswas D. Effect of age on presentation
23. Seggara F, Sherman DS. Rodriguez AJ. Lower lung field with diabetes: Comparison of nondiabetic patients with new
tuberculosis. Am Rev Respir Dis 1963;87:37-40. smear-positive pulmonary tuberculosis patients. Lung India
24. Parmar MS. Lower lung field tuberculosis. Am Rev Respir Dis 2011;28:187-90.
1967; 96:310-3. 39. Chiang CY, Lee JJ, Chien ST, Enarson DA, Chang YC, Chen YT,
25. Tripathy SN, Nanda CN. Lower lung field tuberculosis in adults. et al. Glycemic control and radiographic manifestations of
J Assoc Physicians India 1970;18:999-1008. tuberculosis in diabetic patients. PLoS One 2014;9:e93397.
26. Mathur KC, Tanwar KL, Razdan IN. Lower lung field tuberculosis. 40. Lin CH, Chen TM, Chang CC, Tsai CH, Chai WH, Wen JH.
Indian J Chest Dis and Allied Sci 1974;16:31-41. Unilateral lower lung field opacities on chest radiography: a
27. Berger HW, Granada MG. Lower lung field tuberculosis. comparison of the clinical manifestations of tuberculosis and
Chest 1974;65:522-6. pneumonia. Eur J Radiol 2012;81:e426-30.
28. Chang SC, Pui YL, Perng RP. Lower lung field tuberculosis. 41. Perez-Guzman C, Torres-Cruz A, Villarreal-Velarde H, Salazar-
Chest 1987;91:230-2. Lezama MA, Vargas MH. Atypical radiological images of
29. Wang JY, Heush PR, Lee CH, Chang HC, Lee LN, Liaw YS, pulmonary tuberculosis in 192 diabetic patients: a comparative
et al. Recognizing tuberculosis in lower lung field: an age- and study. Int J Tuberc Lung Dis 2001;5:455-61.
sex-matched controlled study. Int J Tuberc Lung Dis 2006;10: 42. Chang SC, Lee PY, Perng RP. The value of roentgenoand
578-84. fiberbron­choscopic findings in predicting outcome of adults with
30. Kuaban C, Fotsin JG, Koulla-Shiro S, Ekono MR, Hagbe P. lower lung field tuberculosis. Arch Intern Med 1991;151:1581-3.
Lower lung field tuberculosis in Yaounde, Cameroon. Cent Afr J 43. Lin SM, Chung FT, Huang CD, Liu WT, Kuo CH, Wang CH,
Med 1996;42:62-5. et al. Diagnostic value of endobronchial ultrasonography for
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field tuberculosis. J Infect Chemother 2003;9:272-5. 179-84.
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field tuberculosis cases among young adult and elderly people RIF in lower lung field tuberculosis: sensitive, superior, and
in a teaching hospital of Madhya Pradesh, India. J Trop Med rapid in comparison with conventional diagnostic techniques.
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33. Sokoloff MJ. Lower lung tuberculosis. Radiology 1940;34: 45. Ren S, Zhang Z, Jiang H, Wu C, Liu J, Liang L, et al. Combination
589-94. of endobronchial ultrasound-guided transbronchial needle
34. Fernandez MZ, Nedwicki EG. Lower lung field tuber. Mich Med aspiration with standard bronchoscopic techniques enhanced
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Huang MS. Impact of type 2 diabetes on manifestations and 2001;68:595-600.
 12
Endobronchial Tuberculosis
Samjot S Dhillon, Nicola A Hanania

INTRODUCTION to the timely and more effective chemotherapy received by

patients with TB (5-9). In fact, the current prevalence rate may
Endobronchial tuberculosis [TB], which refers to the
be as low as 0.18% in areas where TB is not endemic (31).
involvement of trachea and bronchi by TB, was first described
The difference in prevalence between autopsy and broncho­
in 1689 by an English physician, Richard Morton (1).
scopy studies is likely due to the inclusion of microscopic
However, it remained mainly a post-mortem diagnosis and
involvement of airways in autopsy data that is not detected
was infrequently reported until the advent of bronchoscopy
by bronchoscopy (26). Bronchoscopy is also not done
in the late 1920s (2-4). Subse­quently, the natural history
routinely in patients with TB due to concerns of spread
of endobronchial TB was described in large clinical and
of infection (32), and thus, most bronchoscopy studies
pathological series (2-4). Following the introduction of
likely underestimate its true prevalence. Endobronchial
effective chemotherapy for TB, reports on endobronchial
TB is mostly described in patients between 21-40 years of
TB decreased dramatically to the extent that no cases were
age (12,19,26), although similar prevalence has also been
reported in several large studies on the bronchoscopic
reported in the geriatric population (33). The majority of
evaluation of patients with TB (5-9). The resurgence of TB
studies report a female preponderance (4,12,14,19,26,34,35).
in 1990s and recent advances in interventional pulmonary
This may be due to the fact that the implantation of organisms
techniques have rekindled interest in endobronchial TB and
from infected sputum occurs easily in women who tend to
the last two decades have seen several publications in this
voluntarily suppress their cough because of socio-cultural
field (10-23).
and cosmetic issues (19,36,37). Small airways in women may
also contribute to this difference in prevalence.
EPIDEMIOLOGY
The exact prevalence of endobronchial TB is not known. PATHOPHYSIOLOGY
In autopsy studies on patients with TB, the reported
prevalence has ranged from 3% (24) to 72% (25) although Mechanisms of Endobronchial Infection
most series report a rate of about 40% (26,27). This variation Endobronchial spread of TB can be via multiple mechanisms,
in prevalence rate may be due to the difference in severity which, alone or in combination, contribute to the development
of cases of TB studied and/or the extent of tracheobronchial of endobronchial TB. Five potential mechanisms for the
tree evaluation (26). For e.g., in a study published in the spread of endobronchial TB have been suggested (3).
pre-chemotherapy era, more than 30% of the patients with
endobronchial TB had concomitant pulmonary TB for the
Extension from the Lungs by Direct Infiltration
duration of more than two years, a fact, that may explain the
high prevalence of endobronchial TB noted (26). Direct spread probably occurs when bronchi in the immediate
Based on previously published bronchoscopic studies, neighbourhood of an infected lung are involved. In general,
endo­bronchial TB was reported in 10%-20% of patients tracheobronchial ulceration is more commonly seen
with active TB (4,27-30). However, in recent studies, a lower adjacent to areas of extensive and progressive parenchymal
prevalence rate has been reported, which is most likely due TB (26).
 Endobronchial Tuberculosis 161

Implantation of Organisms from Infected Sputum ulcers are deep, healing will be complicated by stenosis
secondary to extensive fibrosis. Bronchial stenosis may
The finding of endobronchial disease on the wall of bronchi
also result from oedema or from extrinsic compression
opposite the opening of a diseased lobe is likely due to
by a lymph node (26). On rare occasions, post-obstructive
the implantation from infected material passing over the
pneumonia, lung abscess, obstructive emphysema and
mucous membrane. Auerbach observed the presence of gross
subsequent bronchiectasis may develop distal to this
airways ulcerations on the same side where cavities in the
stenosis (26).
lung were present (26). These cavities are a potential source
Earlier autopsy studies suggested that ulcers are more
of bacilli causing the endobronchial involvement. However,
common in region of the carina and posterior surface of the
in some cases, cavity formation may follow the diagnosis
tracheo­bronchial tree (26). The size of these ulcers varies
of endobronchial TB, pointing to the possibility of other
from 1-5 mm and their long axes are usually parallel to
mechanisms (15). In addition, the absence of endobronchial
the cartilaginous rings (26). Ulcers may progressively
involvement in cases where large cavities are present argues
coalesce leaving the cartilage partially exposed at the base
against this as the only mechanism (38).
of the ulcer (26).
Endobronchial TB may be an integral part of the
Haematogenous Dissemination parenchy­mal lung involvement with TB but this involvement
Haematogenous spread is uncommon and endobronchial is over­looked, as smaller airways cannot be accessed by
TB is infrequently described in miliary TB [MTB] (26,39). bronchoscopy. Diffuse stenosis of small bronchi distal to
the fourth generation mimicking bronchiolitis obliterans
Lymphatic Spread has been described (46).

This mechanism involves retrograde passage of the tubercle Microscopic Appearance

bacilli through lymphatics from bronchioles and sub-
segmental bronchi to the main stem bronchus. Peribronchial Small, oval and round foci of epithelioid granulomas, with or
infection of the lymphatics may be seen histologically in without a central zone of caseation within the wall especially
some cases. However, the data by Auerbach suggests that in the subepithelial region and in the region of mucous
in most cases the infection starts in the submucosal region glands are the early microscopic findings with endobronchial
and progresses towards the adventitia (26). Only in few TB. In advanced cases, these foci are also present in the
cases, infection is limited to or starts from the adventitia, adventitia and in rare occasions they may only seen in the
where lymphatics are located. This fact argues against the adventitia (26). The involvement of the cartilage is usually
lymphatic spread as a common mechanism. limited to very extensive cases. Rupture of these submucosal
foci results in ulceration and gradual destruction of the wall
As Part of the Primary Infection of bronchus. The zone of caseation is usually surrounded by
vascular granulation tissue and is occasionally covered by a
In certain cases of primary TB, a lymph node erodes pseudo-membrane formed by fibrin exuded from capillaries
into a bronchus. The lymph node becomes attached to in this granulation tissue. During the process of healing,
the bronchial wall because of the ongoing inflammatory granulation tissue replaces the inner zone of caseation and
changes, and thus, the infection spreads through the walls regenerating epithelium from all sides eventually covers
of the bronchus to the mucosal lining. This mechanism is the ulcer. Connective tissue ultimately replaces the cells
predominantly seen in children (40,41). Chang et al (42) and capillaries within the granulation tissue. If this process
reported endobronchial involvement in 12 out of 16 patients is extensive and involves most of the circumference of the
with intrathoracic TB lymphadenopathy. Baran et al (43) also airway, stenosis will eventually occur.
reported endobronchial abnormalities in 15 of 17 patients
with intrathoracic TB lymphadenopathy in the absence of CLINICAL COURSE
parenchymal lesions. Four of these patients had ulcerating
endobronchial granulomas. Direct perforation of TB lymph The clinical presentation of endobronchial TB is variable. In
nodes into the bronchi is relatively uncommon in adults, adults, it may occur in primary or reactivation TB, however, in
especially now in the post-chemotherapy era (44,45). children, it is usually a complication of primary TB. The pre­
sentation of endobronchial TB may be acute respiratory failure
Macroscopic Appearance requiring mechanical ventilation (47), subacute mimicking
asthma, pneu­mo­nia, foreign body aspiration (3,31,48,49) or
The earliest bronchoscopic sign of endobronchial TB is insidious, simulat­ing lung cancer (10,33,50-53). Symptoms may
the finding of erythematous mucous membranes. Discrete start years after the diagnosis and treatment of pulmonary
tubercles may have a rough granulated appearance to the TB (54,55). A barking cough has been reported in majority
naked eye or may lead to shallow ulcers of the mucous of the patients. Dyspnoea, chest pain, fever, generalised
membrane that progress to deep ulcers involving the weakness, weight loss and haemoptysis may also be
bronchial wall. Formation of extensive granulation tissue may present (10,12). Sputum production is variable; bronchorrhea
occasionally result in a tumour-like growth into the lumen [>500 mL/day] has been reported in rare cases (56). Physical
of the bronchus mimicking a neoplasm. In most cases where examination may reveal diminished breath sounds or a
 162 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

localised fixed wheeze (3,34). Wheezing is classically low- bronchial granulation tissue (10). Furthermore, ulceration
pitched, constantly present, and heard over the same area of the involved mucosa may be necessary for obtaining a
of the chest wall (2) but may disappear as the airways positive sputum smear (12). Thus, a negative smear for AFB
become progressively narrowed. Partial airway obstruction does not exclude the diagnosis.
may, on rare occasions, act as a one-way valve leading to
tension pneumothorax (3). Unusual presentations include Chest Radiograph
expectoration of bronchial cartilages (57,58) and fistula
formation between the right and left main bronchi (59,60). Endobronchial TB usually coexists with extensive pulmonary
In addition to usual chronic infections due to atelectasis parenchymal or intrathoracic lymph node infection.
and bronchiectasis, rare infectious complications, such as, How­ever, 10%-20% of the patients have a normal chest
pseudomembranous tracheobronchial aspergillosis on radiograph (10,12,28,34,62-67). Chest radiograph may show
endobronchial TB stenotic area can occur (61). patchy infiltrates (15), evidence of collapse [25%-35%] or
Bronchial stenosis is the most significant complication of consolidation [35%-60%] (10,12). Other radiographic features
endobronchial TB. It may present with slowly progressive include hyperinflation, cavity formation, pleural effusion,
shortness of breath years after the diagnosis and treatment miliary infiltrates and mediastinal lymphadenopathy (10,15).
of pulmonary TB. Respiratory failure, difficult endotracheal
intubation, need for tracheostomy and death by suffocation Computed Tomography
may occur as a consequence of tracheal stenosis (15). Computed tomography [CT] of the chest is a very important
Simultaneous involvement of other organs has been tool in evaluating endobronchial TB. While the findings are
reported. Auerbach hypothesised that endobronchial non-specific, it may show endobronchial involvement of
TB represents a tendency towards the development of large, medium and small airways. In fact, in some studies
“tract TB”. Concomitant intestinal and laryngeal involvement the endobronchial involvement is more pronounced in
with TB was noted in 82% and 60% of autopsy cases, small airways than large airway (68-71). These CT findings
respectively (26). However, these findings have not been have been found to correlate well with corresponding
reported in more recent studies and were limited to older pathological findings (70). Findings on CT of endobronchial
studies, which included patients with progressive TB of disease in small airways may include: poorly defined
long duration. nodules, centrilobular nodules, bronchial wall thickening
and tree-in-bud appearance [Figure 12.1A] (68-70). All
LABORATORY AND RADIOLOGICAL these findings are best visualised on high resolution CT
INVESTIGATIONS [HRCT] (69). Centrilobular lesions reflect solid caseation
material within or around the terminal or respiratory
Sputum Examination
bronchioles. Terminal tufts of the “tree-in-bud” may
Sputum smear examination for acid-fast bacilli [AFB] represent the lesions within the bronchioles and alveolar
has a low yield [15%-20%] (10,12) for the diagnosis of ducts, while the stalk may represent a lesion that affects
endobronchial TB. This may be because expectoration of the last order bronchus within the secondary lobule
sputum is difficult due to mucus entrapment by proximal [Figure 12.1B] (70). CT may show aneurysmal dilatation of

A B
Figure 12.1: CT of the chest showing “tree-in-bud” pattern seen in endobronchial tuberculosis [A]. This pattern refers to peripheral, small
centrilo­bular, and well-defined nodules that are connected to linear, branching opacities that have more than one contiguous branching site, thus
resembling a tree-in-bud [B]. In histopathological studies, the tree-in-bud appearance correlates well with the presence of plugging of the small
airways with mucus, pus, or fluid; dilated bronchioles; bronchiolar wall thickening; and peribronchiolar inflammation
 Endobronchial Tuberculosis 163

medium sized bronchi due to endobronchial inflammatory Bronchoscopy

tissue (72).
Bronchoscopy is the gold standard for the diagnosis of
The CT may also show stenosis or obstruction of the
endo­bronchial TB. The diagnosis can be missed in some
major airways. A peribronchial cuff of soft tissue may
cases with normal chest radiograph if bronchoscopy is not
be seen (71,73). During the active TB stage, irregular and
considered (81,82). Unlike pre-chemotherapy era where
circumferential luminal narrowing may be visualised.
tracheal ulcerations were commonly seen, most of the recent
However, during the fibrotic stage, wall thickening is much
bronchoscopy series report more common involvement of
less prominent and an equal distribution of smooth and
the main stem and upper lobe bronchi (12,16) and some
irregular narrowing occurs (74,75). CT may on occasion
recent studies report left main stem as the most commonly
show enlarged lymph nodes in the mediastinum and
involved site (35,47,83). Endobronchial biopsies usually
other parenchymal lesions, such as, segmental collapse,
reveal the classic histological features of TB. These range
collapse with multiple low density areas, cavities and
from non-necrotic epithelioid cell granulomas with no
round low density lesions which most likely represent
AFB to necrotic granulomas with abundant AFB. Bronchial
mucoid impaction distal to obstruction (71,73). An intra-
brushings obtained along with biopsy increase the diagnostic
luminal lower density polypoid mass with narrowing may,
yield (84). Cryobiopsy may aid in getting bigger samples and
sometimes, be seen in a bronchus (71).
needs to be further explored (85).
While the CT is extremely accurate in detecting focal
Bronchoscopy has been useful in learning about the
bronchial lesions, it is inaccurate in predicting whether
natural history and progression of endobronchial TB. Salkin
the lesion is endobronchial, submucosal or outside the
et al presented one of the earliest serial follow-up data (27)
airway (71,73). In addition, it may not be possible to
and documented the progression of bronchial ulceration
accurately assess the thickness of the bronchial wall in
to polyp formation and stenosis in three to six months.
many cases because of the loss of silhouette of the outer
Bronchostenosis develops in 50%-90% of patients despite
wall of the involved bronchus by the adjacent consolidation
effective therapy (10,19). This complication that can present
or of the inner wall by the absence of intraluminal air.
years after diagnosis and therapy, may involve the trachea
It is often extremely hard to differentiate endobronchial TB
or mainstem bronchi. Ip et al (10) showed that stenosis
from bronchogenic carcinoma by CT, and thus, broncho­
developed in all but one of the 12 patients who had a follow-
scopy is ultimately needed. However, CT has the advantage up bronchoscopy within eight to 49 months of completing
of revealing areas of the airway beyond the stenosis anti-TB treatment. Eight of these patients were asymptomatic
as well as the length of stenosis and the extent of peri­ including one who had severe stenosis of the left main stem
bronchial soft tissue/lymph nodes involvement (20,76). bronchus (10).
Thus, CT complements bronchoscopy in evaluating these Several bronchoscopic classifications of endobronchial
patients and can also be used to monitor response to TB have been proposed (14,19,20,86). Chung and Lee (19)
treatment (76). described seven forms of bronchoscopic findings [Figure 12.2].
While it is very helpful, radiographic findings of In their report, they performed serial bronchoscopy on 81
endobronchial TB are non-specific and can be seen in patients with endobronchial TB to examine the predictive
other diseases. Conditions that may show bronchial wall value of this classification. Broncho­s copic examination
thickening and luminal narrowing on CT like sarcoidosis, was initially performed every month until there was no
amyloidosis, relapsing polychondritis and tracheopathia subsequent change in the endobronchial lesions followed
osteochondroplastica should always be kept in mind (74). by an examination every three months until the comple­tion
Newer radiographic techniques such as multi-planar and of anti-TB treatment. The seven forms of bronchoscopic
three-dimensional [3D] helical CT images with recon­ findings are described below.
struction [virtual bronchoscopy] allow a better assessment
of tracheobronchial tree and can be helpful in evaluating Non-specific Bronchitic Endobronchial TB
endobronchial TB (74-79).
Only mild mucosal swelling and/or hyperaemia are seen on
Spirometry bronchoscopy in this form. The prognosis is overall good and
all cases resolve within two months of treatment.
The most common abnormality seen on spirometry in
endo­bronchial TB is restriction (20,35). Lee and Chung (20) Granular Endobronchial Tuberculosis
evaluated spirometry findings in 68 patients and demon­
In granular endobronchial TB, the bronchoscopic appearance
strated a restrictive abnormality in 47%, obstructive
mimics scattered grains of boiled rice, and the underlying
abnormality in 5.9%, mixed in 23.5%, and normal spirometry
bron­chial mucosa shows severe inflammatory changes. Only
in 23.5% of the patients. The flow volume loop abnormalities
20% of the cases develop fibrostenosis.
classically seen in patients with upper airway obstruction
are rarely seen in endobronchial TB. Unlike patients with
bronchial asthma, patients with endobronchial TB do Oedematous Hyperaemic Endobronchial TB
not have increased bronchial hyper-reactivity to inhaled In the oedematous-hyperaemic endobronchial TB, severe
histamine (80). mucosal swelling with surrounding hyperaemia causing
 164 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B C D

E F G
Figure 12.2: Classification of endobronchial TB by bronchoscopic findings: actively caseating type [A]; oedematous-hyperaemic type [B];
fibrostenotic type [C]; tumourous type [D]; granular type [E]; ulcerative type [F]; and non-specific bronchitic type [G]
Reproduced with permission from “Chung HS, Lee JH. Bronchoscopic assessment of the evolution of endobronchial tuberculosis.
Chest 2000;117:385-92” (reference 19)

narrowing of the bronchial lumen is seen. Patients with with caseous material. This endobronchial mass may
these findings have poor prognosis as 60% of cases develop occlude the bronchial lumen and is frequently mistaken for
fibrostenosis within two to three months after treatment, and lung cancer. The prognosis of tumourous endobronchial
30% progress to complete obstruction of the bronchial lumen. TB is grave and the most unpredictable; 70% of patients in
this report had fibrostenosis at the end of treatment. More
Actively Caseating Endobronchial TB tumourous lesions can appear subsequently at different
segmental bronchi.
Actively caseating endobronchial TB is the most commonly The above classification closely correlates to the micro­
seen form and bronchoscopy shows swollen and hyperaemic
scopic changes seen in endobronchial TB. Non-specific
mucosa that is diffusely covered with whitish cheese-like
bronchitic endo­b ronchial TB corresponds to the initial
material. Luminal narrowing at diagnosis is usually seen
lesion, which presents as simple erythema and oedema of
whether granulation tissue is present or not. Significant
the mucosa with lymphocytic infiltration of the submucosa.
improvement of bronchial stenosis is seen with treatment,
This is followed by submucosal tubercle formation, which
although 65% of patients progress to fibrostenosis.
produces the erythema, granularity and partial bronchial
stenosis seen at bronchoscopy caused by considerable
Ulcerative Endobronchial TB congestion and oedema of the mucosa. These represent the
Ulcerative endobronchial TB is characterised by the presence granular and oedematous-hyperaemic type, respectively.
of ulcers in the tracheobronchial tree. The prognosis is With more progressive disease, caseous necrosis with
generally good as most of the cases will completely resolve formation of TB granulomas at the mucosal surface is seen
within three months of treatment. and constitutes the actively caseating endobronchial TB.
When the inflammation progresses through the mucosa,
Fibrostenotic Endobronchial TB an ulcer, which may be covered by caseous material, is
formed and this represents the ulcerative class. Finally,
In firbostenotic endobronchial TB, marked narrowing of
the bronchial mucosal ulcer may evolve into hyperplastic
the bronchial lumen due to fibrosis is seen and patients
inflammatory polyps, and the endobronchial TB lesion heals
show no response to treatment. Progression of fibrosis,
by fibrostenosis, explaining the next two stages seen on
despite treatment, may result in complete obstruction of the
bronchoscopy.
bronchial lumen two or three months after treatment.
On rare occasions, TB lymph nodes may rupture into
a bronchus (87). In the early stage, the lymph node may
Tumourous Endobronchial TB
be seen as a greyish-yellow mass protruding through the
Tumorous endobronchial TB is characterised by the presence mucosa sometimes obstructing the lumen. The bronchial wall
of an endobronchial mass whose surface is often covered may show haemorrhage and granulation tissue formation.
 Endobronchial Tuberculosis 165

A fistula may subsequently develop in the bronchial wall of malignancy or TB coexisting with malignancy (96),
with caseous material protrusion. The mucous membrane atypical mycobacterium (97-103), sarcoidosis (104), actino­
then becomes less inflamed and evacuation of the node mycosis (105) and papillomatosis (106). Presence of airway
occurs. The opening then gradually closes and fibrosis with stenosis may be seen in other conditions. Focal stenosis
scarring of the bronchial wall followed by bronchial stenosis may be a result of previous endotracheal intubation, or
may subsequently develop. Perforation of a lymph node various systemic diseases that may involve the airways
into the lumen of a bronchus may present as a pigmented such as Crohn’s disease and Behçet’s syndrome (106).
mass or stenotic bronchus with black pigmentation Diffuse stenosis of the central airways may be seen in
overlying the mucosa (11,45,51,53,88,89). This pigmentation Wegener’s granulomatosis, relapsing polychondritis,
is likely from the anthracotic material in lymph nodes and tracheobronchopathia osteochondroplastica, amyloidosis,
has been termed “anthracofibrosis” (89). Chung et al (89) papillo­matosis, and rhinoscleroma (106). Anthracofibrosis,
demonstrated that 60% of patients whose bronchoscopy typically described in non-smoking elderly woman exposed
showed bronchial narrowing and black pigmentation had to biomass fuel, can also cause airway stenosis along with
active TB. Endobronchial TB should be strongly considered anthracotic pigmentation in the airway and peribronchial
when such findings are encountered on bronchoscopy. lymphadenopathy (89,107). Anthracofibrosis can pose as a
All forms of endobronchial TB lie between the two ends of diagnostic challenge as it can co-exist with TB and anthra­
the spectrum of healing and fibrostenosis. Actively caseating, cotic airway pigmentation can also be seen in endobronchial
oedematous hyperaemic, and the granular subtypes are the TB. Bronchiostenosis due to anthracofibrosis usually
most common (19). Different subtypes can be seen in the involves multiple lobar or segmental bronchi and unlike
same patient and one subtype may transform into another endobronchial TB spares the central airways (107).
except the fibrostenotic subtype (90). The extent of disease
progression (14), formation of granulation tissue (11) and SPECIAL SITUATIONS
innate factors are important determinants of the different
forms and outcome. Elevation of interferon-gamma [IFN-γ], Lower Lung Field Tuberculosis
transforming growth factor-beta [TGF-β] levels and increased TB involving the right middle lobe, lingular division of left
metalloproteinase-1 activity is associated with increased upper lobe and both lower lobes (108,109) occurs in 1%-7%
risk of fibrosis and stenosis in endobronchial TB (91,92). of patients with pulmonary TB. It is more commonly seen
Bronchial stenosis is inevitable in the presence of progressive in patients with diabetes mellitus, pregnancy, chronic renal
disease. Therefore, prompt diagnosis including timely disease and malignancies. Endobronchial involvement has
bronchoscopy and efficacious treatment are of paramount been reported in up to 75% of these patients (108-114).
importance in order to minimise the progression to bronchial Therefore, there should be a low threshold to perform a
stenosis. The concern of worsening of TB and asphyxia­tion bronchoscopic examination in such patients. The reader
as a result of aspiration of caseous particles to opposite is referred to the chapter “Lower lung field tuberculosis”
lung as a result of bronchoscopy should not be a limiting [Chapter 11] for details.
factor to perform a bronchoscopy. These complications have
not been described recently despite the large number of Children
bronchoscopies performed on such individuals (10,16). The
importance appropriate air-borne precautions for TB while Endobronchial TB in children is a part of spectrum of
performing bronchoscopy cannot be overemphasised. primary TB. The incidence is high due to mediastinal lymph
In addition to type of lesions founding bronchoscopy, node involvement in primary TB and is reported to be
addi­tional risk factors for progression of bronchostenosis 40%-60% (115-117). Lymph node erosion and subsequent
include age greater than 45 years and initiation of anti-TB drainage into the bronchus can spread infection and result
treatment more than 90 days after initial symptoms (93,94). in similar endobronchial findings as described in adult
airways. Endobronchial TB can cause lobar collapse due to
Bronchography extrinsic compression (118) and can also masquerade foreign
body aspiration (49,119). The most common finding on
Bronchography was once used for the definitive diagnosis bronchoscopy is external bronchial compression followed by
and preoperative evaluation of bronchial stenosis (29,95). other similar lesions described in adults. Addition of gastric
However, with improved CT imaging, this procedure is lavage sampling to bronchoscopy improves diagnostic
rarely performed now. yield (116). Small double-blinded studies of corticosteroid
treatment in childhood endobronchial TB have shown a
DIFFERENTIAL DIAGNOSIS favourable response in the steroid treated group (120-122).
Prompt diagnosis requires a high-index of suspicion.
Elderly
Several cases can be misdiagnosed as bronchial asthma
in the initial course (35). Endobronchial TB can imitate At least 15% of elderly patients with pulmonary TB have
presentation of foreign body aspiration in children. Presence con­comitant endobronchial TB, although this is likely still
of an endobronchial mass should always raise the suspicion an underestimation (33). Many of these cases are diagnosed
166 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

during a work-up for lung cancer, or non-resolving pneumonia and opportunistic infections including bacterial, viral and
and delay in diagnosis is not uncommon (33,51,123). atypical mycobacterial infections (130).
The pathogenesis of endobronchial TB in the elderly is
considered to be similar as in other age groups. Cough is the Immune Reconstitution Inflammatory Syndrome
most commonly observed symptom. Other symptoms, such
The immune reconstitution inflammatory syndrome [IRIS]
as, dyspnoea, haemoptysis, chest pain and hoarseness of
is the paradoxical worsening of symptoms or appearance
voice may be present. Constitutional symptoms, such as
of new symptoms in immune compromised patients
anorexia, weight loss and fatigue are usually present in most
after restoration of immune functions due to therapy.
patients. In one series (124), almost 75% of the patients with
The host’s reinstated ability to mount an inflammatory
right middle lobe syndrome due to endobronchial TB were
response unmasks the subclinical manifestations and
elderly. Endobronchial findings on bronchoscopy are similar
unabated inflammation results in multi-organ symptoms.
to those described in younger subjects. Bronchial stenosis
Pulmonary manifestations include increasing mediastinal
occurs in about 60% of elderly patients with endobronchial
lymphadenopathy [with purulent aspirate and negative
TB (33).
cultures for TB], pleural effusions, worsening pulmonary
infiltrates and recurrent respiratory symptoms (131). IRIS
Pregnancy is typically described in HIV patients with concomitant TB
The hormonal and vascular changes in pregnancy result in infection who get started on antiretroviral therapy, thus,
airway oedema and increase secretions. This can unmask or resulting in improve­ment in immune functions (131-134).
worsen symptoms of airway stenosis. A recent report (125) It is also reported in HIV patients with atypical mycobacterial
describes a woman with asymptomatic post-tubercular infections and in patients without HIV including patients
tracheobronchial stenosis who became progressively with TB, leprosy, solid organ transplant recipients, women
symptomatic during pregnancy. Heliox was used due to after pregnancy, neutropenic patients and those on tumour
the perceived high risk of airway inter­v entions in late necrosis factor [TNF] antagonists after restoration of
pregnancy and the patient underwent successful caesarean immune function (135). Treatment is generally supportive
section under spinal anaesthesia. Heliox is a mixture of 79% and sometimes non-steroidal anti-inflammatory agents
helium and 21% oxygen and has lower density than room air or corticosteroids are used. Endobronchial extension of
and results in laminar flow and decreased airway resistance inflammed mediastinal inflammatory lymph node due to IRIS
and thus, lower work of breathing. Patient’s symptoms in HIV positive patient with TB has been well documented
improved to baseline after delivery without any airway in a recent case report (136). Similarly endobronchial
lesions due to IRIS in TB patients without HIV have been
intervention. The hormonal changes of pregnancy may
described (137,138).
unmask underlying airway stenosis. Airway intervention
should preferably be performed earlier in pregnancy as
changes of pregnancy and the process of labour increases South-East Asian and Indian Experience
the work of breathing considerably. Several case reports and few case series have been published
describing endobronchial TB in Indian adults (139-143). A
Human Immunodeficiency Virus Infection study of bronchoscopic evaluation of 85 Indian children with
active TB reported 9.4% prevalence of endobronchial TB in
Endobronchial TB is not uncommon in patients with human
this cohort (144). Another series from Chandigarh, described
immunodeficiency virus [HIV] infection. In one study (126),
24 patients most of whom underwent bronchoscopy due to
6 out of 25 HIV-positive patients with TB had endobronchial
suspicion of malignancy (145). Two-thirds of these patients
TB on bronchoscopy. Endobronchial TB may be a part had right bronchial tree involvement and three patients had
of primary infection in patients with HIV and hilar and left vocal cord paralysis. All patients clinically improved
mediastinal lymphadenopathy is commonly seen on chest with anti-TB treatment although follow up bronchoscopy
radiograph (126-129). Other radio­logical findings described was not done. In another older series, 42% of the 50 patients
in these patients include a normal chest radiograph, a miliary with lower lobe TB from a sanatorium in Amritsar were
pattern and a small pleural effusion. Pulmonary infiltrates thought to have endobronchial TB based on clinical and
are rare (126). The findings on bronchoscopy are similar radiographic findings, although it was confirmed in 5 out
to those observed in HIV-negative patients, although, the the 13 patients who underwent a bronchoscopic examination.
tumorous form has been more commonly reported (126-128) In a study (146) assessing the usefulness of bronchioalveolar
likely because the erosion of a lymph node into a bronchus lavage in the diagnosis of sputum smear-negative pulmo­
causes the tumourous form. Lymph node perforation into nary TB from New Delhi, endobronchial TB was not
the airway in HIV-associated TB has also been described by described in any of the 50 adult HIV-negative patients.
bronchoscopy (126,129). Progressive bronchostenosis was A recent study of bronchoscopic evaluation of immigrants
not reported in HIV-associated endobronchial TB (126,128). to Canada with diagnosis of TB revealed significant higher
The diffe­r en­tial diagnosis of endobronchial lesions in prevalence of associated anthracofibrosis in patients from
patients with HIV can be extensive including Kaposi’s Indian subcontinent as compared to other Asian countries
sarcoma, bacillary angiomatosis, lung cancer, lymphoma [50% versus 3.7%; p<0.001] (147).
 Endobronchial Tuberculosis 167

Endobronchial Involvement by bronchial obstruction (120-122). However, the benefit of

Nontuberculous Mycobacteria corticosteroids in this situation remains speculative (10,15,93)
and a randomised trial in adults with endobronchial TB
Endobronchial involvement with nontuberculous myco­ failed to show any beneficial effects from corticosteroid
bacteria is rare and mostly seen in patients with HIV (97-103). therapy (162). As of now, there is not enough evidence to
Most cases respond to therapy without any residual stenosis. suggest routine use of corticosteroids in endobronchial TB.

TREATMENT Bronchoscopic Modalities

Before the introduction of streptomycin and para-amino­ A variety of bronchoscopic modalities are helpful in relieving
salicyclic acid [PAS] for clinical use, the treatment of airway stenosis if used alone or in combination with anti-TB
endobronchial TB lesions involved painting the small treatment depending on the clinical situation in symptomatic
ulcers directly with caustic soda or silver nitrate to enhance patients. These techniques are useful in patients who are not
fibrosis (3,148). These methods, however, caused more surgical candidates due to comorbidities or have stenosis in
fibrosis due to their effect on the surrounding normal both lungs or have multiple areas of stenosis or sometimes
tissue (3,148). Salkin et al (27) demonstrated that many of the when an emergent airway intervention is needed. Due to
endobronchial TB ulcers heal when the parenchymal disease advances and wider availability of interventional pulmonary
is adequately treated. Effective drug therapy and preventive techniques, the recent literature on endobronchial TB has
measures have altered the natural history of endobronchial focused significantly on these modalities (47,163-166). These
TB (149,150). A high clinical index of suspicion and prompt modalities are briefly discussed below.
bronchoscopy are essential for the early diagnosis of this
condition as it can present several years after the actual
Mechanical Dilatation
treatment of pulmonary TB (54,55,151).
Treatment options currently available for patients with Dilatation of the narrowed airway can be achieved with the
endo­bronchial TB are described below. barrel of a rigid bronchoscope or sequentially with the use of
dilators, bougienage or balloons [balloon bronchoplasty]. A
Anti-TB Treatment rigid scope can also help in securing the airway in emergent
situation. Bougienage imparts a shearing force to airway wall
Chemotherapy of endobronchial TB is similar to that used
as compared to radial force of balloon dilatation and causes
for treatment of pulmonary TB. The reader is referred to the
more airway trauma (167). Balloon dilatation produces less
chapter “Treatment of tuberculosis” [Chapter 44] for details.
mucosal trauma and granulation tissue as compared to the
Cases of endobronchial TB in patients with multidrug-resistant
rigid scope (168). Balloon dilatation has been described
organisms have been reported only on rare occasion (83).
successfully in cases of airway stenosis due to endobronchial
The addition of inhaled streptomycin (150,152,153) and
TB (164,167,169,170). Balloon dilatation is usually successful
inhaled isoniazid (154) to the standard therapy has been
when the stenotic segment is short (167,171). In general,
reported to improve outcomes in some studies but their
the primary and secondary patency rates in benign strictures
efficacy in large randomised, blinded trials has not yet been
are low (163,172) and repeated dilatation of the stenotic
evaluated. Similarly efficacy of bronchoscopic injection of
segment are required. Balloon dilatation is mostly helpful
isoniazid and amikacin along with cryotherapy has been
to dilate a stenotic airway for stent placement. Potential
described in few cases of endobronchial TB (155,156) but
complications of balloon bronchoplasty include airway
need further validation with properly designed clinical trials.
malacia, airway laceration and sometimes rupture, bleeding,
pneumothorax and pneumomediastinum (172-174).
Corticosteroids
Corticosteroids have used empirically with anti-TB medi­ Debulking
cations in some cases to prevent bronchial stenosis (10,12,19). Debulking of tissue obstructing the airway can be achieved
Lee and colleagues (12) felt that corticosteroids may suppress by using a rigid bronchoscope to core the tissue. Curettage
the barking cough but may not alter the course of the disease with forceps during bronchoscopy for the removal of the
or prevent bronchostenosis. Hypersensitivity reaction pseudomembrane has been described (12).
associated with anti-TB treatment is another situation where
corticosteroid therapy may be beneficial (48,157,158). Local Thermal Debulking Using Electrocautery and
endoscopic injection of corticosteroids in endobronchial TB
Argon Plasma Coagulation
lesions with benefit has been described in one case report (159).
Another group has advocated use of aerosolised streptomycin Electrocautery uses an electric current to generate heat
and dexamethasone for preventing progression of ulcerative and destroy tissue while argon plasma coagulation [APC]
endobronchial TB to fibro­stenosis based on a small study causes superficial coagulative necrosis caused by ionised
with comparison to retrospec­tive controls (153,160,161). argon plasma. APC has minimal risk of airway perforation
Some studies have suggested a positive role for corti­ and also achieves excellent haemostasis. These modalities
costeroid therapy in children with lymph node TB causing have to be used with caution in patients with pacemakers.
168 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The fractional of inspired oxygen should be less than 40% Metal stents Metal stents are relatively easier to place but
to avoid airway fire. Effective use of APC in improving are hard to extract. Granulation tissue can grow through
symptomatic obstruction has been described in few series spaces between metal struts. A review of 25 patients
of endobronchial TB (164,175). who underwent metal stent placement showed frequent
complications at the time of removal including retained
Thermal Debulking Using Lasers metal pieces, mucosal tear with bleeding, re-obstruction,
Lasers also use thermal energy for tissue destruction. The tension pneumothorax and respiratory failure requiring
commonly used lasers are neodymium-yttrium aluminium mechanical ventilation (184). Similarly another study of 10
garnet [Nd-YAG] or carbon dioxide [CO2] laser. The Nd- patients with benign strictures reported frequent occurrence
YAG laser is preferred as it can achieve tissue vaporisation of granulation tissue, one case of new subglottic stricture
along with coagulation (172). CO2 laser is a better cutting due to stent and a case each of broncho-pleural and tracheal-
tool but has limited ability to coagulate tissue. Similar to oesophageal fistula (185). Some patients who were deemed
APC and electrocautery, the fractional of inspired oxygen surgical prior to stent placement become non-operable. These
should be less than 40% to avoid airway fire during laser complications have prompted a black-box warning from the
treatment. Several precautions including wearing protective United States Food and Drug Administration [FDA] in 2005,
eyeglasses specific to the laser being used are required. and thus, metal stents should be avoided in benign airway
Thermal debulking therapies should not be attempted when stenosis (186).
the obstruction is purely extrinsic and caution should be Hybrid stents Hybrid stents have a membrane covering
exercised when using them to destroy and remove tissue the metallic cross-filaments and this avoids granulation
in the vicinity of major blood vessels. Re-expansion of ingrowth. They can be placed using flexible bronchoscopy,
a segment collapsed for more than four weeks (83,176) are easier to remove compared to uncovered metallic stents
or segment with chronic damage like bronchiectasis and but have a higher migration rate. Just like other stents,
parenchymal calcification (177) is typically not beneficial. mucous plugging remains a significant problem requiring
Nd-YAG (47,163,164,166,178,179) and CO2 laser (180,181) repeat bronchoscopy procedures and sometimes stent
have been used to relieve stenosis in endo­bronchial TB replacement. They may have higher rate of complications
although most of the data are about successful use of necessitating removal in benign disease (187) although
Nd-YAG laser. further studies are needed to evaluate their exact role in
endobronchial TB.
Bronchoscopic Cryotherapy The stents come in various sizes and shapes including
Bronchoscopic cryotherapy involves a contact cryoprobe that the carinal Y-stent depending on the location of the lesion.
utilises repeated freeze-thaw cycles for tissue destruction. Stents are most beneficial in trachea or main-stem bronchi
It is comparatively safe as the fibrous tissue and cartilage although rarely stenting of subsegments has been described.
are cryo­r esistant, thus minimising the risk of airway There is a significant body of literature showing utility of
perforation (168). It is helpful in achieving haemostasis and silicone stents in endobronchial TB (47,164,170,188-190).
there is no risk of airway fires. However effect is slow and Metal stents have been attempted (191) but do not fare
usually a repeat clean-out procedure is needed. Few reports com­p aratively well (164) and should be avoided (184).
have descried favourable use of cryotherapy in cases of Successful placement of Y-stents (179) and Montgomery
stenosis due to endobronchial TB (182,183). Recently, spray T-stent (192) have been described to alleviate symptoms of
cryotherapy has been introduced that uses liquid nitrogen airway obstruction in cases of endobronchial TB in carina
spray as a cryogen which comes in direct contact with and long segmental tracheal stenosis.
tissue and delivers significant more energy than the catheter A recent study of 17 patients with post-TB silicone
cryoprobe and causes immediate cell death without any risk stent placement showed that patients tolerated these stents
of damage to deeper tissue (172). Spray cryotherapy use in well for long period [range 3-11 years] but the granulation
the context of endobronchial TB has not yet been studied. tissue formation rate was 76%, migration rate was 70% and
mucostasis rate was 17% (166). A total of 132 stents were
Airway Stents inserted over 23 site requiring 1-32 rigid bronchoscopies
[median 11] and 1-12 [median 3] flexible bronchoscopies
Airway stents are tubular prosthesis placed in the airways showing that this is extremely health care resource intensive
to maintain patency of the airway. The stents also support management. Other studies have reported slightly lower rate
weakened cartilage and can also close a airway fistula due of complications albeit the rate is still high: granulation tissue
to TB (164). Three main types of stents are available: metal 65%, migration 52% and mucostasis rate of 18% (83). Multi-
stents, silicon stents and hybrid stents [covered metal stents]. detector row spiral computed tomography [MDCT] can be
Silicon stent Placement of silicon stent requires rigid useful non-invasive method of detecting stent complications
broncho­scopy and has a higher migration rate but is easier to and reducing the number of invasive procedures (193).
remove. Frequent bronchoscopic procedures for replacement Removal of a stent is another complex issue. The ideal
may be needed. They seem to be the most successful stents time to remove an airway stent in endobronchial TB is not
in cases of endobronchial TB. known. The stents are usually left in place for 6-18 months
 Endobronchial Tuberculosis 169

in cases of benign stenosis allowing the stenotic area to for the above procedures due to the high incidence of
mature and stiffen (163,165). Stent should be removed when subsequent atelectasis, unexpandable lungs, empyaema and
the stenotic segment has adequately healed to allow airway anaerobic infections (197). Pneumonectomy and lobectomy
patency after stent removal. However, it is hard to determine were commonly performed for endobronchial TB in the past,
when the stenosis has regressed. Stent removal can fail but became unpopular because of high operative mortality
in 44%-76% of patients with endobronchial TB (83,165). of about 27% (197). Recently, new surgical techniques have
Bronchoscopic features that can be used to make determi­ evolved and several series report very low mortality when
nation about stent removal include: improvement of mucosal resection along with surgical bronchoplasty [sleeve resection
inflammation, stabilization of wall at end of stents, loosening with end-to-end anastomosis] is done (198-203).
of device suggesting dilatation of airway lumen and stent Surgery should ideally be performed when the patient is
dislocation due to loosening without residual stenosis (194). no longer considered to have active disease (202). Resection
Non-invasive methods include measuring the length of of lung parenchyma should be minimal, as the objective of
air pockets between the outer wall of stent and tracheo- the surgery is to restore pulmonary function to the hypo­
bronchial tree on a 3-D CT can be helpful as longer length of ventilated lung. The mode of operation is determined by
air pocket suggests improvement of stenosis (165). Damage the location, extent and degree of stenosis (202). For lesions
to underlying cartilage as seen by radial probe ultrasound involving lobar or segmental bronchi, lobectomy may need
may suggest difficulty in stent removal (164). A recent to be performed. For lesion involving the trachea or main
analysis showed that absence of complete lobar collapse stem bronchus, bronchoplastic surgery along with lobectomy
at presentation and bronchoscopic intervention within less [if needed] is performed. Pneumonectomy should be left
than one month of atelectasis were associated with successful as the last resort when the involved lung has extensive
stent removal (83) at 6-12 months of clinical stabilization and bronchiectasis/damage from recurrent infections or when
this should be kept in mind at the time of stent placement the main-stem bronchus is completely obliterated (203).
and removal. Restenosis at the site of anastomosis may occur and repeated
bronchoscopic dilatation may be needed (202). The reader is
Endobronchial Ultrasound also referred to the chapter “Surgery for pleuropulmonary TB”
Endobronchial ultrasound [EBUS] has been a revolution [Chapter 46] for details on this topic.
in the field of interventional pulmonary medicine. The
curvilinear ultrasound is very useful in obtaining lymph MULTIDISCIPLINARY MULTIMODALITY
node samples while the radial probe ultrasound with MANAGEMENT
balloon is useful for visualizing the layers of the airway
While most of the experts clearly feel that the prevalence
wall (164,195). The radial EBUS can show destruction of
of endobronchial component in pulmonary TB is high and
airway cartilage, which can aid in the decision to place a
a prompt diagnosis and management of endobronchial TB
stent, as cases with damaged cartilage will not stay open
can prevent serious sequelae (19,90,204-211), yet there is
just after dilatation or local debulking.
no clear evidence to recommend routine bronchoscopy
Special Situation: Endobronchial Tuberculosis without for all patients with pulmonary TB. There is also concern
Critical Stenosis of significant risk of nosocomial spread of TB during
bronchoscopy (32,212). The current approach is to perform
Another group of patients that has received attention bronchoscopy in TB suspect patients if they have three
recently is the group that does not have a critical airway negative smears or if patients with diagnosed TB has intrac­
obstruction at presentation. Early intervention in this group table symptoms suggesting airway stenosis like refractory
is being advocated since a significant proportion of these cough, localised wheezing, persistent or worsening dyspnoea,
patients eventually develop airway stenosis. Jin et al (196) diminished breath sounds or radiographic evidence of
demonstrated that utilizing APC with anti-TB treatment in atelectasis/collapse or tracheo-bronchial involvement or lack
patients with non-obstructive tumorous endobronchial TB of clinical or radiological response to anti-TB treatment (90).
accelerated the healing of lesions and prevented progressive Some of these clinical symptoms and findings are encountered
airway stenosis as compared to similar patients who received late in course of endobronchial TB and timely treatment is not
anti-TB treatment alone. Similar benefit of cryotherapy possible. Furthermore, even with timely anti-TB treatment,
along with anti-TB treatment was described in granular a significant proportion of patients have progression of
endobronchial TB (94). endobronchial TB (11,12,15), thus needing airway inter­
ventions. Close surveillance, radiographic monitoring and
Surgery timely bronchoscopic assessment of such patients is very
In the early part of last century, collapse therapy by inducing important. A multidisciplinary team with expertise in
a pneumothorax, phrenic nerve paralysis or thoracoplasty multiple modalities is ideal for management of such complex
[surgical removal of several rib bones from the chest wall in patients. Patient factors, initial clinical presentation and
order to collapse a lung] for pulmonary TB was commonly findings [location, duration, degree and length of stenosis],
performed. Endobronchial TB was noted to be an exception local expertise and availability of equipment, determine the
170 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

preferable method of management. Surgery, when possible 20. Lee JH, Chung HS. Bronchoscopic, radiologic and pulmonary
is the desired modality but a significant proportion of function evaluation of endobronchial tuberculosis. Respirology.
patients may not be surgical candidates. Bronchoscopic inter­ 2000;5:411-7.
21. Ozkaya S, Bilgin S, Findik S, Kok HC, Yuksel C, Atici AG.
ventions provide a valuable alternative but usually require
Endobron­ chial tuberculosis: histopathological subsets and
multiple procedures as discussed above. MDCT can be very microbiological results. Multidiscip Respir Med 2012;7:34.
useful for initial evaluation, directing therapy including 22. Miguel Campos E, Puzo Ardanuy C, Burgues Mauri C, Castella
size of stents and recognizing procedural complications. Riera J. A study of 73 cases of bronchial tuberculosis. Arch
Close coordination between interventional pulmonologist, Bronconeumol 2008;44:282-4.
radiologists, thoracic surgeons and infectious disease/TB 23. Qingliang X, Jianxin W. Investigation of endobronchial
specialist could be invaluable in appropriate management tuberculosis diagnoses in 22 cases. Eur J Med Res 2010;15:309-13.
24. Flance IJ, Wheeler PA. Postmortem incidence of tuberculous
and follow-up of patients with endobronchial TB.
tracheobronchitis. Am Rev Tuberc 1939;39:633-6.
25. Sweany HC, Behm H. Tuberculosis of trachea and major bronchi.
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 13
Tuberculosis Pleural Effusion
AN Aggarwal

INTRODUCTION demonstrate such a focus in lung contiguous to the pleura

in 12 of 15 patients with TB pleuritis; the remaining patients
The frequency of tuberculosis [TB] as a cause of pleural
had parenchymal TB, although this focus was not adjacent to
effusion depends on the prevalence of TB in a particular
the pleura. More recently, such foci have been demonstrated
population. In many regions of the world where TB is
on thoracic computed tomography [CT] in patients with
more common, TB pleural effusion maintains its position
TB pleural effusion (22). Possibly, rupture of such a focus
as the leading inflammatory pleural disease (1-9). In
allows the TB protein to enter the pleural space and generate
fact, pleural disease is one of the most common form of
hypersensitivity responsible for most clinical manifestations.
extra-pulmonary TB in developing countries (10-12). The
Pleural effusions may also be seen with direct contiguous
increasing prevalence of human immunodeficiency virus
spread of the disease to the pleura or by haematogenous
[HIV] infection in some of these geographical locations may
spread (13). Occasionally, it can also occur as a complication
be an additional factor explaining the higher frequency of TB
of tubercle infested thoracic vertebra with paravertebral
pleural effusion (4,7). The entity is relatively uncommon in
abscess (23). TB osteitis of the rib may also be associated
the developed world where prevalence of TB is low (13-16).
with pleural effusion.
For example, the annual incidence of TB pleural effusion in
One might speculate that the intense pleural inflammation
the United States is only about 1000 patients. Approximately
and consecutively increased vascular permeability would
1 in every 30 cases of TB is TB pleuritis, and this ratio has
provide an obvious and satisfying explanation for fluid
remained constant even after the advent of the acquired
retention. However, at least in animal models, no signifi-
immunodeficiency syndrome [AIDS] epidemic (14,17).
cant alterations in vascular permeability have been demonst­
In other areas, the incidence of TB pleural effusion has
rated (24). It is now believed that the intense inflammatory
significantly declined over the years (18). However, there is
reaction obstructs the lymphatic pores in the parietal
some evidence to suggest that that these low figures may be
pleura, causing proteins to accumulate in pleural space with
an underestimation of the true disease burden in the general
subsequent retention of fluid (24,25).
population (19).
Delayed-type hypersensitivity [DTH], rather than TB
infection per se, plays an important role in the development
PATHOGENESIS AND IMMUNOLOGY of TB pleural effusion. This explains the poor rate of
TB may affect the pleura at different stages of pulmonary or isolation of mycobacteria from pleural fluid samples
systemic disease and by a number of different mechanisms. from these patients [vide infra]. Pleural effusion has been
TB pleural effusion may represent a manifestation of either shown to develop in non-sensitised animals who have
primary infection or reactivation of latent disease, the latter received cells from immunized animals, and shown not
being more common (20). Pleural effusion is believed to to develop in sensitised animals if they are administered
occur secondary to the rupture of a subpleural caseous anti-lymphocyte serum (24,26). TB pleural fluid is also rich
focus in the lung [or less commonly a lymph node] into in several potentially immunoreactive cells and substances
the pleural space. Supportive evidence comes from the that contribute to the vigorous local cell mediated immune
operative findings of Stead and coworkers (21), who could response (27,28). Mycobacterial antigens enter the pleural
176 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

space and interact with T-lymphocytes previously sensitised inflammatory protein and monocyte chemotactic peptides,
to mycobacteria, resulting in DTH reaction and accumulation and that these two proteins account for more than 75%
of fluid. There is a general increase in the proportion of of the mononuclear chemotactic factor in the TB pleural
total CD3+ and CD4+ T-cell subsets in pleural fluid, as fluid (41,42). After 3-4 days, in the following intermediary
compared to peripheral blood. Several investigators have stage, lymphocytes are the prominent cell in the pleural
demonstrated T-lymphocytes specifically sensitised to TB fluid (43). They are mostly T-cells comprising CD4+
protein in TB pleural fluid (29-33). The concentration of such helper cells as well as CD8+ cytotoxic [natural killer, NK]
lymphocytes in pleural fluid is nearly eight-fold than that cells with a CD4+/CD8+ ratio of about 4.3, and so-called
found in peripheral blood (31). It is not clear whether this unconventional cells including T-cell receptor double
represents sequestration of these cells from peripheral blood negative [DN] αβ T-cells and gd-T cells (44,45). IFN-g, a
into pleural space, or local expansion in the pleural cavity. strong promoter of macrophage activation and granuloma
In addition, these lymphocytes show greater responsive­ formation [together with TNF], is the predominant IL at this
ness to purified protein derivative [PPD], and when co stage. Initially, these lymphocytes do not respond to PPD.
cultured with PPD, produce far greater levels of cytokines However, reactivity is restored over the next few days, and
than do peripheral blood lymphocytes (30,34). The ratio parallels the reactivity of lymphocytes in the peripheral
of CD4+ [helper-inducer] to CD8+ [suppressor/cytotoxic] blood (46). Lymphocyte activation can occur in the pleura of
lymphocytes is also much higher in TB pleural fluid as some patients who fail to react to cutaneous PPD, a fact that
compared to peripheral blood [3:4 versus 1:7] (27,35). These is explained by the presence in the circulation of suppressor
CD4+ T-cells are predominantly of effector and effector cells that inhibit response in the skin; these suppressor
memory phenotypes, and are most poised to generate a cells are apparently lacking in the pleural fluid (29).
polyfunctional inflammatory response and also to contain Helper T-cells in pleural fluid express a battery of homing
mycobacterial infection (36). Patients with TB pleural receptors, such as, cluster of differentiation [CD] 11a, c-C
effusion have significantly higher gamma interferon [IFN-γ] chemokine receptor type-5 [CCR5] and chemokine receptor
levels in their pleural fluid than in peripheral blood, thus CXCR3, which are important in modulating cell trafficking
exhibiting localisation of predominantly T-helper cell type 1 and recruitment in pleural space and tissue (45). The
[Th1] type immunity in the pleural space (35,37). More late phase of TB pleural effusion is characterized by an
recently, there is experimental evidence to link other T-cell equilibrated and sustained CD4+/CD8+ cell-based response
subpopulations as well [e.g. Treg cells, etc.] in pleural with continued IFN-γ release and consecutive granuloma
inflammation (38). formation that is modulated by the release of Th1-cells
According to current views and based on experimental supporting interleukin-12 [IL-12] and counter-regulatory
evidence the sequence of immunological processes involved anti-inflammatory cytokines like interleukin-10 [IL-10] and
in TB pleuritis follows a recently described three-stage transforming growth factor-beta [TGF-β]. Toll-like receptors
pattern of cellular and granulomatous tissue reactions. [TLRs] may have a role in enhancing this antigen-specific
Experimental data suggests that neutrophils are the first Th1-cell function (47).
cells responding to mycobacterial protein in the pleural Recent studies have improved our understanding of
space. When intrapleural bacille Calmette-Guerin [BCG] the immunological pathways involved in TB pleuritis.
is administered to previously BCG-sensitised animals, the After phagocytos­ing mycobacteria, macrophages act
resultant pleural fluid is rich in neutrophils in the first as antigen presenting cells and present TB antigen to
24 hours (39). The accumulation of pleural fluid and inflam­ T-lymphocytes. This results in activation of T-lymphocytes
matory cells is markedly decreased in neutropenic animals, and subsequent promotion of macrophage differentiation
and appears to be restored by intrapleural injection of and granuloma formation. Some components of the
neutrophils. Any trigger mechanism that allows access mycobacterial cell wall, such as protein/proteoglycan
of mycobacterial protein to the pleura will set off a rapid complex and lipoarabinomannan, can stimulate macro­
mesothelial-cell initiated and interleukin-8 [IL-8] mediated phages to produce TNF, which is a regulator of granuloma
polymorphonuclear neutrophil cell influx, within a few formation (48). Activated pleural macrophages can also
hours. In addition macrophages and blood-recruited produce IL-1, which along with TNF, is involved in
monocytes determine this early stage with the predominant lymphocyte activation (49). On exposure to mycobacterial
expression of pro-inflammatory chemokines interleukin-1 antigens, pleural T-lymphocytes produce IFN-γ, which is an
[IL-1], interleukin-6 [IL-6] and tumour necrosis factor [TNF]. important activator of macrophage killing capacity, as well
In animal models, after the initial neutrophil-rich phase, as interleukin-2 [IL-2] which is a regulator of T-cell prolife­
macrophages predominate in the pleural fluid from second ration (49-51). Cytotoxic cell activity could be an additional
to fifth days (39). Neutrophils in pleural space appear to defense mechanism. CD4+ and NK cells present in pleural
secrete a monocyte chemotaxin that recruits monocytes to fluid of these patients demonstrate cytotoxic activity when
the pleural space and helps in granuloma formation (39). stimulated with PPD (52,53).
In addition, mesothelial cells may also play an important On the other hand, there is also strong evidence that
role (40). Animal models have shown that mesothelial infectious invasion of the pleural space actually occurs
cells stimulated with BCG or IFN-γ produce macrophage at a substantial, albeit variable degree. At thoracoscopy,
 Tuberculosis Pleural Effusion 177

even with negative fluid studies, extensive inflammatory weight loss, anorexia and fatigue are also common. On
granuloma formation and fibrin deposits with unexpected physical examination, non-specific signs of pleural effusion,
abundant mycobacteria recovery are a common finding (54). including mediastinal shift, stony dullness to percussion and
Also the increasingly emerging evidence of a preferred the occasional demonstration of a pleural rub at auscultation
asso­ciation of TB pleurisy with reactivated TB in Western may be evident. Untreated, this pleural effusion will usual­ly
populations may be interpreted in favour of true infec­tious resolve spontaneously.
mechanisms (20). Thus the concept of exudative pleurisy
representing exclusively delayed type hypersensitivity IMAGING
[DTH] may not hold true. Infectious as well as immunological
mechanisms are obviously closely interrelated and operative TB pleural effusion is unilateral in more than 90% instances,
in complex patterns. and usually small to moderate in size, although it may occupy
the entire hemithorax [Figure 9.8] (56,59,60). Although
conventionally regarded as a rare cause of massive pleural
CLINICAL MANIFESTATIONS
effusion, recent data suggests that TB may represent more
TB pleural effusion is typically a disease of young men (55,56). than 10% of all cases of large pleural effusion in high
Patients with post-primary TB pleural effusion tend to be prevalence areas (61,62). In up to half of these patients,
older than those with post-primary TB pleural effusion (20). co-existing parenchymal disease can be demonstrated
The clinical presentation of TB pleural effusion may vary by conventional chest radiographs (56,59,63). In such
from an acute illness simulating bacterial pneumonia to an patients, the pleural effusion is almost always on the side
indolent disease first suspected on a chest radiograph in a of the parenchymal infiltrate and usually indicates active
patient with minor constitutional symptoms. TB pleuritis parenchymal disease [Figure 13.1] (63). In three-fourths of
occurs as an acute illness in about two-thirds of cases, with such cases, the parenchymal disease is located in the upper
symptoms often of less than a month duration (57-59). lobe, suggestive of reactivation TB (64). In the remaining
In fact, the illness often mimics bacterial pneumonia with patients, the parenchymal disease involves the lower lobe
parapneumonic effusion (59), as a general rule an acute illness and resembles primary disease. It is likely that even in cases
is more likely to occur in younger and the immunocompetent with no radiographic evidence of parenchymal involvement;
patients. Older patients more frequently present with an the effusion is associated with a subpleural focus of infection.
insidious onset of symptoms (48). Non-productive cough If carefully searched for, thoracic CT can demonstrate
[70%] and chest pain [75%] are the two most common this subpleural focus in many such patients (22,65-67).
symptoms at presentation (59). If both cough and pleuritic CT is more sensitive than chest radiography, showing
chest pain is present, the pain usually precedes the cough (58). parenchymal disease in over 80% of cases. Almost half of
Despite the frequency of pleuritic chest pain, a pleural these patients have smooth pleural thickening exceeding
friction rub is unusual. The patient is usually febrile, but a 1 cm on a thoracic CT; involvement of mediastinal pleura
normal temperature does not rule out the disease (59). Other is uncommon (65). Uncommonly, pleural-based nodular
systemic manifestations, such as, night sweats, weakness, masses [pseudotumours] can also be identified (68-70).

A B
Figure 13.1: Chest radiograph of a woman being investigated for pulmonary TB [A]. Sputum examination was non-contributory, but bronchoalveolar
lavage showed presence of acid-fast bacilli. During the course of her evaluation, she developed ipsilateral exudative pleural effusion [B]. Both
pulmonary and pleural lesions responded to anti-TB treatment
TB = tuberculosis
178 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Positron emission tomography-CT [PET-CT] may document in majority of patients, but a negative test does not rule
high metabolic activity in the affected pleura (71). out the diagnosis. Up to 30%-50% patients can manifest a
Classically, TB effusion associated with acute symptoms negative TST at the time of initial evalu-ation (56,59,81).
and the absence of radiographically evident parenchymal Such negative tests may be even more common in HIV
lung disease has been felt to represent primary infection. infected patients (82). This anergy to PPD appears to be due
By contrast, TB effusion that is associated with an indolent to an antigen-specific extra-pleural immunosuppression.
course and with parenchymal lung disease on the chest Although pleuritis is considered to be related to a DTH,
radiograph has been seen more frequently in older patients circulating adherent cells in the acute phase of the disease
and has been considered to be a manifestation of post­ may suppress the specifically sensitised T-lymphocytes in
primary [reactivation] disease [Figure 13.1]. However, such the peripheral blood and in the skin [but not in the pleural
a clear-cut distinction between primary and reactivation fluid], accounting for the negative results in these patients
disease cannot always be made with confidence based solely (29). Anergy may occasionally result from pleural compart­
on chest radiography. mentalisation of PPD-sensitised lymphocytes occurring in
On conventional chest radiography, presence of at least the early phase of infection, resulting in a relative depletion
200 mL of pleural fluid becomes detectable as blunting of of these cells in the circulation. If the patient is not anergic
the costophrenic angle in standard projections. Thoracic or immunosuppressed, the skin test will almost always
ultrasonography may detect much smaller effusions. Specific become positive within eight weeks of the development of
advantages of thoracic ultrasonography are a more precise the symptoms.
volumetry than by chest radiography, localisation of septae,
membranes and pleural thickening, along with its clinical Pleural Fluid Analysis
versatility for bedside diagnosis and in addition intervention The pleural fluid in TB pleuritis is often a serous exudates;
guidance on demand [Figure 9.9]. the pleural fluid may be serosanguinous in less than 10%
cases. Frequently, the pleural fluid protein level exceeds
DIAGNOSIS 5 g/dL (81,83,84). Biochemical analysis of the pleural fluid
The step-wise diagnosis of TB pleural effusion is essentially is otherwise of limited value. Although in the past it was
the same as for any other pleural exudate. An initial observed that pleural fluid glucose was reduced in most
diagnostic thoracentesis is always indicated. The diagnosis patients of TB pleural effusion (85), more recent studies (59,79)
of TB pleural effusion can be difficult because of the show that majority of patients have a pleural fluid glucose
low sensitivity of the various diagnostic tools. No single of more than 60 mg/dL. A low pleural fluid pH was once
laboratory test has 100% sensitivity and specificity for thought to be suggestive of TB pleural effusion, but sub­
diagnosis of TB pleural effusion. Most patients undergo sequent reports have not confirmed this (86-88). Glucose
a battery of investigations, and the diagnosis is often and pH values are in general not substantially different
established after careful consideration of clinical features from exudates due to other aetiologies, and their diagnostic
and results of several laboratory parameters (72-76). Despite significance has probably been overestimated in the past.
a comprehensive evaluation, almost 20% of TB pleural fluids In most patients, the pleural fluid differential white
will defy a definitive diagnosis. blood cell count reveals more than 50% lymphocytes, with
a reported median of 82% in a recent large series (84). In
Sputum Examination another study, only 11% had a polymorphonuclear-rich
pleural fluid; however, these patients showed a higher
Only a minority of patients with TB pleural effusion demon­
yield on sputum or pleural fluid mycobacterial culture (89).
strate sputum smear-positivity for acid-fast bacilli [AFB].
In another series [n = 49], only 5 patients had fewer than
Sometimes, AFB can be demonstrated in the sputum even
50% lymphocytes in the pleural fluid (59). In fact, the
in patients with no radiographic evidence of pulmonary
overwhelming predominance on lymphocytes on pre­
involvement (77). Sputum mycobacterial culture yield ranges
parations examined cytologically can sometimes result in a
from 30%-50% in patients having both pulmonary and
misdiagnosis of lymphoma (90). The percentage and absolute
pleural TB (59,78). However, yield of mycobacterial culture is
numbers of CD4+ T-lymphocytes in pleural fluid are higher
less than 5% of patients with isolated TB pleural effusion (79).
than in the blood (91-94); by contrast, the percentage and
The yield of sputum mycobacterial culture obtained after
number of B-lymphocytes are significantly lower (30,31,95).
sputum induction may be much higher even in patients with
However, the separation of lymphocytes into T- and B-subsets
no apparent radiological parenchymal lesions (80).
is not useful diagnostically. In patients with symptoms
of less than two-week duration, the pleural fluid may
Tuberculin Skin Test reveal predominantly polymorphonuclear leucocytes (58).
In populations with a low prevalence of TB infection, a If serial thoracenteses are performed, the differential count
positive tuberculin skin test [TST] in a patient with exudative will reveal a shift to predominantly small lymphocytes (59).
pleural effusion strongly suggests the diagnosis of TB, The fluid rarely contains more than 5% mesothelial cells,
whereas, the diagnostic value of a positive test in countries although the finding is not diagnostic (96,97). Several
with a high preva­lence of TB is lower. A TST is positive other disorders associated with pleural inflammation
 Tuberculosis Pleural Effusion 179

and infiltration are associated with decreased shedding T-lymphocytes. For that reason ADA has been looked on as
of mesothelial cells in the pleural cavity, and numerous a marker of cell-mediated immunity, which encompasses
mesothelial cells can sometimes be found in some patients the DTH. ADA activity correlates with CD4+ T-lymphocyte
with pleural TB (98). Presence of eosinophils in a significant cell infiltration in the pleura and the pleural fluid (120).
number in the fluid makes the diagnosis of TB unlikely, Determination of pleural fluid ADA level appears to be a
except in patients having a hydropneumothorax due to promising marker in the diagnosis of TB pleural effusion
previous thoracentesis (99,100). It is reasonable to assume because of the ease, rapidity, and cost-effectiveness of the
that effusions containing more than 50% of these cells are ADA assay (121). ADA estimation is performed using a
of a non-TB aetiology. simple colorimetric method that is quite suitable for use
Pleural fluid smear for AFB is positive in less than 10% ins­ in the field setting (122). Adequately frozen and stored
tances in most reports, while mycobacteria can be cultured from pleural fluid samples maintain ADA activity for more than
pleural fluid in 10%‑70% cases (57,60,78,79,81,84,90,101-103). 2.5 years (123). However, haemolysed blood in the fluid
Corticosteroid use, concurrent TB involving another site, sample may cause false underestimation of ADA activity
increased neutrophils and decreased glucose levels in using colorimetric method (124).
pleural fluid are some of the predictive factors associated Meta-analyses of published literature has shown that
with culture positivity (104,105). Sensitivity of mycobacterial ADA estimation is reasonably accurate in diagnosing TB
cultures is improved, if pleural fluid is transported in pleural effusion (125,126). It appears that pleural fluid
heparinised containers, bedside inoculation of pleural fluid ADA in excess of 70 U/L is highly suggestive of TB
is substituted for laboratory inoculation, large fluid volumes pleuritis, whereas as a level below 40 U/L virtually rules
are cultured, or if liquid culture media and/or BACTEC
out the diagnosis (127-129). In addition, higher the pleural
system are used (106-109).
fluid ADA, the more likely the diagnosis of TB. However,
very high pleural fluid ADA activity may also be seen in
Pleural Biopsy empyema or lymphoma (130). Essentially, observations
Closed parietal pleural biopsy can be performed using from the developed countries (131) and more recent
a Cope or Abram needle. The demonstration of parietal reports from Asia (132) have found that pleural fluid ADA
pleural granulo­m ata on histopathological examination level is useful diagnostically. It is not clear whether these
is suggestive of TB pleuritis; caseous necrosis and AFB differences represent methodologic differences or true ethnic
are often not evident (83). Although other disorders, variation. Some of the differences could also be explained
such as, fungal dis­e ases, sarcoidosis and rheumatoid by differences in methodology used for ADA estimation, as
arthritis may produce granulomatous pleuritis, more than well as delays in transportation and processing of pleural
95% of patients with this histopathology on pleural fluid samples. It is well known that ADA levels in pleural
biopsy have TB pleural effusion. The initial biopsy fluids maintained at ambient temperatures, and without the
reveals granulomas in 50%‑97% patients with TB pleural use of specific additives, decrease with passage of time (133).
effusion (60,78,79,81,84,101,102,110,111). The yield increases In fact, in properly refrigerated and stored samples, pleural
if multiple biopsies are performed (112-114). However, fluid ADA estimates remain stable up to four weeks after
if properly obtained, even a single high quality sample should collection (134). Several investigators have reported the use
be enough to obtain a diagnosis (114,115). Mycobacteria can of pleural fluid ADA in the diagnosis of TB effusions in
be cultured from pleural biopsy specimens in 33%‑80% India (135-159). Overall, the sensitivity and specificity of
cases (60,78,79,81,84,102,110,116). When culture of biopsy the test in diagnosis of TB have not been as good as that
specimen is combined with microscopic examination, the observed in Western datasets [Table 13.1]. However, based
diagnosis can be established in up to 95% instances (117). on epidemiological and Bayesian considerations, positive
Even when granulomata are not demonstrated, the biopsy predictive value of pleural fluid ADA in diagnosis of
specimen should be examined for AFB. In less than 10% TB pleural effusion should be far better in geographical
of cases, organisms may still be demonstrated when no regions with a higher prevalence of TB as a cause of pleural
granulomas are present in the biopsy (59,78). Visceral effusion (125). Hence elevated ADA can provide a reliable
pleural biopsy can sometimes yield diagnosis in patients
basis of diagnosing TB pleural effusion in such areas (160).
with a negative parietal pleural biopsy (118). CT or ultra­
It also appears that ADA is a poor discriminator when used
sonographic guidance may improve the yield and safety of
as a single investigation, but may be more useful when
closed pleural biopsy (119).
results are interpreted in conjunction with clinicoradiograhic
data and results of other investigations (161,162)
Adenosine Deaminase There are several isoforms of ADA, but the prominent
Adenosine deaminase [ADA] is an enzyme involved in ones are ADA1 and ADA2, which are coded by different
the purine catabolism. It catalyses the deamination of gene loci (163). ADA1 isoenzyme is found in all cells,
adenosine to inosine and of deoxyadenosine to deoxyinosine. with the highest concentration found in lymphocytes
ADA is found in most cells, but its chief role concerns the and monocytes, whereas ADA2 isoenzyme is found only
proliferation and differentiation of lymphocytes, especially in monocytes (164). ADA2 is the predominant isoform
180 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 13.1: Performance of ADA estimation in the diagnosis of TB pleural effusion in Indian patients
Study [year] (reference) Cases/Controls Cut-off [U/L] Sensitivity Specificity
Raj [1985] (135) 30/25 40 1.000 –
Sinha [1985] (136) 22/14 30 1.000 1.000
Sinha [1987] (137) 37/16 30 1.000 1.000
Chopra [1988] (138) 37/27 – 0.892 0.852
Gilhotra [1989] (139) 30/43 40 1.000 0.907
Gupta [1990] (140) 36/57 50.75 1.000 0.941
Subhakar [1991] (141) 62/18 38 0.984 1.000
Kaur [1992] (142) 21/52 30 0.667 0.923
Prasad [1992] (143) 21/26 30 1.000 1.000
Nagaraja [1992] (144) 30/18 50 1.000 1.000
Maldhure [1994] (145) 83/42 40 1.000 0.348
60 0.806 0.623
80 0.417 0.812
Singh [1998] (146) 41/43 – 0.902 0.870
Ghelani [1999] (147) 54/27 40 0.722 0.593
Parandaman [2000] (148) 25/09 47.3 0.760 0.714
Sharma [2001] (149) 48/27 35 0.833 0.666
100 0.400 1.000
Nagesh [2001] (150) 20/40 50 0.550 0.550
Dil [2006] (151) 48/34 – 0.583 –
Bandyopadhyay [2008] (152) 34/15 30 0.588 0.600
Verma [2008] (153) 34/16 36 1.000 0.777
Gupta [2010] (154) 56/40 40 1.000 0.974
Pandit [2010] (155) 20/42 70 0.500 1.000
Ambade [2011] (156) 48/33 71 0.875 0.697
Kalantri [2011] (157) 50/50 44.8 0.980 0.880
Kelam [2013] (158) 39/18 40 0.897 0.500
Mehta [2014] (159) 49/73 40 0.857 0.808
ADA = adenosine deaminase; TB = tuberculosis

in the TB pleural fluid, accounting for approximately IFN-γ

90% of total ADA activity, whereas ADA1 is elevated in
empyema (165). This would suggest that ADA2 is a more IFN-γ is produced by the CD4+ lymphocytes in patients
efficient marker of TB pleural effusion. ADA2 has been with TB pleural effusion in response to mycobacterial anti­
shown to be increased in TB pleural effusions (165-168). In gens (51,171). In fact, the concentration of tubercle bacilli
pleural fluids with a high ADA level, a ADA1:ADA2 ratio in pleural liquid correlates with the amount of IFN-γ (172).
less than 0.45 is highly suggestive of TB, whereas a ratio Patients with pleural effusion may have up to 25-fold
greater than 0.45 may be seen in malignancy, empyema, higher IFN-γ levels in the pleural fluid as compared to their
and other conditions (146,169). Although determination peripheral blood, suggesting homing of Th1 cells in the
of this ratio may increase the diagnostic accuracy of ADA pleural fluid from the peripheral blood and enrichment of
estimation in TB pleural fluids, in clinical practice the pleural space with Th1 cytokines (37). IFN-γ can be estimated
difference in the use of total ADA and isoform ADA2 either by enzyme-linked immunosorbent assay [ELISA] or
may not be significant (170). In fact, there may be an radioimmunoassay [RIA] methods. Estimation of pleural
advantage in the measurement of total ADA because of its fluid IFN-γ levels is reported to be useful in differentiating
low cost and rapid turnover. ADA1 activity is determined TB pleural effusion from other causes (125,173). A number
by subtracting ADA2 from total ADA. The measurement of of reports have demonstrated that IFN-γ levels in patients
ADA2 is almost 10 times more expensive than estimation with TB pleurisy are high, with sensitivity and specificity
of total ADA. ranging from 90%-100% (51,129,172,174-188). However,
 Tuberculosis Pleural Effusion 181

proper comparison of results from different studies is not Over the past few years, some investigators have
possible due to variability in methods of estimation and explored the use IGRAs as a diagnostic marker for TB
units used for quantification. Although the test is promising, pleural effusion (191-208). In addition to the whole blood
it is expensive and still not widely available. The cost of tests, IGRAs have also been adapted for use on pleural
performing a single test in India is, in fact, equivalent to fluid specimens with mixed results [Table 13.2]. Overall test
the cost of a complete course of anti-TB treatment for six performance does not look encouraging. A meta-analysis (209)
patients, and therefore does not appear to be a cost-effective of seven studies reported an overall sensitivity and
investigation for differentiating TB from non-TB pleural specificity of 75% and 82%, respectively for pleural fluid,
effusions (189). and 80% and 72%, respectively for whole blood. In low
prevalence settings, pleural fluid responses appear to be
Interferon Gamma Release Assays greater than whole blood responses (210,211). However, in
high prevalence settings, the reverse seems true, and the
Interferon Gamma Release Assays [IGRAs] were developed sensitivity is also much inferior (210,211).
as in vitro whole blood tests to assess a person’s cellular Specific problems have been noted with pleural fluid
immune reactivity by quantifying gamma-IFN production IGRAs. For one, IGRAs are standardised for whole blood,
by T cells after stimulation with specific mycobacterial and not pleural fluid T-cell responses. Sample volumes,
antigens. Two systems, with established protocols for test antigen concentrations, and response cut-off values are
performance and reporting, are commercially available (190). therefore not clearly defined for pleural fluid. Secondly,
The ELISA-based Quantiferon-TB Gold assay uses early background IFN-γ levels may be high in pleural fluid,
secretory antigen-6 [ESAT-6], culture filtrate protein-10 especially in TB, resulting in poorer stimulation on antigenic
[CFP-10] and TB7.7 as antigens, and the ELISpot-based stimulation. Both these factors can result in frequent negative
T-Spot TB test uses ESAT-6 and CFP-10 as antigens. or indeterminate responses (210,211). In addition, pre-
Much like the TST, positive IGRA results point more to TB sensitised circulating T-cells can passively enter into non-TB
infection rather than active disease. pleural effusions, giving rise to false-positive results (210).

Table 13.2: Performance of IGRAs for diagnosis of TB pleural effusion*

Whole blood Pleural fluid
Study [year] (reference) Technique Sensitivity Specificity Sensitivity Specificity
Wilkinson [2005] (191) ELISpot 1.000 – 1.000 0.875
Ariga [2007] (192) ELISA 0.778 0.702 0.964 0.978
Losi [2007] (193) ELISpot 0.900 0.667 0.950 0.762
Baba [2008] (194) ELISA 0.708 1.000 0.444 1.000
Chegou [2008] (195) ELISA 0.727 0.706 0.565 0.867
Nishimura [2008] (196) ELISA 0.600 0.923 – –
Dheda [2009] (197) ELISpot 0.811 0.800 0.826 0.800
ELISA 0.867 0.692 0.793 0.632
Lee [2009] (198) ELISpot 0.778 0.857 0.947 0.905
Liao [2009] (199) ELISpot 0.737 0.846 0.857 0.333
Katiyar [2010] (200) ELISA 0.904 0.860 – –
Ates [2011] (201) ELISA 0.698 0.517 0.488 0.793
Chung [2011] (202) ELISA 0.741 0.611 – –
Losi [2011] (203) ELISA 0.788 0.633 0.833 0.533
Eldin [2012] (204) ELISA 0.700 0.778 0.600 0.833
Gao [2012] (205) ELISA 0.931 0.900 – –
Kang [2012] (206) ELISpot 0.857 0.571 0.714 0.727
ELISA 0.476 0.500 0.235 0.538
Keng [2013] (207) ELISpot – – 0.387 0.553
Liu [2013] (208) ELISpot 0.927 0.628 0.945 0.929
* Both confirmed and probable TB patients were considered as having disease. For sensitivity calculations, any indeterminate test was
regarded as being a ‘false negative’. For specificity calculations, any indeterminate test was excluded
IGRAs = interferon-gamma release assays; TB = tuberculosis; ELISpot = enzyme-linked immunospot assay; ELISA = enzyme-linked
immunosorbent assay
182 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

As a result, IGRAs cannot be recommended for diagnostic and/or serum using ELISA based [or similar] techniques to
use, especially in high prevalence settings. This is consistent assess their utility in the diagnosis [Table 13.3]. The sensitivity
with the World Health Organization [WHO] policy statement reported in most studies is much less than desirable. The
on use of IGRAs (212). problem of false-positive results has also been troublesome
in other studies (147,217,218,224,226,228,230). The kaolin
Serodiagnosis agglutination test, which detects anti-tuberculophospholipid
antibodies, may also provide equivalent sensitivity and
Several studies are available on the immunodiagnosis of TB specificity, while being much simpler (234). Recently, a
pleural effusion (146,213-233). Both mycobacterial antigens multi-antigen and antibody assay developed in-house at
and their antibodies have been estimated in pleural fluid Sevagram [SEVATB ELISA using a cocktail of mycobacterial

Table 13.3: Evaluation of antigens and antibodies in the diagnosis of TB pleural effusion
Study [year] (reference) Target Sensitivity Specificity
Antibody in pleural fluid
Samuel [1984] (213) 0.683 1.000
Murate [1990] (214) Anti-PPD IgG 0.226 0.949
Caminero [1991] (215) Anti-A60 IgG 0.500 1.000
Caminero [1993] (216) Anti-A60 IgG 0.500 1.000
Ghelani [1999] (147) Anti-A60 IgG 0.907 0.333
Chierakul [2001] (217) IgG to five purified antigens 0.254 0.904
Kunter [2003] (218) Anti-A60 IgM 0.841 0.730
Yokoyama [2005] (219) Anti-lipoarabinomannan IgG 0.500 0.938
Kaisermann [2005] (220) Anti-MPT64/MPT10.3 IgA 0.764 0.963
Morimoto [2006] (221) Anti-mycobacterial glycolipid 0.526 0.957
Trajman [2007] (222) Anti-MPT64/MPT10.3 IgA 0.817 0.941
Araujo [2010] (223) Anti-MPT64/MPT10.3 IgA 0.814 0.955
Limongi [2011] (224) Anti-HspX IgA 0.690 0.830
Antibody in serum
Caminero [1991] (215) Anti-A60 IgG 0.550 1.000
Caminero [1993] (216) Anti-A60 IgG 0.533 1.000
Arora [1993] (225) Anti-A60 IgM 0.900 0.950
Chierakul [2001] (217) IgG to five purified antigens 0.463 0.596
Kunter [2003] (218) Anti-A60 IgM 0.591 0.811
Limongi [2011] (224) Anti-HspX IgA 0.300 0.840
Fernandez [2011] (226) Anti-PPD IgG 0.500 0.725
Anti-PPD IgA 0.900 0.300
Kaushik [2012] (227) Anti-HspX IgG + IgA 0.633 0.947
Antigen in pleural fluid
Samuel [1984] (213) Soluble antigens 0.488 1.000
Baig [1986] (228) Soluble antigens 0.600 0.800
Ramkisson [1988] (229) Soluble antigens 1.000 0.983
Dhand [1988] (230) Soluble antigens 0.800 0.381
Banchuin [1990] (231) Soluble antigens 0.115 1.000
Anie [2007] (232) Mycobacterial glycolipid 0.855 1.000
Feng [2011] (233) ESAT-6 0.868 –
CFP-10 0.763 –
Antigen in serum
Banchuin [1990] (231) Soluble antigens 0.000 1.000
TB = tuberculosis; PPD = purified protein derivative; Ig = immunoglobulin; ESAT-6 = early secretory antigen-6; CFP-10 = culture filtrate
protein-10
 Tuberculosis Pleural Effusion 183

antigens ES-31 and ESAT-6 and their specific antibodies] mycobacterial deoxyribonucleic acid [DNA]. In respiratory
showed 100% specificity and 83% sensitivity in pleural fluid, specimens, PCR can be performed rapidly and has a
and 78% specificity and 92% sensitivity in serum, in patients diagnostic yield comparable to that of culture (249). PCR
with TB pleural effusion (235). In view of the rampant misuse offers the option of referring the sample, rather than the
of serodiagnostic tests in several developing countries, patient, to a specialised centre or laboratory. This procedure
despite documented suboptimal diagnostic performance, has also been used to detect mycobacterial DNA in pleural
WHO has recommended that these tests should not be fluid (148,150-152,157,206,222,232,250-276). The Xpert MTB/
used in persons suspected to have active TB (236). The RIF [Cepheid, Sunnyvale, CA, USA], another promising
Government of India has also issued an advisory against auto­mated, real-time PCR assay used for the detection of
the use of these tests and has banned import of commercial TB pleural effusion (277). The sensitivity of the PCR in the
serodiagnostic kits. diagnosis of TB pleural effusion ranges from as low as 17% to
The origin of antibodies to mycobacterial antigens as high as 100%, depending on the patients selected, genomic
in pleural fluid of these patients is not clear. Levy and sequence amplified, and the procedure used in the extraction
coworkers (237) found close correlation between pleural of DNA [Table 13.4]. Specificity ranges from 61%‑100%.
fluid and serum levels, reflecting passive diffusion. Other The parameter that determines the sensitivity of PCR is
investigators have demonstrated higher titres of antibodies probably the number of bacilli in the sample of pleural fluid
in pleural fluid, indicating local accumula­tion (238). Assays analysed. Series with a pleural fluid culture positivity of as
based on detection of tuberculostearic acid in pleural fluid high as 69% report more than 80% sensitivity of PCR (253).
have not yielded encouraging results (239). Further work PCR may be positive in 100% of culture positive TB pleural
needs to be done before immunodiagnostic techniques can be fluids and only in 30%‑60% of culture negative pleural
recommended for routine use in the diagnosis of TB pleural fluids (250-252,255-257,260,263,265). The lower sensitivity
effusions. is most likely attributable to the inefficient recovery of
genomic DNA from the characteristically low number of
Thoracoscopy mycobacteria in patients with pleural TB. Genomic sequences
present in multiple copies in mycobacteria give better results
Thoracoscopy, often considered the ‘gold standard procedure’
than sequences present in only a single copy (250-252).
for the diagnosis of TB pleuritis, may have a role in
Contamination of samples by mycobacterial DNA in
evaluation of pleural effusions undiagnosed by less invasive
the laboratory environment is partly responsible for the
investigations (240-242). The diagnostic accuracy of this
low specificity. In general, use of commercial assays
procedure is greater because multiple selected biopsies can be
[such as, Amplicor or Xpert MTB/Rif] have shown poor
obtained, which have a higher yield both on microbiological
sensitivity (257,262,263,266). In particular, Xpert MTB/Rif
as well as histopathological examination (243-245). The
assay has poor sensitivity in patients clinically diagnosed
endoscopic appearance of pleural TB is well described (246).
as TB pleural effusion and a slightly better sensitivity
It is characterised by greyish-white granulomata blanketing
[although still not useful clinically] using culture as gold
the whole parietal and diaphragmatic pleura, and in parti­
standard (278). Based on available data WHO considers
cular, the costovertebral gutter (247,248). However, lesions
pleural fluid as a sub-optimal specimen for such testing, but
have often lost their specific appearance by the time of
recom­mends initiation of therapy based on a positive Xpert
thoracoscopy and may mimic a simple inflammatory process.
MTB/Rif result (279). The recently published Guidelines for
Rarely, mass-like lesions mimicking malignancy may be
extrapulmonary TB for India [INDEX-TB Guidelines] (280a),
seen (68). In addition, the examination itself may be difficult
also suggest that Xpert MTB/RIF should not be used to
because of numerous bands and adhesions. Complication
diagnose pleural TB [strong recommendation, low quality
rates for thoracoscopically guided pleural biopsy are
evidence for sensitivity estimate, high quality evidence for
minimal, and similar to closed pleural biopsy (245,247,248).
specificity estimate]. A recent systematic review (280b),
Apart from cost concerns, the performance of thoracoscopy
reported that, while the sensitivity of Xpert MTB/RIF in the
is limited by availability of equipment, and of personnel
pleural fluid was low overall, the sensitivity was higher in
with expertise to perform this procedure.
areas with higher TB prevalence.
Other approaches such as transcription-mediated
Nucleic Acid Amplification Tests amplification of 16S ribosomal ribonucleic acid [RNA],
The various nucleic acid amplification tests [NAAT] that using the commercially available Amplified Mtb Direct
have been used in the diagnosis of mycobacterial infection [AMTD] test, have also shown poor results (281). Few
include target amplification techniques, such as, polymerase investigators have also evaluated the value of various
chain reaction [PCR], strand displacement amplification, and nucleic acid extraction and amplification tech­niques in
transcription mediated amplification, as well as probe/primer formalin-fixed and paraffin-embedded pleural tissue
amplification techniques, such as, ligand chain reaction samples (282-288). Although specificity of these techniques
and Q-Beta replicase amplification. PCR, the most widely is high, approaching 100% in several instances, sensitivity
used of these techniques, is based on the amplification of was seen to be low [47%-90%]. However, in these studies,
184 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 13.4: Pleural fluid polymerase chain reaction in the diagnosis of TB pleural effusion
Study [year] (reference) Sequence amplified Sensitivity Specificity
de Wit [1992] (250) 336 bp repetitive sequence 0.811 0.774
de Lassence [1992] (251) IS6110 sequence 0.600 1.000
Gene coding 65 kD antigen 0.200 1.000
Verma [1995] (252) 150 bp sequence 0.632 0.931
Querol [1995] (253) IS6110 sequence 0.809 0.977
Tan [1995] (254) IS6110 sequence 0.700 1.000
MPB64 fragment 0.700 1.000
Villena [1998] (255) IS6110 sequence 0.424 0.990
Seethalakshmi [1998] (256) IS6110 sequence 0.409 –
Parandaman [2000] (148) IS6110 sequence and TRC4 1.000 0.850
Mitarai [2000] (257) Amplicor kit 0.273 0.976
Martins [2000] (258) MPB64 fragment 0.684 0.909
Villegas [2000] (259) IS6110 sequence 0.738 0.898
Reechaipichitkul [2000] (260) 16S-23S rRNA gene spacer sequence 0.500 0.613
Nagesh [2001] (150) 150 bp sequence 0.700 1.000
Lima [2003] (261) IS6110 sequence 0.313 0.966
Kim [2004] (262) Amplicor kit 0.333 1.000
Moon [2005] (263) Amplicor kit 0.175 0.981
Dil [2006] (151) MPB64 gene 0.667 1.000
Trajman [2007] (222) IS6110 sequence 0.821 0.852
Anie [2007] (232) IS6110 sequence 0.870 0.930
Liu [2007] (264) IS6110 sequence 0.434 0.955
Bandhopadhyay [2008] (152) IS6110 sequence, dnaJ gene and 65 kD 0.824 0.750
antigen gene
Kumar [2010] (265) hupB gene 0.517 1.000
Kalantri [2011] (157) 16S rRNA gene 0.649 0.980
Friedrich [2011] (266) Xpert MTB/RIF Assay 0.250 1.000
Maurya [2011] (267) IS6110 sequence 0.607 –
Rosso [2011] (268) IS6110 sequence 0.428 0.942
Gao [2012] (205) IS6110 sequence and MPB64 fragment 0.948 0.900
Alvarez-Uria [2012] (269) Xpert MTB/RIF Assay 0.320 –
Porcel [2013] (270) Xpert MTB/RIF Assay 0.152 1.000
Christopher [2013] (271) Xpert MTB/RIF Assay 0.121 1.000
Montenegro [2013] (272) IS6110 sequence 0.333 0.944
Meldau [2014] (273) Xpert MTB/RIF Assay 0.225 0.980
Trajman [2014] (274) COBAS TaqMan MTB assay 0.160 0.860
Xpert MTB/RIF Assay 0.030 1.000
Detect-TB assay 0.020 0.970
Maheshkumar [2014] (275) IS6110 sequence 0.240 –
Lusiba [2014] (276) Xpert MTB/RIF Assay 0.287 0.966
TB = tuberculosis

nucleic acid amplification techniques resulted in a similar or However, Xpert MTB/Rif testing was negative on all TB
higher positivity as compared to histological examination or pleural tissues tested in a recent study from India (271).
culture of pleural biopsy specimens. PCR of pleural biopsy Although these techniques are promising, the high cost
specimens can thus be useful when employed in combination and the technology involved in the procedure do not permit
with microbiological and histological examinations (287). the routine diagnostic use of PCR at present (289).
 Tuberculosis Pleural Effusion 185

Other Biomarkers lymphocyte proportion [> 80%] and ADA [> 45 U/L] were
diagnostic of TB with a specificity of 100% (84). Another
Lysozyme is a low molecular weight bacteriolytic protein
group demonstrated improvement in sensitivity and specifi­
distributed extensively in organic fluids. Mean lysozyme
city using a combination of pleural fluid ADA, IFN-γ,
levels in TB pleural fluid have been reported to be higher
and NAAT, as compared to single tests alone (261). A
than in other exudative effusions (128,290-293). However,
there is so much overlap that the levels themselves are not Brazilian study developed a predictive model using pleural
diagnostic. Pleural fluid to serum lysozyme ratio of more fluid ADA, globulins and absence of malignant cells to
than 1.0 or 1.2 can differentiate better between TB and non- differentiate TB from malignant effusions with greater
TB pleural fluids (290,292,293). All studies have, however, than 95% sensitivity and specificity (309). More recently, an
not duplicated these good results (129). artificial neural network model based on results of pleural
A preliminary study showed that pleural fluid leptin fluid investigations has been developed to support the
levels were reduced in patients of TB effusion, as compared diagnosis of pleural TB (310). Recently it has been reported
to those with other exudative effusions [82.4% sensitivity that medical thoracoscoy, ADA and T-SPOT.TB together
and 82.1% specificity, at a cut-off of 9.85 ng/mL] (294). can rapidly and accurately detect TB pleural effusion (311).
A subsequent study (295) from Chennai confirmed these Considering clinical and other laboratory parameters may
findings, but concluded that the decrease in leptin level was also be helpful. A study from Brazil found that a combination
influenced by reduction in body mass index [BMI], rather of symptom duration, blood leucocyte count, and pleural
than disease status per se. fluid protein, lymphocytes proportion and ADA yielded
Pleural fluid levels of IFN-γ inducible 10 kDa protein [IP-10] greater than 95% sensitivity and specificity (312). A Spanish
have been studied by some investigators. Three studies have study (313) developed a decision tree for differentiating
demonstrated a relatively high sensitivity (188,296,297). TB from malignant effusions using age, fever, and pleural
Another study (296) concluded that although IP-10 has a fluid ADA and lactate dehydrogenase [LDH] as predictors.
suboptimal specificity, it might still be a useful investigation Another Spanish study (314) developed two regression
to rule out TB. Combining pleural IP-10 measurement with models—one based on pleural fluid lymphocyte proportion
estimation of other cytokines can improve the diagnostic and ADA level, and another based on fever, cough and
performance of this test (189,298). pleural fluid lymphocyte proportion—in diagnosing TB
Few investigators have shown high levels of matrix in young patients. A Turkish study (315) also proposed a
metalloproteinases [MMP] in TB pleural effusion. Pleural similar simple model based on age and pleural fluid ADA.
fluid MMP-9 concentrations are substantially elevated in The role of interleukin-33 [IL-33] along with ADA have also
these patients, more so in those showing granulomatous been identified in the diagnosis of TB pleural effusion (316).
inflammation on pleural biopsy (299,300). Both blood A composite algorithm showing the diagnostic approach is
and pleural fluid levels of MMP-1, MMP-8, MMP-9 were outlined in Figure 13.2.
found elevated in patients with TB pleural effusions in
another study and showed positive correlation with other
NATURAL HISTORY
inflammatory cytokines (301).
Levels of neopterin, a marker of Th1 immune response, In the short-term, TB pleural effusion seems to be a self-
have been shown to be elevated in pleural fluid of patients limited inflammatory process in most instances. The natural
with TB (302-304). However, high levels are also seen in history of untreated TB pleuritis and effusion is usually
uraemic pleural effusions, suggesting poor specificity (305). complete absorption of fluid and apparently complete
One study (300) has shown higher levels of pleural fluid restoration of the patient’s health to normal [although some
angiotensin converting enzyme [ACE] in patients of TB degree of pleural fibrosis may be evident pathologically or
effusion (300). High pleural D-dimer levels, measured by radiographically]. However, the likelihood of the subsequent
immunonephelometry assay, had a sensitivity and specificity development of pulmonary TB is high; for example, in a study
of 84.4% and 85.5%, respectively in another study (306). from the pre-chemotherapy era conducted in 2816 members
Isolated reports have also indicated elevated levels of other of the Finnish army with pleural effusion followed-up for
cytokines, such as, interleukin-1B [IL-1B], IL-2, IL-12, IL-18, seven years, 43% developed active TB during the follow-up
and TNF-alpha in pleural fluid, but the sensitivity and period (317). Confirmatory evidence was provided in
specificity are inadequate for clinical use (185,307,308). another study on 141 American military personnel who had
presented with pleural effusion and a positive TST; nearly
Composite Algorithms and Predictive Models two-third subsequently developed some form of TB (318).
As none of the individual diagnostic investigations is In this study, isolation of mycobacteria from pleural fluid or
a good discriminator for identifying [or excluding] TB size of pleural effusion was not correlated with subsequent
pleural effusion, scoring systems based on more than one appearance of active TB. Thus, the long-term prognosis in
pleural fluid parameters have been proposed. A recent patients who have TB pleurisy is determined by its prompt
large study, from a medium TB prevalence setting, showed recognition and the early initiation of effective therapy,
that a combination of high pleural fluid protein [> 5 g/dL], which lowers the risk of subsequent disease (319).
 186 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 13.2: Algorithm for diagnosis of TB pleural effusion

TB = tuberculosis; AFB = acid-fast bacilli; CBNAAT = cartridge-based nucleic acid amplification test; TST = tuberculin skin test; +ve = positive;
–ve = negative; PCR = polymerase chain reaction; ADA = adenosine deaminase; ATT = anti-TB treatment

TREATMENT
intermittent Category III treatment regimen used earlier is no
The goals of therapy in patients with TB pleural effusion longer currently being used, it has earlier been shown to be
are [i] prevention of subsequent development of active TB; effective and safe under programme conditions for unilateral
[ii] relief from symptoms; and [iii] minimising the occurrence small effusions in immunocompetent patients (322).
of pleural fibrosis. The Category I DOTS treatment is well accepted by patients,
Patients with TB pleural effusion respond well to treat­ and has a relapse rate of less than 3% (323). As per the
ment with standard short-course anti-TB treatment (320,321). recently published INDEX TB Guidelines (280), six months
Under the Revised National Tuberculosis Control Programme treatment with rifampicin, isoniazid, pyrazinamide and
[RNTCP] of Government of India, new patients with TB ethambutol administered for the first two months followed
pleural effusion are treated with thrice-weekly intermittent by rifampicin and isoniazid for the subsequent four
DOTS Category I treatment. Although the thrice-weekly months is considered adequate for pleural TB. Significant
 Tuberculosis Pleural Effusion 187

improvement in pleural effusion is usually evident by TB Guidelines (280), corticosteroids are not routinely recom­
6-8 weeks. The INDEX-TB guidelines (280) suggest a follow-up mended in pleural TB. Corticosteroids are occasionally to
chest radiograph at eight weeks after starting anti-TB be used only in selected patients if acute symptoms, such
treatment to assess progress. An increase in the size of pleural as fever, chest pain, or dyspnoea, are disturbing to the
effusion despite treatment may be due to paradoxical patient. If needed, corticosteroids should be prescribed
reaction, or an alternative diagnosis requiring further work- only after the institution of appropriate anti-TB treatment.
up and investigation. Oral prednisolone 0.5-0.75 mg/kg [or equivalent alternate
Because patients with TB pleural effusion have low day doses] are administered until acute symptoms have
myco­bacterial burden, less intensive regimens may also subsided, with rapid tapering thereafter (350).
prove effective (324,325). With treatment, patients generally In general, surgical procedures have no place in the
become afebrile within about two weeks, and the pleural routine management. Therapeutic thoracentesis is only
effusion resolves within two months (326). Lung functions indicated if the patient has a moderate-sized or larger
continue to improve even after completion of therapy (327). pleural effusion producing significant breathlessness. In
There appears no medical reason to confine these patients to fact, routine serial therapeutic thoracentesis, or continuous
bed, and patients need to be isolated, only if their sputum pigtail catheter drainage, does not alter the course of illness
examination demonstrates AFB. or development of residual pleural fibrosis (351,352). Early
In some patients, the pleural effusion may worsen after surgery for pleural thickening is also not recommended,
anti-TB treatment is initiated. In this situation, the possibility as the thickening decreases with treatment. A recent study
of a wrong diagnosis must be considered, but paradoxical also suggests that instillation of a fibrinolytic agent into a
worsening can also occur with a correct diagnosis and loculated collection may help in subsequent reduction of
appropriate anti-TB medications (328-330). One hypothesis pleural thickening (353). Although medical thoracoscopy
is that these paradoxical responses are related to isoniazid- can open intrapleural loculations, completely evacuate
induced lupus pleuritis (331-333). New pleural effusion may the pleural fluid, and to some extent produce effective
occasionally arise on the contralateral side as well (334-337). debridement, no controlled study has so far proven the value
Similarly, new parenchymal lesions may also be noticed of these efforts.
within three months of start of medications, which eventually
resolve on the same treatment (338). HUMAN IMMUNODEFICIENCY VIRUS
Even after successful completion of treatment, nearly CO-INFECTION
10% patients may have a residual restrictive ventilatory
defect on pulmonary function testing (339). Mild degrees of It appears that co-infection with HIV is the main factor
pleural fibrosis may be present on chest radiographs a year responsible for the increase in TB pleurisy in the West
after therapy is begun in up to 50% of patients (81). With and in Africa (354,355). Pleural effusion is seen in 6%-28%
the strict definition of fibrothorax as a pleural membrane of of HIV-infected patients with TB (355-358). Affected
patients tend to develop pleural effusion in early stages of
at least 5 mm thickness extending across major portions of
immunosuppression and the frequency of pleural effusion is
the hemithorax, a figure of around 5% is perhaps the more
higher in patients with CD4+ lymphocyte counts exceeding
realistic and widely accepted rate of this complication. The
200 cells/mm3 (359). Pooled estimates from several reports
presence of fibrosis is not related to the initial pleural fluid
reveal that TB is responsible for almost a quarter of all
findings and is of limited clinical significance, although a
pleural effusions seen in patients with HIV infection, and
higher pleural fluid glucose or IFN-γ may be associated
that the condition is second only to bacterial parapneumonic
with increased residual pleural thickening (340-342). A faster effusions in terms of frequency (356). In addition to the
resolution of pleural effusion during the initial phase of DTH persistence of mycobacteria in the pleural space as
treatment may decrease the occurrence of significant pleural result of failure of immune system has been proposed as an
thickening (343). The correlation between radiographic and alternative explanation for the higher incidence of pleural
functional sequelae [as assessed by pulmonary function disease in these patients (360). It is not clear if the higher
testing] is poor (339). rate of pleural disease reflects a greater burden of pleural
Evidence regarding efficacy of systemic corticosteroids in mycobacteria or dysregulation of immune function in the
the treatment of TB pleuritis remains insufficient (344-346). pleural space. TB effusions may similarly also occur in
Three randomised, double-blind, placebo-controlled trials patients immunodeficient because of other reasons (361).
have been completed, but all had important methodologic Affected patients usually are symptomatic for longer
differences. There were no benefits with the use of systemic periods, have additional symptoms [fever, dyspnoea, night
corticosteroids in two controlled studies in which therapeutic sweats, fatigue, diarrhoea, etc.] and more commonly have
thoracentesis was also performed (347,348). However, the hepatomegaly, splenomegaly and lymphadenopathy than
duration of fever and the time required for fluid resorption patients who are seronegative (362-364). The diagnostic
were decreased in a third study in which no therapeutic approach in patients with HIV infection is largely similar
thoracentesis was performed (349). Administration of to other patients with TB pleural effusion, although the
corticosteroids did not influence residual pleural thickening performance of some of the diagnostic tests is different.
in any of these studies. As per the recently published INDEX Patients are more likely to be anergic to TST (362,365).
188 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

AFB can be demonstrated in the pleural fluid smears empyema is characterized by chronic, active mycobacterial
in 6%-15%; and on pleural biopsy specimens in infection of the pleural space. It usually represents the
44%-69% cases (82,359,363). AFB smears are more likely failure of a primary TB effusion to resolve and subsequent
to be positive when CD4+ T-lymphocyte counts fall below progression to a chronic suppurative form, and may develop
200 cells/mm3 (233). Pleural fluid and/or biopsy cultures in fibrous scar tissue resulting from pleurisy, artificial
grow mycobacteria in 30%-50% cases (82,360,365,366). pneumothorax, or thoracoplasty (380). In addition, TB
Despite the impaired T-lymphocyte function, pleural biopsy empyema can also occur due to extension of infection from
specimens show granulomatous inflammation in 44%-88% intrathoracic lymph nodes or a sub-diaphragmatic focus, or
cases (82,360,366). The role of PCR, and measurements of haematogenous spread (381). In TB empyema, the pleural
ADA, lysozymes, or IFN-γ in the diagnosis of TB pleural fluid is purulent, and it is common to find mycobacteria on
effusion in HIV-seropositive patients is still not clear (364). direct smear examination or culture of pleural fluid (382). TB
Management guidelines for these patients are similar empyema represents nearly 20%-35% of all cases of empyema
to those for other patients, and standard four-drug anti- seen in high TB prevalence countries like India (383,384).
TB treatment is the treatment of choice (367). The clinical In many patients with chronic TB empyema, the inflam­
and microbiologic response to treatment in these patients matory process may be present for years with a paucity of
appears to be similar to that in patients not infected with clinical symptoms (380,385). This prolonged asymptomatic
HIV. Most HIV-infected patients with TB pleural effusion course is largely related to the marked pleural thickening
respond favorably to standard treatment, with mortality that isolates the tubercle bacilli to the empyema cavity.
rates less than 10% after an average follow-up of more than Patients are often diagnosed only after a routine chest
two years (360,368). Patients with poor or absent tissue radiograph or after development of complications such as
reaction on pleural biopsy histology appear to have a less bronchopleural fistula or empyema necessitans (386). Other
favorable response to therapy and higher mortality (365). The patients may present with low-grade fever, night sweats and
reader is referred to the chapters “Treatment of tuberculosis” constitutional symptoms, such as fatigue and weight loss.
[Chapter 44]; and “Tuberculosis and human immunodeficiency Patients often have respiratory symptoms for several months
virus infection” [Chapter 35] for details. prior to diagnosis (384,387).
The typical radiological findings of chronic TB empyema
PLEURAL EFFUSION DUE TO include a moderate to large loculated pleural effusion
NONTUBERCULOUS MYCOBACTERIA with pleural calcification and thickening of the overlying
ribs [Figures 9.10, 9.11] (22). Diagnosis is confirmed after
As with pulmonary disease, the vast majority of cases of
thoracentesis by finding grossly purulent fluid that is smear
pleural mycobacterial infection are caused by Mycobacterium
positive for AFB and subsequently grows mycobacteria on
tuberculosis [Mtb]; only occasional cases are related to
culture. Pleural fluid cell counts usually exceed 100,000/mm3,
nontuberculous mycobacteria [NTM] (369-376). Pleural
with virtually all cells being neutrophils (382). The pleural
effusions without parenchymal disease analogous to the
fluid has low glucose [usually below 20 mg/dL] and high
post-primary pleural effusion with Mtb do not occur.
protein concentration [usually more than 5 g/dL], and is
Approximately 5% of patients with parenchymal disease
acidic [with pH usually below 7.20]. Anaerobic and aerobic
due to either Mycobacterium intracellulare or Mycobacterium
cultures should also be performed to exclude concomitant
kansasii have an associated small pleural effusion (377).
bacterial and mycobacterial infection.
About 15% patients with parenchymal disease due to
The principles of treatment, pleural space drainage, and
Mycobacterium. intracellulare have marked pleural thickening
antimicrobial chemotherapy are similar for bacterial and TB
as well (377). In patients with AIDS and disseminated
empyema. Difficulties specific to management of TB empyema
disease due to Mycobacterium intracellulare or Mycobacterium
include the inability of the trapped lung to re-expand
avium [collectively referred to as Mycobacterium avium
adequately and failure to achieve therapeutic drug levels in
intracellulare complex or MAIC], pleural fluid cultures are
pleural fluid, which can lead to drug resistance (382,388).
sometimes positive for MAIC (378). However, it is not clear
It is therefore important to use multiple drugs at their
whether these atypical mycobacteria are actually responsible
maximum tolerated dosages. Pleural drainage is indicated
for the pleural effusion. Even in immunocompetent patients
for large empyemas and mixed empyemas, especially if there
one must be cautious regarding the interpretation of isolation
is a bronchopleural fistula. Because intensive chemotherapy
of atypical mycobacteria from pleural fluid. It has been
coupled with serial thoracentesis can be curative at times, this
suggested that NTM cultured from pleural fluid should not
approach should be attempted initially (389). In addition to
be considered aetiologic, unless there is evidence of the same
standard anti-TB treatment, patients usually require surgery
organism infecting other tissues (379).
(390). Surgical procedures include standard decortication,
decortication limited to the parietal sides of the empyema
TB EMPYEMA
collection, thoracoplasty, muscle flap, plombage, parietal
TB empyema is an entity distinct from, and much less common wall collapse, open drainage, or resection of the entire lung
than, TB pleural effusion. In contrast to DTH leading to along with the empyema (381). Most patients have associated
pleural fluid accumulation in a TB pleural effusion, TB significant pulmonary parenchymal involvement (382,247).
 Tuberculosis Pleural Effusion 189

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 14
Silicotuberculosis
Prasanta Raghab Mohapatra

INTRODUCTION in developed countries (8,9), but new outbreaks still occur

occasionally (2,10).
Silicosis is an occupational fibrotic lung disease caused by
The exact prevalence of silicosis in India is not known.
inhalation of respirable free crystalline silicon dioxide or
Majority of these studies have utilised radiographic findings
silica. Tuberculosis [TB] frequently accompanies silicosis as
to make a diagnosis of silicosis. Studies (11,12) from Rohtak
a comorbid condition particularly in TB endemic countries
in Haryana state have shown radiographic evidence of
and contributes significantly towards mortality of patients
silicosis in 35.2% of 227 stone-cutters. In Madhya Pradesh,
with silicosis (1,2). Silicotuberculosis is a major occupational
silicosis was reported in 57% slate pencil workers (13).
comorbid lung disease in both industrialised and developing
A report from Gujarat cited the prevalence of silicosis as
countries.
14% to 30.4% amongst 85 female workers in a quartz
mill and 56 employees of open silica-grinding stones,
SILICOSIS respectively (14,15). Silicosis was also commonly reported
Silicosis, one of the most common forms of pneumoconiosis, from central India and mid-western states, such as, Madhya
caused by the inhalation of crystalline silicon dioxide or Pradesh, Chhattisgarh, Jharkhand, Gujarat and Rajasthan.
silica is an ancient occupational disease worldwide (1). Prevalence of silicosis was reported to be very high amongst
Environmental settings posing the greatest occupational unorganised sectors in India (16,17). India has witnessed
risk include the following: mining and processing of rapid industrialisation and growth in the construction
stone; mining of gold and precious stones; well drilling, of buildings, roads, bridges in the last decades and it has
sandblasting; ceramic and glass production; and iron been an ongoing process. The problems of dust exposure
smelting (3,4). Workers involved in mining, rock breaking, and prevalence of silicosis are, therefore, increasingly
sandblasting, construction and the founding of ferrous and anticipated (2,18).
non-ferrous metals are at risk of silicosis. The disorder is
reported in all countries, but is more prevalent in low- and Pathophysiology
middle-income countries, where the burden is often under-
reported because of a poor surveillance system. China has Pathological diversities of silicosis include simple [nodular]
the most reported patients with silicosis, with nearly 6000 silicosis, progressive massive fibrosis, silicoproteinosis, and
new cases and more than 24000 deaths reported annually (5). diffuse interstitial fibrosis and discrete hard nodules, usually
In the Brazilian gold-mining area in Minas Gerais alone, with upper-lobe predominance (19). Hilar and peribronchial
more than 4500 workers were reported to have had silicosis lymph nodes are often enlarged. Microscopically, the
between 1978 and 1998 (6). Less than100 cases were reported characteristic silicotic nodules are seen in hilar lymph nodes
every year in the UK between 1996 and 2009. In the USA, and lung parenchyma. Under polarised light microscopy,
overall age-adjusted mortality rates declined from 8.9 per bi-refringent particles are often seen in the centre of silicotic
million in 1968 to 0.7 in 2004 (7,8). Protective measures nodules. In progressive massive fibrosis [PMF], lung nodules
[e.g., dust control and respirators] have caused a steady become confluent, resulting in lesions nearly a centimeter or
decline in death rates due to silicosis in the past few decades bigger in diameter. Inhaled respirable silica dusts usually
 Silicotuberculosis 201

are deposited in distal airways. Reactive oxygen species massive fibrosis. Other patients with chronic silicosis could
being activated by silica can produce directly on freshly present with comorbidity like TB and lung cancer (2).
cleaved particle surfaces or indirectly through its effect on
the phagocytic cells (20). Macrophage receptor expressed in Accelerated Silicosis
alveolar macrophages help in the recognition and uptake
of silica (21). The interleukin-1 [IL-1] signalling pathway Accelerated silicosis occurs after a few years of exposure to
and other inflammatory cytokines, such as tumour necrosis silica. Accelerated silicosis develops 5-10 years after initial
factor [TNF] play crucial roles in subsequent inflammation exposure and is associated with rapidly progressive features
and fibrosis (2,22). of dyspnoea and pulmonary fibrosis. Clinically it is similar
Clinically, silicosis can remain present in three different to chronic silicosis, but progresses rapidly (1,2).
forms: acute; accelerated; and chronic.
Radiographic Findings
Acute Silicosis Chest radiograph is the primary method of diagnosis. The
Acute silicosis also called silicoproteinosis, occurs rarely radio­graphic features of silicosis are varied and range from
after exposure to high concentrations of respirable crystal­ diffuse, fine, rounded, regular nodularity resembling miliary
line silica for a few weeks to five years. It commonly TB to coarse irregular nodules [Figures 14.1 and 14.2] or
affects sandblasters. In addition to dyspnoea and cough, extensive fibrosis resembling progressive massive fibrosis
constitutional symptoms could be present, such as fatigue, [Figures 14.3 and 14.4]. In simple silicosis, chest radiography
fever, and weight loss. Respiratory failure and death often
occur within a few months.
Acute silicosis occurs after exposure to a very high
concentration of dust over a few months and is usually
rapidly fatal within years (23). Currently, sandblasters and
silica flour mill workers are the two groups considered at
high risk of developing acute silicosis (2).

Chronic Silicosis
Chronic silicosis, the commonest form of silicosis, usually
develops after at least a decade long exposure at low
concentrations of silica (24). It is usually seen in industries
with rigorous environ­m ental control procedures. The
patients with simple silicosis are usually asymptomatic
in early stages and diagnosed by the way of radiological
examination. Shortness of breath is more common at later Figure 14.1: Chest radiograph [postero-anterior view] showing coarse
stages than it is initially, especially with progression of irregular nodules and fibrosis in a patient with silicosis

A B
Figure 14.2: Chest radiograph [posetro-anterior view] [A] and CT chest [B] in a patient with silicosis showing nodular pattern
 202 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

usually shows small round opacities, often symmetrically with a tendency towards peripheral calcification, which
distributed with upper-zone predominance. With extensive produces the so-called egg-shell appearance [Figures 14.3
fibrotic structure, hilar structures are usually pulled up, and 14.4]. The hilar and mediastinal groups are often
leaving hyper translucent zones of lung in the periphery and affected, but other thoracic and extra-thoracic nodes may
lower-lung zones, often with several bullae. The involve­ment also be affected. The visceral pleura when involved are
of lymph nodes by chronic silicosis is fairly characteristic, often diffusely thickened by fibrosis with occasional focal

A B

Figure 14.3: HRCT chest in a patient with silicosis showing

C conglomerate and subpleural nodules, multifocal fibrosis

A B
Figure 14.4: Chest radiograph [posetro-anterior view] [A] in a patient with complicated silicosis showing extensive fibrosis, egg shell calci­fication.
Chest radiograph [postero-anterior view] [B] in another patient with complicated silicosis showing extensive fibrosis, egg shell calcification, bulla
formation
 Silicotuberculosis 203

calcification. Involvement of the middle and lower zones the mycobacterial disease in some populations (13,40),
of the lungs is more frequent in accelerated silicosis (25,26). M. kansasii being the most common type (13,41). When
compared to the healthy control, the risk of developing
Management pulmonary TB is reported to be 2.8-39 times higher and
EPTB is also as much as 3.7 times more for patients with
No curative treatment for silicosis exists. There is no silicosis (13).
evidence of benefit of using corticosteroid treatment for
long-term benefit for patients with chronic or accelerated
Pathogenesis
silicosis, and such treatment could increase the risk of
TB. Silicosis patients should generally be removed from Several pathogenetic processes are common to TB and
further exposure. Empirical treatment with bronchodilators silicosis which are synergistic in producing more fibrosis
should be considered for symptomatic patients with airflow and in enhancing susceptibility to mycobacterial infection
obstruction. Cough suppressants and mucolytics could be or reactivation of a latent focus of infection [Figure 14.5,
useful for symptomatic relief. Antibiotics should be given Table 14.1] (30). Evidence from experimental studies suggests
as necessary for intercurrent chest infections. Complications, that silica alters the immune response of the lungs, impairs
such as, pneumothorax, chronic cor pulmonale, and
respiratory failure should be managed accordingly (1).

SILICOTUBERCULOSIS
Epidemiology
The coexistence of silicosis and TB has been called silico­
tuber­culosis. This has been reported since the early part of
the twentieth century (23). Prolonged exposure to silica dust,
even in the absence of radiological silicosis, also predisposes
individuals to TB (27,28). On the other hand, TB may
complicate simple silicosis to advanced disease (29). As an
end result of inflammation, TB can contribute to the further
development of fibrosis in patients with silicosis (30). With
poor environmental conditions, the prevalence of silicosis
and silicotuberculosis is shown to be higher (31).
Even after exposure ceases, there is increased life-long
risk of both pulmonary and extra-pulmonary TB [EPTB] (27).
In endemic area, the TB rates in advanced simple silicosis
is up to three-fold higher and the relative risk of death
from TB is three- to six-fold greater in patients with silicosis
than in the general population. The risk is higher in
patients with acute and accelerated silicosis (32). The pre­
valence of pulmonary TB is correlated with age and service
duration of the workers as well as the severity of underlying
silicosis (33,34). There is 27% incidence of TB over five years
among a group of 679 patients with silicosis in Hong
Kong (35). TB were diagnosed in 43% patients with silicosis
in a Chinese study with a follow up over a period of Figure 14.5: Pathogenesis of silicotuberculosis
18 years (36). TB was attributed to 11.8% deaths in patients IL-1 = interleukin-1; TNF = tumour necrosis factor; TB = tuberculosis
with silicosis of 595 workers in Italy (37).
From India, available studies have shown 3-7 times
higher incidence of TB in persons with silicosis compared Table 14.1: Influence of TB on silicosis
to matched control (11,12). The fraction of silicosis suffering Exposure of silica has an unfavourable influence on the course of
from TB has been reported in earlier reports from 4.8% to induced TB
up to 60% and on average; it appears that TB occurs in There is more fibrosis produced by the combination
20%-25% of all silicosis patients in their lifetime. The Synergistic effect of silicosis and TB—proliferative fibrous reaction
mortality risk is higher if TB develops among silicosis (38). TB may complicate simple silicosis as well as advanced disease
Mycobacterium kansasii and Mycobacterium avium-intra­
It may develop massive fibrosis
cellulare were reported in 12 of the 22 cases of silicosis with
mycobacterial infection (39). Also nontuberculous myco­ Exposure of silica has an unfavourable influence on the course of
induced TB
bacteria [NTM] were detected in 14% of 234 gold miners
studied (34). NTM may account for a large proportion of TB = tuberculosis
204 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

the function of pulmonary macrophages, and, with frequent Diagnosis

exposure, causes macrophage apoptosis (8,13). The silica
particles are phagocytosed by the alveolar macrophages. Early diagnosis of active TB not only helps limiting own
Phagocytosis of crystalline silica in the lung causes lysosomal disability by early treatment but also stops spreading of
damage, activating the NALP3 inflammasome and triggering the bacilli to silica-affected co-workers and the community.
the inflammatory cascade with subsequent fibrosis. Silica has The diagnosis of active TB in patients with silicosis demands
the capacity to cause damage to the cell membranes which a high degree of suspicion and primarily on the basis
leads to the death of the macrophages with re-exposure of a history of exposure, clinical sympto­m atology and
of the other macrophages to the same particles. Prior to chest radiographic appearances [Table 14.2]. It is difficult
the death, the macrophages become activated and secrete to differentiate abnormalities in the chest radiograph of
interleukin 1β [IL-1β] and TNF-α (42). These cytokines a patient with silicosis who has superimposed TB. The
are responsible for fibroblast activation and fibrosis. The radiographic abnormalities are seen in the apical area of
TNF-α also stimulates neutrophils to release oxidants which either of the lungs. These radiographic abnormalities are
produce local damage. usually poorly demarcated infiltrates of variable size that do
It has been seen that surfactant protein A are present at not cross the lung fissures (49). These opacities may surround
high levels in the broncho-alveolar lavage [BAL] fluid of pre-existing silicotic nodules. Presence of a cavity in a nodule
patients with silicosis. An excess of this protein seems to be is usually indicative of TB (30,49) although fluid-filled
associated with higher susceptibility to TB, possibly because cavities can be found in silicosis also (50). TB cavities in
it allows mycobacteria to enter the alveolar macrophages patients with silicosis are usually not traversed by large
without triggering cytotoxicity and inhibits the formation of vessels possibly due to vascular obstruction frequently seen
reactive nitrogen species by the activated microphages (43,44). in these patients (51). Additional suggestive findings include
It is also believed that the bacilli can remain encapsulated rapid changes in the radiographic picture, development
within the silicotic nodules, which would be responsible for of pericardial or pleural effusion, or onset of bronchial
the reactivation of TB in such patients (13). Impairment of stenosis, especially of the right middle lobe (49). Computed
lung function increases with disease progression, even after tomography [CT] of the chest is useful in some patients
the patient is no longer exposed. [Figure 14.6].
Lung fibrosis occurs in both diseases and may interfere Establishing the diagnosis of pulmonary TB in a
with the clearance of dust-laden alveolar macrophages or patient with silicosis by bacteriological methods is often
mycobacteria-laden material from the lung. Lymphatic difficult (49,52). Therefore, more frequent sputum smear
obstruction causes macrophages to accumulate in the examination for acid-fast bacilli [AFB] is recommended (52a).
interstitial tissues resulting in local fibrosis (45). Another The need for mycobacterial culture is more important in
hypothesis for the unexplained incidence of pulmonary TB areas where there is a high prevalence of NTM infection.
in patients with silicosis is through the surface coordination Occurrence of human immunodeficiency virus [HIV]
of iron by dust particles (45). By this process, the body iron infection and silicosis can result in profound susceptibility
is absorbed by the silica crystals in the lung. Indeed, low to Mycobacterium kansasii disease (52b). The reader is referred
serum iron has been observed among people exposed to to the chapter “Nontuberculous mycobacterial infections”
silicates (46). Evidence that iron is complexed on the silicate [Chapter 41] for further details. Differentiating silicosis from
dust can be found by the use of specific stains for iron or by other conditions [Table 14.3] is important. Establishing
measurement of the iron content of lungs in which silicate the diagnosis of miliary TB in patients with silicosis is
content is increased (47). This iron can be mobilised from
the silicate surface by a strong iron chelator. Mycobacteria
are dependent on iron for growth and produce the iron Table 14.2: Features suggestive of TB in patients with
chelators, namely, mycobactin and exochelin to mobilise the silicosis
metal from body stores; indeed iron is considered a virulence Radiographic abnormalities in the apical area of either lungs
factor for mycobacteria. It has been hypothesised that silicate Coalescence of nodules to form focal opacity of >1 cm, fibrotic
particles act as a reservoir of iron which can be used by the mass, conglomerate massive shadowing
mycobacteria, thereby explaining the increased incidence Poorly demarcated infiltrates of variable size that do not cross the
of TB among those who inhale silica dust (45). The iron lung fissures
made available from silicato-iron complexes may activate
Opacities surrounding pre-existing silicotic nodules
dormant tubercle bacilli by a mechanism similar to the effect
of iron repletion (48). Adjacent emphysema with abrupt sharp border, presence of a cavity
in a nodule
Clinical Features Radiographic abnormalities in the apical area of either lungs
Poorly demarcated infiltrates of variable size that do not cross the
The manifestations of TB in patients with silicosis are similar lung fissures
to those in general population. However, since weakness,
Distortion of lung parenchyma due to fibrosis, bronchial stenosis
fatigability, dyspnea and night sweats occur in silicosis
which may be irregular
also, at times, it may be difficult to detect concomitant TB
TB = tuberculosis
clinically.
 Silicotuberculosis 205

A B
Figure 14.6: CT chest coronal section [A] and axial section [B] in a patient with silicotuberculosis showing bilateral coarser irregular nodules
with fibrosis, conglomerate masses and calcification

Table 14.3: Differential diagnosis Table 14.4: Complications of silicosis, silicotuberculosis

Tuberculosis Cor-pulmonale
Sarcoidosis Spontaneous pneumothorax
Coal worker pneumoconiosis Broncholithiasis
Welder’s pneumoconiosis Tracheobronchial obstruction
Pulmonary alveolar proteinosis Lung cancer
Talcosis Hypoxaemic ventilatory failure

important as some patients can have both conditions. In within first two years after completion of treatment but the
some cases if diagnosis remains uncertain about active TB, risk of relapse likely to continue indefinitely after completion
BAL and transbronchial lung biopsy wherever possible; of treatment (58). In several recent trials, the efficacy of a
biopsies significantly increase the diagnostic yield of the short-course chemotherapy has been established in patients
test, even in patients whose sputum and BAL are negative with silicotuberculosis (40,57,58). However, a few studies
for mycobacteria (53). These should be performed routinely have suggested the need for a longer duration of anti-TB
if the diagnosis from sputum is inconclusive to facilitate treatment (41). Treatment of silicotuber­culosis is similar to
accurate diagnosis and management (54). the treatment of TB elsewhere in the body. Long-term follow-
up is recommended to diagnose possible relapse after the
Treatment completion of treatment. In India, patients with TB receive
DOTS under the Revised National Tuberculosis Control
The silicosis per se is incurable, but TB is treatable; the Programme [RNTCP] of the Government of India. The
manage­ment goals are aimed at early detection of silicosis, reader is referred to the chapter “Revised National Tuberculosis
disability limitation and treating associated TB at the Control Programme” [Chapter 53] for details.
earliest opportunities. Careful monitoring of both recently Generally a longer duration of anti-TB treatment
and formerly exposed workers to establish surveillance is required for these patients and the outcome is often
programmes, to prevent TB and to reduce disability remains unsatisfactory due to irreversibility of lung fibrosis due
the important aspects of the management. The success rates to silica deposition. It is important to implement smoking
of the treatment of TB in patients with silicosis were lower cessation programmes in the work-place. The environmental
than that in patients without silicosis (52,55,56). It has been factors and living conditions, those that predispose to TB and
postulated that the deep fibrotic lung tissue and vascular diseases must be taken care of. Complications in patients
obstruction seen in patients with silicosis make it difficult for with silicosis and silicotuberculosis are listed in Table 14.4.
the drugs to reach the target. However, it was shown later that
once the febrile phase of the disease subsides on treatment
Recommendations for Prevention
with anti-TB drugs, the return to underground work has not
adversely affected the treatment outcome in regards to the As the TB is reasonably common in patients with silicosis,
relapse rate which may be same (57,58), as in pulmonary TB, there is a strong opinion as per literature available on anti-
maximum relapses in patients with silicotuberculosis occur TB treatment in patients with silicosis (59). Accordingly
206 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

those who have periods of exposure to silica longer than 14. Tiwari RR, Narain R, Sharma YK, Kumar S. Comparison of
10 years, irrespective of silicosis disease, should have periodic respiratory morbidity between present and ex-workers of quartz
chest radiographs and tuberculin skin test [TST] in the initial crushing units: Healthy workers’ effect. Indian J Occup Environ
Med 2010;14:87-90.
evaluation (60). If TST is positive [induration ≥10 mm],
15. Tiwari RR, Sharma YK. Respiratory health of female stone
a 6-month course of isoniazid at 300 mg/day [or 10 mg/ grinders with free silica dust exposure in Gujarat, India. Int J
kg/day] should be instituted (61-63). If the TST is negative Occup Environ Health 2008;14:280-2.
[induration <10 mm], the test may be performed again in 16. Saiyed HN, Ghodasara NB, Sathwara NG, Patel GC, Parikh DJ,
two weeks for confirmation, considering that exposure to Kashyap SK. Dustiness, silicosis & tuberculosis in small scale
the TST can stimulate the immunological memory against pottery workers. Indian J Med Res 1995;102:138-42.
the TB bacillus. If the negative result still persists, the test 17. Jindal SK. Silicosis in India: past and present. Curr Opin Pulm
Med 2013;19:163-8.
should be done annually (63). There is a strong evidence to
18. Tiwary G, Gangopadhyay PK. A review on the occupational
support the concept that silica dust control is associated with health and social security of unorganized workers in the
a major reduction in risk TB in silica-exposed patients (64). construction industry. Indian J Occup Environ Med 2011;15:
Systematic testing and treatment of latent TB infection [LTBI] 18-24.
should be performed in people with silicosis (65). Short 19. van Zyl Smit RN, Pai M, Yew WW, Leung CC, Zumla A,
course prophylactic regimens using rifampicin alone have Bateman ED, et al. Global lung health: the colliding epidemics
not demonstrated higher rates of active TB when compared of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J
2010;35:27-33.
with long-term isoniazid. A weekly regimen of rifapentine
20. Hamilton RF, Jr., Thakur SA, Holian A. Silica binding and toxicity
and isoniazid has higher completion rates, and less liver in alveolar macrophages. Free Radic Biol Med 2008; 44:1246-58.
toxicity (66). An active surveillance of the workers should be 21. Thakur SA, Hamilton R Jr, Pikkarainen T, Holian A. Differential
carried out in both pre-employment and post-employment binding of inorganic particles to MARCO. Toxicol Sci
periods. Careful individualised clinical evaluations and close 2009;107:238-46.
follow-up of tuberculin converters are essential to reduce 22. Huaux F. New developments in the understanding of
the risk of developing TB. There is also a need for evolving immunology in silicosis. Curr Opin Allergy Clin Immunol
a comprehensive policy for the prevention, treatment, 2007;7:168-73.
23. Mazurek JM, Attfield MD. Silicosis mortality among young
rehabilitation, compensation and follow-up in patients with
adults in the United States, 1968-2004. Am J Ind Med 2008;51:
silicotuberculosis (67). 568-78.
24. Cocco P. The long and winding road from silica exposure to
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 15
Abdominal Tuberculosis
Govind K Makharia

INTRODUCTION Mtb can affect many organs including gastrointestinal

[GI] tract, peritoneum, hepatobiliary system and pancreas
While one-third of the world’s population is infected with [Table 15.1]. Marshall et al (11), after pooling data from
Mycobacterium tuberculosis [Mtb], only about 10% of them six studies [n = 596] reported that 42%, 50% and 8% had
ever develop active TB (1-3). Extra-pulmonary tuberculosis peritoneal, GI and lymph node TB, respectively (11). While
[EPTB] accounts for approximately 20% of all cases with GI and peritoneal TB usually do not co-exist, in some
TB in immunocompetent individuals; of these 3%-5% have patients with peritoneal TB intestinal involvement may
abdominal TB (4-6). While abdominal tuberculosis [TB] be observed on cross-sectional imaging such as contrast-
still remains an important disease in countries where enhanced computed tomography [CECT].
TB is still endemic; increasing population migration and
epidemic of human immuno­deficiency virus [HIV] infection INTESTINAL TUBERCULOSIS
and acquired immunodeficiency syndrome [AIDS] have
led to resurgence of this disease in regions where TB had Site of Involvement
previously been largely controlled (4-10). While any part of GI tract may be involved by Mtb, the most
common site of involvement is ileocaecum [ileum, ileocecal
Table 15.1: Classification of abdominal TB valve and caecum] (11). Other common sites of involvement
Gastrointestinal TB
include the colon [where the frequency decreases segmentally
from the ascending colon to the rectum], jejunum, stomach,
Small and large intestinal TB
duodenum and oesophagus (11-18). The ileocaecal region
Gastroduodenal TB
Oesophageal TB is the preferred site of involvement by TB because of
abundance of lymphoid tissue, relative physiologic stasis,
Peritoneal TB
and minimal digestive activity permitting greater contact
Chronic peritoneal TB time of acid-fast bacilli [AFB] with the mucosal surface of
Ascitic form the ileocaecum, among others (11).
Encysted [loculated] form
Dry type
Pathogenesis
TB of the solid viscera
TB can develop primarily within the intestinal tract or
Hepatobiliary TB
secondary to a focus elsewhere in the body. There are four
TB of the spleen
TB of the pancreas possible ways by which an infection can reach the GI tract:
[i] direct invasion by the ingested Mtb; [ii] transport by the
TB of the abdominal lymph nodes
way of infected bile; [iii] extension from adjacent diseased
TB mesenteric lymphadenitis organs or tissues; and [iv] haematogenous spread. Intestinal
TB of lymph nodes at porta hepatis
TB retroperitoneal lymphadenitis
involvement is probably related to the number and virulence
of the ingested organisms and the nutritional status of the
TB = tuberculosis
patient (7,11,13).
 Abdominal Tuberculosis 209

Pathological and Clinical Correlation Pathology

The diameter of a normal intestine decreases from the Traditionally, intestinal TB is described to be of three types,
duodenum to jejunum and then to the ileum. The diameter namely, ulcerative, hypertrophic and ulcero-hypertrophic.
of the jejunum is 3 cm and that of the ileum is 2.5 cm (18,19). The ulcerative form of the disease is mainly due to
The content which flows through the intestine is mostly deprivation of blood supply, because of endarteritis. In GI
liquid chyme. At what diameter of the intestinal lumen TB, ulcerogenesis is relatively slow, and an inflammatory
the obstruction to the flow of chyme occurs, is not well- wall develops ahead of the advancing ulcer. Thus, if
established. In a rat model, it was observed that the pressure perforation occurs, it will remain contained. There is an
in the intestine started rising and the flow of the contents accumulation of collagenous tissue during the process of
started decreasing when the luminal diameter decreased ulcer healing that subsequently contracts and results in
to 60% (20). Therefore, in the early stage intestinal TB, circumferential stricture of the intestinal lumen. The diseased
when the lesions are superficial and there is no cicatrisation segment is moderately indurated and the serosa is studded
of the lumen, the flow of chyme is not affected and patients with nodules. Mesenteric lymph nodes are usually enlarged.
may not have any intestinal symptoms. As the disease The mucosal surface may show single or multiple ulcers,
progresses, the effective diameter of the intestinal lumen and skip areas may be present with normal appearing
decreases, resulting in obstruction to the flow of contents. mucosa between the involved segments. The ulcers are
The severity of symptoms increases as the intestinal luminal characteristically transverse and circumferential, but may be
diameter decreases. The initial symptoms of intestinal colic round, stellate, or longitudinal. The ulcers are deep, however,
are usually episodic and are precipitated by episodes of GI they generally do not penetrate the muscularis propria.
involvement resulting in temporary mild intestinal wall In the acute phase, there may be a functional stenosis of
oedema and further decreasing the diameter of the already the involved segment because of the spasm of a segment
compromised intestinal lumen. As disease progresses, the of intestine. In the more chronic phase, circumferential
interval between the episodes of symptoms decreases. strictures may develop. In hypertrophic form of the disease,
Ultimately, the symptoms of intestianl colic become more there is a marked inflammatory fibroblastic reaction in the
frequent and patients develop partial intestinal obstruction. submucosa and subserosa of the involved segment, mostly
The ulcerations and nodularity caused by the tissue ileocaecum (12,13,25). Caseating granulomas [vide infra] are
destruction can lead to oozing of blood from the ulcers, the histologic hallmark of TB (12,13,26,27)
resulting in anaemia.
After effective treatment of the disease, there is resolution Clinical Features
of active inflammation and healing of ulcers, which results
Intestinal TB is commonly seen in persons aged between 20
in the improvement in symptoms. As it is well-known that
and 40 years; however, it can occur at any age (11,12,28-30).
chronic inflammatory process heals with fibrosis, the healing
Both genders are equally affected. The symptoms in a patient
of ulcers and inflammation of the intestine leads to scarring
with intestinal TB arise because of [i] intestinal ulcero-
of the intestinal lumen, and thus, compromise the normal
constrictive disease [intestinal colic, abdominal distension,
intestinal diameter (21). There is a fundamental difference
nausea, vomiting, constipation, bleeding manifestations];
in the diseases affecting solid or spongy organs and luminal
[ii] chronic inflammatory process [fever, weakness,
organs. In spite of residual changes in a part of the solid
weight loss, night sweats]; [iii] associated adjacent tissue
or spongy organ, there still may be sufficient volume to involvement [ascites, lymph node enlargement or tubo-
maintain the functions of the organ. On the contrary, healing ovarian symptoms]; and [iv] coincident pulmonary TB
of the intestinal lesions may result in the fibrotic stricture and [chronic cough, expectoration, haemoptysis].
may continue to be symptomatic. The resulting intestinal Intestinal TB should be suspected in patients presenting
stricture or narrowing mostly remains sufficient to allow with recurrent intestinal colic, partial or complete intestinal
the passage of intestinal contents. A superimposed infection obstruction. Intestinal TB should also be suspected in
can precipitate intestinal colic or even partial intestinal patients having weight loss and pyrexia of unknown origin.
obstruction, which mostly can be treated conservatively. On There should be a high index of suspicion for intestinal TB
occasions, healing of lesions can result in a critical stricture in immunocompromised individuals.
resulting in frequent symptoms and may require resection. The symptoms of GI TB depend upon the site[s] of
It is important to differentiate an active unresponsive involvement of the GI tract and also the type of lesions.
stricture caused by treatment failure or multidrug-resistant The ileocaecal area is the most common site of involvement
TB [MDR-TB] from the fibrotic stricture. An active ulcerated in patients with intestinal TB, and most of the lesions are
lesion on colonoscopic examination confirms non-healing ulcerative or ulcero-constrictive type. Abdominal pain is
of lesion at the end of the therapy. CECT enterography the most common manifestation and can occur because of
is also useful to differentiate between the two conditions. a stricture of the intestinal lumen, mesenteric inflammation
While active inflammatory lesions will show contrast and peritoneal involvement. While pain arising from the
enhancement, fibrotic strictures will show no enhancement intestine is mostly colicky in nature, pain arising from
of CT enterography (22-24). the mesentery or the peritoneum is mostly diffuse and
210 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

non-specific. As disease advances with time, the severity and extra-intestinal structures, which is detected by cross-
and frequency of painful episodes increase and the patient sectional imaging, such as computed tomography [CT] and
may develop partial intestinal obstruction [abdominal magnetic resonance imaging [MRI]. Combined imaging
distension, gurgling in the abdomen, partial or complete modalities, such as, CT-enteroclysis or magnetic resonance
cessation of flatus, vomiting or movement of ball of wind [MR-] enteroclysis is also helpful.
in the abdomen] or even complete intestinal obstruction.
Diarrhoea is seen in 20%-30% of patients and can be because Imaging
of both small and large intestinal involvement. Patients with
intestinal TB can also have malabsorption which results from Pulmonary lesions, either active or healed, may be evident
[i] decrease in small intestinal mucosal surface; [ii] lymphatic in a quarter of subjects on the chest radiograph. In a patient
obstruction; [iii] fistula formation between the small and with ulcero-constrictive disease of the intestine where
large intestine; [iv] deconjugation of bile salts secondary intestinal TB is a differential diagnosis, presence of an
to bacterial overgrowth; and [v] decreased bile salt pool active pulmonary lesion may point towards intestinal TB as
because of impaired active absorption in the distal ileum. a cause of ulceroconstrictive disease (28-30,36). In patients
While lower GI bleeding is seen in 10%-15% of patients, presenting with abdominal pain, where a diagnosis of
the bleeding is rarely massive. Almost half of the patients intestinal obstruction cannot be ruled out, a plain radiograph
with intestinal TB report having constipation. Constitutional of the abdomen may, sometimes, provide an important clue
symptoms in the form of fever, malaise, night sweats, to the clinical diagnosis.
anorexia, and weight loss are common. A few patients may Although there are many suggestive features on radio­
have active TB elsewhere, especially lungs (11,12,28-30). graphic investigations, none of them are diagnostic for
There are no very specific clinical signs in patients with intestinal TB. The radiological features depend upon stage of
GI TB. They may have poor nutritional status and anaemia. the disease, site of involvement and severity of the disease.
One-half to two-thirds of patients have low-grade fever. In the early stage of mucosal invasion and ulceration, barium
Abdominal tenderness is frequently present in the right findings of ileocaecal TB are non-specific and include spasm
lower quadrant. A mass may be palpable in 10%-20% of and hyper-motility of the intestinal segment, oedema of
patients and is because of a conglomerate of adhered bowel the ileocaecal valve and mucosal thickening (37-41). TB
loops, lymph nodes and, sometimes, mesentery. Extensive ulcers are circumferential or transverse in orientation. With
fibro-adhesive inflammation in the peritoneum can make the progression of the disease, the ulcers become confluent. The
dough consistency of the abdominal wall. Complications of features on barium imaging are more definitive in advanced
intestinal TB are listed in Table 15.2 (7,9-11,29-31). stages of the disease. There is a thickening of the ileocaecal
valve with narrowing of the terminal ileum [Fleischner’s
sign or inverted umbrella sign]. In further advanced disease,
Table 15.2: Complications of intestinal TB the characteristic deformities include symmetric, annular
stenosis with obstruction, and shortening of the intestine and
Partial or complete intestinal obstruction
the colon. The caecum classically becomes conical, shrunken,
Lower GI bleeding and pulled up from the iliac fossa due to contraction of the
Intra-abdominal abscess mesocolon. There may be a loss of the normal ileocaecal
Malnutrition angle (37-41). The ileocaecal valve classically becomes
Intestinal perforation incompetent, rigid and fixed with an irregular outline
[Figure 15.1]. TB strictures are typically short and multiple,
TB = tuberculosis; GI = gastrointestinal
separated by unaffected segments [Figure 15.2]. Enteroliths
may form proximal to the strictures and may vary from a
Laboratory Investigations single large lamellated calculus to multiple small stones
visible on the radiograph (37-41).
Laboratory investigations in patients suspected to have Contrast-enhanced CT [CECT] or CT-enteroclysis,
intestinal TB aim at detection of site, extent, and type MR-enteroclysis are essential for the evaluation of extra-
of lesion[s]; associated complication[s]; confirming the luminal, peritoneal, nodal and visceral involvement. CECT
diagnosis of TB histopathological, microbiological and is more accurate than ultrasonography in detecting most
molecular methods; and documenting active or healed of these manifestations including peritoneal and intestinal
TB elsewhere in the body. In a patient suspected to have involvement. CT-enteroclysis may show intestinal wall
intestinal TB, haematological and biochemical investi­ thickening [unifocal or multifocal], a stricture with proximal
gations are non-diagnostic. However, these should be dilation of the intestine, and regional lymphadenopathy.
done to estimate the effects of the disease and also as a The pattern of lymphadenopathy in TB may vary widely,
baseline for monitoring the effects or complications of the including increased number of normal sized nodes, mildly
therapy (7,11,12,28,29-35). All patients suspected to have enlarged nodes to large confluent nodal masses (42-46).
intestinal TB should be screened for HIV infection. The involved lymph nodes typically show hypodense
The imaging studies of the intestine include: luminal centre and peripheral enhancement which reflects central
imaging [endoscopic, barium studies], imaging of the wall necrosis [Figure 15.3] in 40%-70% cases. Since intestine
 Abdominal Tuberculosis 211

A B C
Figure 15.1: Barium meal follow-through examination showing ulcerations, contracted caecum, and stricture in the terminal Ileum [arrows]
with proximal dilatation of the terminal ileum [asterisk] [A and B]; barium meal follow-through examination in another patient showing contracted
caeum and terminal ileum, giving an appearance of swan-neck deformity [arrow] [C]

A B
Figure 15.2: Barium enterography showing eccentric stricture in the jejunum [A]; barium meal follow-through examination showing long stricture
in the duodenum [B]

A B C
Figure 15.3: CECT abdomen [sagittal section] showing thickening and enhancement of caecum and terminal ileum [A]; CECT abdomen
[sagittal section] showing markedly enhancing and thickening with narrowing of the terminal ileum [B]; CECT abdomen showing mesenteric
lymphadenopathy with central hypodensity and caecal thickening [C]
 212 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

remains collapsed, imaging of the luminal component of the Microbiological Tests Isolation of Mtb using mycobcacterial
intestine is not complete unless the intestine is distended. culture is the most specific method for the diagnosis of active
In CT-enterography or MR-enterography, intestinal lumen TB. Mtb can be cultured from 10%-30% of mucosal biopsies
is distended using a negative contrast, such as, polyethylene in patients with colonic TB (58-61). However, this method
glycol which allows simultaneous cross-sectional imaging of has a low sensiti-vity (58-61). A presumptive diagnosis of
the intestinal lumen, the intestinal wall and the surrounding TB may be considered by demonstrating AFB on intestinal
tissues. Therefore, CT-enterography or MR-enterography are biopsies which may be evident in 25%-36% in patients with
preferable imaging technique to CECT or MRI for imaging intestinal TB (39,62,63).
of the small intestine (44-46). Polymerase chain reaction [PCR] using Mtb specific
primer shows a positivity varying from 20%-64%. Detection
Endoscopy of Mtb by PCR has a high sensitivity and the positive results
Since ileocaecal area is involved in majority of the patients should be interpreted cautiously (40,63-65). PCR may be
with intestinal TB, colonoscopy with retrograde ileoscopy reported positive because of contamination in laboratories.
is the investigation of choice (14-17,42,47-52). Colonoscopic Presence of saprophytic mycobacteria may also result in a
examination provides an opportunity to visualise the lesion positive test result in colonic biopsies. In one study (58),
directly and one can obtain biopsies from the lesions at the in situ PCR for TB in mucosal biopsies tested positive in six
same time. The morphological appearance of intestinal TB of the 20 intestinal TB patients.
depends upon the stage of the disease. The lesions may
vary from mild lesion[s], such as loss of vascular pattern, Mucosal Biopsy With the increasing use of endoscopic
erythema, small ulcerations and superficial ulcerations, procedures to visualise the intestinal lumen and obtain
to more advanced lesions including deep ulcerations, targeted biopsies from diseased areas, endoscopic mucosal
nodularity and strictures. The evolution of intestinal TB may biopsy has now mostly replaced the surgical biopsies
take months to years; therefore, timely identification of the for micro­scopic examination. Granulomas are found in
early lesions can help in preventing the progression of the 50%-80% of intestinal mucosal biopsies from patients with
disease. Intestinal TB classically causes ulceration [50%-80%], clinically confirmed TB (7,14,15,26,27,50,66-70). Presence of
short strictures, marked thickening of the bowel wall due caseation and AFB, the diagnostic features of TB, are found
to inflammation, fibrosis and adhesions, or a combination in only 18%-33% of cases and in as low as 5% of cases,
of these (14-17,42,47-52). The ulcers [Figure 15.4] are respectively (7,14,27,66-70). Other suggestive features include
transverse, often circumferential, with ill-defined, sloping
confluent granulomas, presence of a lymphoid cuff around
or overhanging edges (14-17,42,47-52). The surrounding
granulomas. Further, granulomas larger than 400 μm in
mucosa may show flattening of folds, ulcers, erosions and
diameter, presence of five or more granulomas in biopsies
pseudopolyps. Multiple biopsies are obtained from the
lesions histopathological exami­nation, staining for AFB, from one segment, granulomas located in the submucosa
mycobacterial culture, as well as for molecular diagnostic or in granulation tissue, often as palisaded epithelioid
tests [vide infra]. histiocytes, and disproportionate submucosal inflammation
For small intestinal lesions, newer endoscopic techniques [Figure 15.5] are all considered features suggestive of
such as single and double balloon enteroscopic examination intestinal TB (27,66-70). In a recent meta-analysis (71), three
can be done (53-56). Capsule endoscopic examination is histopathological features, namely, caseation, confluent
generally not done for those patients where obstructive granuloma and presence of a lymphoid cuff around the
lesion such as intestinal TB is suspected (57). granulomas were found to be specific for TB.

A B C
Figure 15.4: Colonoscopic image showing marked nodularity, ulceration and stricture in the ascending colon [A]; colonoscopic image showing
ulceration and stricture in the caecum and ileocaecal valve [B]; enteroscopic examination showing ulcerations and stricture in the jejunum [C]
 Abdominal Tuberculosis 213

A B C

D E F

G H
Figure 15.5: Photomicrograph showing an ileum with broad drum stick like villi, crypt branching and pyloric metaplasia [arrow], indicating changes
of chronic ileitis [A] [Haematoxylin and eosin × 40]. Both broad superficial [B] and deep rail track like ulcers [C] [arrows] can be seen in TB
[Haematoxylin and eosin × 40]. Photomicrograph of the mucosa showing cryptitis and crypt abscess [arrow] [D], [Haematoxylin and eosin × 100].
TB granulomas [arrows] are large and can be seen in the mucosa [E], submucosa [F] and in the deeper layers [G]. These are mostly confluent;
central necrosis [G] and Langhans’ giant cells [arrow] [E] are also seen [Haematoxylin and eosin × 100]. Presence of granulomas and necrosis
[arrow] in abdominal lymph nodes is characteristic of TB [H] [Haematoxylin and eosin × 100]
TB = tuberculosis

Serological Tests Diagnostic Criteria for Abdominal Tuberculosis

Antibody to Saccharomyces cerevisiae antigens [ASCA] is As per the recently published Guidelines for extrapulmonary
often used to distinguish Crohn’s disease from ulcerative TB for India [INDEX-TB Guidelines ] (75), a “bacteriologically
colitis, being positive in the former. In India, the diagnostic confirmed case” of abdominal TB is defined as a patient
difficulty usually lies in distinguishing intestinal TB from who has a microbiological diagnosis of abdominal TB,
Crohn’s disease. However, antibody to Saccharomyces based on positive microscopy, culture or a validated PCR-
cerevisiae antigens has not been found to be helpful in based test [e.g., Xpert MTB/RIF]. A patient with negative
studies from India (72-74). A study (72) from New Delhi, microbiological tests for TB [microscopy, culture and
India, that included 59 patients with Crohn’s disease validated PCR-based tests], but with strong clinical suspicion
and 30 patients with intestinal TB reported ASCA to be and other evidence of EPTB, such as compatible imaging
positive in 61% of Crohn’s disease patients compared findings, histopathological findings, ancillary diagnostic
to 66% of intestinal TB patients. In another study (73) tests or response to anti-TB is designated as a “clinically
8 of the 16 patients with intestinal TB and 10 of the 16 diagnosed case” of abdominal TB.
patients with Crohn’s disease had tested positive for ASCA While a positive culture, demonstration of AFB on smear
antibodies (73). and histopathological evidence of a caseating granuloma
 214 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

are “gold standard” tests for the definitive diagnosis of TB, Table 15.3: Clinical, endoscopic and histological
the sensitivity of the combination of these tests is approxi­ differen­tiation between intestinal TB and Crohn’s
mately 30%-50% (63). In rest of the patients, the diagnosis is disease
considered presumptive based on clinical, endoscopic, radio­
Intestinal TB Crohn’s disease
graphic and histopathological evidences. Good response Variables [% present] [% present]
to anti-TB treatment supports the diagnosis of TB in these
Symptoms
patients. It should be emphasised that adherence to treatment
is extremely important in those with presumptive diagnosis Chronic diarrhoea 20-40 60-80
of TB who are receiving anti-TB treatment empirically. Non- Blood in the stools 10-20 50-70
response to treatment may occur because of non-adherence Abdominal pain 90 60-80
of the treatment, an alternative diagnosis, or MDR-TB. Constipation 50 10-30
Partial intestinal obstruction 50-60 20-30
Differential Diagnosis
Perianal disease 5 30-80
The closest differential diagnosis for intestinal TB is Crohn’s Fever 40-70 30
disease (14,27,39,41,42,63,70-72,76). Both intestinal TB and Loss of appetite 40-80 40-60
Crohn’s disease are granulomatous diseases of the intestine.
Weight loss 60-90 50-60
The clinical, morphological and histopathological features
of intestinal TB and Crohn’s disease are so similar that Extra-intestinal manifestations 10 20-50
it becomes difficult to differentiate between these two Involvement of intestine
entities (14,27,39,41,42,63,70-72). In geographical regions Anal canal <5 15-50
like Asia where both intestinal TB and Crohn’s disease Rectum 10-20 40-60
are prevalent, differentiating these two conditions may be Sigmoid colon 5-10 10-50
challenging. In Asia, intestinal TB is common, but Crohn’s Descending colon 5-10 10-50
disease is also being increasingly reported (77-80). Natural
Ascending colon 40-60 50-70
history of Crohn’s disease is quite different from that of
intestinal TB. While intestinal TB gets cured by appropriate Ileocaecal area 70-90 60
anti-TB treatment, Crohn’s disease has a remitting/relapsing Ileum 10-20 20-40
or persistent course and usually stays lifelong. Because Endoscopic features
of similarity in the clinical presentation and morphology Aphthous ulcers 5-10 30-50
of these two entities, at times, such patients are treated Linear ulcers 5 20-30
empirically with anti-TB drugs (14). Deep ulcers 50-70 30-40
The clinical, endoscopic and histopathological features
Nodularity 50 20
which can differentiate these two diseases as reported are
summarised in Table 15.3 (14,27,39,51,52,63,70-72,76). It is Cobblestoning ND 15-20
obvious that almost all the features are present in these two Histopathological features
conditions and not many are diagnostic feature of one or Granuloma 30-60 30
another. However, with the use of a combination of these Necrosis in the granuloma 10-30 ND
features, one is able to make a diagnosis of either TB or TB = tuberculosis; ND = not described
Crohn’s disease in almost half of the patients.
There are often situations where a differentiation between
intestinal TB and Crohn’s disease remains unclear despite In patients treated for intestinal TB, it is expected that
extensive investigation. Under these circumstances, both there will be a complete resolution of the lesions, detectable
the Asia Pacific Association of Gastroenterology [APAGE] by endoscopy or by imaging, following therapy. It is,
and Indian Society of Gastroenterology [ISG] consensus on therefore, appropriate to subject the patients who were
Crohn’s disease suggest a trial with anti-TB treatment (81,82). treated empirically for intestinal TB to endoscopy once
This is based on the rationale that the treatment of TB is again to establish complete mucosal healing at the end of
finite, whereas treatment for Crohn’s disease continues six months of treatment (81,82).
indefinitely (80,81). Further, there is a risk in treating patients The problem of differentiation between intestinal TB
diagnosed to have Crohn’s disease with corticosteroids and Crohn’s disease is also further compounded by the
if there is a possibility that the diagnosis may actually be fact that a proportion of patients with Crohn’s disease
TB. Obviously, the decision to treat for one disease or the have also been obser­ved to respond to with anti-TB at least
other would take into account other clinical considerations symptomatically (63,83,84).
including the nature of presentation of the patient, whether
acutely ill and requiring immediate definitive therapy or
PERITONEAL TUBERCULOSIS
not. It would also be accompanied by a complete discus­
sion with the patient of the possibilities and therapeutic Peritoneal TB is a subacute disease and its symptoms evolve
alternatives. over a period of several weeks to months (36,85). Peritoneal
 Abdominal Tuberculosis 215

TB frequently complicates patients with under­lying end- While at least 5000 bacilli/mL of specimen is required for
stage renal or liver disease. The disease can present in a positive smear, only a few bacilli/mL may be sufficient for
three different forms, such as ascitic form [wet type], a positive culture and for detection by molecular methods.
encysted [loculated] form and dry form. All of them have Ziehl-Neelsen staining of the ascitic fluid for mycobacterial
almost similar clinical manifestations except for abdominal detection has a very low yield [3%-5%] in proven patients
distension which does not occur in dry type TB peritonitis. with peritoneal TB. In order to increase the yield, it is
Abdominal pain [60%-70%] is a common presenting recommended that a larger volume of ascitic fluid should
symptom and is frequently accompanied by abdominal be sent to the laboratory and that the fluid should be
distension. Abdominal pain in peritoneal TB is usually non- centrifuged before staining (85). Cartridge-based nucleic acid
localised and non-specific in nature. The pain is largely due amplification tests [CBNAAT] are increasingly being used
to the inflammation of the peritoneum and the mesentery. to diagnose peritoneal TB (75,90a). In a recently published
Less often, it could be due to involvement of the intestine. systematic review (90a), Xpert MTB/RIF was found to have
Tenderness on palpation is common in peritoneal TB and a high pooled specificity in peritoneal fluid [97.9%] as well as
occurs in almost half of the patients. Rebound tenderness is peritoneal tissue [92%]; however, the pooled sensitivity was
rare as the presence of ascitic fluid prevents approximation low both in peritoneal fluid [59.2%] as well as in peritoneal
of the parietal with the visceral peritoneum. A smaller tissue [50%].
percentage of patients [5%-10%] present with the classical Elevation of cancer antigen [CA]-125 has been documented
‘doughy’ abdomen. This is described as dry or plastic type in majority of the patients with peritoneal TB mimicking
of TB peritonitis (31,32,36,85,86). advanced ovarian carcinoma. The levels of CA-125 fall
rapidly with anti-TB treatment paralleling clinical response
Ascitic Fluid Analysis and resolution of ascites (85).
The ascitic fluid is usually straw coloured. While red blood
cells are seen frequently on microscopic examination, frank Imaging Studies
haemorrhagic ascites is uncommon. The ascitic fluid white Ultrasonography of abdomen is generally the first diagnostic
blood cells [WBC] in peritoneal TB varies widely from less test in patients with ascites. Ultrasonography reveals echo­
than 100 cells/mm 3 to 5000 cells/mm 3. However, most genic debris seen as fine mobile strands or particulate matter
patients have cell counts between 500 and 1500 cells/mm3. within the ascitic fluid in patients with peritoneal TB. An
The WBCs are predominantly lymphocytes with the possible encysted fluid can also be detected by ultrasonography (90b).
exception of patients with underlying renal failure where, The thickened and nodular peritoneum due to TB can
for unknown reasons, the cells are mostly neutrophils. The be detected well by CECT [Figure 15.6]. The attenuation
protein content of ascitic fluid is high [>2.5 g/dL] and the value of ascitic fluid in tubercular fluid on CT scan is high
ascitic fluid glucose levels are low. The serum ascites albumin ranging from 20-45 Hounsfield units [HU]. The fibrotic
gradient [SAAG] has more diagnostic yield than ascitic fluid type of peritoneal TB is characterised by a hypervascular
total protein measurement. It is calculated by measuring peritoneum, matting of the loops, and omental masses.
both serum and ascitic fluid albumin on the same day and CECT can also show thickened mesentery [>15 mm] with
subtracting the ascitic albumin from the serum albumin mesenteric lymph node enlargement. One of the most
concentration. While the SAAG is usually low [<1.1 g/dL] important reasons to perform CECT in patients with high
in TB peritonitis, a high SAAG [>1.1 g/dL] suggests portal protein ascites is to differentiate TB peritonitis from the
hypertension. peritoneal carcinomatosis. While symmetrical thickening
Adenosine deaminase [ADA] is an enzyme that converts of the peritoneum with enhancement suggests peritoneal
adenosine to inosine and its activity is more in activated TB, nodular and irregular peritoneal thickening suggests
T-lymphocytes than in B-lymphocytes. There is an increase carcinomatosis (91). The fine needle aspiration cytology
in the number of activated T-cells in closed cavity infection, [FNAC] or biopsies can be done under ultrasonography or
such as TB ascites or pleural effusion.With attrition of CT guidance.
these lymphocytes, ADA along with other enzymes and
end products are released in the closed compartment and,
Laparoscopy
therefore, there is an increase in the ADA levels. A high
value of ADA in any fluid cavity, in fact is a reflection of In those patients with suspected diagnosis of peritoneal
high T-cell activity. An ADA value of more than 32 IU/L in TB, where a diagnosis cannot be confirmed on imaging,
ascitic fluid has been reported to have high sensitivity and direct inspection and biopsy of the peritoneum are perhaps
specificity for the diagnosis of TB ascites (85,87,88). High the most effective methods of diagnosing peritoneal
ADA may be seen in malignant ascites and even ascites TB. Three forms of features have been described in
due to cirrhosis. Interferon-gamma [IFN-γ] has also been patients with peritoneal TB such as thickened, hyperaemic
reported to be higher in TB ascites compared to malignant peritoneum with ascites and whitish miliary nodules
and cirrhotic ascites (89). The clinical significance and utility [<5 mm] scattered over the parietal peritoneum, omentum
of estimating IFN-γ in ascitic fluid for diagnostic purposes and bowel loops [66%]; thickened and hyperaemic
is not very clear. peritoneum with ascites and adhesions [21%]; markedly
 216 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B C
Figure 15.6: CECT abdomen, sagittal section showing thickened peritoneum and ascites [A]; loculated ascites [B]; and coronal section showing
loculated ascites [C]

thickened parietal peritoneum with possibly yellowish obtained from the lesions both for histopathological and
nodules and cheesy material along with multiple thickened microbiological tests including culture. TB of the oesophagus,
adhesions [fibro-adhesive type] [13%] (35). The diagnostic although uncommon, should be suspected in persons
yield of laparoscopic examination is very high with a presenting with dysphagia and oesophageal ulcerations
sensitivity of the macroscopic appearances approaching 93%. or strictures. The extent of the disease can be assessed
The cumulative data of 402 patients from 11 studies showed using endosonography which also allows indentification of
sensitivity and specificity rates of 93% and 98%, respectively mediastinal lymphadenopathy. If endoscopic biopsies are
when the macroscopic appearances were combined with the inconclusive, fine needle aspiration cytology [FNAC] of
histological findings [epithelioid granulomata with caseation the lymph nodes can be done using endosonography (97).
or mycobacterial identification] (92). Peritoneal biopsies All these patients should also undergo a cross-sectional
should always be examined whenever possible for culture imaging of the abdomen, such as CECT or MRI for evaluation
and sensitivity. Differential diagnosis of TB of peritoneum of the extent. If a definitive diagnosis of TB is not achieved,
include peritoneal carcinomatosis, sarcoidosis, starch malignancy must be ruled out before initiating such patients
peritonitis, fungal peritonitis and chlamydial peritonitis. on a therapeutic trial with anti-TB drugs. Patients receiving
In a patient with lymphocytic, exudative ascites with low therapeutic trial with anti-TB drugs must be carefully
SAAG and high ADA; TB peritonitis is the most likely cause. monitored at periodic intervals. An endoscopic examination
However, one should remember the possibilities of fungal should also be done at the end of anti-TB treatment to see if
peritonitis, and malignant ascites in such patients. Some of the lesions have healed. A response is defined if the ulcers
the patients with abdominal TB have marked thickening have healed completely. The healing process, however, can
of the peritoneum which may grow so much so that the leave behind some fibrotic nodules and even a stricture,
intestinal loops get encased in the cocoon (93). which can be dilated endoscopically if need ever arises.

OESOPHAGEAL TUBERCULOSIS GASTRODUODENAL TUBERCULOSIS

Oesophageal involvement in TB occurs mostly due to direct Because of acidic environment, stomach and duodenum are
extension of infection from adjacent affected structures, generally spared by Mtb infection. The TB lesions produce
such as mediastinal lymph nodes or the lung and isolated ulcerations and strictures in the duodenum and rarely in
TB of the oesophagus is unusual. Upper part of the the stomach. Therefore, symptoms include abdominal pain,
oesophagus is more often involved than the lower part. nausea, vomiting, GI bleeding, fever and weight loss (98-100).
TB of the oesophagus as in the other parts of GI tract leads Once luminal obstruction occurs because of the lesion, the
to formation of ulcerations and strictures. There­fore, main patient presents with obstructive features such as copious
presenting features in them are dysphagia, odynophagia, vomiting of stale food ingested four hours or more earlier.
chest discomfort/pain, and systemic symptoms (93-95). Endoscopic examination is the best investigation, wherein,
Some of these patients may develop tracheo-oesophageal the lesion can be visualised and biopsies can be obtained.
or broncho-oesophageal fistula (96). Upper GI endoscopy The extent and characteristics of the stricture can be
is the first investigation in patients with mechanical type assessed using barium meal or barium meal follow-through
of dysphagia, which shows ulcerations and strictures. examination. Cross-sectional imaging should also be done
There are no specific characteristics of these lesions and to evaluate completely the extent of the disease. Presence of
they may mimic malignancy. Multiple biopsies should be surrounding lymph node enlargement with central necrosis
 Abdominal Tuberculosis 217

makes the diagnosis of TB more likely. The gastro-duodenal The lesion can also be approached using endoscopic
stricture, if symptomatic, can be dilated using endoscopic ultrasound (109).
balloon dilator (101). Endoscopic mucosal resection has
also been done which yields a larger tissue for diagnosis. SPLENIC TUBERCULOSIS
While the inflammatory component heals well with anti-TB
treatment; it may leave behind a scarred antroduodenal area As the liver, spleen can also be involved by tuberculous
or duodenum. Most of these scarred lesions remain either infection in two ways, mostly as a part of disseminated
asymptomatic or mildly symptomatic. If the narrowing or miliary form of the disease and occasionally as isolated
produced by the healed lesions remain sympto­matic, one splenic TB. Most of these patients are immunocompromised;
can resort to endoscopic balloon dilatation or even surgery. splenic TB, however, has been reported in otherwise
immunocompetent individuals too (110). Most of the patients
of splenic TB are recognised on imaging and sometimes,
HEPATOBILIARY TUBERCULOSIS
as a surprise on operated splenectomy specimen. In those
The term hepatobiliary TB refers to either isolated hepatic, with disseminated form of the disease, there are enough
biliary, or hepatobiliary involvement with other organ clinical clues in other organs; there is no specific feature in
system involvement. Liver is involved in Mtb in two major isolated splenic TB to suggest a clinical diagnosis of splenic
forms. The more common involvement of the liver in TB is TB. Fever, left upper quadrant abdominal pain, weight loss,
as a part of a miliary or a disseminated disease (101-105). splenomegaly and/or hepatomegaly are usual features. On
In such type of involvement, there may not be any specific abdominal ultrasonography or CT, spleen may be enlarged
signs or symptoms related to the liver except for the and there may be one or multiple lesions (111). The treatment
presence of hepatomegaly. Liver biopsy in such patients is similar as elsewhere except that a splenectomy may be
may show the presence of granulomas. The second form, required in a few patients where the spleen is studded with
which is seen less often, is a localised form of TB involving tubercular abscesses.
the liver and the biliary ducts. Localised hepatobiliary TB
may occur as the following: [i] localised solitary or multiple TREATMENT
nodules, tuberculoma and TB hepatic abscess without bile
duct obstruction; [ii] bile ductal epithelium involvement In general, patients with intestinal strictures should be
producing inflammatory strictures resulting in obstructive advised to avoid high fibre diets. All these patients should
jaundice; and [iii] enlarged lymph nodes at porta causing undergo a nutritional assessment and nutritional deficiencies
obstruction to the bile duct. Obstructive jaundice is more should be addressed.
common in those having biliary system involvement. In All patients with TB should receive anti-TB drugs (112-115).
most patients, an increase in alkaline phosphatase, gamma Whether the optimal duration of treatment for gastrointestinal
glutamyl transferase, and a mild rise in serum transaminases TB and peritoneal TB should be six months or longer
is evident. Ultrasonography and subsequently CECT are has been debated (116-118). As per the recent INDEX-TB
required for complete imaging. In suspected patients, the guide-lines (75), six months daily treatment with a standard
bile ductal abnormality [stricture, unifocal or multifocal; first-line regimen using a combi­n ation of rifampicin,
ductal irregularity] can be seen by magnetic resonance isoniazid, ethambutol, and pyrazinamide for two months,
cholangiopancreatography [MRCP] or endoscopic retrograde followed by rifampicin, isoniazid and ethambutol for the
cholangiopancreatography [ERCP] (101-105). sub­sequent four months is recommended for abdominal TB
[strong recommendation, very low quality evidence]. The
reader is referred to the chapters “Treatment of tuberculosis”
PANCREATIC TUBERCULOSIS
[Chapter 44] and “Revised National Tuberculosis Control
TB of pancreas is uncommon and most often occurs due to Programme” [Chapter 53] for further details.
lymphatic or haematogenous dissemination or direct spread Since the treatment of TB is prolonged, adherence to
from other adjacent organs. The involvement of pancreas by treat­ment is a major problem in many parts of the world
TB infection can occur as part of miliary or disseminated including India (119,120). A study from Kerala in South India
form of TB or as isolated pancreatic TB. The usual lesion in showed that daily treatment and thrice-weekly intermittent
such patients is a pancreatic mass, and therefore, symptoms DOTS [where treatment was directly observed to ensure
depend upon the type and site of the mass (106,107). As treatment adherence], were equally effective for treating
other sites, anorexia, malaise, low-grade fever, weight loss, ileocaecal and colonic TB (121). In a multicentre randomised
night sweats are seen in majority of the patients. The specific controlled trial [RCT] (122) in patients with abdominal TB
symptoms include abdominal pain and obstructive jaundice [n = 197] evaluated thrice-weekly intermittent DOTS, no
if the pancreatic head is involved. Imaging shows mass in the difference was observed in the complete clinical response
pancreas which is a conglomerate of lesions in the pancreas rate both on per protocol analysis [91.5% versus 90.8%] and
and peri-pancreatic lymph nodes. Therefore, pancreatic intention-to-treat analysis [75% versus 75.8%] in groups
TB mimics a pancreatic malignancy (108). FNAC and a randomised to six months and nine months of treatment.
radiographically guided biopsy and mycobacterial culture Only one patient in the nine months treatment group and
helps in differentiating TB from pancreatic malignancy. none in six months group had recurrence of the disease.
218 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

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mized, single-centre study. Aliment Pharmacol Ther 2003;18: Sundar TS. Abdominal tuberculosis: diagnosis by laparoscopy
85-91. and colono­scopy. Trop Gastroenterol 2002;23:150-3.
 16
Granulomatous Hepatitis
Vineet Ahuja, SK Acharya

INTRODUCTION Table 16.1: Common causes of hepatic granulomas

Granulomas in the liver may be found incidentally and Infections
perplex the clinician, but more often reflect an underlying Bacterial: Brucella, Salmonella
clinically rele­vant disease. The search for an aetiology of Mycobacterial: Tuberculosis, Leprosy, NTM
granulomas usually suggests a systemic disorder rather Rickettsiae: Q fever
than primary liver disease. Granulomas represent the Spirochaetal: Syphilis
Fungal: Histoplasma, Coccidioidomycosis, Cryptococcosis
inflammatory response of the mononuclear phagocytic
Parasitic: Schistosomiasis
system to the presence of a foreign antigen. An extremely Viral: Hepatitis C, Cytomegalovirus
diverse array of inciting agents can result in the formation
Sarcoidosis
of granulomas in the liver. These granulomas often have a
Primary biliary cirrhosis
common histopathological pattern but may sometimes differ
in detail (1-4). However, in spite of an extensive work-up Hodgkin’s disease
and evaluation, the aetiology remains obscure in 10%-25% AIDS related opportunistic infections
patients with hepatic granulomas and these patients have Drugs: Carbamazepine, chlorpromazine, chlorpropamide,
been labelled as having “granulomatous hepatitis” (2-6). phenylbutazone, procainamide
The word “hepatitis” implies that there is hepatic NTM = nontuberculous mycobacteria; AIDS = acquired immuno­
cell destruction. However, in most patients with hepatic deficiency syndrome
granulomas, hepatic destruction is seldom seen. Therefore,
several workers have proposed that the term “granulomatous
hepatitis” should be avoided and have suggested “hepatic granulomas are listed in Table 16.1. However, this list is by
granulomatous disease” or “hepatic granulomas” as no means exhaustive. The relative frequency of occurrence
alternatives (3,4,7). of hepatic granulomas in some of the published studies is
shown in Table 16.2. In many studies, TB and sarcoidosis have
AETIOLOGY been the two most common causes of hepatic granulomas.
With the advent of the human immunodeficiency virus [HIV]
Hepatic granulomas have varied aetiology and show
infection and the acquired immunodeficiency syndrome
considerable geographic variation. There are numerous
[AIDS], hepatic granulomas due to rare causes such as
causes of hepatic granulomas, both infective and non-
nontuberculous mycobacteria [NTM], cryptococcosis etc.,
infective. While the occur­r ence of sarcoidosis, primary
are being increasingly encountered (1-4).
biliary cirrhosis and fungal disease is high in the Western
hemisphere, tuberculosis [TB] is the most common cause
PATHOLOGY
in India.
Hepatic granulomas usually represent a generalised Hepatic granulomas are the result of a cell mediated immune
disease process and have been described in 5%-10% of response by hepatic reticuloendothelial system to antigen/
needle liver biopsy specimens (2,4). The causes of hepatic foreign substances (1-4).
 Granulomatous Hepatitis 223

Table 16.2: Major causes of hepatic granulomas in various case series

Guckian and Neville Cunnigham Kanel and Sabharwal
Perry (8) et al (1) Klatskin (9) et al (10) Ferrell (11) Reynolds (3) et al (12)
Variable [n = 63] [n = 54] [n = 565] [n = 77] [n = 35]* [n = 202] [n = 51]
Tuberculosis 53 2 12.4 10.4 2.5 25.2 55
Sarcoidosis 12 54 38 10.4 20 27.2 1.9
Primary biliary cirrhosis ND 19 10.4 6.5 22.8 0† 0
Malignancy 5 1.4 4.4 7.8 8.5 3.5 7.8
Unknown 20 10 6.5 31.2 20 17.3 12
All values are shown as percentages
ND = not described
* Patients with epithelioid cell granulomas only
† Patients with primary biliary cirrhosis were excluded

Histopathological features of hepatic granulomas primary biliary cirrhosis among other conditions. Caseating
depend on the aetiology. Generally, hepatic granulomas [necrotising] granulomas have been classically associated with
consist of pale-staining epithelioid cells with surrounding TB. Fibrin ring granulomas with a characteristic “doughnut”
lymphocytes. Sometimes, the foreign body/infecting appearance occur in Q fever and have been described in
organism can be identified with the granuloma. Central several other conditions (13-15). Granulomatoid reaction
area of caseation necrosis, foreign body and Langhans’ giant with poorly formed granulomas occurs in patients with
cells can also be seen. Fibrous capsule and hyaline change haematological malignancies and AIDS (3). Bile granulomas
representing healing may also be found. have been described in areas of cholestasis. Lipogranulomas
Six basic morphological types of hepatic granulomas have can be seen in fatty liver. Microgranulomas can sometimes
been described [Table 16.3]. Epithelioid granulomas are often occur in patients with AIDS, cytomegalovirus [CMV]
encountered in patients with TB [Figure 16.1], sarcoidosis, hepatitis and can occur along with other types of granulomas.
Klatskin (9) estimated that in a patient with one granuloma
Table 16.3: Morphological types of hepatic granulomas in the needle biopsy specimen, the entire liver would
Epithelioid cell granulomas contain about 15 million granulomas assuming that there
is a generalised distribution. Hepatomegaly is, therefore,
Caseating [necrotising] granulomas
Non-caseating granulomas commonly observed in patients with granulomatous liver
disease (1-4,16-18).
Fibrin ring granulomas
Granulomatoid reactions with poorly formed granulomas
CLINICAL PRESENTATION
Bile granulomas
Clinical presentation of patients with hepatic granulomas
Lipogranulomas
depends on the causative disorder. These patients often
Microgranulomas
present with pyrexia of unknown origin [PUO]. Mild to

A B
Figure 16.1: Granulomatous hepatitis. Photomicrograph showing a well-defined epithelioid granuloma [arrow], Langhans’ giant cells, ballooning
and fatty degeneration [asterisk] of hepatocytes [A], [Haematoxylin and eosin × 200]. Epithelioid granuloma and Langhans’ giant cells [arrow] are
also seen amidst hepatocytes showing ballooning degeneration [B] [Haematoxylin and eosin × 400]
224 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

moderate hepatomegaly, which is usually non-tender, Primary Hepatic Tuberculosis

is common. When the disease is due to TB, sarcoidosis,
Primary hepatic TB is said to occur when there is involve­
associated peripheral mediastinal lymphadenopathy,
ment of the hepatobiliary tract by TB without apparent
erythema nodosum, clinically apparent jaundice may be
involvement elsewhere, or, only with local lymph node
found. In some conditions, such as, Hodgkin’s lymphoma
and splenic involvement (18). Some workers have called
and primary biliary cirrhosis where hepatic granulomas are
this condition “local hepatic TB” (18,19). Cinque et al (20)
an incidental finding, jaundice may be prominent.
suggested that the tubercle bacilli reach the liver via the
portal vein as opposed to miliary TB, where the organism
LABORATORY ABNORMALITIES
reaches the liver via the hepatic artery. Alvarez and
In a patient with PUO, marked elevation of serum alkaline Carpio (21) reported clinical and histopathological features
phos­phatase [SAP] [three to six times the normal] with of 130 patients with localised hepatic TB seen over a 20-year
mild elevation of serum transminases [two to six times period at Manila, Philippines. The disease was more
normal], well preserved hepatic synthetic function, normal common in males and most patients were in the 11-30 years
prothrombin time, serum albumin and a normal to slight age range. Most of them were symptomatic for one to two
increase in serum bilirubin should arouse a suspicion years prior to the time of confirmation of the diagnosis. The
regarding the presence of hepatic granulomas (2-4). Anaemia paper described two major forms of clinical presentation.
and elevated erythrocyte sedimentation rate [ESR] may be A hard, nodular liver with fever and weight loss mimicking
found. Peripheral blood eosinophilia may suggest Hodgkin’s cancer was observed in 65% of the patients. In the remaining
disease, parasitic infestation and drug sensitivity (2-4). 35% patients, chronic recurrent jaundice mimicking extra-
hepatic obstruction was observed. Percutaneous liver biopsy
DIFFERENTIAL DIAGNOSIS [positive in 48 of 71 patients; 67%] and laparoscopy [positive
in 49 of the 53 patients; 92%] were the main methods of
Hepatobiliary Tuberculosis confirmation of the diagnosis. On laparoscopy, hepatic
TB involvement of the hepatobiliary system can occur in lesions appeared as cheesy white, irregular nodules. Hepatic
several ways [Table 16.4]. Liver involvement in TB, though calcification was evident in 49% of the patients. In patients
common both in pulmonary and extra-pulmonary TB with jaundice, serum aminotransferases were elevated in
[EPTB], is usually clinically silent. Occasionally, local signs more than 90% and SAP was elevated in all patients. In those
and symptoms may be prominent in hepatic TB, and may without jaundice, serum aminotransferases were elevated in
constitute the initial or sole presenting feature of the disease. about 5% and SAP was elevated in 60% patients. Overall,
Using needle biopsy specimen, epithelioid granulomas 12% patients died in this series (21).
can be demonstrated in hepatic TB in 80%-100% of cases; In another series (22), hepatic TB was confirmed in
caseation necrosis in 30%-83% and acid-fast bacilli [AFB] on 96 patients presenting with the features of liver disease,
smear examination in up to 59% of cases (2-4). only 14 of whom had other concomitant hepatic pathology.
Although respi­ratory symptoms occurred in 74% of cases,
Congenital Tuberculosis these were overshadowed by the abdominal manifestations
which included pain in the right hypochondrium, abdominal
Hepatic involvement is very common in congenital TB and
distension, firm, tender hepatomegaly, splenomegaly and
has been recently incorporated into the diagnostic criteria for
ascites. Icterus was observed in 11 cases [only one of whom
this condition (19). When an infant born to a mother with
active TB manifests hepatomegaly, jaundice and failure to had concurrent hepatic pathology] and liver failure was
thrive, congenital TB should be considered in the differential found in 10 patients. A surgical presentation occurred in
diagnosis. The reader is referred to the chapter “Tuberculosis three patients. Coagulation abnormalities were noted in
in pregnancy” [Chapter 25] for details on this topic. 26 patients [24 with low prothrombin index and 2 with
moderately raised fibrinogen degradation products].
The characteristic serum profile included hyponatraemia
[64%], raised SAP [3%] and γ-glutamyl transferase [77%],
Table 16.4: Clinical syndromes of hepatobiliary
tuberculosis hypoalbuminaemia [63%] and hypergammaglobulinaemia
[83%]. Transaminase levels were moderately elevated
Congenital tuberculosis
in 78% of the cases. Hepatic imaging techniques were
Primary hepatic tuberculosis frequently misleading. Chest radiographs were normal in
Disseminated/miliary tuberculosis 25% of cases. Liver biopsy was the most useful aid to correct
Tuberculoma diagnosis, which was suspected clinically in only 47% of
Tuberculosis of the biliary tract cases. Histopathologically, AFB, caseation [Figure 16.2]
Drug induced hepatic failure and granulomas were seen in 9%, 83% and 96% of cases,
respectively. The overall morality was 42% (22).
Granulomatous hepatitis
Yu et al (23) have described computed tomography
Tuberculosis pylephlebitis
[CT] in hepatic TB in 12 cases. The patterns described by
 Granulomatous Hepatitis 225

In patients with pulmonary TB, hyperglobulinaemia is

frequently present and mild hyperbilirubinaemia may
occasionally be present (30). Serum aminotransferase
levels are usually normal. Kupffer cell hyperplasia is often
present (16,31,32).

Tuberculoma
Sometimes, hepatic TB lesions can present as masses larger
than 2 mm in diameter (33). Symptoms of fever, malaise
and loss of weight are common. Occasionally, abdominal
pain and diarrhoea may occur. Hepatomegaly is frequently
present. Jaundice and a palpable abdominal mass are
uncommon presenting signs. Obstruction to bile flow due
to compression at the porta hepatis by a tuberculoma has
Figure 16.2: Granulomatous hepatitis. Photomicrograph showing
balloon­
ing degeneration of hepatocytes [asterisk] and caseation
been postulated to be the cause of jaundice. Bleeding into
necrosis [arrow] [Haematoxylin and eosin × 400] a solitary tuberculoma presenting as an acute abdomen
and progressive anaemia have also been reported (34).
Consistent with a pattern characteristic of space occupying
them include [i] multiple nodular lesions in the subcapsule
lesions of the liver, serum transaminases are normal or
of liver; [ii] multiple, miliary, micronodular and low-
only slightly elevated; SAP levels are moderately elevated.
density lesions with military calcifications; [iii] singular,
low-density mass with multiple flecked calcifications; On liver scan and arteriography, these lesions may mimick
[iv] multiple cystic lesions; and [v] multiple micronodular the appearance of a primary or metastatic carcinoma.
and low-density lesions fusing into multiloculated cystic They may also be confused with pyogenic or amoebic liver
mass or “cluster” sign. Balci et al (24) reported the spectrum abscess (31,35). While blind percutaneous needle biopsy
of magnetic resonance imaging [MRI] features in 18 patients was not very helpful in the diagnosis (31,36), aspiration
with a histopathological diagnosis of granulomatous cytology at the time of laparoscopy was more useful in
hepatitis. Diffuse nodular liver involvement was visualised confirming the diagnosis (37). Most often these lesions
in all patients. Nodules were consistent with granulomas resolve with effective anti-TB treatment.
and were 0.5-4.5 cm in diameter. Caseating granulomas
were intermediate and high signal on T2-weighted, low Tuberculosis of Bile Ducts
signal on T1-weighted images. Non-caseating granulomas
TB of the bile ducts is uncommon. The disease is thought
revealed intermediate signal on T1, and T2-weighted images
to result from rupture of tubercles in the periportal region
and increased enhancement on arterial phase images with
into the walls of contiguous biliary ductules or by primary
persisting enhancement in late phase images.
infection of bile ducts (38). Stemmerman (39) found TB of
Most patients respond to anti-TB treatment. For
patients with obstructive jaundice, in addition to anti-TB the biliary ducts in 45 of 1500 autopsies and estimated the
treatment, biliary decompression should be performed incidence to be 3%. In these patients, symptoms and signs
either by stent insertion during endoscopic retrograde attributable to the biliary ducts are seldom found. Only
cholangiopancreatography, by percutaneous trans­hepatic three of the 45 patients [6.7%] reported by Stemmerman (39)
biliary drainage or by surgical decom­pression whenever manifested clinical jaundice, and hepatomegaly was evident
feasible (25). only in one-third of them. However, evidence of TB of
other organ systems draining into the portal circulation
Disseminated and Miliary Tuberculosis [e.g., caseous mesenteric lymph node TB, intestinal TB, and
TB peritonitis] was observed in 41 of the 45 patients this
Hepatic involvement is a common finding in patients with
series (39). Biliary stricture (40) and cholangitis (2) due to
disseminated and miliary TB (17). Granulomas has been
TB have also been described.
reported in 75%-100% patients in autopsy series (26-28)
and in 25%-100% needle biopsy specimens in patients with
miliary TB (17,29,30). Miliary lesions are small 1-2 mm Tuberculosis of Gallbladder
epithelioid granulomas. The reader is also referred to the Gallbladder is an uncommon site of involvement by TB. Most
chapter “Disseminated and miliary tuberculosis” [Chapter 29] cases occur in association with other organ involvement.
for details on this topic. Rarely, isolated TB of the gallbladder can occur (41,42)
and is usually a retrospective diagnosis, becoming evident
Pulmonary Tuberculosis on histopathological examination of the cholecystectomy
Up to two-thirds of the patients with pulmonary TB have specimen. Management consists of administration of anti-TB
been shown to have evidence of hepatic involvement (2,4,16). treatment (2,31,41,42).
226 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Hepatobiliary Tuberculosis in Patients with show characteristic clustering which is also seen in the lymph
Human Immuno­deficiency Virus Infection and nodes. As the granuloma ages, there may be deposition of
Acquired Immunodeficiency Syndrome collagen in a lamellar manner at the periphery of granuloma.
Sarcoidosis may present with chronic cholestasis, destruction
Hepatobiliary involvement is very common in patients of interlobular ducts and limiting plates may be evident in
with HIV infection and AIDS (7). Both, Mycobacterium liver biopsy specimens (54-56).
tuberculosis [Mtb] and NTM can cause the disease (2,31).
In patients with AIDS, it is important to distinguish hepatic Primary Biliary Cirrhosis
granulomas due to TB from other causes.
In the early stages, the hepatic granulomas in patients with
Other Hepatic Lesions primary biliary cirrhosis may be indistinguishable from
sarcoidosis. The granulomas are epithelioid and are most
Granulomatous hepatitis has been described in 12%-28% often found in the portal tracts. Lymphocytes are scattered
patients receiving bacille Calmette-Guérin [BCG] vacci­ within the granuloma. Plasma cells are often present in
nation (43-45). Clinically, constitutional symptoms, hepato­ perigranulomatous location. Multinucleated giant cells
megaly, mildly elevated serum transaminases, bilirubin and are not common and necrosis is not present. Sometimes
moderately elevated SAP levels are present. Focal defects epithelioid cells may surround the interlobular bile ducts
or non-homo­geneous uptake on technetium liver scan may undergoing non-suppurative destruction. Liver granu­lomas
be present. On histopathological examination, granulomas, may also be seen in primary sclerosing cholangitis (14).
hepatocellular necrosis, lymphohistiocytic aggregates
and Kupffer cell hyperplasia have been described (43-45). Drugs
Direct effect of viable BCG bacilli and hypersensitivity
Many drugs have the potential to produce hepatic granulomas
reaction have been proposed as the underlying pathogenetic
that may be eosinophil rich (57). Pyrazinamide which is
mechanisms (46).
given for the treatment of TB has also been implicated as a
Amyloidosis has been described in 10% of patients with
cause of granulomatous liver disease (58,59).
con­comi­tant hepatic TB which may occasionally present
as marked hepatomegaly (28). Most of these patients have
Chronic Hepatitis
long standing advanced disease frequently involving the
intestinal tract (28,47). Nodular regenerative hyperplasia Hepatitis C Infection
had been described in TB and several other disorders,
Chronic hepatitis C virus [HCV] infection has recently
such as, collagen vascular disorders [e.g., systemic lupus
been recognised as an aetiological cause of hepatic granu­
erythematosus, rheumatoid arthritis, progressive systemic
lomas (60). Hepatic granulomas have been described in up
sclerosis], antiphospholipid syndrome, macroglobulinemia,
to 10%, patients with chronic HCV infection. Development
among others (48,49). In Bantus of Africa, haemosiderosis of of hepatic granulomas following interferon treatment has
the liver has often been described (50). Whether these are been reported in patients with HCV infection (61). A recent
mere associations or the cause/effect of TB needs further multicentre study (60) evaluated a total of 725 liver biopsies
clarification. from 605 patients with chronic HCV infection to identify an
Hepatobiliary TB can rarely present as hepatic failure (51). association between the presence of granuloma and response
Severe degree of immunosuppression following liver trans­ to interferon treatment and also to see whether interferon
plantation also predisposes to the development of TB (52). treatment leads to the formation of hepatic granulomas.
In eight patients, hepatic granulomas were detected in the
Sarcoidosis initial liver biopsies. Four patients had repeat biopsies,
Sarcoidosis is a multi-system granulomatous disorder of and all had hepatic granulomas again. The prevalence of
hepatic granulomas in patients with chronic HCV was
unknown aetiology. In patients with sarcoidosis, hepatic
calculated to be 1.3%. The presence of granulomas was not
granulomas are widely distributed in the liver; very often in
found to be a predictor of response to interferon therapy.
the portal and periportal regions. Often, hepatic involvement
The development of hepatic granulomas during interferon
seems incidental, but a few patients may present with signs
therapy was also not found to be a common phenomenon
and symptoms of hepatic dysfunction. In some patients,
in this study. Hence, the clinical relevance of finding hepatic
the clinical presentation may resemble primary biliary
granulomas in HCV infected patients still needs further
cirrhosis (52).
studies. Development of systemic sarcoidosis many years
The granulomas are numerous enough to make it unlikely
after interferon-α treatment for chronic HCV infection has
that could be missed in a liver biopsy sample of even also been documented (62).
moderate size (53). Central necrosis in these granulomas is
less frequent than in TB and they contain abundant reticulin.
Hepatitis B Infection
The granulomas are made of epithelioid cells [often with
a thin rim of lymphocytes] and giant cells, some of them Tahan et al (63) studied the prevalence of hepatic granu­
containing stellate [asteroid] bodies. The granulomas may lomas in 663 patients with chronic hepatitis B virus [HBV]
 Granulomatous Hepatitis 227

infection, to determine its significance regarding treatment The intermediate type granulomas consist of epithelioid
outcome. Hepatic granulomas were found in 10 cases cells with only scanty number of lymphocytes. Giant cells
[1.5%]. Of these 10 patients with hepatic granulomas, are seldom seen.
four responded to interferon therapy, two dropped out, and
four were non-responders. This study (63) concluded that Schistosomiasis
hepatic granuloma is a rare finding in chronic HBV infection
and its presence does not seem to predict the response to Hepatic granulomas are caused by Schistosoma mansoni
interferon therapy. and Schistosoma japonicum. The granulomas are quite
disease specific and ova may be seen in the centre of the
granuloma. Presence of eosinophils may point to parasitic
Brucellosis
aetiology (4).
Brucella suis, Brucella abortus, Brucella melitensis and Brucella
canis cause granulomatous reaction in the liver. Brucellosis is Hodgkin’s Lymphoma
acquired by contact with cattle, goats, dogs or by ingestion
of unpasteurised dairy products. The infection presents as Hepatic granulomas have been described in 8%-17% patients
undulating fever with remissions and relapses. Excessive with Hodgkin’s disease (64,65). The presence of hepatic
weakness and depression are present during the acute granulomas does not appear to be related to disease outcome
illness. The diagnosis is made by brucella serology and or prognosis in Hodgkin’s lymphoma.
positive reactions in titres of 1:320 or more are considered
diagnostic. The most reliable method of establishing the Typhoid Fever
diagnosis is by blood or bone marrow culture. Hepatic granuloma is a rare complication of typhoid fever.
A report has described two cases of typhoid fever with
Systemic Mycoses hepatic, splenic and bone marrow granulomas (66).
Histoplasma capsulatum and Coccidioides immitis usually infect
humans by inhalation of organisms with primary infection Q Fever
occurring in the lungs. Chronic pulmonary lesions develop in Fibrin ring granulomas are often present in patients with
a few and rarely there is widespread dissemination to other Q fever. These granuloma contain a ring-like array of
organs including the liver. The hepatic reaction to these fungi fibrin [stainable with phosphotungstic acid-haematoxylin]
is usually by granuloma formation (2-4). producing a “halo” effect around a central empty space (2-4).
Histoplasma usually colonises in immunosuppressed These granulomas have also been described in allopurinol
patients but occasionally immunocompetent individuals hypersensitivity, cytomegalovirus hepatitis, leishmaniasis,
may also be affected. The disease usually manifests as fever toxoplasmosis, hepatitis A and systemic lupus erythe­
with hepato­splenomegatly and oral ulcers. Commonly there matosus (2-4).
is associated adrenal involvement with Addison’s disease.
Liver usually contains granulomatous lesions, sometimes Acquired Immunodeficiency Syndrome
with central caseation necrosis resembling TB. Use of
Several conditions result in hepatic granulomas in patients
specials stains like methenamine silver, Hotchkiss-McManus
with AIDS (4,15,16,57). These are listed in Table 16.5.
stain makes identification easier, although the organism
The diagnosis is confirmed with histopathological and
can often be found in the granuloma by haematoxylin and
microbiological examination of the liver biopsy specimen.
eosin staining. Diagnosis is best confirmed by culture of the
organisms from blood, bone marrow, sputum and oral ulcer
scrapings (2,4).
Table 16.5: Causes of hepatic granulomas in patients
Leprosy with acquired immunodeficiency syndrome
Mycobacterium tuberculosis
Three types of granulomas have been described in patients
Mycobacterium avium-intracellulare complex
with leprosy (3). The tuberculoid type, consists of abundant
epithelioid cells with scattered lymphocytes. Multinucleated Cytomegalovirus
cells may be present and these granulomas are most Histoplasmosis
often present in the parenchyma. It is seldom possible to Toxoplasmosis
identify the bacilli even when special stains are used. The Cryptococcosis
lepromatous type granuloma is inflammatory in nature Neoplasms
and consists of histocytes with clear to foamy cytoplasm.
Hodgkin’s lymphoma
Lymphocytes are infrequent and multinucleated giant Non-Hodgkin’s lymphoma
cells are not present. These granulomas can be seen within
Drugs
the portal tracts or the parenchyma and contain abundant
numbers of acid-fast organisms identified by Fite stain. Adapted from references 2-4
228 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Idiopathic Granulomatous Hepatitis a high mean caseation score were found to be predictors
of a poor outcome. Drug related granulomas often resolve
Despite extensive investigations, 10%-25% of patients are
when the offending agent is withdrawn (59). The presence
labelled as having “idiopathic” hepatic granulomas (2-6,67).
of hepatic granu­lomas in patients with Crohn’s disease,
Idiopathic granulomatous hepatitis is a condition charac­
Hodgkin’s disease and primary biliary cirrhosis is thought
terised by recurrent fever and granulomas in the liver and
to indicate a better prognosis (69,71-74).
other organs where other causes of hepatic granulomas have
been carefully excluded (5,68,69). Patients are usually in the
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 17
Neurological Tuberculosis
Pournamy Sarathchandran, Kurupath Radhakrishnan

INTRODUCTION because this diagnosis is seldom suspected as TB is rare in

these regions. For example, in the United States, compared
Involvement of the central nervous system [CNS] is one
to nearly 4000 cases of bacterial meningitis, only 100 to 150
of the most dreaded complications of tuberculosis [TB].
cases of TB meningitis [TBM] are seen annually (8). However,
Autopsy studies have revealed that 5%-15% of individuals
as a consequence of a large scale immigration of infected
exposed to Mycobacterium tuberculosis [Mtb] develop
people from developing countries, neurological TB is being
active pulmonary TB; and of these, 5%-10% develop
encountered increasingly in industrialised countries.
neurological TB (1). The burden of neurological TB is
Neurological TB may be classified into three major clinic-
largely borne by resource-poor regions of the world (2).
pathological categories: TBM, tuberculoma, and TB radiculo­
Neurological TB disproportionately afflicts children and
human immunodeficiency [HIV] infected persons (3-7). Even myelitis [TBRM] [Table 17.1]. In addition, there are less
with modern-day anti-TB treatment, neurological TB carries common clinicopathological entities, such as, TB abscess and
a high morbidity and mortality. TB optochiasmatic arachnoiditis. Despite the considerable
Last two decades have witnessed major changes in advances that have been made during the last few years
several aspects of neurological TB. These include a change with regard to the diagnosis and treatment of TB, following
in the clinical picture of neurological TB with an increasing questions on neurological TB have largely remained
number of cases with atypical presentation and an alarming unanswered: How can we rapidly diagnose neurological TB?
increase in the number of patients with multidrug-resistant What is the optimum treatment of neurological TB? How can
TB [MDR-TB]. Widespread availability and utilisation of we minimise the significant morbidity among the survivors
computed tomography [CT] and magnetic resonance imaging of neurological TB? In this chapter, we intent to address
[MRI] have facilitated early diagnosis of neurological TB and these questions with respect to TBM, intracranial tuberculoma
detection of complications. Research on reliable molecular and TBRM. In addition, diagnosis and management of
markers for early diagnosis of neurological TB is being chronic meningitis are also described. Spinal TB is covered
intensively pursued both in resource-rich and resource-poor in the chapter “Skeletal tuberculosis” [Chapter 19].
countries.
However, considerable barriers in the diagnosis and Table 17.1: Classification of neurological TB
treatment of neurological TB still exist, especially in
TB meningitis
resource-poor countries. While the most consistent factor
that determines the outcome for neurological TB is early TB arachnoiditis
  Basal
diagnosis and prompt institution of treatment (3-7), the
  Opticochiasmatic
protean nature of the symptoms and lack of sensitive   Spinal
diagnostic methods poses a huge challenge for early
Tuberculoma
diagnosis. A majority of the patients with neurological   Intracranial
TB in developing countries are diagnosed and treated too   Spinal
late because of the non-availability, inaccessibility and/or
TB abscess
inability to afford quality medical care. Late diagnosis
TB = tuberculosis
of neurological TB occurs in developed countries as well
 Neurological Tuberculosis 231

TUBERCULOSIS MENINGITIS advanced age, malnutrition, alcoholism, HIV/acquired

immunodeficiency syndrome [AIDS], use of corticosteroids
Sir Robert Whytt, the Scottish physiologist, is credited with
and other immunosuppressive drugs may compromise
the first clinical description of TBM in the late eighteenth
cellular immunity of the host leading to reactivation of a
century (9); this was even prior to isolation of Mtb by Robert
latent infection (3-7,13). However, a majority of cases of
Koch in 1882 (10). TBM, which accounts for 70%-80% of
TBM occur in the absence of any clinically demonstrable
cases of neurological TB, is still an important public health
extra-cranial infection or overt disturbance in host immune
problem in developing countries (2,4). The challenges in the
function.
management of TBM are listed in Table 17.2. Despite the
common occurrence, extensive research and widespread
Pathology
public awareness, there is often a delay in the diagnosis
and institution of specific therapy for TBM. The average The pathology of TBM comprises [i] inflammatory meningeal
duration of symptoms before presentation in patients with exudate; [ii] ependymitis; [iii] vasculitis; [iv] encephalitis;
TBM has varied widely from 11-72 days (11,12). This delay and [v] disturbance of cerebrospinal fluid [CSF] circulation
in diagnosis is unfortunate as the promptness with which and absorption [Table 17.3]. The leptomeningeal reaction is
anti-TB treatment is initiated is the single most important charac­terised by a serofibrinous exudate lying between the
physician-controlled factor influencing the prospects for pia and arachnoid intermixed with areas of caseous necrosis.
recovery without serious neurological sequelae (3-7). The cellular exudate consists predominantly of lymphocytes
and plasma cells with infrequent epithelioid cells and giant
cells. The proliferative arachnoiditis is most marked at the
Table 17.2. Challenges in the management of TB base of the brain, most prominent in the area of the optic
meningitis chiasma. As the process of optico-chiasmatic arachnoiditis
becomes more chronic, it may progress and encircle the
Variable clinical history and clinical features
brainstem to involve the function of other cranial nerves. For
Lack of sufficient sensitivity and specificity of existing diagnostic a detailed description of the pathology of TBM, the reader is
methods referred to the chapter “Pathology of tuberculosis” [Chapter 3].
Incomplete knowledge on the value of new rapid diagnostic methods
Unsuitability of most of the improved diagnostic methods for low
income countries Table 17.3: Pathology of TB meningitis
Missed and delayed diagnosis Meningitis
Inflammatory leptomeningeal exudate
Uncertain duration of chemotherapy Caseous necrosis
Noncompliance to long duration of anti-TB treatment Proliferative opticochiasmatic arachnoiditis

Emergence of multiple drug resistance Vasculitis

Arteritis
Uncertainties with respect to timing of anti-retroviral therapy in HIV- Phlebitis
associated disease
Ependymitis and choroid plexitis
TB = tuberculosis; HIV = human immunodeficiency virus
Encephalitis
Cortical
Subependymal
Vasculitis and infarction
Pathogenesis Encephalopathy
A majority of cases of TBM are caused by Mtb. Isolated Hydrocephalus
cases of TBM caused by bovine, avian mycobacteria and Communicating
nontuberculous mycobacteria [NTM] have also been Obstructive
documented (13). Infection with specific mycobacterial TB = tuberculosis
genotypes may predispose to neurological TB (14,15). TBM
is invariably secondary to TB elsewhere in the body. It is
generally believed that the critical event in the development Ependymitis is almost a constant feature of TBM and
of TBM is the rupture of a subepen­dymally located tubercle may even be more severe than the meningeal reaction. The
[Rich focus] resulting in the delivery of infectious material choroid plexus may show varying degrees of inflammatory
into the subarachnoid space (16). In the bacteraemic phase process. The terminal portion of the internal carotid artery
of primary lung infection, metastatic foci can get established and proximal middle cerebral artery in the sylvian fissure
in any organ, which can become active after a variable period are the vessels most frequently involved by vasculitis
of clinical latency. Whether the critical subependymal tubercle with inflammation, spasm, constriction and thrombosis.
develops during primary haematogenous dissemination or The meningeal veins traversing the inflammatory exudate
due to secondary haematogenous spread from an area of show varying degrees of phlebitis and thrombosis. The
extra-cranial extra-pulmonary TB [EPTB] is still a matter brain parenchyma immediately underlying the meningeal
of dispute. Conditions such as intercurrent viral infections, exudate as well as the subependymal region shows a variable
232 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

degree of oedema, perivascular inflammation and microglial of optic nerve involvement in clinical reports varies from
reaction. A majority of infarcts occur in the territory of the 4%-35% (13,22). Visual evoked potentials testing has shown
middle cerebral artery. disturbance in over 50% of patients examined in the acute
Hydrocephalus develops in the majority of patients stage of the disease (23).
with TBM who have been symptomatic for more than In untreated cases, adhesions in the basal brain progress
2-3 weeks (17,18). In the majority, it is a communicating and result in expensive cranial nerve palsies, internal carotid
hydrocephalus due to the blockage of the basal cisterns by constriction and stroke, increasing hydrocephalus with
the exudate in the acute stage and adhesive leptomeningitis tentorial herniation, pupillary abnormalities, pyramidal
in the chronic stage. Less frequently, the hydrocephalus is signs and prog­ressive deterioration in the consciousness
obstructive due to either narrowing or occlusion of aqueduct state. The terminal illness is characterised by deep coma
by ependymal inflammation or by a strategically placed and decerebrate or decorticate posturing. Without treatment,
brainstem tuberculoma, or at the outlet foraminae of the death usually occurs in five to eight weeks.
fourth ventricle. Hydrocephalus is more frequent and severe According to the severity of the illness, patients with TBM
in children than in adults. can be categorised into three to five clinical stages (24-26).
A pathological entity predominantly seen in the One of the clinical staging systems is shown in Table 17.4.
paediatric age group, designated as TB encephalopathy, The clinical staging helps to optimise therapy [e.g., addition
characterised by diffuse brain oedema, perivascular of dexamethasone to anti-TB drugs] and to predict the
myelinolysis and haemorrhagic leucoencephalitis with little prognosis. The prognosis of TBM is determined by the
evidence of meningitis has been described from India (19). clinical stage at the time of initiation of treatment.
This syndrome is ascribed to hyper­sensitivity reaction to During the last two decades, the picture of TBM has
tuberculoproteins. Clinical and pathological distinction changed in developed countries with an increasing number
of this entity from Reye’s syndrome, acute disseminated of atypical cases (3-7). Atypical presentations of TBM include
encephalomyelitis and acute haemorrhagic leucoencephalitis acute meningitis syndrome simulating pyogenic meningitis,
will be difficult. There is little pathological evidence for the progressive dementia, status epilepticus, psychosis, stroke
existence of TB encephalopathy without TBM. syndrome, locked-in-state, trigeminal neuralgia, and infantile
spasm and movement disorders (13,22,27). The factors that
are thought to be responsible for this changing pattern
Clinical Features
include delay in the age of onset of primary infection,
In developing countries, TBM is still a disease of child­ immunisation, problems related to immigrant populations
hood with the highest incidence in the first three years of and HIV infection (3,5,6).
life (3-7,20). Recent contact with TB, when elicited, can be
found in 70%-90% of children with TBM (21). The disease
usually evolves gradually over 2-6 weeks although an acute Table 17.4: Clinical staging system for TB meningitis
onset of illness can occur in 50% of children and in 14% of Stage Description
adults (21). The prodromal phase is non-specific and usually
1 Conscious and rational, with or without neck stiffness,
lasts 2-3 weeks with a history of vague ill-health, apathy, but no focal neurological signs or signs of hydrocephalus
irritability, anorexia and behavioural changes. As a part
2 Conscious but confused or has focal signs such as
of the prodrome, headache, vomiting or fever may occur cranial nerve palsies or hemiparesis
in 13%-30% of patients and herald the onset of meningitis.
3 Comatose or delirious with or without dense neurological
Focal neurological deficits and features of raised intracranial deficit
tension may precede signs of meningeal irritation. Focal
4 Deeply comatose with decerebrate or decorticate
or generalised convulsions are encountered in 20%-30% posturing
of patients sometime during the course of illness and are
TB = tuberculosis
particularly common in children and the elderly (3-7,13). Source: references 24-26
The underlying mechanism could include hydrocephalus,
tuberculoma, cerebral oedema, and hyponatraemia due
to the syndrome of inappropriate antidiuretic hormone
Tuberculosis Meningitis and Human
[SIADH] secretion. Cranial nerve palsies can occur in
20%-30% of patients, the sixth nerve involvement being the Immunodeficiency Virus Infection
most common (3-7,13). HIV-associated TB accounts for nearly 25% of global HIV/
Exudate around the optic chiasma is the central feature AIDS deaths each year (28).The risk of neurological TB is
of the pathology in TBM. Hence, complete or partial 5 times more frequent in HIV-seropositive compared to
loss of vision is a major complication of the disease. The HIV-seronegative patients (28-31). Berenguer et al (29)
other mechanisms for vision loss may include arteritis reported that 10% of 455 patients co-infected with both
or compression of the anterior visual pathways due to TB and HIV-developed TBM. Yechoor et al (31) observed
hydrocephalus or tuberculoma. Ethambutol toxicity too that 20 of the 31 patients [65%] identified as definite or
may contribute to the visual impairment. The frequency probable TBM over a 12-year period were co-infected with
 Neurological Tuberculosis 233

HIV. Neurological TB, either alone or associated with other of the symptoms and signs of TBM after initiation of anti-
opportunistic infections [OIs], was found in 35 of the 100 TB treatment are also important supportive features for a
HIV-seropositive patients seen over seven years at the diagnosis of TBM.
National Institute for Mental Health and Neurosciences
[NIMHANS] in Bengaluru [earlier called Bangalore], in Laboratory Investigations
south India (32).
Routine laboratory studies are rarely helpful in establishing
Although HIV-infected patients are at an increased risk
the diagnosis of TBM. Elevated erythrocyte sedimentation
for TBM, the HIV status generally does not alter the clinical
rate [ESR], anaemia and lymphocytosis are not seen in
manifestations, CSF findings and response to therapy (28-31).
majority of the patients.
How­e ver, CSF examination may frequently be normal
in HIV-seropositive subjects with TBM. In such patients,
Imaging Studies
radiographic clues to the diagnosis of neurological TB include
multiloculated abscess, cisternal enhancement, and basal Chest radiograph The chest radiographs reveal findings
ganglia infarction and communicating hydrocephalus, which consistent with pulmonary TB in 25%-50% of adult patients
are not the findings associated with the more commonly and 50%-90% of children with TBM seen in western
encountered CNS lymphoma or toxoplasma encephalitis. countries (35).
Extra-meningeal TB is seen more often [65%-77%] in patients Neuroimaging The CT or MRI of the brain may reveal
co-infected with HIV and TB com­pared to HIV-seronegative thickening and enhancement of basal meninges, hydro­
individuals [9%] (29,33). Likewise, an associated tuberculoma cephalus, infarction, oedema [often periventricular], and
may be present in more than half of HIV-infected patients mass lesions due to associated tuberculoma or TB abscess
with TBM (34). Neurological TB can also be the initial pre­ [Figures 9.37, 9.38]. Common sites of exudates are basal
sentation of AIDS. Bishburg et al (30) noted that intravenous cisterna ambiens, suprasellar cistern and sylvian fissures
drug abusers with AIDS were more likely to develop TB of [Figures 17.1, 17.2 and 17.3]. Bhargava et al (36) classified
the CNS and TB brain abscesses. exudates as [i] mild, when cisterns were obliterated but not
enhanced; [ii] moderate, when the cisterns were outlined
Diagnosis by enhancing exudates and [iii] severe, when enhancing
exudates enlarge the cisterns. Hydrocephalus is the single
TBM should be differentiated from other causes of subacute
most common abnormality and is reported in 50%-80% of
and chronic meningitis [Table 17.5]. Early and accurate
cases. The degree of hydrocephalus generally correlates with
diagnosis of TBM can substantially reduce the morbidity and
the duration of disease. Enhancements of basal meninges
mortality, especially in children (3-6,13). Diagnosis of TBM
[60%] followed by cerebral infarction [28%], most frequently
is based on history, neurological symptoms, signs and CSF
in the middle cerebral artery territory are other common
findings. Support­ing features include radiological evidence
findings. Bhargava et al (36) demonstrated the presence
from CT or MRI, such as, basal exudates, hydrocephalus, of hydrocephalus [83%], cerebral infarction [28%] and
infarcts, tuberculomas and gyral enhancement. However, a
definite diagnosis of TBM is fraught with difficulties because
demonstration of Mtb in CSF is difficult and is often time-
consuming.
Exposure to TB is important supportive evidence,
especially in children. Evidence of TB outside the CNS
with appropriate microbiological, molecular, radiolographic
or histopathological proof, a positive tuberculin skin test
[TST] in the absence of a previous sub-clinical infection or
bacille Calmette-Guérin [BCG] vaccination, and a resolution

Table 17.5: Differential diagnosis of TB meningitis

Partially-treated bacterial meningitis
Cryptococcal meningitis
Viral meningoencephalitis Figure 17.1: Contrast-enhanced axial fat saturated MR images of the
Carcinomatous meningitis brain showing meningeal enhancement in the interpeduncular cistern,
Parameningeal infection perimesencephalic cistern and sylvian fissure. The temporal horns
of the lateral ventricles, aqueduct and fourth ventricle are dilated,
Neurosarcoidosis indicating a communicating hydrocephalus. Also, conglomerate
Neurosyphilis irregular ring enhancing lesion in the cerebellum [tuberculoma] and
enhancing V cranial nerves [arrows] are seen
TB = tuberculosis
MR = magnetic resonance
 234 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and small tuberculomas. Contrast-enhanced MRI has been

found to be superior to contrast-enhanced CT [CECT] in
the detection of diffuse and focal meningeal granulomatous
lesions. The MRI is also superior to CT in delineating focal
infarcts of the basal ganglia and diencephalon [Figure 17.2].
Furthermore, MRI is superior to CT in defining the presence,
location and extent of associated brainstem lesions.
A C
Tuberculin Skin Test
TST with purified protein derivative [PPD] has been reported
to be positive in 40%-65% adults and in 85%-90% children
with TBM in western studies (21,35,37). However, TST lacks
specificity in developing countries because of the possibility
of previous sensitisation to environmental mycobacteria and
BCG vaccination.

Interferon Gamma Release Assays

Interferon gamma release assays [IGRAs] have been used for
detecting infection with Mtb (38). The reader is referred to
B D the chapter “Laboratory diagnosis of tuberculosis: best practices
Figure 17.2: Contrast-enhanced coronal fat saturated [A] and axial and current policies” [Chpater 8] for details.
[B] T1-weighted MR images of a 43-year-old male, who presented
with fever, headache, vomiting of two months duration followed by
Cerebrospinal Fluid Study
acute onset aphasia and right hemiplegia, showing thick enhancing
exudates in the left sylvian fissure and suprasellar cistern. Surrounding Cytology and biochemistry Clear CSF with moderately
parenchymal oedema and mass effect are noted. Post-contrast coronal raised cells and protein and low glucose constitute the
fat saturated [C] and axial [D] T1-weighted images three months after
typical CSF picture of TBM. However, these characteristics
anti-TB treatment show decrease in enhancement, oedema and mass
effect. Lateral putaminal infarct [arrow] secondary to vasculitis can be are shared by other forms of chronic meningitis and partially
seen treated pyogenic meningitis. In TBM, the leucocyte count is
MR = magnetic resonance usually between 100 and 500 cells/μL, but rarely can exceed
1000 cells/μL. Median leucocyte counts in various reports
range from 63-283 cells/μL. Predominantly, lymphocytes
are increased in the CSF, although in the acute stage, a
polymorphonuclear response is not unusual. This response
is transient and is replaced by lymphocytic reaction in the
course of days to weeks. Occasionally the cell count may
be normal. Rarely, the CSF may be haemorrhagic because
of fibrinoid necrosis of vessels. A negative cytology for
malignant cells in the CSF is an essential criterion for the
diagnosis of TBM.
The CSF protein is generally between 100-200 mg/dL.
In the presence of coexisting spinal meningitis and spinal
block, the values can exceed 1 g/dL and the fluid may be
xanthochromic. If allowed to stand, a pellicle or cobweb may
form, indicating the presence of fibrinogen. The pellicle is
highly suggestive but not pathognomonic of TBM. The CSF
Figure 17.3: MRI brain, T1-weighted post-gadolinium contrast axial protein has been reported to be normal in some patients with
images showing ventricular dilatation and meningeal enhancement
AIDS and TBM (29,39).
[arrows]
MRI = magnetic resonance imaging The CSF glucose level is abnormal in majority of cases,
being less than 40% of the corresponding blood glucose
level. Median glucose levels are reported to be between
tuberculoma [10%] on CT in patients with TBM. Vasculitis 18-45 mg/dL. In patients with TBM, CSF glucose levels are
and thrombosis associated with TBM are seen on CT as never undetectable as in patients with pyogenic meningitis.
multiple areas of hypodensity secondary to ischaemia. Serial Low CSF chloride level was previously considered to be
CT are very helpful in assessing the course of tuberculomas a non-specific marker for TBM. It is actually a reflection
and hydrocephalus. Gadolinium-enhanced MRI is superior of co-existent serum hypochloraemia and is presently not
to the CT scan in detection of basal meningeal enhancement considered to be helpful in discriminating between TBM,
 Neurological Tuberculosis 235

bacterial and viral meningitis. Thomas et al (22) observed diagnosis of TBM. As the yield of conventional methods,
the classical TB pattern in 66.8% of cases; pseudopyogenic such as, culture is low when applied to the CSF in patients
pattern in 14.5% patients and normal CSF in 5% cases. with suspected TBM, these methods cannot be considered
Patients with miliary TB and CNS involvement can, to be a gold standard against which immunodiagnosis or
sometimes, present with a normal CSF profile and absence other tests can be compared. In tests, such as, enzyme-linked
of neurologic signs. An acellular CSF may also be found in immunosorbent assay [ELISA], a significant overlap between
elderly patients suffering from TBM (33). In a report, Raman the results of patients with and without TBM necessitates
spectroscopy of the CSF demonstrating silicates was found specification of a cut-off point to separate positive from
to be highly sensitive and specific test for the diagnosis of negative test results. When establishing such a cut-off, there
TBM (40). is usually a trade-off between sensitivity and specificity. With
regards to immunoassays, it is also important to understand
Microbiological tests A negative Gram’s stain, negative
that the sensitivity of any immunoassay depends on
India ink stain and a sterile culture for bacteria and fungi are
standardisation and evaluation of the assay system, whereas
pre-requisites for the diagnosis of TBM. Demonstration of
specificity depends on the type of the probe employed in
acid-fast bacilli [AFB] in the CSF by microscopy is the most
the system. Furthermore, false-negative results of antigen
crucial part of the investigation and the rate of detection
detecting immunoassays can also result from masking of
varies in different reports from 12.5%-69% (37,41). The yield the antigens by specific circulating antibodies.
of CSF smears by Ziehl-Neelsen staining and auramine
staining is low, ranging from 4%-40% in various reports Mycobacterial antibodies Antibodies against glycolipids and
and is found to be a function of the volume and the number proteins isolated from Mtb, BCG, PPD, antigen 5, and lipo­
of samples of CSF. Centrifuging the CSF [10-20 mL] for arabinomannan [LAM] have all been used as a supporting
30 minutes and thick smear examination from the pellicle test in the diagnosis of TBM. Radioimmunoassay [RIA],
and repeat CSF examination enhance the detection rate. ELISA, and immunoblot methods have all been used to
Kennedy and Fallon (25) in a series of 52 patients with TBM detect these antibodies. Various authors have reported
reported a higher yield of AFB with examination of four CSF sensitivity ranging from 61%-90% and specificity ranging
smear samples [37% in the first, and a further 25%, 19% and from 58%-100% with these antibodies (43-48). Assay of
3% in the second, third and fourth samples, respectively]. antibodies against Mtb antigens has a better sensitivity
Lowenstein-Jensen [LJ] culture of CSF takes four to and specificity than PPD or BCG. Recent antibody targets
eight weeks to isolate the organisms because of the slow have included antibodies against A-60 antigen. They have
growth of Mtb. The reported positivity of CSF culture shown a greater sensitivity in sera [95%] compared to CSF
ranges from 25%-70% of cases, but is less than 50% in most and a greater specificity in the CSF [100%] compared to the
reports (3-7). In many Indian reports, the yield has been sera (49,50).
much lower, around 20% (13,22).The yield can be increased
by using liquid culture media, such as, Septi-Chek AFB Mycobacterial antigens There are many reports of detection of
system, and Middlebrook 7H9 instead of the conventional mycobacterial antigens using ELISA and latex particle aggluti-
LJ medium. The isolation rate of Mtb is higher from cisternal nation (51-54). Antigen detection has been shown to be more
and ventricular CSF than lumbar CSF (42), but in routine specific than antibody assays. Rabbit immunoglobulin G
practice, CSF is seldom collected from the ventricles. Similar [IgG] raised against BCG, culture filtrate antigen, antigen 5,
to AFB smear examination, repeated cultures of CSF samples and immuno­absorbent affinity column-purified antigen have
increased the sensitivity from 52% for the first culture up to all been used for antigen detection. The diagnostic yield is
83% after four cultures (25). In patients with disseminated considerably improved by performing both antigen and
and miliary TB with CNS involvement, cultures from extra- antibody assays (46,55). Other mycobacterial antigen targets
neural sites such as the sputum, lymph node and bone have included the 35kDa antigen (56). Unfortunately, many
marrow may be positive. assays showing early promise in highly controlled studies do
not perform with high sensitivity and specificity in clinical
Immunological tests As the CSF picture in patients with practice.
TBM can be variable and non-specific, there is urgent need
for a reliable and rapid test to diagnose TBM. In the Indian Circulating immune complexes Circulating immune complexes
context, the difficulty in differentiating TBM from partially in the serum and CSF of patients have been used in
treated pyogenic meningitis is an added problem. the diagnosis of TBM by isolating these complexes and
Several tests have been devised for these reasons and confirming the presence of mycobacterial antigens and
they are broadly divided into direct tests that measure antibodies by ELISA test. Mathai et al (46) demonstrated
the chemical components or antigens of Mtb and indirect antigen 5 in the immune complexes of CSF in 30% of their
tests that measure the components of the host response patients with TBM. The antigen concentration in the immune
to Mtb. The specificity of immunodiagnosis depends on complexes declined during the course of treatment. Though
the specificity of the antigens or antibodies used. Non- antimycobacterial antibodies were present in 70% patients,
availability of a clear cut “gold standard” has hampered the the immune complexes were not formed probably because
validation of the usefulness of newer diagnostic tests for the of the non-availability of antigen 5 in optimal concentration.
236 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Patil et al (55) detected immune complexes in the CSF in 60% Comparative value of different tests It can be concluded that
and antimycobacterial antibodies in 55% and both in 82% even though there are many recently introduced rapid
patients with suspected TBM. diagnostic methods for TBM, most of them lack the required
combination of reproducibility, high sensitivity and specifi­
Other indirect measures of host response Adenosine deaminase
city. Thus, a negative test does not exclude TBM and many
[ADA], an enzyme produced by T-lymphocytes, is elevated
immunodiagnositc tests show false-positive results in other
in the CSF of 60%-100% of patients with TBM (57-59).
forms of meningitis. Unless stringent measures are adopted
However, false-positive results have been reported in other
to prevent cross-contamination in laboratories, false-positive
forms of meningitis. The CSF lymphocyte transformation results could limit the use of commercial available NAAT
assay, detection of anti-BCG secreting cells in CSF, leucocyte assays.
migration inhibition assay, and T-cell immunoblotting are In the developing countries, confirmation of the diagnosis,
other tests used as indirect evidence of host response to Mtb. either by molecular methods or by immunological methods
Biochemical detection of mycobacterial products Detection is seldom possible in every case, because of the limited
of tuberculostearic acid [TSA], a structural component facilities available. Apart from the investigations, there are
of Mtb has been reported to have a sensitivity of about indirect evi­dences of the disease being TBM, especially in
75% and specificity of 96% (60). Requirement of complex countries with a high prevalence of TB infection. These
instrumentation is a major limitation to its wide application. include clinical diagnosis of chronic meningitis, a history of
Detection of 3-[2-ketohexyl] indoline has also been used as pulmonary TB, especially if inadequately treated, exposure
an evidence of Mtb infection (61). to a patient with pulmonary, a positive TST and CT or MRI
evidence of basal meningitis and/or its sequelae. Though
Molecular methods Amplification of the Mtb specific deoxyri­ none of the above information in isolation is sufficient, a
bonucleic acid [DNA] sequences by polymerase chain combination of these factors should raise the suspicion of a
reaction [PCR] is one of the most frequently used means diagnosis of TBM.
for rapid diagnosis of neurological TB (62-66). The use
of primers derived from the insertion sequence IS6110, Treatment
which is a multiple repetitive element in the genome of the
Mtb complex, has yielded amplification of high analytical If suspicion of TBM is high, anti-TB treatment should be
sensitivity. One-step amplification used in conventional initiated at the earliest. The pros and cons of initiating anti-TB
methods has a low sensitivity, which is attributed to the low treatment before the confirmation of the diagnosis should
copy numbers of the DNA template that could be extracted be carefully weighed in each patient. However, the most
from CSF samples of patients with TBM. In comparison, important principle of therapy is that anti-TB treatment
two-step nested amplification can enhance the sensitivity should be initiated when the disease is suspected. It should
by several folds. Using this technique, Liu et al (64) detected not be delayed until proof of diagnosis of TBM has been
Mtb genome in 19 of the 21 [90.5%] patients with clinically obtained.
suspected TBM. The following situations can be considered as separate
Cartridge-based nucleic acid amplification tests [CBNAAT] management issues in TBM.
[e.g., Xpert MTB/RIF] are increasingly being used for the
diagnosis of TB meningitis. The CSF Xpert MTB/RIF has Uncomplicated Tuberculosis Meningitis
the advantage of being the only available technique besides It is important to stage TBM patients according to one of
AFB smear test, which can confirm the diagnosis of TB the clinical stages described earlier before the initiation of
on the same day. The Xpert MTB/RIF is not affected by treatment (24-26). Primary management of this condition
the presence of other infecting bacteria as may occur in is with first-line anti-TB agents. There are no convincing
an immunocompromised host. In the recently published randomised, controlled clinical trials to suggest that any
Guidelines for extrapulmonary TB for India [INDEX-TB particular regimen is superior in the treatment of TBM.
Guidelines] (67a), pooled sensitivity and specificity of CSF However, enormous clinical experience has accumulated
Xpert MTB/RIF against culture were found to be 80.5% over the past many years to recommend some treatment
and 97.8% respectively. In a recently published systematic regimens (1,3-7,13). It is advisable to commence a four-drug
review (67b) the sensitivity and specificity of CSF Xpert regimen. The recommended drugs are isoniazid, rifampicin,
MTB/RIF were found to be 71.1% and 98% respectively. The pyrazinamide and ethambutol or streptomycin. Though a
INDEX-TB guidelines recommended that Xpert MTB/Rif drug susceptibility result is preferred prior to, or soon after
may be used as an adjunctive test for the diagnosis of TB starting the treatment, it is seldom practical, especially in
meningitis. A negative Xpert MTB/RIF test result on a CSF developing countries. Unless there is a very high suspicion of
specimen does not rule out TB meningitis. The decision to drug-resistant organism in a particular patient, the proposed
give anti-TB treatment should be based on clinical features four-drug regimen is generally effective. After two months
and CSF profile [conditional recommendation, low quality of intensive phase of treatment, pyrazinamide, streptomycin
evidence for sensitivity estimate, high quality evidence for are stopped. In the continuation phase, rifampicin, isoniazid
specificity estimate]. and ethambutol are continued. Pyridoxine is usually
 Neurological Tuberculosis 237

administered along with anti-TB treament to reduce the risk Role of Corticosteroids
of isoniazid-induced peripheral neuropathy. However, there
The role of corticosteroids in the treatment of TBM has been
is no consensus regarding the optimal dose of pyridoxine;
a subject of intense and interesting debate for many decades,
a wide dosage range [10 mg/day to 100 mg/day] of
with both proponents (76,77) and opponents (78,79) for its
pyridoxine has been used to prevent peripheral neuropathy
use. Administration of corticosteroids has been found to be
in high-risk groups. most beneficial in patients with complications of TBM. The
A recently published randomised, double-blind, placebo- common indications for use of corticosteroids in TBM are
controlled trial (68) in patients with TBM compared a listed in Table 17.6.
standard, 9-month anti-TB treatment regimen [that included Seven trials of various degrees of rigour have investigated
rifampicin 10 mg/kg/day] with an intensified regimen the effects of corticosteroids on TBM (80-86). Five of these
[that included a higher-dose rifampicin, 15 mg/kg/day] seven trials, including the best-analysed one (80), clearly
and levofloxacin [20 mg/kg/day] for the first 8 weeks of demonstrated an advantage of adjunctive corticosteroid
treatment. Occurrence of death by 9 months of randomisation therapy over standard therapy for survival, frequency
was defined as as the primary outcome. In this study (68), of sequelae or both. The CSF abnormalities and elevated
intensified anti-TB treatment was not associated with a pressures resolved significantly faster in corticosteroid
higher rate of survival. recipients. Two of the studies (80,83) stratified participants
The reader is referred to the chapters “Treatment of by severity and found no benefit in either mild or severe
tuberculosis” [Chapter 44] and “Revised National Tuberculosis disease, but significant benefit for patients with inter­
Control Programme” [Chapter 53] for further details. mediate disease. Studies with longer regimens [4 weeks to
several ‘months’] demonstrated significant beneficial effects
Duration of Treatment while those with shorter regimens [2-4 weeks] did not.
Dexamethazone at 8 to 12 mg/day (80,81,83) or prednisolone
The optimum duration of treatment for TBM is unknown. of equivalent dose (86,87) was effective and had fewer
Longer duration of treatment possibly lowers the relapse side effects than higher doses. The recommended daily
rates, though the cost, risk of toxicity and chances of poor dose of prednisolone is 0.75 to 1 mg/kg in adults and
compliance are greater. In a large series of 95 children treated 1 to 2.5 mg/kg/day in children.
with a four-drug regimen, with 96% of cases presenting in In a randomised prospective study of 47 patients,
Medical Research Council [MRC] stage 2 or 3, a high rate of Kumaravelu et al (88) reported that the addition of
success and a mortality of as low as 16% was achieved with dexamethasone to anti-TB treatment resulted in better
6 months treatment (69). In another large series [n = 781] outcome in those who had severe disease. In a randomised,
of TBM, nearly all patients with relapse had received less double-blind, placebo-controlled trial [n = 545] from
than 6 months of therapy (70). The maximum duration of Vietnam, Thwaites et al (89) studied whether adjunctive
treatment has varied. The British Thoracic Society [BTS] (71), treatment with dexamethasone reduced the risk of death
the American Thoracic Society [ATS], Centers for Disease or severe disability after nine months of follow-up. In this
Control and Prevention [CDC] and Infectious Diseases study, patients were randomly assigned to groups that
Society of America [IDSA] (72) prescribe 12 months of treat­ received either dexamethasone [n = 274] or placebo [n = 271].
ment for uncomplicated TBM. Although 18 to 24 months It was observed that treatment with dexamethasone was
treatment was recommended in the past (70), there is sub­ associated with a reduced risk of death [p = 0.01]. However,
stantial evidence to suggest that a duration ranging between dexamethasone treatment did not result in a significant
6 to 12 months may be adequate (73,74). As per the recently reduction in the proportion of severely disabled patients
published evidence-based INDEX-TB guidelines (67a), [18.2% among survivors in the dexamethasone group versus
TB meningitis should be treated with standard first-line 13.8% in the placebo group, p = 0.27] or in the proportion
anti-TB treatment for at least 9 months. These guidelines also of patients who had either died or were severely disabled
indicate that extension of anti-TB treatment may, sometimes,
be indicated and this should be assessed by the treating
Table 17.6: Possible indications for corticosteroids in
clinician on a case-by-case basis.
TB meningitis
Additional factors that need to be considered prior to
Clinical
the initiation of treatment include age, co-existent renal or
Clinical stages 2 and above
hepatic disease and pregnancy. One of the most common Evidence of raised intracranial pressure
drug-induced side effects during the treatment of TB is Focal neurological deficits suggesting arteritis
the development of hepatotoxicity (75). It is practically Radiological
impossible to differentiate drug-induced hepatotoxicity Cerebral/perilesional oedema
[DIH] from coincidental viral hepatitis that is highly Hydrocephalus
prevalent in developing countries. The reader is referred Infarcts
Opticochiasmatic pachymeningitis
to the chapter “Hepatotoxicity associated with anti-tuberculosis
TB = tuberculosis
treatment” [Chapter 45] for further details.
238 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

after nine months of treatment. The treatment effect was induced vestibulopathy. These complications develop at
consistent across subgroups that were defined by disease varying intervals and are dose related.
severity grade and by HIV status. A repeat CSF examination may not be required in
As per the recently published evidence-based INDEX-TB patients showing a steady clinical improvement. However,
guidelines (67a), corticosteroids are recommended for TBM in patients, showing neither clinical improvement nor
in HIV-seronegative persons; the duration of corticosteroid deterioration, CSF parameters should be monitored along
treat­m ent to be for at least 4 weeks with tapering as with neuroimaging, if required. In those patients showing
appropriate [strong recommendation]. In HIV-seropositve deterioration in clinical status, neuroimaging should precede
individuals with TBM, corticosteroids may be used where a CSF examination.
other life-threatening opportunistic infections are absent.
Complications of Tuberculosis Meningitis
Drug-resistant Tuberculosis Meningitis
TBM is a devastating disease with about 30% mortality in
TBM caused by multidrug-resistant and extensively drug- the severe forms of the disease and neurological sequelae
resistant Mtb is a serious condition and several newer in a majority of the survivors (3-7). In a series from a
drugs and treatment regimens are available to treat drug- teaching hospital from North-west India (22), only 58 of
resistant TBM (90-92). The reader is referred to the chapter the 170 surviving patients [34%] with TBM were left with
“Drug-resistant tuberculosis” [Chapter 42] for details. no sequelae. In the west, permanent neurological sequelae
was noticed in 47%-80% of children with TBM, with motor
Treatment of Tuberculosis Meningitis Associated with disorders [25%-27%], visual loss [20%] and cognitive and
Human Immunodeficiency Virus Infection behavioural changes [17%-40%] being the three most
common consequences in long-term follow-up studies (37,99).
The management of HIV-seropositive patients co-infected In a study of 65 patients from Lucknow, India (100), neuro­
with TBM requires a combination of anti-TB treatment, anti­ logical sequelae were observed in 78.5% patients [cognitive
retroviral therapy [ART], and trimethoprim-sulphamethoxa­ impairment in 55%, motor deficit in 40%, optic atrophy in
zole prophylaxis against other opportunistic injections (93). 37% and other cranial nerve palsy in 23%]. The complications,
Because of the concern of immune recons­titution disease sequelae of TBM are listed in Table 17.7.
with rapid ART initiation (94,95), which is particularly
severe when associated with neurological TB, the optimal
time to initiate ART during TB treatment is still being Table 17.7: Complications and sequelae of TB
debated (96). The recent revision of the 2010 WHO ART meningitis
guidelines recommended to start ART as soon as possible Raised intracranial pressure, cerebral oedema, stupor
after TB treatment is tolerated, but not later than 8 weeks Basal meningitis with cranial nerve palsies
of anti-TB treatment (97). Treatment of neurological TB in
Focal neurological deficits
patients with HIV infection is the same as in patients without
HIV infection (98). The reader is referred to the chapter Hydrocephalus
“Tuberculosis and human immunodeficiency virus infection” Tuberculoma
[Chapter 35] for further details. TB abscess
Opticochiasmatic pachymeningitis resulting in visual loss
Monitoring Therapy TB arteritis and stroke
Once anti-TB treatment is initiated, the mononuclear Endocrine disturbances
pleocytosis in CSF may briefly become polymorphonuclear. Hypothalamic disorder leading to loss of control of blood pressure
At two months of anti-TB treatment, CSF glucose levels and body temperature
normalise in almost all, patients. Normalisation of CSF Diabetes insipidus
protein levels takes between 4 to 26 months, with a median SIADH
period of eight months (21). The CSF cell counts normalise
Internuclear ophthalmoplegia
in one-third of the patients by 16 months and in almost all
Hemichorea
patients by three years (21).
Clinical improvement in the form of abatement off ever Psychiatric and psychological disturbances
and decrease in meningeal signs occurs over a variable Hearing defects
period of time. However, clinical improvement may not be Intracranial calcifications
reflected in the improvement in CSF parameters. Any clinical Seizures and epilepsy
worsening during treatment warrants neuroimaging to rule
Spinal block
out complications, such as, hydrocephalus, tuberculoma, TB
Spinal arachnoiditis
abscess or arteritis leading to infarction. Vigilance should
also be maintained to detect the development of anti-TB TB = tuberculosis; SIADH = syndrome of inappropriate antidiuretic
hormone secretion
DIH, ethambutol-induced optic neuritis and streptomycin-
 Neurological Tuberculosis 239

Hydrocephalus in TBM, namely the syndrome of inappropriate anti-diuretic

hormone secretion [SIADH] and cerebral salt wasting
Hydrocephalus is common in TBM, occurring in about two-
[CSW], the distinction between them is often difficult to
thirds of patients and is more common in children (17,18).
make (105,106). Given the difficulty of making a definitive
The most frequent cause for hydrocephalus, in almost 75%
diagnosis of the cause of hyponatraemia, fluid restriction
of cases, is obstruction to CSF flow by exudates in the basal
as a treatment for hyponatraemia should be avoided in
cisterns, known as communicating hydrocephalus. In the
patients with TBM. Cautious treatment with hypertonic
remaining 25%, the hydrocephalus is due to a block at the
saline and fludrocortisone is advised (106,107). The reader is
outlet foramina of the fourth ventricle or at the aqueduct referred to the chapter “Endocrine implications of tuberculosis”
causing obstructive [non-communicating] hydrocephalus. [Chapter 34] for more details on SIADH and diabetes
The management of hydrocephalus in TBM is still insipidus.
associated with considerable uncertainties and controversies. Vasuclitis stroke occurs in 15%-57% of patients with TBM,
The clinical grade of the patient appears to be one of the most especially in advanced and severe disease (108,109). Most of
important deter­minants of how to manage these patients. The the infarcts in TBM are multiple, bilateral and located in the
grading system of patients with TBM with hydrocephalus basal ganglia, especially in the caudate, anterior thalamus
evolved at the Christian Medical College, Vellore, India and internal capsule. These are related to the involvement
is shown in Table 17.8 (101). Medical management with of perforating arteries which are embedded in exudates.
furosemide, acetazolamide, steroids and weekly, or more Major territorial infarcts can occur due to involvement of
frequent lumbar punctures has been reported to be successful proximal portions of the middle, anterior and posterior
in a significant proportion of patients with communicating cerebral arteries as well as the supraclinoid portion of the
hydrocephalus in clinical stages I and II (17). Patients internal carotid artery [Figure 17.2].
with altered sensorium [grades III and IV] will require
CSF diverting procedures to reduce the raised intracranial Opticochiasmatic Arachnoiditis
pressure. Surgical measures available are ventricular tap, Early institution of anti-TB treatment may help in preventing
external ventricular drainage [EVD], ventriculoperitonial the occurrence optico-chiasmatic arachnoiditis causing
[VP] shunt and endoscopic third ventriculostomy [ETV]. visual loss. Although steroids have been recommended for
Ventricular tap and EVD are emergency short-term its prevention, treatment of established optico-chiasmatic
procedures for patients in poor condition who require arachnoiditis is disappointing.
reduction in CSF pressure immediately. Because of the
inherent risk of infection, EVD cannot be used for long CHRONIC MENINGITIS
periods. In patients who require EVD for more than 4 or
5 days, it is better to place an Ommaya reservoir and do Definition and Aetiology
regular tapping of the ventricles till meningitis subsides and Chronic meningitis is defined as the clinical syndrome
decision on shunt surgery taken (102). The choice between characterised by symptoms and signs of meningitis or
VP shunt and ETV varies between centers depending upon meningoencephalitis developing in a subacute or chronic
their experience. Most of the centers recommend ETV as fashion associated with CSF abnormalities and persisting for
the first choice for patients with TBM and hydrocephalus, at least four weeks (110-112). In general, chronic meningitis
with VP shunts reserved for failed ETV cases (17,18). Even has an insidious evolution and a gradual progressive course.
children with clinical grade IV with TBM may benefit from Sometimes chronic meningitis may begin relatively acutely
VP shunts (103). and may become chronic later on. Chronic meningitis is
a potential manifestation of several infectious and non-
Hyponatraemia infectious diseases (110-112) [Table 17.9].
Hyponatraemia is common in TBM and is an independent As the aetiology of chronic meningitis is diverse, these
risk factor for poor outcome (104). Although two conditions patients require a thorough diagnostic evaluation to establish
have been implicated in the development of hyponatraemia the cause. Partially treated pyogenic meningitis often needs
to be differentiated from chronic meningitis. In India,
majority of patients with chronic meningitis are presumed
Table 17.8: Clinical grading system for patients with to have TBM and are treated accordingly. A detailed
TB meningitis with hydrocephalus account of various aetiological causes of chronic meningitis
Grade Description is beyond the scope of this chapter. The diagnostic and
I No neurological deficit and normal sensorium [GCS 15] therapeutic approach in patients with chronic meningitis
II Neurological deficit present, normal sensorium [GCS 15] will be discussed briefly.
TB is the most common cause of chronic meningitis in the
III Neurological deficit present, altered sensorium, but easily
arousable [GCS 9-14] developing world, where TB is highly endemic. By contrast,
in areas with a low prevalence of TB, the scenario may be
IV Comatose [GCS 3-8], decerebrate or decorticate posturing
different. In a study from Mayo Clinic (113), sarcoidosis
TB = tuberculosis; GCS = Glasgow coma scale [31%] and metastatic adenocarcinoma [25%] were the most
Adapted from reference 101
frequent causes of chronic meningitis.
240 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 17.9: Causes of chronic meningitis lupus erythematosus [SLE], bacterial [Actinomycetes, Listeria,
Nocardia] and fungal [Aspergillus, Candida, Zygomycetes]
Infectious causes
meningitis. Eosinophilic CSF pleocytosis favours a parasitic
Mycobacterium tuberculosis
Partially-treated bacterial meningitis aetiology. Low glucose in the CSF is non-specific and can
Cryptococcus neoformans occur in a variety of infectious and non-infectious causes of
Treponema pallidum chronic meningitis. The CSF should be exhaustively searched
Borrelia burgdorferi for specific aetiologic clues utilising the currently available
Candida facilities.
Brucella
Contrast-enhanced CT or MRI of the head, in addition
Leptospira icterohaemorrhagiae
Coccidioides immitis to reveal­ing hydrocephalus and parenchymal lesions, may
Histoplasma capsulatum demons­trate meningeal enhancement. In the study from the
Aspergillus Mayo Clinic (113), MRI with gadolinium contrast was the
Toxoplasma gondii most use­ful diagnostic imaging technique demonstrating
Actinomyces meningeal enhancement in 15 of 32 patients [47%] while CT
Nocardia
showed menin­geal enhancement only in 2 of 32 [6%].
Zygomycetes
Larva migrans Despite numerous diagnostic advances, the cause of
chronic meningitis frequently remains a diagnostic dilemma.
Non-infectious causes
Neoplasms Few patients eventually require a leptomeningeal biopsy,
Sarcoidosis with or without sampling of underlying cortex through
Vasculitis suboccipital and pterional craniotomy. In a study (113),
Connective tissue disorders: SLE, Behcet’s disease a definitive aetiological diagnosis of chronic meningitis
Vogt-Koyanagi-Harada syndrome was made in 16 of 41 biopsies [39%]. In patients in whom
Chronic benign lymphocytic meningitis
meningeal enhancement was present on CT or MRI, a
Mollaret’s meningitis
Drug/chemical exposure: iodophendylate dye, sulphonamides, diagnosis was obtained in 80%, while in contrast only 9% of
isoniazid, ibuprofen, and tolmentin non-enhancing regions were diagnostic. Therefore, CECT or
TB = tuberculosis; SLE = systemic lupus erythematosus
MRI findings provide valuable assistance in predicting the
yield and selecting the site for biopsy.

Management
Clinical Evaluation In patients with inconclusive clinical and laboratory data
The history is critical to distinguish partially treated pyogenic concern­ing the aetiology of chronic meningitis, the decision
meningitis and TBM [which may present as acute onset between empirical therapeutic trial and meningeal biopsy
chronic meningitis], chronic meningitis with remission is critical. The clinical presentation, especially the pace of
and exacer­bations, and recurrent meningitis [Mollaret’s progression of course of the disease, will often dictate the
meningitis]. Useful aetiological clues such as a known choice. Anti-tuberculosis treatment is indicated early in
systemic disease, immuno­compromised state, exposure to the course of chronic meningitis in a patient whose clinical
drugs and infectious agents [such as Borrelia, Treponema, condition shows deterioration. If PCR, serological tests and
Leptospira and Brucella] can be obtained from a carefully culture of the CSF for Mtb are all negative, TST continues
taken history. Physical examination may reveal a systemic to remain non-reactive even after re-testing at two weeks,
disease, erythema nodosum [EN] which may occur in TB, and no clinical response occurs, then anti-TB treatment may
sarcoidosis, histoplasmosis, coccidioidomycosis, erythema be stopped after six weeks. The decision to empirically use
chronicum migrans [Lyme disease], oral and genital ulcers potentially toxic antifungal drugs such as amphotericin-B
[Behcet’s disease], pulmonary abnormalities [suggestive of in chronic meningitis is more difficult. In the absence of a
TB, sarcoidosis, fungal infections], heart murmurs [bacterial positive proof for a fungal aetiology, the following situations
endocarditis] and splenomegaly [lymphoproliferative diseases, may warrant such a strategy: [i] a host with neutropenia
brucellosis]. Ophthalmoscopic examination may show or compromised cell-mediated immunity; [ii] presence of
choroid tubercles, sarcoid granulomas or uveitis [Behcet’s unequivocal clinical evidence or culture or biopsy proven
disease, Vogt-Koyanagi-Harada syndrome]. Granulomatous systemic fungal disease, and [iii] a patient with obscure
myositis [tender, nodular muscles and proximal weakness] chronic meningitis, hypoglycorrhachia and progressive
may be found in sarcoidosis. neurological deterioration in spite of anti-TB treatment.
A well-preserved patient with undiagnosed chronic
meningitis and a static or slowly progressive course is a
Diagnostic Evaluation
candidate for meningeal biopsy, especially when the neuro­
Chest radiograph, bronchoscopy with transbronchial lung imaging studies suggest an enhancing lesion accessible
biopsy, open lung biopsy, and lymph node or liver biopsy through a pterional or suboccipital craniotomy. Empirical
may help in identifying systemic diseases. Neutrophilic corticosteroid therapy in chronic meningitis is inappro­
CSF pleocytosis may occur in chemical meningitis, systemic priate because it can result in the rapid progression of
 Neurological Tuberculosis 241

an undiagnosed fungal disease. Of the 168 patients with the CT appearance, was wrong in 80% of cases. The rupture
chronic meningitis who were treated with anti-TB drugs of a parenchymal tuberculoma or tuberculoma en plaque
at the Sri Chitra Tirunal Institute for Medical Sciences and of the meninges can result in TBM. In a study reported by
Technology [SCTIMST], Thiruvananthapuram [earlier called Bhargava et al (36), tuberculomas occurred in 10% of patients
Trivandrum], India (114,115), 19% required ventriculo- with TBM. Brainstem tuberculomas, although uncommon,
peritoneal shunt for symptomatic hydrocephalus. At one and constitute 2%-8% of all intracranial tuberculomas and are
half years follow-up, 20% patients had died, 44% were fully more commonly seen in children (122). Ventricles form a
functional, the remaining 36% of patients had significant relatively rare site for tuberculomas (123).
neurological sequelae. The characteristic CT features of neurocysticercosis are
shown in Figure 17.8, 17.9 and 17.10. The imaging features of
INTRACRANIAL TUBERCULOMAS intracranial tuberculomas are shown in Figures 17.11, 17.12,
17.13, 17.14, 17.15 and 17.16. The features differentiating
Definition and Pathology various types tuber­c ulomas are listed in Table 17.10.
Tuberculoma is a mass of granulation tissue made up of a Comparison of salient imaging findings of tuberculomas
conglo­meration of microscopic small tubercles. A tubercle and neurocysticercosis is shown in Table 17.11.
consists of a central core of epithelioid cells surrounded by
lymphocytes. Giant cells are scattered among epithelioid Management
cells. The centre of the tuberculoma becomes necrotic,
In the past, management of tuberculoma was mainly
forming caseous material, while the periphery tends to be
surgical (114-117,124). With the availability of CT and MRI,
encapsulated with fibrous tissue. There may be liquefaction
therapeutic trial with anti-TB treatment in patients with
of the caseous material resulting in the formation of a TB
a solitary lesion suspicious of a tuberculoma is a widely
abscess.
accepted option (125,126). Short-course chemotherapy may
The size of cerebral tuberculomas is highly variable. In
be adequate for the treatment of tuberculoma (125) although
most cases their diameters range from a few millimeters to
its efficacy is not yet established. Corticosteroids are helpful
three to four centimeters (116). Intracranial tuberculomas in
in selected patients who have cerebral oedema and are
patients under the age of 20 years are usually infratentorial,
symptomatic. Tuberculomas begin to decrease in size within
but supratentorial lesions predominate in adults. Solitary
the first two months of anti-TB treatment. Choudhury (125)
tuberculomas are more frequent than multiple lesions.
reported that 17 [68%] of 24 patients treated conservatively
showed complete recovery, while only 2 patients [8%] had
Epidemiology significant residual neurological problems. Paradoxical
In the early decades of the twentieth century, cerebral expansion of intracranial tuberculomas during anti-TB
tuberculoma was a common lesion, accounting for 20%-40% treatment for neural or extra-neural TB has been observed
of all intracranial tumours (116,117). In 1972, Maurice- rarely (127-129). This phenomenon is thought to have an
Williams (118) from Great Britain reported a frequency of immunological basis similar to immune reconstitution
0.15%. Ramamurthi and Varadarajan (119) noted that the inflammatory syndrome [IRIS]. Surgery is still indicated for
tuberculomas formed 20% of all intracranial tumours at large lesions producing midline shift and severe intracranial
Chennai [then called Madras] in the 1950s. Although the hypertension, expanding lesions during anti-TB treatment,
frequency has decreased in the last two to three decades, when clinical and neuroimaging findings favour alternate
tuberculomas still constitute about 5%-10% of intracranial possibilities, such as, glioma or metastasis, and when the
space occupying lesions in the developing world (13,120). expected improvement is not forthcoming in the clinical and
CT picture during follow-up of medical treatment.
Diagnosis
TUBERCULOSIS ABSCESS
The CT and MRI have facilitated the diagnosis and
assessment of intracranial tuberculomas. The characteristic TB abscess is an uncommon manifestation of neurological
CT and MRI finding is a nodular enhancing lesion with a TB [Figure 17.7], most often occurring as a complication in
central hypointensity (36,119) [Figures 17.4, 17.5 and 17.6]. immunosuppressed patients receiving anti-TB treatment
The pattern of enhancement can be quite variable; homo­ for systemic or neurological TB. It is characterised by
geneous, patchy, serpentine and ring enhancement, have an encapsulated collection of pus that contains viable
all been observed. A lipid peak on proton MR spectroscopy TB bacilli without evidence of the classic TB granuloma.
is characteristic of tuberculoma (121) [Figures 17.4, 17.7]. The differentiation between tuberculoma and TB abscess
The spinal cord is less frequently involved by tuberculoma is often diffi­cult by conventional MR images. Diffusion-
[Figure 17.7]. Unless treated with steroids, oedema is nearly weighted images may show diffusion restriction that
always present and can be quite marked. These CT findings favours abscess (130); however, even this finding may not be
are non-specific and may simulate the appearance of gliomas, reliable (131). TB abscess develops in the brain parenchyma
metastasis, abscess, cysticercosis and fungal granulomas. In a although intraventricular (132) and subdural (133) sites have
study from Saudi Arabia (120), the initial diagnosis, based on also been reported. Differentiation from pyogenic abscess can
 242 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A C

D
Figure 17.4: Axial [A] and coronal fat saturated [B] contrast-enhanced T1-weighted MR images of a 9-year old child, who presented with fever,
headache, encephalopathy showing conglomerate ring enhancing lesions in the left temporal lobe and thalamus extending to left ambient cistern.
Abdominal ultrasonography revealed matted abdominal nodes. Tuberculin skin test was positive. Coronal post-contrast T1-weighted fat saturated
image [C] three months after anti-TB treatment shows a decrease in the size of the ring enhancing lesions. Single voxel MR spectroscopy [D] at
TE of 135 ms reveals a large lipid peak at 1.2 ppm, related to the predominant lipid content in the cell wall of Mycobacterium tuberculosis
MR = magnetic resonance; TE = echo time; ppm = parts per million

often be difficult and presence of indirect evidence of TB, been observed in the wall of the pyogenic abscess com­
mycobacterial culture of the aspirate or response to anti-TB pared to that in the TB abscess (134). Imaging features that
treatment may be needed. Elevated lipid and lactate levels help differentiating TB abscess from pyogenic and fungal
if accompanied by an elevated amino acid levels favour a abscesses is shown in Table 17.12.
pyogenic abscess over a TB abscess on MR spectroscopy (134). Surgical aspiration of the abscess or excision of a multi­
A significantly higher magnetisation transfer ratio has also loculated abscess may be required as these lesions harbour
 Neurological Tuberculosis 243

A C

A B

B D C D
Figure 17.5: Axial [A] and sagittal [B] contrast-enhanced T1-weighted Figure 17.6: Contrast-enhanced T1-weighted fat saturated coronal [A]
MR images of the cervico-dorsal spine of a 28-year-old male, who and axial [B] MR images of a 5-year old child, who presented with simple
presented with low-grade fever, weight loss and progressive myelopathy partial seizures involving left lower limb, showing a thick ring enhancing
with bladder involvement, showing intramedullary ring enhancing lesion with surrounding oedema behind the right motor cortex. Physical
conglomerate lesions [arrow] at T2 vertebral level. Four months after examination revealed cold abscess in the neck. Tuberculin skin test
anti-TB treatment axial [C] and sagittal [D] post-contrast T1-weighted was positive. Coronal [C] and axial [D] T1-weighted fat saturated post-
fat saturated images reveal complete resolution of the lesion contrast images three months after anti-TB treatment show a decrease
MR = magnetic resonance; TB = tuberculosis in size of the lesion and the oedema surrounding the lesion
MR = magnetic resonance; TB = tuberculosis

A B C
Figure 17.7: MRI of the brain, T2-weighted, axial view [A], diffusion weighted image [B], showing a TB abscess. Magnetic resonance
spectroscopy [C] of the lesion showing a large lipid peak at 1.2 ppm suggestive of TB abscess
MRI = magnetic resonance imaging; TB = tuberculosis

TB bacilli and their thick capsules are often impervious to lesions, SSEL], have been described almost exclusively from
anti-TB agents. Draining the abscess decreases the myco­ India (136). These enhancing lesions are less than 2 cm
bacterial load. Development of fulminant TBM following in size, but may show considerable oedema around it.
surgical excision of TB abscess remains a problem (135). Epidemiologically, the occurrence of SSEL corresponds
to the endemicity of cysticercosis. For example, in Kerala
SINGLE, SMALL, ENHANCING BRAIN LESION ON state in India, where cysticercosis is not endemic, SSEL are
COMPUTED TOMOGRAPHY AND SEIZURES encountered only in subjects who have lived outside Kerala.
Rajashekhar et al (137) compared clinical and CT data of six
Patients, who present with new onset focal seizures and consecutive patients with histologically proven tuberculomas
ring enhancing single CT lesions [single, small, enhancing and 25 consecutive patients with histologically verified
 244 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B A B
Figure 17.8: Neurocysticercosis [arrow] with scolex [arrow head]. Figure 17.10: CECT head, axial view in a patient with neurocysticercosis
NCCT head, axial view [A], showing single small lesion in the right showing a contrast-enhancing ring lesion [arrow] in the right fronto-
fronto-parietal region, eccentric nodule, perilesional oedema. CECT parietal region with perilesional oedema. Midline shift is also seen [A].
head, axial view [B] of the same patient showing ring enhancement Post-treatment image of the same patient showing significant resolution
NCCT = non-contrast computed tomography; CECT = contrast- of the lesion [arrow] [B]
enhanced computed tomography CECT = contrast-enhanced computed tomography

A B
Figure 17.11: NCCT head, axial view [A], showing conglomerate
Figure 17.9: CECT head, axial view showing calcified nodules tuberculomas. CECT head, axial view of the same patient [B] showing
[black arrows] and a ring lesion with perilesional oedema [white arrow] riming-enhancement
CECT = contrast-enhanced computed tomography NCCT = non-contrast computed tomography

A B C
Figure 17.12: MRI of the brain, T1-weighted, axial view [A], T2-weighted, axial view [B], post-gadolinium T1-weighted, axial view [C], showing
caseating tubercuolma with liquefied centre [arrow]
MRI = magnetic resonance imaging
 Neurological Tuberculosis 245

A B C
Figure 17.13: MRI of the brain, T1-weighted, axial view [A], T2-weighted, axial view [B], post-gadolinium T1-weighted, axial view [C],
showing tubercuolma with caseation [arrow]. Perilesional oedema is also seen
MRI = magnetic resonance imaging

A B
A B

C D
Figure 17.15: Gyriform tuberculoma. MRI of the brain, T2-weighted,
C D
axial view [A], showing gyriform hypointensity with perilesional oedema
Figure 17.14: MRI of the brain, T2-weighted, axial view [A], T2-weighted, left parieto-occipital region. The lesion appears isointense in T1-
gradient echo sequence [B], post-gadolinium T1-weighted, axial view weighted axial view [B]. Post-gadolinium T1-weighted, axial view [C],
[C], showing tubercuolma in the cerebellum [arrow]. Perfusion image shows gyriform enhancement in left, parieto-occipital lesion. Perfusion
shows no perfusion in the lesion [arrow] [D] image showing low perfusion in the lesion [arrow] [D]
MRI = magnetic resonance imaging MRI = magnetic resonance imaging

Table 17.10: MRI findings in different types of intracerebral tuberculomas

T1-weighted post-gadolinium
Type of tuberculoma T1-weighted images T2-weighted images contrast images
Non-caseating granuloma Isointense/hypointense Hyperintense Homogeneous enhancement
Caseating granuloma with solid centre Hypointense/isointense Isointense/hypointense Rim-enhancement
Caseating granuloma with liquid centre Hypointense Hyperintense; rim hypointense Rim-enhancement
MRI = magnetic resonance imaging
 246 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B C

D E F
Figure 17.16: MRI of the brain, axial view, T1-weighted image [A], T2-weighted image [B], diffusion weighted image [C], apparent diffusion
coefficient image [D], post-gadolinium T1-weighted image [E and F] showing multiple ring lesions [white arrows] and meningeal enhancement
[black arrow, F]
MRI = magnetic resonance imaging

Table 17.11: Imaging features helpful in differentiating neurocysticercosis from intracerebral tuberculoma*
Variable Neurocysticercosis Intracerebral tuberculoma
Size Usually <20 mm Usually >20 mm
Scolex Present, seen as eccentric hyperdensity on CT or hypointensity Absent
in T2-weighted image on MRI; not seen in racemose
neurocysticercosis
Core of ring lesion on May get suppressed in vesicular stage of neurocysticercosis Never gets suppressed
FLAIR images [differential diagnosis arachnoid cyst, neurenteric cyst]
MR spectroscopy Difficult to get good spectrum in smaller lesions; large lesions have Core: lipid-lactate peak; wall: increased
succinate and acetate peaks; succinate peak larger than acetate choline may be seen
peak
Leptomeningeal disease Seldom seen More common
Multiple lesions Multiple lesions are seen in different stage of evolution Multiple lesions are seen in same stage
of evolution
*Degree of oedema, location, presence of mass effect or presence of midline shift may not be a differentiating feature in differentiating
neurocysticercosis from intracerebral tuberculoma
CT = computed tomography; MRI = magnetic resonance imaging; FLAIR = fluid-attenuated inversion recovery; MR = magnetic resonance
 Neurological Tuberculosis 247

Table 17.12: Imaging features helpful in differentiating pyogenic abscess, TB abscess and fungal abscess
Morphology on conventional Intra-cavitatory Contrast Diffusion weighted
Type of abscess images projections enhancement imaging MR spectroscopy
Pyogenic abscess Ring lesion Absent Rim-enhancement Restricted in core Elevated succinate,
T1 hypointense/T2 acetate, cytosolic
hyperintense core with T2 aminoacids
hypointense wall
TB abscess Ring lesion Absent Rim-enhancement Restricted in core Lipid lactate peak
T1 hypointense/T2 with absence of other
hyperintense core with T2 metabolites within
hypointense wall core. Wall may show
increased choline
Fungal abscess Ring lesion Present Rim-enhancement Projections cause Lipid lactate peak
T1 hypointense/T2 [T2 hypointense] with non-enhancing diffusion restriction; with trehalose peak
hyperintense core with T2 projections Variable in core
hypointense wall
TB = tuberculosis; MR = magnetic resonance

cysticercus granulomas. Evidence of raised intracranial Clinical Stage of the Disease

pressure and a progressive focal neurological deficit was seen
only in patients with tuberculomas. On CT, all tuberculomas When anti-TB treatment and corticosteroids are initiated
were greater than 2 cm in size and majority were irregular in clinical stage 1 or early stage 2 diseases, high cure rates
in outline. In contrast, all cysticercous granulomas were ranging from 85%-90% have been observed. Clinical stages 3
less than 20 mm and majority were regular in outline. Only and 4 are usually accompanied by very high morbidity and
tuberculomas were associated with a midline shift on CT. mortality. A multivariate analysis of 199 Chinese patients
The authors (137) concluded that based on clinical findings with TBM (138) showed that only the age and the stage
[evidence of raised intracranial tension and a progressive of presentation affected the outcome and with respect
neurological deficit] and CT appearance [size, shape and to the disease stage and the mortality raises from none
association with a midline shift], it is possible to distinguish to 4% in stage 1, to 22%-30% in stage 2, to 78%-79% in
between tuberculoma and neurocysticercosis in a majority stages 3 or 4.
of patients presenting with SSEL and seizures.
Age
PROGNOSIS AND OUTCOME OF NEUROLOGICAL The outcome of TBM, particularly in children, is often poor
TUBERCULOSIS irrespective of the region where they live. Extremes of age have
The two most important factors determining the outcome poorer outcome; children below 3 years and adults above
of TBM are early diagnosis and prompt initiation of 50 years of age generally have a poor prognosis (37,139).
treatment (3-7,138). The factors contributing to poor outcome
are listed in Table 17.13. Cerebrospinal Fluid Parameters
Though earlier studies suggested that lower glucose levels
Table 17.13: Factors contributing to poor outcome of in CSF had a poorer outcome, studies with larger number
TB meningitis of patients have failed to show any correlation between CSF
Advanced clinical disease at presentation sugar levels and the clinical outcome (21). The only CSF
Delayed diagnosis and initiation of therapy parameter that correlated with a poor outcome was high
Extremes of age protein levels [greater than 2 g/L], as it was associated with
a more advanced stage of the disease at presentation.
Infection with drug-resistant mycobacterial strains
HIV infection, AIDS associated with a low CD4+ T-lymphocyte count
Neuroimaging
Hydrocephalus
Raised intracranial pressure Patients with dense exudates in the basal cisterns and visual
Brain ischaemia due to vasculitis loss due to organised exudates over optico-chiasmatic
region respond poorly to treatment (36). Similarly, patients
Direct parenchymal injury
with diencephalic infarcts and angiographic evidence of
Hyponatraemia
narrowing in the middle or anterior cerebral arteries have
Seizures higher morbidity (17,109). It is also important to note that
TB = tuberculosis; HIV = human immunodeficiency virus; AIDS = diencephalic infarcts give rise to SIADH, which is a poor
acquired immunodeficiency syndrome
prognostic indicator.
 248 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Others Variables to occur in patients with TBM on inadequate or adequate

anti-TB treatment regimens (140,141). Lumbosacral region is
Poor outcome has also been associated with raised
the most commonly affected site in TBRM, although cervical
intracranial pressure with hydrocephalus and infection with
involvement is not unknown [Figure 17.17]. In contrast,
drug-resistant mycobacterial strains. Children who have
TBRM secondary to vertebral TB is relatively more common
not received BCG vaccination also have a poor outcome.
in the dorsal region.
Infection with HIV does not seem to alter the prognosis
of TBM except in patients with CD4+ lymphocyte counts
below 0.2 × 109/L (29,31).
Investigations
In most patients with TBRM, if the lumbar puncture is
TUBERCULOSIS RADICULOMYELITIS not a dry tap, CSF shows lymphocytic pleocytosis, hypo­
glycorrhachia and characteristically, a very high protein
TB radiculomyelitis [TBRM] is a form of spinal TB and may
level [probably secondary to a CSF flow block]. These
develop in one of the three ways: [i] as a primary TB lesion;
findings may persist despite sterilisation of CSF. Although
[ii] as a downward extension of TBM; and [iii] as a secondary
in practice, CT myelography or contrast MRI of the spine is
extension from vertebral TB. The first two varieties of TBRM
often preferred over the conventional spinal myelography
are discussed here briefly. Wadia and Dastur (140) suggested
in patients with TBRM, a study (141) comparing these
TBRM as a generic term to include cases designated as
modalities of imaging found conventional myelography
arachnoiditis, intradural spinal tuberculoma or granuloma
to be the primary radiographic method for diagnosis
and spinal cord complications of TBM.
of suspected TBRM, particularly in those cases that are
characterised by chronic adhesive changes. In patients with
Pathology and Clinical Features active intrathecal inflammatory process or with myelopathy,
Pathologically, it is characterised by extensive, copious and gadolinium-enhanced MRI was found to be the optimal
tenacious exudates that may occupy the entire space between choice. In contrast to this observation, MRI was favoured
the spinal dura mater and the leptomeninges that may encase as the primary imaging modality for screening patients
the cord and impinge on the roots. Clinical features include a with suspected intraspinal TB, regardless of the stage of
subacute to chronic progressive flaccid paraparesis, often in the disease, in another study (142), an opinion that may
the presence of a positive Babinski’s sign, that is frequently find wider acceptance in view of the non-invasive nature
preceded by root pains, paraesthesias, bladder disturbances of the investigation and the recent advances in spinal
and focal muscle wasting. Secondary TBRM may follow TBM MRI technology. CT myelography has no superiority
during the acute stage but can also occur after a variable over contrast-enhanced MRI, except perhaps in cases with
periods of months to years (140). Furthermore, it is known extensive vertebral TB. The MRI features of TBRM include

A B C D
Figure 17.17: Contrast-enhanced sagittal fat saturated cervical [A] and lumbar [B] spine MR images of a 35-year-old male, who presented
with fever, headache, radicular pains and quadriparesis, show enhancement of the meninges with CSF loculations anterior to the cord [arrows]
suggestive of arachnoiditis. Post-contrast fat saturated sagittal lumbar [C] and cervical [D] spine MR images one year after anti-TB treatment
along with corticosteroids reveal marked reduction of the enhancement of the meninges. The CSF loculations are no longer evident
MR = magnetic resonance; CSF = cerebrospinal fluid; TB = tuberculosis
 Neurological Tuberculosis 249

loculation and obliteration of the spinal subarachnoid spaces, 7. Delfino LN, Fariello G, Lancella L, Marabotto C, Menchini L,
loss of outline of the spinal cord in the affected region, Devito R, et al. Central nervous system tuberculosis in non-HIV-
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Some researchers consider TBRM as a form of paradoxical 11. Katrak SM, Shembalkar PK, Bijwe SR, Bhandarkar LD. The
reaction to TB treatment, which might represent a delayed clinical, radiological and pathological profile of tuberculous
hypersensitivity response in a recovering patient to myco­ meningitis in patients with and without human immune
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this view might support the use of corticosteroids to prevent 12. Tan EK, Chee MWL, Chan LL, Lee YL. Culture positive
and treat TBRM, reports on the efficacy of corticosteroids for tuberculous meningitis: clinical indicators of poor prognosis.
Clin Neurol Neurosurg 1999;101:157-60.
this condition are conflicting (143-145) and the studies are
13. Tandon PN, Bhatia R, Bhargava S. Tuberculous meningitis. In:
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Mrs S Vasanthy of the Medical Illustrations Division for
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 18
Tuberculosis and Heart
SS Kothari, A Roy

INTRODUCTION TB pericarditis was more than 80% during the acute phase
of illness and still more at a later stage due to constrictive
Cardiovascular involvement is a relatively uncommon pericarditis (12-14). Even with the advent of modern anti-
mani­festation in patients with tuberculosis [TB] and has TB treatment, the mortality rate in patients with TB still
been described in 1%-2% of patients (1). It mainly effects remains worrisome with reported death rates of 3%-17% in
pericardium, but very rarely myocardium, valves or large the pre-HIV era (15,16) and as high as 27%-40% in patients
arteries are involved. Although cardiovascular involvement with HIV infection, acquired immunodeficiency syndrome
is always secondary to TB elsewhere in the body, it may [AIDS] (17).
be the sole clinical manifestation of TB. Mycobacterium
tuberculosis [Mtb] is the usual infective agent. Cardiovascular
Pathogenesis
TB caused by nontuberculous myocobacteria [NTM] has
been documented in patients with human immunodeficiency Pericardial involvement most commonly results from direct
virus [HIV] infection (2). extension of infection from adjacent mediastinal lymph
nodes or through lymphohaematogenous route from a focus
TUBERCULOSIS PERICARDITIS in lungs, kidneys, or bones. The TB pericarditis has following
stages: [i] dry stage; [ii] effusive stage; [iii] absorptive stage;
Pericardial TB may present as acute pericarditis, chronic and [iv] constrictive stage (18). The disease may progress
pericardial effusion, cardiac tamponade or pericardial sequentially from first to fourth stage or may present at any
constriction. Hence, TB should always be considered in the of the stages. The factors that lead to a dominant exudative
differential diagnosis of pericardial disease. In developing inflammation in some patients and fibrosis in others are not
countries where the disease is endemic, TB is an important known (19). While acute pericarditis appears to be a primary
cause of pericardial disease (3-5). In India, TB is responsible for hypersensitivity response to tuberculoprotein[s], chronic
nearly two-thirds of the cases of constrictive pericarditis (3,4). effusion and constriction reflect granuloma formation and
Over all, TB accounts for 60%-80% of cases of acute peri­ fibrosis. Epithelioid granulomas, Langhans’ giant cells
carditis in the developing countries. However, recently and caseation necrosis are evident on histopathological
published literature suggests that, in the developed world, examination (20). The T-lymphocytes, in addition to activated
TB is a relatively rare cause of pericardial disease and it macro­phages, are important in granuloma formation. The
occurs in HIV negative, immunocompetent persons and accompanying exudative pericardial fluid may contain
accounts for 2% of the cases of acute pericarditis (6,7), polymorphonuclear leucocytes in the initial 1-2 weeks, but
2% of cardiac tamponade (8) and less than 1% of constrictive later on, it is predominantly lymphocytic with high protein
pericarditis (9,10). TB pericarditis has been described in content. In 80% of the cases, the fluid is straw coloured or
1%-8% of patients with pulmonary TB (11). sero-sanguinous, and may be grossly bloody resembling
Pericarditis is the predominant form of cardiovascular venous blood at times (1). Very rarely, severe inflammation
TB. Before the advent of anti-TB treatment, TB pericarditis may result in pyopericardium due to TB (21). The amount
carried a grave prognosis. The reported mortality rate in of pericardial fluid may vary from 15-3500 mL (22).
254 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Development of cardiac tamponade due to TB pericarditis relieves increased pericardial tissue tension due to inspiration
depends on the rapidity of collection of pericardial fluid. and truncal extension and also splints the diaphragm (26).
It may occur even with a slowly accumulating large Pain radiation to shoulder and jaw can mimic angina rarely.
pericardial effusion. Fibrinous exudates, pericardial effusion Radiation of pain to trapezius ridge though the phrenic
and thickening of pericardium from fibrosis [especially nerve is virtually pathognomonic of pericardial pain (26).
the visceral layer] result in features of effuso-constrictive However, TB pericarditis may also present with an acute
pericarditis within weeks of development of TB pericarditis. illness in 20% of the cases (5). The reported frequency of
Continued inflammation and fibrotic activity may lead to various symptoms in different series is shown in Tables 18.1
chronic constrictive pericarditis [CCP]. With effective anti- and 18.2 (1,24,25,27-29).
TB treatment, the pericardial effusion may resolve without
development of CCP in nearly half the patients (5). Many Pericardial Effusion
patients with CCP, however, have no history of previous
Patients with TB pericarditis may develop chronic pericardial
TB pericarditis. Complete obliteration of pericardial space
effusion with mild or severe constitutional symptoms (1,25).
by a fibrotic constricting shell results in impairment of
Patients may also present acutely with cardiac tamponade
cardiac function. In chronic cases, the inflammatory process
and may manifest severe distress, retrosternal compress,
may extend into myocardium resulting in myonecrosis
tachycardia and raised jugular venous pressure [JVP] with
and muscle atrophy. The constriction, at times, may be
blunted descent. In patients with cardiac tamponade, the
patchy and localised to certain areas like mitral or tricuspid
heart sounds are usually distant. A pericardial rub may
annulus (23). The space around transverse and oblique sinus
be heard despite significant pericardial effusion. Pulsus
is often spared from fibrosis, and, therefore, some degree of
paradoxus [inspiratory decline of systolic blood pressure of
left atrial enlargement commonly occurs in CCP.
more than 10 mmHg] is the hallmark of bedside diagnosis
of cardiac tamponade.
Clinical Features
TB pericarditis can develop at any age but commonly Subacute Effusive-Constrictive Pericarditis
occurs in the middle ages. In the series, reported by Strang This subacute stage of TB pericarditis is also termed as
et al (16) more than 80% patients were older than 35 years subacute “elastic” pericarditis. It has features of both
with nearly half of them being more than 55 years old. Like pericardial effusion and constriction. The fluid-fibrin layer
other forms of TB, it is more common in patients who are leads to relatively elastic compression of heart, which has
immunosuppressed. However, the majority of patients do been compared to “wrapping the heart tightly with rubber
not have any other co-morbid conditions. It is more common bands” (30). The haemodynamics of the non-rigid fibroelastic
among the black race as compared to whites in the western form of constrictive pericarditis resembles tamponade
world (1,23,24). The clinical features depend on the stage because the fibroelastic constriction compresses the heart
and severity of the disease. The pericarditis is often insidious throughout the cardiac cycle, and respiratory changes
in onset and presents with fever, malaise and weakness. in intra-thoracic pressure are transmitted to the cardiac
Attention to the diagnosis is drawn by the presence of peri­ chambers (30). Thus, the pattern of ventricular filling is
cardial rub, vague chest pain or cardiomegaly on chest radio­ similar to cardiac tamponade rather than constrictive
graph. Dyspnoea, non-productive cough and weight loss are pericarditis and includes a systemic venous waveform
common symptoms. Chest pain, orthopnoea and ankle with a predominant x descent or equal x and y descent,
oedema occur in nearly 40%-70% of patients (1,22,25). Chest an inconspicuous early diastolic dip in the ventricular
pain is usually pleuritic in nature and is characteristically waveforms, an inspiratory dip in systemic venous and
relieved by sitting up and leaning forward. This manoeuvre right atrial pressures, and presence of pulsus paradoxus.

Table 18.1: Clinical symptoms in patients with tuberculosis pericarditis

Hageman et al (24) Rooney et al (25) Fowler (1) Komsuoglu et al (27) Yang et al (28) Reuter et al (29)
Variable [n = 44] [n = 35] [n = 19] [n = 20] [n = 19] [n = 162]
Weight loss ND 85 40 ND 32 79
Night sweats 14 37 58 10 ND 62
Chest pain 39 57 76 40 37 27
Cough 48 85 94 50 47 90
Haemoptysis ND 17 14 ND ND ND
Dyspnoea 80 74 88 60 84 86
Orthopnoea 39 66 53 ND ND 38
All values are shown as percentages
n = number of patients; ND = not described
 Tuberculosis and Heart 255

Table 18.2: Physical signs in patients with tuberculosis pericarditis

Hageman et al (24) Rooney et al (25) Fowler (1) Komsuoglu et al (27) Yang et al (28) Reuter et al (29)
Variable [n = 44] [n = 35] [n = 19] [n = 20] [n = 19] [n = 162]
Fever 73 97 83 ND 58 75
Tachycardia [> 100/min] 68 94 83 73 47 74
Pulsus paradoxus 45 23 71 33 11 27
Ankle oedema 64 49 39 24 42 38
Raised JVP 70 46 61 47 68 78
Pericardial rub 41 37 84 ND 32 ND
Cardiomegaly 90 85 95 98 79 ND
Pleural effusion ND 71 58 10 42 38
Hepatomegaly 68 63 65 67 26 62
Ascites 34 3 ND ND 26 ND
Pulmonary infiltrates ND ND ND ND 42 ND
All values are shown as percentages
n = number of patients; JVP = jugular venous pressure; ND = not described

This stage can develop within weeks of TB pericarditis. disease. Sometimes, patients may also present with subtle
With effective anti-TB treatment the disease may resolve signs like fatigue, without obvious clinical findings of CCP.
in some patients, but commonly chronic constriction These patients with “occult” constrictive pericarditis often
supervenes (5,16). manifest pericardial thickening on radiological imaging.
The clinical signs of constrictive pericarditis often manifest
Chronic Constrictive Pericarditis pericardial thickening on radiological imaging. The clinical
signs of constrictive pericarditis may become evident on
In hearts with CCP, the inflow of blood is impeded due fluid challenge in such patients. These patients improve with
to thickened unyielding pericardium, especially in the late pericardiectomy. Other patients may present with congestive
diastole. Thus the patients usually present with predominant splenomegaly and protein losing enteropathy resulting in
symptoms of systemic and pulmonary venous congestion. hypoproteinemia. Rarely, nephritic syndrome due to CCP
Abdominal swelling [from ascites or hepatomegaly] and has been described (31). Cardiac cirrhosis may also develop
peripheral oedema are the most common presenting after many years of hepatic venous congestion.
symptoms. Dyspnoea and orthopnoea are also present in The disease worsens gradually and in chronic cases,
nearly half the patients requiring surgical intervention (31). significant myocardial atrophy occurs due to extension
Cardiac output is mildly reduced at rest. These patients of inflammation and possibly disuse of muscle. These
have compensatory tachycardia to maintain cardiac output. patients have suboptimal results and high mortality with
Since more than 75% of diastolic filling occurs in the first pericardiectomy (23).
25% of the diastole, shortening of diastole does not reduce
stroke volume much but helps in augmenting cardiac output.
Differential Diagnosis
Other clinical signs seen are raised JVP with rapid y descent
[Friedreich’s sign], which increases further on inspiration The differential diagnosis of TB pericarditis includes a
[Kussmaul’s sign]. Pulsatile hepatomegaly, ascites with number of conditions like idiopathic, viral, or, infectious
an impalpable apex or systolic retraction of precordium pericarditis and pericarditis due to neoplasia, collagen
[Broadbent’s sign] are also seen commonly. A pericardial vascular disorders and uraemia among others. The
knock that occurs 0.11-0.12 sec after the second heart aetiological diagnosis in pericarditis is often established on
sound may be present; murmurs are uncommon. In one the basis of “guilt by association”.
Indian study (32), atrio-ventricular regurgitation was present Majority of patients with idiopathic or viral pericarditis
in 78% of patients with CCP on Doppler examination, but have acute onset with characteristic chest pain. Pericardial
an audible murmur was present in only 2 of the 33 patients. effusion may be small or absent. Idiopathic or viral
In general, presence of cardiomegaly, third and fourth heart pericarditis is a self-limited illness lasting two to three
sounds, significant mitral or tricuspid regurgitation, and weeks (33). However, a more protracted course, large
severe pulmonary hypertension favour restrictive cardio­ pericardial effusion or cardiac tamponade are not infrequent
myopathy rather than CCP. in idiopathic or viral pericarditis. On the other hand, TB
Other atypical manifestations include clinical presenta­ pericarditis may have an acute onset. The differentiation
tion with ascites disproportionate to the peripheral oedema of TB pericarditis from idiopathic or viral pericarditis may
[ascites precox] which may be mistaken for primary liver present a diagnostic dilemma.
 256 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Diagnosis with predominance of lymphocytes and monocytes. In the

initial weeks, predominantly polymorphonuclear leucocytes
Chest Radiograph may be seen and very rarely TB may cause purulent
Cardiomegaly has been commonly reported in various pericarditis (21). A smear of pericardial fluid rarely identifies
published series on TB pericarditis. It was present in 40 of acid-fast bacilli [AFB] on Ziehl-Neelsen [Z-N] staining.
44 patients described in one study (24) and in 190 of the Fluorochrome staining is a more sensitive technique for
193 patients in another (16). Active pulmonary TB has been identi­fying mycobacteria than conventional Z-N staining (37).
reported in nearly 30% patients with TB pericarditis (1,16,34,35). Culture of pericardial fluid grows Mtb in about 50%-60%
However, pericarditis may be the only manifestation of cases using Lowenstein-Jensen [LJ] or double strength
extra-pulmonary TB [EPTB] in several patients. Reduced Kirchner medium (16,25). However, the major drawback
cardiac pulsations on fluoroscopy have been reported in is that six to eight weeks are needed for the conventional
76% patients (24). Pleural effusion has also been frequently mycobacterial cultures to yield results. Newer radiometric
described and may be bilateral in some patients (25). culture techniques like BACTEC yield quicker results.
Pericardial calcification [Figure 18.1] commonly occurs Molecular diagnostic methods like cartridge-based nucleic
around the annulus and has been observed in 15% patients acid amplification tests [CBNAAT], especially Xpert
in western series (3,23). MTB/RIF® has been found to be useful in the diagnosis
of TB pericarditis (38). In a recently published systematic
Electrocardiogram review (39) pooled sensitivity and specificity of pericardial
The most common electrocardiogram [ECG] findings in fluid Xpert MTB/RIF were found to be 65.7% and 96.0%,
patients with TB pericarditis are presence of low voltage respectively. Pericardial fluid adenosine deaminase [ADA]
complexes and T-wave inversion with or without ST- levels above 70 IU/L has been shown to be highly sensitive
segment changes [Figure 18.2]. One of these findings is and specific for the diagnosis of TB pericarditis (27).
present in over 90% patients (24,25). In a recent study (36) However, ADA which is produced by activated macro­
of 88 patients with TB pericarditis, presence of low voltage phages and lymphocytes may also be raised in malignant
in the extremity and/or precordial leads correlated with effusions. Simultaneous measurement of lysozyme, which
the presence of greater than 750 mL of pericardial fluid. is raised in TB effusions, along with ADA may help in
However, no ECG parameters were predictive of cardiac distinguishing TB pericardial effusion from malignant peri­
tamponade (36). The presence of classical ST-segment cardial effusion (40).
elevation of acute pericarditis is rare and is seen in 2%-9%
of patients (24,25). Pericardial Biopsy
Pericardial biopsy, though rarely done, is another useful
Pericardial Fluid method for confirming the aetiology of pericarditis and it
The pericardial fluid is usually straw coloured or serosangui­ gives results earlier than pericardial fluid culture. Tissue
nous and has high protein content. The cell count is high can be obtained by open biopsy or percutaneously using a

A B
Figure 18.1: Chest radiograph [postero-anterior view] [A] showing moderate cardiomegaly, dense, plaque-like calcification of the pericardium in
the anterior and inferior atrioventricular groove. Right basal pneumonitis and pleural effusion are also seen. Extensive calcification of hilar, anterior
mediastinal and right paratracheal lymph nodes is seen. Chest radiograph [lateral view] of the same patient [B]. Pericardial calcification [arrow]
is better appreciated in this view
 Tuberculosis and Heart 257

effusions, a clear space of 2 cm or more is evident; or when

an anterior and posterior clear space can be seen in systole
and diastole (43).
Collapse of right atrial and right ventricular free wall
in diastole by pericardial fluid and exaggerated respiratory
variation in atrio-ventricular valve flow velocities are diag­
nostic of tamponade and may precede clinical evidence.
Pericardial fluid often contains fibrinous exudates. Rarely,
these exudates may appear as a fleshy tumour that disappears
with anti-TB treatment (44). Thickened pericardium and
Figure 18.2: Three-channel recording of a 12-lead electrocardiogram
at 25 mm/s in a child with chronic constrictive pericarditis. Limb leads pericardial effusion are seen in the effusive-constrictive stage
show a low-voltage graph and non-specific T-wave inversion in leads [Figures 18.8, 18.9, 18.10, 18.11, 18.12 and 18.13]. Pericardial
V4-V6. Left atrial enlargement is also evident thickening is best visualised anteriorly over the right ventri­
cular free wall. Transoesophageal echocardiography is
bioptome (41,42). Percuta­enous biopsy is taken from multiple
sites and has been shown to be safe in a selected group of
patients, including children. Histopathological examination
of pericardial tissue may be diagnostic of TB in 70% of
cases when performed prior to initiation of therapy (16).
However, it is important to note that in some patients with
culture positive TB, histopathology may show non-specific
changes. Thus, a non-specific histopathological change in
the pericardial biopsy does not exclude TB (16). The peri­
cardial tissue culture also provides an additional source for
isolating Mtb and increases the diagnostic yield (16,42).

Echocardiogram
The echocardiogram is highly sensitive and specific for
the diagnosis of pericardial effusion and cardiac tampo­
nade [Figures 18.3, 18.4, 18.5, 18.6 and 18.7]. When 1 cm of
posterior echo-free space is evident in systole and diastole,
with or without fluid accumulation elsewhere, the peri­
Figure 18.4: Two-dimensional echocardiogram short-axis view
cardial effusion is classified as ‘small’. When a posterior showing thickened pericardium [arrows] and massive pericardial
clear space of 1-2 cm is maintained in systole and diastole, effusion [asterisk]
the effusion is classified as ‘moderate’. In ‘large’ pericardial RV = right ventricle; LV = left ventricle

Figure 18.5: Two-dimensional echocardiogram, apical four-chamber

Figure 18.3: Two-dimensional echocardiogram in parasternal long axis view showing diastolic compression of RA and RV in a patient with
view of a child with tuberculosis pericardial effusion pericardial effusion [asterisk] and cardiac tamponade
RV = right ventricle; LV = left ventricle; PEff = pericardial effusion LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle
 258 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 18.6: Pulse Doppler study of mitral valve in a patient with cardiac tamponade showing significant respiratory variation [>25%] in mitral inflow

Figure 18.7: M-mode echocardiogram in a patient with cardiac Figure 18.8: Two-dimensional echocardiogram, short-axis view, in
tamponade showing IVC plethora with no respiratory variation a patient with chronic constrictive pericarditis. Thickened calcified
IVC = inferior vena cava pericardium [arrows] can be seen along basal ventricles and AV groove.
The pericardium was 4.7 mm thick
AV = atrio-ventricular
superior to transthoracic echocardiography in the detection
of pericardial thickening. The normal pericardium is a thin, The other findings in CCP include abrupt flattening
bright line of 1.2 ± 0.8 mm. In one study (45), the pericardium in of mid to late diastolic movement of the left ventricular
patients with constrictive pericardtis measured 9.8 ± 1.6 mm. posterior wall on M-mode, reflecting a sudden decline
Pericardial thickness as measured by transoesophageal in diastolic filling (47). Other M-mode features include
echocardiography was found to have an excellent correlation rapid early closure of the mitral valve and, uncommonly,
with computed tomography [CT] (46). When a value of 3 mm premature pulmonary valve opening from increased right-
was used as a cut-off for defining pericardial thickness sided diastolic pressures. A diastolic septal bounce is also
as measured by transoesophageal echocardiography, the commonly seen. Diastolic septal motion is controlled by
sensitivity and specificity of this technique for CCP were the pressure gradient across the septum. The abrupt
calculated to be 95% and 86% respectively (46). bounce may be caused by sudden changes in the trans-
 Tuberculosis and Heart 259

Figure 18.11: Continuous Doppler study of aortic valve in a patient

Figure 18.9: Two-dimensional echocardiogram, apical four-chamber with chronic constrictive pericarditis showing significant respiratory
view, in a patients with effusive-constrictive pericarditis showing variation in aortic flow demonstrating ventricular interdependence
thickened pericardium adjacent to the basal lateral LV [arrows], biatrial
enlargement. Moderate pericardial effusion [asterisk] is also present
LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle

A B
Figure 18.12: Tissue Doppler study showing increased excursion
velocity of lateral [A] and septal [B] mitral annulus suggestive of
constrictive pericarditis

Figure 18.10: Pulse Doppler study of mitral valve in a patient with

constrictive pericarditis showing restrictive pattern of mitral filling
with E/A >2. Also demonstrated is the significant respiratory variation
[> 20%] in mitral inflow characteristic of ventricular interdependence
E = mitral valve flow velocity during early diastole; A = during late diastole

septal gradient during diastole, when filling is particularly

rapid (48). Additional echocardiographic abnormalities
include mild atrial dilatation and dilatation of inferior vena
cava [IVC].
Doppler studies also help in diagnosing CCP and differ­
entiating it from restrictive cardiomyopathy [Figures 18.10,
18.11, 18.12 and 18.13]. The mitral flow velocities show more Figure 18.13: Pulse Doppler study of hepatic vein in a patient with
than 25% respiratory variation [decrease with inspiration], constrictive pericarditis showing diastolic flow reversal [arrow]
most pronounced in the first heartbeat after inspiration from
apnoea (49). Similarly, an expiratory increase in diastolic preserved in CCP [Figure 18.12] and this feature helps to
flow reversal [>25%] of the hepatic venous flow velocities distinguish it from restrictive cardiomyopathy wherein tissue
is suggestive of CCP. Tissue Doppler velocities are usually velocities are commonly impaired.
260 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Cross-sectional Imaging right and left ventricular end-diastolic pres­sures. These

pressures are within 5 mmHg of each other [Figure 18.18].
Cross-sectional imaging with CT or magnetic resonance
The other classical haemodynamic criteria favouring CCP
imaging [MRI] can reveal pericardial effusion [Figures 9.42,
over restrictive cardio­myopathy (52) are a right ventricular
18.14], are very useful in the diagnosis of CCP and in
systolic pressure less than or equal to 50 mmHg and a ratio
distinguishing it from restrictive cardiomyopathy. The diag­
of right ventricular end-diastolic pressure to right ventricular
nostic hallmark is the presence of pericardial thickening
systolic pressure greater than or equal to 1:3. If all these three
with or without calcification [Figure 18.15]. Additionally, CT
haemodynamic criteria are met, the probability of CCP is
scan is useful in demonstrating mediastinal lymphadeno­
over 90%. If one or none of these criteria are present, then
pathy [Figure 18.16]. While CT scores over MRI in detec­
probability of CCP is less than 10%. However, one-fourth
tion of minimal amounts of pericardial calcification, MRI
of patients may not be classified by these haemodynamic
provides better soft tissue characterisation (50), this may be
criteria (53).
useful in distinguishing restrictive cardiomyopathy from
Measuring respiratory variation in ventricular haemo­
CCP. Pericardial thickening of more than 3 mm is usually
dynamics during catheterisation is another useful criteria
considered abnormal. Often a localised process, pericardial
for the diagnosis of CCP (49,53). As a manifestation of
thickening is most frequently seen over the right ventricle.
ventricular interdependence, respiratory discordance occurs
In a study of 29 patients (51), MRI was found to be 88%
in peak right ventricular systolic pressure and left ventricular
sensitive and 100% specific, with a diagnostic accuracy of
systolic pressure. In CCP, right ventricular systolic pressure
93% for detecting CCP. However, pericardial thickening
increases with inspiration while left ventricular systolic
can be seen without constrictive physiology. Similarly, in a
pressure simultaneously decreases. Wedge pressure declines
small proportion of patients with constrictive physiology,
more than the left ventricular pressure leading to reduction
no pericardial thickening can be identified. Therefore, it is
in mitral flow, which translates into the observed reduction
important to search for additional findings suggestive of
in left ventricular systolic pressure. This criterion has 100%
CCP like tubular shaped ventricles, enlarged atria, focal
sensitivity and 95% specificity for diagnosis of CCP (53). In
contour abnormalities of the ventricles, dilated IVC, ascites
restrictive cardiomyopathy, both right and left ventricular
and pleural effusion on CT or MRI (50).
systolic pressures decrease concordantly with inspiration (53).
Positron Emission Tomography–Computed
Treatment
Tomography
Once diagnosis of TB pericarditis is established, prompt
Positron emission tomography–computed tomography
initiation of anti-TB treatment is mandatory (54). Recom­
[PET-CT] using 18F labelled 2-deoxy-D-glucose [FDG] is
mended therapy consists of four-drug regimen containing
increasingly being used in the evaluation of patients with
isoniazid, rifampicin, pyrazinamide and ethambutol for two
EPTB, including TB pericarditis and has been found to be
months followed by isoniazid, rifampicin and ethambutol
useful in disease localisation and assessing response to
for next four months. Some physicians prefer to administer
treatment on follow-up [Figure 18.17].
longer duration of treatment. However, no randomised
controlled trial has compared different durations of anti-
Cardiac Catheterisation tuber­c ulosis drug regimens in TB pericarditis. Similar
Cardiac tamponade or CCP due to any cause produces a simi­ duration of treatment is recommended for HIV-positive
larly elevated right, left atrial [or pulmonary arterial wedge], patients. As per the recently published evidence-based

A B C
Figure 18.14: CT chest in a patient with TB pericardial effusion [topogram] [A] showing cardiomegaly [known as “money bag” or
“water bottle” sign]. CECT chest of the same patient axial view [B], coronal reconstruction [C] showing pericardial effusion [arrows]
CECT = contrast-enhanced computed tomography
 Tuberculosis and Heart 261

pericarditis and the need for repeat pericardiocentesis, and

was associated with a higher propotion of patients with an
overall favourable status. In both trials, the prednisolone
was used for a period of 11 weeks of anti-TB treatment
in a dosage of 60 mg/day for four and tapered over the
next seven weeks. The authors (57), reported results of
10 years follow-up of the same cohort. In multivariate
survival analysis [stratified by type of pericarditis], adjuvant
prednisolone treatment reduced the overall death rate after
adjusting for age and sex, and substantially reduced the risk
of death from pericarditis.
In another trial (17) in HIV-seropositive patients with TB
pericarditis, there was a significant reduction in all-cause
mortality with use of steroids at 18 months of follow-up (17).
A systematic review of all trials on adjuvant steroids
concluded that while case fatality rate was markedly
reduced by steroids, this did not reach statistical significance
due to the small number of patients in the studies (58). A
recently published international multicentre, randomised
Figure 18.15: Sagittal reconstruction of a contrast-enhanced CT of the controlled clinical trial, the Investigation of the Management
chest showing shell-like thickening [11 mm] of the pericardium [arrow] of Pericarditis [IMPI] trial (59), evaluated the effects of
in a patient with tuberculosis pericardial effusion. Echocardiography did
not reveal any evidence of constriction
adjunctive glucocorticoid therapy and Mycobacterium indicus
pranii immunotherapy in patients with TB pericarditis. In
this trial (59), it was observed that there was no signifi­
Guidelines for Extrapulmonary TB for India [INDEX- cant difference in the primary outcome [a composite of
TB Guidelines] (55), a treatment duration of 6 months is death, cardiac tamponade requiring pericardiocentesis, or
considered adequate for TB pericarditis. The reader is constrictive pericarditis] between patients who received
referred to the chapter “Treatment of tuberculosis” [Chapter 44] prednisolone and those who received placebo; or between
for details. Under the Revised National Tuberculosis Control those who received M. indicus pranii immunotherapy and
Programme [RNTCP] of the Government of India, pericardial those who received placebo.
TB is categorised as serious form of EPTB and new patients As per the INDEX-TB Guidelines] (55), corticosteroids
with TB pericarditis are treated with Category I daily treat­ are recommended for HIV-seronegative [conditional, low
ment for six months. quality evidence] and HIV-seropositive patients [conditional,
low-quality evidence] with TB pericarditis with pericardial
Role of Adjuvant Corticosteroid Treatment effusion.
In small controlled clinical trials, the addition of prednio­
solone to anti-TB treatment has been shown to reduce Pericardiocentesis and Pericardiectomy
mortality and the need for repeated pericardiocentesis Pericardiocentesis is life-saving in patients with cardiac
in patients with TB pericarditis and effusion (5,16). The tamponade and also provides an opportunity to confirm the
effectiveness of adjunctive corticosteroids in patients with aetiology of the pericardial effusion. This can be performed
TB pericarditis is now well justified (56). percutaneously and by open surgical drainage. The latter
In a double-blind study, addition of prednisolone, as method abolishes the need for repeat pericardiocentesis
an adjuvant to six months of anti-TB treatment, in patients but does not reduce subsequent mortality or need for
of active TB constrictive pericarditis (5) increased the pericardiectomy (16). Furthermore, open surgical drain­
rate of clinical improvement, reduced the risk of death age requires general anaesthesia unlike percutaneously
from pericarditis and the need of pericardiectomy was performed procedure, but provides an opportunity to
compared to placebo. It was associated with a higher obtain pericardial tissue for histopathological examination.
proportion of patients with an overall favourable status. In Reuter et al (60) from South Africa studied 233 patients with
a subsequent randomised controlled trial with a factorial TB pericardial effusion and reported that these patients
design by the same group (16), [i] immediate, complete, open responded well to closed pericardiocentesis and a six-month
surgical drainage of pericardial fluid versus percutaneous anti-TB treatment.
pericardiocentesis as required; and [ii] predniosolone versus Chronic constrictive pericarditis requires pericardiec­
placebo, double-blind, as a supplement to six months of anti- tomy, which is preferably avoided in the subacute stage
TB treatment were compared. The authors reported that open when a plane of cleavage has not clearly developed (61).
drainage eliminated the need for repeat pericardio­centesis, However, pericardiectomy can be done after two to four
though it did not reduce subsequent constriction. They also weeks of chemotherapy and should not be unduly delayed,
observed that prednisolone reduced the risk of death from if indi­c ated. Various approaches to peri­c ardiectomy,
 262 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

B C

D E
Figure 18.16: Tuberculosis effusive-constrictive pericarditis. Chest radiograph [postero-anterior view] showing cardiomegaly [A]. CT of the chest
of the same patient [mediastinal window] showing pericardial effusion along with well-defined pericardial thickening [arrows], left-sided pleural
effusion [arrow head] [B] and media­stinal lymphadenopathy [arrow] [C]. The lymph nodes show the characteristic peripheral rim enhancement
with central attenuation. Repeat CT after completion of antituberculosis treatment showing significant regression in pericardial effusion and
thickening [D] and mediastinal lymphadenopathy [E]

i.e. median sternotomy, lateral thoracotomy, bilateral mortality of pericardiectomy is still high, especially in
thoracotomy, with or without use of cardiopulmonary patients with calcification, in whom it was reported as
bypass; and anterior or total removal of pericardium 19% in a recent series (62). Other adverse predictors of
have been described depending on patient population or outcome are long-standing disease, baseline poor functional
personal surgeon preferences. Cardiopulmonary bypass is class, low-voltage ECG complex, significantly increased
needed for more difficult cases with extensive calcification, atrial pressure, associated organ failure and myocardial
coronary involvement or large vessel involvement. Surgical involvement.
 Tuberculosis and Heart 263

A B C F

G H J
Figure 18.17: 18F FDG PET-CT, maximum intensity projection image [A] showing sites of abnormal 18F FDG accumulation in the mediastinum.
Coronal NCCT [B] reveals multiple paratracheal, subcarinal and right hilar lymph nodes which show FDG accumulation on fused coronal
PET-CT [C]. Transaxial fused PET-CT [D] showing tracer accumulation in right supraclavicular node [arrow], transaxial NCCT [E] showing
pericardial effusion [arrow] and transaxial fused PET-CT [F] reveals tracer uptake in the pericardial attachment [arrow]. 18F FDG PET-CT,
maximum intensity projection image [G] of the same patient at six months of anti-TB treatment, showing sites of abnormal 18F FDG accumulation
in the mediastinum. Fused coronal PET-CT [H] showing paratracheal and right hilar lymph nodes which show FDG accumulation [C]. Transaxial
fused PET-CT [I] showing tracer accumulation in right supraclavicular node [arrow], Transaxial fused PET-CT [J] showing tracer accumulation in
subcarinal node [arrow]. Significant resolution of pericardial effusion is evident
PET-CT = positron emission tomography-computed tomography; FDG = fluorodeoxyglucose; TB = tuberculosis

CARDIAC TUBERCULOSIS
submitral or left ventricular anterior wall (66). Occasionally,
Myocardial TB is very rare (63,64). However with improving a lymphocytic myocarditis without demonstration of Mtb has
imaging techniques, it is being detected with increasing been described in patients with TB (63). Rare case reports
frequency. In patients with diffuse cardiac TB, myocardial of TB endocarditis have also been reported (67). Coronary
involvement occurs but is overshadowed by the diffuse arteritis from TB occurs infrequently in patients with TB
involvement. Nodular myocardial TB can, sometimes, pericarditis (68).
produce a tumour-like granulomatous mass which may Myocardial TB is also an under-recognised aetiological
involve any of the cardiac chambers and multiple chambers cause in patients presenting with idiopathic venricular
at times (65) [Figure 18.19]. Most of these masses respond tachycardia [VT] or unexplained ventricular dysfunction (69).
well to anti-TB treatment and may completely disappear These patients may not have constitutional symptoms;
without need for surgical excision. TB involvement with associated intrathoracic lymphadenopathy with or
caseation necrosis of myocardium may cause aneurysm in without peripheral lymphadenopathy is often present.
 264 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Cardiac MRI and PET-CT are helpful in disease localisation.

Image-guided lymph node sampling and diagnostic
testing has been found to be helpful in confirming the
diagnosis (69). The condition responds well to standard
anti-TB treatment.

TAKAYASU’S ARTERITIS
Takayasu’s arteritis, also referred to as non-specific
aorto­a rteritis, is an inflammatory disease involving
aorta and its large branches and pulmonary arteries
[Figure 18.20]. The disease occurs more commonly in
Asia, Africa, Mexico and South America. The role of Mtb
in aetiopathogenesis of Takayasu’s arteritis has been the
subject of debate for a long time. As many as one-third
of patients with Takayasu’s arteritis have associated
past or present TB and a large number of patients have
a strongly positive tuberculin skin test. Evidence of
Figure 18.18: LV and RV pressure tracing at paper speed of 100 mm/s mycobacterial involvement has also emerged from recent
and 100 mmHg gain [each small square = 5 mmHg]. Early [thick arrow] cytochemical and serological studies (70). There is no
and late [thin arrow] diastolic pressures of the two ventricles are similar consensus regarding the role of anti-TB treatment in patients
[30 mmHg] and markedly elevated. Right ventricular systolic pressure
is also elevated to 60 to 65 mmHg
with Takayasu’s arteritis. However, patients with evidence
LV = left ventricular pressure tracing; RV = right ventricular pressure of active TB should be treated with anti-TB treatment and
tracing corticosteroids.

A B

C D E
Figure 18.19: Cardiac MRI, axial T1-weighted images [A and B] showing isointense masses [arrows] along the anterior right atrium [*], right
ventricular outflow tract [#], and along both ventricles [+ indicates left ventricle]. Short-axis T2-weighted image [C] showing that the lesions are
mildly hyperintense. Steady state free precession image [D] revealing the infiltrative nature of the lesion along the left ventricle. The delayed
enhanced short-axis image [E] shows heterogeneous enhancement of the mass
MRI = magnetic resonance imaging
Reproduced with permission from “Gulati GS, Kothari SS. Diffuse infiltrative cardiac tuberculosis. Ann Pediatr Cardiol 2011;4:87-9” (reference 65)
 Tuberculosis and Heart 265

4. Das PB, Gupta, Sukumar IP, Cherian G, John S. Pericardiectomy:

indications and results. J Thoracic Cardiovasc Surg 1973;66:58-70.
5. Strang JI, Kakaz HH, Gibson DG, Girling DJ, Nunn AJ, Fox W.
Controlled trial of prednisolone as adjuvant in treatment of
tuberculous constrictive pericarditis in Transkei. Lancet 1987;2:
1418-22.
6. Bruch C, Schmermund A, Dagres N, Bartel T, Caspari G, Sack S,
et al. Changes in QRS voltage in cardiac tamponade and
pericardial effusion: reversibility after pericardiocentesis and
after anti-inflammatory drug treatment. J Am Coll Cardiol 2001;
38:219-26.
7. Zayas R, Anguita M, Torres F, Gimenez D, Bergillos F, Ruiz M,
et al. Incidence of specific etiology and role of methods for
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Cardiol 1995;75:378-82.
8. Oliver Navarrete C, Marin Ortuno F, Pineda Rocamora J, Lujan
Martinez J, Garcia Fernandez A, Climent Paya VE, et al. Should
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Rev Esp Cardiol 2002;55:493-8.
A 9. Ling LH, Oh JK, Schaff HV, Danielson GK, Mahoney DW,
Seward JB, et al. Constrictive pericarditis in the modern era:
evolving clinical spectrum and impact on outcome after
pericardiectomy. Circulation 1999;100:1380-6.
10. Oh KY, Shimizu M, Edwards WD, Tazelaar HD, Danielson GK.
Surgical pathology of the parietal pericardium: a study of
344 cases [1993-1999]. Cardiovasc Pathol 2001;10:157-68.
11. Larrieu AJ, Tyers GF, Williams EH, Derrick JR. Recent experience
with tuberculous pericarditis. Ann Thorac Surg 1980;29:464-8.
12. Meguire J, Kotte JH, Helm RA. Acute pericarditis. Medicine
1937; 9:425-42.
13. Harvey AM, Whitehill MR. Tubercular pericarditis. Medicine
1937;16:45-94.
14. Myers TM, Hamburger M. Tubercular pericarditis; its treatment
with streptomycin and some observation on natural history of
disease. Am J Med 1952;12:302-10.
15. Desai HN. Tubercular pericarditis. A review of 100 cases. S Afr
Med J 1979;55:877-80.
16. Strang JI, Kakaza HH, Gibson DG, Allen BW, Mitchison DA,
Evans DJ, et al. Controlled clinical trial of complete open surgical
drainage and of prednisolone in treatment of tuberculous
pericardial effusion in Transkei. Lancet 1988;332:759-64.
17. Hakim J, Ternouth I, Mushangi E, Siziyha S, Robertson V,
Malin A. Double blind randomised placebo controlled trial of
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Figure 18.20: Non-specific aortoarteritis. CECT chest, axial view
18. Fewell JW, Cohen RV, Miller. Tubercular pericarditis. In: Cortes
[A] showing aortic wall involvement [arrow head], subcarinal lympha­
FM, editor. The pericardium and its disorders. Springfield:
denopathy [thick arrow] and left sided pleural effusion [thin arrow].
Charles C Thomas; 1971.p.140.
Volume rendered CT angiography image showing irregular aortic wall
19. Suwan PK, Potjalongsilp S. Predictors of constrictive pericarditis
and left subclavian artery [arrow] [B], bilateral renal artery stenosis
[yellow arrows] [C] after tubercuous pericarditis. Br. Heart J 1995;73:187-9.
CECT = contrast-enhanced computed tomography 20. Sheffield EA. The pathology of tuberculosis. In: Davis PDO,
editor. Clinical tuberculous. London: Chapman and Hall Medical;
1994:p.44-54.
ACKNOWLEDGEMENTS 21. Delacroix I, Thomas F, Godart J, Ravaud Y. Purulent tuberculous
pericarditis with cardiac tamponade. Am J Med 1992;93:105.
Kind help rendered by Dr C Narasimhan, CARE Hospital, 22. Oribals DW, Avioli LV. Tuberculous pericarditis. Arch Intern
Hyderabad and Dr Madhavi Tripathi, Department of Nuclear Med 1979;139:231-4.
Medicine, All India Institute of Medical Sciences, New Delhi, 23. Talwar JR, Bhatia ML. Constrictive pericarditis. In Ahuja MMS,
in providing Figures is thankfully acknowledged. editor. Progress in clinical medicine in India. New Delhi: Arnold-
Heinemann; 1981.p.177-89.
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3. Bashi VV, John S, Ravikumar E, Sukumar IP, Shyamsunder K, 26. Spodick DH. Acute, clinically noneffusive [“dry”] pericarditis.
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27. Komsuoglu B, Goldeli O, Kulan K, Komsuoglu SS. The diagnostic 48. Voelkel AG, Pietro DA, Folland ED, Fisher ML, Parisi AF. Echo­
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28. Yang CC, Lee MH, Liu JW, Leu HS. Diasgnosis of tuberculous 49. Hatle LK, Appleton CP, Popp RL. Differentiation of constrictive
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Immunol Infect 2005;38:47-52. 50. Glockner JF. Imaging of pericardial disease. Magn Reson Imaging
29. Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing Clin North Am 2003;11:149-62.
tuberculous pericarditis. QJM 2006;99:827-39. 51. Masui T, Finck S, Higgins CB. Constrictive pericarditis and
30. Hancock EW. On the elastic and rigid forms of constrictive restrictive cardiomyopathy: evaluation with MR imaging.
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31. Myers RB, Spodick DH. Constrictive pericarditis: Clinical and 52. Vaikus PT, Kussmaul WG. Constrictive pericarditis versus
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32. Mantri RR, Radhakrishnan S, Sinha N, Goel PK, Bajaj R, nostic criteria. Am Heart J 1991;122:1431-41.
Bidwai PS. Atrio-ventricular regurgitations in constrictive peri­ 53. Hurrell DG, Nishimura RA, Higano ST, Appleton CP,
carditis: incidence and postoperative outcome. Int J Cardiol Danielson GK, Holmes DR Jr, et al. Value of dynamic respiratory
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care centre in India. Eur Respir J 2014;44:1090-3. 59. Mayosi BM, Ntsekhe M, Bosch J, Pandie S, Jung H, Gumedze F,
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 19
Skeletal Tuberculosis
S Bhan, HL Nag

INTRODUCTION and formation of tubercles and fibrin deposits. Caseation

necrosis of the synovium and the joint capsule is rare. When
Existence of “tuberculosis [TB]-like” disease has been known
a destructive caseating lesion of the bone penetrates into the
since time immemorial. Evidence of osteoarticular TB has
joint, the synovium too gets affected. Two classical forms
been found in pre-historic humans (1). In immunocompetent
of the disease have been described: granular and exudative
individuals, the osteoarticular involvement occurs in 10% of
[caseous]. Though both the patterns have been observed in
patients with extra-pulmonary TB [EPTB] (2). Commonly, TB
patients with skeletal TB, one form may predominate.
affects the spine and the hip joint; other sites of involvement
include knee joint, foot bones, elbow joint and hand bones;
rarely, it also affects shoulder joint (3-5). Osseous Granular Type
In the osseous granular type, the bone involvement occurs at
SKELETAL TUBERCULOSIS metaphysis or epiphysis often following trauma. The onset is
insidious. Hydrarthrosis of the adjacent joint is non-specific
Skeletal TB occurs due to haematogenous spread and affects
and appears following exertion. Constitutional symptoms
almost all bones. The disease process can start either in the
bone or in the synovial membrane. Thereafter, it spreads to are rare. Overlying soft tissues are slightly warm and tender.
other structures in a short time. Typically, an active focus Muscle atrophy appears rapidly.
forms in the metaphysis [in children] or epiphysis [in adults]
and the inflammation extends peripherally along the shaft Osseous Exudative [Caseating] Type
to reach the sub-periosteal space. The inflammatory exudate Onset of the osseous exudative [caseating] type is more
may extend outwards through the soft tissues to form rapid. Constitutional symptoms, muscle pain and spasm are
cold abscess and sinuses. Frequently, secondary infection more marked. The overlying soft tissues are warm, swollen,
occurs through the sinus tract. The epiphy­seal plate is not indurated and tender. When the caseous material penetrates
destroyed as the cartilage is resistant to destruction by the TB into the joint, a severe destructive arthritis ensues.
inflammatory process. The granulation tissue can, however,
invade the area of calcified cartilage and interfere with Synovial Granular Type
longitudinal growth. Metaphyseal infection reaches the joint
through sub-periosteal space by penetrating the capsular The synovial granular type is characterised by intermittent
attachment. In adults, the inflammation can spread up to the joint effusion with little or no pain. Later, joint effusion occurs
subchondral area and enter the joint at the periphery where more frequently and becomes persistent. Constitutional
synovium joins the cartilage. Destruction of the subchondral symptoms are mild and muscle atrophy gradually sets in.
bone loosens the attachments of the articular cartilage which This form of syno­vitis can continue for a long time without
may become displaced in the joint. involving the bone. Rarely, the synovial granular form
Sometimes the synovium may be infected first and the may get converted into caseous form and the patient
bone becomes infected secondarily. Usually, there is a low- may experience increase in the local and constitutional
grade synovial infection with moderate increase in joint fluid symptoms.
268 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Synovial Exudative [Caseous] Type Formation of Cold Abscess

The synovial exudative [caseous] type has an acute onset Vertebral TB develops as an exudative lesion due to hyper­
with marked local and constitutional symp­toms. Overlying sensitivity reaction to Mycobacterium tuberculosis [Mtb]. The
soft tissues are very tender. The joint movements are painful exudate consists of serum, leucocytes, caseous material,
and regional lymph nodes are enlarged. Abscess and sinus bone fragments and tubercle bacilli. It penetrates ligaments
formation are common. and follows the path of least resistance along fascial planes,
blood vessels and nerves, to distant sites from the original
Prognosis bony lesion and forms a swelling commonly called as
“cold abscess”.
The availability of modern anti-TB drugs has changed the In the cervical region, the exudate collects behind pre­
outlook of patients with bone and joint TB. In the granular vertebral fascia and may protrude forward as a retropharyn­
form of disease, healing is possible without residual joint geal abscess. The abscess may track down in mediastinum
scarring and ankylosis. Effective anti-TB treatment com­bined to enter into the trachea, oesophagus or the pleural cavity.
with resection of large caseous destructive foci ensures early It may spread laterally into the sternomastoid muscle and
healing and prevents the spread of infection into joint and form an abscess in the neck.
soft tissues. In recent years, the occurrence of multidrug- In the thoracic spine, the exudate may remain confined
resistant and extensively drug-resistant TB have, however, locally for a long time and may appear in the radiographs
become a matter of concern. as a fusiform or bulbous paraver­tebral abscess. Tension may
force the exudate to enter into the spinal canal and compress
SPINAL TUBERCULOSIS the spinal cord. Rarely, a thoracic cold abscess may follow
Spinal TB is the most common form of skeletal involvement. the intercostal nerve to appear anywhere along the course of
nerve. It can also penetrate the anterior longitudinal ligament
Pathology of Spinal Tuberculosis to form a mediastinal abscess or pass downwards through
medial arcuate ligament to form a lumbar abscess.
Infection of Bone The exudate formed at lumbar vertebrae most com­monly
Lower thoracic and lumbar vertebrae are the most common enters the psoas sheath to manifest radio­logi­cally as a psoas
sites for spinal TB followed by middle thoracic and cervical abscess or clinically as a palpable abscess in the iliac fossa.
Abscess can gravitate beneath the inguinal ligament to
vertebrae. Usually, two contiguous vertebrae are involved,
appear on the medial aspect of thigh. It can spread laterally
but several vertebrae can be affected and skip lesions may
beneath the iliac fascia to emerge at the iliac crest near the
also be seen. The infection begins in the cancellous area
anterior superior iliac spine. Sometimes an abscess forms
of vertebral body commonly in epiphyseal location and
above the iliac crest posteriorly. Collection can follow the
less commonly in the central or anterior area of vertebral
vessels to form an abscess in Scarpa’s triangle or gluteal
body. TB infection produces an exuda­tive reaction with
region if it follows femoral or gluteal vessels, respectively.
marked hyperaemia. The infection spreads and destroys the
epiphyseal cortex, the intervertebral disc and the adjacent
vertebrae. It may spread beneath the anterior longitudinal
Paraplegia
liga­ment to reach neighbouring vertebrae. The vertebral While neurological complications of spinal TB are rarely
body becomes soft and gets easily compressed to pro­ encountered in developed countries, their incidence remains
duce either wedging or total collapse. Anterior wedging quite high in the developing world. Paraplegia is the most
is commonly seen in the thoracic spine where the normal serious complication of spinal TB and its occurrence is
kyphotic curve accentuates the pressure on the anterior part reported to be as high as 30% in patients with spinal TB (6,7).
of vertebrae. In the cervical and lumbar spine, the centre Neurological involvement is common when the dorsal spine
of gravity is posteriorly located due to lordotic curve, and is involved because [i] diameter and space of the spinal canal
therefore, wedging is minimal. are smallest in the dorsal region; [ii] the abscess remains
A single large caseating lesion of the vertebral body confined under tension and is thereby forced into the spinal
is rare. This type of lesion remains isolated and calcifies canal; [iii] TB infection is common in this area; and [iv] the
centrally, appearing as a sequestrum. In this form, mechanical spinal cord terminates below the first lumbar vertebra.
strength of vertebral body is reduced to lesser extent and Paraplegia due to spinal TB has been known for a very
deformity may not occur. Adjacent intervertebral disc is long time. It is also known as Pott’s paraplegia. It can be of
affected gradually. early or late onset (8-11). Early onset paraplegia develops
TB infection starting in the posterior bony arch and during the active phase of infection. Paraplegia of late
transverse processes is uncommon. With healing, exudate onset can appear many years after the disease has become
is resorbed, osteoporosis decreases and density of body quiescent even without any evidence of reac­ti­vation. Most
gradually increases to normal. When the intervertebral discs commonly paraplegia develops due to mechanical pressure
have been completely destroyed, the adjacent bodies fuse on the cord, but in a small number of patients, it may occur
with each other. due to non-mechanical causes as well. The mechanisms
 Skeletal Tuberculosis 269

Table 19.1: Mechanisms underlying the development head may be held with hands. Muscle spasm obliterates
of Pott’s paraplegia normal spinal curves and all spinal movements become
restricted and painful. Careful palpation, percussion or
Extrinsic or mechanical causes
During active disease
pressure will reveal tenderness over the affected vertebrae.
Cold abscess [fluid or caseous material] Sometimes a boggy, dusky thickening of skin may be seen
Granulation tissue over the affected area. In patients presenting late, when
Sequestrated bone and disc fragments vertebral wedging and collapse have occurred, a localised
Pathological subluxation or dislocation of vertebra knuckle kyphosis becomes quite obvious especially in
Following healing of lesions the dorsal spine. Occasionally, patients with dorsal spine
Pressure of ridge of bone anterior to cord
Fibrosis of dura mater involvement present very late with an extensive destruction
Gliosis of cord of multiple vertebrae. These patients have deformity of
Intrinsic or non-mechanical causes thoracic cage with a large gibbus.
Spread of tuberculosis inflammation through the dura to
meninges and eventually to the spinal cord
Rare causes
Cold Abscess
Spinal tumour syndrome Local pressure effects such as dysphagia, dyspnoea, or
Thrombosis of anterior spinal artery
hoarseness of voice may occur due to a retro­pharyngeal
Adapted from reference 11 abscess. Further, dysphagia may also occur due to a
mediastinal abscess. Flexion deformity of the hip develops
due to a psoas abscess. The abscesses may be visible and
palpable if they are superficially located. Therefore, in
underlying the development of Pott’s para­plegia are listed in
addition to the physical examination of the bony lesion, a
Table 19.1. Frequently, more than one of these mechanisms
careful search for the presence of cold abscess in the neck,
may be operative in a given patient.
chest wall, groin, inguinal areas and thighs can be rewarding.
The fact that paraplegia can sometimes recover even after
many years suggests that the inflammatory exudate and the
resultant oedema may temporarily inhibit the nerve cell Paraplegia
function (12). In most cases, early onset paraplegia results Rarely, paraplegia may be the presenting symptom. But,
from cord compression due to multiple causes and these in a majority of cases, the diagnosis of TB of the spine is
include inflammatory oedema, caseous material, TB pus and already established when paraplegia develops. Spontaneous
the granulation tissue. Recovery in these cases is favour­able. twitching of muscles in lower limbs and clumsiness in walking
Late onset paraplegia occurs due to long-standing persistent due to muscle weakness and spasticity are the earliest signs
mechanical causes. These include internal gibbus, severe of neurological involvement. With passage of time, paralysis
kyphotic deformity, dural fibrosis and stenosis of spinal progresses through various stages. These include muscle
canal. Prognosis in these cases is much less favou­rable (13). weakness, spasticity, incoordination, difficulty in walking
and paraplegia in extension. Subsequently, paraplegia in
Clinical Features flexion, sensory loss and loss of sphincteric control occur.
Spinal TB, once a disease of children and adolescents, is Exaggerated deep tendon reflexes, clonus, and extensor plan­
now often seen in the adults. Majority of patients are under tar reflex can be elicited. Anteriorly located motor tracts in
30 years of age at the time of diagnosis. Constitutional the spinal cord are in close proximity to the disease process
symptoms, such as, weakness, loss of appetite and weight, and are sensitive to pressure effect. Therefore, the motor
evening rise of temperature and night sweats gene­rally occur functions are affected first due to the cord compression.
before the symptoms related to the spine manifest. Increasing compression of cord pro­duces uncontrol­led flexor
spasms. In later stages, limbs remain in flexion [paraplegia
in flexion] with complete loss of conduction in pyramidal
Vertebral Disease
and extra-pyramidal tracts. In very advanced cases of cord
A young child may be disinclined to play and may not compres­sion, varying degrees of sensory deficit and loss
complain of anything else. Localised pain over the site of bladder and sphincter control occur. The sense of posi­
of involvement is the most common early symptom and tion and vibration is the last to disappear. In severe cases,
the pain may worsen with activity or unguarded move­ spasticity disappears and flaccid paralysis, sensory loss and
ments. Pain may be referred along the spinal nerves to loss of sphincter control [areflexic paraplegia] can develop.
be misdiagnosed as neuralgia, sciatica or intra-abdominal Rarely, the cord compression may be so sudden and
pathology. As the infection progresses, pain increases and complete that the patient presents with sudden onset of
paraspinal muscle spasm occurs. Relaxation of muscles flaccid paralysis simulating the picture of spinal shock.
during sleep permits painful movements which may cause This may occur due to rapid accumu­­lation of TB pus and
the child to cry during night [night cries]. caseation, pathological dislo­cation of vertebra and ischaemia
Patient walks carefully to avoid sudden jerks which can of cord due to thromboembolic phenomenon. Rarely,
exacerbate the pain. With the involvement of cervical spine, presenting features may simulate the features of spinal
 270 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

tumour syndrome. These features occur due to localised the disease process per se, but due to the pressure effect of
tuberculoma, granuloma or peridural fibrosis produc­ing the paravertebral cold abscess.
partial or complete block without any pathology being Radiologically, paradiscal infection first appears as
visible on radiographs. Such cases should be differentiated demineralisation with indistinct bony margins adjoining
from lathyrism in endemic areas since lathyrism also the disc [Figure 19.1]. Gradually, the disc space narrows
presents as pure motor paraplegia of insidious onset. signifying either atrophy of disc tissue due to lack of
However, patients with lathyrism will not reveal block to nutrition, or, prolapse of nucleus into the soft necrotic
cerebrospinal fluid flow on lumbar puncture, myelography vertebral body. The disc space may even­tually disappear
and magnetic resonance imaging [MRI]. and vertebral bodies reveal an enlarging area of destruction
Clinically, the severity of paraplegia has been classified and wedging. Rarely, disc space may remain intact for a
into four grades (14-16). long time. It takes about three to five months for the bony
des­truc­tion to become visible on a radiograph. More than
Grade I Negligible paraplegia The patient is unaware of
30% of mineral must be removed from the bone for a
the neurological deficit but examination reveals clonus and
radiolucent lesion to be discernable on the plain radiograph.
extensor plantar response.
Compu­ted tomography [CT] and MRI allow identification
Grade II Mild paraplegia The patient is aware of weakness of bony lesions including prever­te­bral and paravertebral
and difficulty in walking but manages to walk with or abscess shadows at an early stage [Figures 19.2, 19.3,
without support. and 19.4]. Abscess in the cervical region presents as a soft
Grade III Moderate paraplegia The patient is bedridden
and cannot walk due to severe weakness. Examination
reveals para­plegia in extension and sensory deficit if present
is less than 50%.
Grade IV Severe paraplegia Features of grade III with flexor
spasm/paralysis in flexion/flaccid para­lysis and sensory
deficit of more than 50%.
The higher the grade of paralysis, more severe is the com­
pression of cord and poorer is the prognosis for recovery of
neurological deficit.

Radiographic Features
On an average, involvement of 2.5 to 3.8 vertebrae has been
described (14-19). There are mainly four sites of infection in
the vertebra: paradiscal, central, anterior and appendicial.
The most common site of vertebral involvement is paradiscal.
The appendicial type includes the involvement of pedicle,
Figure 19.1: Plain radiograph of the lumbosacral spine [lateral view]
lamina, spinous process and transverse process. Nearly 7% showing early changes of paradiscal involvement of L2 and L3
of patients may show skipped lesions (17-19). Some of the vertebrae, indistinct bony margins of adjacent vertebrae along with loss
vertebral bodies may become eroded not necessarily due to of disc space [arrow]

A B C
Figure 19.2: Chest radiograph [postero-anterior view] [A] showing left-sided empyema [arrow]. CECT of the chest [sagittal reconstruction] [B] and
[C] showing destruction of vertebral body [black arrow], paraspinal cold abscess [white arrow] and left-sided empyema [asterisk]
CECT = contrast-enhanced computed tomography
 Skeletal Tuberculosis 271

A B
Figure 19.3: Plain radiograph of the dorsolumbar spine [antero- Figure 19.4: CECT of the lower abdomen showing hypodense
posterior view] [A] showing the involvement of D10 and D11 vertebrae, collections [asterisks] in bilateral psoas muscles [bigger on the left side]
narrowing of intervening disc and paravertebral abscess [arrows]. CT in a patient with disseminated tuberculosis. The adjacent vertebral
of the dorsal spine [B] showing bilateral psoas abscesses [arrows] body appears normal
CT = computed tomography CECT = contrast-enhanced computed tomography

tissue shadow between the vertebral bodies, pharynx and

trachea. Early detec­tion of an abscess in the area of seventh
cervical to fourth dorsal vertebrae requires a good quality
radio­graph. Abscess in the dorsal spine area produces a
typical fusiform shape [bird-nest appearance] and a large
abscess in this region may appear as mediastinal widening.
An abscess arising below the attachment of diaphragm forms
a psoas abscess and in a good quality radiograph appears
as a bulge of the lateral border of the psoas muscle shadow.
A long-standing, tense paravertebral abscess [usually in
the dorsal spine] may produce concave erosions along the
margin of verte­bral bodies [aneurysmal phenomenon]. Canal
com­pro­mise and cord status are best demonstrated by CT
or MRI [Figures 19.5 and 19.6].
Central type lesion starts in the centre of the vertebral Figure 19.5: CT [transverse section through the body of C7 vertebra]
body. Infection at this site probably reaches through Batson’s showing its destruction and anterior compromise of canal by bony
venous plexus or through branches of posterior vertebral fragments [arrow]
artery. A lytic area develops in the centre of the vertebral CT = computed tomography
body and may gradually enlarge resulting in the ballooning
out of the vertebral body mimicking a tumour. In the later
stages of advanced destruction, a concentric collapse occurs of disease, the erosive bony lesions of posterior elements
almost resembling vertebra plana. In this type of lesion, can be seen in the radiographs. However, CT or MRI is
the disc space is either not affected or affected minimally invaluable in detecting these lesions at an early stage.
and paravertebral shadow is also usually not well-marked. Paravertebral abscess shadow may be present but the disc
Therefore, this type of lesion should be differentiated from space remains intact. Sometimes more than one lesion
a tumour or Calve’s disease. may be present in vertebral column with one or more
Anterior type lesion occurs when the infection starts in healthy vertebrae intervening between the diseased vertebrae
front or on sides of the vertebral body beneath the ante­rior [called “skip lesions”].
longitudinal ligament and periosteum. Radio­logically, it is In late stages, anterior wedging or vertebral collapse
seen as a shallow excavation on anterior or lateral surface results in the development of kyphotic deformity. Sometimes
of vertebral body. Similar excavations will also appear due this deformity can be very severe. Destruction of vertebral
to the aneurysmal pheno­menon in patients with paradiscal body on one side can produce lateral deviation and rotation
type of lesion and a long-standing, tense, paravertebral similar to that seen in patients with hemivertebra, especially
abscess. when the disease affects the lower dorsal and lumbar spine
TB of the posterior elements of vertebra is not detected [Figure 19.7]. On very rare occasions, a vertebral body may
in its early stage in the plain radiographs. In the late stage dislocate anteriorly due to destruction of the pedicles.
 272 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B C
Figure 19.6: MRI of the dorsolumbar spine. Sagittal view showing profound destruction of D10 and D11 vertebrae with anterior compression of
the cord [arrow] [A]. Sagittal spin-echo T1-weighted image showing hypointense L1 and L2 vertebral bodies, intervening disc and an epidural
soft tissue component at L1 level [arrow] [B]. The bodies of L1 and L2 vertebrae and epidural soft tissues are brightly enhanced in T2-weighted
image [arrow] [C]
MRI = magnetic resonance imaging

all contiguous affected vertebrae is then added together to

get the value of ‘x’.

Differential Diagnosis
Usually, clinical presentation and radiological findings
of spinal TB are characteristic. However, in doubtful
cases, clinical examination and radiological investigations
including CT or MRI will help in making an accurate
diagnosis. In a very small percentage of cases, biopsy of the
diseased vertebra for histopathological and microbiological
exami­­nations may be required to confirm the diagnosis.
Cartridge-based nucleic acid amplification tests [CBNAAT]
are increasingly being used for the diagnosis of bone and
joint TB (20b). In a recently published systematic review (20b)
Figure 19.7: Plain radiograph of the lumbosacral spine [antero-posterior Xpert MTB/RIF was found to have a high pooled sensitivity
view] showing mild scoliotic chage due to the relative destruction of one [97.2%] and specificity [90.2%] in bone and joint fluid. The
side of vertebra involving L2 and L3 levels [arrows] sensitivity and specificity of Xpert MTB/RIF in bone and
joint tissue were found to be 94.6% and 85.3% respectively.
The severity of a gibbus can be predicted with 90% However, some conditions [Table 19.2] may mimic TB of
accuracy using the following formula (20a): the spine and these conditions need to be differentiated
y = a + bx where: from spinal TB, especially in patients with atypical clinical
y = final angle of gibbus presentation.
a = constant with a value of 5.5
b = constant with a value of 30.5 Management
x = amount of initial loss of height of vertebral body
Anti-TB Treatment
Amount of initial loss of height of vertebral body is
calcu­lated as follows. Height of vertebral body on lateral Anti-TB treatment for skeletal TB is essentially the same as
radiograph is divided into 10 equal parts. Loss of height of for TB elsewhere in the body. However, there is a difference
 Skeletal Tuberculosis 273

Table 19.2: Conditions resembling spinal tuberculosis Table 19.3: Indications for surgery in patients with
Developmental defects like hemivertebra, Calve’s disease, spinal tuberculosis regardless of paraplegia
Schmorl’s nodes and Scheuermann’s disease Doubtful diagnosis where open biopsy is necessary
Infections like pyogenic osteomyelitis, enteric fever, brucel­losis, Failure to respond to antituberculosis drugs
mycotic infections and syphilis Radiological evidence of progression of bony lesion and/or
Benign neoplasms like haemangioma, aneurysmal bone cyst, giant paraspinal abscess shadow
cell tumour Imminent vertebral collapse
Primary malignant tumours like Ewing’s tumour, chor­doma, Prevention of severe kyphosis
osteosarcoma, fibrosarcoma, chondrosarcoma, multiple myeloma Instability of spine and subluxation or dislocation of vertebral body
and lymphoma
Secondary neoplastic deposits
be done. Ante­riorly placed grafts provide good stability
Langerhan’s cell histiocytosis
and heal well. An additional use of metallic implants and
Paget’s disease titanium cage filled with cancellous bone grafts may be
Traumatic fracture required when nearly whole of the vertebral body has been
Hydatid disease removed during debridement.
Surgical prevention of severe kyphotic deformity requires
extensive panvertebral operative procedures. These consist
of opinion regarding the duration of drug therapy. Though of anterior debridement, anterior interbody fusion and
many orthpaedicians favour 18-24 months of anti-TB posterior fusion of affected vertebrae (15,24). It has also been
treatment, short-course treatment for nine months has suggested that, a severe deformity in the presence of active
also been shown to be equally effective in patients with disease should be an absolute indication for debridement,
disease caused by drug-susceptible microorganisms in correction and stabilisation since late correction of TB
whom the diagnosis has been established early (21,22). As kyphosis is difficult and dangerous. Correction of a fixed
per the recently published evidence-based Guidelines for spinal curve and severe kyphosis is a formidable surgical
Extrapulmonary TB for India [INDEX-TB Guidelines] (23), undertaking and should only be done in selected patients
extended course of anti-TB treatment with a two-month inten­ by a specially trained surgeon (25).
sive phase consisting of four drugs [isoniazid, rifampicin, Formerly, posterior spinal fusion by the methods of
pyrazinamide, ethambutol], followed by a continuation Hibbs [fusion between laminae, articular facets and spinous
phase consisting of isoniazid, rifampicin and ethambutol processes] and Albee [fusion between spinous processes
lasting 10-16 months, depending on the site of disease and with tibial cortical graft] were frequently used. Fusion was
the patient’s clinical course has been advocated. successful because posterior elements were seldom involved
Direct observation of treatment, an integral component in disease process. However, by these interventions, pro­
of DOTS provided by the Revised National Tuberculosis gression of lesion in body was not affected. Posterior spinal
Control Programme [RNTCP] of Government of India, will fusion is now rarely used, except to reinforce an anterior
ensure compliance. Community DOT providers facilitate spinal fusion in regions of greatest stress at junctional areas
like cervicothoracic and dorsolumbar junctions; and for
administration of drugs in non-ambulatory patients. The
panvertebral fusion in children who are at risk of developing
reader is referred to the chapters “Treatment of tuberculosis”
severe kyphosis.
[Chapter 44] and “Revised National Tuberculosis Control
Programme” [Chapter 53] for details.
Cold Abscess
Antibiotics With anti-TB treatment, a small cold abscess will heal along
with the bony lesion. Tense and large cold abscesses are
Persistently draining sinuses are often secondarily infected usually located in the neck, chest wall, iliac fossa, lumbar
and therefore appropriate antibiotic[s] should be adminis­ triangle, inguinal region and thigh. These abscesses are
tered along with anti-TB treatment after culture and drug- frequently painful and tend to burst and form sinuses.
susceptibility testing. Therefore, these abscesses must be drained as early as
possible by the standard surgical approach which depends
Surgery on the location of the abscess. Most sur­geons do not use a
Efficacy of anti-TB treatment has significantly reduced the drain after evacuation of abscess for fear of sinus formation.
need for operative intervention. Indications for adjunct Paravertebral abscess need not be drained on its own but
surgery in patients with spinal TB lesions per se [regardless should be evacuated at the time of debridement of bony
lesion when indicated.
of paraplegia] are listed in Table 19.3.
Common operative procedures include anterolateral
decom­pression with interbody bone grafting or costotrans­ Paraplegia
versectomy with decomp­res­­sion. If a large gap is left behind Three schools of thought exist in the treatment of Pott’s
after debridement, ade­quate bone grafting must always paraplegia. One of the views is that immediate operative
274 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

decompression of the cord by extensive anterior debridement Treatment of paraplegia in severe kyphosis is by excising
results in maximum improve­ment in the shortest possible internal gibbus through antero-lateral approach or by
time (26). According to these workers, operation should anterior transposition of cord through laminectomy. Antero-
be performed at an earliest because they feel that the TB lateral decompression is a surgery of lesser magnitude
infection can penetrate into the dura mater and infect the compared to anterior decompression and is preferred in
cord making recovery impossible. This view recommends resource limited settings. Details of surgical techniques
early radical anterior debridement, decompression and are beyond the scope of this chapter. However, it must be
arthrodesis in all patients with Pott’s paraplegia except in pointed out that obtaining adequate surgical exposure of
patients with spinal tumour syndrome and those with para­ junctional areas of spine is difficult and this type of surgery
plegia resulting from posterior spinal disease. must be undertaken only by experienced and well-trained
The second view favours initial treatment with immo­ surgeons.
bilisation or complete bedrest. If this does not produce Laminectomy and intraspinal exposure must be deferred
improvement and recovery within a specified time period, if the neurological deficit is non-progressive or if the
then the surgical decompression of the spinal cord is radiographs are normal. Following decompression with or
performed (9,10,27-29). The widely accepted indications for without bone grafting, bedrest for a period of 10-12 weeks
surgical treatment are listed in Table 19.4. is indicated. Thereafter, the patient is gradually mobilised
The third view, proposes the “middle path regimen” (6) with a suitable brace.
Reactivation or reinfection may result in a relapse in
and advocates rest and anti-TB treatment for four weeks
a small percentage of cases and may be complicated by
and surgical decompression if there is no improvement in
neurological involvement. In such situations, early operation
the neurological deficit by this time. This regimen is useful
and administration of appropriate anti-TB treatment are
for developing countries with limited resources.
indicated.

Table 19.4: Indications for surgical treatment in TUBERCULOSIS OF HIP JOINT

patients with spinal tuberculosis and paraplegia TB of the hip joint occurs in about 15%-20% of all cases
Absolute indications of osteoarticular TB and is the next common form after
Onset of paraplegia during conservative treatment spinal TB.
Surgery is not performed for pyramidal tract signs but delayed till
motor weakness is evident Pathology
Paraplegia getting worse or remaining stationary despite adequate
conservative treatment TB of the hip joint almost always starts in bone and the
Persistence or complete loss of motor power for one month initial focus is in the acetabular roof [Figures 19.8 and 19.9],
despite sufficient conservative treatment femoral epiphysis, proximal femoral metaphysis or greater
Paraplegia accompanied by uncontrolled spasticity of such trochanter. Rarely, the initial focus may be in the synovial
severity that reasonable rest and immobilisation are impossible or membrane and the disease may remain as synovitis for a few
there is a risk of pressure necrosis of skin months. In these patients, the diagnosis may be considerably
Severe paraplegia of rapid onset. This usually indicates severe delayed. TB of the greater trochanter may involve the
mechanical pressure but may also be due to vascular thrombosis. overlying trochanteric bursa. Since the head and neck of
Surgery is not helpful when thrombosis causes paraplegia
Severe paraplegia, paraplegia in flexion, flaccid paraplegia,
complete sensory loss or complete loss of motor power for more
than six months. All these are indications for immediate surgery
without trial of conservative treatment
Relative indications
Recurrent paraplegia even with paraplegia that would cause no
concern in the first attack
Paraplegia with onset in old age to avoid hazards of
immobilisation
Painful paraplegia. Pain may be due to spasm or root
compression
Complications, such as, urinary tract infection and stones
Rare indications
Posterior spinal disease
Spinal tumour syndrome
Severe paralysis from cervical disease
Severe cauda equina paralysis
Figure 19.8: Plain radiograph of the hip joint showing lesions [arrows]
Adapted from references 28 and 29
at the acetabulum in a six-year-old boy at the beginning of treatment
 Skeletal Tuberculosis 275

A B
Figure 19.9: Plain radiograph of the hip joint showing early TB lesion at the acetabulum [circle] in a 34-year-old man which was missed initially
[A]. Same lesion, three months after starting anti-TB treatment [rectangle] [B]
TB = tuberculosis

femur are intracapsular, a bony lesion here invades the joint rheumatic disease, low-grade pyogenic infection, Perthes’
early and later spreads to involve the aceta­bulum as well. disease and spasm of iliopsoas muscle due to an abscess
When the disease starts in the acetabulum, symptoms related in its sheath or nearby inflammed lymph nodes. In such
to joint involvement appear late [Figure 19.10]. Extensive situations, clinical and radiological examinations must be
destruction may result in patho­logical dislocation of the hip repeated at two to three weeks intervals till a defini­tive
joint. A cold abscess forms in the joint, may perforate the diagnosis has been made.
capsule and extend anywhere around the hip joint. It may
per­forate the thinned acetabular floor to form an intra-pelvic Stage II: Stage of Early Arthritis
abscess.
As the capsule thickens by fibrosis and contracts, and
damage to the articular surface progresses, the hip joint
Clinical Features
assumes a position of flexion, adduction and internal
TB of the hip frequently affects the children. Constitutional rotation. Limb appears short but true shorte­ning may not
symptoms may precede the joint symptoms. Pain around be present and, if present, is not more than one centimetre.
the hip joint or along the thigh or inner aspect of the knee All movements of the hip joint remain painful and limited.
joint. parti­cularly on weight bearing, is usually the first
symptom. The patient limps while walking and avoids Stage III: Stage of Advanced Arthritis
weight bearing on the affected side. During the acute stage,
muscle spasm is severe. At night, relaxation of muscle The capsule becomes further destroyed, thickened and
spasm and unguarded move­ments produce “night cries”. contracted along with advanced bony destruction producing
All movements of the hip joint are painful and limited to true shortening of the limb. The joint movements become
a variable degree. As the acute stage subsides, pain and more restricted and the flexion, adduction, inter­nal rotation
muscle spasm become less severe and muscle atrophy deformity may become severe. With further destruc­tion
develops. of the acetabulum, femoral head, capsule and liga­ments,
Classical untreated TB of the hip joint passes through the the joint dislocates with the destroyed head coming to
following three clinico-pathological stages and each stage lie proximally and poste­riorly in wan­der­ing or migrating
has a definite pattern of clinical deformity. acetabulum. Instead of proximal migra­tion sometimes
protrusio acetabuli can develop with destruction of medial
Stage I: Stage of Synovitis wall of acetabulum.

The stage of synovitis is the earliest manifestation of disease. Radiographic Features

Intra-synovial effusion and exudate distend the joint capsule.
The hip joint assu­mes a position of flexion, abduction and In the earliest stage, radiographs may reveal diffuse
external rotation. During this stage, capacity of the hip decalcification of upper end of femur. Osteolytic bony focus
joint is maximum. Limb appears lengthened but there is of infection may be visible in the acetabulum or femur a
no real lengthening. This is the stage when the disease is little later and this lesion may be seen to be enlarging on
seldom diagnosed since similar physical findings are seen sequential radiographs. Soft tissue swelling may be evident
in traumatic synovitis, non-specific transient synovitis, on the radiograph, but ultra­sono­graphy is useful at this stage
 276 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Normal Type
The disease is mainly synovial. There may be cysts in the
femoral neck, head or acetabulum, but there is no gross
destruction of subchondral bone and the joint space is
normal.

Perthes’ Type
Most patients are under five years of age. The whole femoral
head is sclerotic and differentiation from Perthes’ disease can
be difficult though meta­physeal changes seen in the classical
Perthes’ disease are not seen.

Dislocating Type
A Subluxation or dislocation of the femoral head occurs. This is
mainly due to capsular laxity and synovial hyper­trophy
and not due to accumulation of pus. Results are better after
open relocation of the hip joint.

Wandering Acetabulum, Protrusio Acetabuli,

Mortar and Pestle Type
These appearances occur due to the erosion of subchondral
bone [Figure 19.12]. Results of surgery are generally poor in
these types of TB of the hip joint.

B Atrophic Type
The femoral head is irregular and the joint space is narrow.
It is seen almost exclusively in adults and the results
of treatment are poor and the condition almost always
progresses to fibrous ankylosis [Figure 19.13].
These radiographic appearances in general also cor­
respond to the duration of the disease before diagnosis. In
the normal Perthes’ dislocating and atrophic types, the mean
duration of symptoms varies from four to seven months.
In wandering acetabulum, protrusio acetabuli and mortar
and pestle types, the mean duration of symptoms is usually
longer, ranging from 10-14 months.

Management
C In patients with TB of the hip joint, the prognosis depends
on the stage of disease when treatment is initiated. Anti-TB
Figure 19.10: Plain radiograph of the hip joint of the patient shown in
Figure 19.9 showing increase in the size of the lesion [square] despite treatment started at stages I and II of disease may allow an
five months of anti-TB treatment [A]. Destruction of acetabulum and almost or near normal hip joint at the end [Figures 19.14
granulation tissues [arrows] are seen better in transverse section in and 19.15]. The deformities should also be corrected as
MRI [B]. Biopsy confirmed the diagnosis of TB. Radiograph at 13 early as possible, or else fibrous ankylosis in the position
months of treatment showing regression of lesion with extension into of deformity will occur. Neglected cases will eventually
the hip joint [square] limiting the movements [C]
have a markedly deformed hip joint and a short limb. The
TB = tuberculosis
shortening is partly due to gross bony destruction and
partly due to growth arrest at proxi­mal femoral epiphysis.
to confirm soft tissue swelling. Late stages of the disease Occasionally, if the limb has been immobilised for more than
will reveal increasing destruction of acetabulum, wandering one year, pre­ma­ture fusion of distal femoral epiphyseal plate
aceta­bulum, small atrophic femoral head, subluxation or can result in shortening.
dislocation. Seven different types of radiological appearances Anti-TB drugs should be administered in adequate
have been described in advanced stage of TB arthritis of hip dosages for a suffi­cient length of time along with supportive
joint (30) and are described below [Figure 19.11]. measures to improve the general health. Skin traction is
 Skeletal Tuberculosis 277

Figure 19.11: Different radiological types of the hip joint tuberculosis

A B
Figure 19.12: Plain radiograph of the hip joint showing the “protrusio Figure 19.13: Plain radiograph of the hip joint [antero-posterior view]
acetabuli” type of hip involvement showing marked atrophy of head and neck of femur [A]. Radiograph
of the hip joint [lateral view] of the same patient showing extensive
involvement of upper shaft of the femur [B]

usually required initially in all cases. Traction corrects permitted early, since chances of collapse and deformity of
deformity, relieves muscle spasm and pain. It also maintains acetabulum and femoral head may persist till bones have
joint space, minimises chances of development of migrating become fully calcified after control of infection. However,
acetabulum and prevents dislocation. In the presence of currently, early weight bearing is recommended depending
abduction deformity, traction should be applied to both on the pain tolerance by the patient, since this boosts the
limbs to stabilise the pelvis. Otherwise, traction to the patients’ confidence and activity level (31). Drainage of cold
defor­med limb alone would further increase the abduction abscess should be done without undue delay to prevent the
deformity. In stages I and II, a prolonged period of traction sinus formation.
[up to 12 weeks] may be required. Traction should be conti­ In patient with stage II disease, partial synovec­tomy
nued till disease activity is well-controlled, hip move­ments and curettage of large or enlarging osteolytic lesions in the
improve and become pain free and muscle spasm does not acetabulum [Figure 19.10] and femoral head should be done.
recur. Gentle hip mobilisation and sitting in bed for short At operation, the hip joint should not be dislocated in order
periods are started during the period of traction. For next to remove all TB tissue. After curettage, large lesions may
12 weeks, non-weight bearing walking is allowed with be filled with cancellous grafts. Curettage of extra-articular
crutches followed by another 12 weeks period of partial lesions prevents spread of infection in the joint if done
weight bearing. Unprotected weight bearing should not be early enough. Post-operatively, the regimen of traction,
 278 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 19.14: Plain radiograph of the hip joint [antero-posterior view] Figure 19.15: Plain radiograph the hip joint [antero-posterior view] of
showing good healing of the lesion involving superior portion of the patient shown in Figure 19.8, showing healed lesion [square] at
acetabulum following antituberculosis treatment completion of treatment. The patient recovered with a good function of
the hip joint

non-weight bearing mobilisation, partial weight bearing and of retaining a good range of movements; the patient can
then unprotected weight bearing are followed as described even squat and sit cross-legged Total hip arthroplasty
above. [THA], which has been so successful in osteoarthritis and
In patients presenting with advanced arthritis, or stage III rheumatoid arthritis [RA], is also now being performed in
disease, the aim is to achieve fibrous ankylosis in a functional selected patients. For this procedure the disease must be
position. Traction is applied first and, if indicated, limited clinically healed for over five years. At present, THA is also
operative procedure of partial synovectomy and curettage performed with success for active TB, though controversial,
of extra-articular lesions and joint debridement are done. along with anti-TB treatment (35,36).
Once the deformities are corrected and operative wound
has healed well, a plaster spica is applied. Immo­bi­li­sation in TUBERCULOSIS OF KNEE JOINT
the plaster is continued for six to nine months followed by
partial weight bearing for another six months. Unprotected Knee joint is the third common site for osteoarticular TB.
weight bearing is usually possible after about 12-18 months It accounts for more than 10% of cases of osteoarticular TB.
from the beginning of treatment.
Corrective osteotomy of proximal femur at a level just Pathology
above the lesser trochanter is required in patients presenting In the past, the knee joint involvement was mainly a disease
with ankylosis in an unacceptable posi­tion. Further, with of children presenting as “synovial type”. Presently, it is
corrective femoral osteotomy, a painful, fibrous ankylosis increasingly being seen in adults and presents as an osseous
may be converted into a painless, bony ankylosis. meta­physeal lesion which spreads to the joint. The synovial
Arthrodesis to achieve bony ankylosis and painless hip type of infection is a low-grade inflammation. The synovial
joint is done after about 20 years of age when proximal membrane becomes congested, oedematous and is studded
femur has no more potential for longitudinal growth. In the with tubercles. The synovial fluid is increased. It is thin,
era prior to the availability of anti-TB drugs, extra-articular watery, opalescent and contains flakes of fibrin and an
arthrodesis was done due to fear of reactivation of infection increased number of mono­nuclear cells. Healing at this stage
if the joint was opened. Two popular methods of arthrode­ leaves the synovial membrane thickened with fibrosis and
sis were iliofemoral arthrodesis [Hibb’s arthrodesis] (32) and the articular surfaces remain largely intact. If healing does
ischiofemoral arthrodesis [Britain’s arthro­desis] (33). With not occur and the infection persists, the granulation tissue
the availability of effective anti-TB treatment, a direct intra- forms and the synovial space is obliterated by fibrous adhe­
articular fusion between the raw surfaces of femoral head sions. The granulation tissue erodes the cartilage, invades
and acetabulum is performed when arthrodesis is indi­cated. the subchondral bone, capsule and cruciate ligaments.
Excision arthroplasty of the hip joint (34) [Girdle­stone When initial infection starts in metaphysis, it produces
arthroplasty] consists of excision of head and neck of femur an acute exudative infection with casea­tion necrosis.
along with debridement. Post-operati­vely, 10-12 weeks of This lesion can invade the joint to produce granulation
traction is required and this is followed by gradual weight tissue and extensive destruction of the articular cartilage
bearing. The limb becomes shorter by about two centimeters [Figure 19.16]. Sinus formation can occur [Figure 19.17].
in addition to the pre-operative shortening and the joint also Wasting of thigh and calf muscles occurs early in this type
becomes unstable. But this procedure offers the advantage of infection [Figure 19.18].
 Skeletal Tuberculosis 279

A low-grade synovial infection stimulates osteo­genesis

and ossification centers in adjoining tibia and femur. These
bones may become longer than on the opposite side. If
infection is not controlled early, a premature closure of
neighbouring growth plate can occur and in this situation,
the limb becomes shorter.

A B Clinical Features
The synovial type of infection is insidious in onset and starts
as intermittent episodes of synovial effusion. The affected
joint remains normal in appearance and function during each
remission. Excessive activity and strain tend to precipitate
effusion. Aspirated joint fluid is not abnormal except for
the presence of some mononuclear cells. At this stage, other
causes must be considered in the differential diagnosis.
C D These include meniscal tear and synovitis due to trauma,
Figure 19.16: Tuberculosis synovitis with osteomyelitis. Photomicro­
rheumatic fever, RA and pyogenic arthritis, osteochondritis
graph showing synovial lining, chronic inflammatory changes and small dessicans, chon­dromalacia patellae, haemart­h­rosis, villo­
necrotic bone spicules [arrow] [Haematoxylin and eosin × 100] [A], nodular synovitis and synovial chondromatosis. In
epithelioid granuloma with lympho­cytic infiltration [arrow] [Haematoxylin doubtful cases, synovial bio­psy for histopathological and
and eosin x 200] [B], caseation necrosis, Langhans’ giant cells [arrow], microbiological investi­gations are necessary. When a patient
foreign body giant cells [Haematoxylin and eosin × 400] [C] and
presents with recurrent or persistent knee joint swelling
caseation necrosis, giant cells [arrow] and lymphocytes [Haematoxylin
and eosin × 400] [D] of insidious onset, a possi­bility of TB must be considered.
Caution must be exercised while administering intra-
articular corticosteroids in such patients as a flare-up of TB
can occur.
Gradually, the attacks of synovitis become more intense
and presistent. The synovium and capsule become palpably
thickened and tender. This feel of swelling of the knee joint
in synovial TB is classically described as “doughy swelling”
[Figure 19.18]. At first, the muscles, particularly, hamstrings
develop spasm, atrophy and contractures may develop
later. The biceps femoris muscle pulls the leg in deformity
of flexion [Figure 19.19], abduction and external rotation. If
this deformity persists, capsular contracture occurs and tibia
gradually subluxates posteriorly. The synovial fluid is thin,
opales­cent and contains a large number of mononuclear
Figure 19.17: Clinical photograph showing healed tuberculosis sinus cells and flakes of fibrin. When healing takes place in the
and flexion deformity of the left knee joint at eight months of treatment early stage of intermittent synovial effusion, the knee joint

Figure 19.19: Clinical photograph showing hamstrings spasm due to

Figure 19.18: Clinical photograph showing early quadriceps wasting tuberculosis synovitis leading to early flexion deformity of the left knee
due to tuberculosis synovitis in the right knee joint joint
 280 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

may almost remain near normal. Healing in the later stages In the stage of intermittent effusion, administration of
leaves behind thickened and fibrotic synovial membrane and standard anti-TB treatment alone may be sufficient. Traction
capsule. Intra-articular adhesions lead to a fibrous ankylosis. is useful in all stages of the disease in children and only in the
In the form commonly seen in adults, metaphyseal stage of persistent synovitis in adults. Pre-operative traction
focus of infection spreads to the joint. Inflammatory signs is used in the acute fulminating form and surgery is deferred
develop suddenly and include severe pain, muscle spasm, till the acute stage of disease has been controlled. Trac­tion
local warmth, tenderness and restriction of movements. is also necessary in the post-operative period following
Constitu­tional symp­toms are present and include fever, synovectomy and debride­m ent. Simple skin traction is
anorexia and night sweats. Destruction is greater and abscess adequate in patients with minimal flexion deformity. But,
and sinus formation are frequent. Stimulation of ossifi­ in cases where triple deformity has developed, the double
cation may result in bony enlargement most notably in the traction technique should be used. It consists of applying
medial femoral condyle and valgus deformity of the knee both horizontal and vertical tractions from a pin passed in
joint. A premature epiphyseal fusion results in retardation proximal tibia. But traction has its limitations in correction
of longitudinal growth. In advanced cases, characteristic of deformity of patients with advanced stage TB of the
“triple deformity” of flexion, abduction, external rotation knee [Figure 19.21E]. Double traction helps in correction of
and posterior subluxation of tibia, painful fibrous ankylosis, deformity and prevents posterior subluxation of tibia. With
abscess and sinus for­mation become evident. quie­scence of acute local signs, intermittent, gentle active
and passive knee bending exercises are started. Gradual
Radiographic Features mobilisation and weight bearing are started with clinical and
In the first stage of intermittent synovitis, radio­graphs are
normal [Figure 19.20]. In next stage of persistent synovitis,
radiographs show generalised osteo­porosis, loss of definition
of articular margins [Figure 19.21]. Occasionally, marginal
erosions are also seen. Thickened synovium and capsule may
cast soft tissue shadow. In patients with advanced disease,
radiographs may reveal marked narrow­ing of the joint
space and the joint appears grossly disorganised. Osteolytic
cavities and TB sequestra in bones may also be evident in an
advanced stage of the disease, the classical triple deformity
[Figure 19.22] is seen. When the clinical presentation is
atypical, and the findings on the plain radiograph do not
support the clinical features, an MRI of the knee joint can
be helpful [Figure 19.23].

Management
In the early stages of synovial disease, a synovial biopsy and
histopathological and microbiological examination of the Figure 19.20: Plain radiograph of the knee joint [antero-posterior view]
material obtained may facilitate confirmation of the diagnosis. in a patient with tuberculosis synovitis showing normal bones

A B C D E
Figure 19.21: Sequentially taken plain radiographs of the left knee joint in a 54-year-old man, showing stage of synovitis with the knee in flexion
before initiation of treatment [A and B]. Three months later, while on treatment, juxta-articular rarefaction of bones in early arthritis stage is evident
[C and D]. The radiograph taken at the completion of treatment showing ankylosed knee joint approximately at 100° flexion despite skeletal
traction [E]
 Skeletal Tuberculosis 281

radiological improvement. Clinical improvement is indicated synovitis persists in spite of adequate anti-TB treatment for
by improvement in local and constitutional symptoms. three months, an open arthrotomy and subtotal synovec­tomy
Re-ossification of radio­lucent areas and increased density of are indicated. The main objective is the removal of infected
joint margins are signs of radiological improvement. In the tissues to render the chemotherapy more effective.
early period of mobilisation, a bivalved plaster cast or brace Mode­rately advanced disease, in addition, requires debri­
can be used to prevent recurrence of flexion deformity. If the dement with removal of loose bodies and debris. Excision
of pannus covering the articular cartilage and curettage of
superficial cartilage erosions and osseous necrotic foci are
also done. If large meta­physeal lesions are present, they
are exposed through a window at a distance from joint,
curetted and packed with cancellous bone grafts. Post-
operatively, traction must be continued for at least six weeks
in order to prevent or to correct flexion deformity and avoid
compressive forces acting against the articular surface.
Thereafter, the knee joint must be protected in a bivalved
plaster cast or brace and the weight bearing is started slowly
and cautiously. The range of knee joint flexion is likely to
remain limited to moderate or significant extent. In patients
with advanced/progressive destructive arthritis or a painful
fibrous ankylosis, arthrodesis may be required. During
surgery, sufficient bone is removed to overcome deformity
and expose normal cancellous bone and a compression
device is used to obtain rapid fusion (37).
A B
Whenever possible, arthro­desis must be deferred till the
Figure 19.22: Plain radiograph of the knee joint in a patient with completion of growth in distal femur and proximal tibia.
advanced knee joint TB. Antero-posterior view showing gross
With arthro­desis, the knee joint remains stable and allows
destruction of bones, lateral subluxation, flexion deformity and tricom­
partmental involvement can be seen [A]. Lateral view [B] of the same long hours of standing and walking. However, arthrodesis
patient showing flexion deformity does not allow flexion of the knee joint and the leg remains
TB = tuberculosis sticking out while sitting.

A B C
Figure 19.23: Plain radiograph of the left knee joint in an 18-year-old boy with a history of significant injury who developed pain and stiffness in
the left knee joint not responding to symptomatic treatment, showing rarefaction [small oval] [A], and patellofemoral sclerosis [large oval] [B]. MRI
[sagittal section] of the same patient showing infective changes affecting epiphyseal part of the femur more than tibia [C]. Biopsy confirmed the
diagnosis of TB
MRI = magnetic resonance imaging; TB = tuberculosis
282 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Healing of the wound after surgery in patients with

advanced arthritis is often slow and wound dehis­cence may
occur. This is because, the capsule, subcutaneous tissue and
the skin [that is often scarred] may also be affected by the
disease process.

TUBERCULOSIS OF ANKLE AND FOOT

TB of the ankle joint and foot accounts for less than 5% of
all cases of osteoarticular TB. Tarsals and the ankle joint are
usually involved together in TB. This occurs due to spread
of the TB infection through intercom­municating synovial
channels or along soft tissue planes. The extent of bony
involvement and the clinically evident swelling around
the ankle joint and foot are more extensive than what is
discernible on the plain radiograph.
Figure 19.24: Clinical photograph of the left ankle joint showing doughy
swelling [arrows] due to TB arthritis
Pathology TB = tuberculosis
TB of the ankle joint and foot most commonly starts as
synovitis which may be either due to infection of the
synovium or less often due to inflammation in response to
an adjacent focus of TB in the bone. Usually, the disease
presents as synovial disease or extrasynovial soft tissue
disease associated with a bony focus. The disease spreads
fast to involve several joints and is clinically characterised
by early occurrence of signs of inflammation. Sometimes, a
central bony focus may remain clinically quiescent for some
time or may produce low-grade symptoms for some weeks.
Local inflammatory signs develop late, only after the cortex
has been penetrated and when the adjacent soft tissues and A B
synovium are involved.
Figure 19.25: Clinical photograph of a young girl showing mid-foot
The most commonly affected bone is calcaneum, followed
swelling [A] [arrow] extending up to ankle [arrow] [B] due to TB arthritis
in frequency by talus, first metatarsal, navicular and involving right foot and ankle joint
medial two cuneiform bones. Certain bones appear to be TB = tuberculosis
predisposed to TB at different ages. In infants, metatarsals
are most often affected. Tarsal bones in children and bones
of the ankle joint in adults are frequently involved. Talus is In the less common type of disease, which starts as
most often affected in old age. Multiple lesions, abscess and a central bony focus, usual clinical features include dull
sinus formation are common in adults. On the other hand, aching pain of a few weeks duration. The foot may appear
fulminating synovial disease is more common in children. A deceptively normal. A careful clinical examination may
meta­physeal focus in tibia can involve the growth plate and reveal minimal swelling, tender­ness and warmth. Sometimes,
produce deformity of the ankle joint. An infective focus can a sinus may form adjacent to the bony lesion [Figure 19.26].
develop in the epiphysis and destroy a part of it. In a child,
intramedullary extension of the bony focus may precede the Radiographic Features
perforation of cortex.
An isolated destructive lesion may be seen in tarsal bones,
commonly in calcaneum and talus [Figure 19.27]. In
Clinical Features
small tarsal and metatarsal bones and phalanges, single
In the common variety of synovial disease, the onset is intraosseous lesion usually first produces expansion of
insidious. The clinical presentation includes pain, limp, bone. Early dif­fuse osteoporosis is a prominent feature.
local warmth, tenderness and a diffuse doughy swel­ling Early radiological signs, before bony destruction becomes
[Figures 19.24 and 19.25]. The soft tissue swelling is initially evident, are narrowing of joint space, cortical irregu­larities
intermittent; subsides with rest and reappears with walking. and minimal destruction of cortical margins. In late stages
Eventually the swelling becomes persistent, pain increa­ses of the disease, radiographs show com­plete obliteration and
and movements of the ankle joint become restricted. The disorganisation of joint, large bony lesions and soft tissue
boggy and tender swelling usually starts at dorso­lateral swelling.
aspect of tarsal areas and with the spread of infection it In selected clinical situations where either the diagnosis
extends towards tarsometatarsal joints. is not clear or radiological features are inconclusive, an MRI
 Skeletal Tuberculosis 283

A B
Figure 19.26: Clinical photograph of the left foot showing TB sinus over the lateral malleolus [arrow] [A]. Clinical photograph showing healed TB
sinus [arrow] overlying the bony lesion in another patient [B]
TB = tuberculosis

A B
Figure 19.27: Plain radiograph of the calcaneum [axial view] [A] showing lytic lesion [arrow] in a patient with histopathologically proven calcaneal
TB. The lytic lesion [arrow] is evident in the posterior part of the calcaneum in the lateral view [B]
TB = tuberculosis

is helpful. This will show the extent of the bony as well as produce either completely normal or functionally normal
soft tissue lesions [Figures 19.28 and 19.29]. ankle joint in over 80% of the cases.
An extensive, long-standing synovial disease requires
Management arthro­tomy and synovec­tomy. Along with synovectomy,
pannus should be carefully peeled off the articular cartilage.
Synovial biopsy may be needed at times for confirmation The articular cartilage tends to survive for long periods
of diagnosis. Anti-TB treatment is the mainstay of therapy. and destroyed articular cartilage heals by formation of
Plaster of paris cast is used to give rest to the affected fibrocartilage.
area. The ankle joint should be immobilised in 10o equinus An isolated bony lesion should be curetted and large
position. This allows ankylosis, if at all it occurs, to develop cavities should be packed with bone grafts. This ensures
in functional position. Immobilisation and non-weight early healing and prevents spread of disease into the joint
bearing should be continued till the disease becomes and adjoining bones. An extensive destruction of one or
quiescent as evidenced by improvement in local signs. When multiple tarsal bones requires complete excision of the
treatment is started early, this conservative treatment will affected bone. Any portion of tarsus can be excised from
 284 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

the level of neck of talus proximally to metatarsal bases

distally by two transverse saw cuts. The cut bone surfaces are
approximated and cast applied. This results in a shortened
but a well-func­tioning foot.
When the joint destruction is so extensive that a
functional joint cannot be expected, arthrod­esis of ankle or
subtalar joint alone or together can result in a painless albeit
stiff foot. The technique of arthro­desis is beyond the scope
of this chapter.

TUBERCULOSIS OF THE SHOULDER JOINT

TB of the shoulder joint is relatively rare. It accounts for
only 1%-2% of all cases of osteoarticular TB. In contrast to
A B
TB at other skeletal sites, involvement of shoul­der joint by
TB occurs more frequently in adults than children (38-40).

Pathology
TB of the shoulder joint seldom begins in the synovium and
the clinical presentation as synovitis is rare. Commonly,
the disease starts as an osseous lesion in the humeral
head or glenoid. The joint is involved early and is filled
C D
with granulation tissue. Capsular contracture and fibrous
ankylosis occur early and, therefore, stiffness and limitation
of movements also appear early. Small osseous foci gradually
enlarge and become confluent. Subsequently, a large fibro­
caseous cavity forms which may lead to deformity of
humeral head and glenoid. This common variety of TB of
the shoulder joint is considered to be a dry and atrophic
E F type, and hence the name “caries sicca”. Swelling, abscess
Figure 19.28: Plain radiograph of the right foot of the patient shown in and sinus formation occur rarely. In children, osseous lesion
Figure 19.25 antero-posterior [A] and oblique [B] views showing loss of may start in metaphyseal region of humerus and interfere
outline of individual tarsal bones. An MRI [sagittal section] of the right with the longitudinal growth.
foot shows involvement of talus, navicular, calcaneum, and cuboid by
tuberculosis [C, D, E, and F] Clinical Features
The onset is insidious, the early symptoms are non-specific
and include sensation of heaviness or muscle weakness.
Pain on movements of the shoulder joint appears next and
prog­ressively worsens. Muscle spasm fixes the shoulder
joint in adduction. Examination reveals painful limita­tion
of all movements of the shoulder joint especially external
rotation and abduction. In early stages of the disease, some
swelling, thickening and tenderness in soft tissues around
the shoulder joint may be present. A marked wasting of
deltoid supraspinatus and infraspinatus muscles may occur
[Figure 19.30]. Axillary lymph nodes may be enlarged and
A B
rarely a cold abscess may be present.
In early stages, TB of the shoulder joint has to be
differentiated from periarthritis of the shoulder joint. In the
advanced stage, RA must be considered in the differential
diagnosis. In RA, the marked soft tissue swelling and
synovial effusion occur. In doubtful cases, synovial biopsy
should be submitted for microbiological and histopatho­
logical examinations.
C D
Figure 19.29: Plain radiograph of the foot showing no lesions in Radiographic Features
antero-posterior [A] and lateral [B] views. But MRI reveals extensive
tuberculosis involvement of the mid-tarsal bone in the sagittal [arrow] Diffuse osteoporosis is an important radiological feature
[C] and transverse [arrow] [D] sections in early stages. Later, some soft tissue swelling occurs
 Skeletal Tuberculosis 285

A
Figure 19.31: Plain radiograph of the right shoulder joint [antero-
posterior view] showing late tuberculosis arthritis with destruction of
the glenohumeral joint

Figure 19.32: Plain radiograph of the right shoulder joint [antero-

posterior view] showing pathological dislocation and a large cold
abscess in axilla [arrow]. Patient had multiple sinuses located posteriorly

C
Management
Figure 19.30: Clinical photograph showing front [A], side [B], and In patients with a doubtful diagnosis, a synovial biopsy
posterior view [C] of left shoulder joint. Gross muscle wasting involving should be perfor­med early to confirm the diagnosis. In
deltoid, supraspinatus and infraspinatus can be seen. addition to the general measures, the affected shoulder joint
should be immobilised in plaster spica for three months.
Currently, removable polythene brace is commonly used
and cortical margins become indistinct. Osteolytic osseous for this purpose. The immobi­li­sation should be in functional
lesions, narrowing of the joint space and deformity of position in the event of eventual healing with ankylosis. The
the humeral head and glenoid develop in the late stages optimum position for immobilisation is 80° abduction, 30°
of disease [Figures 19.31 and 19.32]. Rarely, pathological forward flexion and 30° of internal rotation. Usually, fibrous
subluxation or dislocation of the shoulder joint may develop ankylosis occurs. Patient can perform routine activities due
[Figure 19.33]. to compen­satory movements at scapulothoracic level.
 286 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

occurs, the eventual outcome will be a fibrous ankylosis. If

caseous arthritis conti­nues for a long period, dis­charging
sinuses also develop. TB starting as a synovial disease is
uncommon in the elbow joint.

Clinical Features
Disease is generally insidious in onset and produces pain,
muscle spasm and limitation of movements. Generalised
joint tenderness, boggy oedema of periarti­cular tissues and
increased synovial effusion occur [Figure 19.34]. Swelling
is most easily appreciated at the back of the elbow on
both sides of the olecranon and triceps tendon. Wasting
of arm and forearm muscles occurs early. Supratrochlear
or axillary lymph nodes are enlarged in about one-third of
cases. In advanced un­trea­ted disease, discharging sinuses
Figure 19.33: Plain radiograph of the right shoulder joint [antero- may be present.
posterior view] showing pathological superior migration and osteo­
porosis of the right humeral head [arrow] in treated tuberculosis arthritis
of the right shoulder joint Radiographic Features
In early stage of the disease, bones around the joint show
TB of the shoulder joint responds well to anti-TB generalised osteoporosis and the articular margins become
treatment. Occasionally, despite adequate anti-TB treatment, fuzzy and irregular [Figure 19.35]. Osteolytic bony lesions can
fibrous ankylosis of the shoulder joint remains painful and be seen in the olecranon, coronoid, distal humerus or radial
has to be distinguished from a relapse. In selected cases with head [Figure 19.36]. In late stages of the disease, marked
fibrous ankylosis, surgical arthrodesis of the glenohumeral joint space narrowing and destruction of articular margins
joint in the optimum functional position is helpful. This appear. Rarely, due to marked destruction of ligaments and
relieves pain and provides a stable joint. A shoulder spica bones, the elbow joint may develop pathological posterior
or internal fixation with metallic implants is necessary for dislocation. As the disease heals, fibrous ankylosis develops
the success of arthrodesis. Shoulder spica is to be continued more frequently than bony ankylosis.
for two to three months till the radio­­logical confirmation of
arthrodesis. Subsequently, limb is supported on a sling after Management
removal of the spica. Gradual physiotherapy is started to
encourage the scapulo-thoracic movement. If the disease starts from an osseous focus or has progressed
An alternative to arthrodesis is available for patients with to an advanced stage of arthritis, clinical and radiological
a painful shoulder joint due to TB. In the procedure known features are usually diagnostic. In the stage of synovitis and
as excision arthroplasty of the shoulder joint, the diseased during early stages of the joint destruction, differentiating
tissues are removed by thorough debridement, and the TB of the elbow joint from RA can be difficult. In doubtful
affected bony parts are removed from proximal humerus cases, an open biopsy of the synovium should be done to
and glenoid. The resultant pseudoarthrosis preserves the ascertain a definitive diagnosis.
movement at the shoulder joint. However, this procedure The principles underlying the management of TB of the
may render the joint unstable. Possibility of development elbow joint are similar to those applicable to TB of other
of future relapses of the disease is also another risk with synovial joints. Anti-TB treatment forms the mainstay of
this procedure. All major surgical procedures are to be therapy. In cases where sinuses have formed secondary
undertaken under the cover of anti-TB treatment. infection with pyogenic bacteria is likely. In these cases, a
broad spectrum antibiotic should also be administered.
TUBERCULOSIS OF ELBOW JOINT In all stages of the disease, with or without opera­tive
intervention, the elbow joint should be immobili­sed for about
TB of the elbow joint accounts for about 2% or less of
3 months in a plaster cast or remov­able polythene brace.
all osteoarticular TB. Children are less often affected as
When the disease is unilateral, immobilisation of the elbow
compared to adults.
joint in 90° flexion and forearm in the midprone position
is recommended to avoid the development of ankylosis in
Pathology nonfunctional position. After removal of splintage, overuse
The disease commonly begins as an osseous focus in the of the joint should be avoided for further six to nine months.
olecranon, coronoid, lower end of the humerus or upper Functionally, satisfactory range of movements at the elbow
end of the radius in order of decreasing frequency. These joint is retained in a majority of cases. Results, however,
caseous bony lesions involve the joint to produce destruction also depend on the stage and extent of the disease and joint
of cartilage and pannus formation. At this stage, if healing destruc­tion when treat­ment is started. The results are much
 Skeletal Tuberculosis 287

A B
Figure 19.34: Clinical photograph with arms abducted [A] and held by the side [B] showing a doughy swelling at the left elbow joint, more marked
on lateral and posterior aspects. Flexion of the elbow joint and muscle wasting in the arm are also evident

A B C D
Figure 19.35: Plain radiograph of the elbow joint, antero-posterior [A] and lateral [B] views showing generalised rarefaction, fuzziness of joint
surfaces [rectangles]. Plain radiograph [antero-posterior view] [C], [lateral view] [D] of the patient shown in Figure 19.34 showing soft tissue
swelling and fuzziness of joint surfaces [circles] [C and D]

better in the early stage disease of synovitis and in unicom­­­ eradicate a source of future relapses and extension of disease
partmental disease. In advanced arthritis with involvement into the joint. Synovectomy and joint debridement are
of all compartments of joint, the usual end result is fibrous indicated in patients with early arthritis when response to
ankylosis in a majority of patients. The bony ankylosis is chemotherapy and immobilisation is not adequate.
uncommon. When advanced arthritis has healed with elbow joint in
A localised destructive lesion near the joint [usually in tight fibrous anklylosis or anklyosis in unacceptable position,
the olecranon or coronoid] should be curetted early to a good and functionally useful range of movements at the
 288 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

tendon sheaths. Still less commonly, the infection may

spread to wrist joint from the infected teno­synovitis (41,42).
Abscess and sinus formation are common.

Clinical Features
The onset of the disease is insidious. Exacerbation of
pain by movements is the early symptom. Soft tissue
swelling, tenderness and limitation of flexion and extension
movements at the wrist joint occur later. In progressive
disease with destruction of bones and ligaments, subluxation
or dislocation of radiocarpal joints occurs. This gives rise to
a marked deformity and further limitation of movements.
Abscess and sinus forma­tion are frequent in advanced
disease. Exten­sion of disease to flexor and extensor tendon
sheaths produ­ces a localised boggy swelling and difficulty in
Figure 19.36: Plain radiograph of the elbow joint [lateral view] involved move­ments of fingers. A monoarticular RA may be difficult
by tuberculosis showing lytic lesion in olecranon [arrow] and loss of
to differentiate from TB.
joint space with flexion deformity

Radiographic Features
elbow joint can be regained with excision arthroplasty. The In the early stages, radiographs show deminerali­sation of
surgery should be deferred till growth is complete and bones, bony erosions and some reduction of the joint space.
should not be done in persons engaged in heavy manual Osteolytic bony lesions in the radius and car­pal bones may
work. The surgery consists of removing an “inverted be seen. In advanced stages of the disease, joint spaces of
V-shaped” segment of the lower end of humerus with the both wrist and intercarpal joints become obliterated. Bony
apex of “V” reaching the olecranon fossa. Supracondylar destruction and even subluxation or dislocation of the wrist
ridges, epicondyles and collateral ligaments should be joint may occur [Figures 19.37 and 19.38].
carefully preser­ved. Upper end of the ulna [rarely along
with upper end of the radius] should be sparingly trimmed Management
and allowed to slide in the “inverted V-gap” in the humerus.
After seven to ten days of operation, movements of active TB of the wrist joint is quite likely to be mis­diagnosed as
and assisted active flexion, extension, supination and monoarticular RA and, therefore, it is essential to confirm
pronation are started. Night splint should be used for three the diagnosis with synovial biopsy.
An early diagnosis and early institution of anti-TB
months. Light work without splint is allowed three months
treatment are indicated. Periodic follow up with imaging
after the surgery (19).
is required. If indicated, the continuation phase may be
In heavy manual workers, arthrodesis of the elbow joint
extended and this practice of extension of treatment
is indicated when the joint has become exten­sively dis­
should be individualised. More clinical trials are required
organised. For unilateral disease, a position of 90° of flexion
to say definitely about the efficacy as well as duration of
is desirable. For bilateral cases, one elbow joint should be
anti-TB treatment. A prolonged splintage in plaster cast
placed in 110° flexion to enable the hand to reach mouth
or polythene splint with wrist in 10° dorsiflexion and in
and face and the other in 65° flexion to attend to personal
midprone position is always required. Splintage should be
hygiene. The opti­mum position is best decided after a trial
gradually discarded during daytime but night splint is used
immobi­lisation of the elbow joint in plaster cast for few for nearly one year. The heavy physical work should be
weeks before operation. The surgical techni­que of arthrodesis avoided for 18-24 months in order to avoid collapse of the
of the elbow joint is beyond the scope of this chapter. bones and minimising the risk of development of deformity.
The combination of modern anti-TB treatment and proper
TUBERCULOSIS OF WRIST JOINT splintage are adequate in nearly two-thirds of patients. Good
TB of the wrist joint is rare and is seen mainly in adults. functional range of movements can be regained with these
if the treatment is started at the early stage of the disease.
Pathology Gross fibrous ankylosis occurs in one-third of patients.
Synovectomy of the joint or tendon sheaths [if involved]
The most common site of initial focus of TB in the wrist joint and curettage of bony lesions are indicated in patients
is in the distal radius and capitate. The disease spreads to not responding to treatment or whenever there is doubt
involve the wrist and inter­carpal joints. Less often, the disease regarding the diagnosis. With the avai­lability of better
starts from a primary focus in the synovium and infection imaging modalities for an early diagnosis, effective drugs,
soon gets disseminated to intercarpal and wrist joints. use of better orthopaedic splintage and surgical intervention
Infection then spreads to involve both flexor and extensor is rarely required (41,42).
 Skeletal Tuberculosis 289

supination. Optimum position of the wrist joint arthrodesis

is in 10°–15° of dorsi­flexion.

TUBERCULOSIS OF SACROILIAC JOINT

Sacroiliac joint is a true synovial joint. This joint is involved
in 2%-5% cases with osteoarticular TB (43).

Pathology
TB of the sacroiliac joint may start in the synovium, in lateral
masses of sacrum or ilium. Infection can either start at these
sites or occur as an extension of TB from ipsilateral hip joint
and lumbosacral area of spine. Destructive caseous lesions
form and destroy the joint. Abscess formation is common
and the abscess may present dorsally or inside the pelvis.
A B
Intrapelvic extension can lead to severe visceral lesions
Figure 19.37: Post-treatment radiograph of the wrist joint [antero- making the prognosis quite serious. Dorsal abscess or its
posterior view] [A] showing ankylosed wrist, gross destruction of carpals,
loss of intercarpal and radiocarpal joints. Mild volar subluxation of
extension along the iliac crest is likely to result in sinus
carpals with loss of radiocarpal joints can be seen in the lateral view [B] formation. These sinuses heal with difficulty. Superadded
bacterial infec­tion through the sinuses is common.

Clinical Features
Sacroiliac TB is rare in infancy and child­hood and affects
adults more frequently. Females are affected more frequently
than males [male: female = 2:5]. Concomitant TB at some
other site is present in about half the patients. In patients
with a poor general health and nutritional status, bilateral
sacroiliac joint involvement is common.
The onset of the disease is insidious and it may follow
trauma or pregnancy. Pain over the affected joint is the
main symptom. It is referred to groin and less commonly in
the sciatic nerve distribution. Pain worsens on lying either
supine or on affected side. Prolonged standing and walking
also aggravate pain. Sitting on the buttock on affected side
is painful, whereas sitting on opposite buttock relieves
A B
pain. Bending forwards with the knee joints in extension
Figure 19.38: Plain radiograph of the right wrist, antero-posterior [A] produces tension on the hamstrings and exacerbates the
and lateral [B] views of a patient who has received a full course of anti-
TB treatment showing bony ankylosis [rectangles] of distal radioulnar,
pain, but, bending forwards with the knee joints in flexion
radiocarpal and intercarpal joints is less painful as this manoeuvre relaxes the hamstrings.
TB = tuberculosis Sudden jerks, coughing and sneezing also worsen the pain.
Localised tenderness and some boggy swelling or abscesses
are present. Stressing the involved sacroiliac joints by any
Arthrodesis of the wrist joint is the treatment of one of the following three manoeuvres increases pain:
choice to minimise the disability in patients where wrist [i] distraction of both sacroiliac joints by simulta­neous
joint has dislocated due to the advanced destruction, in pressure on both anterior superior iliac spines; [ii] stressing
patients with painful fibrous ankylosis or ankylosis in non- the sacroiliac joint with forced flexion, abduction and
functional position [e.g., flexion]. Thorough debridement external rotation of ipsilateral hip joint [Faber’s test]; and
and arthrodesis are also useful for painful wrist joint with a [iii] by performing the Gaenslen’s test of rotating the ilium
history of recurrence of infection. Arthrodesis of both wrist on sacrum. In the Gaenslen’s test, the hip on the unaffected
and intercarpal joints is performed together from a dorsal side is first firmly flexed to fix the pelvis and lumbosarcal
approach. The diseased tissue, synovium and arti­c ular junction. The affected hip is then hyperextended, thereby
cartilage are removed as far as possible and joint spaces are rotating the corresponding ilium forwards. This stresses
packed with cancellous grafts. In the Darrach’s procedure, the inflammed liga­mentous structures about the sacroiliac
a large cortico-cancel­lous graft is placed in a trough made joint and produces pain.
in distal radius, lunate, capitate and proximal part of the Rectal examination is important to detect intra­plevic
third metacarpal. Along with this, the distal end of ulna abscess. In advanced disease, large cold abscesses and
should be excised to provide useful range of pronation and sinuses may be present.
290 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Radiographic Features Symphysis Pubis

In the early stages, the plain radiographs are normal. The TB of symphysis pubis is rare. The disease usually begins
earliest radiographic evidence is in the form of haziness or in pubic bone and spreads to symphysis. Localised pain
loss of definition of joint margins. Thereafter, an irregularity and sometimes abscess and sinuses are presenting features.
of the articular surface with areas of erosions may become Radiological assessment of this area reveals osteolytic areas in
evident. If the disease is controlled at this early stage, the pubic bones and destruction of margins of pubic symphysis.
joint space narrowing and sclerosis of the joint margins Concomitant T ­ B lesions in sacroiliac joint are not uncommon
occur. Progressive destruction causes marked cavitation and some of these patients may develop displacement of
in the bone and narrowing of the joint space. Healing of symphysis. Treatment is essentially with anti-TB drugs. Cold
advanced disease occurs by bony ankylosis and increased abscess may require antigravity aspiration.
density of the joint margins. Ankylosing spondylitis, RA,
pyogenic infection and juxta-articular bony lesions should Ilium, Ischium and Ischiopubic Ramus
be considered in the differential diag­nosis. The CT and MRI
are of great value in detecting early joint erosions, cavitation Isolated TB lesions are rarely seen in one of these bones.
and abscess. Usual presenting features include pain, swelling, tenderness,
cold abscess and discharging sinuses. Radiologically, these
Management lesions show varying number of lytic areas and some of
these lesions may contain sequestra. Superimposed pyogenic
TB of the sacroiliac joint is difficult to diagnose in the early infection will produce sclerosis around lytic areas. One must
stages as the clinical manifestations are atypical. Also, it be aware of these conditions in order to diagnose them at
responds slowly and less favou­rably to anti-TB treatment an early stage. Treatment is with anti-TB drugs. Exploration
and surgical treatment becomes necessary quite often. In and debridement of bony lesions is indicated in the following
the pre-chemotherapeutic era, TB of the sac­ro­iliac joint was situations: [i] patients with doubtful diagnosis; [ii] disease
commonly encountered in patients with generalised severe not responding to anti-TB treatment; and [iii] recurrent
infection and the mortality was high in these patients.
disease.
Standard anti-TB treatment and general supportive
therapy are initiated. Surgical intervention is indicated
in patients not responding to drugs and in those with
Sternum and Ribs
recurrence of infection or when the diagnosis is in doubt. It TB very rarely involves the sternum and ribs. Often, the
consists of debridement of joint, freshening of joint margins disease is not diagnosed till sinuses have formed. Nearly
and packing the area with adequate bone grafts to achieve one-third of patients will have detec­table TB lesion in lungs
arthrodesis. Postoperative bedrest is required for about three or other parts of the skeleton. Radiographic assessment of
months followed by gradual mobilisation in a lumbosacral both these sites is very difficult and may reveal irregular
belt or plaster jacket till clear bony fusion of joint is evident destruction and cavities. The diseased ribs may be thickened
radiologically. very much or expanded with “punched out” erosions.
Surgery is not required routinely in these patients. However,
TUBERCULOSIS AT RARE SITES it may be done to establish the diagnosis or for the removal
Sternoclavicular Joint of sequestrum. Response to anti-TB treatment is good.

TB of the sternoclavicular joint is rare. Often, the disease Scapula

may be misdiag­nosed to be low-grade pyogenic infec­tion,
RA, multiple myeloma or metastases. The disease usually The scapula is another rare site for TB. Infection may start
starts in the bone at the medial end of clavicle and presents in the angle of acromion, spine, neck of scapula and inferior
with a painful swelling of an insidious onset. The swelling or superior angle of scapula. Pain and occasionally swelling
may be warm, tender and boggy. A cold abscess and a are the present­ing clinical features. This is another bone
sinus can form in late stages of the disease. Radiographic where radiological evaluation is difficult. CT or MRI can
examination of this joint is very difficult and MRI is useful be helpful to detect early lesion of the disease in scapula.
to detect early erosion and soft tissue swelling. Biopsy is Treatment is with anti-TB drugs.
necessary if the diagnosis is in doubt. Response to anti-TB
treatment is usually good. Clavicle
Occurrence of TB of the clavicle without involvement of
Acromioclavicular Joint acromioclavicular or sternoclavicular joint is rare. Children
Acromioclavicular joint is also a rare site for TB and the are most often affected. Presenting clinical features include
disease may start from the lateral end of clavicle or acromion painful swelling of clavicle with or without cold abscess or
and spreads to the joint. Clinical features include pain and sinuses. Radiograph shows any one of the following types
swelling of an insi­dious onset. The diagnosis is often missed. of appearances: diffuse thickening and honeycombing,
Anti-TB treatment often yields satisfactory results. multiple cystic cavities and sequestra formation similar
 Skeletal Tuberculosis 291

to pyogenic infection. The mainstay of therapy is anti- Tuberculosis Bursitis

TB treatment. The role of surgery is limited. Biopsy may
Bursa over greater trochanter, subdeltoid bursa and pes
be done to confirm the diagnosis. Debridement may be
anserinus bursa are known to develop TB. All are rare
helpful in patients with slow or no response to drugs. Large lesions. Clinical presentation includes mild pain, localised
sequestrum should be removed surgically. If neces­sary, a swelling and tenderness. Differentiation from RA, ganglion
part of clavicle can be excised without loss of function (44). and synovial tumours can be difficult and biopsy may be
required for an accurate diagnosis.
TUBERCULOSIS TENOSYNOVITIS AND BURSITIS TB bursitis responds well to anti-TB treatment. Large
TB of the tendon sheaths and bursa is rare. Any synovial swellings may require aspiration.
sheath or bursa can be affected but tendon sheaths around
hand are more commonly affected as compared to other sites. TUBERCULOSIS OSTEOMYELITIS
TB of the bone alone can occur without involvement of
Tuberculosis Tenosynovitis joint (45). Any bone can be affected but long tubular bones
are rarely involved. These are often diagnosed and treated
Hand is the most common site of involvement. People like bacterial chronic osteomyelitis (40). Usually, adults
who work with cattle are predisposed to disease caused are affected. The common presenting features include
by Mycobacterium bovis. Infection can also reach the tendon pain, swelling of bone with warmth, tenderness, boggy
sheath by haematogenous route or from neighbouring soft tissue swelling and regional lymphadenopathy. In
affected bone and joint. The disease usually starts as a simple late cases, abscess and sinus formation occurs. A high
inflammation of the tendon sheath with serous exudate and index of suspicion is required for the diagnosis. Radio­
fibrinous deposits covering the inner surface. Gradually, graphs show irregular cavities and areas of destruction
the tendon sheath thickens and the exudate becomes with little surrounding sclerosis [Figures 19.39 and 19.40].
seropurulent. With move­ment and friction the broken villi
and fibrinous exudate get moulded to resemble “rice bodies”
closely resembling similar looking rice bodies sometimes seen
in RA. The tendon sheath may undergo caseation necrosis
and the exudate pene­trates the soft tissues to form sinuses.
Rarely, necrosis of underlying tendons may occur. With
healing, the sheath becomes fibrotic. The infection spreads
in the sheath to involve all areas from muscle to tendi­nous A
insertion. Para­tendon and fascial structures are involved
by the spread of disease. TB tenosynovitis of the common
sheath of forearm flexor tendons distends the sheath both
proximally and distally up to flexor retinaculum. This
produces a dumb­-bell shaped swelling, classi­cally known
as “compound palmar gang­lion”. Cross fluc­tua­tion can be B
demonstrated between the swelling proximal and distal to Figure 19.39: Plain radiograph of the forearm antero-posterior [A]
flexor retinaculum. and lateral [B] views showing TB osteomyelitis of entire ulna at the
beginning of treatment [arrows]
The clinical course of TB tenosynovitis is slow and
TB = tuberculosis
insidious. Presenting features include pain, swelling, tender­
ness, weakness of grip and limitation of movements. The
latter is minimal to start with but progressively worsens
with adherence of tendons. Spontaneous tendon rupture
and sinus formation are uncommon and occur as late
compli­cations. Fever and general constitutional symptoms
A
are unusual until neighbouring bone and joint have been
involved.
Treatment in early stage consists of anti-TB treatment
and immobilisation. In extensive and long-standing disease,
surgical resection of the diseased tissue followed by immo­
bilisation should be done. Function becomes better after
B
radical excision. If tendon has become necrotic, it should be
excised and tendon grafting should be done. When infection Figure 19.40: Plain radiograph of the forearm antero-posterior [A] and
lateral [B] views of the patient shown in Figures 19.39A and 19.39B
has spread to bone and joint, especially the wrist joint, showing healed TB osteomyelitis of ulna at completion of treatment
wide excision, debridement and arthrodesis will give best [arrows]
functional results. TB = tuberculosis
292 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

This commonly produces a honeycomb appear­ance. Some In refractory cases involving long and short tubular bones
of the cavities may contain feathery sequestra. After sinus or in the presence of abscess around the involved bone,
formation, superadded bacterial infection produces marked excision of the granulation tissue and infected bone should
sclerosis and occasionally seques­tration of cortical bone be done. Concomitant presence of bacterial infection in the
resembling pyogenic chronic osteomye­litis. Differential same osseous lesion, usually through sinuses, causes a delay
diagnosis includes chronic pyogenic osteo­myelitis, Brodie’s in healing. A short-course of additional antibiotic should be
abscess and tumours. Biopsy for histopatho­logical and given to control bacterial infection.
microbiological investigations may help in the diagnosis.
Occasionally, a presump­tive diagnosis can be confir­med on TUBERCULOSIS OF PROSTHETIC JOINT
the basis of favourable response to anti-TB treatment.
As the prosthetic joint replacement is increasingly being
TB osteomyelitis of short tubular bones like phalanges,
done globally, several reports documenting TB of the
metacarpals and metatarsals is more often seen and is
prosthetic joint have been published (48-51). Prosthetic
predominantly a disease of children. The disease process
joint TB may develop due to the reactivation of the TB
starts in the medullary cavity causing patchy destruction. The
arthritis for which prosthetic replacement was performed.
entire diaphysis sequestrates due to a combination of two
These patients present with slowly progressive joint pain.
interrelated pathological pro­cesses. Firstly, the periosteum
Diagnosis requires a high index of suspicion. Arthrocentesis
becomes lifted up due to granulation tissue. This results in
must be done and specimens must be obtained from multiple
the formation of involucrum and consequently sequestration
sites for mycobacteriological studies. Eradication of TB focus
of dia­physis occurs. Secondly, because of deficient anas­
is not possible without removing the prosthesis. Treatment
tomosis of the osseous arteries in childhood, the thrombosis
consists of removal of the prosthesis followed by appropriate
caused by TB pathology leads to sequestration of diaphysis.
anti-TB treatment.
Rarely, the sequestrated diaphysis may be extruded before
involucrum forma­tion. As a result, gross shortening of
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 20
Musculoskeletal Manifestations of Tuberculosis
Aman Sharma, Kusum Sharma

INTRODUCTION AETIOPATHOGENESIS AND PATHOLOGY

Extra-pulmonary tuberculosis [EPTB] has become a significant The causative agent of MSK-TB almost always is
public health problem, especially in the human immuno­ Mycobacterium tuberculosis [Mtb] (11). MSK-TB due to other
deficiency virus [HIV] era. Musculoskeletal tuberculosis mycobacteria is very rare. Anti-tumour necrosis factor-alpha
[MSK-TB] is one of the important forms of EPTB (1). Unlike [anti-TNF-α] agents are being increasingly used to treat
various other immuno­i nflammatory diseases affecting various rheumatic diseases like RA, spondyloarthropathies,
MSK system, such as, rheumatoid arthritis [RA] where etc. There is a risk of reactivation of TB while using these
achieving a cure is a dream, MSK-TB is potentially curable. agents. It might lead to disruption of tumour necrosis
Therefore, it is important to diagnose these musculoskeletal factor [TNF] dependent cellular migration necessary for
manifestations of TB early, so that anti-TB treatment can be maintaining the integrity of the granuloma (12).
initiated and the tissue damage can be prevented. The MSK-TB infection is mostly secondary to
haematogenous spread from a primary focus, which may
EPIDEMIOLOGY be in the lungs, lymph nodes or other organs and that
the source can be demonstrated in up to 40% of these
There has been a surge in the number of EPTB cases in recent
patients with the help of sensitive imaging modalities like
times (2). Share of EPTB as a proportion of total number of
magnetic resonance imaging [MRI] (13). The joint infection
TB cases in USA has increased from 7.6% in 1962 to 15.7% in
is usually a result of either spread from a TB osteomyelitis
1993, and to 21% in 2006 (3-5). Bone and joint TB accounted
or seeding of the synovium from haematogenous spread.
for 5337 [11%] out of a total of 47293 cases of EPTB reported
There is synovitis in the initial stage of infection, followed
in the USA from 1993–2006 (6). In the absence of a reliable
by formation of granulation tissue and pannus in the later
epidemiological data and sparse published literature, it is not
stages, which eventually results in cartilage destruction (13).
possible to give an exact figure on the relative contribution
This is followed by demineralisation and necrosis resulting
of EPTB to the total number of TB cases in India (1,7). Bone
in severe bone damage. There may be formation of para-
and joint TB constitutes 10%–11% of total EPTB cases which
articular cold abscess without signs of inflammation and
would be approximately 1%–3% of all TB cases (8,9).
external fistulae (11).
Musculoskeletal TB is usually classified into spinal TB
and TB of peripheral joints (10). Spinal TB constitutes nearly
50% of all MSK-TB (11). The other relatively uncommon Risk Factors
forms of MSK-TB are Poncet’s disease [parainfectious TB Host genetic factors do play a role in susceptibility to TB (14).
arthritis], TB soft tissue rheumatism, iatrogenic rheumatism Various studies have shown associations of different
and TB osteomyelitis (10). The main focus of present chapter genetic polymorphisms with either increased or less
will be on TB arthritis, Poncet’s disease and TB soft tissue risk of development of TB (15,16). EPTB like MSK-TB is
rheumatism. TB of the spine and peripheral joints has been predominantly a disease of children and young adults in
covered in the chapter “Skeletal tuberculosis” [Chapter 19]. endemic areas. In the non-endemic areas, it affects older
 Musculoskeletal Manifestations of Tuberculosis 295

individuals and immunocompromised patients (2,17). Development of Tuberculosis during Treatment of

People with HIV infection, diabetes mellitus, and those Rheumatological Diseases
receiving immunosuppressive and cytotoxic therapies are
at increased risk of TB (18-22). Patients on treatment for Many patients with active inflammatory rheumatological
underlying rheumatologic diseases, such as, systemic lupus disorders receive various immunosuppressive drugs, making
erythematosus [SLE], RA or gout may also develop MSK- them susceptible to reactivation of TB. Though anti-TNF
TB (23-26). There may be TB involvement of the prosthetic therapy and corticosteroids are most commonly incriminated
joints also (27). agents, all patients who receive any immunosuppressive
therapy affecting the cellular immunity should be considered
at risk of reactivation of TB (34-36). Data from a large patient
CLINICAL MANIFESTATIONS registry reported a TB incidence of more than 1000 per
The clinical manifestations of MSK-TB can be divided 100,000 patient years of exposure to TNF blockers. This rate
into four major categories (28): [i] direct MSK involvement; was reported to be 6 cases per 100,000 in patients with RA
[ii] development of TB during treatment of rheumatic before the widespread use of TNF blockers (35). Etanercept
disease; [iii] effects of anti-TB drugs; and [iv] reactive has been observed to be associated with relatively lower
phenomenon. risk (34). Reactivation TB occurs most frequently 6-12 months
after initiating the TNF blockers, and is usually in form of
Direct Involvement EPTB. Proper screening for latent TB infection [LTBI] in these
patients results in decrease in active TB (37). Glucocorticoids
Typical TB infection presents as a slow, smouldering localised also increase the risk of reactivation in patients with LTBI.
infection of the bones [osteomyelitis], spine, peripheral joints Though the risk appears to be dose related, it occurs
and soft tissue. TB osteomyelitis is seen both in children and even in patients on low physiological dose of prednisolone
adults, but is more common in children, and may involve 7.5 mg/day.
any bone. Femur and tibia are the most commonly involved
bones, though ribs, skull, phalanx and other bones may also Effects of Anti-tuberculosis Drugs
be involved (12). In children, TB involvement of the phalanx
may cause dactylitis and present as a diffuse ‘spindle-like Drugs used in TB treatment can produce various clinical
swelling of the finger’ (11). The overlying skin is shiny and conditions. Isoniazid and rifampicin may produce drug-
stretched. Radioisotope bone scan may show ‘hot spots’ in induced lupus. These patients have anti-nuclear antibody
the metaphysis of a short bone of the hands and feet (11). [ANA] and anti-histone antibody positivity. The disease is
Joint involvement is usually in the form of chronic generally mild and reverses after stopping the offending
monoarthritis of the large and medium weight-bearing drug. Fluoroquinolones, especially ciprofloxacin and
joints, like hip and knee (29). Clinical manifestations are in levofloxacin, have been associated with tendon rupture (36).
the form of pain and swelling of the involved joint along This risk is higher in older individuals, and those on corti­
with restriction of movements. Constitutional symptoms costeroids. Pyrazinamide can cause hyperuricaemia due to
in the form of fever and weight loss may also be present. interference with renal tubular excretion but rarely results
Other joints like sacroiliac, shoulder, elbow, ankle, carpel in gout (36).
and tarsal joints are less commonly involved. Polyarticular
or oligoarticular involvement is uncommon. There may be Reactive Phenomenon [Poncet’s Disease]
a polyarticular involvement in a debilitated child or adult Poncet’s disease is a form of inflammatory arthritis without
with a past history of TB or exposure to a TB patient (11). any evidence of direct TB involvement of the joint in the
The presentation mimicking juvenile idiopathic arthritis has presence of TB elsewhere in the body. This was described
also been reported rarely (30). The soft tissue TB can present by Poncet in 1887 in patients with current or past history of
as tenosynovitis, bursitis, myositis or fasciitis. There may EPTB (38). In the absence of any diagnostic criteria, other
be a delay in diagnosis of these conditions when there is a disease conditions have been included in this diagnosis,
resemblance to focal soft tissue inflammatory conditions (31). and this has led to controversy over this terminology. In
Myositis is uncommon condition and the usual causative the recently proposed diagnostic criteria (39), there are two
organism is Staphylococcus aureus (32). TB myositis is even essential, two major and three minor criteria. Based on these
rarer. Most of these patients have predisposing conditions for criteria, the diagnosis can be either definite, probable or
TB (33). The proposed mechanism of involvement is thought possible [Table 20.1] (39).
to be due to either a ‘haematogenous’ spread, ‘contiguous’ The definite pathogenesis of Poncet’s is uncertain but
spread from the adjoining bone and soft tissue or ‘iatrogenic’ is similar to ‘reactive arthritis’ as a result of molecular
due to direct inoculation through contaminated instru­ mimicry between Mtb which is arthretogenic and the
ments (33). Abnormalities on chest radiographs have been articular cartilage. A CD4+ T-cell response to mycobacterial
noted in up to half of these patients. Though rare, this has antigens has been shown to play a role (40). Chronic
been reported to have significant mortality of around 14% synovitis resembling RA can be produced by injection of
with even higher mortality [30%] in patients with possible complete Freund’s adjuvant [heat killed and desiccated
haematogenous route of infection (33). Mtb in oil]. Arthritis has also been reported as a side-effect
296 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 20.1: Diagnostic criteria for Poncet’s arthritis*

Essential criteria
Inflammatory, non-erosive, non-deforming arthritis
Exclusion of other causes of inflammatory arthritis
Major criteria
Concurrent diagnosis of extra-articular TB
Complete response to anti-TB therapy
Minor criteria
Mantoux positivity
Presence of associated hypersensitivity phenomenon, such as,
erythema nodosum, tuberculids or
Phlyctenular keratoconjuctivitis
Absence of sacroiliac and axial involvement
* When both essential and two major criteria are present, the
diagnosis is “definite”. In addition to both the essential criteria
if one major and two minor criteria are present, the diagnosis is
“probable”. In addition to both the essential criteria, if either one
Figure 20.1: Clinical photograph showing erythema nodosum on the
major criterion and two minor criteria are present or three minor
left shin
criteria are present, the diagnosis is “possible”
TB = tuberculosis
Source: reference 39 induration of the overlying skin. Occasionally, it may be in
the form of a sheet-like indurated, hyper-pigmented swelling
over the ankles and shin. Though any joint may be involved,
of the bacille Calmette-Guérin [BCG] immunotherapy in but ankle, knee and wrist are the most commonly involved
patients with urinary bladder carcinoma. The description joints (49,50).
of clinical presentations of Poncet’s disease in the literature Erythema induratum [EI] of Bazin type is a lobular
is derived from small case series and case reports (41-48). panniculitis and has a similar presentation in the form of tender
Poncet’s disease is more common in juvenile and young erythematous nodules (51-53). EI has clinicopathological
adults. Female predilection has been osberved. Fever and similarity to nodular vasculitis. However, while EI occurs
constitutional symptoms may be observed in some patients. exclusively due to TB, nodular vasculitis can occur due to
The pattern of joint involvement commonly described causes other than TB also. These are more commonly seen
includes an acute or subacute symmetrical polyarthritis on the calves of young or middle-aged females; shin can also
predominantly involving the large joints, like knees and be involved occasionally. The other sites of involvement are
ankles. Symmetrical small joint involvement resembling trunk, buttocks, thighs and arms. Unlike EN, which heals
RA has also been reported occasionally. The most common without scarring, EI heals with ulceration or depressed scars.
site of TB in Poncet’s disease is pulmonary TB; among This can also be associated with ankle arthritis. Tuberculids
extrapulmonary sites, lymph node TB is the most frequent are result of immunologic reactions to antigenic components
site (11). Erythema nodosum [EN] was present in 6% of of Mtb (51). Histopathology and polymerase chain reaction
patients in one series (42). TB may sometimes develop during [PCR] may confirm TB in some of these patients and these
the course of Poncet’s disease (47). Tuberculin skin test is respond to anti-TB treatment.
usually strongly positive except in disseminated TB. Poncet’s The reader is referred to the chapter “Cutaneous tuberculosis”
disease is a diagnosis of exclusion and there is no evidence [Chapter 21] for details.
of active TB of the joint. It resolves completely with anti-TB
treatment. UNUSUAL MANIFESTATIONS OF
MUSCULOSKELETAL TUBERCULOSIS
Panniculitis Associated with Tuberculosis
Various types of very unusual manifestations of MSK-TB
Panniculitis is a non-suppurative inflammation of the have been reported. Some of these include [i] non-healing
subcutaneous fat without vasculitis. EN, a form of septal ulcerated mass resembling a synovial sarcoma due to TB
panniculitis, is the most common type of panniculitis seen synovitis; [ii] trochanteric bursitis due to TB presenting
in TB (49,50). EN is due to delayed type of hypersensitivity with hip pain; [iii] sternoclavicular mass; [iv] bilateral
reaction to variety of antigens. These several known causes sternoclavicular involvement; [v] involvement of great toe,
of EN like infections [bacterial, mycobacterial and fungal], lower end of fibula, midtarsal joints, and sternum [after
drugs [especially sulphonamides and oral contraceptive pills], sternotomy following bypass surgery] (54-59). Baker’s cyst
inflammatory bowel disease and various rheumatological has also been reported due to TB (60).
conditions like Behcet’s disease and sarcoidosis. This may
be associated with fever and constitutional symptoms in the MUSCULOSKELETAL DISEASES ASSOCIATED
eruptive stage. Arthralgias or arthritis may be seen in up
WITH NONTUBERCULOUS MYCOBACTERIA
to half of these patients. The characteristic presentation is
in the form of erythematous tender nodules over the shins Musculoskeletal involvement due to nontuberculous
[Figure 20.1], which are palpable and often tender. There is mycobacteria [NTM] is uncommon. Mycobacterium kansasii is
 Musculoskeletal Manifestations of Tuberculosis 297

the most common NTM species to cause MSK involvement,

though involvement due to other species like Mycobacterium
xenopi, Mycobacterium avium intracellulare, Mycobacterium
chelonei, Mycobacterium fortuitum has also been reported (61-66).
Synovial sheath infection is more common than infection
of the osseous tissue (13). Most of these patients have some
predisposing conditions though it has been reported in an
immunocompetent patient also (67). These infections have
also been reported in a patient with a rheumatic disease, like
SLE or Still’s disease (68). Arthritis due to NTM has also been
reported after exposure to contaminated marine life (69,70).
The reader is referred to the chapter “Nontuberculous
mycobacterial infections” [Chapter 41] for details.

DIAGNOSIS OF MUSCULOSKELETAL A B
TUBERCULOSIS Figure 20.2: Radiograph of the knee joint [antero-posterior view] [A],
[lateral view] [B], showing symmetrical decreased joint space in tibio-
A high index of suspicion is required for making the diag­ femoral joint with erosions [arrow]
nosis of MSK-TB. Common MSK manifestations are spondy­
litis or chronic monoarthritis. The cornerstone of diagnosis
is the microbiological or histopathological evidence of TB.
Patients with risk factors for TB such as immunocompromised
individuals, elderly, children, those on immunosuppressive
drugs must undergo these investigations in an appropriate
clinical setting.

Laboratory Investigations
Laboratory abnormalities like elevated erythrocyte sedi­
mentation rate [ESR], C-reactive protein [CRP] level have
been described in patients with MSK-TB. However, these
changes are not specific to TB and are found in several other
inflammatory conditions.

Imaging Studies
Imaging in patients with skeletal TB is covered in detail
in the chapter “Skeletal tuberculosis” [Chapter 19]. Certain Figure 20.3: Radiograph of the pelvis [antero-posterior view] showing
additional features related to imaging in MSK-TB are erosions in femoral head and acetabulum with decreased joint space
in the left hip joint [arrow]
described here. The plain radiograph of knee joint and
pelvis may reveal bone destruction [Figures 20.2, 20.3
and 20.4] suggestive of MSK-TB. Among the various available
imaging techniques, computed tomography [CT] is superior
in depicting the degree of bony destruction and facilitating
image-guided biopsy for spinal TB. On the other hand,
for detailed anatomical evaluation and for distinguishing
different densities of tissues [fibrous tissue, abscess, meninges,
spinal cord etc.], magnetic resonance imaging [MRI] with
contrast [Figures 20.5 and 20.6] is considered superior (71).
The characteristic Phemister’s triad is considered to be
typical of TB. Three components of the Phemister’s triad are
[i] juxta-articular osteoporosis; [ii] peripherally located
osseous erosions; and [iii] gradual narrowing of the joint
space (72-75). On the other hand, in the course of RA and
pyogenic arthritis, the joint space narrowing occurs early. For
soft tissue TB, the ultrasonography is the method of choice
as it shows the extent and degree of involvement. On the Figure 20.4: Radiograph of the pelvis [postero-anterior view] showing
other hand, the MRI shows the extent of soft tissue, osseous decreased joint space with irregularity of left sacroiliac joint with
and joint involvement (74). One of the other typical features minimal subchondral sclerosis [arrow]
 298 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

[PPD] used for TST contains various Mtb antigens which

are similar to antigens of BCG and NTM, TST may also be
positive in BCG-vaccinated or NTM infected individuals.
Interferon-gamma release assays [IGRAs] like QuantiFERON
TB gold® and T-SPOT.TB® are also used to diagnose LTBI.
The reader is referred to the chapter “Laboratory diagnosis”
[Chapter 8] for details.

Arthrocentesis, Synovial Biopsy

Synovial fluid aspiration and synovial biopsy are required for
establishing diagnosis of TB arthritis. The issues concerning
procurement of adequate tissue for histopathological
diagnosis of skeletal TB are discussed in the chapter “Skeletal
tuberculosis”[Chapter 19]. The indications for a synovial
biopsy in patients with MSK-TB from a rheumatologist’s
Figure 20.5: MRI T2-weighted image, [sagittal view] of ankle joint perspective is discussed below.
showing nodular synovitis in tibio-talar joint [arrow] with marrow When clinical evaluation and routine investigations fail to
oedema in talus [arrow-head] provide a diagnosis synovial biopsy is the logical next step.
MRI = magnetic resonance imaging
It is usually the only definitive method of diagnosing
infection with fastidious organisms including TB. An absolute
indication for synovial biopsy is a chronic inflammatory
monoarthritis where synovial fluid examination including
microbiological studies may have failed to give a definitive
diagnosis. Another strong indication for synovial biopsy
would be a patient with persistent disease activity in a
single joint.

Mycobacterial Culture, Molecular Diagnostic Methods

Conventional culture of fluid/tissue specimens on Lowenstein-
Jensen [LJ] medium takes a longer time [4-8 weeks].
Newer liquid culture methods like BACTEC have reduced
the isolation time to two weeks. Molecular diagnostic
techniques yield faster results. Polymerase chain reaction
[PCR] has been shown used for the diagnosis of various
EPTB conditions including osteoarticular TB; and even for
Figure 20.6: Contrast-enhanced MRI of the ankle joint showing
thickening and enhancement of synovium in tibio-talar and subtalar diagnosis of NTM infections like Mycobacterium avium (77).
joints [arrow] with irregularity of articular surface [arrow-head] The recently available molecular diagnostic method, Xpert
MRI = magnetic resonance imaging MTB/RIF® is an automated cartridge-based nucleic acid
amplification test [CBNAAT] which is helpful in detecting
of TB of the bones that have a relatively superficial cortical Mtb and identifying rifampicin resistance in 90 minutes. It
surface [e.g., metacarpals, metatarsals, phalanges, tibia and has enormously contributed to the diagnosis of EPTB (78). A
ulna] is the presence of lytic lesions surrounded by reactive recently published systemic review reported good specificity
subperiosteal new bone formation (13). Positron emission for Xpert MTB/RIF® in the diagnosis of various forms of
tomography-computed tomography [PET-CT] has been EPTB (79). The recent World Health Organization [WHO]
used in the diagnosis of joint involvement in TB (76). With policy recommendation states that “Xpert MTB/RIF may
PET-CT, an increased 18fluorodeoxyglucose [FDG] uptake be used as a replacement test for usual practice [including
in regions of active granulomatous inflammation and conventional microscopy, culture or histopathology] for
cold areas in necrosed tissue containing pus has been testing specific non-respiratory specimens [lymph nodes
reported (76). It needs to be emphasised that despite these and other tissues] from patients suspected of having EPTB
advances, the ‘gold standard’ for the diagnosis of TB of the [conditional recommendation, very low-quality evidence]” (80).
MSK system requires histopathological, microbiological
and/or molecular confirmation. TREATMENT
Treatment of MSK-TB consists of administration of standard
Tuberculin Skin Test
anti-TB treatment (81-84). The reader is referred to the chapters
Tuberculin skin test [TST] detects infection with Mtb and “Treatment of tuberculosis” [Chapter 44], Revised National
is a marker of LTBI. Since the purified protein derivative Tuberculosis Control Programme” [Chapter 53] for details.
 Musculoskeletal Manifestations of Tuberculosis 299

As per the recently published evidence-based Guidelines 20. Fukasawa H, Suzuki H, Kato A, Yamamoto T, Fujigaki Y,
for Extrapulmonary TB for India [INDEX-TB Guidelines] Yonemura K, et al. Tuberculous arthritis mimicking neoplasm
(84), extended course of anti-TB treatment with a two- in a hemodialysis patient. Am J Med Sci 2001;322:373-5.
21. Binymin K, Cooper RG. Late reactivation of spinal tuberculosis
month intensive phase consisting of four drugs [isoniazid,
by low-dose methotrexate therapy in a patient with rheumatoid
rifampicin, pyrazinamide, ethambutol], followed by a arthritis. Rheumatology [Oxford)] 2001;40:341-2.
continuation phase consisting of isoniazid, rifampicin and 22. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J,
ethambutol lasting 10-16 months, depending on the site of Schwieterman WD, et al. Tuberculosis associated with infliximab,
disease and the patient’s clinical course has been advocated a tumor necrosis factor alpha-neutralizing agent. New Engl J
for patients with skeletal TB. Med 2001;345:1098-104.
23. Hernández-Cruz B, Sifuentes-Osornio J, Ponce-de-León Rosales S,
Ponce-de-León Garduño A, Díaz-Jouanen E. Mycobacterium
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 21
Cutaneous Tuberculosis
M Ramam

INTRODUCTION for 0.11%-2.5% of all patients with skin diseases seen at

hospitals located in different parts and this figure seems to
Cutaneous tuberculosis [TB] is an ancient disease. Cutaneous
be constant for all regions of the country (24-36). In a study
lesions of TB were described long before Robert Koch
from Vishakapatnam (24), cutaneous TB constituted 0.025%
identified Mycobacterium tuberculosis [Mtb]. The first
of all patients with TB and 15% of all patients with extra-
description of cutaneous TB is attributed to Laennec (1) in
pulmonary TB [EPTB]. One study (34) found that cutaneous
1826 who described his own Prosector’s wart that followed an
TB was associated with TB in other organs in 22.1% of
injury sustained while performing an autopsy on a patient
patients. The organs affected most commonly were lungs,
with spinal TB. Mtb was first demonstrated in tissue sections
followed by bones, the abdomen, central nervous system and
of lupus vulgaris by Demme (2) in 1883. In 1886, Reihl
the heart. Most studies reveal a male preponderance and a
and Paltauf (3) established that the Prosector’s wart was
significant proportion of those affected are children (24-36).
a TB lesion. Apple-jelly nodules in lupus vulgaris were first
The disease is more common in the poor. In a study from
described in 1888 (4) and tuberculids in 1896 (5).
Chandigarh (34), about 70% of the patients had developed
the disease in spite of having been vaccinated with bacilli
EPIDEMIOLOGY Calmette-Guérin [BCG]. Patients who had not been
World Scenario vaccinated were more likely to have TB in another organ
than those who had received BCG vaccine (34).
Cutaneous TB appears to have been frequently encountered
by dermatologists all around the world during the early part
CLINICAL FEATURES
of this century and comprised 0.1%-2.6% of the total number
of dermatology patients in various hospitals at different Cutaneous TB presents in a variety of ways. The presentation
periods of time (6-22). Some workers had suggested that is determined by the host immune response, the route of
cutaneous TB was uncommon in the tropics and ascribed this inoculation and the previous sensitisation of the host to the
difference to the abundant sunshine and consequent high Mtb. The clinical varieties of cutaneous TB can be divided
levels of vitamin D in the skin (9,23). However, this view into three broad groups [Table 21.1].
appears erroneous as evidenced by the numerous reports Lupus vulgaris is the most common variety reported
of cutaneous TB from India (24-36). from India followed by scrofuloderma and TB verrucosa
cutis. The other types are distinctly rare.
Indian Scenario
Tuberculosis Chancre
No systematic survey for the prevalence and incidence of
cutaneous TB in the community appears to have been carried TB chancre develops at the site of inoculation of Mtb in
out in India. Information on the epidemiology of the disease a previously non-sensitised host. The bacillus enters the
is, therefore, based on hospital records and suffers from skin following minor wounds and abrasions. It may also
the usual drawbacks of such data. Cutaneous TB accounts gain entry following trauma, injections, circumcision and
 Cutaneous Tuberculosis 303

Table 21.1: Clinical varieties of cutaneous TB Lupus Vulgaris

Lesions developing in those not previously exposed to Lupus vulgaris is probably the common mani­fes­­tation
Mycobacterium tuberculosis of cutaneous TB. Classically, it presents as an indolent,
TB chancre asymptomatic, gradually progressive, firm plaque with
Acute miliary TB of the skin
central clearing and peripheral activity [Figure 21.2]. In
Lesions developing in previously sensitised hosts
Lupus vulgaris
some cases, the progressing border of the plaque reveals
Scrofuloderma translucent, erythe­matous papules that show a residual
TB verrucosa cutis yellowish brown colour when blanched with a glass
Tuberculids slide, the so-called “apple-jelly nodules”. Though this term
Lichen scrofulosorum is associated with lupus vulgaris, it may be seen in other
Papulonecrotic tuberculids granulomatous diseases including sarcoidosis and leprosy.
Erythema induratum
Further, apple-jelly nodules are often obscured by the
TB = tuberculosis hyperkeratosis and crusting of lupus vulgaris. Thus, this
is not a particularly useful sign. As the lesion progres­ses,
there is central healing with scarring while the periphery
ear piercing. A non-descript papule or nodule develops at continues to spread [Figure 21.3]. The lesion may be atrophic
the site followed by crusting and ulceration. Spontaneous or may show varying degrees of hyperkera­tosis that may
healing may occur but lesions usually proceed to lupus be severe enough to produce cutaneous horns. The lesion
vulgaris. The regional lymph nodes are enlarged and may is usually dry but may occasionally be accompanied by a
break down to form a discharging sinus in three to six
months. Acid-fast bacilli [AFB] can be demonstrated and
grown from early lesions. Skin biopsy reveals necrosis,
infiltration by neutrophils and numerous AFB in early
lesions. Later, epithelioid cell granulomas develop,
accompanied by the disappearance of bacilli from the lesion.

Acute Miliary Tuberculosis of the Skin

Miliary TB develops following the haematogenous dis­
semination of Mtb (37). It may follow measles or other
viral exanthems (38). The skin lesions of miliary TB present
as pustules, vesicles and papules that have a non-specific
appearance and lack any diagnostic features [Figure 21.1].
Constitutional symptoms are usually severe and the patient
is often gravely ill. The diagnosis may be suspected if the
patient is known to have TB in another system. Mtb can be
demonstrated in the lesions.
Figure 21.2: Lupus vulgaris. Central scarring and peripheral activity in
a long-standing lesion

Figure 21.1: Miliary tuberculosis of the skin. Chest radiograph revelaed

miliary lesions. Polymerase chain reaction from skin lesions detected Figure 21.3: Lupus vulgaris. Annular plaque with erythematous and
mycobacterial deoxy­ribo­nucleic acid scaly papules at the periphery and a relatively clear centre
 304 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

thin sero-purulent discharge and moist crusts. Lesions may

reach enormous sizes over the years and cause considerable
damage and mutilation. Squamous cell carcinoma has been
des­cribed to complicate long-standing lesions (39). The
classical site of lesion is the face but it is seen at least as
commonly on the buttocks [Figure 21.4] and lower limbs in
Indian patients. The lesion is usually single but less com­
monly, multiple lesions may develop in one anatomic area or
may be scattered over the skin surface. Rarely, symmetrical
lesions may develop. Lupus vulgaris may develop at the site
of cutaneous exten­sion of TB from an underlying focus. It
has also been reported as a rare complication of BCG vac­ci­
na­tion (40,41) [Figure 21.5]. The regional lymph nodes may
be slightly enlar­ged but do not show any evidence of TB.
In some patients, the presence of broad, atrophic scarring
indicating the possibility of a previous TB infection of the
regional lymph nodes may be noted [Figure 21.6]. Less
commonly, the regional lymph nodes draining a lesion Figure 21.5: Lupus vulgaris following vaccination with BCG
of lupus vulgaris may show active scrofulo­derma. Most BCG = bacille Calmette-Guérin
patients with lupus vulgaris are well-preserved and do
not have constitutional symptoms even when lesions are
extensive and multiple. The tuberculin skin test [TST] is
positive in many but not all patients. Skin biopsy reveals
epithelioid cell granulomas in the upper dermis abutting the
epidermis which is usually thickened and hyperkeratotic.
The granulomas may show necro­sis though this is not a
common finding. AFB cannot, as a rule, be demonstrated
on sections. Culture of the biopsy material is not rewarding.

Tuberculosis Verrucosa Cutis

TB verrucosa cutis, probably a variant of lupus vulgaris, is
characterised by a striking degree of hyperkeratosis in the
lesions. The lesion usually develops over the acral parts of
the extremities as a gradually progressive indurated plaque
with a rough, horny surface but may also develop at non-
acral sites [Figures 21.7 and 21.8]. With time, the lesions
become progressively larger and hyper­kera­­totic and may Figure 21.6: Lupus vulgaris of the ear lobe. Note scars of healed
involve the entire foot [Figure 21.9]. Multiple lesions are scrofuloderma on the neck

Figure 21.4: Lupus vulgaris. The buttocks are a common site Figure 21.7: Tuberculosis verrucosa cutis. The sole is often affected
 Cutaneous Tuberculosis 305

Figure 21.8: Indurated plaque with a horny, keratotic surface Figure 21.10: Scrofuloderma overlying tuberculosis of the cervical and
axillary lymph nodes

Figure 21.9: Tuberculosis verrucosa cutis. Advanced disease with the Figure 21.11: Scrofuloderma secondary to tuberculosis of the bone.
entire foot appearing to be encased in a keratotic boot Note the thickened metacarpals underlying the sinus on the dorsum
of the hand

unusual and lymph nodes show changes similar to those thin, seropurulent material. The edge of the sinus usually
seen in lupus vulgaris. Constitutional signs are usually shows a purple discolouration, is thinned and may be
absent. The TST is often positive. Skin biopsies must be eroded. The sinus is usually attached to the underlying
taken carefully from the least keratotic area and incised deep structure. Crusts are present and may be large. Some
enough to include the underlying indurated plaque, else, patients show episodic activity in lesions with the amount of
only thickened stratum corneum will be seen. An adequate discharge showing periodic variations and even drying up
biopsy reveals an enormously thicke­ned epidermis with completely to recur after varying periods of time extending
small epithelioid granulomas amidst a lichenoid infiltrate of up to several months. In long-standing lesions, there are
lymphocytes and plasma cells in the upper dermis. Necrosis usually broad atrophic scars that represent spontaneously
is absent and AFB can­not usually be demonstrated or grown healed sinuses. Scarring and fibrosis of lymph nodes may
from biopsy material. lead to lympho­edema and elephantiasis [Figure 21.12]. In
contrast to filariasis, the skin of the lymphoedema­tous area
Scrofuloderma often shows lesions of cutaneous TB, usually lupus vulgaris
Scrofuloderma is the term applied to lesions that develop [Figure 21.13]. AFB may be demonstrated in the discharge
in the skin from contiguous spread or exten­s ion of TB from lesions and Mtb, and rarely nontuberculous mycobacteria
from an underlying or adjacent structure. Most often, the [NTM] such as Mycobacterium avium complex, Mycobacterium
primary focus is in the lymph nodes [Figure 21.10] but bones scrofulaceum can also be cultured. Fine needle aspiration
[Figure 21.11] and joints may also be the source of infection. cytology [FNAC] of the underlying structure, usually lymph
The cutaneous lesion is a sinus or a crusted ulcer discharging node, confirms the diagnosis of TB. Biopsy from the edge
 306 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

of the sinus reveals a mixed cell granuloma consisting of orifices. Usually lesions develop around the perianal
epithe­lioid cells and histiocytes admixed with neutrophils area [Figure 21.15] or around the mouth in patients with
and eosinophils. There are areas of necrosis and AFB may abdominal or pulmonary TB. The lesion is a nodule that
be identified in the biopsy. Culture of biopsy material grows breaks down to form an indolent, deep ulcer. The diagnosis
Mtb or NTM in some patients. is usually suspected when the ulcer does not heal in spite
of antibiotic therapy. Biopsy from the edge of the ulcer
Tuberculosis Gumma reveals epithelioid granulomas. AFB may occa­sionally be
demonstrated or grown from the lesion.
TB gumma refers to soft, subcutaneous swellings which
often break through the overlying skin to produce ulcers
Tuberculids
[Figure 21.14]. The lesions resem­b le scrofuloderma on
clinical, histopathological and microbiological grounds and Tuberculids are skin lesions that develop as a hyper­
can be considered as a variant produced by haematogenous sensitivity response to the presence of a TB focus elsewhere
seeding of sub­cutaneous tissue with Mtb. in the body. The following criteria must be fulfilled to
designate a condition as tuberculid: [i] the skin lesion must
Tuberculosis Cutis Orificialis show a tuber­culoid histopatho­logy; [ii] Mtb must not be
demonstrable in the lesion; [iii] the TST must be strongly
TB cutis orificialis develops by the inoculation of Mtb derived positive; and [iv] treatment of the under­lying TB focus
from visceral infection into the skin around the draining must lead to resolution of the skin lesions. In some cases,
it is easy to document the focus; while in others, this may
not be possible. In clinical practice, physical examination
and simple imaging procedures are undertaken to look for
TB elsewhere. If these tests fail to reveal a focus and clinical
suspicion of a tuberculid is high, presumptive treatment for
TB is administered.
Since Mtb cannot be demon­strated in tuberculids, there
has been consi­derable controversy over the existence of
this entity. Historically, the label was applied to all skin
condi­tions that showed a tuberculoid granuloma on histo­
pathology including some conditions subsequently found
to be unrelated to TB. It was hypothesised that such skin
lesions represented a hypersensitivity response to a manifest
or occult TB focus elsewhere in the body. This led to the
grouping together of a heterogeneous group of conditions
that were subsequently shown to share no aetiologic or
Figure 21.12: Esthiomene secondary to healed scrofuloderma of the pathogenetic similarity. Pre­s ently, three conditions are
inguinal and external iliac lymph nodes. Note the scars in the area of unequivocally accepted as tuberculids: lichen scrofulosorum,
both inguinal ligaments papulonecrotic tuberculids and erythema indura­tum.

Figure 21.13: Lymphoedema of the right lower Figure 21.14: Tuberculosis gummas which Figure 21.15: Orificial tuberculosis. Indolent,
limb with gummas on the skin have broken down to form ulcers non-healing ulcer of the anus. The patient had
abdominal tuberculosis
 Cutaneous Tuberculosis 307

Figure 21.16: Lichen scrofulosorum. Grouped, minute Figure 21.17: Papulonecrotic tuber- Figure 21.18: Erythema induratum. Per­
erythematous papules culid. Indurated papulo-nodules with sistent ulcers with underlying induration
a central necrotic crust on the posterior aspect of the leg

In addition, TB is an important cause of erythema nodosum Erythema Induratum

in Indian patients. Recent studies employing the polymerase
Erythema induratum presents as indolent, mildly tender,
chain reaction [PCR] have demonstrated the presence of
dull red nodules ranging in size from 5–7.5 cm that usually
mycobacterial deoxyribonucleic acid [DNA] in biopsies
develop on the calves. Some nodules soften and break down
from patients with erythema induratum (42,43) and papulo­
to form deep persistent ulcers that gradually heal over
necrotic tuberculids (42,44) providing further evidence of
several weeks with scarring [Figure 21.18]. New nodules
the association between these conditions and TB.
may continue to develop while old lesions are resolving.
The TST is positive. Skin biopsy reveals a granulomatous
Lichen Scrofulosorum
lobular pan­ni­culitis with vasculitis of small and/or medium
Lichen scrofulosorum typically presents as a crop of two vessels. A focus of TB is demonstrable in many patients.
to five mm erythematous papules that show a tendency to However, a signifi­cant proportion of patients who show the
grouping [Figure 21.16]. Many papules show crusting. The typical clinical and histopathological features of erythema
eruption has a predeliction for the trunk but may occur at induratum do not have TB. In these patients, the reaction
other sites also. Individual papules tend to resolve in about pattern has presumably been triggered by some other cause.
two weeks with hyper­pigmentation but crops of lesions
may come and go over several months. Uncommonly, the Erythema Nodosum
eruption may develop after initiation of anti-TB treatment;
Erythema nodosum presents as erythematous, tender, 2.5–5 cm
these lesions subsided on continuing treatment (45). The TST
nodules that usually develop on the shins [Figure 21.19] but
is strongly positive and may show ulceration. Biopsy reveals
focal epithelioid cell granulomas within and around the hair
follicle or the sweat duct. The underlying TB focus may be
in the lymph nodes, lungs or at some other site.

Papulonecrotic Tuberculids
Papulonecrotic tuberculids present as an eruption of
multiple, papulo-nodular lesions ranging in size from two
to five cm occurring over the trunk and extremi­ties. The
eruption may be preceded by fever and constitutional
symptoms. Individual lesions show pustulation and crusting
at the centre [Figure 21.17]. Removal of the crust reveals a
deep ulcer. The lesions heal gradually over four to six weeks
with scarring. Crops of lesions recur at variable intervals.
The TST test is strongly positive and often ulcerates. Skin
biopsy reveals wedge-shaped necrosis of the epidermis
and upper dermis with underlying epi­thelioid granulomas.
A focus of active TB can usually be demonstrated in these Figure 21.19: Erythema nodosum. Tender, erythematous, non-
patients. ulcerated nodules on the shins
 308 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

may also involve the thighs, buttocks and forearms in severe individuals should be biopsied and subjected to culture (47).
cases. Low-grade fever and swelling of the ankle joints Biopsy reveals a neutrophilic infiltrate which may be admixed
accom­pany the skin lesions in some patients. The lesions with histiocytes. Epithelioid cells, giant cells and well-formed
regress spontaneously becoming dull red, violaceous, finally granulomas are uncommon; AFB are usually seen in large
leaving behind macular hyperpigmentation. Ulceration and numbers. Culture from the lesions usually grows Mtb or
scarring are not features of erythema nodosum. Recurrent NTM. Most patients recover with anti-TB therapy but some
crops of lesions may develop. Skin biopsy reveals a may die in spite of appropriate treatment. However, in those
septal panniculitis with an infiltrate of lymphocytes and with less advanced HIV disease, the clinical manifestations
histiocytes. Giant cells may be seen within the thickened are largely similar to those noted in other patients. In one
septum. Erythema nodosum is a reaction pattern that may study, cutaneous lesions were described to be multiple
be provoked by a variety of triggers, infective and non- and larger with involvement of more than one under­
infective. However, in India, TB is still an important cause lying structure, lymph node or bone, with more common
of this condition justifying its inclusion in this section. systemic involvement and less frequent tuberculin test
positivity. However, histopathological findings and treat­
Others ment responses were similar (54).
Multiple episodes of Sweet’s syndrome were recently reported
LABORATORY DIAGNOSIS
during treatment of scrofuloderma and probably represent a
hypersensitivity phenomenon similar to the tuberculids (46). It is easy to obtain tissue specimens in patients with cutaneous
The reader is also referred to the chapter “Musculoskeletal TB; however, the diagnostic yield on direct microscopy or
manifestations of tuberculosis” [Chapter 20] for more details on conventional culture methods is uniformly poor. Mtb has
erythema nodosum and erythema induratum. been demonstrated in 4%-9% of cases (32,33) and is hardly
ever seen in lupus vulgaris and TB verru­cosa cutis. AFB are
CUTANEOUS TUBERCULOSIS IN found in about 35% of cases (35,36). The results of culture
IMMUNOCOMPROMISED HOSTS of biopsy material are equally disappointing. Cultures were
found to be positive in less than 10% of cases (32,33,35,36).
The human immunodeficiency virus [HIV] epidemic has However, a much higher yield has been reported in other
focused attention on the manifestations of TB in patients with studies ranging from 12 of 51 cases [23.5%] (31), 29 of 51
acquired immunodefi­ciency syndrome [AIDS] (37,47-51). [56.9%] cases (55), 112 of 203 cases [55.2%] (56) and 26 of
Similar features may, however, be seen in persons who are 35 cases [74.3%] (57). Availability of radiometric methods
immuno­suppres­sed due to other reasons as well (52,53). has decreased the time taken for culture but is expensive
In patients with advanced immunodeficiency, the lesions and is unlikely to be of much use in cutaneous TB which
do not fit into the above descri­bed categories and usually is paucibacillary (58). One study has recommended the
present as papules, nodu­les, vesicles or induration. use of both conventional and liquid media to increase the
Ulceration and discharge from the surface of the lesions isolation rate (57). Histopathological examination reveals
may be a feature [Figure 21.20]. The diagnosis is usually a granulomatous dermatitis in 82–100% of cases (32-36).
not suspected clinically and it has been suggested that all However, it is difficult to demonstrate Mtb in tissue sections.
atypical cutaneous lesions developing in immunosuppressed The TST is positive in 73%-100% of patients (32-36).
Increasing the cut-off for a positive test increases the
specificity of the test but decreases the sensitivity (59,60).
A study (61) of the utility of the TST in patients with a
doubtful diagnosis of cutaneous TB revealed that the test did
not perform well in differentiating TB from other diseases.
In 1992, Victor et al (44) first described the use of PCR
in cutaneous TB. Several reports have since documented
the use of the test in lupus vulgaris, scrofuloderma and
the tuberculids (43,62-74). Some workers (71,72) have
demonstrated a high sensitivity of the technique in
cutaneous TB though another group (73) did not find it
useful in paucibacillary forms. In a study (74) on 66 cases
and 47 controls from India, a true positive rate of 25.8% and a
false positive rate of 27.7% were reported with PCR. Another
study demonstrated a sensitivity of 25% and a specificity of
73.7% with DNA PCR while none of the cases or controls
were positive on messenger ribonucleic acid [mRNA]
Figure 21.20: Nodules papules and pustules on the buttock of a patient PCR (75). In a recent study (76a), Xpert MTB/RIF was not
with Cushing’s syndrome. Numerous acid-fast bacilli were seen on found to be useful as a diagnostic test for cutaneous TB.
biopsy It appears that clinical decisions about the diagnosis and
 Cutaneous Tuberculosis 309

treatment of patients with cutaneous TB should not be based is rare. Skin biopsy reveals a range of patterns from acute
on PCR results alone. neutrophilic inflammation to granulomas admixed with
Finally, if the results of laboratory tests are inconclusive, neutrophils. AFB are difficult to find in tissue sections (84).
a therapeutic trial with anti-TB drugs is frequently used to The organism grows best at 30 oC–33 oC on mycobacterial
confirm the diagnosis in difficult cases (76b-79). Evidence is media. Several antibiotics have been found to be effective
available suggesting that when a therapeutic trial is under­ including rifampicin and ethambutol, doxycycline and
taken in cutaneous TB, 6 weeks of therapy with isonaizid, minocycline, clarithromycin and cotrimoxazole. Treatment
rifampicin, pyrazinamide and ethambutol drugs appears is recommended for two months after clinical healing; deep
adequate to prove [or disprove] the diagnosis (76b-79). infections require treatment for longer periods. Surgical
If there is no improvement at all after six weeks, anti- debridement should be considered in deep infections,
TB treatment should be stopped and the diagnosis re- immunocompromised patients or if medical therapy fails.
considered. There is no benefit of continuing the trial for Buruli ulcer disease is the third most common myco­
longer periods. bacterial disease in immunocompetent people, after TB and
leprosy (85,86). It is caused by M. ulcerans, a mycobacteria
BACILLE CALMETTE-GUÉRIN AND found in soil and vegetation in many parts of the world,
CUTANEOUS LESIONS especially in tropical rain forests. The organism enters
the skin through abrasions and injuries and is commoner
Skin complications due to BCG vaccination have been on the extremities. Children are affected more frequently
classified into local and generalised forms (80,81). These though no age is exempt. Three clinical stages are described:
details are shown in Table 21.2. pre-ulcerative lesions may be papules, nodules or plaques.
These progress to necrosis of the subcutaneous fat and
undermined ulcers of the overlying skin. Untreated ulcers
Table 21.2: Skin lesions due to BCG vaccination
may extend and reach to large sizes. On skin biopsy, large
Local lesions number of AFB can be detected in about 60% of cases
Keloid
Abnormally large ulcer
at this stage accompanied by necrosis of the dermis and
Subcutaneous abscess subcutaneous fat with minimal inflammation (87). The
Epithelial cyst final stage of scarring follows spontaneous healing of the
Eczematous reaction ulcers. Scarring can lead to contractures and ankylosis and
Granulomatous reaction is a major cause of disability. Antibiotics are the treatment
Lupus vulgaris
of choice with a regimen of rifampicin [10 mg/kg], orally
Warty TB
Generalised lesions and streptomycin [15 mg/kg], intramuscularly for 8 weeks
Erythema nodusum shown to be effective in producing microbiological and
Tuberculids clinical improvement. Alternatively, this combination can be
Scrofuloderma given for 4 weeks followed by an oral regimen of rifampicin
Non-specific haemorrhagic eruptions
and clarithromycin [7.5 mg/kg, twice daily] for 4 weeks.
BCG = bacille Calmette-Guérin; TB = tuberculosis Some workers have used an oral regimen of rifampicin and
Based on references 80,81
clarithromycin for the entire 8-week period. Moxifloxacin,
400 mg daily orally has been used instead of clarithromycin.
Following antibiotic therapy, small and intermediate lesions
CUTANEOUS LESIONS DUE TO may heal completely and surgical debridement may not
NONTUBERCULOUS MYCOBACTERIA be necessary. Larger lesions will require less extensive
Skin involvement due to NTM such as, M. marinum and debridement and grafting if preceded by a complete course
M. ulcerans, are clearly defined clinical entities and are of antibiotics (88).
considered first. This is followed by a description of A large number of other NTM have been reported to cause
miscellaneous lesions caused by a number of other NTM. cutaneous infections in immunocompetent and immunocom­
M. marinum is a pathogen of many species of fish, both promised hosts (89-96). Most of these mycobacteria are
fresh and salt water. Humans acquire the disease from present in the environment and gain access to the skin
infected fish or water through breaches in the skin, usually following an injury, including iatrogenic injuries following
of the upper and the lower limb (82,83). These infections needle pricks and surgery. Rapid growers, M. marinum,
have been termed fish tank granuloma and swimming M. ulcerans are most common species that cause skin, soft
pool granuloma. A nodule, or less commonly, an ulcer, tissue infections, especially at site of skin punctures or surgery.
pustule or abscess develops at the site of injury about two A variety of clinical manifestations are described: papules,
weeks following exposure. In one-third of cases, lesions are pustules, nodules, abscesses, cellulitis, ulcers and sinuses.
arranged linearly along the lymphatics in a “sporotrichoid” The clinical features are not distinctive and the infection may
pattern. In about a third of patients, the infection extends to be suspected from the setting. Skin biopsy reveals diverse
the deeper tissues, usually the tenosynovium; joints and bone inflammatory patterns including suppuration, granulomas,
may also be involved. Systemic dissemination of infection folliculitis, panniculitis and diffuse histiocytic infiltrates (61).
310 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The histopathological features are not specific for any organism. 6. Horwitz O. Lupus vulgaris cutis in Denmark 1895-1954: its
The AFB are easily seen in immunocompromised hosts but relation to the epidemiology of other forms of tuber­ culosis.
may be difficult to find in the immunocompetent. Culture Acta Tuberculosea Scandinavia 1960;49 Suppl:1-145.
7. Forstrom L. Frequency of other types of tuberculosis in patients
and drug-susceptibility testing [DST] testing of the causative
with tuberculosis of the skin. Scand J Clin Lab Invest 1969;
organism is helpful for confirmation of the diagnosis and 23 Suppl:1-37.
treatment. 8. Choudhury AM, Ara S. Cutaneous tuberculosis-a study of 400
M. chelonae also produces skin, soft tissue and bone cases. Bangladesh Med Res Counc Bull 2006;32:60-5.
infections. M. chelonae has been associated with contact lenses 9. Fasal P, Rhodes R. Cutaneous tuberculosis and sarcoi­dosis in
and laser-associated in situ keratomileusis [LASIK] surgery. the American Negro and in inhabitants of tropical countries.
Disseminated disease in immunocompromised individuals In: Simons RDGP, editor. Handbook of Tropical Dermatology
can occur with characteristic skin lesions [painless, fistulised and Medical Mycology, Volume 1. New York: Elsevier; 1952.
nodules and abscesses]. Skin, soft tissue and bone infections p.578-603.
10. Neves H. Incidence of skin diseases 1952-65. Trans St Johns Hosp
due to M. fortuitum are common than pulmonary infections.
Dermatol Soc [London] 1966;52:255-70.
Outbreaks of furunculosis have been reported following 11. de Noronha T, de Almeida Gonclaves JC. O tratamento da
exposure to contaminated water during pedicures. tuberculose cutanea. Acrhivo Pathol 1961;33:20-45. Abstracted in
Excerpta Medica [Dermatology and Venereology] 1962;16:254.
TREATMENT 12. Ustvedt HJ, Ostensen IW. The relation between tubercu­losis of
the skin and primary infection. Tubercle 1951;32:36-9.
The recommended therapy for cutaneous TB is the use of 13. Amezquita R. Tuberculosis cutanea. Aspectos clinicos epidemio­
short-course regimens as used for pulmonary TB. As per logicos en Mexico. Tesis recepcional. Acta Leprologica 1963;
the recently published Guidelines for Extrapulmonary TB 16:1-103. Abstracted in Excerpta Medica [Dermatology and
for India [INDEX-TB Guidelines] (75), standard 6 months Venereology] 1965;19:674.
short-course treatment is considered adequate for cutaneous 14. Mitchell PC. Tuberculosis verrucosa cutis among Chinese in
TB. The reader is referred to the chapter “Treatment of tuber­ Hong Kong. Br J Dermatol 1954;66:444-8.
15. Wong KO, Lee KP, Chiu SF. Tuberculosis of the skin in Hong
culosis” [Chapter 45] for further details. Using these regimens,
Kong. Br J Dermatol 1968;80:424-9.
lupus vulgaris and TB verrucosa cutis were found to heal 16. Goh YS, Ong BH, Rajan VS. Tuberculosis cutis in Singapore:
completely in 4–5 months. The skin lesions of scrofuloderma a two-year experience. Sing Med J 1974;15:223-6.
healed in 5–6 months while the lymph nodes regressed in 17. Li HC. A preliminary study of tuberculosis of skin in Peking.
7–9 months. There were no relapses in the patients who Chinese J Dermatol 1957;5:13-22.
were followed up for three and a-half years (73,97). Drug 18. Lee YB, Cho BK, Houh W. Clinical and histopathological study
resistance in cutaneous TB appears to be rare though recent on skin tuberculosis during 5 years [1970-74]. Korean J Dermatol
reports of culture-documented cases with drug resistant 1975;13:103-8.
TB gummas and scrofuloderma are a worrisome develop­ 19. Kqn KS, Chung TA. A clinical study on skin tuberculosis. Korean
J Dermatol 1977;15:181-9.
ment (98-100). Under the Revised National Tuberculosis
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23. Zoon JJ. Tuberculosis of the skin. Consideration about patho­
treatment of cutaneous NTM disease.
genesis. AMA Arch Dermatol 1957;75:161-70.
24. Satyanarayana BV. “Tuberculoderma” a brief review together
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 22
Lymph Node Tuberculosis
Saurav Khatiwada, Arvind Kumar

INTRODUCTION reports from the developed world (9,10). In Australia (11)

and British Columbia (12), NTM have been detected 10 times
Mycobacterial lymphadenitis has plagued humanity since more frequently than Mtb. In studies reported from the USA,
ancient times. It has been called as “scrofula” [a term Mtb accounted for 95% of all mycobacterial lymphadenitis
derived from the Latin for “glandular swelling” or from in adults, whereas in children, 92% of the myco­bacterial
the French “full necked sow”] and “King’s evil”. Peripheral lymphadenitis was due to NTM (13,14).
lymph node involvement is the commonest form of In addition to geographical variation, there has been
extrapulmonary mycobacterial disease and the cervical a chang­ing trend in the prevalence of these orga­­nisms
region is the most frequently affected site (1-3). In the present over a period of time at some places. In England, there
era, Mycobacterium tuberculosis [Mtb] is the most common has been a decline in TB lymphadenitis and a rise in NTM
cause of mycobac­terial lymphadenitis and lymphadenitis lymphadenitis (15). A high frequency of disease has been
due to nontuberculous mycobacteria [NTM] is also being reported in pop­u­lations hailing from areas where TB is
increasingly encountered. Peripheral and mediastinal lymph hig­hly endemic. In one study (2) patients from the Indian
node tuberculosis [TB] is commonly seen in patients with subcontinent, who othe­r­wise constituted only 10% of the
human immunodeficiency virus infection [HIV] and the popu­lation of that region, accounted for 81% of the 61 cases
acquired immunodeficiency syndrome [AIDS]. of mycobacterial lymphadenitis. Similar results have been
reported among Native Americans and in patients from
EPIDEMIOLOGY South-East Asia and Africa (16,17). A high frequency of
disease has also been reported among Asians and Hispanic
Myocobacterial lymphadenitis has shown marked geogra­
patients in the San Francisco area (17). Patients of Asian
phical variation. In the developing and underdeveloped
origin and African-Americans also seem to have a high
countries, TB lymphadenitis con­­tinues to be the most
predilection for developing lymph­adenitis due to Mtb (18-21).
common and lymph­adenitis due to NTM is seldom seen.
In several studies from India (3-6), Mtb has been the most
com­mon pathogen isolated from patients with myco­bacterial PATHOGENESIS
lymphadenitis accounting for almost all the cases (3-6). TB lymphadenitis is considered to be the local manifesta­tion
Among adults, lymph node TB is the most common form of a systemic disease whereas lymphadenopathy due to NTM
of extra-pulmonary TB [EPTB], accounting for 35% of EPTB is truly a localised disease. Mtb generally enters the body via
cases (7). In a community-based, house-to-house survey of the respiratory tract and undergoes hae­­m­­a­togenous and
a population of 23,229 in 35 neighbouring villages with 7900 lymphatic dissemination. Hilar and mediastinal lymph nodes
children aged 0–14 years in the rural area of Wardha district, are the first lymphoid tiss­ues encountered in the lymphatic
Maharashtra State, Central India, from May 1993 to May 1994 spread from the lung parenchyma. This involvement may
and from March 1995 to February 1996, the prevalence of occur at the time of primary infection or may occur later in
lymph node TB was reported to be 4.43/1000 children (8). life due to reactivation of previous infection. Tonsil is also
On the other hand, NTM are the most freq­uen­tly isolated an important portal of entry. The infection may then spread
pathogens from the lymphadenitis spe­cimens in several via the lymphatics to the nearest cervical lymph nodes.
314 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

In the initial stages, the nodes may be discrete clinically. Some patients with lymph node TB may manifest systemic
Periadenitis results in matting and fixity of the lymph symptoms. These include fever, weight loss, fatigue and
nodes. The lymph nodes coalesce and break down to form occa­sionally night sweats [Table 22.1] (2-4,23,24). Cough
caseous pus. This may perforate the deep fascia and present may be a prominent symptom in patients with mediastinal
as a fluctuant swelling on the surface [collar-stud abscess]. lymph­adenopathy.
Overlying skin becomes indurated, breaks down and leads Jones and Campbell (25) had classified peripheral TB
to the formation of a sinus which if untreated may remain lymph­adenopathy into five stages [Table 22.4]. Physical
unhealed for years. Healing may occur from each of the three examination findings depend upon the stage of the
stages with calcification and/or scarring. disease. The enlarged lymph nodes may be of varying
In NTM lymphadenitis, the pathogens usually enter the size, discrete or matted. The lymph nodes may be firm or
lymph nodes directly via oropharyngeal muc­osa, salivary cystic inconsistency if necrosis and abscess formation has
glands, tonsils, gingiva or con­junctiva (14,22) and lymph taken place [Figure 22.1]. The lymph nodes are usually not
node involvement repr­e­sents a localised disease. The reader tender unless secondary bacterial infection has occurred.
is referred to the chapter “Nontuberculous mycobacterial Physical examination may be unremarkable but for palpable
infections” [Chapter 41] for further details. lymphadenopathy. Sometimes, lymph node abscess may
burst leading to a chronic non-healing TB sinus and ulcer.
CLINICAL PRESENTATION The typical TB sinus has thin, bluish, undermined edges with
scanty watery discharge [Figure 22.2].
Tuberculosis Lymphadenitis
Various complications have also been described due to
Clinical presentation of TB lymphadenitis in several published media­stinal lymph node TB. These include dysphagia due to
studies is summarised in Tables 22.1, 22.2 and 22.3 (2-4,23,24). pressure on the oeso­phagus (26,27), oesophago-mediastinal
TB cervical lymphade­n­itis tends to occur more often in fistula (28-30), tracheo-oesophageal fistula (31,32). Sometimes
females and presents in young adults [Table 22.1]. Patients TB tracheo-oesophageal fistula may mimick a malignant
usu­ally present with slowly enlarging lymph nodes and tracheo-oesophageal fistula. Occasionally, upper abdo­m­­
may otherwise be asymptomatic. Cervical lymph nodes inal and mediastinal lymph nodes may cause thoracic duct
are most commonly affected although axillary and inguinal obstruction and present as chylo­tho­rax, chylous ascites or
lymph nodes may also be involved. Ass­o­ciated media­ chyluria (33). Rarely, jaun­dice occurs because of biliary
stinal lymphadenopathy may also be present sometimes. obs­truction due to enlarged lymph nodes (34). Cardiac

Table 22.1: Demographic characteristics and symptoms at presentation in adult patients with peripheral lymph
node TB
Studies from India­ Studies from other parts of the world­
Dandapat et al (3)­ Subrahmanyam (4) Chen et al (23) Thompson et al (2) Fain et al (24)
[n = 80]­ ­[n = 105] [n = 71]­ [n = 67]­ ­[n = 59]­
Asian group* White group
Variable­ ­[n = 54]­ [n = 13]­
Place of study­ Berhampur­ Solapur­ Taipei­ Leicester­ Leicester­ Paris­
Duration of study [years]­ 1­ 1.5­ 6­ 10­ 10­ 4­
Mean age [years]­ †­­ ‡­ 42­ 41.8­ 46.9­ 37.6­
Male:Female­ 1:12­ 1:1.3­ 1:1.5­ 1:1.5­ 1:2.3­ 1:1.5­
History of contact with a case ND­ 5.7­ ND­ 48­ 7.7­ 23.7­
of TB or family history­[%]
Symptoms [%]­ ­ ­ ­ ­ ­ ­
Fever­ 40­ 45­ 9.9­ 13­ 7.7­ 30.5­
Weight loss­ 85­ 78­ 9.9­ 13­ 23.1­ 47.5­
Night sweats­ 37­ 35­ ND­ 9.3­ 15.4­ 22­
Cough­ 10­ ND­ 8.5­ 14.8­ 0­ 0­
Others­ ND­ ND­ §­ ||­ ||­ ¶­
* Patients from the Indian subcontinent
† Mean age was not described. Age range = 1 to 65 years
‡ Mean age was not described. Age range = 1.5 to 68 years
§ Other symptoms included dysphagia [2.8%]; haemoptysis [2.8%]; vomiting [2.8%]
|| Anorexia occurred in 7.4% patients in the Indian subcontinent group and 15.4% patients in the White group
¶ Asthenia occurred in 47.5% cases
TB = tuberculosis; ND = not described
 Lymph Node Tuberculosis 315

Table 22.2: Physical signs at presentation observed in adult patients with peripheral lymph node tuberculosis
Studies from India­ Studies from other parts of the world­
Dandapat et al (3)­ Subrahmanyam (4) Chen et al (23) Thompson et al (2) Fain et al (24)
[n = 80]­ ­[n = 105] [n = 71]­ [n = 67]­ ­[n = 59]­
Asian group* White group
Variable­ ­[n = 54]­ [n = 13]­
Site of involvement [%]
Cervical 70 93.3 91.5 85 84.5 73.1
Axillary 6 3.8 12.7 11.1 7.7 15.4
Inguinal 9 2.9 7 3.7 7.7 9.6
Multiple sites 15 ND 14.0† ND ND 15.3‡
Physical findings [%]
Matting and fixity 55 68 ND ND ND ND
Discrete nodes 22.5 32 ND ND ND ND
Abscess formation 15 15.2 ND ND ND ND
Sinuses 13 10.5 ND ND ND ND
Ulcers ND 7.6 ND ND ND ND
* Patients from the Indian subcontinent
† Right elbow nodes were enlarged in 1.4% patients. Two sites were involved in 14%; three sites were involved in 7% and four sites were
involved in 4.4% patients
‡ Of the 59 patients studied, 69 different lymph node sites were noted; 46 patients [78%] had exclusive lymph node disease. A superficial
distribution was found in 52 cases [88.1%] and isolated superficial lymph node involvement was found in 32 patients [54.2%]. Deep lymph
node involvement [mediastinal and abdominal] was observed in 17 patients [32.7%] and isolated deep lymph node involvement was found in
7 patients [11.9%]
ND = not described

Table 22.3: Evidence of associated pulmonary TB in adult patients with peripheral lymph node TB
Studies from India­ Studies from other parts of the world­
Dandapat et al (3)­ Subrahmanyam (4) Chen et al (23) Thompson et al (2) Fain et al (24)
[n = 80]­ ­[n = 105] [n = 71]­ [n = 59]­* ­[n = 59]­
Asian group† White group
Variable­ ­[n = 11]­ [n = 48]­
Associated pulmonary 5 16.2 42‡ 44 18 ND
TB [%]
* Chest radiographs were done in 59 of the 67 patients studied
† Patients from the Indian subcontinent
‡ Among those with cervical lymph node TB, 33% of those with upper-third cervical lymph node involvement and 58.7% of patients with
lower-third cervical lymph node involvement had radiological features of pulmonary TB
TB = tuberculosis; ND = not described

tamponade (35) due to TB mediastinal lym­p h­­adenitis, focal cervical lymph­a­denopathy with other groups of lymph
massive haemoptysis due to tracheo-pulmonary artery fistula nodes being occasionally involved [Table 22.2] (2-4,23,24).
and pseudoaneurysm of the pulmonary artery (36) have also The disease often presents as multifocal lymphadenopathy in
been reported. HIV-positive patients. Comparison of clinical presentation of
TB lymphadenitis in HIV-positive and HIV-negative patients
Tuberculosis Lymphadenitis in Patients with Human is shown in Table 22.5 (37,38).
Imm­uno­deficiency Virus Infection
Nontuberculous Mycobacterial Lymphadenitis
Lymph node enlargement is a common feature in patients with
HIV infection. In HIV-positive patients, lymphadenopathy Nontuberculous mycobacterial lymphadenitis often occurs
can result from primary HIV-induced pathology and from in children. Constitutional symp­toms seldom occur and the
diseases, such as, TB lymphadenitis, lymphadenopathy due to disease generally remains localised to the upper cervical
NTM, nodal Kaposi’s sarcoma and nodal lymp­homa (37,38). area [Table 22.6]. If untreated, the nodes often progress to
In HIV-negative patients, TB lymphadenitis often occurs as a softening, rupture, sinus formation, healing with fibrosis
 316 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 22.1: Clinical photograph showing left sided [A], right sided [B] TB cervical lymphadenitis
TB = tuberculosis

A B

C D
Figure 22.2: TB lymphadenitis. Clinical photograph showing chronic non-healing sinus and ulcers over right cervical region and chest wall [A];
suprahyoid, bilateral cervical and axillary lymphadenitis with chronic non-healing ulcers [B]; and suprasternal and left supraclavicular lymphadenitis
with discharging sinuses [C]. Clinical photograph of another patient showing right sided cervical TB lymphadenitis with a chronic non-healing sinus
and ulcer [D]
TB = tuberculosis
 Lymph Node Tuberculosis 317

Table 22.4: Physical appearance of lymph node and calcification (16,22,25). Appropriate laboratory tests
tuberculosis must be performed to differentiate lymphadenitis due to
NTM and Mtb as response to anti-TB is not good in the
Stage 1
former. The reader is referred to the chapter “Non-tuberculous
Enlarged, firm, mobile, discrete nodes showing non-specific
mycobacterial infections” [Chapter 41] for further details.
reactive hyperplasia
Stage 2
DIFFERENTIAL DIAGNOSIS
Larger rubbery nodes fixed to surrounding tissue owing to
periadenitis There are numerous causes of peripheral lympha­denopathy.
Stage 3 This list includes reactive lymphadenitis [secondary to viral,
bacterial infections], TB, lymphoma, sarcoidosis, secondary
Central softening due to caseation necrosis and abscess
formation carcinoma and uncommon causes like fungal diseases, toxo­
Stage 4
plasmosis and diseases of the reticulo-endothelial system,
among others. Multiplicity, matting and casea­tion are three
Collar-stud abscess formation
features which help in the diagnosis of TB lymphadenitis.
Stage 5 In patients with lymphoma, the lymph nodes are rubbery in
Sinus tract formation consistency and are not matted. In patients with secondary
Based on “Jones PG, Campbell PE. Tuberculous lymphadenitis in deposits in the lymph node [from a primary somewhere in
childhood: the significance of anonymous mycobacteria. Br J Surg the drainage area], the lymph node is usually hard and may
1962;50:302-14 (reference 25)”
be fixed to surrounding structures.

Table 22.5: Comparison of clinical characteristics of lymph node TB in HIV-positive and HIV-negative patients
Bem (37)­ ­Mohan et al (38)­­
HIV-positive­­ HIV-negative­­ HIV-positive­­­ HIV-negative
Variable­ [n = 157] [n = 71] [n = 34] [n = 390]­
Mean age [years]­ 30.6­ 30.6­ 28.4­ 27.8­
Male:Female­ 1:0.9­ 1:1.2­ 1:1.3­ 1:1.3­
Site of involvement [%]­­ ­ ­ ­ ­
Cervical­ 99*­ 96­ 96­ 90­
Axillary­ 82­ 43­ 82­ 37­
Inguinal­ 84­ 14­ 71­ 10­
Multiple sites­ 90­ 39­ 89­ 33­
Physical findings [%]­ ­ ­ ­ ­
Firm and mobile­ 51­ 51­ ND­ ND­
Matted, irregular/hard and 49†­ 49­ ND­ ND­
   additional local signs­ ­ ­ ­ ­
Histopathlogical type­ ­ ­ ­
Epithelioid granulomas
   with caseation necrosis­ ND­ ND­­ 18­­ ­75­
   without caseation necrosis­ ND­ ND­ 21 23
Suppurative variety­ ND­ ND­ 29­ 01­
Non-reactive­ ND ND 32­ 01­
Chest radiograph findings [%]­­ ­ ­ ND­ ND­
Pulmonary infiltration­ 46‡­ 60§­ ND­ ND­
Cavitation­ 3‡­ 0§­ ND­ ND­
Pleural effusion­ 17‡­ 13§­ ND­ ND­
Pericardial effusion 13‡­ 0§­ ND­ ND­
* Among patients with lymph node TB, lymphadenopathy was confined to the neck in 10% HIV-positive patients compared to 57% HIV-negative
patients. Further, isolated unilateral TB cervical lymphadenitis was observed in only 1 of the 157 HIV-positive patients compared to 32% in
HIV-negative patients
† Among HIV-positive patients with lymph node TB, local signs included sinuses [n = 2]; cold abscess [n = 3]; tender nodes [n = 3];
inflammatory mass [n = 3]. Among HIV-negative patients with lymph node TB, local signs included sinuses [n = 2]; tender nodes [n = 1];
inflammatory mass [n = 1]. None of the patients with primary HIV lymphadenopathy demonstrated local signs
‡ Tested in 110 patients
§ Tested in 15 patients
TB = tuberculosis; HIV = human immunodeficiency virus
318 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 22.6: Comparison between TB lymphadenitis and NTM lymphadenitis

Variable TB lymphadenitis NTM lymphadenitis
Age Any age group Children

Sex Female preponderance Equal between sexes

Constitutional symptoms Common Rare
Lymph node involvement Cervical lymph nodes are most commonly Localised disease often involving cervical lymph nodes
involved [jugulodigastric, submandibular, preauricular]. Unilateral
Axillary and inguinal lymph nodes may also involvement is common
be involved. Bilateral involvement is common
Chest radiographic evidence of Common Rare
pulmonary or pleural TB
Tuberculin skin test Often reactive Non-reactive
Response to antituberculosis Good Poor
treatment
NTM = nontuberculous mycobacteria; TB = tuberculosis

DIAGNOSIS lymph­adenitis, abnor­ma­lities are often discernible on the

chest radio­graph [Table 22.3] (2-4,23,24). However, there
Apart from a focussed history and a detailed clinical
is a wide variation in the reported incidence of chest
examination, several other investigations are required for
radiographic abnormali­ties with the figure ranging from
confirming the diagnosis of lymph node TB. Often, one
5%-44% [Table 22.3] (2-4,23,24). The reported incidence
diagnostic modality might not be sufficient to make a
of paratra­cheal, hilar and mediastinal lymphadeno­pathy
diagnosis of TB. Hence, the concept of a composite reference
in patients with peripheral lymphadenopathy has varied
standard [CRS] has been developed to make a diagnosis of
widely from 5%-12% (2,3,14,16). In a patient with lymph
EPTB including lymph node TB (39). The CRS includes yield
node TB, presence of infiltrates in the chest radiograph will
from mycobacterial culture, histopathology, cytopathology,
reclassify the patient to pulmonary TB as per the Revised
molecular diagnostic methods and response to treatment. In
National Tuberculosis Control Programme [RNTCP] of
patients symptomatic for other forms of EPTB, screening with
Government of India. From a clinician’s point of view, such
appropriate modality in such form of organ involvement
a patient would be considered to have disseminated TB as
should be simultaneously done. For example, in a patient
they have involvement of two non-contiguous sites, i.e.
with lymph node TB, presence of severe headache, evalua­
lymph node and lung.
tion for TB meningitis is warranted.
Ultrasonography
Tuberculin Skin Test and Interferon-gamma
Release Assays Peripheral lymph node TB patients can have concomitant
abdominal lymph node involvement. Although data on
Tuberculin skin test [TST] is positive in about 75% immuno­ prevalence of abdominal lymphadenopathy in peripheral
com­petent patients with lymph node TB while it is often lymph node TB patients has not been studied in large
non-reactive in patients with NTM lymphadenitis (1,9,10). cohorts, studies conducted in patients co-infected with HIV
Interferon-gamma release assays [IGRAs] have also become and TB have revealed a high prevalence of concomitant
available for the diagnosis of TB infection. However, a involvement of peripheral and abdominal lymph nodes (40).
negative TST or IGRA does not rule out the possibility of Hence, ultrasonography of the abdomen should be
active TB. The reader is referred to the chapter “Laboratory carried out in all patients with peripheral lymph node TB.
diagnosis of tuberculosis: best practices and current policies” Abdominal ultrasonography may reveal retroperitoneal,
[Chapter 8] for further details. portal or mesenteric lymphadenopathy. On ultrasonography,
enlarged lymph nodes or a confluent mass with central
Imaging necrosis may be evident. Adrenal deposits, terminal ileal
Imaging modalities facilitate anatomical localisation, extent thickening, caecal fat, stranding, ascites may also be detected.
of disease. In addition, these modalities facilitate image-
guided diagnostic or therapeutic aspiration from deep-seated Computed Tomography
lesions. Computed tomography [CT] of the chest is required for
accurate evaluation of the intrathoracic lymph nodes if the
Chest Radiograph chest radiograph shows any evidence of mediastinal or hilar
A chest radiograph should be routinely performed in patients lymphadenopathy. CT of the abdomen is helpful in assessing
suspected to have lymph node TB. In patients with TB the retroperitoneal, porta hepatis or mesenteric lymph
 Lymph Node Tuberculosis 319

or calcification [Figures 11.4, 11.5A, 11.5B, 11.5C, and 22.3].

With modern CT scanners, a simultaneous acquisition of
high resolution CT [HRCT] and contrast-enhanced CT
[CECT] images is possible. A simultaneous HRCT of the
chest may delineate chest infiltrates that may not have been
visualised on the plain chest radiograph. CT enterography
which utilises administration of both oral and intravenous
contrast, provides better delineation of intestinal mucosa.

Magnetic Resonance Imaging

Magnetic reso­nance imaging [MRI] of the chest is emerging
as a useful modality to characterise and monitor mediastinal
lymphadenopathy (41). MRI is useful especially when
radiation hazard is considered an important concern as
A in children and pregnant women. The image resolution
of lymph nodes and parenchymal lesions are considered
slightly better than CT, although adequate studies have
not been performed in this area (42). Important drawbacks
of MRI include longer acquisition time, patient discomfort
and high cost.

Positron Emission Tomography and Fusion Modalities

Positron emission tomography [PET] is fast emerging as a
modality of choice to assess the disease extent [Figure 22.4]
and monitor response to treatment. A study conducted in
HIV-TB co-infected patients documented PET response
in the form of change in maximum standardised uptake
value [SUVmax] after 6 weeks to be highly predictive of
response to anti-TB treatment (43). Similar studies in HIV-
seronegative patients with lymph node TB are lacking. Also,
B as PET detects active inflammation, it is also being seen as a
promising modality to help in deciding the end of treatment
in future. As on date, PET is still an unproven yet promising
investigational tool for TB. Drawbacks of PET include high
cost, operational difficulty, radiation hazard to patients and
operators, among others.
Fusion modalities like PET-CT, PET-MRI are fast
developing imaging modalities which combine the anatomic
precision of CT or MRI with the sensitivity of PET in
determining active disease. These have not been adequately
tested in TB. High costs and low availability may also
preclude their common-place use in near future in addition
to the usual drawbacks of CT, MRI or PET.
The reader is referred to the chapter “Roent­geno­graphic
manifes­tations of pulmonary and extrapulmonary tuber­culo­sis”
[Chapter 9] for further details.
C
Figure 22.3: CECT of the neck and chest showing bilateral cervical Cytopathology/Histopathology
[A] [asterisk]; right-sided axillary [asterisk] [B] and intrathoracic [arrow]
lymphadenopathy [B,C]. Peripheral rim enhancement with central The definitive diagnosis of lymph node TB is established
attenuation can be seen. Fine needle aspiration cytology of the cervical by mycobacterial culture, nucleic acid amplification tests
lymph node confirmed the diagnosis of tuberculosis [NAAT]. But, it is not possible to obtain microbiological
diagnosis in a large proportion of cases with lymph node
nodes. Lymph node calcification is best picked up by CT. TB. Cytopathological and histopathological examination of
The lymph nodes show enlargement with hypodense areas, lymph nodes are highly sensitive for diagnosis of TB and
sometimes central necrosis with peripheral rim-enhancement are, therefore, useful in such circumstances.
 320 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B

C D
Figure 22.4: CT of the chest [mediastinal window] [A], FDG-PET [B] showing left axillary lymphadenopathy [arrows]. PET-CT image of the same
patient showing increased uptake aorta [arrows] [C]. Volume rendered CT angiography image showing diffuse long segment narrowing of left
subclavian artery and abdominal aorta at the renal artery origin level as well as infrarenal segment suggestive of non-specific aortoarteritis [D].
Left axillary lymph node histopathological examination confirmed the diagnosis of TB
CT = computed tomography; FDG-PET = F-18 fluorodeoxyglucose positron emission tomography; PET-CT = positron emission tomography-
computed tomography; TB = tuberculosis

Fine needle aspiration cytology [FNAC], a rela­tively non- false negative result in 14% and equivocal results in 3%.
invasive, pain-free, out-patient procedure has established Similar results have been documented in other studies
itself as a safe, cheap and reliable procedure for the diagnosis [Table 22.7] (2-4,23,24).
of peripheral lymphadenopathy (44-47). The characteristic In cases with suspected mediastinal lymph node
cytopathological changes include epithelioid cell granulomas TB, various techniques including transbronchial needle
with or without multinucleate giant cells and caseation aspiration (49), endobronchial ultrasound [EBUS] (50)
necrosis (44-48). Several authors have evaluated the sensiti­ or endoscopic ultrasonography [EUS] guided FNAC or
vity and specificity of FNAC in the diag­nosis of peripheral biopsy (51), ultrasonography or CT-guided transthoracic
lymphadenopathy by comparing it with histopathological percutaneous FNAC or biopsy (52) are helpful. Cervical media-
exami­nation and found it to be a useful tech­nique (44-48). stinoscopy and video-assisted thoracoscopic surgery (53)
Lau et al (47) reported the sensitivity and speci­ficity of have been used to obtain lymph node sample for diagnosis
FNAC in the diagno­sis of lymph node TB to be 77% and in the past, but are infrequently being used presently.
93%, respec­tively compared to histopathology. Dandapat As the mycobacteria are not documented in every case,
et al (3) reported a true positive diagnosis in 83%, a certain histopathological changes have been accepted as
 Lymph Node Tuberculosis 321

Table 22.7: Method of diagnosis in adult patients with peripheral lymph node tuberculosis
Studies from India­ Studies from other parts of the world­
Dandapat Subrahmanyam Chen Thompson Fain
et al (3)­ (4) et al (23) et al (2)* et al (24)
Variable­ [n = 80]­ ­[n = 105] [n = 71]­ [n = 67]­ ­[n = 59]­
Fine needle aspiration 83† ND ND ND 38‡‡
cytology [n = 26]
Lymph node biopsy
Histopathology 100‡ 100 100|| 100** 100§§
[n = 64] [n = 60] [n = 39]
Microbiology 65 § 80¶ 100†† 36
[n = 10] [n = 7] [n = 39]
All values are shown as percentages
Numbers in square brackets indicate number tested
* Included 54 patients of Asian origin and 13 White patients
† False-negative results were observed in 14% and equivocal results were observed in 3% patients
‡ 80% patients had caseating granulomas; and 20% had non-caseating granulomas
§ Microbiological examination was not done in this study
|| A total of 64 specimens were obtained for histopathological exmamination: excision biopsy [n = 32]; total excision [n = 29]; neck dissection
[n = 3]. Acid-fast bacilli were found in 35 of the 64 specimens
¶ Only 10 of the 64 specimens were subjected to culture on Lowenstein-Jensen medium and eight yielded Mycobacterium tuberculosis.
**Histopathological examination was done in only 60 of the 67 patients. Biopsy specimens were not sent for microbiological examination in 13
of these 60 patients. Histopathology was positive in all the 60 patients. In 13 of these 60 patients, both histopathological and microbiological
methods yielded the diagnosis
†† In 7 patients, histopathological exmination was not done and microbiological examination alone was done
‡‡ Of the 26 patients in whom fine needle aspiration was performed, bacteriological diagnosis was possible in 38% cases and acid-fast bacilli
were positive in 2 of them
§§ Of these 39 patients, histopathological examination revealed caseating granulomas in 82%, isolated granulomata in 13% and non-specific
inflammatory lesions which revealed Mycobacterium tuberculosis in 5%

suggestive of TB. These include granulomatous inflammation

with caseation necrosis [Figure 22.5]. However, it must be
clarified that, although highly suggestive, these changes are
by no means specific and may sometimes be seen in other
diseases also (54). Therefore, the pathological features of
lymph node TB are classified as ‘consistent’ or ‘compatible’
with TB. A pattern ‘consistent with TB’ demonstrates acid-
fast bacilli [AFB] with caseating granulomas which is almost
confirmatory for Mtb. A pattern ‘compatible with TB’ has
granulomas or caseation only without AFB positivity. The
latter justifies treatment with anti-TB treatment if a high
clinical suspicion of TB is present. In such a patient, close
follow-up is necessary to monitor response as alternate
diagnosis is possible.

Microbiological Methods
Figure 22.5: Tuberculosis lymphadenitis. Photomicrograph showing
Microbiological tests form the backbone of investigations epithelioid granulomas with caseation necrosis and peripheral lympho­
in lymph node TB and are summarised below. cyte infiltration [upper panel, left; Haematoxylin and eosin × 100],
well-defined epithelioid granulomas with lymphocytic infiltration [upper
Smear Microscopy panel, right; Haematoxylin and eosin × 200], epithelioid granuloma,
caseation, lymphocytic infiltration [lower panel, left; Haematoxylin and
Smear microscopy, a fast, cheap and readily available method, eosin × 200] and multinucleated Langhans’ giant cell and lymphocytic
is still an important diagnostic modality for the diagnosis of infiltration [lower panel, right; Haematoxylin and eosin × 400]
lymph node TB, especially in resource-limited settings (55).
culture on Lowenstein-Jensen medium is the “gold standard”
Mycobacterial Culture and Drug-Susceptibility Testing
for drug-suscepti­bility testing [DST]. The sensitivity and
Currently, liquid culture is considered to be the “gold specificity of TB culture is comparable to Xpert MTB/
standard” for the diagnosis of TB while conventional solid RIF (56). Unlike the molecular methods which detect the
322 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

deoxyribonucleic acid [DNA] of dead bacilli, mycobacterial The number of drugs required and the ideal duration of
culture documents the presence of live multiplying bacteria. treatment for lymph node TB have been an area of intense
Therefore, mycobacterial culture is also useful in assessing research. Observations from a series of randomised clinical
deciding treatment completion in patients with residual trials conducted by the British Thoracic Society [BTS]
lymphadenopathy at the end of treatment. The reader is resulted in the shortening of the duration of treatment from
referred to the chapter “Laboratory diagnosis of tuberculosis: 18 months to 9 months initially and later to 6 months (6).
best practices and current policies” [Chapter 8] for details. In 1990, the group from Tuberculosis Research Centre
[TRC], Chennai (5) reported results of their prospective trial
Molecular Methods evaluating a supervised short-course [6 months] intermit­
tent chemotherapy regimen consisting of streptomycin,
In-house polymerase chain reaction [PCR] that uses locally
rifampicin, isoniazid and pyrazinamide three times a week
developed probes has been used since the 1990s for the
for two months followed by streptomycin and isoniazid
diagnosis of lymph node TB. Though this method was highly
twice a week for four months on an out-patient basis in
sensitive, problems like occurrence of contamination, false
children with lymph node TB. Out of 168 patients finally
positive test results, lack of reproducibility and high cost
analysed, favourable clinical response was noted in most
have restricted its wide applicability.
patients at the end of the treatment. They concluded
Presently, a newer diagnostic modality, Xpert MTB/RIF
that in children, TB lymph­a ­d enitis can be success­fully
is increasingly being used for the diagnosis of lymph node treated with a short-course chemotherapy regimen of six
TB. The Xpert MTB/RIF® is a cartridge-based nucleic acid months. Thereafter, the British Thoracic Society’s next
amplification test [CBNAAT] which amplifies rpoB gene in trial (63,64) compared the following regimens: rifampicin,
the body fluid/tissue samples and uses molecular beacons to isoniazid, ethambutol for the initial two months, followed
identify the resistance conferring mutations. In a systematic by rifampicin and isoniazid for the subsequent seven
review (56) [598 samples, 5 studies], the pooled sensitivity months; rifam­picin, isoniazid, pyrazinamide for the initial
and specificity of Xpert MTB/RIF in the diagnosis of lymph two months, followed by rifampicin and isoniazid for the
node TB considering CRS as the gold standard was found subsequent four months. The six months regi­m en was
to be 81.2% and 99.1% respectively. Sharma et al (39) from found to be equally effective in terms of response with an
New Delhi [n = 273], reported the sensitivity and specificity advantage of increased convenience and reduced cost. There
of Xpert MTB/RIF in the diagnosis of lymph node TB to be was no difference in the speed of reso­lution of nodes, in
78% and 91%, respectively. By detecting rifampicin resis­ the percentage of patients with residual nodes at the end of
tance, Xpert MTB/RIF is also useful for rapid diagnosis of the treatment or in the numbers developing fluctuation or
drug-resistant TB. The Xpert MTB/RIF has been approved sinuses. However, seven patients in the ethambutol group
by the World Health Organization [WHO] for use in initial and only one in the pyrazinamide group required aspiration
diagnosis of TB in sputum, and extra-pulmonary tissue of pus from lymph nodes. This may be because pyra­zina­­
specimens, such as, lymph node aspirate, biopsy material (57). mide, being bactericidal kills bacteria which are intracellular,
The recently published Guidelines for Extrapulmonary making glands less likely to become fluctuant on treatment.
TB for India [INDEX-TB Guidelines] (58a), and a recent In a study reported by Jawahar et al (6), patients with biopsy
systematic review (58b), suggest that Xpert MTB/RIF may confirmed superficial lymph node TB were randomly allo­
be used as additional test to conventional smear microscopy, cated to receive two-drug regimens of either a daily self-
culture and cytology in FNAC specimens for lymph node administered six-month regimen [n = 136] of rifampicin and
TB [strong recommendation]. isoniazid, or a twice-weekly, directly observed, six-month
regimen of rifampicin and isoniazid plus pyrazinamide for
Serodiagnostic Methods the first two months [n = 141]. Of the 277 enrolled patients,
Over 50 types of serological tests for different TB antibodies data were available for analysis in 268 patients [n = 134 from
and antigen have been marketed with high claims (59). These each group]. At the end of treatment, 87% patients in each
tests have performed poorly with low sensitivity, specificity. treatment group had a favourable clinical response; 14 [11%]
Serological tests are discouraged by the WHO, and banned and 17 [13%] patients had a doubtful response, and 4 [3%];
by the Government of India (60-62). and one [1%] patients had an unfavourable response among
those treated with the daily and twice-weekly regimen,
respectively. The authors suggested that these regimens
TREATMENT
may be considered as alternatives to the existing regimens.
Presen­tly, it is generally agreed that anti-TB treat­ment alone Experience at the Paediatric Tuberculosis Clinic at the AIIMS
is sufficient for majority of the cases and surgical intervention hospital, New Delhi (65) [n = 459], indicated that pulmonary
is required only in selected cases for specific situations. In TB was the the most common followed by lymph node TB.
India, patients with lymph node TB receive daily treatment Of the 16 children with isolated lymph node TB who received
under the RNTCP of the Government of India. The reader is category III treatment [thrice-weekly intermittent therapy
referred to the chapter “Revised National Tuberculosis Control with rifampicin, isoniazid and pyrazinamide administered
Programme” [Chapter 53] for details. for the first two months followed by rifampicin and isoniazid
 Lymph Node Tuberculosis 323

for the subsequent four months], 12 were cured with the

primary regimen; three children achieved cure with extended
primary regimen; and one child was lost to follow-up.
A multicentric study (66) conducted in 8 centres in
India assessed the efficacy of the 6-month thrice-weekly
intermittent directly observed treatment [DOT] and need
for prolongation of treatment to 9 months for non-resolution
of lymphadenopathy in patients with peripheral lymph node
TB. Patients with poor resolution at the end of 6-months
treatment were randomised to extended treatment up to
9 months or observation without additional treatment. At the
end of 6-months of treatment, resolution of lymphadenopathy
was evident in 517/551 (93.8%) patients. In the 34 patients
with poor resolution at 6 months, there was no difference
in response in the remaining 34 patients with [n = 16] or
Figure 22.6: Antiretroviral treatment associated immune reconstitution
without [n = 18] extension of treatment to 9 months. inflammatory syndrome manifesting as left sided cervical lymphadenitis
The evidence-based INDEX-TB guidelines (58) recom­ in a human immunodeficiency virus-seropositive patient
mend 6 months standard first-line anti-TB treatment for
peripheral lymph node TB [strong recommendation, low quality
evidence]. described (68). Symptomatic management of fever, cough,
How­ever, some patients with lymph node TB invariably pain and other complains may be sufficient in vast majority
require longer duration of treatment. While response to of cases (69). Severe reactions like acute respiratory distress
anti-TB treatment may be delayed in patients with TB syndrome [ARDS], tuber­culomas and pericardial effusion
lymphadenitis, it is a common practice among physician may require glucocorticoid therapy for few weeks (70).
and surgeons to label these patients with a diagnosis of If DST pattern is unknown, it is usually advised to get
multidrug-resistant TB [MDR-TB] lymphadentitis. But it tissue sampling done in such cases as around 10% cases
must be understood that MDR-TB is a laboratory diagnosis of initially suspected paradoxical reactions are found to
and for establishing this, the organisms must be grown harbour drug resistance or secondary infection (69). A recent
in the laboratory and in vitro resistance to rifampicin and study (71a) on immunological alterations in TB-associated
isoniazid must be demonstrated. Since lymphadentitis IRIS in people living with HIV/AIDS showed dominance
is a paucibacillary disease, it is not easy to grow Mtb in of proinflammatory cells, such as, interleukin-17A cell,
cultures in most instances. Therefore, a label of MDR-TB cytokines and chemokines, interferon-gamma [IFN-γ], IFN-γ
lymphadenitis should be used judiciously. Where ever inducible protein-10 and monokine induced by IFN-γ in TB-
possible, initial phenotypic and genotypic DST should be IRIS patients favours the development of IRIS event.
carried out, on the lymph node tissue. Sometimes, residual lymphadenopathy may persist at
The results of various studies have shown that lymph the end of the course of anti-TB treatment. These can be left
nodes may enlarge in size during anti-TB treatment, or, new as such and the patients observed under close follow-up as
nodes may appear during or after anti-TB treatment (5,6,67). many of these nodes are expected to resolve over a period
The develop­ment of new lymph node enlargement while of time. If the nodes increase in size further or systemic
on treatment may represent an immuno­logical response, features reappear, an exci­s ion biopsy of the gland for
sometimes called the “paradoxical reaction”. This pheno­ histopathology and mycobacterial culture should be done.
menon is usually transient and the nodes ultimately regress Some workers recommend biopsy of all significant [>10 mm]
in size. Fluctuation may appear in some lymph nodes while residual lymph nodes and re-treatment only if cultures are
on treatment. This cold pus should be aspirated under positive. All culture positive isolates must be sent for DST
strict aseptic conditions. In case there is secondary bacterial and treatment should be tailored according to DST results.
infection presenting as a classical abscess, drainage and The second-line anti-TB drugs should not be added unless
appropriate broad-spectrum antibiotics may be required in MDR-TB is proven in an accredited laboratory. Apart from
addition to anti-TB treatment. the biopsy of the lymph nodes, surgical intervention is
While the term “immune reconstitution inflammatory required only for aspi­ration or drainage of abcesses in a
syndrome [IRIS]” is usually used in HIV-seropositive few patients or total clearance of that lymph node in some
patients who are receiving antiretroviral treatment [ART], others.
the term “paradoxical reaction” is generally used to Treatment of mediastinal TB poses special problems
describe a clinical worsening of TB disease in HIV- in diagnosis, monitoring as well as decision on end of
seropositive and HIV-seronegative patients after initiation therapy. A cohort study (71b) had evaluated the efficacy
of anti-TB treatment (67). Case definitions for paradoxical of anti-TB treatment in mediastinal lymph node TB. Out
TB-associated IRIS, ART-associated TB [Figure 22.6] and of 41 patients enrolled, 36 [87%] had adequate response
unmask­i ng TB-associated IRIS [provisional] have been with sub-centrimetric lymph nodes at the end of therapy,
324 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

three had intercurrent paradoxical reactions and three had 15. Yates MD, Grange JM. Bacteriological survey of tuber­culous
lymph node size greater than 1 cm at the end of therapy. The lymph­adenitis in South-east England, 1981-1989. J Epidemiol
later 2 subsets were given additional treatment of 3 months Community Health 1992;46:332-5.
16. Pang SC. Mycobacterial lymphadenitis in Western Australia.
and all six patients had good response. The outcomes of
Tuber Lung Dis 1992;73:362-7.
long-term follow-up in these patients is also unknown. These 17. Lee KC, Tami TA, Lalwani AK, Schecter G. Contemporary
observations suggest that a standard 6 months course of management of cervical tuberculosis. Laryngoscope 1992;102:
anti-TB treatment is adequate in isolated mediastinal lymph 60-4.
node TB with an uncomplicated course. 18. Cantrell R, Jensen JH, Reid D. Diagnosis and manage­ment
It is generally acce­p ­ted that anti-TB treatment is of tuberculous cervical adenitis. Arch Otolaryngol 1975;101:
ineffective and complete surgical excision is recommended 53-7.
19. Comstock GW, Edwards LB, Livesay VT. Tuberculosis morbidity
for lymphadenitis caused by NTM (72). Therefore, whenever
in the US Navy: its distribution and decline. Am Rev Respir Dis
a biopsy is being performed for diagnosis, especially if it 1974;110:571-80.
happens to be from a preferred site for NTM lymph­adenitis 20. Rich AR. The pathogenesis of tuberculosis. Springfield: Thomas;
such as submandibular or pre-auricular area, a complete 1950.
excision or preferably selective nodal dissection of that area 21. Kent DC. Tuberculous lymphadenitis: not a localized disease
should be performed. A macrolide-based regimen should process. Am J Med Sci 1967;254:866.
be considered for patients with extensive Mycobacterium 22. Olson RN. Nontuberculous mycobacterial infections of the
avium-intracellulare complex lymphadenitis or poor response face and neck-practical considerations. Laryngoscope 1981;91:
1714-26.
to surgical therapy (72). The reader is referred to the chapter
23. Chen Y-M, Lee P-Y, Su W-J, Perng R-P. Lymph node tuber­­­culosis:
“Nontuberculous mycobacterial infections [Chapter 41]” for 7-year experience in Veterans GeneralHospital, Taipei, Taiwan.
further details. Tuber Lung Dis 1992;73:368-71.
24. Fain O, Lortholary O, Djouab M, Amoura I, Bainet P,
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 23
Tuberculosis in Head and Neck
Arvind Kumar Kairo, SC Sharma

INTRODUCTION TUBERCULOSIS OF SPINE

In the pre-chemotherapeutic era, patients with active Patients with TB of cervical spine may occasionally present
pulmonary tuberculosis [TB] often developed laryngeal, to the otorhinolaryngologist with torticollis, stiffness of neck
otological, nasal and paranasal sinus involvement and due to spasm of the neck muscles and painful movement
deteriorated progressively. The classical description of the spine. Difficulty in swallowing and breathing, and
of TB involving head and neck emanated from that a midline bulge in the posterior pharyngeal wall suggest
period. With the advent of effective anti-TB treatment a retropharyngeal or paravertebral abscess. Children with
the incidence of otolaryngological TB has come down this condition may present with stridor. Pus from the TB
significantly. The resurgence of TB as a consequence lesion of the spine may track downwards and laterally
of human immunodeficiency virus [HIV] infection and along the prevertebral muscles and manifests in the neck as
acquired immunodeficiency syndrome [AIDS] has brought an abscess. Epidural sepsis in the neck can be the cause of
otolaryngological TB into focus once again not only in musculoskeletal symptoms [polyradiculopathy] which can
endemic countries but also in developed countries (1-3). go undiagnosed before it manifests with some more obvious
features (8). The reader is referred to the chapter “Skeletal
TUBERCULOSIS IN HEAD AND NECK REGION tuberculosis” [Chapter 19] for further details on this topic.
Although not as common as pulmonary TB, head and neck
Prevertebral Abscess
involvement by TB occurs in a significant proportion of
cases. Head and neck TB develops due to: [i] spread of the Prevertebral space extends from one transverse process
bacilli to the upper airway by contaminated sputum from to another and from the skull base superiorly to the
a pulmonary focus; [ii] haematogenous; and [iii] lymphatic mediastinum inferiorly. It lies directly posterior to the
dissemination (4). Primary involvement of the tonsil as the retropharyngeal space and postero­medial to the carotid
portal of entry with subsequent involvement of the cervical space (9). Vertebral body destruction with associated soft
lymph nodes is also known. The site of involvement in some tissue mass may be seen [Figures 23.2A and 23.2B]. The
of the published series on head and neck TB is shown in spinal canal and dural sac may get compromised because of
Table 23.1 (1-3). vertebral body destruction and spread of abscess. The bulge
and the obstruction caused by these abscesses can be so large
TUBERCULOSIS OF CERVICAL LYMPH NODES that it may cause symptoms of paraesthesia, neck stiffness.
Respiratory distress, dysphagia and paraplegia may develop
Cervical lymph node involvement [Figures 23.1A and 23.1B] depending on site and extent of infection.
is the most frequently seen head and neck manifestation of
TB (5-7). The chapter “Lymph node tuberculosis” [Chapter 22]
TUBERCULOSIS OF ORAL CAVITY
covers this topic in detail. Nontuberculous mycobacterial
lymphadenitis is covered in the chapter “Nontuberculous The oral cavity is an uncommon site of involvement
mycobacterial infections” [Chapter 41]. by TB. Infection in the oral cavity is usually acquired
 Tuberculosis in Head and Neck 327

Table 23.1: Site of involvement in some of the recently published series on head and
neck TB
Menon et al (1) Nalini and Vinayak (2) Prasad et al (3)­
Variable­ [n = 128]­ [n = 117]­ [n = 165]*­­
Place of study­ Bradford, UK­ Mumbai, India­ Mangalore, India­
Male:Female­ 68:60­ 41:76­ 108:57­
Site of involvement†­ ­ ­ ­
Cervical lymph nodes­ 111 [87]­ 111 [95]­ 121 [73.3]­
Larynx­ 02 [1.6] ­ 02 [1.7]­ 24 [14.5]­
Cervical spine­ 0­ 01 ­ 03 [1.8]­
Oropharynx­ 02 [1.6]­ 01­ 08 [5]­
Nasopharynx­ 01­ 0­ 01­
Ear­ 02 [1.6]­ 01­ 04 [2.4]­
Eyes­ 02 [1.6]­ 0­ 0­
Retropharyngeal abscess­ 01 ­ 01­ 0­
Salivary glands­ 05 [3.9] ­ 0­ 03 [1.8]­
Thyroid­ 01­ 0­ 0­
Temporomandibular joint­ 0­ 0­ 01­
Skin­ 01­ 0­ 0­
Associated pulmonary TB and 20­ 31­ 24.2­
TB of other organs
* Of the 65 patients who were tested, 30% were found to have co-existing HIV infection
† Values in square brackets indicate percentage
UK = United Kingdom; TB = tuberculosis; HIV = human immunodeficiency virus

A B
Figure 23.1: Clinical photograph showing TB cervical lymphadenitis with scrofuloderma [A]; healed TB cervical lymphadenitis with scarring
and residual lymphadenopathy [B]
TB = tuberculosis

through infected sputum coughed out by a patient with Tongue is the most common site of involvement and
open pulmonary TB. Infection may also be acquired by accounts for nearly half the cases. The lesions are usually
haematogenous spread. In general, the intact mucosa of the found over the tip, borders, dorsum and base of the tongue.
oral cavity is relatively resistant to invasion and saliva has These may be single or multiple, painful or painless (10).
inhibitory effect on the growth of mycobacteria. A breach Usually, the lesions are well-circumscribed, but, irregular
in the mucosa due to any reason is one of the important ulcers may also occur [Figure 23.3]. These lesions sometimes
predisposing factors for the development of TB of the oral begin as nodules, fissures or plaques (11). Initial picture may
cavity. resemble a malignant process and histopatho­logy confirms
 328 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

the diagnosis of TB (12). Other sites of involvement include:

floor of mouth, buccal mucosa [Figure 23.4], soft palate,
anterior pillars and uvula (13). Secondary involvement of the
draining lymph nodes may occur. Majority of these patients
also have pulmonary TB (10-12,14-16).

TUBERCULOSIS OF LARYNX
Pathogenesis
Laryngeal TB classically develops due to direct spread
to the larynx from contaminated sputum [bronchogenic
spread]. This form of involvement, frequent in patients with
sputum smear-positive pulmonary TB, most commonly
A B
involves the posterior glottis. It is thought to develop due
Figure 23.2: Cervial spine radiograph [lateral view] showing soft to the pooling of infected sputum when the patient is in
tissue shadow suggestive of prevertebral abscess. Wedging of verte­ the recumbent position (17). The bronchogenic spread
brae is also evident [arrow] [A]. Magnetic resonance imaging [T2-
weighted image; saggital view] in a paediatric patient with TB of spine
to the larynx results in localised oedema, granuloma or
showing wedging of vertebrae [arrow], prevertebral abscess causing ulcerations (18). The laryngeal involvement may also occur
compression of trachea and oesophagus [B] due to lymphohaematogenous spread. Isolated laryngeal
involvement may occur without any evidence of pulmonary
TB. Laryngeal TB with oedematous, polypoid panlaryngitis
as a consequence of lymphohaematogenous spread is not
easily distinguishable from chronic laryngitis (19-23).

Epidemiology
Before the availability of anti-TB treatment, laryngeal
involvement was considered a grave prognostic sign
indicative of severe disease. It was seen in nearly one-third
of cases with pulmonary TB (24). With the availability
of effective anti-TB treatment, there has been a gradual
decline in the burden of laryngeal TB. However, with the
advent of the HIV infection and the AIDS, the incidence of
laryngeal TB is increasing (19,21). In the present era, it has
been observed that in countries where TB is highly endemic,
almost all patients with laryngeal TB have been found to
Figure 23.3: Tuberculosis of the tongue. Patient recovered completely have radiographic evidence of pulmonary TB and many
with antituberculosis treatment of them may be sputum smear-positive (24-26). On the
contrary, most of the patients with laryngeal TB in countries
with a low prevalence of TB seldom have any evidence
of pulmonary TB (27,28). However, patients with a heavy
bacillary load and strongly positive sputum specimens
may not have laryngeal involvement. The incidence of
laryngeal involvement in patients with pulmonary TB has
ranged from 1.5% to 50% in published studies (25,29-32).

Pathology
The tubercle bacilli induce low-grade inflammation with
the formation of typical TB granulation tissue. Coagulation
necro­sis occurs in large TB granulomas. Later, caseation may
develop. Laryngeal lesions reveal oedema and hyperaemia,
granu­lo­m as or ulceration. Vocal cord thickening and
palsy can occur. Epiglottis may show irregular margins
and nibbled appear­ance. Mycobacterium tuberculosis [Mtb]
Figure 23.4: TB of buccal mucosa [black arrow]. Ulceration in posterior may be found in the subepithelial tissue. The process of
most part is secondary to biopsy from the lesion [yellow arrow] destruction and the repair often proceeds simultaneously.
TB = tuberculosis The submucosa of epiglottis and aryepiglottic folds is likely
 Tuberculosis in Head and Neck 329

to undergo fibrous infiltration resulting in pseudoedema. laryngitis. Because of the acute onset, TB is rarely suspected
Described as turban epiglottis, this lesion is not commonly as the cause. When these patients fail to respond to con­
seen in the present era. servative management, microlaryngo-scopic examination,
biopsy and histopathological examination may confirm
Clinical Features the diagnosis of vocal cord TB. Coexistence of laryngeal
TB and carcinoma is well-known. Clinical features of
Patients often present with hoarseness of voice and laryngeal
TB should be considered in the differential diagnosis in these conditions may overlap and the lesions may look
any patient with unexplained hoarseness of voice. Pain similar (26,27). The incidence of this coexistent TB and
is also an important feature which may radiate to one cancer of larynx has been reported to be 1.4% (35). Anti-
or both ears and may lead to odynophagia. In a study TB treatment should be administered for at least two to
of laryngeal TB (25) hoarseness [98.6%], dysphagia and three weeks before the treatment of laryngeal carcinoma is
odynophagia or pain in throat [35.8%] and referred otalgia initiated. When TB develops after antineoplastic therapy, the
[28.6%] were reported to be common symptoms; in 14.3% infection is more severe with a higher mortality (26-28,35,36).
patients, the symptoms were not referred to larynx. The
physical examination findings associated with laryngeal TUBERCULOSIS OF THE SALIVARY GLANDS
TB include oedema, hyperaemia, nodularity, ulceration,
TB of the salivary glands is usually secondary to TB of the
exophytic mass, vocal cord thickening, and obliteration of
oral cavity or primary pulmonary TB. Primary infection of
anatomic landmarks. The ulcero-infiltrative lesions which
the salivary glands is also known, but, is rare. Parotid is
predominantly affected the posterior larynx were observed
the most common salivary gland involved [Figures 23.6A
frequently in the past and are rare now. Diffuse oedema
and 23.6B]. TB of the submandibular gland is also known (37).
or a pseudotumoural image located in any zone is often
seen. Laryngeal TB should be suspected in a patient with Parotid gland involvement is much more common because
non-specific chronic laryngitis (23). The epiglottis may be of its intraparotid lymph nodes. Clinical presentation can
markedly oedematous [turban epiglottis] and the vocal cord be acute or chronic. Acute presentation may resemble
oedema can resemble polypoid corditis. The epiglottis may acute non-TB sialitis and clinical differentiation may be
show irregular margins or nibbled appearance. Subglottic difficult. Occasionally, the diagnosis of TB may be a surprise
oedema or granulation in the true vocal cord can result in following surgery performed for a suspected salivary
stridor. Stridor may also result from vocal cord paralysis gland tumour (38). Unsuspected TB parotid abscess may
secondary to mediastinal lymphadenopathy (32). Any be wrongly drained mistaking it to be a pyogenic [non-TB]
laryngeal structure can be affected by TB [Figure 23.5] and abscess. This may lead to the formation of a persistent sinus.
the common sites include true vocal cord, the epiglottis, the In one such case (39), the diagnosis of TB was made when
false vocal cord, the aryepiglottic fold, the arytenoids, the superficial parotidectomy was performed as part of the
interarytenoid area and the subglottis (22,33,34). treatment for fistula. In patients with suspected TB sialitis,
Occasionally, patients may present with rapid onset of chest radiograph and fine needle aspiration cytology are
hoarse­ness of voice similar to that encountered in acute viral useful in confirming the diagnosis.

A B
Figure 23.5: Endoscopic view of the laryngeal TB Figure 23.6: TB parotitis with facial nerve palsy before anti-TB
TB = tuberculosis treatment [A]. Following anti-TB treatment, facial nerve palsy recovered
and parotid gland swelling subsided [B]
TB = tuberculosis
 330 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

TUBERCULOSIS OF PHARYNX to form a large perforation which may involve annulus

as well. Pars flaccida is usually not involved by TB. Facial
TB involvement of the tonsils and pharynx is uncommon
nerve palsy may occur in patients with TB of the ear with or
at present. These cases may be confused with pharyngeal
without a sequestrum. Persistent non-healing granulations
carci­noma at the time of presentation (40). The presenting
in a post-mastoidectomy patient may occasionally be the
features include: [i] ulcer on the tonsil or oropharyngeal
result of TB. Pre-auricular lymphadenopathy with post-
wall; [ii] granuloma of the nasopharynx; and [iii] neck
abscess. Co-existence of TB (41) and cancer of pharynx auricular fistula has been considered to be pathognomonic
could be: [i] a mere coincidence; [ii] metastatic carcinoma of TB otitis media (48). TB of the external ear is uncommon.
developing secondarily in a recent or old TB lesion; [iii] However, lupus vulgaris of the external ear has been
TB infection engrafted on cancer in full evolution; and reported (50). Very rarely it may present as turkey ear.
[iv] chronic progressive TB in which cancer develops (42).
Lymphoreticular malignancy may be associated with TB TUBERCULOSIS OF NASOPHARYNX
abscess and sinus of the neck. Rarely, malignancy and TB
TB of the nasopharynx is uncommon. The most common
may involve two different organs (41).
complaint is nasal obstruction and rhinorrhoea. Physical
examination may show adenoid hypertrophy without any
TUBERCULOSIS OF THE EAR distinguishing features. In a study [n = 40] (51), young females
While the association between pulmonary TB and TB of the in the age range of 20 to 40 years were frequently affected by
middle ear cleft is known since early nineteenth century, nasopharyngeal TB. The most common clinical manifestation
primary infection of ear is rare (43-45). was cervical lymphadenopathy [53%], followed by hearing
loss [12%], tinnitus, otalgia, nasal obstruction and postnasal
Pathogenesis drip [6% each]. Systemic symptoms, such as fever, weight
loss and night sweats were evident in 12% patients. Direct
Ear can become infected with Mtb by the bacilli invading
endoscopic examination showed nasopharyngeal mucosal
the Eustachian tube while the infant is being fed, or, by
haematogenous spread to the mastoid process. irregularity or mass in the nasopharynx in a majority [70%]
of the patients. Primary infection of nasopharynx by TB is
Clinical Manifestations very rare (52). Nasal obstruction or middle ear effusion is
the common presenting features.
Patients with aural TB present with painless otorrhoea and
hearing loss. However, patients with TB mastoiditis may TUBERCULOSIS OF THE PARANASAL
complain of otalgia. Pale granulation tissue may be present SINUSES
in the middle ear with dilatation of vessels in the anterior
part of the tympanic membrane (46-49). Multiple perforations Paranasal sinus TB is a rare entity and is nearly always
of tympanic membrane may occur as a result of caseation secondary to pulmonary or extra-pulmonary TB [EPTB] (53-55).
necrosis [Figure 23.7]. These perforations may coalesce The sinuses most frequently affected are maxillary and
ethmoid though any sinus may be affected. The infection
reaches the sinus either via the bloodstream or by a direct
extension from TB of the skull base (56). In sinonasal TB,
infection may be limited to the submucosa only. Here,
the sinus mucosa may be thickened or filled with a polyp,
which has a pale and boggy appearance with minimal
purulent discharge. This form is more common than the
second type, which is characterised by the bony involvement
[osteomyelitis] with a sequestrum and fistula formation. The
latter form is more difficult to treat. Like any other pyogenic
infection, the sinonasal TB can also spread to the brain or
orbit resulting in brain abscess, epiphora and deterioration
of vision. Rarely, TB of the maxillary sinus may be associated
with a carcinoma (57).
TB of the sphenoid sinus can present with blindness and
features of cavernous sinus thrombosis which is of gradual
onset and slow progression (55). Computed tomography
[CT] may show a heterogeneous soft tissue mass lesion in a
Figure 23.7: Otoscopic view in a patient with aural TB showing multiple
pin-point size granulomas over the tympanic membrane [thin arrows].
sinus with bone erosion and extension to the surrounding
These granulomas coalesce to form multiple perforations [thick arrow] tissue. Magnetic resonance imaging [MRI] may delineate
TB = tuberculosis the soft tissue extension better.
 Tuberculosis in Head and Neck 331

NASAL TUBERCULOSIS modalities have limitations in the evaluation of head and

neck TB (52). The radiographic features are variable and
TB of nasal cavity usually manifests as nasal obstruction
non-specific. However, CT and MRI have a definitive role
and catarrh. Physical examination may reveal pallor of the
in the diagnosis of TB of spine. TB lymphadenitis is often
nasal mucosa with minute apple-jelly nodules that do not
characterised by areas of low attenuation or low signal
blanch with nasal decongestants. Other sites which can
intensity with peripheral rim enhancement or calcification
be involved include inferior turbinate, septal mucosa and
on CT. The CT findings in laryngeal TB are also non-specific.
the vestibular skin. These nodules may coalesce to form a
There may be a diffuse thickening of the epiglottis or vocal
granular lesion with subsequent perforation of the septal
cords. Deep submucosal infiltration to pre-epiglottic space
cartilage (19). Involvement of nasolacrimal duct can rarely
or paraglottic space and cartilage destruction is usually not
occur. TB of the nose can cause complications like septal
perforation, atrophic rhinitis and scarring of nasal vestibule. seen unlike laryngeal carcinoma. In a study [n = 12] (60),
CT findings in 12 patients with laryngeal TB were reported.
Bilateral involvement was noted in nine patients [75%], while
DIFFERENTIAL DIAGNOSIS
unilateral involvement was seen in three [25%]. Diffuse
Laryngeal TB must be differentiated from squamous cell thickening of free margin of the epiglottis was a characteristic
carcinoma and other granulomatous inflammatory diseases, and frequent finding in TB [50%]. No deep submucosal
such as, fungal infections, syphilis, leprosy, Wegener’s infiltration of the pre-epiglottic and paralaryngeal fat spaces
granulomatosis, and sarcoidosis. Multiple biopsies may be was seen even when there was extensive involvement of
required to confirm the diagnosis. the laryngeal mucosa. Cartilage destruction was not found
TB of the nose and paranasal sinuses results in ulceration, in any case. By comparison, laryngeal carcinoma presented
granuloma formation and pain in the nose and the infected with unilateral involvement, infiltration of the pre-epiglottic
sinus cavity. Usually, other granulomatous disorders of the and paralaryngeal fat spaces by a submucosal mass, cartilage
paranasal sinuses are painless. TB of the oral cavity should destruction, and extralaryngeal invasion.
be differentiated from primary syphilis, fungal infections, In patients with TB mastoiditis, the plain radiograph
chronic traumatic ulcers and squamous cell carcinoma. or CT may reveal the presence of a sequestrum. Further,
in patients with aural TB, CT of temporal bone may
DIAGNOSIS demonstrate destruction of the osseous chain, sclerosis of
Diagnosis of laryngeal TB involves demonstration of the mastoid cortex, and opacification of the middle ear
Mtb in sputum, laryngeal swab by smear and culture and mastoid air cells. CT evidence of widespread bone
methods and histopathological examination of the biopsy destruction without clinical signs of aggressive infection,
material (45). Co-existent pulmonary TB should be carefully should suggest TB mastoiditis (61). MRI may show thickened
looked for by sputum smear microscopy and the chest seventh and eighth nerve complex in the internal auditory
radiography (19,50,58). A high index of suspicion is required meatus. This finding is frequently seen in the post-contrast
to diagnose TB of the ear. Tissue biopsy should be done to scans in patients with sensory neural hearing loss and facial
confirm the diagnosis. However, due to the atypical nature nerve paralysis [Figure 23.8].
of the clinical presentation, TB is not suspected initially and Positron emission tomography-computed tomography/
the patient may frequently undergo middle ear exploration. magnetic resonance imaging [PET-CT/MRI] has been found
The diagnosis may become evident subsequently when the
histopathology reveals the classical changes.
Diagnosis of TB otitis media is ascertained by smear
and mycobacterial culture examination of the ear discharge
and histopathologic study of the affected tissue. Smear and
culture examination of the nasal discharge, nasopharyngeal
secretions collected by nasal endoscopy along with histo­
pathological examination of biopsy material are useful in the
diagnosis of TB of the nose, paranasal sinuses and pharynx.
Histopathological and microbiological examination of biopsy
material is useful in confirming the diagnosis of TB of the
tongue, oral cavity and salivary glands.
Diagnosis of cervical lymph node TB is covered in the
chapter “Lymph node tuberculosis”. Molecular methods of
diagnosis such as Xpert MTB/RIF seem to be useful in the
diagnosis of otolaryngological TB (59a,59b).

IMAGING IN HEAD AND NECK TUBERCULOSIS

Figure 23.8: Post-contrast MRI scan showing thickened seventh and
Although CT and MRI can accurately demonstrate the eighth nerve complex in the internal auditory meatus and arachnoiditis
site, pattern and extent of the disease, however, both these [arrow]
332 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

to be useful in defining the extent of disease and monitoring for India [INDEX-TB Guidelines] (59a) suggest that patients
response to treatment. with otorhinolaryngological TB should be treated for six to
nine months; patients with bone involvement, including those
IMPACT OF HUMAN IMMUNODEFICIENCY with TB otitis media, should receive 9 months treatment.
VIRUS INFECTION These guidelines (59a) also suggest that corticosteroids
have no role in the treatment of otorhinolaryngological
Sparse literature is available on otorhinolaryngological TB TB. As the larynx heals, fibrosis of laryngeal tissue can
in patients with HIV infection and AIDS (58,62-64). Singh occur resulting in the following sequelae: cricoarytenoid
et al (64) reviewed the clinical presentation of laryngeal TB joint fixation, posterior glottis stenosis and anterior glottic
in HIV-positive patients. In this study (64), eight of the 146 web, subglottic stenosis, vocal cord scarring. These specific
patients with head and neck TB had laryngeal involvement complications are to be treated accordingly (26,28).
and two of these patients were HIV-positive. The most Indications for surgery in patients with head and neck
common symptoms were hoarseness, odynophagia and TB are outlined in Table 23.2. Superior laryngeal nerve block
shortness of breath. The majority of the patients had white has been advocated for odynophagia (27), but, is rarely
exophytic lesions involving any area of the larynx and these required at present as effective anti-TB drugs are available.
lesions resembled carcinoma or chronic laryngitis. Systemic In patients with TB of the cervical spine and cold abscess,
symptoms, such as, fever, night sweats, and weight loss repeated aspirations may be required to decompress the
were very common in patients with AIDS and coupled with abscess and relieve the difficulty in breathing and swallowing.
other illnesses masked the possibility of laryngeal disease Usually, open drainage is avoided. However, if required,
and resulted in a delay in the diagnosis. In another recent external approach rather than peroral drainage is recom­
retrospective study (58) the characteristics of TB confined to mended to avoid sinus formation and prevent the abscess
the head and neck region in 38 patients infected with HIV from draining into the oropharynx. Prevertebral abscess
were reported. These patients were divided into two groups can be drained either transorally or through transcervical
on the basis of the HIV status at presentation. Group 1 approach. In the transoral approach, airway is secured
included 11 patients [29%] with AIDS at presentation. with a cuffed endotracheal or tracheostomy tube to
Group 2 included 27 patients [71%] with HIV infection prevent aspiration and drained through transoral incision
but without AIDS. The authors reported that the cervical through the posterior pharyngeal mucosa. For transcervical
lymphatics were the most common site for isolated head drainage an incision along the anterior border of the
and neck TB [89%], with the supraclavicular lymph nodes sternocleidomastoid muscle is employed. The space is
most often involved [53%]. Extralymphatic involvement explored by blunt dissection between the carotid sheath and
was less common [11%], but involved a variety of anatomic pharyngeal constrictor muscle with placement of drains.
locations [skin, spinal cord, larynx, parotid salivary gland]. Occasionally, debridement of the diseased bone and bone
The presenting history and physical examination had a low grafting may be required. Paraplegia may develop in patients
sensitivity for TB in patients with HIV infection, mainly with severe and advanced involvement of the cervical spine.
because of the presence of multiple confounding factors. To prevent this, prophylactic neck collar support is helpful.
Purified protein derivative [PPD] testing was highly Neck collar support also relieves the pain when there is
sensitive for TB in patients with HIV infection alone [61%]; severe spasm of the muscles of the neck.
however, its usefulness was diminished in patients with As per the INDEX-TB guidelines (59a) surgery may be
AIDS [14%]. Fine-needle aspiration biopsy was 94% sensitive indicated in some circumstances to treat complications or
for diagnosing TB and was not affected by the status of
HIV infection. Surgical biopsy was the gold standard for
diagnosing TB but was associated with chronically draining Table 23.2: Indications for surgery in patients with
fistulas in a significant number of cases [14%]. These data head and neck TB
suggest that TB should be considered in the differential Diagnostic
diagnosis of all head and neck lesions in patients infected Biopsy of mucosal lesions
with HIV, even in the absence of pulmonary involvement.
Lymph node biopsy where the fine needle aspiration cytopathology
Six of the fourteen children with HIV-1 infection described fails to give conclusive result
by Schaaf et al (63) presented with otorrhoea. Ear swabs
Therapeutic
were the source of Mtb culture in three of them. Chest radio­
graphs were abnormal in all of them. Excision of a sinus or fistula which fails to heal even after adequate
anti-TB therapy

TREATMENT OF TUBERCULOSIS IN Drainage of neck abscess

THE HEAD AND NECK Repeated drainage or external drainage of retropharyngeal

abscess
Anti-TB treatment is the mainstay of treatment for patients Presence of sequestrum in the mastoid region
with TB of head and neck region. The reader is referred to
Revision of cosmetically bad scars left after TB has healed
the chapter “Treatment of tuberculosis” [Chapter 44] for details.
TB = tuberculosis
The recently published Guidelines for Extrapulmonary TB
 Tuberculosis in Head and Neck 333

for reconstruction of the ear or nose. Where facial nerve 18. Bull TR. Tuberculosis of the larynx. Br Med J 1966;2:991-2.
palsy complicates TB otitis media, surgical decompression 19. Williams RG, Douglas-Jones T. Mycobacterium marches back.
should be considered if there is no improvement after three J Laryngol Otol 1995;109:5-13.
20. Soda A, Rubio H, Salazar M, Genem J, Berlanga D, Sanchez A.
to four weeks of anti-TB treatment. Surgical drainage of
Tuberculosis of the larynx: clinical aspects in 19 patients.
retropharyngeal abscess complicating TB of the cervical Laryngo­scope 1989;99:1147-50.
spine may be considered, but requires specialist judgement. 21. Lazarus AA, Thilagar B. Tuberculosis of pericardium, larynx,
Surgery should be avoided in TB of the salivary glands and other uncommon sites. Dis Mon 2007;53:46-54.
or thyroid as medical treatment is usually considered to 22. Levenson MJ, Ingerman M, Grimes C, Robbett WF. Laryngeal
be adequate. Second-line anti-TB drugs may be required tuberculosis: review of twenty cases. Laryngoscope 1984;94:
in patients with drug-resistant TB [DR-TB]. Therefore, 1094-7.
23. Porras AE, Martin MA, Perez RJ, Avalos SE. Laryngeal
diligent efforts should be made to procure and subject the
tuberculosis. Rev Laryngol Otol Rhinol 2002;123:47-8.
tissue specimens to mycobacterial culture and susceptibility 24. Looper EA, Lyon IB. Laryngeal tuberculosis. Ann Otol Rhinol
testing in an accredited laboratory whenever nontuberculous Laryngol 1948;57:754-68.
mycobacterial infections or DR-TB is suspected. 25. Soni NK, Chatterjee P. Laryngeal tuberculosis. Indian J
Otolaryngol 1978;30:115-7.
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Otolaryngol 1979;31:92-2. 38. El Hakim IE, Langdon JD. Unusual presentation of tuberculosis
11. Tyldesley WR. Oral tuberculosis–an unusual presentation. of the head and neck region. Report of three cases. Int J Oral
Br Med J 1978;2:928. Maxillofacial Surg 1989;18:194-6.
12. Brennan TF, Vrabec DP. Tuberculosis of the oral mucosa. 39. Kant R, Sahi RP, Mahendra NN, Agarwal PK, Shankhdhar R.
Ann Otol Rhinol Laryngol 1970;79:601-5. Primary tuberculosis of the parotid gland. J Indian Med Assoc
13. Komet H, Schaefer RF, Mahoney PL, Antonio S. Bilateral 1977;68:212.
tuberculosis granulomas of the tongue. Arch Otolaryngol 40. Srirompotong S, Yimtae K, Srirompotong S. Clinical aspects of
1965;82:649-51. tonsillar tuberculosis. Southeast Asian J Trop Med Public Health
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15. Mcandrew PG, Adekeye EO, Ajdukiewicz AB. Miliary malignancy of the nasopharynx. Indian J Otolaryngol 1981;33:
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44. Skolink PR, Nadol JR Jr, Baker AS. Tuberculosis of the middle 56. Page JR, Jash DK. Tuberculosis of the nose and paranasal sinuses.
ear: review of literature with an instructive case report. J Laryngol Otol 1974;88:579-83.
Rev Infect Dis 1986;8:403-10. 57. Vrat V, Saharia PS, Nayyer M. Co-existing tuberculosis and
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osteomyelitis of the mastoid temporal bone. Int J Otolaryngol 58. Singh B, Balwally N, Har-El G, Lucente FE. Isolated cervical
1977;29:20. tuberculosis in patients with HIV infection. Otolaryngol Head
46. Awan MS, Salahuddin I. Tuberculous otitis media: two case Neck Surg 1998;118:766-70.
reports and literature review. Ear Nose Throat J 2002;81:792-4. 59a. Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD,
47. Di Rienzo L, Tirelli GC, D’Ottavi LR, Cerqua N. Primary Mohan A, et al. Index-TB guidelines: Guidelines on extra­
tuberculosis of the middle ear: description of 2 cases and pulmonary tuber­culosis for India. Indian J Med Res 2017;145:
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48. Greenfield BJ, Selesnick AH, Fisher L, Ward RF, Kimmelman CP, 59b. Kohli M, Schiller I, Dendukuri N, Dheda K, Denkinger CM,
Harrison WG. Aural tuberculosis. Am J Otol 1995;16:175-82. Schumacher SG, Steingart KR. Xpert[®] MTB/RIF assay for extra­
49. Vital V, Printza A, Zaraboukas T. Tuberculous otitis media: pulmonary tuberculosis and rifampicin resistance. Cochrane
a difficult diagnosis and report of four cases. Pathol Res Pract Database Syst Rev 2018;8:CD012768.
2002;198:31-5. 60. Kim MD, Kim DI, Yune HY, Lee BH, Sung KJ, Chung TS, et al.
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ear. Indian J Otolaryngol 1978;30:136-7. carcinoma. J Comput Assist Tomogr 1997;21:29-34.
51. Tse GM, Ma TK, Chan AB, Ho FN, King AD, Fung KS, et al. 61. Mandpe AH, Lee KC. Tuberculous infections of the head and
Tuberculosis of the nasopharynx: a rare entity revisited. neck. Curr Opin Otolaryngol Head Neck Surg 1998;6:190-6.
Laryngo­scope 2003;113:737-40. 62. Srirompotong S, Yimtae K, Srirompotong S. Tuberculosis in the
52. Mair IWS, Johannessen TA. Nasopharyngeal tuberculosis. upper aerodigestive tract and human immunodeficiency virus
Arch Otolaryngol 1970;92:392-3. coinfections. J Otolaryngol 2003;32:230-3.
53. Kukreja HK, Sacha BS, Joshi KC. Tuberculosis of maxillary sinus. 63. Schaaf HS, Geldenduys A, Gie RP, Cotton MF. Culture positive
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 24
Ocular Tuberculosis
Pradeep Venkatesh, Rohan Chawla, SP Garg

INTRODUCTION and TB. In this study TB was entirely extrapulmonary in 30%

and both pulmonary and extrapulmonary in 32% of patients
Tuberculosis [TB] is a serious public health problem. Even
and no ocular involvement was reported. However, there are
in the developed countries, it has re-emerged as an issue of
a few published case reports of ocular TB in HIV-infected
serious health concern (1). The incidence of ocular TB in a
patients (14,15). In a study (16) from Africa in patients with
population is difficult to estimate (2). Estimates of incidence
TB, choroidal granulomas were seen in 2.8% cases and
and prevalence of ocular TB have usually been drawn from
these patients had both AIDS and mycobacteraemia. In a
reports of histopathological- proven ocular TB, studies on study (17) from India on ocular findings in HIV-seropositive
experimental ocular TB, and surveys of ocular disease in individuals, 3.8% patients were found to have evidence of
patients with proven systemic TB (3). In one report from intra­ocular TB. Interestingly, all these patients also had
a sanato­rium in the USA, 1.4% of 10,524 patients were pulmonary TB. In a series on ophthalmic manifestations in
treated for ocular TB between 1940 and 1966 (4). Of these, paediatric cases with HIV co-infection, choroidal tubercles
14 patients had interstitial kerati­tis, 23 had sclerokeratitis were seen in about 2.5% cases (18). In a recent study (19), it
and 3 had corneal ulcers. The incidence of TB uveitis in was found that amongst 980 patients with uveitis, studied
India has varied from 2%-30% (5,6). The large variation in over a two-year period at a tertiary care centre, only 54
the incidence rates in different reports possibly stems from patients gave a positive history of being treated in the past
differences in the diagnostic criteria. In the studies reporting for proven pulmonary TB or EPTB.
higher incidence rates, the diagnosis of TB uveitis was often
based on a positive tuberculin skin test [TST].
PRIMARY AND SECONDARY OCULAR
While TB can affect all areas of the visual system, the
choroid is probably the most commonly infected intraocular
TUBERCULOSIS
structure. Intraocular TB is unique amongst all forms Two different definitions have been given to “primary”
of TB in that it is paucibacillary in nature and displays ocular TB. The term “primary ocular TB”, has been used
multiple clinical manifestations (7). Woods (8) estimated when the TB lesions are confined to the eyes and no systemic
that the choroid is involved in about 1% of patients with lesions are clinically evident. The term has also been used to
pulmonary TB. Primary TB of the eyelid, conjunctival sac describe the cases where the eye has been the initial portal
and optic nerve is rare. TB periphlebitis has been reported of entry (20-23). “Secondary ocular TB” has been defined
to probably account for a large number of cases of Eale’s as ocular infection resulting from contiguous spread from
disease (9,10). Further, ocular TB is usually not asso­ciated adjacent structures or haematogenous spread from the
with manifestations of systemic TB (11). lungs (24).
The impact of acquired immunodeficiency syn­drome Although rare, well-documented cases of primary ocular
[AIDS] epidemic on the rates of ocular TB remains unclear. TB do exist in the literature (21,25,26). In many of these
Shafer and associates (12) did not report a single case of patients, pulmonary disease could have been clinically
ocular TB in a study of 199 consecutive patients with human and radiographi­cally inapparent and perhaps would have
immuno­­deficiency virus [HIV] infection and extra-pul­monary been evident only on autopsy examination (27). It has been
TB [EPTB]. Small et al (13) reviewed 132 patients with AIDS suggested that it is extremely unusual for a primary ocular
336 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

infection to result in disseminated TB (28). Intraocular Conjunctival tuberculomas start insidiously and
and orbital TB are considered to represent secondary 3-4 weeks later lead to regional lympha­deno­pathy. The
infections (29,30). enlarged preauricular and rarely the submandibular
Studies to detect the ability of Mycobacterium tuberculosis lymph nodes may suppurate and drain forming a sinus.
[Mtb] to penetrate only intact conjunctival or corneal Thus, conjunctival TB is one of the causes of Parinaud’s
epithelium have revealed conflicting results. Finoff (30) oculoglandular syn­d rome of an infectious conjunctivitis
reported that a breach in the epithelium was necessary to accompa­nied by regional lymph node enlargement. Very
initiate an infection. Therefore, epithelial injury to the cornea rarely, the disease may start as an acute purulent or muco­
may lead to primary ocular TB (31,32). However, Bruckner (33), purulent conjunctivitis with symptoms of fever and malaise.
experi­menting on guinea pigs, observed that Mtb could be Several types of conjunctival granulomas have been
carried into the sub­epithelial tissue by phagocytosis with described (40,41) and include ulcerative, nodu­lar, polypoid
chronic con­junc­­tivitis even when the epithelium is intact. or hyperplastic lesions. These lesions may be solitary
Besides Mtb, nontuberculous mycobacteria [NTM] can also or multiple. Solitary tuberculomas involving the bulbar
cause ocular TB. conjunctiva are observed in 2%-30% of cases (42). The
nodular prototype may simulate a trachomatous lesion.
EYELID TUBERCULOSIS It has a propen­sity to involve the bulbar and upper fornix
TB affects the eyelids infrequently. The disease occurs as a of con­junctiva (21). Associated follicles and corneal infiltra­
result of spread of infection from the face and lymph nodes tion may be present. The nodule may enlarge to assume a
or by the haematogenous route. Primary eyelid involvement cauliflower-like lesion with central ulceration. The ulcerative
is extremely rare. TB eyelid abscess has been reported in form has a propensity to involve the inferior cul-de-sac.
the literature in conjunction with lung infection or sinus It can also involve the bulbar conjunctiva and tarsus and
disease (34-36). may also spread to involve the cornea, lid or sclera. Mtb can
Eyelid lesion begins as a red papule that becomes often be found in the ulcer crater (40,41). The hyperplastic
indurated. Eventually, it enlarges to form a nodule or plaque variety deve­lops most commonly in the fornix and rarely on
that ulcerates. The ulcer is chronic and pain­less. In most the tarsus. This form is associated with severe conjunctival
cases, regional lymph­adenopathy also occurs. Rarely the chemosis and lid oedema. It may assume a pedun­culated
skin lesion is hyperkeratotic and papular. appearance like the polypoid form.
Lupus vulgaris of the face may spread to involve Conjunctival tuberculids are a manifestation of hyper­
the eyelid. The disease progresses slowly leading to the sensitivity reaction. These appear as small conjunctival
characteristic soft “apple-jelly” nodule appea­rance. This nodules. These could be evanescent or remain localised.
feature is said to be best appreciated on diascopy. Atrophic They are associated with TB involvement of the uveal tract,
scars, ectropion and destruction of the lid, may develop. sclera, skin or other regions of the body. TB of the bulbar
TB of the tarsal plate can simulate recurrent chalazion and conjunctiva is usually associated with an interstitial keratitis.
finally causes its destruction (37). Phlyctenulosis can involve the lid margin, cornea or
When lid involvement occurs by spread from the conjunctiva. A phlycten [from the Greek word for blister]
underlying bone, lacrimal sac or lymph node, the initial is a hyper­sensiti­vity reaction to tuberculo­protein. In the
manifestation is a red, fluctuant nodule with induration. This conjunctiva, it can affect the bulbar, conjunctival or limbal
lesion ulcerates in several cases and a fistula surrounded by region. However, the most com­mon site is the limbal region.
granulation tissue develops in the ulcer crater. Tuberculids It usually appears as a small nodule with surrounding
of the eyelid present as small, multiple papular and chronic hyperaemia. It gradually ulcerates and heals without
lesions. It is not clear whether these are a non-specific form of scarring. This is in contrast to the corneal phlyctenulosis
granuloma or a hypersensitivity reaction to tuberculo­protein. which leaves a scar on healing. Limbal phlyctenules leave
The reader is referred to the chapter “Cutaneous tuberculosis” a charac­teristic triangular scar because the conjunc­tival
[Chapter 21] for further details. portion, unlike the corneal portion, heals without scar
formation. TB phlcytenular kerato­con­junctivitis also occurs.
CONJUNCTIVAL TUBERCULOSIS Mtb has been demonstrated in only one-fourth of patients
TB can involve the conjunctiva primarily or secondarily. with conjunctival TB (21).
Conjunc­tival TB and lupus vulgaris are manifestations of In the west, staphylococcal infection has replaced TB
primary infection while tuberculids and phlyctenulosis as the leading cause of phlyctenular keratoconjunctivitis.
are manifestations of secondary conjunctival infection. TB phlycte­n ular kerato­­conjunctivitis usually occurs in
Primary lesions present as unilateral nodular or ulcerative malnourished older children and is more common in girls.
conjuc­tivitis (38,39) associated with regional lymphadeno­ Symptoms usually last 1-2 weeks and consist of excessive
pathy. Children are most commonly affected (20,38). lacrimation, pain, photophobia and blepharospasm. The
Secondary lesions due to spread from contiguous disease or severity of symptoms depends on the site of involvement.
haematogenous dissemination are more common in older Corneal involvement indicates a much more severe form
patients. The disease may be bilateral and may cause of the disease. Recurrence is frequent and may occur at a
regional lymphadenopathy (38,39). different site.
 Ocular Tuberculosis 337

CORNEAL TUBERCULOSIS often secondarily affected and granulo­matous uveitis may

also develop. The scleral nodules may undergo caseation
The corneal manifestations in TB are phlyctenulosis, inter­
necrosis and ulcera­tion. Subse­quently, perforation may
stitial keratitis, ulceration and infiltrations (43-46). Rarely,
develop.
these patients may also have active pulmonary TB (47,48).
Phlyctens of the cornea usually arise from limbus. Corneal
involvement is characterised by intense photophobia, pain TUBERCULOSIS OF LACRIMAL SYSTEM
and blepharospasm. Marginal, miliary and fasicular phlycte­ TB involvement of the lacrimal gland, lacrimal canaliculi and
nular patterns have been described. Corneal phlyctenules lacrimal sac is unusual. TB dacryoadenitis usually develops
heal with a variable degree of scarring and vascularisation.
during the haematogenous dissemination, occasionally due
Interstitial keratitis is uncommon in TB. However, as
to spread from conjunctival or corneal disease and still
compared to syphilitic interstitial keratitis, TB interstitial
infrequently due to an injury. It appears as a gra­dually
keratitis is asso­c iated with more intense scarring and
enlarging painless swelling. When eyelid is involved, lid
vascularisation in the deeper layers (49). Apart from being
usually unilateral, TB often has selective propensity to oedema and pseudoproptosis are promi­nent features. If the
involve the lower part of the cornea. Sclerosing kerati­tis orbit is involved, proptosis and restriction of upward gaze
may evolve as sequelae to TB involvement of the sclera. are evident. Abscess formation with a chronic draining
Clinically, sclerosing keratitis appears as peripheral corneal fistula in the upper lid can also occur. Regional lymphadeno­
scleralisation. On resolution, it leaves behind a triangular pathy is a prominent manifestation in patients with TB of
or tongue shaped opacity with the base directed towards lacrimal system.
the limbus.
Corneal ulceration due to TB usually develops due to the ORBITAL TUBERCULOSIS
contiguous spread of infection from the conjunctiva or uveal
Abadie (54), in 1881, was the first to describe orbital TB. Since
tract. These ulcers are indolent and refractory to treatment.
then, several cases of orbital TB have been reported. Orbital
TB can take several forms, notably, periostitis, tuber­culo­mas
SCLERAL TUBERCULOSIS
and myositis. A case of TB osteo­myelitis involving the orbit
Although TB was reported as a frequent cause of scleritis and masquerading as post-traumatic haematoma has also
earlier, it was considered rare by 1926 (50). Watson and been reported (55).
Hayreh (51) found TB of the sclera in only one of the Orbital TB occurs by haematogenous spread or by
217 cases with epi­scleritis. extension of infection from adjacent structures such as the
TB of sclera is characterised by scleral and con­junctival paranasal sinuses. It is usually unilateral and typically occurs
ulceration. Focal necrotising ante­rior scleritis is the most in the first two decades of life. It usually has a protracted
common presentation, but a diffuse presentation is also course. TB peri­ostitis has an insidious onset and presents
known (52,53). Physical examination may reveal preauricular as a chronic, pain­less inflammation, most commonly of the
and submandibular lymphadenopathy. The scleritis malar bone. Over months, oedema and discoloura­tion of the
develops due to direct scleral infection or, by spread from overlying skin can progress to cold abscess, fistula formation,
the conjunctiva, uveal tract or by haematogenous route and
cicatrisation and regional lymphadenitis. Tuberculomas,
produces a nodular lesion [Figure 24.1]. Peri­pheral cornea is
firm masses of chronic granulo­matous inflammation, can
occur anywhere in the orbit. These lesions can occur at any
age. These cause gradual painless proptosis and sclerosis
and thus mimic benign and malignant tumours, orbital
pseudotumours and fungal infec­tions. Occasionally, they
involve extraocular muscles and are bilateral in location.
Tuberculomas may also start in the maxillary or ethmoid
sinuses, erode into the orbit and form fistula in the skin.
Overt signs of chronic sinusitis accompany this presentation.
Epiphora and epistaxis are also common symptoms.

TUBERCULOSIS OF THE UVEAL TRACT

Mycobacterium tuberculosis [Mtb] can involve the two principal
internal layers of the eye: the uveal and the retinal layers. TB
involving the uvea commonly presents as choroidal tubercles
or disseminated choroiditis, choroidal mass/abscess, chronic
granulomatous iridocyclitis, intermediate and pan­uveitis.
Figure 24.1: Nodular scleritis in a patient with miliary TB It can rarely present as panophthalmitis (56). The authors
TB = tuberculosis have seen a child with pulmonary TB presenting with a
 338 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 24.2A: Pre-treatment photograph of a patient with tuberculosis Figure 24.2B: Post-treatment photograph of the same patient showing
anterior diffuse endophthalmitis considerable resolution of the lesion

diffuse anterior endogeneous endophthalmitis-like picture. may be rewarding. The finding of choroidal tubercles in TB
The patient responded well to standard anti-TB treatment meningitis is still rarer. In one study, 28%-60% of patients
[Figures 24.2A and 24.2B]. TB involves the choroid more with miliary TB were reported to have choroi­dal tuber­cles
frequently than the iris and ciliary body. In a series of on ophthal­mo­scopic examination (60). However, in the same
40 patients with histopathological evidence of TB affecting study, only one of the 18 patients with TB meningitis without
the internal layers of the eye (3), the mean age at diagnosis miliary disease had choroidal tubercles. Sharma et al (61)
was 32 years. Male and female genders were equally affected found choroidal tubercles in only 4 of the 88 patients with
and the disease was mostly unilateral. miliary TB who were HIV-seronegative. Massaro et al (59)
found choroidal tubercles in 30% of patients with pulmonary
CHOROIDAL TUBERCULOSIS TB. In patients with choroidal TB, blurred vision may be
the only symp­tom. Some patients may be asymptomatic
Choroidal tubercles and tuberculomata [large, solitary and the tubercles may be detected on detailed fundus
masses] are the most common ocular manifesta­tions of TB evaluation of a case of suspected miliary TB referred for
[Figures 24.3, 24.4, 24.5A, 24.5B and 24.6]. Choroid is a highly fundus evaluation. In such patients, detection of choroidal
vascular structure and choroidal TB usually results from tubercles helps the clinician in making a diagnosis of TB.
haematogenous dissemination. The presence of choroidal On clinical examination, choroidal tubercles may be solitary
tubercles or choroidal masses is not diagnostic of miliary or multiple and of varying dimensions ranging from about
TB (57-60), although investigation for the same in a patient a quarter of the disc diameter to several disc diameters.

Figure 24.3: Solitary tuberculoma in miliary TB Figure 24.4: Multiple choroidal tubercles in miliary TB [arrows]
TB = tuberculosis TB = tuberculosis
 Ocular Tuberculosis 339

Figure 24.5A: Pre-treatment photograph in a patient with a large Figure 24.5B: Post-treatment photograph of the same patient showing
solitary choroidal tuberculoma significant resolution of the choroidal tuberculoma

Figure 24.6: Choroidal lesion in a patient with intestinal tuberculosis Figure 24.7: Ultrasonography showing a choroidal tuberculoma

They are most frequently situated in the posterior pole (59). Some workers consider a subset of patients of serpiginous
Up to 60 choroidal tubercles have been described but, usually choroiditis to be of TB origin (65). A recent review on the
less than 5 are seen. These appear as yellowish-grey elevated subject provides evidence in favour and against TB as
nodules with overlying inflammation in the vitreous during the aetiology of serpiginous choroiditis (66). The authors
the active stage [Figure 24.6]. The overlying and surroun­ feel that serpiginous choroiditis is an autoimmune disorder
d­ing retina may be detached when the tubercles are large and should be treated with corticosteroids and immuno­
[tuberculoma]. Choroidal granulomas, though suggestive of suppressive agents (67,68).
TB, are not diagnostic and may occur in other conditions,
such as, sarcoi­d osis and cryptococcosis. Most patients TUBERCULOSIS IRITIS AND IRIDOCYCLITIS
with miliary TB and choroidal tubercles have no anterior
segment involve­ment (62,63) perhaps because these patients Gradenigo (69), in 1869, first reported histopatho­logical
are unable to mount an effective immunologic response. evidence of TB of the iris in a patient with miliary TB
Rarely, however, choroidal tubercles may co-exist with at autopsy. TB was considered an important cause of
panuveitis (64,65). Brightness mode [B-mode] ultrasono­ granulomatous uveitis until the early 1960s. However,
graphy of larger choroidal masses using a 10 MHz ocular there has been a dramatic decline in the number of these
probe is considered suggestive of TB abscess if it reveals a cases probably due to identification of other diseases, such
central hypoechoic zone in a moderately reflective choroidal as, sarcoidosis and toxoplasmosis. Traditionally, mutton
mass [Figure 24.7]. fat keratic precipitates, early formation of dense synechiae
340 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and formation of iris nodules of Koeppe or Bussaca were or not. If, at all, it does have a role whether bacterial activity
considered to be characteri­stic of TB iridocyclitis. Such or secondary immunological processes are responsible for
lesions must be distinguished from sarcoid nodules which the ocular manifestations, also needs to be determined.
are larger and more pink. Non-granulomatous anterior
uveitis may also be seen in patients with systemic TB. PATHOLOGY
This may be an immune reaction.
Histopathologically, phlyctenules are characterised by a
dense accumulation of lymphocytes, histiocytes and plasma
RETINAL TUBERCULOSIS
cells. Neutrophils may be seen in the acute stage. There is a
TB can affect the retina either by direct infection or because notable absence of giant cells and eosinophils. Mtb is seldom
of a hypersensitivity reaction. Isolated involvement of the seen. Choroidal tubercles are similar to the tubercles found
retina by direct infection is extremely rare. Experimental elsewhere in the body. Granulomas may be caseating or
and clinical studies have revealed that Mtb rarely affects non-caseating. The characteristic giant cells may be absent.
the retina directly (4,47,48,70). The retina is more commonly In contrast to the histopathology of choroidal tubercles,
affected secondarily from adjacent choroidal lesions. Some TB endophthalmitis is characterised by marked caseation
workers have attributed retinal peri­p hlebitis to direct necrosis and exudation.
infection (71,72). In an atypical presentation, Saini et al (73)
found histopathological evidence of TB in an eye that had DIAGNOSIS
been enucleated for presumed retino­blastoma.
Eale’s disease, an idiopathic, non-infective, inflammatory Definitive diagnosis of ocular TB can be made only by
vasculitis of the retinal vasculature has been attributed the demonstrating Mtb in the ocular tissues. However, obtaining
hypersensitivity to tuberculoprotein. This disease is an ocular tissue for diagnostic purposes is not only difficult, but,
important cause of visual morbidity in healthy young adults, is also associated with significant ocular morbidity. Hence,
especially from the Indian subcontinent. It affects persons the diagnosis of TB can rarely be definitely confirmed before
in their second and third decade (74). Males are more enucleation. Only 25% of patients with ocular TB have a
frequently involved (75). In about 90% of the patients, the history of TB and approximately 50% have normal chest
disease becomes bilateral within a few years. Most patients radiographs (8,9,11). Orbital radiographs may reveal bony
present with painless, sudden visual loss in one eye due to erosions. A high degree of clinical suspicion is, therefore,
vitreous haemorrhage. the key to early diagnosis. Easily accessible sites such as
Eale’s disease is characterised by retinal periphlebitis eyelid, conjunctiva (52), lacrimal gland and sclera (83) should
and capillary non-perfusion that results in hypoxia. Retinal preferably be biopsied to demonstrate the characteristic
hypoxia leads to neovascularisation either on the retinal findings of caseating granulomas with Langhans’ giant
surface or on the optic nerve head. These new vessels cells and Mtb. The emergence of multidrug-resistant TB
being extremely fragile have a propensity to bleed into the [MDR-TB] is a compelling reason to subject ocular specimens
vitreous. In some cases, this can lead to retinal detachment to mycobacterial culture and sensitivity testing.
and an irreversible visual loss.
Ophthalmoscopically, the peripheral retinal vessels, Tuberculin Skin Test
which usually are the first to be involved, show signs of
inflammation with sheathing of the vessel wall, surrounding A positive TST in a patient with granulomatous uveitis is
retinal oedema and haemorrhage. New vessels may also consi­dered to be a positive evidence of ocular TB (84-87).
be present on the retina or the disc. The disease can be A positive TST is indicative of infection with Mtb and does
segmental or can involve a large area. Though uncommonly not necessarily reflect the disease activity. Rosenbaum
used, a clinical classification and grading system has been and Wernik (88,89) calculated that a patient with uveitis
proposed for Eale’s disease (76). and a positive TST has only 1% probability of having
The reasons for associating Eale’s disease with TB active TB. However, recent conversion of a previous non-
include: [i] increased prevalence of tuberculoprotein hyper­ reactor favours the diagnosis of active TB. Use of systemic
sensitivity (28,74,76-78); [ii] presence of concurrent active corticosteroids for severe ocular inflammation can interfere
or healed pulmo­nary TB (77,78); and [iii] response to anti- with the interpretation of the TST. Therefore, though routine
TB treatment in some patients. Further, polymerase chain TST has been advocated in patients with uveitis, it is rarely
reaction [PCR] positivity for TB from vitreous samples of diagnostic (87,90-93).
cases of Eale’s disease has been reported (80). Schlaegel and Weber (87), Abrams and Schlaegel (94) have
Histopathologically, no features typical of TB inflam­ advocated the isoniazid therapeutic test for the diagnosis
mation have been described (77,81,82). In most cases, a of suspected TB uveitis. However, therapeutic effect of
non-specific perivascular cuff of lymphocytes was the only isoniazid and a natural fluctuation in the course of chronic
finding. These patients may have associated neurological uveitis of some other aetiology needs to be distinguished.
disease. Also most cases of Eale’s vasculitis respond well to Furthermore, administration of isoniazid monotherapy can
steroids alone. As of date, it is not fully established whether result in the development of drug resistance. Therefore,
TB has a role to play in a subset of patients of this disease this is not widely used.
 Ocular Tuberculosis 341

Interferon-Gamma Release Assays Table 24.1: Diagnostic categories of ocular TB

Interferon-gamma release assays [IGRAs], like the TST, Possible ocular TB
also cannot differentiate latent TB infection [LTBI] from Patients with presence of the following [i], [ii] and [iii] together; or [i]
active TB. In countries endemic for TB, the utility of these and [iv] are diagnosed as having possible ocular TB:
tests is very uncertain. Presently both the World Health [i] At least one clinical sign suggestive of ocular TB,* and other
Organization [WHO] and Revised National Tuberculosis aetiology excluded
[ii] Chest radiograph/CT not consistent with TB infection and no
Control Programme [RNTCP] of the Government of India
clinical evidence of extraocular TB
do not encourage use of these tests to make a diagnosis of [iii] Presence of at least one of the following:
active TB (95,96). • Documented exposure to TB
• Immunological evidence of TB infection
Serological and Molecular Methods [iv] Molecular evidence of Mtb infection
Clinically diagnosed ocular TB
The usefulness of enzyme-linked immunosorbent assay
Patients with presence of all the following [i], [ii] and [iii] together are
in the diagnosis of ocular TB is still being evaluated. The diagnosed as having probable ocular TB:
WHO and the RNTCP strongly recommend against use of [i] At least one clinical sign suggestive of ocular TB,* and other
serological tests for diagnosing TB (97). aetiologies excluded
Polymerase chain reaction [PCR] offers to be a promising [ii] Evidence of chest radiograph consistent with TB infection or
tool to establish the definitive diagnosis of ocular TB. Kotake clinical evidence of extraocular TB or microbiological confirmation
from sputum or extraocular sites
et al (98) confirm the presumptive clinical diagnosis of ocular
[iii] Documented exposure to TB and/or immunological evidence of
TB using PCR in two patients. They used a sequence for TB infection
the coding of MPB64 protein that is specific for Mtb (98,99).
Bacteriologically confirmed ocular TB
However just the presence of mycobacterial DNA alone does
A patient with at least one clinical sign of ocular TB,* along with
not confirm active TB (100).
microbiological [smear/culture] or histopathological confirmation of
More recently, detection of Mtb genome has been reported Mtb from ocular fluids/tissues
in vitreous samples of patients with presumed ocular
* A patient with one of the following clinical presentations: granulo­
TB (101b). Three methods were used in this study (101b), matous anterior uveitis; non-granulomatous anterior uveitis, not
namely, multitargeted PCR, Gene Xpert MTB/RIF [Cepheid, associated with any other known clinical entity, e.g., HLA-B27; inter­
Sunnyvale, CA] and line probe assay [LPA] [GenoType mediate uveitis, with/without healed/active focal lesions; posterior
MTBDRplus; Hain Lifescience, GmbH, Nehren, Germany]. uveitis, including subretinal abscess, choroidal/disc granu­ loma,
multifocal choroiditis, retinal periphlebitis and multifocal serpiginous
Of the 11 samples tested, positive results were obtained in
choroiditis; panuveitis; rarely, scleritis [anterior and posterior],
10, 4 and 6 subjects with multitargeted PCR, Gene Xpert interstitial and disciform keratitis has presumptive ocular TB
MTB/RIF and LPA, respectively. This study (101b) also TB = tuberculosis; Mtb = Mycobacterium tuberculosis; HLA = human
documented the presence of rifampicin resistance bacillus in leucocyte antigen
some of the samples. In a recently published study (101b), Source: reference 104
LPA [MTBDRplus assay] testing of vitreous fluid was found
to be an effective tool for the rapid diagnosis of intraocular
drug-resistant TB. The utility of these molecular tests merits In the past several criteria have been proposed for ocular
further study. TB (10,103). However, the diagnosis remains presumptive
in most patients with suspected intraocular TB due to
Imaging Studies difficulty in obtaining the ocular tissue for histopathological
In cases of suspected ocular TB, a chest radiograph must be examination and lack of consensus on diagnostic accuracy
done to rule out presence of pulmonary TB. In cases where of molecular methods. The diagnostic categories for ocular
clinical suspicion based on ocular findings is very high, a TB defined in the recently published evidence-based
high-resolution computed tomography [HRCT] of the chest Guidelines for Extrapulmonary TB for India [INDEX-TB
can be done even if the chest radiograph is normal. Studies Guidelines] (104) are shown in Table 24.1.
in miliary TB have shown computed tomography [CT] to
be superior to the chest radiograph in picking up active TB TREATMENT
lesions (102). Ultrasonography of the abdomen can help When patients with TB elsewhere in the body develop clinical
in detecting ascites, retroperitoneal lymphadenopathy and features of ocular involvement, a thorough ophthalmologic
other features of abdominal TB. evaluation is warranted. Similarly, when patients are
Despite rapid advances in medicine, ocular TB still detected to have ocular involvement, systemic work-up to
remains an important diagnostic challenge. The criteria rule out active TB must be carried out. Treatment of ocular
for the diagnosis of ocular TB differ greatly and very often TB is on the same lines as treatment of pulmonary TB. The
the diagnosis is based on a compatible clinical picture and disease responds well to standard anti-TB treatment. The
good therapeutic response to anti-TB treatment rather than recently published Guidelines for Extrapulmonary TB for
mycobacterial isolation. India [INDEX-TB Guidelines] (104) suggest that patients with
342 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

otorhinolaryngological TB should be treated with standard in confirming the involvement of the optic nerve and retina
anti-TB treatment with rifampicin, isoniazid, pyrazinamide in patients receiving ethambutol.
and ethambutol for the first two months followed by Ethambutol related ocular toxicity is strongly dose
rifampicin, isoniazid and ethambutol for the subsequent related (109-118). In a study (109), 45% of patients receiving
four to seven months. ethambutol in a dose of 60-100 mg/kg/day developed
Adjunctive treatment with local or systemic corti­ ocular toxicity. At that time the older racemic mixture
costeroids, immunosuppressants and others will also be of ethambutol was used (117). Another report showed
required in speci­fic cases. In cases of choroidal granulomas the incidence of ocular toxicity to be 18.6% in patients
and panuveitis systemic steroids need to be started receiving more than 53 mg/kg/day of ethambutol (111).
48-72 hours after initiating anti-TB treatment. The treatment With 25 mg/kg/day, the reported incidence of ethambutol
of TB phlyctenulosis involves administration of topical related optic neuritis was 1.3%-15% (110). However, less
corticosteroids and cycloplegic agents in addition to standard than 2% patients develop this complication with doses below
anti-TB treatment. Conjunctival lesions causing only mild 15 mg/kg/day (112-117).
symptoms may respond to local astringents. Mucopurulent As the incidence of ethambutol toxicity is low with
discharge suggests secondary bacterial infection and should the currently favoured dose of 15-20 mg/kg/day, and
be treated accordingly. Conjunctival lesions heal without also because it is reversible in most cases, sophisticated
scarring, but corneal phlyctenules leave superficial scars of electrophysiological tests like electroretinography and
variable severity. Adjunctive therapy with topical antibiotics visual evoked response potentials are not required in all
such as streptomycin, amikacin or isoniazid has also been cases. However, in all patients receiving ethambutol, a
tried in the treatment of TB scleritis (59). baseline best corrected visual acuity and colour vision
The INDEX-TB guidelines (104) indicate surgery in the record should be routinely obtained. Thereafter, patients
follow­ing situations: [i] complications of retinal vasculitis, should be questioned monthly about any changes in
such as retinal neovascularisation, vitreous haemorrhage, vision. Any significant alteration in vision needs to be
tractional or combined retinal detachment, epiretinal promptly investigated. Guidelines have been proposed
membrane; [ii] diagnostic vitrectomy when conventional by the British Joint Tuberculosis Committee with respect
methods fail to establish diagnosis; [iii] non-resolving to ethambutol-related ocular toxicity (119). These include:
vitreous inflammation; [iv] visually significant vitreous [i] avoiding ethambutol in patients with impaired renal
floaters after completion of medical therapy; and [v] for function; [ii] not exceeding the recommended ethambutol
management of complications of uveitis, such as, cataract dose and duration; [iii] pretreatment record of any ocular
and glaucoma. disease previously and present visual acuity must be
documented; [iv] informing patients about the possibility
of ethambutol affecting their vision and also the need for
ANTI-TUBERCULOSIS TREATMENT-INDUCED
stopping the drugs if vision becomes impaired. That this
OCULAR TOXICITY information has been provided to the patient must also be
Several anti-TB drugs can cause adverse effects involving the entered in the records; [v] routine testing for visual acuity
eye, which if not recognised early, can result in an irreversible during treatment is not recommended; [vi] avoiding use of
loss of vision. Often patients are referred to ophthalmologists ethambutol in children and in adults in whom assessment of
for evaluation of ocular toxicity following prescription of the visual status is difficult; and [vii] referral to a patient on
drugs for TB elsewhere in the body. Sometimes patients ethambutol treatment, who presents with visual disturbance,
themselves note a diminution in vision while on anti-TB to an ophthalmologist for a detailed evaluation. Treatment
drugs and get evaluated by an ophthalmologist. with ethambutol should be discontinued pending this
examination. Patients receiving ethambutol in a dosage
Ocular toxicity due to ethambutol, isoniazid and
greater than 15-20 mg/kg for longer than 2 months and
streptomycin has been well-documented. Of these,
patients with renal insufficiency receiving ethambutol are
etham­b utol has the greatest potential to cause ocular
recommended to get visual acuity and monocular color
toxicity. Three types of optic neuritis have been described
vision testing every month till completion of treatment (120).
with ethambutol (105). These include the axial, the periaxial Isoniazid has also been reported to cause optic
and the mixed type. Both eyes are usually involved and neuritis (121-126). In these cases, the dose of isoniazid
the visual loss may vary from mild to severe. Colour has ranged from 200-900 mg/day and symptoms have
vision is also variably affected. In the axial form of optic been reported as early as the tenth day. Isoniazid has
neuritis on visual field testing pericentral or peripheral to be discontinued at the first sign of ocular toxicity
scotoma may be evident. Quadrantic field defects have also and pyridoxine may probably be beneficial both in the
been commonly found. Although mild disc hyperaemia treat­ment as well as prophylaxis (123,124).
and disc oedema have been reported, fundus exami­ There have been a few reports of ocular toxicity due to
nation may be normal in the acute phase of ethambutol streptomycin; of which, only the report by Sykowski (125)
toxicity (106). Peripapillary splinter haemorrhages, macular has been widely accepted.
oedema and focal pigementary changes have also been The most common adverse effect of rifampicin in the eye
described (107,108). Electophysiological studies are useful is conjunctivitis. It can result in the production of tears that
 Ocular Tuberculosis 343

are orange coloured and this can stain contact lenses (126). mani­festations in pediatric human immunodeficiency virus
Rifabutin has been associated with the development of an infection. Ophthalmology 2013;120:1942-3.e2.
19. Venkatesh P, Gogia V, Shah B, Gupta S, Sagar P, Garg S. Patterns
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 25
Tuberculosis in Pregnancy
Sunesh Kumar, Vatsla Dadhwal, K Aparna Sharma

INTRODUCTION In 2011, it was estimated that more than 200,000 cases

of active TB occurred among pregnant women globally; the
Since the days of Hippocrates, the initial presentation of
greatest burdens were in Africa and South-East Asia (9).
tuber­culosis [TB] in temporal relation to pregnancy has
Various countries have been classified as high-burden
been a subject of concern and controversy. TB in a pregnant [>60 cases/100,000 population per year] or low-burden
woman can present in several ways. Pregnant women may [<20 cases/100,000 population per year] countries depending
give a past history of TB. Occasionally, the disease may on the prevalence of active TB. The increasing occurrence of
be diagnosed in a pregnant woman when she develops co-infection of human immunodeficiency virus [HIV] and
symptoms and signs suggestive of TB. Many a times, TB adds an entirely new dimension to the natural history
pregnant women may remain asymptomatic and TB may of the disease.
be diagnosed either incidentally or by way of a screening The epidemiology of latent TB infection [LTBI] in
programme. Atypical presentation of TB in pregnant women pregnancy is a reflection of the prevalence in general
poses difficulties in confirmation of the diagnosis. TB in population. Small studies report prevalence of LTBI in
pregnancy, thus, has important implications for the mother pregnancy to be 19%-34% among HIV-negative women in
and child (1,2). India (10) and up to 49% in HIV-seropositive women in South
Africa (11). In another prospective study from Pune (12),
EPIDEMIOLOGY 24 of the 715 HIV infected women who were followed-up for
During the year 1985, the Centres for Disease Control and 480 postpartum person-years developed TB, yielding a TB
Prevention [CDC], Atlanta, estimated the TB in association incidence of 5 cases per 100 person-years. A baseline CD4+
with pregnancy occurred at a rate of 49.6/100,000 population cell count less than 200 cells/mm3, and viral load greater
among the Asians and the Pacific Islanders compared than 50,000 copies/mL and a positive tuberculin skin test
[TST] result were found to be predictors for the development
to a figure of 5.7/100,000 in the American whites and
of active postpartum TB disease in HIV-seropositive women.
26.7/100,000 in the African-Americans (3,4). In the series
During pregnancy, pulmonary TB is the most common
reported by Schaefer et al (5), between 1966 and 1972, 3.2%
lesion and extra-pulmonary TB [EPTB] occurs less commonly.
of patients with active TB at the New York Lying-in Hospital
Miliary TB and TB of lymph nodes, bones and kidneys are
were first diagnosed during pregnancy. Bailey et al (6)
also encountered during pregnancy (13). TB meningitis (14),
estimated the incidence of TB during pregnancy to be 4.8%
TB mastitis (15), TB peritonitis (16), and perineal TB (17) have
at New Orleans. Margono et al (7) reported that, between
also been described.
1985-1990, 12.4 cases of active TB were identified per 100000
deliveries and during 1991-1992, this number increased
CLINICAL PRESENTATION OF TUBERCULOSIS
to 94.8 per 100,000 deliveries. In another study (8) from a
district general hospital in a high prevalence area in London,
DURING PREGNANCY
UK, the incidence of active TB disease during pregnancy was About one-half to two-thirds of pregnant women with
reported to be 252/100,000 deliveries. TB remain asymptomatic (18). Some of the symptoms,
 Tuberculosis in Pregnancy 347

Table 25.1: Clinical presentations of TB in pregnancy haemoptysis has been found to be less common as compared
to men (21). Presence of cough for more than 2 weeks was
Variable Good et al (19) Maurya and Sapre (20)
reported in 60% of antenatal women in a study from South
Study period 1965–1974 1989–1992 Africa (22).
Place of study Denver Gwalior Co-infection with HIV further complicates the pre­
No. of patients sentation and causes atypical symptoms. World Health
Pulmonary TB 27* 172† Organization [WHO] recommends screening in symptomatic
Extrapulmonary TB 0 0 women with cough of any duration, fever or malaise (23).
Total 27 17 The Centers for Disease Control and Prevention, Atlanta,
HIV-seropositive [%] ND ND in addition recommends screening in women with a recent
Tuberculin positive [%] 96 ND
TB contact (24). Screening for LTBI is recommended only in
high risk women in the low-burden countries. These include,
Method of diagnosis those with known or suspected TB contacts, injection drug
Microbiological [%] 100‡ §
Histopathological [%] 0 §
use, HIV or other immunosuppression, foreign birth, and/
or residence in congregate settings (25). Pregnancy by itself
* In 6 patients TB was diagnosed during pregnancy [first trimester
is not considered high-risk. In high-burden countries, LTBI
n = 3; second trimester n = 1; third trimester n = 2]. In the remaining
11 patients, TB was diagnosed during the postpartum period [up to screening is not routinely done.
12 months following delivery]
†Of the 209 patients studied, 6 patients had no evidence of TB and EFFECT OF PREGNANCY ON TUBERCULOSIS
were tuberculin negative; 31 patients had past history of adequately
treated TB At the start of the twentieth century it was believed that
‡16 patients had drug-resistant TB pregnancy had a deleterious effect on TB (13). In fact,
§ Detailed break up not given therapeutic abortion was advocated for pregnant women
TB = tuberculosis; HIV = human immunodeficiency virus; ND = not with pulmonary TB. During this period, a number of
described conflicting reports evaluating the impact of pregnancy on
TB appeared (13).
However, it is currently believed that pregnancy
such as increased respiratory rate and fatigue may mimic neither predisposes to the development of TB nor results
the physiological changes that occur in pregnancy, and in the progression of the disease. Two large studies (26,27)
thus, make the diagnosis difficult. In the series reported although somewhat old, clearly showed that pregnancy
by Schaefer et al (5), minimal symptoms were observed in does not appear to result in the progression of the disease.
65% pregnant women with TB. Good et al (19) found 19% One study (26) described 250 pregnant women; 189 with
women to be asymptomatic among 371 women admitted pulmonary and 61 with EPTB. None of them were given
to the National Jewish Hospital, Colorado. Of these, 27 anti-TB treatment and the treatment largely consisted of
patients had reactivation of TB during or within 12 months sanatorium therapy. It was found that TB improved in
after pregnancy. They also reported cough [74%], weight 9.1% women while the disease progressed in 7% and most
loss [14%], fever [30%], malaise and fatigue [30%], and of the women remained stable (26). In another study, de
haemoptysis [19%] as the common presenting symptoms. March (27) evaluated the influence of pregnancy as a relapse
Maurya and Sapre (20) screened 209 pregnant women for factor for pulmonary TB in 215 patients who received
TB by TST, direct sputum examination for acid-fast bacilli adequate treatment and concluded that pregnancy, labour,
and chest radiograph [done after 12 weeks of gestation puerperium, and lactation did not predispose to the risk of
with abdominal shielding]. Of these 209 patients, 12% had relapse of pulmonary TB when the disease was adequately
active TB; 70.3% were sputum smear-negative, but had treated.
chest radiographic evidence of TB and a raised erythrocyte Schaefer et al (5) compared the course and outcome
sedimentation rate, 14% had a past history of adequately of TB in pregnant women during the pre-chemotherapy
treated TB but no evidence of active disease; and 2.9% had and chemo­therapy era; 88% women in pre-chemotherapy
no evidence of TB and were tuberculin negative. They found and 91% in the chemotherapy era remained stable during
cough [75%], weight loss [23%], fever [15%] and malaise pregnancy. Eleven of the 27 cases of reactivation or relapse
[30%] to be the common symptoms in 100 symptomatic of pulmonary TB described by Good et al (17) occurred in
women. Clinical presentation of TB in pregnancy as reported the post-partum period. However, these and other studies
in some published studies is shown in Table 25.1 (19,20). highlight a small but definite of relapse and deterioration in
the post-partum period (10).
Screening for Tuberculosis in Pregnancy
EFFECT OF TUBERCULOSIS ON PREGNANCY
In the low-burden countries, the lack of awareness towards
the possibility of diagnosis of TB could be a hindrance while Contrary to old reports, following the advent of effective
in the high-burden countries it is the lack of resources. Also, anti-TB treatment, current literature does not suggest that
in women, clinical presentation with fever, night sweats and TB has much of an adverse impact either on the course of
348 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

pregnancy or labour (1,2). The effects of TB on pregnancy Maurya and Sapre (20) reported two preterm deliveries
may be influenced by many factors, including the severity and on intrauterine foetal death in the subgroup with
of the disease, how advanced the pregnancy has progressed active TB. Maternal mortality and foetal complications were
to at the time of diagnosis, the presence of extrapulmonary more frequent in pregnant women with drug-resistant TB
spread, HIV co-infection and the treatment instituted. The compared to those with drug-sensitive disease in the study
prognosis is the worst in women in whom a diagnosis of by Good et al (19).
advanced disease is made in the puerperium as well as those In another study (30), 33 patients with EPTB [12 with TB
with HIV co-infection. Failure to comply with treatment also lymphadenitis, 9 with intestinal, 7 with skeletal, 2 with renal,
worsens the prognosis (28). 2 with meningeal, and 1 with endometrial TB] were followed
Obstetrical complications like prematurity, foetal growth through their deliveries. Of the 33 patients, 29 received anti-
retardation, low birth weight and increased perinatal TB treatment during pregnancy. The antenatal complications,
mortality have been commonly reported (29a,29b). Lympha­ intrapartum events, and perinatal outcomes were compared
denitis is the most common form of EPTB reported and has with those among 132 healthy pregnant women without
no adverse effect on the maternal and foetal outcome. Other TB who were matched for age, parity and socio-economic
forms of EPTB, such as, intestinal, spinal, endometrial and status. It was observed that TB lymphadenitis did not
meningeal TB are associated with an increased frequency affect the course of pregnancy or labour or the perinatal
of maternal disability, foetal growth retardation and infants outcome. However, as compared with the control subjects,
with low Apgar scores (30). 21 women with involvement of other extrapulmonary sites
However, in a prospective study from India (31), there had significantly higher rates of antenatal hospitalisation
were no statistically significant differences in pregnancy [24% versus 2%], infants with low Apgar scores [<6] soon
complications and pregnancy outcomes in women diagnosed after birth [19% versus 3%], and low birth-weight [less than
with and treated for TB during pregnancy compared to 2.5 kg] infants [33% versus 11%]. The authors concluded that
matched controls who were pregnant and had no TB. The EPTB that is confined to the lymph-nodes has no effect on
only exception was in women who started TB treatment late obstetrical outcomes; but TB at other extrapulmonary sites
in pregnancy; neonatal mortality and extreme prematurity does adversely affect the outcome of pregnancy (23).
were significantly higher in this group.
TRANSPLACENTAL TRANSMISSION OF
Abortions TUBERCULOSIS
Selikoff and Dorfmann (32) reported seven early spontaneous Transplacental transmission of TB infection has now been
abortions and nine antepartum or intrapartum foetal deaths conclusively proven by a number of case reports (34-36).
in 616 pregnant women with TB, where 600 pregnancies In the literature, cases where newborn babies were found
resulted in the birth of 602 normal live infants. Maurya and to have acquired TB from the diseased endometrium have
Sapre (20) reported four spontaneous abortions in the group been described. Nemir and O’Hare (34) described one female
previously treated for TB. child carefully investigated and treated for congenital TB in
neonatal period. This child had positive subumbilical lymph
Preterm Delivery nodes indicating umbilical vein as the route of transmission.
Mycobacterium tuberculosis [Mtb] has also been demon­
Schaefer et al (5) did not find any evidence of increased risk of
strated in placental specimens and tissues from stillborn
prematurity in their series. Maurya and Sapre (20) reported
infants (37,38). Kalpan et al (39) reported two interesting
only two premature deliveries among 31 pregnant women
cases. In the first case, 25-year-old pregnant woman had
with a past history of TB. Bjerkedal et al from Norway (33)
been treated with multiple drugs for cavitary pulmonary TB.
described the course and outcome of pregnancy in 542
She desired an elective abor­tion of six weeks of gestation.
women with TB [study group] and 112,530 women with
Endometrial curettage smear revealed Mtb. In the second
TB [control subjects]. Study group had increased frequency
case, a 24-year-old pregnant woman presented at 34 weeks
of pregnancy induced hypertension [7.4% versus 4.7%] and
of gestation with premature rupture of membranes. An
vaginal bleeding [4.1% versus 2.2%]. Labour was induced
emergency caesarean section performed 24 hours later
more often in the study group than among the control subjects
revealed fibrinous exudates on peritoneal surface and a
[14.6% versus 9.6%]. Labour was also reported to be more
placenta densely adherent to the uterus. Both exudates and
often complicated in the study group than in control subjects
tissue from the endometrium grew Mtb. These findings
[15.1% versus 9.6] and interventions during labour were
suggest that subclinical endometrial infections can be an
required more often in the study group [12.6% versus 7.7%].
important source for transplacental transmission of disease
Intrauterine foetal death rate between 16 and 28 weeks was in patients with congenital TB.
nine-fold higher in the study group [20.1/1000 in cases
versus 2.3/1000 control subjects]. However, no difference was
CONGENITAL TUBERCULOSIS
found in the number of congenital anomalies or subsequent
conception rate. There was no difference in mean gestational Congenital TB (40-43) is a relatively uncommon but an
age, preterm births or mean birth weight among live births. impor­tant entity. The reader is referred to the chapters
 Tuberculosis in Pregnancy 349

“Pathology of tuberculosis” [Chapter 3] and “Tuberculosis in available interferon-gamma release assays [IGRAs], offer
children” [Chapter 36] for more details. several advantages over the TST however, they should
not replace TST in low-income and other middle-income
DIAGNOSIS countries. The reader is referred to the Chapter “Laboratory
diagnosis of tuberculosis: best practices and current policies”
It is important to identify pregnant women suffering from [Chapter 8] for more details.
TB as it may help to prevent transmission of disease to the
newborn and close contacts.
Microbiological, Molecular Methods
Chest Radiograph Demonstration of Mtb in sputum, body fluids or material
by Ziehl-Neelsen staining and Lowenstein-Jensen culture
In the past, a routine chest radiograph was advocated during
confirms the diagnosis of TB disease. However, low yield
preg­nancy in order to detect active and inactive TB (44,45).
in these specimens remains a practical problem. The utility
Bonebrake et al (46) advised against such a policy as most
of liquid culture, cartridge based nucleic amplification
patients with significant findings on chest radiograph also
tests [CBNAAT] in the early diagnosis of TB and drug-
had positive findings on physical examination and a positive
susceptibility testing in pregnancy (58) merits further study.
TST result. Concern about radiation exposure to foetus does
not justify the policy of routine chest radiograph examination
during pregnancy [34-36 weeks]. However, if a chest TREATMENT OF ACTIVE TUBERCULOSIS
radiograph is indicated, pregnancy should not be considered DURING PREGNANCY
as an absolute contraindication. A chest radiograph should Pregnant women with active TB should be immediately
be taken with abdominal shielding, preferably after the first started on ATT as untreated TB is far more hazardous to
trimester of pregnancy. a pregnant woman and her foetus than the adverse effects
Estimated radiation from a chest radiograph is approxi­ related to the treatment of the disease (59). Though first-
mately 50 mrad to the chest and 2.5 to 5 mrad to the line drugs, such as isoniazid, rifampicin, streptomycin
gonads (47-49). Prenatal radiation exposure has been and ethambutol cross the placenta, with exception of
correlated with subsequent risk of malformations and cancer. streptomycin induced ototoxicity, none of these drugs
Mole (49), in a detailed analysis estimated such a risk to be appear to be teratogenic or toxic to the foetus (60).
zero to one case per 1000 patients of irradiated by one rad in
utero during the first four months of pregnancy. Therefore,
Isoniazid
a chest radiograph carried out during pregnancy does not
seem to carry a measurable risk to the foetus since radiation Even though isoniazid crosses the placenta, no significant
exposure from a chest radiograph is much less. terato­genic effects have been noted even when used during
In symptomatic women and asymptomatic women with the first four months of pregnancy (61). However, one report
a recent TB contact, a shielded chest radiograph, which mentioned about two-fold increase in risk of malformations
poses minimal risk to the foetus, sputum smear microscopy, when mothers were exposed to isoniazid (62).
mycobacterial culture are recommended (50,51). Hepatitis is a frequently observed side-effect of isoniazid.
Pregnancy and postpartum women may be particularly at
Detection of Tuberculosis Infection higher risk for isoniazid induced hepatitis. An addition of
pyridoxine in a dose of 50 mg/day has been recommended
The TST identifies persons infected by Mtb but does
during pregnancy to prevent neurotoxicity in the mother
not define the activity or extent of disease. Generally,
and the foetus (59). This regimen has been shown to
the TST becomes positive two to ten weeks after initial
prevent seizures in neonates born to mothers treated with
exposure (52). In the past, a concern had been expressed
regarding the effect of pregnancy on TST positivity (53). isoniazid during pregnancy (1). The reader is referred to
However, subsequent studies have not found pregnancy to the chapter “Hepatotoxicity associated with anti-tuberculosis
affect the TST reactivity (54,55). Present and Comstock (55) treatment”[Chapter 45] for further details.
evaluated 25,000 patients over a one-year period and
reported that pregnancy did not affect the TST results. There Rifampicin
appears to be no risk either to the pregnant woman or her Snider et al (60) failed to detect increased incidence of terato­
foetus from the TST (56). genicity among mothers taking rifampicin during pregnancy.
Carter and Mates (57) while reviewing cases of TB during Presently, rifampicin is considered to be an essential
pregnancy over a four-year span in Rhode Island found component of anti-TB treatment during pregnancy (1,63).
that most patients with TB infection remain asymptomatic.
They concluded that the TST screening in pregnancy may
Ethambutol
prevent risk to the foetus, new born and the obstetric ward
workers. Although ethambutol is known to be teratogenic in experi­
However, usefulness of such a policy in areas where TB mental animals, there are no reports of maldevelopment
is highly endemic remains doubtful. Although, the recently including ocular injury in human foetuses (64-66).
350 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Streptomycin to the mother and the child. In a recent study (74), exposure
to second-line anti-TB drugs was associated with delivery
Use of streptomycin during pregnancy has been reported to
of healthy term infants. However, studies involving large
be associated with vestibular and auditory impairment in
sample size with a long-term follow-up are awaited.
the new born (67,68). Streptomycin induced ototoxicity has
As the majority of teratogenic effects occur in the first
been reported irrespective of period of gestation. Therefore,
trimester, treatment should be delayed until the second
streptomycin should not be used during pregnancy.
trimester. The decision to postpone the treatment should be
based on the analysis of the risks and benefits and should
Pyrazinamide be acceptable to both the doctor and patient. Injectable
Due to faster sputum conversion rate, this drug is commonly agents, aminoglycosides and capreomycin should be
used in the short-course treatment regimens. The WHO avoided during pregnancy and if possible ethionamide
guidelines suggest that pyrazinamide can be safely used in should also be avoided (74,75). The decision should also
pregnancy (69). If pyrazinamide is not included in the initial take into consideration the severity of illness. Treatment
treatment regimen, the minimum duration of treatment is should consist of combination of three or four drugs with
nine months. Benefits of the use of pyrazinamide in HIV- demonstrated efficacy against the infecting strain.
seropositive pregnant women outweigh the undetermined
potential risks to the foetus. Treatment of Human Immunodeficiency Virus-
Tuberculosis Co-infection During Pregnancy
Principles of Treatment With increasing incidence of HIV and TB co-infection,
Active disease discovered in antenatal period should be the management of such cases present newer challenges
promptly treated. Daily treatment with isoniazid, rifampicin, especially in the pregnant women. Standard treatment
pyrazinamide and ethambutol during the first two months guidelines (76,77) should be followed.
followed by isoniazid, rifampicin and ethambutol for
the subsequent four months should be used. The reader TREATMENT OF LATENT TUBERCULOSIS
is referred to the “Treatment of tuberculosis” [Chapter 44] INFECTION
for more details. Duration of anti-TB treatment need not
Evidence-based guidelines are available from the WHO
modified because of pregnancy. Active TB disease discovered
for a public health approach to the management of LTBI in
close to the time of delivery should also be actively treated.
high risk individuals in countries with high or middle upper
Neonate should be carefully examined and kept under
income and low TB incidence (78). However, efficacy and
surveillance for development of TB. Placenta should be
safety of isoniazid chemoprophylaxis during pregnancy, in
examined for possible infection by Mtb. If patients receiving
areas where TB is highly endemic, like India, are unclear (79).
anti-TB treatment conceive, pregnancy should be allowed
A recently published systematic review (80) suggested
to continue while the patient continues anti-TB treatment.
that pregnant women benefit from screening for LTBI. The
Appropriate steps should be taken to prevent TB infection
systematic review (80) also suggested that IGRAs and TST
in the newborn.
were comparable in screening for LTBI during pregnancy.
The question whether the treatment should be started in
Second-line Drugs
pregnancy needs to be answered. For HIV-seronegative
Little is known about the teratogenic effects of the second- women, the Centers for Disease Control [CDC] recommends
line anti-TB drugs. Due to high incidence off side-effects, delaying treatment of LTBI until two to three months
their usefulness is limited. Teratogenic effect has been postpartum, unless the patient has had a recent known
attributed to ethionamide (70). Kanamycin and capreomycin TB contact. Both the CDC and the WHO recommend
theoretically share the potential for producing ototoxicity early treatment of LTBI in HIV-seropositive pregnant
with streptomycin. The potential hazard of such treatment women (81,82), but these women are at an increased risk
must be considered by the parents and the treating physician. of hepatotoxicity due to anti-TB drugs (83,84). An ongoing
study (85), International Maternal Pediatric Adolescent AIDS
Treatment of Drug-resistant Tuberculosis Clinical Trials Network [IMPAACT] P1078, assessing the
During Pregnancy safety of antepartum versus postpartum initiation of isoniazid
preventive treatment in HIV-infected women residing in TB-
Women who are being treated for drug-resistant TB should endemic settings is expected to provide more.
receive counselling concerning the risk to the foetus because
of the known and unknown risks of second-line anti-TB MANAGEMENT OF TUBERCULOSIS IN INFANTS
drugs. There have been occasional case reports and case
BORN TO MOTHERS WITH TUBERCULOSIS
series in the published literature regarding the management
of multidrug-resistant TB [MDR-TB] during pregnancy If the mother had been receiving treatment for TB during
using second-line drugs (71-75). These data suggest that preg­nancy, the newborn should be assessed for symptoms
treatment of MDR-TB during pregnancy is beneficial both and signs of congenital TB. Infant should undergo the TST
 Tuberculosis in Pregnancy 351

at birth. Chest radiograph and smear and culture examination 11. Nachega J, Coetzee J, Adendorff T, Msandiwa R, Gray GE,
of the gastric aspirate should be performed. If active TB is McIntyre JA, et al. Tuberculosis active case finding in a mother-
to-child HIV transmission prevention programme in Soweto,
ruled out, the child should be treated with isoniazid for
South Africa. AIDS 2003;17:1398-400.
two to three months, or till such time the mother, known to 12. Gupta A, Nayak U, Ram M, Bhosale R, Patil S, Basavraj A, et al.
be complying with treatment, becomes smear and culture Byrampjee Jeejeebhoy Medical College-Johns Hopkins University
negative (13). Study Group. Postpartum tuberculosis incidence and mortality
The child should be carefully followed up thereafter. among HIV-infected women and their infants in Pune, India,
If active disease is detected, the child should receive a full 2002-2005. Clin Infect Dis 2007;45:241-9.
course of anti-TB treatment with rifampicin, isoniazid and 13. Hamadeh MA, Glassroth J. Tuberculosis and pregnancy. Chest
1992;101:1114-20.
pyrazinamide. Ethambutol should be preferable be avoided 14. Stands JW, Jowers RG, Bryan CS. Miliary-meningeal tuberculosis
in neonate as it is difficult to monitor the ocular toxicity. during pregnancy: case report and brief survey of the problem of
extra-pulmonary tuberculosis. JSC Med Assoc 1977;73:282-5.
Breast Feeding 15. Banerjee SN, Ananthakrishnan N, Mehta RB, Prakash S.
Tuberculosis mastitis: a continuing problem. World J Surg
Breast feeding should not be discouraged in nursing mothers 1987;11:105-9.
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 26
Female Genital Tuberculosis
Sunesh Kumar, JB Sharma

INTRODUCTION tertiary referral centres and in assisted reproduction (24.5%)

and even higher in tubal factor infertility [up to 48.5%] and
Female genital tuberculosis [TB], though known to have in repeated in vitro fertilisation [IVF] failures (6,10-16). In a
existed for centuries, was first described by Morgagni in study from Islamabad, Pakistan, 2.43% of the 543 women
1744 during an autopsy on a 20-year-old girl known to have with infertility were found to have FGTB (17). FGTB can
died of TB peritonitis (1). Infertility, menstrual irregularities also cause abnormal uterine bleeding and postmenopausal
and chronic pelvic or lower abdominal pain are the most bleeding and involves genital organs as observed on
common manifestations of female genital TB [FGTB] (2-4). laparoscopy in pulmonary TB cases (18-21). FGTB affects
It is almost always secondary to a focus elsewhere in the older women in western countries with most women being
body. Fallopian tubes are the first and the most commonly between 40–50 years (22,23). However, in most large series
affected genital organs, followed by endometrium, ovary from India, 68%–89% cases of genital TB were between 20
and cervix (5). Occasionally, other sites may also be affected. and 30 years of age [Table 26.1] (11,24-27). It may be due to
A number of patients may remain asymptomatic and the younger age at marriage and child bearing in developing
disease may also be discovered incidentally (6). The last countries as compared to the western world. Female genital
century has witnessed changing trends in incidence of TB is less common in postmenopausal women as the atrophic
FGTB, initially due to improvement in economic standards endometrium in them offers a poor milieu for the growth of
in developed countries and subsequently by the global the bacillus (4,22-23).
pandemic of the human immunodeficiency virus [HIV]
infection (6). More liberal immigration from high to low PATHOGENESIS
risk areas due to globalisation has increased risk in all
countries (7). Emergence of multidrug-resistant TB [MDR-TB] Genital tract TB is almost always secondary to TB infection
else­where in the body. Although pulmonary TB is most
and extensively drug-resistant TB [XDR-TB] is a cause of
common, extra­p ulmonary organs, such as, kidneys,
serious concern (7,8).
gastrointestinal tract, bone or joints may also be the primary
source of infection (11,24-27). In patients with miliary TB,
EPIDEMIOLOGY
genital organs may be one of the many organs involved.
Genital tract TB has been reported in patients presenting with Primary genital TB, though extremely rare, has been
infertility, chronic pelvic pain and menstrual irregularities, described in the female partners of males affected by active
in autopsy series, and recently in laparoscopy series of genitourinary TB through their semen (28,29). In patients
infertility cases and pelvic pain (5,9). Twentieth century with primary genital TB, cervix or vulva may be the site of
witnessed dramatic reduction of FGTB cases in the developed involvement.
world. However, a similar trend has not been observed in the Haematogenous or lymphatic route is the usual mode of
developing countries. Incidence of genital TB varies greatly spread. However, direct contiguous spread from other intra­
depending upon the geographical location ranging from less peritoneal organs may occur in a minority of patients (10,30).
than 1% in the USA and Sweden to about 10% in infertile Simultaneous occurrence of peritoneal TB in patients with
women in India with incidence being higher [up to 26.7%] in genital TB increases the possibility of ruptured caseous
 Female Genital Tuberculosis 355

Table 26.1: Age distribution of patients with female genital TB

Age group [years]
Study (reference) No. of patients <20 20-30 30-40 >40
Gupta (11) 47 13.0 68.0 19.0 0
Devi (24) 144 12.0 70.0 14.0 4.0
Hafeez and Tandon (25) 120 3.3 89.0 6.0 1.7
Chhabra (26) 58 1.7 74.2 8.6 15.5
Rattan et al (27) 50 0 76.0 24.0 0
Distribution of patients in various age groups is shown as percentage
All values are corrected to first decimal place.
TB = tuberculosis

lymph nodes or involvement of genital organs during the of 1,436 cases of genital TB, Nogales-Ortiz et al (32) reported
haematogenous spread. endometrial involvement in 79% of cases. Oosthuizen
Fallopian tube is usually the initial site of focus, with et al (34), in a study of 109 patients with infertility, found
subse­quent spread to other genital organs (6,31). evidence of genital TB in the form of positive culture in
menstrual blood in 16 and positive endometrial tissue for
Fallopian Tube Tuberculosis Mycobacterium tuberculosis [Mtb] in four patients.
Gross appearance of endometrium is mostly unremark­
Fallopian tubes are involved in almost all patients [90%-100%]
with genital TB (5,10). Ampullary portion of the fallopian able. However, in advanced cases, ulcerative or atrophic
tube is the most common site of the disease. Isthmus is endometrium or an obliterated endometrial cavity due
less commonly involved and involvement of the interstitial to extensive intrauterine adhesions may be seen. Total
portion is unusual. Generally, the disease tends to be destruction of endometrium by the disease process with
bilateral. Disease may start on the peritoneal surface or resultant secondary amenorrhoea has been reported in a few
in the muscularis, mucosa of the tube; however, involvement of cases (32).
the mucosal layer is almost universal. Gross appearance of the Microscopically [Figure 26.1], diagnosis is based upon
fallopian tube may vary depending upon the severity of the presence of chronic inflammatory cells with or without
disease and stage at which it is encountered. In early cases,
congestion of tubes and other pelvic organs with flimsy
adhesions and fine miliary tubercles on the surface of
the tube and other pelvic organs may be seen. In severe
disease, dense plastic adhesions between the fallopian
tubes and surrounding organs are seen. In old healed
cases, hydrosalpinx or pyosalpinx may be present. Failure
to visualise pelvic organs at laparoscopy or laparotomy
may be due to dense adhesions in patients with pelvic TB.
In 25%-50% cases, the fallopian tubes remain patent with
everted fimbriae giving rise to so called “tobacco pouch
appearance” (32).
Microscopically, presence of chronic inflammatory cells,
with or without caseation, granulomas with Langhans’ giant
cells may be evident. However, microscopic appearance
may be variable depending upon the severity of disease and
whether the disease is in active or healing phase. The tubal
mucosa may be totally destroyed or may have hyperplastic
or adenomatous appearance which may be confused with Figure 26.1: Endometrial TB. Photomicrograph showing endometrial
adenocarcinoma (33). Papillae in the endosalpinx are usually glands with clusters of epithelioid cells and lymphocytic infiltration
fused, and may lead to implantation of embryo in the [asterisk] [upper panel, left; Haematoxylin and eosin × 60], stroma
of endometrium, epithelioid granulomas [asterisk], Langhans’ giant
fallopian tubes resulting in ectopic pregnancy.
cell [arrow] and lymphocytic infiltration [upper panel, right; Haema­
toxylin and eosin × 200]. Fallopian tube TB. Photomicrograph showing
Endometrial Tuberculosis congested tubal plicae with epithelioid clusters and lymphocytic
infiltration [asterisk] [lower panel, left; Haematoxylin and eosin × 60],
Endometrial involvement in genital TB is secondary to tubal epithelioid granulomas in the fallopian tube [asterisk] [lower panel,
involvement (31,32). Schaefer (31) reported endometrial right; Haematoxylin and eosin × 60]
involve­ment in 50%-80% cases of genital TB. In a large series TB = tuberculosis
356 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

caseation, granulomas with lymphocytes, Langhans’ giant Microscopic examination reveals granulomatous inflam-
cells and epithelioid cells. Such lesions may be focal or mation. Inflammatory atypia with frequent hyperplastic
generalised. Due to cyclical shedding of endometrium, such mucosal changes may be seen along with caseation (1). The
lesions may be seen close to the surface of endometrium. endocervical involve­ment is common (32) and may explain
Granulomas may be better seen in premenstrual phase or increased mucus production.
within 12 hours after onset of menstrua­tion (35). Cervical TB has been diagnosed cytologically by various
However, typical granulomas may not be seen in all workers (39-40). Multinucleated giant cells, histiocytes,
cases (36). Bazaz-Malik et al (2) in a series of 1000 cases of epithelioid cells arranged in clusters simulating the
TB endometritis noted discrete granulomas and caseation in appearance of granulomas are characteristic of the disease
in Papanicolaou smear examination. Cytological diagnosis
60% cases only. They suggested presence of dilated glands,
of genital TB in association with carcinoma in situ and
destruction of epithelium, inflammatory exudates in the
Trichomonas vaginalis has been described (40).
lumen as additional criteria for diagnosis of TB endometritis.
Bourno and Williams (37), suggest that focal collection of
Tuberculosis of the Vagina, Vulva and
lymphocytes in the endometrium should be considered to
Bartholin Gland
be of TB origin unless proved otherwise.
TB of the vulva and vagina occurs in 1% of cases (5,9). TB of
Ovarian Tuberculosis Bartholin gland and vesicovaginal fistula due to genital TB
have been described (41,42). Involvement of the vagina or
Ovarian involvement occurs in 15%-25% cases (5,9) and vulva is usually secondary to the involvement of other parts
most often results from direct extension of the disease from of genital tract. However, transmission of the disease by a
fallopian tubes (10). In such cases, ovary may be surrounded male partner due to involvement of epididymis or seminal
by adhesions or may be the site of tubo-ovarian cyst vesicles has been reported (28).
formation or tubo-ovarian mass with adhesions surrounding Lesions on vulva and vagina may present as hypertrophic
them. In patients with haematogenous spread caseating lesions resembling malignancy, less often non-healing ulcers
granulomas may be seen in the parenchyma of ovary (10,32). in the vulva may be seen. Histopathological examination of
the lesion is useful in confirming the diagnosis.
Tuberculosis of Cervix
CLINICAL PRESENTATION
TB of the cervix may be seen in 5%-15% cases of genital
TB (5,9). Cervix mostly gets affected by downward spread of Symptoms
the disease from the endometrium. However, rarely cervical The most frequent presenting symptoms in patients with
disease may occur secondary to deposition of infected semen FGTB include infertility, pelvic pain, menstrual distur­
by the male partner (28,29). Mostly, cervical lesions tend to bances, vaginal discharge and poor general condition
be hypertrophic resembling cervical carcinoma (38) and less [Table 26.2] (2,3,10,12,13,15,18,22,26,36,43,44). However, none
often an ulcerative lesion may be seen (32). of these are specific for FGTB.

Table 26.2: Clinical presentation of patients with genital TB

Menorrhagia/ Postmenopausal Chronic pelvic
Study (reference) No. of patients Infertility Amenorrhoea oligomenorrhoea bleeding pain
Sutherland (18) 250 40 10 18 20 ND
Malkani and Rajani (13) 106 ND 43.4 43 ND ND
Mukherjee et al (43) 138 100 60 19.7 ND ND
Munjal et al (36) 140 37.1 42.8 41.4 1.4 ND
Klein et al (3) 20 70 20 ND ND 30
Falk et al (10) 187 12.8 41.2 ND ND ND
Bazaz-Malik et al (2) 1000 47 26 15 1.0 2.4
Bobhate et al (12)* 337 58.6 26.4 ND ND ND
Chhabra (26) 58 29.3 18.9 15.5 3.4 43.1
Sfar et al (44) 118 81 ND ND ND ND
Saracoglu et al (22) 72 47 11 ND ND 32
Gupta et al (15) 40 40 10 40 ND 20
All values are shown as percentages
* These series included patients with TB endometritis only
TB = tuberculosis; ND = Not described
 Female Genital Tuberculosis 357

Infertility Table 26.3: Signs in female genital TB

Primary and secondary infertility are the most common No physical sign [common]
presenting symptom in patients with FGTB. All reported Systemic examination
series have identified this association [Table 26.2]. Fever
Lymphadenopathy
Chest signs [PTB]
Chronic Lower Abdominal or Pelvic Pain Other signs as per site of EPTB
Abdominal examination
Chronic lower abdominal or pelvic pain is the second most
Ascites
common symptom in patients with FGTB [Table 26.2]. Pain Doughy feel of abdomen
is non-characteristic and is usually localised in the lower Abdominal lump/vague or definite
abdomen or pelvis. Pain tends to be chronic and is usually Vaginal examination
dull aching. Occasionally, acute pain may occur similar to Enlarged uterus [pyometra]
that of acute pelvic inflammatory disease or a twisted pelvic Induration and tenderness in adnexa
organ. Episodes of acute pain, as a result of superadded Tubo-ovarian and adnexal masses
Fullness and tenderness in pouch of Douglas
bacterial infection, can occur and require administration of
Unusual signs
antibiotics. Acute episodes of pain may occur after diagnostic Ulcerative lesions on vagina, vulva, cervix [may mimic venereal
procedures, such as, endometrial biopsy, dilatation and diseases or cancer]
curettage or hysterosalpingography [HSG]. Patients with Hypertrophic lesions on vagina, vulva, cervix [may mimic cancer]
chronic pain are more likely to have abnormal findings on Uterocutaneous fistula
pelvic examination. Tubo-intestinal fistula
Tubo-peritoneal fistula
Tubo-vesical fistula
Alterations in Menstrual Pattern Rectovaginal fistula
All types of menstrual irregularities, such as, amenorrhoea, Vesicovaginal fistula
Bartholin swelling
menor­rhagia, oligomenorrhoea or even postmenopausal
bleeding can occur [Table 26.2]. TB = tuberculosis; PTB = pulmonary tuberculosis; EPTB = extra­
pulmo­nary tuberculosis

Persistent/Abnormal Vaginal Discharge

Occasionally, patients with persistent vaginal discharge may
be found to have genital TB affecting cervix or vagina (38-40).
Table 26.4: Differential diagnosis of female genital TB
Such a symptom is more likely to occur in women with
For women presenting with pain and adnexal mass, following
endocervical TB or in patients with TB of the cervix or
possibilities should be considered
vagina.
Ectopic gestation
Acute and chronic pelvic infections
Unusual Symptoms Appendicular lump
Endometriosis
Several unusual symptoms as presentation of FGTB have
Ovarian malignancy
been described from time to time. These include vulval For granulomatous lesions in the pelvis
lesions, Bartholin gland swelling (41), vesicovaginal Actinomycosis
fistula (42), pelvic masses (45), uterocutaneous fistula (46), Brucellosis
and retention of urine due to pelvic masses of TB origin (47). Crohn’s disease
Female genital TB may manifest and masquerade as ovarian Filariasis
cancer with rise in CA 125 levels as has been the experience Granuloma inguinale
of us and others (48,49). Histoplasmosis
Leprosy
Schistosomiasis
Physical Signs
Silicosis
No physical sign on abdominal or pelvic examination is Syphilis
characteri­stic of genital TB. A high index of suspicion is, Ulcerative or hypertrophic lesions
therefore, required to make an early diagnosis. The various Vaginal cancer
signs of FGTB depend on the site of involvement of genital Cervical cancer
Bartholin abscess
organs and are shown in Table 26.3 (5,23,50).
Vulval cancer
Condyloma lata
DIFFERENTIAL DIAGNOSIS Condyloma acuminata
Vaginal cyst
As FGTB can present in different ways with no definitive
Vulval and vaginal warts
symptoms and signs, the differential diagnosis varies as per
TB = tuberculosis
presentation [Table 26.4].
358 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

DIAGNOSIS hysteroscopy and laparoscopy have emerged as the most

useful investigations. These investigations not only facilitate
As genital TB is a paucibacillary disease, it is not possible
the visual examination of the lesions and confirmation of
to demonstrate Mtb in every case. Therefore, one has to
the diagnosis, but also help in picking up unsuspected
rely on imaging and histopathology. Endometrial biopsy
pathology, such as, endometriosis or malignancy in a
for histopatho­l ogical examination and mycobacterial
number of cases.
culture remains the most commonly used procedure for
the diagnosis of FGTB (51-54). Guinea pig inoculation is
Endometrial Biopsy
presently not being used for the diagnosis of FGTB (53,55).
Laparoscopy, HSG, ultrasonography of pelvic organs, Endometrial tissue obtained by endometrial biopsy curette
computed tomography [CT] and magnetic resonance imaging or by aspiration with a plastic disposable cannula or by
[MRI] are other investigative procedures which are carried dilatation of the cervix and curettage of the endometrium
out if the endometrial biopsy is not conclusive. Recently, a [D and C] is useful for the diagnosis of TB [Figure 26.1].
number of newer investigations such as polymerase chain Best time to perform such a procedure is shortly before the
reaction [PCR] have been applied for the diagnosis of genital menstruation (5,9) as lesions are likely to be close to surface
TB [Table 26.5] with variable results. However, diagnostic of endometrium during this phase of the menstrual cycle.
Histopathologically proven TB is present in 50%-76%
patients with genital TB [Table 26.6] (3,10,13,15,19,32,44,51,52).
Table 26.5: Diagnostic modalities for female genital TB In the absence of granulomas, and caseation necrosis, other
Site Diagnostic procedures features such as dilatation of glands, destruction of epithelium
Fallopian tube Laparoscopy, hysterosalpingography, peritoneal
and inflammatory cells are seen on histopathology (3).
fluid smear for AFB and mycobacterial culture, Malkani and Rajani (13) suggested that the focal collection
tubal biopsy of chronic inflammatory cells or presence of proliferative
Endometrium Endometrial histology endometrium in the premenstrual week in a patient with
Endometrial aspirate smear for AFB and past history of TB in other parts of the body or a family
mycobacterial culture history of TB would favour a diagnosis of FGTB.
Hysteroscopy A negative endometrial biopsy does not rule out the
Menstrual blood culture for pelvic involvement since sampling errors are common and
Mycobacterium tuberculosis
disease may have involved other pelvic organs without
Cervix Biopsy associated TB endometritis (1).
Exfoliative cytology
Vagina and Biopsy Mycobacterial Isolation
vulva
Endometrial biopsy specimen, menstrual blood, cervical and
TB = tuberculosis; AFB = acid-fast bacilli
vaginal secretions, tubal biopsy material or peritoneal fluid

Table 26.6: Comparison of the mycobacterial culture and histopathological examination of endometrium in the
diagnosis of female genital TB
Both culture and
Study (reference) No. of patients Culture positive HPE positive HPE positive
Malkani and Rajani (13) 57 17.5 100.0 *
Halbrecht and Petah Tiqua (51) 103 36.9 10.6 52.5
Klien et al (3) 20 37.5† 62.5† ND
Nogales-Ortiz et al (32) 1436 100.0‡ 76.1§ ND
Falk et al (10) 187 29.4 69.5 ND
Chhabra et al (52) 150 6.0 6.7 1.3
Sfar et al (44) 118 7.0 46.0 ND
Roy et al (19) 800 10.9 9.8 11.8
Gupta et al (15) 40 2.5 25 2.5
Positive yield is shown as percentage
All values have been corrected to first decimal place
* 57 endometrial biopsy-proven patients were included in the study
† Culture and histopathology yield available for 16 patients
‡ Culture yield available for 30 patients
§ Histopathology yield available for 201 patients
TB = tuberculosis; HPE = histopathological examination; ND = not described
 Female Genital Tuberculosis 359

obtained during diagnostic laparoscopy have been subjected

to Mtb smear and culture examination (6,11,23).

Endometrial Culture versus Histopathology

A number of studies have evaluated histopathology and
mycobac­terial culture for the diagnosis of endometrial TB
[Table 26.6]. Most studies have found a higher diagnostic
yield with histopathological examination of endometrium
than culture of biopsy material (6,11,23,44,51,52).

Hysterosalpingography
The HSG visualisation of uterine cavity and fallopian tubes
by injecting a radio-opaque contrast medium into the uterus
through cervix, is routinely performed for investigation
of infertility [Figure 26.2]. A number of findings on HSG Figure 26.3: Hysterosalpingogram showing ragged and jagged contour
may suggest genital tract TB (56,57). The HSG performed of the tube. Only one tube could be visualised in this case [black
arrow]. Terminal end of the tube presents leopard skin-like speckled
during the acute stage of the disease, may however, result in appearance [white arrow]
exacerbation of the disease and is, therefore, contraindicated.
Winifred (57) noted such an event in four of the fourteen
cases subjected to HSG. Seigler (58) reported fever as the
most common complication following HSG. Serious pelvic
infections have been reported in 0.3%-1.3% of cases.
Magnusson (59) described two typical forms of the
disease based upon HSG findings: [i] ragged and jagged
tubal contour with small lumen defects [Figure 26.3];
[ii] straight rigid contour of the lumen with stem pipe-like
configuration of the tube. Seigler (58) described rigid tubes,
irregular tubal outline, calcification of the tubes and ovary,
filling defects in the line of tubal shadow and fistulous tracts
on HSG as suggestive of TB.
Rozin (60) has described several radiographic signs that
were presumptive of TB. These include: [i] golf club appearance,
when only isthmus and proximal ampulla are visualised,
isthmic segment has a rigid stove pipe appearance [Figure 26.4];
[ii] a beaded appearance due to alternate areas of tube filled with Figure 26.4: Hysterosalpingogram showing rigid stove pipe-like
and without radiographic contrast [Figure 26.5]; [iii] maltese appearance of the fallopian tubes [arrows]. There is a small area of
cross appearance, completely filled tube with rigid, irregular irregularity along the right uterine wall [arrow head]

Figure 26.2: Hysterosalpingogram with normal findings. The uterine Figure 26.5: Hysterosalpingogram showing irregular uterine outline
cavity has a normal outline. Both the fallopian tubes are outlined with and patchy filling of the dye in the right fallopian tube resulting in
free peritoneal spill of radio-opaque contrast [arrows] beaded appearance [arrow]
 360 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

outline [Figure 26.6]; [iv] rosette appearance where the distal

end of tube is filled with dye [Figure 26.7]; [v] numerous
diverticula in isthmic area; and [vi] leopard skin-like
speckled appearance of the ampulla due to tube being
partially filled with the contrast [Figure 26.3].
The presence of calcified tubes, ovary or pelvic lymph
nodes is considered as the most significant finding. In
addition, uterine cavity may be shrivelled and deformed.
There can be extensive extravasation of radio-opaque
contrast in pelvic vessels in FGTB [Figure 26.8]. The tubes
may be patent in 37% of cases of TB endometritis (61).
We found tubal calcification, irregularity of tubal wall,
unilateral or bilateral cornual block, unilateral or bilateral
hydrosalpinx, venous and lymphatic intravasation of dye
in cases of genital TB in our study (62). Chauhan et al (63)
observed synechiae formation, a distorted, and obliterated Figure 26.8: Hysterosalpingogram showing extensive extravasation of
or T-shaped cavity and venous and lymphatic intravasation radio-opaque contrast in pelvic vessels [arrows]. Fallopian tubes are
in their study on HSG in FGTB (63). not visualised indicating bilateral cornual occlusion

Laparoscopy
Laparoscopy is an important procedure in the diagnostic
work-up of patients with infertility (64-73). Laparoscopy
provides direct visualisation of the pelvic organs and
peritoneal surfaces. In addition, it helps in confirming tubal
patency. A number of observations may be made during
laparoscopy in these cases. These include endometriosis,
pelvic inflammatory disease or fibroids. It is important to
carefully visualise whole of abdominal cavity including
intestines, peritoneum, liver and gallbladder during
laparoscopy to observe any TB lesion there. We have obser­­
ved change in position of gallbladder [Sharma’s hanging
gallbladder sign] in patients with abdomino-pelvic TB (64).
Despite normal physical examination, several abnormalities
Figure 26.6: Hysterosalpingogram showing completely filled tube on can be detected in about 60% of the cases during laparo­
the right side with a rigid outline [white arrow]. Dilatation of the distal scopy (65) [Figures 26.9A, 26.9B and 26.9C]. Diagnostic yield
half of the left tube with doubtful spill of the contrast is seen [black of laparo­­scopy in patients with infertility due to suspected
arrow]. A small filling defect is also seen in the uterine cavity FGTB has been documented in several studies (64-70)
[Table 26.7] (15,65,69,70). Based upon various laparoscopic
findings and guided biopsy, Palmer and Olivera (66) have
described subacute and chronic stages in the natural history
of pelvic TB.

Subacute Stage
The subacute stage of FGTB is characterised by the pre­
sence of whitish-yellow and opaque miliary granulations,
surrounded by hyperaemic areas over the fallopian tubes
and uterus. The pelvic organs may be congested, red and
oedematous with adhesions. Multiple fluid filled pockets
may also be seen.

Chronic Stage
The chronic stage of FGTB is recognised by the presence of
the following findings.
Figure 26.7: Hysterosalpingogram showing dilated portion of the left
fallopian tube without any spill of dye [arrow]. Only proximal part of the Nodular salpingitis A series of yellow coloured small nodes
right fallopian tube is seen may be seen on a normal looking tube.
 Female Genital Tuberculosis 361

Figure 26.9A: Laparoscopy view in a patient with pelvic TB showing

a large [5 × 4 cm] caseous nodule near right fallopian tube [arrow]. Figure 26.9D: Hysteroscopy image showing pale looking cavity
Biopsy from the nodule confirmed the diagnosis of TB
TB = tuberculosis

Figure 26.9B: Laparoscopy view of pelvis in a patient with pelvic TB

showing surface tubercles on uterus [arrows]. Biopsy from the tubercle Figure 26.9E: Hysteroscopy image showing grade 3 adhesions
confirmed the diagnosis of TB [arrows]
TB = tuberculosis

Table 26.7: Incidence of genital TB at laparoscopy

Study (reference) No. of patients Incidence [%]
Krishna et al (70) 697 10.3
Deshmukh et al (69) 500 9.0
Merchant (65) 687 14.1
Gupta et al (15) 150 26.7
TB = tuberculosis

Patchy salpingitis Short and swollen tubes with agglutinated

fimbriae may be seen.
Hydrosalpinx Fallopian tubes are distended at their terminal
end due to agglutination of fimbriae. These tubes tend to be
“retort shaped”. Bilateral involvement of the tubes is almost
Figure 26.9C: Laparoscopy view of pelvis in a patient with confirmed always seen.
FGTB showing caseous nodules on the surface of right fallopian tube
[white arrow] and in the Pouch of Douglas [black arrow]. Both fallopian Caseosalpinx Ampulla of the tube is deformed by an ovoid
tubes are dilated and blocked dilatation which is whitish-yellow with poor vascularisation.
362 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The tube is distended with caseous material. This finding of varying grade [grade 1 to grade 4] often involving ostia
also tends to be bilateral. as observed by us (75,76) [Figure 26.9E]. Hence, FGTB is an
important cause of Asherman’s syndrome in India (76). There
Adhesions Bands of adhesions may be seen between loops may be a small shrunken cavity. One has to be careful while
of intestine and the omentum. Sometimes broad bands may performing hysteroscopy in genital TB as the procedure is
mask the whole adnexae. Laminar adhesions covering the associated with increased difficulty to distend the cavity and
tubes and ovary and fixing them are occasionally seen in the to do the procedure and increased chances of complications
chronic phase of genital TB. like excessive bleeding, perforation and flare up of genital
Tripathy and Tripathy (20) performed laparoscopy in TB as observed in our study (77). Hence, hysteroscopy in
62 sputum smear-positive pulmonary TB patients. They a patient of genital TB should be done by an experienced
found bands of adhesion, tubercles and hyperaemia in 59.6% person preferably under laparoscopic guidance to avoid false
and intestinal adhesions in 24.2% patients. Tubercles were passage formation and injury to the pelvic organs.
observed on the fallopian tubes in 22.6% and adhesions in The frequent use of laparoscopy and hysteroscopy has
the pouch of Douglas were evident in 11.3% patients. made it possible to diagnose a number of cases of genital
Bhide et al (67), in a laparoscopy study of 71 patients TB among women with infertility and chronic pelvic pain.
with genital TB reported pelvic adhesions in 48%, tubercles
in 33.8%, unilateral adnexal mass in 11.3% and bilateral
Ultrasonography
adnexal masses in 21.1% patients. Further, encysted effusion
[8.45%] and lesions on the bowel and/or omentum [25.4%] Ultrasonography, being non-invasive with no radiation
were also observed. Marana et al (68), in a laparoscopy study hazard, has been increasingly used in evaluating pelvic
of 254 patients with primary or secondary infertility from and other abdominal masses. Lee et al (78) described
Italy, found tubal factor to be responsible in 101 patients. Of sonographic features of TB endo­metritis in a 59-year-old
these, only two patients had histopathological and culture female. Demonstration of bilateral, predominantly solid,
positive endometrial TB. In a third patient with laparoscopic adnexal masses containing scattered small calcifications is
findings suggestive of TB, the organisms were cultured highly suggestive of TB (78).
from urine. Deshmukh et al (69) and Krishna et al (70) also The authors have encountered a number of patients with
found laparoscopy useful in diagnosis of FGTB [Table 26.7]. infertility or chronic pelvic pain with adnexal masses and
In a study on FGTB in infertile women from New Delhi free fluid in the pelvis on ultrasonography that were found to
[n = 40] (15), laparoscopic examination revealed abnormally have genital TB on subsequent investigations [Figure 26.10].
dilated, tortuous, and blocked fallopian tubes [n = 13];
peritubal and periovarian adhesions [n = 18]; Fitz-Hugh- Computed Tomography
Curtis syndrome [n = 15]; omental adhesions [n = 18]; and
A number of findings have been described on CT as
bowel adhesions [n = 15]. In a laparoscopic study on 85 women
suggestive of abdominal and pelvic TB. These include
with FGTB, we observed tubercles on peritoneum [15.9%
low density ascites, uncommon patterns of adenopathy,
cases], tubo-ovarian masses [26%], caseous nodules [7.2%],
presence of multiple pelvic lesions, and hepatic, adrenal
encysted ascites [8.7%], various grades of pelvic adhesions
[65.8%], hydrosalpinx [21.7%], pyosalpinx [2.9%], beaded
tubes [10%], tobacco pouch appearance [2.9%] and inability
to see tubes due to adhesions [14.2%] (71). The authors
have observed a new laparoscopic sign [python sign] in
tubal involvement of FGTB in which fallopian tubes become
distended like a blue python with alternate constriction
and dilatation on injection of methylene blue dye (72).
We also observed a very high prevalence of perihepatic
adhesions [Fitz-Hugh-Curtis syndrome] on laparoscopy in
FGTB (73). However, we observed increased complications
on laparoscopy for FGTB as compared to laparoscopy
performed for non-TB patients [31% versus 4%] like inability
to see pelvis [10.3% versus 1.3%], excessive bleeding [2.3%
versus 0%], peritonitis [8% versus 1.8%] (74). The adhesions
are typically vascular and adhesiolysis can increase the risk
of bleeding and flare up of the disease (6,74).

Hysteroscopy Endoscopic visualisation of the uterine cavity

in genital TB may show a normal cavity [if no endometrial
Figure 26.10: Ultrasonography in pelvic tuberculosis. A longitudinal
TB or early stage TB] with bilateral open ostia. More often, scan in a 33-year-old parous woman with a history of oligomenor­rhoea.
however, the endometrium is pale looking [Figure 26.9D], The scan shows fluid collection in the Pouch of Douglas [asterisk].
the cavity is partially or completely obliterated by adhesions Investigations confirmed the diagnosis of genital tuberculosis
 Female Genital Tuberculosis 363

and splenic lesions. Though these lesions may mimic Positron Emission Tomography
malignancy, these should raise a suspicion of TB, especially if
Positron emission tomography [PET] demonstrates glucose
encountered in young patients suffering from infertility (79).
uptake by TB lesions [Figure 26.12] and is particularly useful
to know whether the lesion is active or not. An active lesion
Magnetic Resonance Imaging
shows increased glucose uptake (81). The reader is referred
Magnetic resonance imaging [MRI] is being increasingly to the chapter “Roentgenographic manifestations of pulmonary
used for evaluating pelvic and other abdominal masses and extrapulmonary tuberculosis” [Chapter 9] for details.
[Figures 26.11A and 26.11B] and has been found to be
useful in localising soft tissue abnormalities in patients Serological Tests
with FGTB (80). The presence of hypodense masses with
Serological tests have been banned by Government of India
rim enhancement abutting the pelvic walls is suggestive
and are not to be used for the diagnosis of TB presently.
of TB [Figures 26.11A and 26.11B]. Unilateral or bilateral
tubo-ovarian masses, unilateral or bilateral hydrosalpinx,
adnexal cysts or TB deposits on peritoneum or liver have Polymerase Chain Reaction
been described in the study of MRI in tubo-ovarian masses The polymerase chain reaction [PCR] is a useful supporting
due to TB (80). test for the diagnosis of FGTB (82-84). Used judiciously,
the PCR can help in the diagnosis of TB in certain clinical
situations. However, some authors have doubted the value
of PCR in the diagnosis of TB (85). Further, false positivity of
PCR, especially in-house PCR, has been observed to be high.
Anti-TB treatment should not be started just on the basis of a
positive PCR test result unless there is some other evidence
of FGTB on clinical examination or on investigations
like presence of tubercles or other stigmata of TB on
laparoscopy (5).

Cartridge-based Nucleic Acid Amplification Tests

Cartridge-based nucleic acid amplification tests [CBNAAT]
are increasingly being used for the diagnosis of FGTB.
The Xpert MTB/RIF® is a new fully automated diagnostic
molecular test with an analytic sensitivity of five genome
copies of purified deoxyribonucleic acid [DNA] and 131
Figure 26.11A: Magnetic resonance imaging in pelvic tuberculosis.
Post-gadolinium T1-weighted coronal scan in a 26-year-old nullipara colony-forming units [cfu]/mL of Mtb in sputum. The Xpert
with history of chronic pelvic pain unresponsive to usual treatment. MBT/RIF is also able to detect more than 99.5% rifampicin
Hypointense masses with rim enhancement [arrows] abutting the left resistance mutations, an indicator of multidrug-resistant TB
pelvic wall and tracking to subgluteal region suggestive of abscesses in less than two hours time (86a). Recent evidence (86b,86c)
is available suggesting that in women with female genital
TB with tubo-ovarian masses who are not responding to
first-line anti-TB drugs, Xpert MTB/RIF is useful in early
diagnosis of MDR-TB.

Figure 26.11B: Magnetic resonance imaging T1-weighted coronal Figure 26.12: PET-CT showing left tubo-ovarian mass with increased
scan of the same patient one year after antituberculosis treatment. uptake suggestive of active disease [arrow]
Scan shows complete resolution of abscesses PET-CT = positron emission tomography-computed tomography
364 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Diagnostic Algorithm recommend 6 months standard first-line anti-TB treatment

regimen for FGTB. Prior to the availability of effective drug
The diagnosis of FGTB is made based on good history,
therapy, surgery produced a significant degree of morbidity
careful systemic and gynaecological examination; and
and complications. These included bowel fistula [14%] and
judicious use of diagnostic modalities like endometrial an operative mortality rate of 2.2% (31). These complications
biopsy in conjunction with imaging methods and endoscopic are rarely seen now. Indications for surgical intervention in
visualization, especially with laparoscopy. Algorithm for patients with FGTB are shown in Table 26.8.
accurate diagnosis of FGTB by combining history taking,
examination and investigations, has been reported (87).
Minimal Genital Tuberculosis
A diagnostic algorithm for FGTB is shown in Figure 26.13.
Minimal disease is usually asymptomatic, except for inferti­
TREATMENT lity and is diagnosed by finding TB endometritis on curettage
or biopsy or tubercle bacilli on culture of the curettings of
Treatment of FGTB is similar to treatment of the disease menstrual blood. The patient is started on standard anti-TB
as elsewhere in the body. Availability of effective anti- treatment and is examined at monthly intervals. After six
TB treatment has significantly decreased the requirement months, a procedure of dilatation and curettage is done and
for surgical treatment in patients with FGTB. In India, the endometrial curettings are examined histologically and
patients with FGTB receive DOTS under the Revised bacteriologically.
National Tuberculosis Control Programme of Government of Wherever feasible, the patient should be followed up
India (8). The reader is referred to the chapters “Treatment of annually for an indefinite period of time as exacerbations
tuberculosis” [Chapter 44], and “Revised National Tuberculosis have been reported up to 10 years after apparent cure before
Control Programme” [Chapter 53] for details. The recently the advent of modern short-course treatment. This is highly
published evidence-based INDEX-TB guidelines (88) unlikely with current therapy.

Figure 26.13: Algorithm for diagnostic work-up of FGTB

FGTB = female genital tuberculosis; RIF = rifampicin; AFB = acid-fast bacilli; TB = tuberculosis; USG = ultrasonography; CT = computed
tomography; MRI = magnetic resonance imaging; PET = positron emission tomography
 Female Genital Tuberculosis 365

Table 26.8: Indications for surgical intervention in Of the 206 patients with FGTB treated by Sutherland (99),
female genital TB 45 pregnancies were reported in 26 women. Of these, 11 were
ectopic pregnancies and 11 pregnancies ended in abortions.
Persistence or increase of pelvic masses after a six-month course
of anti-TB treatment
Fourteen women had 23 live births (99). Merchant (65) in a
study of 101 patients with FGTB, diagnosed on laparoscopy,
Recurrence of positive endometrial culture or histology after six
months course of anti-TB treatment
reported 3 ectopic pregnancies, 11 intrauterine pregnancies
and 9 term pregnancies. In two patients, abortion was
Persistence or recurrence of pain or bleeding after six months of
induced for medical reasons. Jindal et al (95) reported three
anti-TB treatment
pregnancies among 14 women with histopathologically
Postmenopausal patient with a recurrent pyometra due to TB
proven endometrial TB. Falk et al (10) in a study of 187
TB = tuberculosis patients from 47 Swedish hospitals reported four ectopic
Adapted from reference 9 pregnancies and no intrauterine pregnancy after anti-TB
treatment. Saracoglu et al (22), in a series of 72 patients with
pelvic TB from Turkey, reported one intrauterine pregnancy
Advanced Genital Tuberculosis without any surgical or medical treatment of pelvic TB.
Advanced genital TB is diagnosed by the presence of palpable
tubo-ovarian masses and histopathologic or bacteriologic Tuboplasty
evidence of TB. The patient is started on standard anti-TB Since infertility is the most common symptom in patients
treatment and is examined at monthly intervals. with genital TB, reconstructive tubal surgery is often
Schaefer (9) has suggested that, if palpable adnexal masses performed after adequate medical treatment. Reactivation
persist after six months, total abdominal hysterectomy of silent pelvic TB following tuboplasty procedure has been
and bilateral salpingo-oophorectomy are performed (9). reported by Ballon et al (100). Schaefer (9) advocates against
However, there is no consensus regarding this view (9) as a such procedures in patients with FGTB.
number of these patients suffer from infertility and are also
young. Modern short-course anti-TB treatment is highly In Vitro Fertilisation and Embryo Transfer
effective for the treatment of FGTB with rare need of surgery.
There are much higher chances of complications during Most women with genital TB present with infertility
surgery in women with genital TB in hysteroscopy, laparo­ and have poor prognosis for fertility in spite of anti-TB
scopy, vaginal hysterectomy and laparotomy (74,77,89,90). treatment. The conception rate is low [19.2%] with live birth
There is excessive haemorrhage and non-availability of rate being still low [7%] (93). Parikh et al (101) found IVF
surgical planes at time of laparotomy with a higher risk of with embryo transfer [ET] to be the only hope for some of
injury to the bowel and other pelvic and abdominal organs. these women whose endometrium was not damaged and
In case of abdomino-pelvic TB, bowel loops may be matted reported a pregnancy rate of 16.6% per transfer. Jindal (95)
observed IVF-ET to be most successful of all the assisted
together with no plane between them and uterus and adnexa
reproductive technology modalities in FGTB patients with
may be buried underneath the plastic adhesions and bowel
17.3% conception rate in contrast to only 4.3% observed
loops and may be inapproachable. Even trying to perform
with fertility enhancing surgery. Dam et al (14) found
a diagnostic laparoscopy or laparotomy in such cases can
latent genital TB responsible for repeated IVF failure in
cause injury to bowel necessitating resection of injured
young patients presenting with unexplained infertility with
bowel. It is better to obtain biopsies from the representative
apparently normal pelvis and non-endometrial tubal factors.
areas, close the abdomen without pelvic clearance and start
If after anti-TB treatment their tubes are still damaged
standard anti-TB treatment, awaiting biopsy report in cases
but their endometrium is receptive [no adhesions or mild
where laparotomy is done for suspected pelvic tumours
adhesions which can be hysteroscopically resected], IVF-ET
but the appearances are suggestive of TB. However, limited
is recommended (6). However, if they have endometrial TB
surgery like drainage from residual large pelvis or tubo-
causing damage to the endometrium with shrunken small
ovarian abscesses, pyosalpinx can be performed followed uterine cavity with Asherman’s syndrome, adoption or
by administration of anti-TB treatment (91). gestational surrogacy may be considered (5,6).

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Singh N, et al. Comparison of PET/CT with other imaging infertility in Indian women. Fertil Steril 1997;67:497-500.
 27
Genitourinary Tuberculosis
Rajeev Kumar, AK Hemal

INTRODUCTION at least one extrapulmonary site in nearly 50% of the cases (6),
with the kidney being the most common genitouri­nary site
Genitourinary tuberculosis [GUTB] is a common term used
of involvement (7).
for tuberculosis [TB] infection affecting either the urinary or
Mycobacterium tuberculosis [Mtb] is the usual cause of
genital systems. It is one of the most common forms of extra-
GUTB. Genitourinary involvement is often secondary to
pulmonary tuberculosis [EPTB] and, depending upon the
haematogenous dissemination from a pulmonary focus.
endemicity of TB in a country, may account for up to 27% of
Spread to the kidney often occurs to multiple foci which may
all EPTB; making it the second or third most common form
heal with no evidence of disease or may form microscopic
of EPTB (1-3). The common term, GUTB, is used because
granulomas (8). The intensity of infection depends upon the
the pathology frequently involves both systems due to their
infecting dose, virulence of the organism and the resistance
anatomical and functional proximity, and it is usually not
of the host. Macroscopic progression of the disease is
possible to separate affliction of one part from the other.
mostly unilateral (9). Usually, these multiple tubercles heal
The disease often affects individuals in the reproductive age
either spontaneously or as a result of anti-TB treatment
group of 20-40 years with significant morbidity in both the
administered for the primary focus. Involvement of the
renal and reproductive functions, which could include renal
remaining urinary system is by contiguous spread of the
failure and infertility.
infection down from the kidney. Similar haematogenous
spread occurs to the epididymis which may be involved
EPIDEMIOLOGY AND PATHOGENESIS in up to 78% of all cases (10). The globus minor of the
The GUTB complicates three to four per cent of all cases epididymis is the preferred site of involvement, possibly
of pulmonary TB. Colabawalla (4), in a multicentric study due to its high vascularity. Another route of involvement
from India, reported a prevalence of 10%-34% among of the genital tract is via retrograde spread from the urinary
patients with various urological diseases. While this may bladder. Infection may travel along the ejaculatory ducts
be an over-estimate of current prevalence, a meta-analysis and vas deferens to involve the prostate, seminal vesicles,
of world-wide epidemiologic trends of GUTB found the epididymis and testis, highlighting the common involvement
incidence in men to be twice that in women with the mean of the urinary and genital systems (11).
age of involvement being 40 years (5). Overall, only about The pathophysiologic manifestations of TB occur through
a third of these cases had evidence of previous pulmonary a number of mechanisms; infective destruction of tissue,
TB but this was almost 50% in patients from the developing distor­tion due to formation of space-occupying lesions, and
world. Another important finding of this analysis was fibrosis resulting in strictures, contractures and architectural
that patients in the developing world presented late and deformity. Reactivation of the renal focus may take place
consequently had a higher incidence of severe disease any time after the initial event and a latent period of up to
and renal failure and were also more likely to have a 46 years has been reported (12). This reactivation is usually
bacteriological diagnosis than patients from the developed unilateral and one or more tubercles may enlarge after
world. TB occurs in approximately 10% of patients with years of inactivity and rupture into the collecting system,
acquired immunodeficiency syndrome [AIDS] and involves producing bacilluria without a radiographically visible renal
 Genitourinary Tuberculosis 369

lesion (8). The bacilli descend along the nephrons and form
more granulomas within the medulla and papilla. These
granulomas may coalesce and form cavities which may
communicate with the pelvicalyceal system [PCS] following
rupture. These may also result in necrosis and sloughing.
These cavities are visible on radiologic studies, often giving
a ‘moth eaten’ appearance to the kidneys. Tuberculomas in
the renal parenchyma occupy space and displace calyces
with obstruction to their drainage. These may appear as
dilated ‘hydrocalyces’. Further, hydrocalyces may also
arise as a consequence of scarring of the infundibular
necks. On an intravenous contrast study, these calyces
do not fill with contrast which is a characteristic feature
in GUTB. Similar cicatrisation may affect the renal pelvis.
Parenchymal lesions may undergo calcification and an
extensively involved kidney may have extensive caseous
necrosis and calcification, resulting in a ‘putty’ kidney. The Figure 27.1A: Plain X-ray of the kidney, ureter and bladder [KUB]
combination of obstruction and parenchymal damage leads showing calcified kidney [arrows] on the left side resulting in
autonephrectomy
to a non-functioning, calcified kidney in a process called
‘autonephrectomy’ [Table 27.1, Figures 27.1A and 27.1B].
Gross pathological examination of the kidney may reveal
destroyed papillae, ulcerated calyces, caseous masses, and
cavities of varying sizes with ragged edges and containing
creamy, sterile pus in the cortex. Renal calcification is often
found though its aetiology is unclear. These calcific shadows
tend to be ill defined and irregular, neither as dense nor
as well defined as renal calculi. These lie in the cortex
and strongly suggest the presence of TB. Calcification is
an unfavourable prognostic sign with a high likeli­hood of
surgical intervention as medical management will rarely cure
the infection.
Ureteric pathology is typically manifest in the form
of strictures (13). Downstream infection from the kidney
causes mucosal and wall ulceration and fibrosis with
strictures. Strictures may develop at multiple sites, giving
a radiologically beaded appearance. The ureter often fails

Table 27.1: Pathologic changes in renal TB

Early changes
Papillary necrosis/papillitis
Cavity formation
Figure 27.1B: Intravenous urogram of same patient showing normally
From sloughed off papilla
functioning kidney on the right side and calcified nonfunc­tioning kidney
From rupture of abscess into the pelvi-calyceal system
[arrow] on the left side
Strictures
Caliectasis
Calyx cut-off to dilate on the contrast studies, appearing like a fixed
Infundibular stenosis pipe-stem. The infection frequently occurs at the vesico-
Hydronephrosis ureteric junction and causes progressive changes in the
Cicatrised pelvi-ureteric junction ureteric orifice within the bladder (14). The orifice may take
Ureteric strictures, reflux
a ‘golf-hole’ appearance, cause obstruction, reflux or both.
Small capacity bladder
Perinephric abscess Involvement of the urinary bladder begins around one or
Rupture of TB abscess into the perinephric space the other ureteric orifice which becomes red, inflammed
Pseudocalculi and oedematous. Later, bullous granulations appear and
Due to calcification in lesions completely obscure the ureteric orifice. TB ulcers may be
Caseous masses present, but these are rare and are a late finding. Progressive
‘Putty’ kidney
inflammation of the mucosa leads to contractures such that
Dystrophic calcification
results in a bladder with negligible capacity or ‘thimble
TB = tuberculosis
bladder’ [Figure 27.2].
 370 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

[AIIMS], New Delhi [n=241], the mean age at presentation

in patients with GUTB was 34.6 years and nearly one in four
had azotemia. The most common involved organ was the
kidney in 130 [53.9%] cases (18).

Kidney, Ureter and Bladder

Isolated renal TB may have no symptoms initially. Progres­
sive lesions may result in hematuria if there is cavitation into
the pelvicalyceal system, back or flank pain and constitutional
symptoms of fever, fatigue and malaise. Occasionally,
advanced cases may present with renal, perirenal or
psoas abscess. Some of these abscesses may rupture
externally, resulting in a chronic sinus or fistula (18,19).
Ureteric strictures may be present at the time of diagnosis.
However, these often develop or progress during treat­
ment with anti-TB drugs. Obstruction may lead to hydro­
Figure 27.2: Cicatrised, small [thimble] bladder nephrosis which may manifest as pain and progress to a
non-functioning renal unit. Typical symptoms of dysuria,
haematuria, frequent voiding and nocturia usually signify
Genital involvement may occur through haemato­
a concomitant cystitis due to involvement of the bladder.
genous dissemination from an extragenital source (8,15),
These are the most common presenting symptoms and
downstream involvement from the bladder or contiguous
could be associated with GUTB involving any organ. As
spread from an affected organ. In men, the epididymis is
the bladder capacity progressively decreases, the patient
the most common site; while in women, the principal site of
develops incapacitating frequency to the extent of voiding
involvement is the fallopian tube. Spread from the fallopian
every few minutes. Obstruction or reflux in the ureter and
tube to the uterus can occur in up to 50% of patients with
primary renal involvement result in renal impairment and
tubal infection (16). Involvement of the testis is uncommon
may progress to end-stage renal failure. Occasionally, calcifi­
but may occur contiguously from the epididymis. Similar
cations may be detected in the renal area.
spread may involve the vas deferens, seminal vesicles and
the prostate (11).
Genital Tuberculosis
CLINICAL PRESENTATION TB epididymitis may present as an acute infection
with pain and swelling or with abscesses and sinuses
The clinical presentation of genitourinary TB is summarised [Figure 27.3] (11). The acute involvement may not be
in Table 27.2. Irritative voiding symptoms are the most significant and the patient may present with chronic
common manifestation of GUTB (17). Over a half of all epididymitis or infertility if the disease involves both sides.
patients present with urinary storage symptoms, haematuria Occasionally, this may be manifest as scrotal masses (20,21).
and flank pain each of which occurs in about a third of all
cases. Scrotal abnormality seems to be the most common
physical finding, present in almost half of all cases (5). In
the study from the All India Institute of Medical Sciences

Table 27.2: Clinical presentation of genitourinary TB

Common
Irritative voiding symptoms
Haematuria
Flank pain
Renal mass
Sterile pyuria
Recurrent urinary tract infection
Azotemia
Urinary calculi
Acute presentation mimicking pyelonephritis
Uncommon
Non-healing wound/sinuses/fistula
Haemospermia
Urinary fistula Figure 27.3: TB scrotal abscess
Scrotal abscess TB = tuberculosis
Reproduced with permission from “Kumar R. Reproductive tract tuber­
TB = tuberculosis
culosis and male infertility. Indian J Urol 2008;24:392-5” (reference 11)
 Genitourinary Tuberculosis 371

Involvement of the vas deferens results in infertility and DIAGNOSIS

clinically may be evident as a ‘beaded’ vas. Testicular
Undiagnosed and untreated urinary tract TB can cause
involvement is always secondary to infection of the
renal failure and death. Diagnostic difficulties in GUTB
epididymis and orchitis without epididymal involvement
are due to the often insidious nature of disease onset, lack
is very rare. During the early phase, the testicular lesion
of bacteriological confirmation and failure to consider the
rapidly responds to anti-TB treatment after the epididymis
diagnosis on the basis of the symptoms. The combination
has been surgically removed if the destruction of the
of a high index of suspicion and use of bacteriologic,
testicular tissue is not extensive.
radiologic and endourologic tools can frequently lead to the
Involvement of the prostate is rare and difficult to
appropriate diagnosis.
document. It may be diagnosed, most often, on prostate
The typical symptoms and features on history have been
biopsy or pathological examination of a prostatectomy
described in the segment on clinical presentation. A full
specimen. Very rarely, the disease spreads rapidly and
blood count, erythrocyte sedimentation rate [ESR], renal
cavitation may lead to a perineal sinus (22). Prostatic
function tests and serum electrolytes should be obtained. In
involvement may lead to a fibrotic obstruction of the
addition, if calcification is present, a complete biochemical
ejaculatory ducts that pass through it. This can lead
assessment of calcium metabolism is performed. In cases
to a reduction in the semen volume which may be a
with elevated ESR, measurement at monthly intervals may
presenting symptom. Obstruction of the ejaculatory ducts
may also result in infertility. Some patients may develop give some indication regarding response to treatment.
haematospermia or blood in the ejaculate as a sign of TB. Tuberculin skin test is usually positive in most patients with
On palpation, the gland may have a nodule or feel firm. GUTB.
Chronic granulomatous inflammation of the prostate may
result in caseation necrosis followed by fibrosis or sloughing, Urine Examination
resulting in “autoprostatectomy” (23). Microscopic haematuria or pyuria may be found on urine
TB of the penis is very rare. Historically, it has been exami­nation. Urine culture and sensitivity testing should be
reported as a complication of ritual circumcision, when it performed. ‘Sterile pyuria’ refers to the presence of leucocytes
was the usual practice for the operators, many of whom in the absence of any bacterial growth on culture. Secondary
had open pulmonary TB, to suck the penis (24). TB lesions bacterial infection is found in about 20% of patients with
of the penile shaft are still occasionally seen although their TB and the culture may not be sterile. The usual organism
aetiology is unclear. The lesion appears as a superficial is Escherichia coli. Persistent sterile pyuria and haematuria
ulcer of the glans penis. It may be indistinguishable from in the absence of recent antibiotic treatment supports a
malignant disease and may progress to involve the urethra clinical suspicion of TB. Figueiredo et al (5) observed that
[Figure 27.4]. The diagnosis is confirmed by biopsy. The detection of Mtb in urine was the most common method of
transmission of genital TB from male to female is rare and diagnosing GUTB. This included a combination of smear and
poorly documented, even though Mtb may be present in the culture tests. However, in a number of cases, there may be
semen of men with genital TB. There have been documented no bacteriological evidence of TB and the diagnosis is made
cases of primary urethral TB, but, despite the frequent on the basis of a clinical and radiological picture.
contact of the urethra with organisms in the urine, this is
anecdotal (25).
Microbiological Methods
Urinary excretion of bacilli is intermittent and in order to
maximise the probability of a positive growth, at least three
but preferably five consecutive early morning specimen
should be used for both smear examination and culture. In
addition, secretions from a discharging sinus or material
procured by fine-needle aspiration may be similarly
investigated. In patients who have a nephrostomy placed
for bypassing obstruction, urine from both the nephrostomy
tube and the bladder should be examined.
Smears are stained with the Ziehl-Neelsen stain to look
for acid-fast bacilli [AFB]. Bacterial cultures are performed
on two slopes; Lowenstein-Jensen culture medium and
a pyruvate egg medium containing penicillin to identify
M. bovis, which is partially anaerobic and grows on the
surface of the culture medium. If the cultures are positive,
sensitivity tests are always conducted, in order to determine
the most effective course of chemotherapy. The low
Figure 27.4: TB of the glans penis mimicking malignancy sensitivity and time intensiveness of these tests means that
TB = tuberculosis additional tests are often required.
372 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Molecular Methods
Polymerase chain reaction [PCR] has been used in the early
diagnosis of GUTB with mixed results. However, caution
must be exercised before starting anti-TB treatment on the
basis of a positive PCR test alone as false-positive PCR test
results can also occur in a significant number of cases and
the specificity may be as low as 57% (26-29). The use of
PCR testing for TB in the setting of infertility is also an area
of concern. Since TB is a known cause for infertility and
may often be asymptomatic, screening infertile men for TB
with semen PCR tests is often performed. However, these
screening tests are rarely positive and, even when the test is
positive, it does not add to the management since the patient
is frequently diagnosed to have GUTB based on other clinical
and diagnostic tests (30,31). Similarly, the male partner of an
infertile couple where the woman is diagnosed to have TB Figure 27.5A: Plain radiograph of the abdomen showing bilateral
is often subjected to a screening semen TB-PCR test. Such calyceal calcification [arrows]
screening does not yield any positive outcomes and should
be avoided (30,31).
Considering the low yield on most bacteriological tests
and the time taken for culture, newer cartridge-based
nucleic acid amplification tests [CBNAAT] based on the PCR
technology are now available, particularly for pulmonary TB.
One of these is the Xpert MTB/RIF® [Cepheid, Sunnyvale,
CA, USA] which allows detection within a two-hour period.
While the test has been studied extensively for pulmonary
TB, its use in GUTB is not clear. A study (32a) evaluated
55 urine samples in men with suspected GUTB TB and
found 33% sensitivity and 100% specificity using cultures as
the reference standard, suggesting a possible role for this
test. Unlike PCR, if a sample tests positive by Xpert MTB/
RIF, the case is more likely to be a true case of TB (32a).
In a recently published systematic review (32b), pooled
sensitivity and specificity of Xpert MTB/RIF testing in urine
in the diagnosis of GUTB was reported to be 82.7% and
98.7% respectively.

Serological Tests, Interferon Gamma

Release Assays
Figure 27.5B: Intravenous urogram showing lobar calcification of the
Currently serodiagnostic tests are not recommended for inferior pole [white arrow] and dilated upper and middle calyces in the
the diagnosis of active TB. Interferon gamma release assays left kidney [black arrow]
[IGRAs] are useful in detecting latent TB infection [LTBI],
but should not be used in the diagnosis of active TB (33). infundibular stenosis and the radio-opacity seen is due to
The reader is referred to the chapter “Laboratory diagnosis” the stone and not renal parenchymal calcification.
[Chapter 8] for details.
Ultrasonography
Imaging Studies Ultrasonography is often the first imaging investigation
Plain Radiograph performed in patients presenting with complaints of
abdominal pain and haematuria. However, it often fails to
Plain radiographs of the urinary tract may show calcification contribute to the diagnosis of GUTB. Its principal role is in
in the renal areas [Figures 27.5A and 27.5B] and in the monitoring hydronephrosis and bladder capacity during the
lower genitourinary tract. Ureteric calcification is rare in the course of disease progression and response to treatment. It is
absence of extensive renal calcification. Renal calcification is also used to guide aspiration and biopsy of renal, prostatic,
parenchymal and may be patchy or extensive. Occasionally, epididymal and testicular lesions and for placement of
patients may form secondary stones following calyceal nephrostomy tubes for drainage.
 Genitourinary Tuberculosis 373

Contrast Imaging cysto­urethrogram is very useful in delineating bladder

pathology. There is progressive decrease in bladder capacity
Despite major advances in radiology, intravenous urography
which appears small and contracted or irregular. The bladder
[IVU] is the principal imaging modality in suspected
outline may be irregular due to localised deformity from
GUTB (34). This investigation helps in localising the disease,
assessing renal function and helps in planning intervention cicatrisation or due to a hyperplastic inflammatory lesion (14).
and follow-up strategies. The renal lesion may appear as Fibrosis in the region of the trigone produces gaping ureteric
distortion of a calyx or a calyx that is fibrosed and completely orifices, which may show vesico-ureteric reflux on voiding
occluded [lost calyx]. The renal pelvis or infundibulum of cystourethrogram [Figure 27.8].
a calyx may appear cicatrised with proximal dilatation. Computed tomography [CT] urography provides a less
There may be hydroureteronephrosis, a poorly functioning detailed image than conventional IVU and is not routinely
or a non-visualised kidney. TB ureteritis is manifested by indicated in evaluating GUTB. CT may, however, be useful
dilatation above a ureterovesical stricture, or if the disease in delineating parenchymal lesions, granulomatous masses
is more advanced, by a rigid fibrotic ureter with multiple in the kidney [Figure 27.9] and seminal vesicles (35).
strictures [Figures 27.6 and 27.7]. Magnetic resonance urography [MRU] has a role in patients
The cystographic phase of the urogram often provides with renal failure where iodinated contrast medium cannot
signi­ficant supportive evidence of TB. Similarly, a voiding be used. MRU can provide anatomical images of the urinary

Figure 27.6: Intravenous urogram showing no excretion of contrast Figure 27.8: Retrograde urethrocystogram showing a thimble bladder
on the left side, hydroureteronephrosis on the right side with a lower with reflux into the left ureter
ureteric stricture and a nephrostomy tube in the right kidney

Figure 27.7: Intravenous urogram showing non-functioning kidney Figure 27.9: CECT of the abdomen showing an irregular hypodense
on the right side, hydroureteronephrosis on the left side and thimble lesion in the right kidney [arrow]
bladder CECT = contrast-enhanced computed tomography
 374 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

system and needs supplementation with functional studies a biopsy may be performed. In addition, sampling urine
such as a radioisotope renal scan in planning intervention. from each kidney and stent placement as described in the
Retrograde pyelography involves cystoscopic placement section on retrograde pyelography may also be performed.
of a catheter into the ureteric orifice and injection of Cystoscopic findings which suggest TB include a small,
radiographic contrast through it under fluoroscopic control. inflamed bladder, dilated, retracted ureteric orifices, ulcers
This investigation is useful in patients with a poorly and granulations.
functioning kidney where the kidney does not concentrate
intravenous contrast. It is also used to collect urine samples TREATMENT
separately from each kidney. However, the procedure
is invasive with attendant risks of infection. It is usually The recently published Guidelines for Extrapulmonary TB
performed in conjunction with retrograde stent placement for India [INDEX-TB Guidelines] (36) suggest that a short-
for ureteric obstruction. course [6 months] standard anti-TB treatment is considered
Percutaneous antegrade pyelography is an alternative to adequate for GUTB. All patients, irrespective of the sequelae
retrograde ureterography in patients with hydronephrotic, at presentation, are started on anti-TB treatment before
obstructed kidneys. Antegrade puncture allows both further intervention (37). Several patients with GUTB will
instillation of contrast to visualise the system and placement require surgical intervention at some point in time during the
of either a ureteric stent or a nephrostomy tube to drain course of their disease. A list of the potential interventions
the obstructed system. It also allows aspiration of the is listed in Table 27.3.
collected urine for examination and culture and estimation The manifestations of GUTB continue to evolve even
of split renal function from the two kidneys. This procedure during the treatment phase and pathologic changes may
becomes particularly relevant in advanced cases, where, develop due to the fibrosis and cicatrisation that occur
following cystitis, the bladder becomes inflamed and small during healing. Imaging of the kidneys and ureter is
and visualisation of the ureteric orifice and placement of performed, mandatorily in all patients of GUTB. In patients
a retrograde ureteric stent becomes almost impossible. with genital TB with no involvement of the kidney, ureter
Occasionally, it may demonstrate additional pathologies and or bladder, if the initial screening ultrasound shows no
fistulous communications [Figure 27.10]. abnormality, an IVU may be avoided. However, in all
other patients of urinary TB, an IVU should be obtained at
baseline. Another imaging study should be obtained after
Cystoscopy
starting treatment with anti-TB drugs. The timing and nature
Cystoscopy serves both diagnostic and therapeutic roles of this imaging depend on the initial findings. If the first
in a patient suspected to have GUTB. In the absence of
bacteriological confirmation, a cystoscopic examination for
appearance of the bladder and ureteric orifices and taking Table 27.3: Surgical interventions in genitourinary TB
Renal TB
Nephrostomy or ureteral stenting
Nephrectomy or nephroureterectomy
Partial nephrectomy
Pyeloplasty
Ureterocalicostomy
Ureteric stricture
Dilatation/endoureterotomy and stenting
Ureteroneocystostomy
Percutaneous nephrostomy
Ileal replacement
Urinary bladder: small capacity
Hydraulic dilatation
Augmentation cystoplasty
Cystectomy + orthotopic neobladder
Urinary diversion
TB of urethra
Endoscopic dilatation
Urethroplasty
Genital TB
Epididymectomy
Orchiectomy
Excision of fistula
Partial penectomy
De-roofing of prostatic abscess
Figure 27.10: Retrograde ureteropyelogram showing reno-colo- Excision of seminal vesicles
cutaneous fistula, narrow ureter [black arrow], colon, extravasation of
TB = tuberculosis
the cont­rast through the sinus tract [white arrows]
 Genitourinary Tuberculosis 375

the skin surface and all such tracts and fistulae are excised
en masse. Laparoscopy is traditionally contraindicated in TB
non-functioning kidneys due to these adhesions. However,
in patients where the disease is not as extensive, laparoscopy
may be successfully used (40). In patients where the ureter
is also involved with strictures, the ureter is resected in
continuity with the kidney [nephroureterectomy] till below
the lowest stricture or the vesicoureteric junction.

Partial Nephrectomy
In patients with a localised polar lesion, partial nephrectomy
may be contemplated after at least six weeks of anti-
TB treatment. Renal calcification may indicate regions
harbouring viable mycobacteria in up to 28% cases (41). If the
remaining kidney looks normal, these may be candidates for
partial nephrectomy. Small lesions can be kept under review
Figure 27.11: Ultrasonography showing an enlarged hypoechoic left on an annual basis. Larger areas of calcification should
kidney [thick arrow] with an anechoic cavity in the lower pole [asterisk]
due to TB. A large psoas abscess [thin arrows] is also seen
be excised and non-functioning kidneys with extensive
TB = tuberculosis calcification should be removed.

Pyeloplasty, Ureterocalicostomy
imaging was normal, the repeat may be performed at three to
Involvement of the renal pelvis, calyceal infundibulum
four weeks. If there is evidence of renal, ureteric or bladder
and upper ureter may result in stricture formation. Short
involvement on the first imaging, there is a likelihood of
segment obstructions can be managed endoscopically with
rapidly increasing obstruction and renal function loss and
incision and stenting. However, the involvement is usually
the repeat imaging may be performed as early as two weeks
extensive and fibrotic and required surgical reconstruction.
after starting the treatment.
If there is sufficient pelvis available, a ureteropyelostomy or
In GUTB, surgical interventions aim at preventing renal
pyeloplasty can be performed. Often the pelvis is completely
damage, preserving renal function, improving drainage of
cicatrised, precluding anastomosis. In such cases, the
the kidney and symptomatic relief. The initial intervention,
which may be done concurrent with starting anti-TB upper patent ureter is anastomosed to the lower calyx in
treatment, involves placement of either a ureteric stent ureterocalicostomy may be required.
or a nephrostomy to drain an obstructed kidney or calyx
(38). Renal abscesses not resolving within two weeks of the Stricture of the Ureter
treatment can be drained under ultrasonography guidance Ureteric strictures are initially managed with internal stents
[Figure 27.11]. Definitive treatment usually is delayed till at or nephrostomy tubes to preserve renal function. Definitive
least four to six weeks of drug therapy are completed when intervention is planned usually after six weeks of anti-TB
no further change in the lesions is expected. treatment. Short segment strictures may be balloon dilated
In a study from the AIIMS, New Delhi 248 surgical or endoscopically incised. For longer strictures, reconstruc­
procedures including 33 endoscopic, 87 ablative and tion is required and depends on the site and length of
128 reconstructive surgeries were conducted (18). Early stricture (42). Upper ureteric strictures may require a pyelo­
complications occurred in 8% and primarily involved the plasty or ureterocalicostomy if the kidney is functioning. In
bowel; 54 patients had azotemia and 81% of them had the middle ureter, Davis’ intubated ureterostomy technique
functional stabilisation or improvement. over a silastic stent may be attempted. Other options include
interposition of appendix or creation of a Boari’s flap if
Nephrectomy, Nephroureterectomy the bladder capacity is still good. In the lower ureter, if
Nephrectomy is indicated in patients where the kidney is strictures are identified early in the disease process, some
either non-functioning or harbours disease that cannot be workers have proposed that addition of corticosteroids to
eradicated with anti-TB treatment alone (39). The disease anti-TB treatment may limit their extent. However, there
and inflammation tend to result in extensive peri-renal is no convincing evidence from the published literature for
fibrosis and surgery is often very difficult in these cases. the use of corticosteroids as of now. Surgical reconstruction
On occasions, segmental or subcapsular nephrectomy may usually involves reimplantation into the bladder or creation
have to be performed due to the adhesions. There may be of a Boari’s flap. If the bladder is also of a small capacity,
contiguous involvement of the bowel, spleen and pancreas, the bladder is augmented and a ureteroneocystostomy is
primarily in the inflammatory process, which may require performed. If a cystectomy is being contemplated, the ureters
extended resection. A peri-renal abscess may have burst onto are reimplantation in the neobladder [Figure 27.12].
 376 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 27.12: Resected surgical specimen of nephroureterectomy and

cystectomy with thimble bladder

Figure 27.14A: Intravenous urogram showing small capacity thimble

bladder [arrows]. The kidney is not visualised on the right side

Figure 27.13: Intravenous urogram showing ileal replacement of ureter

[arrows]

Patients with multiple or long segment strictures are not

suitable for these interventions. If the kidney has limited
function and the opposite kidney is normal, a nephro­
ureterectomy may be planned. If the kidney function is good,
the ureter is replaced by an ileal segment [Figure 27.13],
joining a tailored or plicated ileum to the calyx of the kidney Figure 27.14B: Cystogram in the same patient following augmentation
cranially, and to the urinary bladder caudally. cystoplasty utilising sigmoid colon [arrows]

Surgery for Urinary Bladder Tuberculosis

or stomach (43,44). The stomach is generally reserved for
Surgery for urinary bladder TB involvement aims at patients with azotemia since it does not absorb urinary
increasing its capacity. The procedure used depends on constituents as much as the other two segments. However,
the residual capacity of the native bladder. If the bladder it is technically more difficult and has potential complication
capacity is greater than 30-50 mL but small enough to of hematuria-dysuria syndrome which can be debilitating.
incapacitate the patient [with frequency and urgency], When the bladder capacity is less than 10-20 mL [thimble
augmentation of the native bladder is performed using a bladder], a simple cystectomy with neobladder formation is
bowel segment. This can be a segment of the ileum, sigmoid required [Figures 27.14A and 27.14B].
 Genitourinary Tuberculosis 377

Surgery for Other Forms of Genitourinary 19. Hemal AK, Gupta NP, Wadhwa SN, Songra MC, Batura D,
Bhuyan UN. Primary repair of colorenocutaneous fistula in
Tuberculosis
patients with genitourinary tuberculosis. Urol Int 1994;52:
Involvement of seminal vesicles, vas deferens and the 414.
prostate, can manifest as infertility. A few patients may 20. Kumar R, Hemal AK. Bilateral epididymal masses with infertility.
respond to anti-TB treatment alone. Surgical intervention ANZ J Surg 2004;74:391.
21. Viswaroop BS, Kekre N, Gopalakrishnan G. Isolated tuberculous
too has limited role in these cases. Discrete obstructions to
epididymitis: a review of forty cases. J Postgrad Med 2005;51:
the ejaculatory ducts within the prostate may be amenable 109-11.
to endoscopic resection (45,46). More extensive involvement, 22. Sporer A, Auerback MD. Tuberculosis of the prostate. Urology
the fibrotic ejaculatory duct obstruction, fails to respond 1978;11:362-5
to surgery. Similarly, bypassing vasal obstructions with a 23. Hemal AK, Aron M, Nair M, Wadhwa SN. ‘Autoprostatectomy’:
vasoepididymostomy is possible only in a minority of cases an unusual manifestation in genitourinary tuberculosis. Br J Urol
as the involvement is multifocal. Epididymal involvement 1998;82:140-1.
24. Lewis EL. Tuberculosis of the penis: a report of 5 new cases and a
may result in chronic pain or fistulae, which would require
complete review of the literature. J Urol 1946;56:737-45.
surgical excision or an epididymectomy. Rarely, a prostatic 25. Singh I, Hemal AK. Primary urethral tuberculosis masquerading
abscess may require either trans-rectal or endoscopic as a urethral caruncle: a diagnostic curiosity! Int Urol Nephrol
drainage. 2002;34:101-3.
26. Hemal AK, Gupta NP, Rajeev TP, Kumar R, Dar L, Seth P.
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2. Kennedy DH. Extrapulmonary tuberculosis. In: Ratledge C, Rapid diagnosis of genitourinary tuberculosis by polymerase
Stanford JL, Grange JM, editors. The biology of mycobacteria. chain reaction and non-radioactive DNA hybridization. J Urol
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3. Abbara A, Davidson RN. Etiology and management of 28. Chawla A, Chawla K, Reddy S, Arora N, Bairy I, Rao S, et al. Can
genitourinary tuberculosis. Nat Rev Urol 2011;8:678-88. tissue PCR augment the diagnostic accuracy in genitourinary
4. Colabawalla BN. Reflections on urogenital tuberculosis. Indian J
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Urol 1990;6:51-9.
29. Sun L, Yuan Q, Feng JM, Yang CM, Yao L, Fan QL, et al. Rapid
5. Figueiredo AA, Lucon AM, Junior RF, Srougi M. Epidemiology
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chain reaction on renal biopsy specimens. Int J Tuberc Lung Dis
6. Naidich DP, Garay SM, Leitman BS, McCauley DI. Radiographic
2010;14:341-6.
manifestations of pulmonary disease in the acquired immuno­
30. Gupta R, Singh P, Kumar R. Should men with idiopathic
deficiency syndrome. Semin Roentgenol 1987;12:14-30.
obstructive azoospermia be screened for genitourinary
7. Becker JA. Renal tuberculosis. Urol Radiol 1988;10:25-30
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8. Elkin M. Urogenital tuberculosis. In: Pollack HM, editor.
31. Regmi SK, Singh UB, Sharma JB, Kumar R. Relevance of
Clinical urography. Philadelphia: WB Saunders Company; 1990.
semen polymerase chain reaction positive for tuberculosis in
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asymptomatic men undergoing infertility evaluation. J Hum
9. Amis SE Jr, New House JH. Essentials of uroradiology. Boston:
Little, Brown and Company; 1990.p.1640-66. Reprod Sci 2015;8:165-9.
10. Tzvetkov D, Tzvetkova P. Tuberculosis of male genital system– 32a. Sharma SK, Kohli M, Chaubey J, Yadav RN, Sharma R, Singh BK,
myth or reality in 21st century. Arch Androl 2006;52:375-81. et al. Evaluation of Xpert MTB/RIF assay performance in
11. Kumar R. Reproductive tract tuberculosis and male infertility. diagnosing extrapulmonary tuberculosis among adults in a
Indian J Urol 2008;24:392-5. tertiary care centre in India. Eur Respir J 2014;44:1090-3.
12. Figueiredo AA, LuconAM. Urogenital tuberculosis: update 32b. Kohli M, Schiller I, Dendukuri N, Dheda K, Denkinger CM,
and review of 8961 cases from the world literature. Rev Urol Schumacher SG, Steingart KR. Xpert[®] MTB/RIF assay for extra­
2008;10:207-17. pulmonary tuberculosis and rifampicin resistance. Cochrane
13. Carl P, Stark L. Indications for surgical management of Database Syst Rev 2018;8:CD012768.
genitourinary tuberculosis. World J Surg 1997;21:505-10. 33. Fan L, Chen Z, Hao XH, Hu ZY, Xiao HP. Interferon-gamma
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16. Greenberg JP. Tuberculous salpingitis. A clinical study of 200 35. Premkumar A, Newhouse JH. Seminal vesicle tuberculosis: CT
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17. Gupta NP, Kumar R, Mundada OP, Aron M, Hemal AK, 36. Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD,
Dogra PN, et al. Reconstructive surgery for the management Mohan A, et al. Index-TB guidelines: Guidelines on extra­
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38. Krishnamoorthy S, Gopalakrishnan G. Surgical management of 43. Chan SL, Ankenman GJ, Wright JE, McLoughlin MG. Caecocysto­
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41. Wong SH, Lan WY. The surgical management of non-functioning it different? Indian J Urol 2011;27:98-101.
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42. Goel A, Dalela D. Options in the management of tuberculous current status of diagnosis and management. Transl Androl Urol
ureteric stricture. Indian J Urol 2008;24:376-81. 2017;6:222-33.
 28
Tuberculosis in Chronic Kidney Disease
SK Agarwal

INTRODUCTION of the alternate complement pathway leading to changes

in granulocyte cell adhesion molecules CD11b, CD18
Tuberculosis [TB] is one of the major causes of morbidity and
[macrophage-1 antigen, MAC-1] and L-selectin. These
mortality throughout the world. Susceptibility to TB has been
changes correlate with development of leucopenia and its
attri­buted to host resistance, socioeconomic (1) and environ­
reversal (10). Similarly, phagocytosis is impaired both before
mental factors (2). Because of the immunosuppressive effect
and during haemodialysis. Impairment of phagocytosis
of uraemia, use of corticosteroids and immunosuppressive
during haemodialysis is more often encountered with cupro­
drugs during renal transplantation [RT], these patients are
phane membrane than with newer membranes (11). Dialysis
at a high risk of developing TB. Consequently, TB has been
with cuprophane membrane also increases production of
found to occur more frequently in patients with chronic
reactive oxygen species, thus decreasing responsiveness to
kidney disease [CKD], during maintenance haemodialysis
an infectious challenge (12). With change of cuprophane
[MHD] and following RT than in general population (3-7).
membrane to newer more biocompatible membranes, these
issues have almost eliminated.
PATHOGENESIS Another major defect in lymphocyte function in uraemia
Uraemia is also an acquired immunodeficiency state and in patients on haemodialysis is decreased interleukin-2
leading to excessive morbidity and mortality related to [IL-2] production by activated T-helper cells (13). Whether
infections. Func­tional abnormalities of neutrophils, T- and the major defect is in the T-cells, antigen presentation to the
B-lymphocytes, monocytes and natural killer [NK] cells have T-cell or is monocyte derived, is still controversial. Altered
been described in these patients. These abnormalities are macrophage Fc-receptor function in vivo and in vitro has been
often exacerbated by chronic haemodialysis and following demonstrated in persons undergoing haemodialysis. This
RT. Bioincompatibility during haemodialysis frequently correlated very well with the incidence of severe infection
leads to immune activation and subsequent leucocyte during a two-year follow-up period. Defective antigen
dysfunction, thus exacerbating the underlying immune presentation by monocyte has also been demonstrated in
defect of uraemia. However, currently, due to change in patients on haemodialysis (14).
membranes of dialysers, bioincompatibility has not remained Following successful RT, infection remains the leading
an important issue. cause of morbidity and mortality, more so in high TB
Granulocyte functions such as chemotaxis, adherence burden count­ries like India. The inflammatory response to
and phago­cytosis are marginally defective in uraemia but microbial invasion in the transplant patients is attenuated
patients on haemodialysis have pronounced defects in by concomitant immunosuppressive therapy. The risk of
these functions. Leucocyte chemotaxis has been reported infection in these patients is primarily determined by the
to be diminished in patients with end-stage renal disease interaction between exposure to mycobacteria and immune
[ESRD] and MHD. In these patients, in vitro and in vivo status of the patient. Immuno­suppression is a complex state
administration of 1,25 dihydroxy vitamin D 3 has been determined by the interaction of a number of factors, the
shown to improve leucocyte adhesion and chemotaxis (8,9). most important of which are the dose, duration and temporal
Use of conventional cellulose membrane causes activation sequence of immunosuppressive drugs employed.
380 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

MAGNITUDE OF THE PROBLEM A recent meta-analysis [12 eligible studies, 71,374 ESRD
patients and 560 TB cases] revealed consistent evidence
There is limited information on the magnitude of the
suggestive of an increased risk of active TB in ESRD
problem of TB in patients with CKD. However, a published compared to the general population which had persisted in
study from China (15) reported 30 times higher prevalence of spite of variability in study population, design and modality
TB in patients with CKD as compared to general population of renal replacement therapy [RRT] (40).
of same city. The study reported inverse association between
renal function and TB. Problem of TB in patients already on
CLINICAL PRESENTATION
MHD has been more commonly studied and the incidence
of TB in such patients has varied from 1%-13.3% (4-6,16-21). Clinical Presentation of Tuberculosis during
It has been estimated that patients undergoing dialysis Maintenance Haemodialysis
have a 10- to 12-fold higher risk of developing TB compared
to the general population (5,6). The incidence of TB in Clinical presentation of TB in patients on MHD is summarised
in [Table 28.1] (4-7,41). The age distribution of patients on
Indian patients receiving MHD has been reported to be
MHD who developed TB was similar to that observed in
3.7%-13.3% (16,17). Majority of these patients have under­
general population (4). Males were nearly twice as commonly
gone haemodialysis for 12 to 24 months only. A report (22)
affected as compared to females (4,18). This probably reflects
also indicates transmission of TB from a healthcare worker
the gender difference observed in patients with CKD.
to 29 patients and 13 employees in a dialysis centre.
Regular MHD usually tends to improve the general immune
The incidence of TB in RT recipients has been more
status of the patients with CKD. Therefore, a majority of
systemati­c ally studied as these patients are regularly
these patients develop TB prior to initiation or within a short
followed-up. Incidence of TB in RT patients has ranged
period from the beginning of MHD, a time when effect of
from 1%–4% in Northern Europe (23-26); 0.5%–1% in North
uraemia on immune status is still pronounced. Sasaki et al (4)
America (26,27) and nearly 5%–10% in several studies
and Andrew et al (5) have reported the develop­ment of TB
reported from India (28-33). Incidence of TB in RT patients
within six months of MHD, however, this period was much
has been found to be more or less similar among those who
longer in other study (6). Prior exposure to TB and diabetes
received cyclosporine and those who did not (18,30,31,33). mellitus were found as risk factors in nearly 50% of the
However, few differences have been reported in these patients for the development of TB (6).
two groups. Higgins et al (7) reported that among RT Constitutional symptoms attributable to TB have been
patients who received cyclosporine-based protocols, TB reported in 30%-92% patients in various series (4-6,16) and
developed only in those patients who were clearly at risk of may include low- or high-grade fever. Malhotra et al (17)
developing the disease due to previous exposure. Similarly, reported that 15% of their patients on MHD, who developed
John et al (33) suggested that TB developed in the early TB, presented with pyrexia of unknown origin [PUO]. In
post-RT period in patients on cyclosporine, as compared to other studies (6,18-21,41), this presentation has been rarely
those patients who did not receive cyclosporine. At another observed.
hospital in North India, early occurrence of TB, especially In majority of the studies (6,17-21,41), lung is the most
miliary TB [MTB] has been observed in RT patients receiving common site of involvement in patients on MHD. In these
cyclosporine compared with those who did not (34). With studies (6,17-21,41), incidence of pulmonary TB ranged
the use of tacrolimus and mycophenolate, it was expected from 40%–92%. However, in some studies (5,6,41), isolated
that the incidence of TB in renal transplant will increase extra-pulmonary TB [EPTB] has been found in 56%–60%
as these drugs are more potent than previously used cases. Malhotra et al (17) have reported that pleural effusion
immunosuppressive medication. In a study (35), a higher occurred more frequently than pulmonary parenchymal
incidence of TB was found in patients receiving these drugs lesions. However, this observation has not been corroborated
as compared to cyclosporine and also TB developed earlier by other workers who have found parenchymal lesions to
in these patients. However, these results have not been be more common than pleural effusion (6,18-21). Lymph
confirmed in another study (36). A recent study (37) from node involvement has been found to be the most common
the author’s centre showed that with a mean follow-up of 47 site of EPTB in patients on MHD [15%-30%] (4,6,17-19,33,41).
[range 1-268] months, a significantly higher proportion of In the series reported by Malhotra et al (17), lymph node TB
patients [17.3%] developed post-RT TB in cyclosporine- occurred in 30% of patients; in 25% of the patients, this was the
based triple immunosuppression as compared to 5.9% in only presenting feature (17). Other sites of extrapulmonary
tacrolimus-based triple immunosuppression group. TB-free involvement include abdomen (4-6), meninges (4), bone and
survival in Kaplan-Meier analysis was significantly better in joints (19,33). In a report from Taiwan, Chuang et al (42),
tacrolimus group as compared to cyclosporine group. while describing EPTB in dialysis patients, have reported
Possible transmission of TB by renal allograft has been involvement of peritoneum [35.3%], cervical lymph nodes
reported (26,38,39). The most definitive report (38) was [17.6%] and involvement of bone marrow, spine, knee joint,
concerning a donor with culture-proven TB meningitis, brain, pericardium, cutaneous tissue and genitourinary
whose kidneys were transplanted in two patients. Both of system [5.7% each]. These observations suggest that almost
them developed definitive TB on days 35 and 39 respectively. any organ can be affected by TB in these patients.
 Tuberculosis in Chronic Kidney Disease 381

Table 28.1: Clinical presentation of TB in patients on maintenance haemodialysis

Rutsky and
Sasaki ­et al (4) Andrew et al (5)­­ Rostand (6)­­ Malhotra et al (17) Venkata et al (41)
Variable­ [n = 367] [n = 172] [n = 885] [n = 150]­ [n = 900]
No. of TB patients [%]­ 12 [3.3]­ 10 [5.8]­ 9 [1]­ 20 [13.3]­ 36 [4]­
Mean age [years]­ 45­ 49­ 48­ 20­ 52­
Male:female­ 2:1­ 1.5:1­ 2:1­ 3:1­ 11:1­
Time of diagnosis of TB in relation 42­ 40­ ND­ 0­ 61.1*­
to duration of HD [%]­
Prior HD­
Less than 6 months ­ 42­ 50†­ ND­ 95‡­ ND­
Six months to 1 year­ 8­ 0­ ND­ 5­ ND­
More than 1 year ­ 8­ 0­ ND­ 0­ ND­
Site of TB [%]§­ || ­
Pulmonary­ 8­ 60­ 33­ 10­ 36­
Pleural­ 8­ 10­ 33­ 45­ 28­
Lymph node­ 17­ 10­ 11­ 30¶­ 14­
Miliary or disseminated ­ 50­ 0­ 11­ 0­ 11­
Neurological ­ 8­ 10­ 0­ 0­ 0­
Colon­ 8­ 0­ 0­ 0­ 0­
Peritoneal­ 0­ 10­ 11­ 5­ 0­
Bone and joints­ 0­ 0­ 0­ 5­ 8­
Renal­ 0­ 10­ 0­ 0­ 0­
Hepatic­ 0­ 0­ 0­ 0­ 0­
Clinical presentation [%]­ ­ ­ ­ ­ ­
Fever­ 92­ **­ ††­ ‡‡­ 72­
Appetite loss­ 100­ **­ ††­ ‡‡­ 72­
Weight loss­ 75­ **­ ††­ ‡‡­ 25­
Cough­ 25­ **­ ††­ ‡‡­ ND­
Neurological deficit­ 50­ **­ ††­ ‡‡­ ND­
Diagnosis [%]§§­ ­ ­ ­ ­ ­
Microbiology |||| 33­ 50­ 90¶¶­ 20­ 16.6­
Histopathology|||| 17­ 40­ 20­ 45­ 30.5­
Autopsy­ 50­ 10­ 0­ 5***­ ND­
Mortality [%]­ ­ ­­ ­ ­
TB mortality­ 75­ 0­ 22­ 10­ 25­
Overall mortality­ 75­ 20­ 44­ 60­ ND­
* 14 patients were on regular dialysis [13 on HD, 1 patient was on continuous ambulatory peritoneal dialysis], and 8 were on irregular dialysis.
Among patients on regular dialysis, TB was identified within 1 year of dialysis in 4, and in the remaining, TB was diagnosed between 1 and
9 years of dialysis
† In 1 patient, the diagnosis of TB was made concurrent with the initiation of HD
‡ In 3 patients, the diagnosis of TB was made concurrent with the initiation of HD
§ More than one site was involved in some patients
|| The site of TB was not clear in one patient. This patient responded well to antituberculosis treatment
¶ One patient had left hilar lymphadenopathy
** Details of clinical presentation were not described. The presenting symptoms were non-specific and constitutional in nature. Fever,
malaise, anorexia and weight loss were most commonly encountered. Headache, chills, and shortness of breath were less common
[<30% of the patients]
†† Of the 885 patients studied, a diagnosis of TB was made in 9 patients on HD and 8 patients who had CRF but did not require long-term
dialysis. The clinical symptoms were not separately described for these 2 groups of patients
‡‡ Consolidated break-up of clinical features was not provided. Of the 20 patients in whom TB was diagnosed, 75% presented with fever,
50% with pleural effusion; 30% had lymphadenopathy, pulmonary abnormalities were found in 20% and ascites and hepatomegaly were
observed in 10% patients. Other features included marked anorexia [10%], abnormal weight loss [5%] and bony swelling [5%]
§§ More than 1 method was positive in some patients
|||| Cumulative yield from various tissue and fluid specimens
¶¶ NTM were isolated from 3 of the 9 patients
*** A patient who had shown TB peripheral lymphadenopathy during life revealed histopathological evidence of TB in hilar and
tracheobronchial lymph nodes on autopsy
TB = tuberculosis; HD = haemodialysis; ND = not described; CRF = chronic renal failure; NTM = nontuberculous mycobacteria
382 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Disseminated TB [DTB], MTB have also been observed Comparison of presentation of TB during haemodialysis
as the present­ing feature in these patients. Nearly half and after RT [n = 923] at the author’s centre is shown in
of the patients studied by Sasaki et al (4) presented with [Table 28.3] (37). Pleuropulmonary TB appears to be more
DTB/MTB. In most of the other series, the incidence of common in both settings. In RT recipients, presentation with
MTB ranged between 10%-15% (6,19). None of the patients PUO and MTB is significantly more common as compared
described by Malhotra et al (17) had MTB. Two of the 100 to patients on MHD. Furthermore, abdominal TB was
patients with MTB reported by Sharma et al (43) had CKD significantly more common during dialysis and neurological
as a predisposing factor. TB was more common after transplantation.
TB peritonitis has been described in patients on Overall, patients with advanced CKD while on MHD
continuous ambulatory peritoneal dialysis [CAPD] (44,45). manifest EPTB more frequently [60%] as compared to pulmo­
In these patients, the ascitic fluid may reveal predominance nary TB [40%] [Table 28.1]. By contrast, site of involvement
of polymorpho­nuclear leucocytes. In addition to causing in RT-recipients resembles that observed in immunocompe­
morbidity, it can also cause ultrafiltration failure of CAPD tent individuals; pulmonary TB is more frequent [60%]
and require shifting to other modality of renal replacement [Table 28.2], probably due to improvement in their immune
therapy. TB peritonitis is also one of the causes of culture- status.
negative peritonitis in CAPD patients (44,45).
In a retrospective cohort study (46) of TB disease in DIAGNOSIS
272,024 patients in the US Renal Data System initiated on
dialysis therapy between April 1995 and December 1999, Definitive diagnosis of TB requires demonstration or
cumulative incidence of TB in patients undergoing either isolation of Mycobacterium tuberculosis [Mtb]. In majority of
peritoneal or haemodialysis was found to be 1.2% and 1.6%, studies (5-7) published from the west, diagnosis of TB was
respectively. In this study (46), advanced age, unemployment, based on demon­stration of the organism in the body fluids
availing health insurance [Medicaid], reduced body mass and/or tissues or on the basis of histopathological findings.
index, decreased serum albumin, haemodialysis, both Asian In contrast, 8.6%-68% of the patients in various Indian
and Native American race, ischaemic heart disease, smoking, studies (30-32) have been diagnosed to have TB only on
illicit drug use and anaemia were found to be risk factors clinical grounds. This is probably due to the low threshold
for development of TB in patients receiving peritoneal or for therapeutic trial with anti-TB treatment in a country like
haemodialysis. Furthermore, in patients receiving dialysis, India, where TB is endemic.
TB was independently associated with increased mortality. Diagnosis of TB in patients with CKD is difficult. Patients
with CKD can have a high erythrocyte sedimentation
Clinical Presentation of Tuberculosis rate [ESR] due to anaemia and various other reasons and,
following Renal Transplantation therefore, ESR is not of much use in these patients. The
tuberculin skin test [TST] is often negative in patients on
TB can be encountered in RT patients in two settings. First, MHD and following RT (21,48,49). A study from North
a patient with advanced CKD suffering from TB in the pre- India also showed that TST in patients on maintenance
transplant phase may continue to suffer from TB in the post- haemodialysis was positive only in 10.5% cases and may
RT phase as well. On the other hand, patients may develop not be reliable test for diagnosis of TB (50). The utility of
TB for the first time following RT. The present description newer diagnostic methods for detecting latent TB infection
is regarding patients in the latter category. [LTBI], such as, interferon-gamma release assays [IGRAs]
Patients who develop TB following RT [Table 28.2] (7,30-33) in the diagnosis of TB infection in patients with CKD seems
are usually younger. Males are more often affected. This promising, but, needs to be explored further (51). Radio­
could be because of the fact that young males undergo logical findings in immuno­c ompromised patients with
RT more often in a country like India (30-32). Similar pulmonary TB are often atypical. In these patients cavitary
observations have been reported from the west as well lesions are seldom seen and lower lung field and multiple
as from other countries (47). Past history of TB has been lobar involvements are often seen. Patients on MHD can
reported in 5.6%–8.9% patients in studies reported from develop pleural effusion due to heart failure, uraemic
India [Table 28.2]. When TB develops, constitutional pleuritis or hypoproteinaemia. Similarly, pericarditis and
symptoms are more often encountered in RT patients than pericardial effusion and ascites in these patients are often
in patients on MHD (31-33). The lung is the most common due to dialysis associated pericarditis and/or ascites (52).
site of involvement in RT patients who develop TB (29-33). Pleural fluid in uraemic pleuritis can also be exudative and
Other sites of TB involvement in RT patients include haemorrhagic with high protein and lactate dehydrogenase
abdomen (7,33); pericardium (30,33); thalamic abscess (30) levels with a pre­domi­nance of lymphocytes (53,54). These
and bone and joints (7,30). MTB has also been reported findings are often encountered in TB pleural effusion and
in 7%–36.4% of RT patients (30-33,38). Thus, RT patients are, therefore, unreliable. Diagnostic value of adenosine
develop pulmonary TB more often, and manifest constitu­ deaminase activity [ADA] in pleural fluid even in RT
tional symptoms more commonly compared with patients patients is also unreliable (55). The acid-fast bacilli [AFB]
on MHD. can seldom be seen and mycobacteria are rarely cultured
 Tuberculosis in Chronic Kidney Disease 383

Table 28.2: Clinical presentation of TB in renal transplant patients

Hariharan Higgins John Sakhuja Agarwal
et al (32) et al (7) et al (33) et al (31) et al (30)*
Variable [n = 550] [n = 633] [n = 808] [n = 305] [n = 461]
No. of patients with TB [%] 46 [8.4] 11 [1.7] 41 [5.1] 36 [11.8] 67 [14.5]
Mean age [years] 32.5 43.9 † 33.9 14
Male:Female 4.1:1 1.8:1 4.9:1 6.2:1 3.5:1
Mean time interval between renal 20 26.4 ‡ 20.7 24
transplantation and detection of
TB [months]
Past history of TB ND ND ND 5.6 8.9
Immunosuppression D D/T D/T D/T D/T
Site of TB [%] §
Pulmonary 39 18 49 31 37
Pleural 13 9 0 14 22
Lymph node 17 0 2 3 8
Disseminated or miliary TB 7 36 27 25 8
Neurological 4 0 0 0 5
Abdominal 4 18 7 3 5
Genitourinary 0 9 5 3 0
Skin, soft tissue 0 0 7 3 0
Pericarditis 0 0 0 0 0
Bone and joints 0 0 2 0 1.5
Diagnosis [%]ll
Microbiology¶ 52 55** 98†† 14 3
Histopathology¶ 26 27 10 33 12
Autopsy 4 0 0 3 11
Mortality [%]
TB-related mortality 4 9 12 6 0
Overall mortality 9 9 46 19.4 0
Percentage values are corrected to the nearest round figures
* Figures from 1992 have been revised and updated till 1997
† Mean age of patients receiving cyclosporine immunosuppression and conventional immunosuppression was 39.9 and 37.3 years,
respectively
‡ Median time [months] of diagnosis of mycobacterial infection after transplantation in patients receiving cyclosporine immuno­suppression
and conventional immunosuppression was 5.5 and 2.4 months, respectively
§ Some patients had involvement of more than 1 site
ll More than 1 method was positive in some patients
¶ Cumulative yield from various tissue fluids and specimens
** 1 patient had infection with Mycobacterium kansasii
†† 2 patients had nontuberculous mycobacterial infection
TB = tuberculosis; ND = not described; D = double immunosuppression; T = triple immunosuppression

from the pleural fluid. Usefulness of modern diagnostic MANAGEMENT

tests, such as polymerase chain reaction [PCR] has not been
systematically explored in the diagnosis of TB in patients Principles of anti-TB treatment during dialysis and following
with CKD, though these are often reported as evidence RT remain similar to that in other patients with TB. The
of diagnosis (56). Recent evidence suggests that cartridge- choice of safe and effective anti-TB treatment for these
based nucleic acid amplification tests [CBNAAT] like patients depends upon the pharmacology of drugs in the
Xpert MTB/RIF have a low sensitivity and is not useful setting of CKD and during MHD and their interaction
in the diagnosis of pleural TB (57). Studies with a large with immunosuppressive drugs used in patients with RT.
sample size are required to establish the usefulness of these Pharmacological properties of anti-TB drugs that determine
investigations. how the levels of these drugs are likely to be influenced by
384 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 28.3: Comparison of site of TB involve­ment in patients. In slow acetylators with severe renal impairment
patients with chronic kidney disease [n = 923] pre- and who are not on dialysis, 5-6 mg/kg body weight
and post-renal transplantation isoniazid will be equivalent to daily dose of 7-9 mg/kg
body weight in normal subjects. It has been shown that
Pre-RT Post-RT
Site of TB No. [%] ­­ No. [%]­
isoniazid is well tolerated at this dose in these patients (64).
Previous recommendation to reduce the daily dose of
Number of cases­ 152­ 156­
isoniazid to 150 mg in patients with severe CKD is, therefore,
Pleural­* 50 [32.9]­ 17 [10.9]­ unjustified (65,66). Also, there is convincing evidence that
Pulmonary­ 44 [28.9]­ 45 [28.8]­ isoniazid at a dosage less than 200 mg/day significantly
Abdominal­* 16 [10.5]­ 4 [2.6]­ decreases therapeutic response (67). Some suggestions
Nodal­ 14 [9.2]­ 13 [8.3] regarding administering isoniazid eighth hourly are un­
warranted (68) and there is no justification for estimation
Pericardial­* 11 [7.2]­ 0­
of isoniazid levels in these patients (62).
Presentation as PUO­* 10 [6.6]­ 46 [29.5]
Genitourinary­ 3 [1.9]­ 0­ Rifampicin
Bone and joints­ 2 [1.3]­ 2 [1.3]
Serum half-life of rifampicin and the proportion of the
Miliary­* 1 [0.6]­ 14 [8.9] unchanged drug excreted in the urine increase steadily as
Neurological­* 1 [0.6]­ 9 [5.8]­ the individual dosages are increased from 300 to 900 mg,
Miscellaneous­ 0 6 [3.9] probably as a result of biliary excretion route becoming
Laryngeal­ 0 2 saturated. Daily treatment with rifampicin for a period of one
week or more, results in the induction of hepatic enzymes,
Orchitis­ 0 1
which deacetylate the drug. Such induction significantly
Skin­ 0 1
reduces half-life of rifampicin and probably reduces urinary
Psoas abscess­ 0 1 excretion of the unchanged drug. About 14% of the dose
Gluteal abscess­ 0 1 is recovered in urine whether or not liver enzymes have
* Statistically significant difference been induced. It is thought that effect of renal impairment
TB = tuberculosis; RT = renal transplant; PUO = pyrexia of unknown on rifampicin excretion is negligible at a dose of 450 mg,
origin modest at 600 mg and substantial at 900 mg (58). Therefore,
rifampicin up to a dose of 600 mg/day does not require
renal impairment have been extensively reviewed by several reduction at any stage of CKD (58).
workers (58-60).
Renal insufficiency complicates the management of TB Pyrazinamide
because some anti-TB drugs are cleared by the kidneys. As little as 3%-4% of ingested pyrazinamide is excreted
Manage­ment may be further complicated by the removal unchanged in the urine. Its half-life is 6-10 hours and very
of some anti-tuberculosis agents via haemodialysis. Thus, little change is expected even in patients with severe renal
some alteration in the dosage of anti-TB drugs is necessary failure (69,70). However, Fabre et al (70), suggested to avoid
in patients with CKD and ESRD receiving haemodialysis. its use in severe renal failure, while Anderson et al (71),
Decreasing the dose of selected anti-tuberculosis drugs may and Andrew et al (5), suggested reduction in the dose to
not be the best method of treating TB because, although 12-20 mg/kg/day. However, such a dosage schedule
toxicity may be avoided, the peak serum concentrations will cause suboptimal therapeutic levels (72). Controlled
may be too low. Therefore, increas­ing the dosing interval clinical trials have shown that thrice weekly treatment is
instead of decreasing the dosage of the anti-TB drugs is therapeutically more effective than daily administration (73).
recommended (61). It is, therefore, recommended that patients with renal
impairment should be treated either thrice or twice weekly
Isoniazid with 40–60 mg/kg pyrazinamide. However, in most of
the published studies, patients had received daily dose of
Of the administered dose of isoniazid, 96% is recoverable in
pyrazinamide (69,70).
the urine as unchanged drug together with its metabolites (62).
All metabolites of isoniazid are devoid of anti-TB activity.
These are less toxic than isoniazid and are more rapidly
Streptomycin
excreted through the kidneys (63). In anuric patients, half- Nearly 80% of the dose of streptomycin, like other aminogly­
life of isoniazid varies with acetylator status. Half-life is cosides, is excreted unchanged in the urine. Aminoglycosides
essentially unaltered in rapid acetylators; while in those who are excreted by glomerular filtration and not by active
are slow acetylators, it has been observed to increase by 40%. secretion (74,75). Line et al (74) demonstrated significant
It is, therefore, recommended that normal daily dosage of correlation between degree of renal failure and serum levels
isoniazid [300 mg or 5 mg/kg body weight] should be given of streptomycin. Therefore, if streptomycin is to be used in
in patients with severe renal impairment, including anuric the treatment of TB in presence of renal failure, its dosage
 Tuberculosis in Chronic Kidney Disease 385

must be decreased. It is preferable to give streptomycin Treatment of Tuberculosis in Patients on Dialysis

twice or thrice weekly without decreasing the usual dose. If
Treatment of TB is imperative as soon as the diagnosis is
possible, drug through level should be measured and should
confirmed or strongly suspected. Isoniazid and rifampicin
not exceed 4 mg/L.
have been used in majority of the studies (4-6,16,21).
Streptomycin is not so commonly used nowadays in patients
Ethambutol
with renal failure. Isoniazid at a dosage of 200-300 mg/day
About 80% of the dose of ethambutol is excreted unchanged does not cause significant toxicity in adult patients with
in urine and major reduction in daily ethambutol doses are renal failure. However, vitamin B6 in a dose of 10-20 mg
recom­mended in patients with renal failure. Recom­mended should be administered prophylactically in all these patients.
dosage in presence of renal failure varies from 5-10 mg/kg/ Dosage modification is not required for rifampicin but it
day by various workers (6,76,77). Ethambutol can result in should be administered cautiously in patients with CKD
blind­ness. Moreover, measurement of streptomycin levels who are not on haemodialysis as it can result in acute renal
is much easier. Therefore, if treatment of TB in renal failure failure or deterioration in the renal functions (82). Dosing
requires administration of a fourth drug, in addition to recommendations for adult patients with reduced renal
rifampicin, isoniazid and pyrazinamide, streptomycin seems function [creatinine clearance <30 mL/min] and for adult
to be a better choice as compared to ethambutol. However, patients receiving haemodialysis are shown in Table 28.4 (61).
in all the recent studies, ethambutol rather than streptomycin The anti-TB drugs should be administered after haemo­
has been used as the fourth drug. There is report of dialysis to avoid any loss of the drugs during the procedure,
irreversible blindness in a patient of ESRD treated with and to facilitate direct observation of treatment (61). The
ethambutol for TB, and thus, very close watch on ophthalmic possibility of impaired absorption of anti-tuberculosis drugs
examination should be done in these patients (78). because of comorbid clinical conditions, such as diabetes
mellitus with gastroparesis that are frequently present in
these patients should also be kept in mind.
Second-line Anti-tuberculosis Drugs
Under the Revised National Tuberculosis Control
Dosages of kanamycin, amikacin, and capreomycin must Programme [RNTCP] of the Government of India, daily
be adjusted in patients with renal failure because of renal standard anti-TB treatment has been advocated for all
excretion of these drugs. Administration of these drugs patients, including those with renal failure on conservative
just prior to haemo­dialysis, removes approximately 40% management, MHD or following RT. Monitoring of renal or
of the dosage (79). Dosing interval of these drugs should hepatic function is not done under programme conditions.
be increased. Ethionamide is not cleared by the kidneys, As of now, there are no published data on the efficacy and
nor is the drug removed with haemo­dialysis, so no dose safety of these regimens in patients with CKD on conserva­
adjust­ment is necessary (80). Para-amino salicylic acid [PAS] tive management or MHD. There is no consensus for the
is moderately cleared by haemodialysis [6.3%] but its meta­ duration of anti-TB treatment in these patients. These issues
bolite, acetyl-PAS, is substantially removed by haemodialysis; merit further studies.
twice daily dosing [4 g] should be adequate (80). Cycloserine Rifampicin is an inducer of hepatic enzymes and is
is excreted primarily by the kidney, and is cleared by known to alter the metabolism of many drugs. In this regard,
haemodialysis [56%]. Thus, an increase in the dosing interval rifampicin use becomes an important issue in patients before
is necessary to avoid accumulation between haemodialysis and following RT. Majority of these patients also receive
sessions, and the drug should be given after hemodialysis anti-hypertensive drugs and with the use of rifampicin,
to avoid under- dosing (80). The fluoroquinolones undergo an adequate blood pressure control may not be achieved
some degree of renal clearance that varies from drug to and the dose modification may be required for the anti-
drug. For example, levofloxacin undergoes greater renal hypertensive drugs. In a recently completed study on effect
clearance than moxifloxacin (81). It should be noted that of rifampicin as part of anti-TB therapy on anti-hypertensive
the fluoroquinolone dosing recommendations for ESRD drug requirement in patients of kidney disease, it was
provided by the manufacturers were developed for treating concluded that there is a significant interaction between
pyogenic bacterial infections. These recommendations may anti-hypertensive drugs and rifampicin, resulting in loss of
not be applicable to the treatment of TB in patients with blood pressure control after initiation of rifampicin-based
ESRD. It is important to monitor serum drug concentrations anti-TB therapy. Most patients require an increase in their
in persons with renal insufficiency who is taking cycloserine, anti-hypertensive drug prescription and there is a poten­
ethambutol, or any of the injectable agents to minimise dose- tial risk of experiencing a hypertensive crisis. Significant
related toxicity, while providing effective doses. Currently, decrease in serum levels of commonly prescribed anti-
enough data are not available on anti-TB drug dosage modifi­ hypertensive drugs was observed, which correlated with
cation in patients receiving peritoneal dialysis and the drug the clinical findings of uncontrolled hypertension. Given the
removal mechanisms differ between haemodialysis and peri­ clinical impact of findings and ease of applicability, it was
toneal dialysis. Therefore, such patients may require close recommended that it would be prudent to monitor patients
follow-up and therapeutic drug monitoring. closely for worsening of hypertension after initiation of
386 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 28.4: Dosing recommendations for adult patients with reduced renal function* and for adult patients
receiving haemodialysis
Change in frequency
Drug­ of administration­ Dosage schedule­
First-line drugs­ ­ ­
Isoniazid­ No change­­ 5 mg/kg [maximum 300 mg] once daily, or 15 mg/kg [maximum 900 mg] per dose,
three times per week­
Rifampicin­ No change­ 10 mg/kg [maximum 600 mg] once daily, or 10 mg/kg [maximum 600 mg] per dose,
three times per week­
Pyrazinamide­­ Yes­ 25 to 35 mg/kg per dose three times per week [not daily]­
Ethambutol­ Yes­ 15 to 25 mg/kg per dose three times per week [not daily]­
Streptomycin­­ Yes­ 12 to 15 mg/kg per dose two or three times per week [not daily]­
Second-line drugs­ ­ ­
Cycloserine­ Yes­ 250 mg once daily, or 500 mg per dose three times per week†­
Ethionamide­ No change­ 15 to 20 mg/kg/day [maximum 1 g; usually 500 to 750 mg] in a single daily dose or
two divided doses‡­
Para-aminosalicylic acid­ No change­ 8 to 12 g/day, in two or three doses­
Capreomycin­ Yes­ 12 to 15 mg/kg per dose two or three times per week [not daily]­
Kanamycin­ Yes­ 12 to 15 mg/kg per dose two or three times per week [not daily]­
Amikacin­ Yes­ 12 to 15 mg/kg per dose two or three times per week [not daily]­
Levofloxacin­ Yes­ 750 to 1000 mg per dose three times per week [not daily]­
* Creatinine clearance less than 30 mL/min
† The appropriateness of 250 mg daily doses has not been established
‡ The single daily dose can be given at bed time or with the main meal. No data to support intermittent administration
The medications should be given after haemodialysis on the day of haemodialysis
Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption without excessive accumulation, and to
assist in avoiding toxicity
Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for
patients receiving haemodialysis and verify adequacy of dosing, using monitoring of serum concentration
Adapted from reference 59

rifampicin [unpublished data]. Rifampicin also decreases the endemic areas. Published data suggest that TST is not a
efficacy of other drugs, such as, corticosteroids, cyclosporine reliable test for diagnosis of LTBI in patients with CKD (86-88).
and tacrolimus. Therefore, dosages of these drugs also need A study from India showed that TST in patients on main­
to be modified. This has led to use of non-rifampicin-based tenance haemodialysis is an insensitive and non-specific test
protocols for treatment of TB in RT recipients with an for the diagnosis of LTBI and this should not be taken as
aim of decreasing the cost of therapy as well as avoiding criteria to prescribe prophylaxis of TB in these patients (50).
frequent monitoring (83,84). However, these findings require The potential role of IGRAs also have been evaluated in
validation in future studies. There are no published data on this setting recently. It has been reported that more number
the efficacy and safety of the standard treatment regimens of patients [35.6%] on haemodialysis test positive for
used in the RNTCP in RT recipients. Controlled trials with QuantiFERON Gold In-Tube test [QFT-GIT] as compared
large sample size are required to establish the efficacy, safety, to TST [17.2%]. However, there is poor agreement between
and optimum duration of these standard treatment regimens the two tests. In patients on haemodialysis, Bacille-Calmette-
in patients with CKD. Guérin [BCG] vaccination and history of TB in past did not
seem to affect both TST and QFT-GIT test results. In the
Treatment of Latent Tuberculosis Infection in absence of a “gold standard” for the diagnosis of LTBI, the
issue concerning ‘true positive’ test results in patients on
Patients with Chronic Renal Failure on Dialysis
haemodialysis needs to be resolved (89).
Treatment
In a randomised, double-blind, placebo-controlled,
The American Thoracic Society [ATS] guidelines (85) mention prospective trial of isoniazid prophylaxis in patients on
the relative risk of developing TB in patients with CKD/ haemodialysis from India (90), some degree of protection
those on MHD to be 10-25.3 and targeted TST and treatment of was shown. This protection appeared to be insignificant
LTBI is a well-accepted strategy in developed countries with when the number of cases who dropped out due to various
low transmission of TB such as the USA (61,85). However, reasons and significant number of patients developing TB
this approach does not seem to have much relevance in highly in the treatment group were also taken into consideration.
 Tuberculosis in Chronic Kidney Disease 387

Another recently published trial on isoniazid prophylaxis in However, it is possible for a person to develop TB in spite
patients due to undergo RT who were receiving MHD (91) of chemoprophylaxis (95). In a recent study published from
documented that TB developed in 16.7% patients in the India (96) isoniazid prophylaxis started at the time of RT
isoniazid group compared with 32.7% patients in the control offered some protection from develop­ment of TB (96). In
group suggesting that there was a significant reduction in this study, 11.1% patients receiving isoniazid prophylaxis
the incidence of TB if isoniazid was started early. These developed TB as compared to 25.8% in the control group
issues need further clarification. [RR 0.36]. However, these differences were not statistically
Another issue, which is not clear, is the optimum duration significant. Keeping with the END-TB strategy of the WHO,
of anti-TB treatment before a patient with CKD can be safely a national policy of LTBI treatment in high-risk groups, like
taken up for RT. Controlled trials have not been conducted patients with CKD, RT-recipients [after ruling our active TB]
to answer this question and there is no consensus. Possibly, is expected to be available in near future.
four to six weeks treatment with an adequate anti-TB drug
regimen should be enough before the surgery, especially if Therapeutic Response and Prognosis
the patient is showing a good clinical response to treatment.
With the proper use of currently available anti-TB drugs,
Treatment of Tuberculosis in Recipients of there is a potential for complete cure in a compliant patient.
Major factors which determine the response to anti-TB
Renal Transplantation
treatment are extent of disease at the time of diagnosis,
Management of TB after RT is similar to the management treatment regimen given to the patients, sensitivity of the
of TB in patients on MHD with few differences. Firstly, mycobacteria to given drugs and compliance with drug
following successful RT, renal function become normal treatment.
and dosage modification done during MHD is no longer In the studies, where the response to anti-TB treatment was
required. Secondly, anti-tuberculosis drug interaction with clearly reported, the cure rate varied from 50%-80% (5-6,17).
immunosuppressive drugs is an important issue in these Mortality varied from 7.7%-75% but TB was seldom the
patients. Three most commonly used immunosuppressive cause of death in these patients. Mortality due to TB occurs
drugs in these patients are prednisolone, tacrolimus and in nearly 10% of the RT patients (29,32,33). In RT patients,
myco­phenolate mofetil. Some­times, cyclophosphamide is anti-TB drug-induced hepatotoxicity has been estimated to
also used. There have been no recommendations to decrease be nearly 20% in two major studies (31,32). The magnitude
the dosage of immunosuppressive medication if patients of the problem of multidrug-resistant TB [MDR-TB] in
develop TB after RT. patients with CRF and following RT needs to be studied
During rifampicin therapy, daily dosage of corticosteroids in detail.
should be increased or maintained to nearly 1.5 times the
baseline dosage, as rifampicin is known to be an inducer of NONTUBERCULOUS MYCOBACTERIAL DISEASE
the enzymes involved in the hepatic metabolism of cortico­ IN CHRONIC KIDNEY DISEASE
steroids (92). Azathioprine if used, sometimes, causes hepa­
totoxicity, which has to be differentiated from hepatotoxicity Nontuberculous mycobacterial disease [NTM] is uncommon
due to anti-TB treatment. The major drug interaction of anti- in patients with CKD and following RT. In a study (6), 17.6%
TB drugs is with tacrolimus. Rifampicin produces lowering of mycobacterial infections in dialysis patients were caused
of blood levels of tacrolimus by producing an increase in by M. avium-intracellulare and M. fortuitum.
its hepatic metabolism (93). Ideally, tacrolimus blood levels NTM disease has been reported more frequently in RT
should be monitored and its dose adjusted if the patient recipients than in patients on MHD. Among these patients,
is also receiving rifampicin. Optimum duration of anti-TB about 10% of mycobacterial infections are due to NTM, of
treatment in RT recipients is again controversial. Patients which M. kansasii and M. chelonae are frequent (26,27,96-101).
who receive DOTS under the RNTCP of the Government Usually these organisms cause chronic infection of bone
of India are treated for six months. In individual cases, and soft tissues. In India, mycobacterial culture and drug-
treatment duration may be prolonged by another three susceptibility testing facilities in reliable, accredited, quality
[e.g., EPTB] to six [e.g., TB meningitis] months. However, assured laboratories are seldom available and it is, therefore,
in some studies most patients have received treatment possible that NTM infections are being missed. The reader
for 12 months or more (29-32,94). The efficacy of short- is referred to the chapter “Nontuberculous mycobacterial
course chemotherapy has not been studied in detail in these infections” [Chapter 41] for details.
patients.
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47. el-Agroudy AE, Refaie AF, Moussa OM, Ghoneim MA. 69. Stamatakis G, Montes C, Trouvin JH, Farinotti R, Fessi H,
Tuberculosis in Egyptian kidney transplant recipients: study of Kenouch S, et al. Pyrazinamide and pyrazanoic acid pharma­
clinical course and outcome. J Nephrol 2003;16:404-11. cokinetics in patients with chronic renal failure. Clin Nephrol
48. Amedia C, Oettinger CW. Unusual presentation of tuberculosis 1988;30:230-4.
in chronic haemodialysed patients. Clin Nephrol 1977;8:363-6. 70. Fabre J, Fox HM, Dayer P, Balant L. Difference in kinetic
49. Habesoglu MA, Torun D, Demiroglu YZ, Karatasli M, Sen N, properties of drugs: implication as to the selection of a particular
Ermis H, et al. Value of the tuberculin skin test in screening for drug for use in patients with renal failure with special emphasis
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50. Agarwal SK, Gupta S, Tiwari SC. Tuberculin skin test for the Pharmacokinetics 1980;5:441-64.
diagnosis of latent tuberculosis infection during renal replace­ 71. Anderson RJ, Gambertoglio JG, Schrier RW. Drugs used in the
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52. Cinque TJ, Letteri JM. Idiopathic ascites in chronic renal failure. 81-114.
NY State J Med 1973;73:781-4. 74. Line DH, Poole GW, Waterworth PM. Serum streptomycin
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effusion: a study of 14 patients on chronic dialysis. Ann Intern 75. Mitchison DA, Ellard GA. Tuberculosis in patients having
Med 1975;82:362-4. dialysis. BMJ 1980;280:1533.
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Health and Family Welfare, Government of India; 2016. Available aminosalicylate, and clofazimine. Chest 1999;116:984-90.
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antibiotic rifampicin. Drug Metab Rev 1981;12:159-218. Dash SC. Acute interstitial nephritis following first exposure to
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drugs. Clin Pharmacokinetics 1984;9:511-44. 83. Vachharajani TJ, Oza UG, Phadke AG, Kirpalani AL. Tuberculosis
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61. Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, 84. Jha V, Sakhuja V. Rifampicin sparing treatment protocols in
Cattamanchi A, et al. Official American Thoracic Society/Centers post-transplant tuberculosis. Int Urol Nephrol 2004;36:287-8.
for Disease Control and Prevention/Infectious Diseases Society 85. Joint Statement of the American Thoracic Society [ATS], and the
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62. Ellard GA, Gammon PT. Pharmacokinetics of isoniazid meta­ September 1999, and the sections of this statement. Targeted
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cological aspects. Bull Int Union Tuberc 1976;51:144-54. 86. Sester M, Sester U, Clauer P, Heine G, Mack U, Moll T, et al.
64. HongKong Treatment Services and East African and British Tuberculin skin testing underestimates a high prevalence of
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90. John GT, Thomas PP, Thomas M, Jeyaseelan L, Jacob CK, 96. Agarwal SK, Gupta S, Dash SC, Bhowmik D, Tiwari SC.
Shastry JC. A double-blind, randomised trial of primary Prospective randomised trial of isoniazid prophylaxis in renal
isoniazid prophylaxis in dialysis and transplant patients. transplant recipient. Int Urol Nephrol 2004;36:425-31.
Transplantation 1994;57:1683-4. 97. Rosen T. Cutaneous Mycobacterium kansasii infection presenting
91. Vikrant S, Agarwal SK, Gupta S, Bhowmik D, Tiwari SC, as cellulitis. Cutis 1983;31:87-9.
Dash SC, et al. Prospective randomised control trial of isoniazid 98. Fraser DW, Buxton AE, Naji A, Barker C, Rudnick M, Weinstein
chemoprophylaxis during renal replacement therapy. Trans AJ. Disseminated Mycobacterium kansasii infections presenting
Infect Dis 2005;7:99-108. with cellulitis in a recipient of a renal homograft. Am Infect Dis
92. Edwards OM, Courtenary Evans RJ, Galley JM, Hunter J, 1975;112:125-9.
Tait AD. Changes in cortisol metabolism following rifampicin 99. Spence RK, Dafoe DC, Rabin G, Grossman RA, Naji A, Barker CF,
therapy. Lancet 1974;2:548-51. et al. Mycobacterium infections in renal allograft recipients.
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94. British Thoracic and Tuberculosis Association. Short-course Pulmonary infection with Mycobacterium kansasii in a renal
chemotherapy in pulmonary tuberculosis. Lancet 1976;2: transplant patient. Nephron 1980;26:187-8.
1102-4. 101. Sanger JR, Stampfl D, Franson T. Recurrent granulomatous
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plantation in India. Transpl Proc 1979;2:1296. patient. Am J Hand Surg 1987;12:436-41.
 29
Disseminated/Miliary Tuberculosis
Surendra K Sharma, Alladi Mohan

The whole surface, in front and behind, as well as within the Table 29.1: Epidemiology of miliary TB
interstitium of the major lobes, was covered with firm small white
Frequency of miliary TB
corpuscles, of the size of millet seeds…..
John Jacob Manget Study (reference) Overall [%] Among TB [%]
Adults, autopsy studies (12-18) 0.3 to 13.3 11.9 to 40.5
INTRODUCTION Adults, clinical studies (19-22) 1.3 to 2.0 0.64 to 20

Disseminated tuberculosis [DTB] refers to concurrent Children, clinical studies (23-26) 0.7 to 41.3 1.3 to 3.2
involvement of at least two non-contiguous organ sites of All age groups, epidemiological – 0.4 to 10.7
the body, or, involvement of the blood or bone marrow by studies, public health data
(27-36)
tuberculosis [TB] process (1-3). One form of DTB, miliary
tuberculosis [MTB], results from a massive haematogenous TB = tuberculosis
Adapted from reference 4
dissemination of tubercle bacilli which results in tiny discrete
foci usually the size of millet seeds [1 to 2 mm] more or less
uniformly distributed in the lungs and the other viscera (4-9). The emergence of the HIV/AIDS pandemic and wides­
Miliary pattern on the chest radiograph is the hallmark of pread use of immunosuppressive drugs have changed the
MTB. epidemiology of MTB. Since its first description by John
Miliary and disseminated TB continue to be a diag­ Jacob Manget, the clinical presentation of MTB has changed
nostic problem even in areas endemic to TB, where clinical dramatically. Especially its occurrence as a complication of
suspicion is very high. Mortality from MTB disease has childhood infection is diminishing and the “cryptic form”
remained high despite effective therapy being available. In [vide infra] in a much older group is emerging (37-39).
patients with human immunodeficiency virus [HIV] infection The modulating effect of Bacille Calmette-Guérin [BCG]
acquired immuno­deficiency syndrome [AIDS] DTB and MTB vaccination resulting in substantial reduction in MTB and
are particularly common (1,3,10,11). TB meningitis among young vaccinees, increasing use of
computed tomography [CT], and wider application of
EPIDEMIOLOGY invasive diagnostic methods could also have contributed to
the demographic shift (4).
The epidemiology of MTB as documented in several
published studies is depicted in Table 29.1 (12-36). Miliary TB
Age and Gender Distribution
accounts for less than 2% of all cases of TB and up to 20% of
all TB cases in various clinical studies in immunocompetent In patients with MTB, presently two additional peaks are
individuals; the corresponding figures in autopsy studies evident—one involving adolescents and young adults and
have been higher [Table 29.1]. Caution must be exercised another later in life among elderly people (4-9). Sparse
while comparing these epidemiological data as these studies published data are available on DTB. In a series from
are hospital based or autopsy studies. northern Taiwan (2), patients with HIV/AIDS who had DTB
392 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

[n = 23] were younger [mean age 37.1 years], compared with patients with MTB (2,17-23). Organomegaly is also a frequent
DTB patients with [n = 64; mean age 61.4 years] and without physical finding.
other co-morbid conditions [n = 77; mean age 58.9 years]. Choroidal tubercles are bilateral, pale, greyish-white and
Male gender seems to be more frequently affected by oblong patches which occur less commonly in adult patients
MTB in children as well as adults (4-9). Similarly, 119 of the with MTB than children (4). If present, choroidal tubercles
164 patients with DTB reported by Wang et al (2) were males. are pathognomonic of MTB and offer a valuable clue to
However, a few recent adult series on MTB (16,20,40,41) the diagnosis [Figures 24.3, 24.4, 24.5A, 24.5B and 24.6].
describe a female preponderance. This shift probably reflects Therefore, systematic ophthalmoscopic examination after
increased awareness and use of health services by women. mydriatic administration must be done in every suspected
Further work is required to understand the influence of patient with MTB. Skin involvement in the form of erythe­
other factors, such as, socio-economic and nutritional status, matous macules and papules have also been described (4-9).
co-morbid illnesses, and host genetic factors other than Signs of hepatic involvement may be evident in the form
ethnic variations in the causation of DTB/MTB. of icterus and hepatomegaly. Neurological involvement
in the form of meningitis or tuberculomas is common. TB
PATHOGENESIS meningitis has been described in 10%-30% of adult patients
with MTB (14,20,40-53) Conversely, about one-third of
Miliary TB develops due to a massive lymphohaematogenous patients presenting with TB meningitis have underlying
dissemination of Mycobacterium tuberculosis [Mtb] from a MTB (57). Clinically significant cardiac or renal involvement
pulmonary or extrapulmonary focus and embolisation to is uncommon in patients with MTB (4-9). Overt adrenal
the vascular beds of various organs (4) [Figure 29.1]. Less insufficiency at presentation, or during treatment has also
commonly, simultaneous reactivation of multiple foci in been described in MTB (58). In some studies, headache and
various organs can result in MTB. This reactivation can abdominal pain when present are supposed to have specific
occur either at the time of primary infection or later during implications in MTB, headache signifying the presence
reactivation of a dormant focus. When MTB develops during of meningitis and abdominal pain signifying abdominal
primary disease [early generalisation], the disease has an involvement (4-9).
acute onset and is rapidly progressive. Late generalisation Clinical presentation of MTB in children is similar to
during post-primary TB can be rapidly progressive [resulting that observed in adults, but with important differences
in acute MTB], episodic, or protracted, leading to chronic [Tables 29.3A and 29.3B]. In children with MTB, chills,
MTB. Re-infection also has an important role, especially night sweats, haemoptysis, and productive cough have been
in areas where TB is highly endemic. Rarely, MTB can reported less frequently, while peripheral lymphadeno­pathy
also develop due to caseation of an extrapulmonary site, and hepatosplenomegaly are more common, compared with
discharge of caseous material into the portal circulation and adults. Likewise, a higher proportion of children with MTB
initial hepatic involvement with the classical pulmonary have TB meningitis compared with adults.
involvement occurring late (4-9). The reader is referred to
the chapter “Immunology” [Chapter 5] for details regarding
Rare Manifestations
the molecular mechanisms underlying the pathogenesis of
DTB/MTB. Table 29.4 (37-53,58-79) shows various atypical manifestations
Miliary TB is a common manifestation of congenital TB in patients with MTB. Atypical presentations can delay
in neonates. Acquisition of infection during the perinatal the diagnosis and DTB/MTB is often a missed diagnosis.
period through aspiration and ingestion of infected maternal Patients with occult DTB/MTB can present with pyrexia
genital tissues and fluid may rarely lead to the development of unknown origin [PUO] without any focal localising
of MTB in neonates. The reader is referred to the chapter clue. Clinical presentation such as absence of fever, and
“Pathology” [Chapter 3] for details regarding congenital TB. progressive wasting strongly mimicking a metastatic
carcinoma can occur, especially in the elderly. Proudfoot
CLINICAL PRESENTATION et al (37) suggested the term “cryptic miliary TB” for this
presentation. Table 29.5 (37-39) highlights the important
Most of the patients with DTB/MTB often have non-specific differences between classical and cryptic forms of MTB.
predisposing/associated conditions [Table 29.2]. Their The reader is referred to the chapter “Tuberculosis and acute
pathogenetic role is unclear. lung injury” [Chapter 32] for details regarding TB and acute
Common presenting symptoms and signs noted at respiratory distress syndrome [ARDS].
presentation in patients with DTB/MTB are listed in
Tables 29.3A and 29.3B (40-56). Although DTB/MTB involves Disseminated/Miliary Tuberculosis in the
almost all organs, most often the involvement is asympto­
Immunosuppressed
matic. Clinical manifestations of DTB/MTB are protean and
can be obscure till late in the disease. Fever and inanition are The clinical presentation of TB in early HIV infection
relatively common. Cough and dyspnoea are often present. [CD4+ cell counts >500/µL] is similar to that observed
Chills and rigors, usually seen in patients with malaria, or, in immunocompetent individuals. With progression
sepsis and bacteraemia, have often been described in adult of immunosuppression in advanced HIV infection
 Disseminated/Miliary Tuberculosis 393

A B

C D

E F
Figure 29.1: Gross pathology of miliary tuberculosis. Multiple lesions of miliary tuberculosis in both lung fields with areas of haemorrhage [A];
liver slice showing multiple confluent as well as discrete tubercles [B]; spleen showing multiple grey-white varying sized lesions [C]; cut-section
of spleen showing miliary seeding [D]; omentum showing multiple tubercles, caseation is evident in larger lesions [E]; kidney with tubercles seen
over the surface [F]

[CD4+ cell counts <200/µL], DTB/MTB are seen more tiny papules or vesiculo-papules variously described as
frequently (54,80-82). Cutaneous involvement is unusual ‘tuberculosis cutis miliaris disseminata’, ‘tuberculosis cutis
in MTB but is more commonly seen in HIV-seropositive acuta generalisita’, and disseminated TB of the skin (84).
patients with CD4+ cell counts below 100 cells/µL (83). Rarely, macular, pustular, or purpuric lesions, indurated
The cutaneous lesions that have been described include ulcerating plaques, and subcutaneous abscesses have also
394 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 29.2: Conditions predisposing to/associated Table 29.3A: Presenting symptoms in miliary/
with miliary/disseminated TB disseminated TB
Childhood infections Miliary TB Disseminated
Malnutrition TB‡
Variable Adults [%]* Children [%]†
HIV/AIDS
Alcoholism Fever 35-100 61-98 48
Diabetes mellitus Chills 15-28 ND ND
Chronic renal failure, dialysis Anorexia 24-100 04-81 06
Post-surgery [e.g., gastrectomy*]
Organ transplantation Weight loss 20-100 04-60 07-46
Drugs Night sweats 08-100 08-75 03
Corticosteroids Weakness/fatigue 25-100 14-54 10-75
Immunosuppressive and cytotoxic drugs Cough/sputum 27-82 17-90 23-33
Immunomodulator drugs [e.g., infliximab, etanercept] Chest pain 03-49 01-03 ND
Connective tissue disorders Dyspnoea 08-100 07-25 11-17
Pregnancy, postpartum
Haemoptysis 03-15 01 ND
Underlying malignancy
Silicosis Headache 02-18 02-08 02
Iatrogenic causes Altered sensorium 05-26 02-08 09
  Ureteral catheterisation*
Seizures ND 07-30 ND
   Extracorporeal shockwave lithotripsy†
  Laser lithotripsy† Nausea 01-19 ND ND
   Cardiac valve homograft replacement‡ Abdominal pain 05-19 03-15 06
   Intravesical BCG therapy for urinary bladder carcinoma Diarrhoea 02-03 ND ND
* Predisposes to TB in general Urinary symptoms 02-06 ND 04
† Patient had undiagnosed genitourinary TB
‡ Contamination of homografts probably occurred at the time of All values are expressed as percentages corrected to the nearest
harvest from cadavers round figures
TB = tuberculosis; HIV = human immunodeficiency virus; * Data from references 13,20,40-54
AIDS = acquired immunodeficiency syndrome; BCG = bacille † Data from references 21,23,26,55,56
Calmette-Guerin ‡ Data from Wang et al (reference 2). In this series, 23 of the 164
Adapted from reference 4 patients were human immunodeficiency virus seropositive
TB = tuberculosis; ND= not described

been reported (84). In HIV/AIDS patients with DTB/MTB,

Table 29.3B: Presenting signs in miliary/disseminated
intrathoracic lymphadenopathy and tuberculin anergy are
TB
more common; sputum smears are seldom positive and
blood culture may grow Mycobacterium tuberculosis, especially Miliary TB Disseminated
Variable Adults [%]* Children [%]† TB‡
in patients with profound immunosuppression (1,2,4-9,54).
Immune reconstitution inflammatory syndrome [IRIS] Fever 35-100 39-75 48
has been implicated as the cause of paradoxical worsening of Pallor 36-59 31 ND
lesions in patients with TB. Consequently, HIV-seropositive
Cyanosis 01-02 ND 06
patients with MTB may develop acute renal failure (85) or
ARDS (86). The reader is referred to the chapter “Tuberculosis Icterus 05-09 03 07-46
and human immunodeficiency virus infection” [Chapter 35] for Lymphadenopathy 02-30 05 03
further details on this topic. Chest signs 29-84 34-72 10-75
Hepatomegaly 14-62 39-82 23-33
LABORATORY FINDINGS
Splenomegaly 02-32 24-54 ND
Haematology and Serum Biochemistry Ascites 04-38 06-09 11-17
A number of haematological and biochemical abnormalities Choroidal 02-12 02-05 ND
are known to occur in DTB/MTB but their significance tubercles
is controversial [Table 29.6]. Anaemia of chronic disease, Neurological signs 03-26 19-35 02
leucocytosis, leucopenia, leukaemoid reactions, thrombo­
All values are expressed as percentages corrected to the nearest
cytopenia and disseminated intra­v ascular coagulation round figures
[DIC], haemophagocytic lymphohistiocytosis are all known * Data from references 13,20,40-54
to occur. Erythrocyte sedimentation rate is usually elevated † Data from references 21,23,26,55,56
in patients with DTB/MTB (4-9). The reader is referred to ‡ Data from Wang et al (reference 2). In this series, 23 of the 164
the chapter “Haematological manifestations of tuberculosis” patients were human immunodeficiency virus seropositive
TB = tuberculosis; ND = not described
[Chapter 33] for further details on this subject.
 Disseminated/Miliary Tuberculosis 395

Table 29.4: Atypical clinical manifestations in MTB Table 29.6: Laboratory abnormalities in miliary/
Cryptic miliary TB disseminated TB
Pyrexia of unknown origin [PUO] Haematological
Anaemia
Acute respiratory distress syndrome [ARDS]
Leucocytosis
“Airleak” syndrome [pneumothorax, pneumomediastinum] Neutrophilia
Myelophthisic anaemia, myelofibrosis, pancytopenia, immune Lymphocytosis
haemolytic anaemia Monocytosis
Thrombocytosis
Acute empyema Leucopenia
Septic shock, multiple organ dysfunction syndrome Lymphopenia
Thrombocytopenia
Thyrotoxicosis
Renal failure due to granulomatous destruction of the interstitium Leukaemoid reaction
Elevated ESR, CRP levels
Immune complex glomerulonephritis
Biochemical
Sudden cardiac death
Hyponatraemia
Mycotic aneurysm of aorta Hypoalbuminaemia
Massive haematemesis Hyperbilirubinaemia
Elevated transaminases
Native valve and prosthetic valve endocarditis Elevated serum alkaline phosphatase
Myocarditis, congestive heart failure, intracardiac masses Hypercalcaemia
Cholestatic jaundice TB = tuberculosis; ESR = erythrocyte sedimentation rate; CRP =
Presentation as focal extrapulmonary TB C-reactive protein

Metastatic abscess
Incidental diagnosis
Syndrome of inappropriate antidiuretic hormone secretion [SIADH] Hyponatraemia in MTB was first described in 1938 by
Deep vein thrombosis Winkler and Crankshaw (87). Shalhoub and Antoniou (88)
Haemophagocytic lymphohistiocytosis postulated an acquired disturbance of neurohypophyseal
Hypercalcaemia
function resulting in unregulated antidiuretic hormone
[ADH] release as the underlying mechanism. Vorherr et al (89)
TB = tuberculosis
demonstrated an antidiuretic principle in the lung tissue
Data from references 37-53,58-79
affected by TB and suggested that it may either produce
ADH or absorb an inappropriately released hormone from
the posterior pituitary. Some have attributed hyponatraemia
Table 29.5: Comparison of classical and cryptic to meningeal involvement (43). Presence of hyponatraemia
miliary TB in patients with MTB is thought be of prognostic significance
[vide infra]. Hypercalcaemia has been documented in MTB
Variable Classical miliary TB Cryptic miliary TB
but is uncommon (4-9).
Age at diagnosis Majority < 40 years Majority > 60 years
Fever Present in >90% Usually absent Tuberculin Skin Test
Weight loss Present in 60%-80% Dominant clinical Majority of patients with DTB/MTB are tuberculin skin test
feature
[TST] positive. In various paediatric series (21,23,26,55,56)
Meningitis Seen in 20%-30% adults Rare unless [Table 29.7] negative TST results were observed in 35%-74%
30%-40% children terminal of patients. In adult series (42-47,49-51,90) [Table 29.7] TST
Lymphadenopathy Present in 20% Rarely present negativity was reported in 20%-70% of patients.
Chest radiograph Classical miliary pattern Normal
common Interferon-gamma Release Assays
HRCT scan of the Required only when Required for The reader is referred to the chapter “Laboratory diagnosis”
chest classical miliary pattern diagnosis
[Chapter 8] for further details on this topic.
is not evident
Tuberculin skin Positive in 60% Rarely positive
test
Imaging
Confirmation of Invasive procedures Usually made at Chest Radiograph
diagnosis autopsy
The radiographic hallmark of MTB is the miliary pattern on
TB = tuberculosis; HRCT = high resolution computed tomography chest radiograph [Figure 9.7]. The term miliary refers to the
Data from references 37-39
“millet seed” size of the nodules [< 2 mm] seen on classical
396 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 29.7: Results of TST in miliary TB*

No. No.
Study (reference) studied tested Negative TST [%]
Paediatric series
Kim et al (23) 84 84 51
Aderele (55) 44 26 35
Rahajoe (56) 80 80 54
Hussey et al (21) 94 94 62
Gurkan et al (26) 23 23 74
Adult series
Biehl (42) 68 26 39
Munt (43) 69 57 48
Campbell (44) 48 30 20
Gelb et al (45) 109 72 44
Grieco and Chmel (46) 28 21 52
Onadeko et al (47) 41 23 65
Prout and Benatar (49) 62 21 62
Kim et al (50) 38 38 68
Maartens et al (51) 109 47 57
Mert (40) 38 38 62
Sharma and Mohan (90) 134 107 70
* Varying strengths and methods were employed for TST in different
studies
TB = tuberculosis; TST = tuberculin skin test Figure 29.2A: Chest radiograph [postero-anterior view] showing
confluent shadows instead of miliary mottling in a patient with miliary
tuberculosis
Reproduced with permission from “Sharma SK, Mohan A, Prasad KL,
Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory
chest radiographs (4). Some patients with MTB, however, characteristics and outcome in miliary tuberculosis. QJM 1995;88:
may have normal chest radiographs when they seek medical 29-37 (reference 52)”
care and some have patterns that are indistinguishable from
interstitial pneumonia (4,52). Some of the patients may
manifest coalescent opacities [Figures 29.2A, 29.2B, 29.3, 29.4].
When patients with MTB develop ARDS, the chest radio­
graph may be identical to that seen in ARDS due to other
causes (4,59). Majority of the patients [88%] in the study
reported by Sharma et al (52) had chest radiographs
consistent with MTB and in some, these classical radiological
changes evolved over the course of the disease. The diagnosis
of MTB is easier when patient presents with classical miliary
shadowing on chest radiograph in an appropriate setting.
However, the diagnosis may be difficult in those situations
where chest radiograph does not show classical miliary
shadows. This fact is highlighted by 12 patients in the
series reported by Sharma et al (52) who had atypical chest
radiographs and the case of a patient with fever of unknown
origin who presented with a very subtle suggestion of miliary
mottling on the chest radiograph. This chest radiograph
was passed off as normal in a busy outpatient department
[Figure 29.5]. High resolution computed tomography
[HRCT] [vide infra] suggested a miliary pattern [Figure 29.6]
and excision biopsy of the supraclavicular lymph node
which developed over the course of the disease confirmed
the diagnosis in this patient [Figure 29.7]. This re-emphasises
the fact that though the clinical and laboratory parameters Figure 29.2B: HRCT of the chest of the same patient in Figure 29.2A,
are indicative of the disease, these are not sensitive enough showing miliary pattern
Reproduced with permission from “Sharma SK, Mohan A, Prasad KL,
to allow an accurate provisional diagnosis. Thus, if there is
Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory
a high index of suspicion of the diagnosis of MTB and the characteristics and outcome in miliary tuberculosis. QJM 1995;88:
chest radiograph is atypical, it is suggested that HRCT be 29-37 (reference 52)”
done to support the diagnosis. HRCT = high resolution computed tomography
 Disseminated/Miliary Tuberculosis 397

Ultrasonography interlobular septal thickening or intralobular fine network

In patients with DTB/MTB, ultrasonography is useful that is evident on HRCT in MTB seems to be caused by the
in the detection of associated lesions, such as, loculated presence of tubercles in the interlobular septa and alveolar
ascites, focal hepatic and splenic lesions, adnexal masses walls. Centrilobular nodules and branching linear structures
[in women] and cold abscess. Diagnostic thoracic or producing a tree-in-bud appearance—a pattern seen in active
abdominal paracentesis under ultrasound guidance is useful post-primary pulmonary TB—may sometimes be evident
to procure fluid for diagnostic testing, especially when it is in MTB. Contrast-enhanced computed tomography [CECT]
loculated. Recently, B-lines, comet-tail artifacts disseminated is better for detecting intrathoracic lymphadenopathy,
throughout multiple lung areas and a pattern of sub-pleural calcification, and pleural lesions (3,4).
granularity have been described on ultrasonography of the Magnetic resonance imaging [MRI] and CECT are also
chest in patients with MTB (91). useful in demonstrating miliary lesions at occult extra­
pulmonary sites, an exercise that was earlier possible only
Computed Tomography and Magnetic at post-mortem examination. Abdominal CECT is useful in
Resonance Imaging identifying lesions in the liver and spleen, intra-abdominal
lymphadenopathy, and cold abscesses (3,4,92). Miliary
High-resolution computed tomography has considerably lesions in the liver and spleen may appear as confluent or
improved the ante-mortem diagnosis of DTB/MTB. The discrete hypodense lesions, sometimes with peripheral rim
enhancement on the CECT scan of the abdomen (3,4,92).

Positron Emission Tomography

Recently, positron emission tomography-CT [PET-CT] and
PET-MRI have been used to assess the disease activity in
patients with TB (93,94). PET-CT and PET-MRI are useful
in defining the disease extent in patients with DTB/MTB.
The utility of these investigations in assessing the activity
of lesions [Figures 29.8, 29.9] that might persist following
anti-TB treatment in DTB/MTB needs to be studied further.
Ultrasonography, CECT, and MRI may help in identifying
adnexal masses, ascites in women, and epididymitis and
seminal vesicle lesions in men with genital tract involvement.
The CECT or MRI of the brain and spine are useful in the
evaluation of patients with concomitant TB meningitis or
spinal TB. Inter­ventional radiological procedures such as
fine needle aspiration for cytological examination and biopsy
under CT or MRI guidance are useful for procuring tissue/
fluid for confirmation of diagnosis.
Imaging findings which are commonly encountered
Figure 29.3: Chest radiograph [postero-anterior view] showing miliary in patients with DTB are shown in [Figures 29.10. 29.11A,
mottling and a cavity in the left upper lobe 29.11B, 29.12A, 29.12B, 29.13A, 29.13B, 29.14 and 29.15].

A B C
Figure 29.4: Chest radiograph [postero-anterior view] showing miliary mottling [A]. HRCT chest of the same patient showing miliary mottling and
bilateral cavitary lesions [B]. CECT head of the same patient showing intracranial tuberculomas [C]
HRCT = high resolution computed tomography; CECT = contrast-enhanced computed tomography
 398 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 29.5: Chest radiograph [postero-anterior view] showing subtle Figure 29.6: CT of the chest of the same patient in Figure 29.5 showing
miliary shadows extensive miliary shadows
Reproduced with permission from “Sharma SK, Mohan A, Prasad KL, Reproduced with permission from “Sharma SK, Mohan A, Prasad KL,
Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory Pande JN, Gupta AK, Khilnani GC. Clinical profile, laboratory
characteristics and outcome in miliary tuberculosis. QJM 1995;88: characteristics and outcome in miliary tuberculosis. QJM 1995;88:
29-37 (reference 52)” 29-37 (reference 52)”

Figure 29.7: Lymph node biopsy showing confluent, caseating epithelioid

cell granulomas with giant cells suggestive of tuberculosis [Haematoxylin and
eosin × 80]
Reproduced with permission from “Sharma SK, Mohan A, Prasad KL, Pande JN,
Gupta AK, Khilnani GC. Clinical profile, laboratory characteristics and outcome in
miliary tuberculosis. QJM 1995;88:29-37 (reference 52)”

A B C F
18F 18F
Figure 29.8: FDG PET-CT maximum intensity projection image [A] showing sites of abnormal FDG accumulation in the mediastinum.
Coronal NCCT reveals multiple paratracheal, subcarinal and right hilar lymph nodes [B] which show FDG accumulation on fused coronal
PET-CT [C]. Transaxial fused PET-CT showing tracer accumulation in right supraclavicular node [arrow] [D], transaxial NCCT showing pericardial
effusion [arrow] [E] and transaxial fused PET-CT reveals tracer uptake in the pericardial attachment [arrow] [F]
FDG PET-CT = fluorodeoxyglucose positron emission tomography-computed tomography; NCCT = non-contrast computed tomography
 Disseminated/Miliary Tuberculosis 399

A B D
Figure 29.9: 18F FDG PET-CT of the same patient shown in Figure 29.8, obtained at 4 months of anti-TB treatment, maximum intensity projection
image showing sites of abnormal 18F FDG accumulation in the mediastinum [A]. Fused coronal PET-CT reveals paratracheal and right hilar lymph
nodes which show FDG accumulation [B]. Transaxial fused PET-CT showing tracer accumulation in right supraclavicular node [arrow] [C] and
subcarinal node [arrow] [D]
FDG PET-CT = fluorodeoxyglucose positron emission tomography-computed tomography; TB = tuberculosis; FDG = fluorodeoxyglucose

Sharma et al (95) assessed the CT appearances of MTB due to widening of alveolar-arterial oxygen gradient. A mild
and the CT findings were correlated with pulmonary reduction in the flow rates suggestive of peripheral airways
functions and gas exchange. The effect of anti-TB treatment involvement was also observed.
on various observed findings was also studied. It was found With anti-TB treatment, mean arterial oxygen tension
that HRCT was superior to the conventional CT in defining [PaO2] showed a significant increase from the pre-treatment
the parenchymal details. A significant positive correlation value. The mean post-treatment values of forced vital
was observed between the visual chest radiograph and capacity [FVC], forced expiratory volume in the first second
CT scores (95). Further, CT scan of the chest also revealed [FEV1], peak expiratory flow rate [PEFR], maximal mid
lymph node enlargement, calcification and pleural lesions in expiratory flow rate FEF25-75, [V50] and V25 did not show
more patients than plain films. Curiously, Sharma et al (95) a significant increase at the end of treatment (88). The
also described air trapping on CT scan both at presentation functional residual capacity [FRC] and residual volume
and during follow-up period and attributed this to TB [RV]/total lung capacity [TLC] [%] also did not decrease
bronchiolitis. The clinical significance of these findings is significantly at the end of treatment. Anti-TB treatment
unclear at present. resulted in improvement in gas exchange.
Pipavath et al (96), in a recent report [n = 16] documented Pipavath et al (96), assessed the correlation between the
the following changes on HRCT in patients with MTB: disease extent score as evaluated by a visual scoring system
miliary pattern [n = 16]; intrathoracic lymphadenopathy and the pulmonary functions in 16 patients with MTB. They
[n = 8]; alveolar lesions such as ground-glass attenuation observed a significant correlation between the disease extent
and/or consolidation [n = 5]; pleural and pericardial score and the FVC, FEV1, TLC, arterial oxygen saturation
effusions [2 patients each]; and peribronchovascular intersti­ [SaO 2 ], and diffusion capacity of the lung for carbon
tial thickening and emphysema [one patient each]. monoxide [DLCO].

Pulmonary Functions, Gas Exchange Cardiopulmonary Exercise Testing

Abnormalities
Patients with MTB have abnormal cardiopulmonary exercise
Miliary TB is associated with abnormalities of pulmonary performance with lower maximum oxygen consumption,
functions typical of diffuse interstitial disease of the lungs (4). maximal work rate, anaerobic threshold, peak minute
The impairment of diffusion has been the most frequent ventilation, breathing reserve, and low maximal heart
and severe abnormality encountered (4). Sharma et al (97) rate (98,99). Other abnormalities include higher respira­tory
studied the pulmonary functions [n = 31] and gas exchange frequency, peak minute ventilation at submaximal work,
abnormalities on arterial blood gas analysis [n = 13] in and high physiological dead space/tidal volume ratio. Some
patients with MTB. They found a mild restrictive ventilatory of these patients manifest a demonstrable fall in oxygen
defect, impairment of diffusing capacity and hypoxaemia saturation [to 4% or more] with exercise. Following successful
 400 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B

Figure 29.11A: CECT of the chest of a patient with disseminated TB

showing bilateral parenchymal lesions
TB = tuberculosis; CECT = contrast-enhanced computed tomography

C D

Figure 29.11B: CECT of the abdomen of the same patient showing

multiple, low attenuation lesions in the liver and spleen [arrows]
CECT = contrast-enhanced computed tomography

E F
Figure 29.10: MRI of the brain [T1-weighted image, axial view] in a
patient with miliary tuberculosis showing multiple hyperintense disk-
like lesions [tubercles] [A] that are enhanced after the administration
of contrast medium [arrows] [B]. Contrast enhanced MRI of the brain
[T1-weighted image, axial section] showing multiple hyperintense
enhancing disk-like lesions of varying sizes scattered within the brain
[C,D, and E]. Some of them have coalesced to produce a hyperintense
enhancing irregularly shaped lesions [arrows] [F]
MRI = magnetic resonance imaging

treatment, most patients reveal reversal of abnormalities.

However, some of these abnormalities may persist following
treatment (98,99).

Immunologic Abnormalities and

Bronchoalveolar Lavage Figure 29.12A: CECT of the abdomen of a patient with disseminated
tuberculosis showing a large, low attenuation lesion in the spleen
Sharma et al (97) reported that patients with MTB had a [arrow]
significantly higher total cell count and increased proportion CECT = contrast-enhanced computed tomography
 Disseminated/Miliary Tuberculosis 401

Figure 29.13A: CECT of the abdomen of a patient with disseminated

tuberculosis showing multiple, low attenuation lesions in the spleen
CECT = contrast-enhanced computed tomography

Figure 29.12B: CECT of the abdomen of the same patient showing

psoas abscess [asterisk] on the right side. Erosion of the vertebral body
[arrow] can also be seen
CECT = contrast-enhanced computed tomography

of lymphocytes, CD3+, and CD4+ T-lymphocytes in the

bronchoalveolar lavage [BAL] fluid. BAL in patients
with MTB showed lymphocytic alveolitis (97,100). The
finding of increased helper lymphocytes in the BAL fluid
and their depletion in the peripheral blood suggested
compartmentalisation of lymphocytes at the site of inflam­
mation. With anti-TB treatment, total cell count in BAL fluid
decreased but continued to be higher than that in normal
control subjects. The proportion of lymphocytes did not
change significantly.
Figure 29.13B: CECT of the abdomen of the same patient showing
Sharma et al (97) also observed that the immunoglobulins
ascites with loculations [arrows]
[Ig] G, IgA, IgM were increased in the peripheral blood CECT = contrast-enhanced computed tomography
and BAL fluid in 18 patients suggesting polyclonal
hypergammaglobulinaemia. With anti-TB treatment, serum
immunoglobulins, IgG and IgA showed an insignificant DIAGNOSIS
increase. The decrease in serum IgM value was not Even in an endemic area, the diagnosis of DTB/MTB can be
statistically significant. The mean BAL fluid IgG, IgA values difficult as the clinical symptoms have been non-specific, the
showed a decline following anti-TB treatment, but the chest radiographs do not always reveal the classical miliary
difference did not attain statistical significance. Although changes and atypical presentations such as ARDS, and
BAL fluid IgM did not show a significant fall with anti-TB shadows larger than miliary on chest radiograph commonly
treatment, the mean post-treatment value in MTB patients occur. In patients with suspected DTB/MTB, attempts must
was quite close to the mean in normal control subjects. be made to ascertain histopathological/microbiological
Sharma et al (97) postulated that elevation of IgM occurred diagnosis. Sputum, pleural fluid, cerebrospinal fluid, urine,
in the acute and active phase of the infection only, whereas, bronchoscopic secretions, blood and histopathological
IgG and IgA continued to be raised even after apparent cure examination of tissue biopsy specimens have all been
of infection. These increased levels were thought to be due to employed to confirm the diagnosis of DTB/MTB with
persistent mycobacterial antigenic stimulus. Increased BAL varying results [Tables 29.8A, 29.8B and 29.8C] (42,49-53,102).
fluid fibronectin (97,101) and serum complement [C3] (97)
have also been described in patients with MTB. The increase
Molecular Methods
in serum C3 has been thought to be the result of “acute phase
response” to ongoing inflammation and elevated BAL fluid In patients with DTB/MTB, the usefulness of molecular
fibronectin compared with peripheral blood suggested local methods like cartridge-based nucleic acid amplification tests
synthesis in the lung. [CBNAAT] [e.g., Xpert MTB/RIF, line probe assay] in the
 402 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

C
Figure 29.14: CECT of the chest of a young woman who presented with low-grade fever for 3 months, cough and dysphagia showing subcarinal
[A] and right hilar [B] lymph nodes. Arrows point to hypodensities which indicate necrosis in the lymph nodes. CECT of the abdomen of the same
patient showing bilateral psoas abscesses [C] [arrows]. Coronal reconstruction of the CECT of the abdomen of the same patient showing bilateral
psoas abscesses [D] [arrows]. CT guided fine needle aspirate from the psoas abscess revealed numerous acid-fast bacilli
CECT = contrast-enhanced computed tomography; CT = computed tomography
Reproduced with permission from “Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53 (reference 3)”

field setting needs to be established. Although a positive pattern, it is a common practice to start the anti-TB treatment
molecular diagnostic method can support the diagnosis in straight-away keeping in mind the potential lethality of the
the appropriate clinical setting, a negative test cannot rule condition. Measures to confirm the diagnosis are initiated
out DTB/MTB and treatment should not be withheld just simultaneously.
because of negative test[s] (3,103a). Sharma et al (52) suggest the following criteria for the
In geographical areas where the prevalence of TB is diag­nosis of MTB: [i] clinical presentation consistent with
high, when a patient presents with a compatible clinical a diagnosis of TB such as, pyrexia with evening rise of
picture and a chest radiograph suggestive of classical miliary temperature, weight loss, anorexia, tachycardia and night
 Disseminated/Miliary Tuberculosis 403

A B
Figure 29.15: Tuberculosis of the spleen. CECT of the abdomen [A] showing multiple hypodense lesions in the spleen. CECT of the abdomen [B]
showing multiple hypodense lesions in the spleen [black arrows] and liver [white arrows]

sweats of greater than six weeks duration responding to Table 29.8A: Body fluids and tissues commonly
anti-tuberculosis treatment; [ii] classical miliary pattern on tested for diagnostic confirmation in miliary/
chest radiograph; [iii] bilateral diffuse reticulonodular lung disseminated TB
lesions on a background of miliary shadows demonstrable
Fluids
either on plain radiograph or HRCT; and [iv] microbiological
 Sputum {spontaneously expectorated, induced with hypertonic
or histopathological evidence of TB. [3% or 5% saline]}
The following criteria (1) have been suggested for the
Bronchoscopic specimens
diagnosis of DTB: [i] clinical features suggestive of TB; Aspirate
[ii] concurrent involvement of at least two non-contiguous Washings
organ sites; or demonstration of Mtb in the blood, or, bone Brush smear
marrow; [iii] microbiological and/or histopathological Bronchoalveolar lavage [BAL] fluid
evidence of TB; [iv] marked improvement on anti-TB Transbronchial lung biopsy [TBLB]
therapy. Cerebrospinal fluid
Pleural fluid
Differential Diagnosis Pericardial fluid
Many conditions that can present with a miliary pattern on Peritoneal fluid
the chest radiograph [Figure 29.16] are shown in Table 29.9. Gastric lavage*
Pus from cold abscess
TREATMENT Tissues
Lymph node
Untreated, DTB/MTB is uniformly fatal within one
Peripheral†
year (1,5,103,104,105a,105b). Delay in confirmation of the Intrathoracic‡§
diagnosis often leads to delay in the institution of specific Intra-abdominal‡||
anti-TB treatment and significantly contributes to the Peritoneum, omentum||
mortality. A high clinical suspicion and efforts towards Liver
confirming the diagnosis by demonstrating Mtb early in the Bone marrow/bone
Skin lesions
disease are imperative. Lung§
There is no consensus regarding the optimum duration of Operative specimens
treatment in patients with DTB/MTB [Table 29.10] (105-108).
Peripheral blood¶
According to the World Health Organization [WHO]
guidelines (105a) patients with MTB receive six months of * Often used in children
† FNAC/excision biopsy
standard anti-TB treatment. The WHO guidelines (105a)
‡ Radiologically guided FNAC/biopsy
mention that some experts recommend 9-12 months of § Mediastinoscopic/video-assisted thoracoscopic surgery, biopsy
treatment for TB meningitis and indicate 9 months of || Laparoscopic biopsy
treatment when bone and joint TB is also present. The ¶ Useful in advanced HIV infection
recently published American Thoracic Society [ATS], TB = tuberculosis; FNAC = fine needle aspiration cytology;
the Centers for Disease Control and Prevention [CDC], HIV = human immunodeficiency virus
404 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 29.8B: Confirmation of diagnosis by conventional methods in adults with MTB*

Prout and Kim et al Willcox et al Maartens et al Sharma et al Al-Jahdali et al Cumulative
Variable Biehl (42) Benatar (49) (50) (102) (51) (52) (53) yield [%]
Sputum† 13/26 31/39 25/33 ND 29/75 10/88 6/22 41.4
Bronchoscopy‡† ND 3/3 12/19 34/41 38/95 2/37 7/10 46.8
Gastric lavage† 20/35 ND 6/8 ND 7/11 ND ND 61.1
CSF† 15/45 1/31 0/26 ND 14/44 ND ND 21.2
Urine† 7/29 3/17 18/27 ND 5/28 ND ND 32.7
Bone marrow§† ND 20/21 9/22 ND 18/22 3/11 8/11 66.7
Liver biopsy ND 12/13 11/12 ND 11/11 6/9 ND 88.9
Lymph node biopsy 3/3 ND ND ND 9/9 16/19 2/2 90.9
* Data are shown as number positive/number tested. Criteria for subjecting the patients to these tests not clearly defined in any of
the studies. Often, more than one test has been performed for confirming the diagnosis. For histopathological diagnosis, presence of
granulomas, caseation and demonstration of acid-fast bacilli have been variously used to define a positive test
† Yield from smear and culture
‡ Includes yield from bronchoscopic aspirate, washings, brushings, bronchoalveolar lavage and transbronchial lung biopsy
§ Yield from aspiration and/or trephine biopsy
MTB = miliary tuberculosis; CSF = cerebrospinal fluid; ND = not described

Table 29.8C: Characteristic body fluid findings in DTB/MTB

Variable Pleural fluid Ascitic fluid Pericardial fluid Cerebrospinal fluid
Appearance Straw coloured Straw coloured Straw coloured or serosanguineous Clear early;
Turbid with chronicity
cob web formation
Cell count
Total count [/mm3] 1000-5000 150-4000 Not well described. Leucocyte count 100-500
is usually increased Rarely >1000
Differential count 50% - 90% lymphocytes, Predominantly PMN preponderant early. Later PMN preponderant
eosinophils <5% lymphocytes mononuclear cells predominate early. Later, up to 95%
mononuclear cells
Protein Usually high [>2.5g/dL] Usually high [>2.5 g/dL] Usually high Usually high [100-500
Serum-ascitic fluid mg/dL] Can be very
albumin gradient high with blockage or
[SAAG] <1.1 chronicity
Glucose Usually less than Low Low Usually 40-50 mg/dL
simultaneously collected [about 50% of blood
peripheral blood value glucose]
Smear microscopy < 10% <3% <1% 5%-37%
Mycobacterial culture 12%-70% <20% 25%-60% 40%-80%
DTB = disseminated tuberculosis; MTB = miliary tuberculosis; PMN = polymorphonuclear leucocytes
Adapted from reference 38

the Infectious Disease Society of America [IDSA] (106) [AAP] (107) advocates the use of the standard six-month
guidelines state that six months of treatment is adequate treatment regimen for DTB/MTB as for pulmonary TB.
in MTB. These guidelines (108) also suggest that, when When TB meningitis is present, the AAP Committee on
associated TB meningitis is also present, treatment needs Infectious Diseases (107) recommends an initial intensive
to be given for at least 12 months [2-month intensive phase phase with isoniazid, rifampicin, pyrazinamide and
with isoniazid, rifampicin, pyrazinamide, and ethambutol, ethionamide or an aminoglycoside [in place of ethambutol]
followed by a 7-10 month continuation phase with isoniazid for 2 months, followed by 7-10 months of isoniazid and
and rifampicin] [Table 29.10]. In the absence of associated rifampicin. The National Institute for Health and Clinical
meningeal involvement, the 2015 Report of the Committee Excellence [NICE] (108) guidelines from UK recommend
on Infectious Diseases, American Academy of Pediatrics 6 months of treatment for MTB.
 Disseminated/Miliary Tuberculosis 405

A B

C D
Figure 29.16: Chest radiograph [postero-anterior view] showing miliary pattern in miliary TB [A], pneumoconiosis [B], pulmonary alveolar
microlithiasis [C], and sarcoidosis [D]
TB = tuberculosis

When TB meningitis is present, the evidence-based Corticosteroids

INDEX TB guidelines (109) advocate treatment for at least Sparse published data are available regarding the usefulness
9 months. The evidence-based INDEX TB guidelines (109) of adjunct corticosteroid treatment in patients with MTB
also suggest that when spinal TB and other forms of bone with conflicting results. A beneficial response was observed
and joint TB are present, a total treatment duration of in some studies (110) although such benefit could not
12 months [extendable to 18 months on a case-by-case basis] be documented in others (111). Presence of associated
is indicated.
adrenal insufficiency is an absolute indication for their
There are no published data from randomised controlled
administration. Adjunctive corticosteroid treatment may be
trials assessing the efficacy of the standard WHO treatment
beneficial in MTB with adrenal insufficiency, TB meningitis,
regimens (105a) that are widely used in national TB control
large pericardial effusion, dyspnoea and/or disabling chest
programmes worldwide. Furthermore, there are sparse data
pain, IRIS, ARDS, immune complex nephritis, and histiocytic
regarding the efficacy of standard treatment regimens in the
phagocytosis syndrome (4,103,104).
treatment of DTB/MTB in HIV co-infected patients.
Under the Revised National Tuberculosis Control Anti-retroviral Drugs
Programme [RNTCP] of Government of India, patients with
DTB/MTB get treated with the DOTS. Though this duration The reader is referred to the chapter “Tuberculosis and human
of treatment is adequate in a majority of the patients, each immunodeficiency virus infection” [Chapter 35] for details
patient needs to be assessed individually, and wherever regarding this topic.
indicated, treatment duration may have to be extended.
The reader is referred to the chapter “Treatment of
COMPLICATIONS
tuberculosis” [Chapter 44], for further details regarding treat­ Complications are often self-limited and improve with
ment of DTB/MTB. anti­tuberculosis treatment alone. However, at times these
406 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 29.9: Common causes of fever with a miliary can be life-threatening, necessitating prompt recognition
pattern on chest radiograph and treatment. Important complications in patients with
MTB include airleak syndromes [e.g., pneumothorax,
Infections
Mycobacteria
pneumopericardium], ARDS, anti-TB drug induced hepa­
Tuberculosis totoxicity, and fulminant hepatic failure. Rarely, cardio­
Fungal infections vascular complications such as myocarditis, congestive
  Histoplasmosis
Blastomycosis
Coccidioidomycosis Table 29.10: Anti-TB drug regimens for drug-
Cryptococcosis susceptible miliary/disseminated TB
Bacteria Guideline [year] Anti-TB drug regimen
Legionellosis (reference)
Staphylococcus aureus bacteraemia
WHO [2010] (105a) 2 months of RHZE + 4 months of RH*
Mycoplasma pneumonia
2 months of RHZE + 7-10 months of RH* if
Nocardiosis
TBM is also present
Melioidosis
2 months of RHZE + 7 months of RH* if bone
Tularaemia
and joint TB is also present
Psittacosis
Brucellosis ATS/CDC/IDSA 2 months of RHZE + 4 months of RH
Parasites [2016] (106) 2 months of RHZE + 7-10 months of RH if
Toxoplasmosis TBM is also present
Strongyloides stercoralis hyperinfection NICE [2016] (108) 2 months of RHZE + 4 months of RH
Schistosomiasis 2 months of RHZE + 10 months of RH if TBM
Immunoinflammatory disorders is also present
Sarcoidosis TB = tuberculosis; WHO = World Health Organization; ATS = American
Pneumoconiosis Thoracic Society; CDC = Centers for Disease Control; IDSA = Infectious
Disease Society of America; NICE = National Institute for Health and
Malignant Clinical Excellence; TBM = tuberculosis meningitis; TB = tuberculosis;
Bronchoalveolar carcinoma Cy = cycloserine; E = ethambutol; Eth = ethionamide; H = isoniazid;
Carcinoma lung with lymphangitis carcinomatosa K = kanamycin; P = para-aminosalicylic acid; R = rifampicin; S =
Bronchial carcinoid streptomycin; Z = pyrazinamide
Metastatic carcinoma * Continuation phase consists of RHE in countries with high levels
Lymphoproliferative disorders of H resistance in new TB patients, and where H drug-susceptibility
Lymphoma testing in new patients is not done [or results are unavailable] before
Lymphomatoid granulomatosis the continuation phase begins

Table 29.11: Predictors of poor outcome in patients with DTB/MTB

Study (reference) Year of publication Predictors of poor outcome
Gelb et al (45)* 1973 Stupor, meningismus, increasing age, cirrhosis of liver, leucopenia, leucocytosis
Grieco and Chmel (46) 1974 Increasing age, presence of underlying disease, history of cough, night sweats
Kim (50) 1990 Female gender, altered mental status
Maartens (51) 1990 Age > 60 years, lymphopaenia, thrombocytopaenia, hypoalbuminaemia, elevated
transaminase levels, treatment delay
Sharma (52) 1995 Dyspnoea, chills, temperature >39.3 oC, icterus, hepatomegaly, hypoalbuminaemia,
hyponatraemia, elevated serum alkaline phosphatase
Long (20) 1997 Presence of one or more risk factors†
Mert (40) 2001 Male gender, presence of atypical chest radiographic pattern, delay in instituting
anti-TB treatment
Hussain (41) 2004 Presence of altered mental status, lung crackles, leucocytosis, thrombocytopaenia
and the need for ventilation
Wang (2)‡ 2007 Hypoalbuminaemia, hyperbilirubinaemia, renal insufficiency, and delay in instituting
anti-TB treatment
Lee (112) 2014 Extent of ground-glass opacity >50%§
* No statistical analysis was performed
† Listed in Table 29.2
‡ DTB
§ Significantly associated with a delay in diagnosis, longer hospital stay, acute respiratory failure; but there was no difference in mortality
DTB = disseminated tuberculosis; MTB = miliary tuberculosis
 Disseminated/Miliary Tuberculosis 407

A B
Figure 29.17: Mortality in children with miliary tuberculosis [A]. Data derived from Kim et al (23), Aderele (55), Rahajoe (56), Hussey et al (21),
Gurkan et al (26). Mortality in adults with miliary tuberculosis [B]. Data derived from Biehl (42), Munt (43), Gelb et al (45), Grieco and Chmel (46),
Onadeko et al (47), Prout and Benatar (49), Kim et al (50), Maartens et al (51), Sharma et al (52), Long et al (20), Al-Jahdali et al (53), Hussain
et al (41)

heart failure, infective endocarditis, pericarditis, intracardiac 9. Sharma SK, Mohan A. Miliary tuberculosis. In: Agarwal AK,
mass, mycotic aneurysm, and sudden cardiac death have editor. Clinical medicine update – 2006. New Delhi: Indian
been described in MTB and should be carefully examined Academy of Clinical Medicine; 2006.p.353-60.
10. Hill AR, Premkumar S, Brustein S, Vaidya K, Powell S, Li P-W,
for (4,103,104). et al. Disseminated tuberculosis in the acquired immuno­
deficiency syndrome era. Am Rev Respir Dis 1991;144:1164-70.
PROGNOSIS 11. Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection:
epidemiology, diagnosis & management. Indian J Med Res
Predictors of poor outcome in DTB/MTB are shown in 2005;121:550-67.
Table 29.11. The mortality related to MTB [Figure 29.17] is 12. Lewison M, Frelich EB, Ragins OB. Correlation of clinical
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Several studies have attempted to identify predictors of
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 30
Tuberculosis at Uncommon Body Sites
Y Mutheeswaraiah, J Harikrishna

TUBERCULOSIS OF THE BREAST EPIDEMIOLOGY

Introduction TB of the breast is thought to be rare because the environment
in the breast does not favour survival and multiplication of
Primary tuberculosis [TB] of the breast is uncommon (1). As
Mycobacterium tuberculosis [Mtb] (2). The first case of breast
the clinical presentation and radiological manifestations are
TB was reported by Sir Astley Cooper in 1829 who called it
non-specific, TB of the breast is a diagnostic problem faced
“scrofulous swelling of the bosom” (13). Since the report of
by clinicians (2-8).
the first case of TB mastitis from India in 1957 (14), there have
been occasional reports on breast TB from India (2,10-11,15-22).
Pathogenesis In developing countries, the incidence of breast TB in
Breast TB could be the only manifestation of TB, or it can surgically resected specimens was found to be 3%-4.5% (23).
occur secondary to TB elsewhere in the body (9-11). The The prevalence of breast TB in India has varied between
postulated mechanisms for the development of breast TB 0.6%-3.6% (2,11,22). A high prevalence of breast TB [5.2%
are shown in Table 30.1. Of these, centripetal lymphatic of all breast diseases; 32% of all infective conditions] has
spread from lungs to breast tissue appears to be the most been reported from India (24). In low TB burden countries,
likely mechanism for the development of breast TB (2,9,12). the prevalence of breast TB is less than 0.1% among breast
Retrograde lymphatic spread from axillary, cervical, lesions examined histopathologically (25,26).
paratracheal and internal mammary lymph nodes can also
cause breast TB (10,11). Direct extension of infection from Clinical Presentation
adjacent ribs, sternum, costal cartilages pleura, chest wall TB of the breast is commonly seen in young women in the
and direct inoculation from abrasions in skin are other reproductive age group; it is rarely seen in the prepubertal
postulated mechanisms (2,9-11). age group and in older women (1,2,24). Breast TB is more
common in pregnant and lactating women because of high
Table 30.1: Pathogenetic mechanisms for vascularity, dilated ducts and higher likelihood of occurrence
development of breast TB trauma (2,10,24). Spread of infection from the tonsils of
Haematogenous spread the suckling infant to the mother’s nipple, and from there
Spread via the lymphatics
to the lactating breast via lactiferous ducts has also been
Centripetal spread via lymphatics from the lung postulated (27). Breast TB is rare in males (28,29).
 Retrograde lymphatic spread from axillary, paratracheal and Breast TB commonly presents as a unilateral disease
internal mammary lymph nodes [Figure 30.1]. Bilateral involvement is very rare being
Direct extension from contiguous structures reported in less than 3% of the cases [Figure 30.2] (10). The
Direct inoculation symptom duration varies from a few months to several
years (1,2,7,8,24). TB of the breast frequently presents as a
Ductal infection
lump in the central or upper outer quadrant of the breast
TB = tuberculosis [Figure 30.1]. The lump may be tender, mobile or fixed to
 412 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 30.1: Clinical photograph showing left breast lump [arrow] and Figure 30.2: Bilateral breast TB. Clinical photograph showing ulcerating
nipple retraction. Histopathological examination and mycobacterial lesions in both the breasts [arrows]. Histopathological examination
culture confirmed the diagnosis of breast TB confirmed the diagnosis of breast TB
TB = tuberculosis TB = tuberculosis

skin, muscle or the chest wall. Clinically, the lump of breast condition presents as a well-circumscribed, slowly growing,
TB is irregular, ill-defined, hard in consistency mimicking usually painless mass mimicking a fibroadenoma of the
breast carcinoma (1,2,7,8,24). Sometimes, nipple retraction breast. The disease progresses to involve the overlying skin;
and peau d’orange appearance may also be seen [Figure 30.3]. ulceration, sinus formation, may develop and the condition
An ulcer in the skin overlying the breast and breast abscess may resemble breast carcinoma (30-33).
have also been described [Figures 30.4, 30.5 and 30.6]. In Disseminated or confluent TB mastitis is rare. It presents
patients with axillary lymphadenitis, breast oedema may with multiple foci throughout the breast that may later
be evident (1,2,7,8,24). undergo caseation necrosis resulting in sinus formation.
When a patient presents with a breast abscess which fails The breast may be tense and tender, overlying skin appears
to heal in spite of adequate surgical drainage and antibiotic thickened and stretched; painful ulcers may sometimes be
therapy, especially when persistent discharging sinuses are seen. Matted axillary lymph nodes are often evident (33).
present underlying TB should be suspected. Sclerosing TB mastitis characterised by excessive fibrosis
Breast TB has been classified into different types (9). The affects involuting breasts of older women. This condition
most common form of breast TB is nodular TB mastitis. This presents as a hard painless slowly growing lump with nipple

Figure 30.3: Clinical photograph showing a breast lump with shiny Figure 30.4: Clinical photograph showing a breast lump, overlying
overlying skin and peau de orange appearance mimicking breast ulceration [arrow] and nipple retraction. Histopathological examination
carcinoma [thick white arrow] and multiple ulcers [thin white arrows] confirmed the diagnosis of breast TB
and nipple retraction. Histopathological examination and mycobacterial TB = tuberculosis
culture confirmed the diagnosis of breast TB
TB = tuberculosis
 Tuberculosis at Uncommon Body Sites 413

A B
Figure 30.5: Clinical photograph showing an ulcer [black arrow] in the left breast and a sinus in the chest wall [white arrow] [A]. Operative
photograph of the same patient [B] showing the sinus tract. Histopathological examination confirmed the diagnosis of TB
TB = tuberculosis

retraction resembling a schirrotic carcinoma (33). TB mastitis Chest Radiograph

obliterans is characterised proliferation of lining epithelium
The chest radiograph may show evidence of active or old
of the ducts, marked epithelial and periductal fibrosis.
healed pulmonary TB or miliary TB (22). Calcified axillary
Occlusion of ducts results in formation of cystic spaces and
lymph nodes may sometimes be evident on the chest
the condition mimicks cystic mastitis. Rarely, breast TB may
radiograph (34).
develop in patients with miliary TB.
Mammography
Diagnosis
In breast TB, various mammographic findings, such as, mass,
Diagnostic work-up is aimed at establishing TB as the
coarse calcification, asymmetric density with spiculated
aetiological diagnosis and ruling out other conditions,
margin, skin thickening, nipple retraction and axillary
especially breast cancer.
lymphadenopathy have been described (35). When TB
abscess is present, a dense tract connecting an ill-defined
Tuberculin Skin Test breast mass to a localised skin thickening and bulge may be
A positive tuberculin skin test [TST] is frequently evident. seen (36). The mammographic features of nodular breast TB
However, a positive TST indicates infection with Mtb and closely resembles breast carcinoma. Disseminated TB mastitis
is not considered to be a marker for active TB. mimicks inflammatory carcinoma. In sclerosing TB mastitis,
a homogeneous dense mass with fibrous septae and nipple
retraction is seen (10,33). However, mammography alone
cannot distinguish breast TB from breast cancer (35-38).

Ultrasonography
On breast ultrasonography, the features of breast TB are
non-specific (39). Ultrasonography is useful in differentiating
cystic from solid breast masses. It may also show a fistulous
connection between retromammary abscess and chest
wall (36,40,41). Ultrasonography-guided fine needle aspiration
can be done for procuring tissue for cytopathological,
microbiological and molecular studies (37).

Computed Tomography
Computed tomography [CT] is helpful in defining the extent
of thoracic wall involvement especially in patients presenting
Figure 30.6: Clinical photograph showing a discharging sinus in the left
breast [arrow]. Histopathological examination confirmed the diagnosis with a deeply adherent breast lump (42,43). On CT, TB
of breast TB abscess appears as smoothly marginated, inhomogeneous,
TB = tuberculosis hypodense lesions; surrounding rim-enhancement may be
414 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

seen on contrast-enhanced CT. Underlying rib osetomyelitis, Differential Diagnosis

fistulous connection with the pleura may also be seen on
CT (41). Further, involvement of pleural disease, pulmonary Clinical examination, imaging findings cannot reliably
parenchyma, intrathoracic and axillary lymph nodes may distinguish breast TB from breast cancer. Sometimes, co-
also be detected on CT (43,44). incidental occurrence of TB and carcinoma of the breast is
known; granulomatous lymphadenitis in the axillary has
Magnetic Resonance Imaging been reported in patients with breast cancer (31,32).

Some investigators have described the magnetic resonance Treatment

imaging [MRI] findings in breast TB (39,44-47). On T2-
weighted gadolinium diethylenetriaminepentaacetic acid The management of breast TB consists of administration of
[Gd-DTPA] enhanced MRI images, breast abscess appears standard anti-TB treatment and surgery in certain situations.
as a smooth or irregular ring like bright signal intensity. Anti-TB treatment is the mainstay of therapy. The standard
Further, MRI is useful in delineating the extramammary six-month anti-TB treatment is considered adequate for
involvement as well. However, these findings are not specific most of the patients; in some patients, the treatment may
to TB and may also be seen in bacterial and fungal abscesses have to be extended by further three months (1,2,24,15,57).
and breast carcinoma (39,44-47). In a recent retrospective study (58) 33 of the 46 [72%]
patients responded to the standard six-month therapy while
Positron Emission Tomography treatment extension to 9-12 months was required in 13 [28%]
cases. The reader is referred to the chapter “Treatment of
There are a few reports of the utility of positron emission tuberculosis” [Chapter 44] for more details.
tomography [PET]-CT in the diagnosis of breast TB. Intense
focal fluorodeoxy glucose [FDG] uptake mimicking breast
Surgical Treatment
cancer has been described (48-50). However, PET-CT or PET-
MRI findings alone cannot distinguish breast TB from breast Surgery may be required for excisional biopsy, drainage of
cancer. Procurement of breast tissue for further diagnostic abscess, procuring biopsy from abscess wall, management of
testing is required to ascertain the diagnosis of TB as the sinuses in the breast; segmentectomy and occasionally simple
aetiological cause. mastectomy (1,2) have been employed. For large ulcerating
masses involving the entire breast and the draining axillary
Fine Needle Aspiration Cytology lymph nodes, simple mastectomy with or without axillary
clearance is required. Modified radical mastectomy is
Fine needle aspiration cytology [FNAC] from the breast
considered only if is a co-existing malignancy is present.
lump has been used to diagnose breast TB (51-54). On
FNAC, features of granulomatous mastitis like epithelioid
cell granulomas, necrosis are present (1); acid-fast bacilli FEVER OF UNKNOWN ORIGIN
[AFB] may also be seen sometimes (51-54). In TB breast Since the initial classical description by Petersdorf and
abscess, the FNAC picture may be dominated by an acute Beeson (59), fever of unknown origin [FUO] is a common
inflammatory exudate. In this situation presence of AFB or diagnostic problem faced by clinicians. As defined by Durack
histopathological evidence of TB is considered to be evidence and Street (60), FUO is diagnosed based on the presence of
of breast TB (51). all of the following criteria: [i] temperature of greater than
38.3°C [>101°F] on several occasions; [ii] duration of fever
Open Biopsy more than 3 weeks; and [iii] a failure to reach a diagnosis
When the FNAC examination is inconclusive open [incision despite three outpatient visits or three days in the hospital
or excision] biopsy, or biopsy from the wall of the abscess without elucidation of a cause or one week of “intelligent
is helpful (1). Histopathological examination reveals and invasive” ambulatory investigation.
granulomatous inflam­mation and must be distinguished
from other granulomaotus disorders like fungal infection Epidemiology
and sarcoidosis.
TB is an important cause of FUO especially in areas where
TB is highly endemic. In patients presenting with FUO,
Microbiological, Molecular Methods
atypical clinical presentation of TB is common. Focal
Breast tissue procured for diagnostic testing should be extrapulmonary TB, disseminated TB and miliary TB that is
subjected to smear and mycobacterial culture examination, not evident initially, but, becomes evident during the course
as well as molecular diagnostic testing (55). The conventional of evaluation are common.
diagnostic testing methods like smear for AFB and In studies conducted at Kolkata (61,62), New Delhi (63)
mycobacterial culture, have a low yield in breast TB. The and Tirupati (64) from India documented that TB was the
scope of using cartridge-based nucleic acid amplification most common cause for FUO. Kejriwal et al (61) in their
tests [CBNAAT] like Xpert MTB/RIF in the diagnosis of study of FUO [n=100] reported that TB was the aetiological
breast TB merits further study (56). cause in 24% of patients. Bandyopadhyay et al (62) studied
 Tuberculosis at Uncommon Body Sites 415

164 patients with FUO and documented that in 46 [28%] with FUO in whom laboratory diagnostic testing is non-
patients, TB was the aetiological cause. In the study from contributory, aspiration and trephine biopsy of the bone
New Delhi [n = 121], Handa et al (63) reported that extra- marrow, cytopathological and histopathological examination
pulmonary TB [n = 26; 21.5%] was a common cause of FUO. [Figure 30.13] and molecular diagnostic testing of the
In the recent study from Tirupati (64), TB was found to be obtained material with Xpert MTB/RIF can be helpful in
aetiological cause in 19 of the 45 [42%] patients with FUO. confirming TB as the aetiological diagnosis.

Diagnosis Treatment
A careful physical examination, and daily re-examination, In resource limited, TB endemic areas, when all FUO
may reveal valuable clues to TB as the aetiology [Figures 30.7, diagnostic work-up including bone marrow examination
30.8, 30.9, 30.10, 30.11, 30.12 and 30.13]. Imaging modalities, is inconclusive, clinicians often resort to a therapeutic
such as ultrasonography, CT, MRI and especially, PET-CT trial with anti-TB treatment as many clinicians consider
are useful to localise the disease site. Diagnosis is confirmed the therapeutic benefits outweigh the risk of adverse
by procuring appropriate tissue/body fluids for diagnostic events (65,66). In patients in whom the diagnosis of TB
testing under image-guidance. has been established, depending on the site and extent of
Molecular testing with CBNAAT like Xpert MTB/RIF involvement, standard anti-TB treatment, that may have to
is helpful in early confirmation of diagnosis. In patients be extended in the individual patient yields good results.

Figure 30.7: Clinical photograph of a patient who presented with fever Figure 30.8: Clinical photograph of a patient who presented with
of unknown origin showing a sinus in the left upper inner thigh [black prolonged low grade fever showing a discharing sinus in the right side
arrow] and left sided external iliac lymphadenopathy. Histopathological of the neck [arrow]. Histopathological examination was suggestive of
examination confirmed the diagnosis of TB granulomatous inflammation; pus on Xpert MTB/RIF testing showed
TB = tuberculosis Mycobacterium tuberculosis sensitive to rifampicin

Figure 30.9: Clinical photograph of a patient who presented with Figure 30.10: Clinical photograph of a patient presenting with
prolonged low grade fever showing multiple discharing sinuses in the prolonged fever showing ulcers with undermined margins [arrows] in
upper left thigh [arrows]. Histopathological examination confirmed the the upper inner thigh. Histopathological examination confirmed the
diagnosis of TB diagnosis of TB
TB = tuberculosis TB = tuberculosis
 416 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 30.11: Clinical photograph showing multiple sinuses [square] in Figure 30.12: Clinical photograph showing multiple ulcers with
the gluteal region. Xpert MTB/RIF examination of material discharging undermined margins [black arrows] and sinuses [white arrows] in the
from the sinuses detected Mycobacterium tuberculosis sensitive to gluteal region. Histopathological examination confirmed the diagnosis
rifampicin of TB
TB = tuberculosis TB = tuberculosis

A B
Figure 30.13: Photomicrograph of trephine biopsy of bone marrow in a patient presenting with fever of unknown origin in whom all laboratory
and imaging testing was inconclusive showing ill-defined epithelioid granuloma with fatty spaces and bony trabeculae [Haematoxylin and
eosin, × 200] [A]; and Langhans’ giant cells amidst fatty spaces [Haematoxylin and eosin, × 200] [B] suggestive of disseminated TB. Mycobacterial
culture grew Mycobacterium tuberculosis
TB = tuberculosis

TUBERCULOSIS PYOMYOSITIS CT and MRI are helpful in localising the disease. TB

pyomyositis must be distinguished from pyogenic bacterial,
TB pyomyositis is an extremely rare form of extrapulmonary
or fungal abscesses, haematoma and neoplasms. Diagnosis
TB. It has been documented in immunocompromised
is established by micro­biological and molecular testing of
indi­v iduals (67-69). There are occasional reports of TB
the aspirated pus. Treat­ment consists of standard anti-TB
pyomyositis in immunocompetent individuals also (70-72).
treatment that may have to be extended in the individual
In human immunodeficiency virus-seropositive individuals,
patient. Effective drainage of the abscess is done by anti-
occurrence of TB pyomyositis as a component of immune
gravity aspiration. When these measures fail, surgical
reconstitution inflammatory syndrome has also been
exploration may be required (72).
documented (73). The disease is characterised by the
formation of an abscess in the skeletal muscle. The rare
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58. Kilic MO, Sağlam C, Ağca FD, Terzioğlu SG. Clinical, diagnostic
70. Sen RK, Tripathy SK, Dhatt S, Saini R, Aggarwal S, Agarwal A.
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60. Durack DT, Street AC. Fever of unknown origin—reexamined et al. A case of tuberculous pyomyositis that caused a recurrent
and redefined. Curr Clin Trop Infect Dis 1991;11:35-51. soft tissue lesion localized at the forearm. Jpn J Infect Dis 2005;58:
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Pyrexia of unknown origin: a prospective study of 100 cases. 72. Narang S. Tuberculous pyomyositis of forearm muscles. Hand
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62. Bandyopadhyay D, Bandyopadhyay R, Paul R, Roy D. Etiological 73. Chen WL, Lin YF, Tsai WC, Tsao YT. Unveiling tuberculous
study of fever of unknown origin in patients admitted to pyomyositis: an emerging role of immune reconstitution
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63. Handa R, Singh S, Singh N, Wali JP. Fever of unknown origin: a Tuberculosis presenting as multiple intramuscular nodules in a
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 31
Complications of Pulmonary Tuberculosis
D Behera

INTRODUCTION the initial manifestation of active TB, during the course of

treatment, or, even after the disease is apparently cured.
Complications of pulmonary tuberculosis [TB] significantly
Haemoptysis can be streaky or massive and life-threatening.
contribute to morbidity and mortality of patients and are
Massive haemoptysis may be associated with atelectasis
listed in Table 31.1.
[Figure 31.1]. Important causes of haemoptysis in patients
with pulmonary TB are listed in Table 31.2.
HAEMOPTYSIS Walls of a TB cavity may be affected by inflammation
Haemoptysis is a common and potentially serious and necrosis and may become atrophic. Increased pressure
complication of pulmonary TB (1-4). The incidence of can lead to weakening of the walls, dilatation of blood
haemoptysis in patients with pulmonary TB is reported to vessels and formation of Rasmussen’s aneurysms (5,6)
range from 30%-35% (1-3). Occurrence of haemoptysis does [Figure 31.2]. Further, these blood vessels rupture due to
not imply that the TB is active. Haemoptysis may occur as increased pressure during strenuous exercise or coughing

Table 31.1: Complications of pulmonary TB

Local
Pulmonary
  Haemoptysis
  Post-TB bronchiectasis
   Fungal ball [aspergilloma]
   TB endobronchitis and tracheitis
  Scar carcinoma
Disseminated calcification of the lungs
Pulmonary function changes, obstructive airways disease
Secondary pyogenic infections
   Nontuberculous mycobacterial disease
Pleural
  Spontaneous pneumothorax
Pleural thickening [fibrothorax] A B
   Acute and chronic empyema Figure 31.1: Chest radiograph [postero-anterior view] of a patient
Systemic who presented with massive haemoptysis showing collapse of the
left lung [A]. Chest radiograph [postero-anterior view] of the same
Secondary amyloidosis
patient following vigorous chest physiotherapy and suction showing
Chronic respiratory failure [Type I and Type II]
bilateral clearance of both the lung fields. Sputum smear revealed
Pulmonary hypertension
Mycobacterium tuberculosis [B]
Chronic cor-pulmonale
Reproduced with permission from “Sharma SK, Mohan A. Pulmonary
TB = tuberculosis tuberculosis: typical and atypical cases. Case track series 1. Mumbai:
Merind; 1997 (reference 3)”
 420 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and can result in haemoptysis [Figure 31.3]. The vessel walls in patients with active TB. However, if the bleeding is
can also be eroded directly either because of endarteritis, massive, and repetitive, fibreoptic bronchoscopy [to localise
or, vasculitis secondary to TB. Sometimes intense allergic the site of bleeding] and high resolution computed tomo­
response to antigen[s] of Mycobacterium tuberculosis [Mtb] graphy [HRCT] are performed. Angiography along with
damages the vessel wall and gives rise to haemoptysis. bronchial artery embolisation is done in patients with
Bleeding from TB granulomas in the bronchi can result in massive haemoptysis [Figure 31.4] (7-9). Bronchial artery
haemoptysis. Blood vessels with aneurysmal dilatation and embolisation [BAE] is a good and relatively safe procedure in
accentuated bronchopulmonary communications are present the management of haemoptysis due to pulmonary TB. The
surrounding these granulomas. In this setting, the bronchial risk of re-bleeding after BAE in active or inactive pulmonary
blood vessels which are under systemic pressure can be the TB is high, particularly in patients with destroyed lung,
source of bleeding. All these factors should be taken into chronic liver disease, the use of anticoagulant agents and/
consideration while managing haemoptysis in patients with or antiplatelet agents, elevated pre-BAE C-reactive protein
TB. [CRP], and the existence of fungal ball (10). Rarely, resection
In most instances bed rest, sedation, and resuscitative of the site of bleeding may be indicated (11-13).
measures aimed at restoring fluid balance and haemodynamic
status control the bleeding. Patients presenting with massive
haemoptysis [> 600 mL of blood in 24 hours] may become ASPERGILLOMA [MYCETOMA; “FUNGUS BALL”]
haemodynamically unstable and require blood transfusion. Mycetoma is a mass of fungal hyphal material that grows
Broad spectrum antibiotics are administered to treat super- in a lung cavity. Although other fungi like Zygomycetes
added bacterial infection. Anti-TB treatment is indicated [mucor] and Fusarium may cause the formation of a fungal
ball, Aspergillus species, particularly, Aspergillus fumigatus,
are by far the most common aetiological agents. The overall
Table 31.2: Causes of haemoptysis in pulmonary TB incidence of aspergilloma in general population has been
Bleeding from cavity wall estimated to be between 0.01% in Great Britain to 0.017% in
Rupture of Rasmussen’s aneurysm the USA (14,15). In a large multicentric study by the British
Direct erosion of capillaries or arteries by granulomatous Tuberculosis Association (14), which surveyed 544 patients
inflammation with healed TB cavities on chest films, measuring 2.5 cm
TB endobronchitis or greater in diameter, 25% had precipitins to Aspergillus
Post-TB bronchiectasis in serum and radiographic evidence of aspergilloma
Aspergilloma was present in 11% patients. Aspergilloma occurred as
frequently in patients with recently healed TB as in those
Broncholith, cavernolith
with inactive disease for long periods (14). A follow-up
Scar carcinoma
study (15) of this group, 3 years after the first survey,
TB = tuberculosis revealed an increase in incidence of aspergilloma to 17%.

A B
Figure 31.2: Rasmussen’s aneurysm. Dynamic and three-dimensional views of the pulmonary and bronchial vasculature on computed tomography
obtained after the injection of contrast material demonstrated a large pulmonary aneurysm [A and B, arrows] obtained from a 54-year-old man
who presented with a 3-month history of haemoptysis. The patient underwent successful embolisation of the pulmonary artery aneurysm and its
feeding vessel. However, the haemoptysis resolved only after subsequent embolisation of the bronchial artery
Reproduced with permission from “van den Heuvel MM, van Rensburg JJ. Images in clinical medicine. Rasmussen’s aneurysm. N Engl J Med
2006;355:e17 (reference 5)” Copyright [2006] Massachusetts Medical Society. All rights reserved
 Complications of Pulmonary Tuberculosis 421

The new aspergilloma cases were generally patients who Clinical Features
had only serum precipitins during the first survey (14,15).
The fungus ball may be present for long periods without
Aspergillomas have been identified in cavities associated
any clinical symptoms and may be an incidental finding
with TB, histoplasmosis, sarcoidosis, bronchial cysts, bullae,
in majority of cases and the lesion remains stable. In
neoplasms, pulmonary infarctions, asbestosis, ankylosing
approximately 10% of cases, it may increase in size or
spondylitis, bronchiectasis, and malignant diseases (16,17).
resolve spontaneously without treatment (21). Rarely, the
Of these, TB is the most frequently associated condition (18).
aspergilloma increases in size (14). But eventually, most of
Occasionally, these are described in cavities due to other
these will manifest with some symptoms. The most common
fungal infections (19,20).
presentation in such cases is haemoptysis and the estimated
The natural history of an aspergilloma is highly variable
and it may remain stable, increase in size or spontaneously frequency varies from 5%-90%. The amount may be very
resolve. In the early phase of its development, the fungus ball minimal to severe particularly in patients with associated
grows inside a lung cavity consisting of both living and dead TB (22). Bleeding usually occurs from the bronchial blood
fungus. The future course depends upon the predominance vessels. The exact cause of haemoptysis associated with
of these living or dead fungi. If local conditions favour death, aspergilloma is not certain, but has been ascribed to [i]
the fungus ball liquefies and the secretions are expectorated mechanical friction of mycetoma; [ii] an endotoxin with
out. Calcification occurs less frequently. haemolytic properties; [iii] an anticoagulant factor derived
from Aspergillus; [iv] local vasculitis; and [v] direct vascular
invasion in cavity wall vessels (23-26). The mortality rate
varies between 2%-14%. Other features include chronic
cough, weight loss, and rarely fever and dyspnoea (23-26).
Risk factors associated with poor prognosis of
aspergilloma include severe underlying disease, increasing
size or number of lesions as seen on chest radiograph,
immunocompromised state including corticosteroid therapy,
increasing Aspergillus-specific immunoglobulin G [IgG]
titres, recurrent large volume haemoptysis, and underlying
sarcoidosis or human immunodeficiency virus [HIV]
infection (27).

Diagnosis
Aspergilloma usually comes to clinical attention as
an incidental finding on a routine chest radiographic
examination or during an evaluation of haemoptysis. The
Figure 31.3: Coronal maximum intensity projection of pulmonary
angiographic image showing hypertrophic and tortous right bronchial typical radiographic appearance of aspergilloma is described
artery [arrow], branches from subclavian artery along with extensive as a bell-like image, with the fungus ball appearing as a
fibrocalcific changes in both upper lobes clapper inside a bell. A semi-circular crescentic air shadow

A B
Figure 31.4: Intra-arterial digital subtraction angiography [IA-DSA] in a patient with right upper lobe pulmonary tuberculosis showing a hypertrophied
intercosto-bronchial trunck [arrow] producing contrast extravasation [asterisk] and pulmonary artery filling in the region of fibrocavitary lesion [A].
The IA-DSA after embolisation with polyvinyl alcohol particles showing obliteration of the angiographic abnormality with patent parent artery [B]
 422 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

appears around the radio-opaque fungus ball located in an aspergilloma due to other Aspergillus species or if the patient
upper lobe lung cavity (28). The fungus ball is mobile and is on corticosteroid therapy (31). Skin tests are less helpful
changes its position as the patient moves, which is best seen and may be positive only in a minority of patients (30). In
on fluoroscopy or by taking chest radiographs or computed some cases bronchoscopy may be helpful in identifying the
tomography [CT] [Figure 31.5] at different positions. A site of bleeding and sometimes one may see the fungus ball
change in position of the aspergilloma with the change in in direct continuity with the bronchial lumen. Bronchial
position of the patient is an interesting but a variable sign (29). washings, brushings and forceps biopsy may be carried out
Occasionally, it may be difficult to recognise the mass on to isolate Aspergillus.
a routine chest radiograph, and tomography or chest CT
may be necessary to visualise the aspergilloma. The adjacent Treatment
pleura may be thickened. The radiographic differential The treatment of aspergilloma is controversial because of
diagnosis includes organised haematoma or pus inside a variability in its natural history. No therapy is warranted
cavity, neoplasm, abscess, Wegener’s granulomatosis and a in asymptomatic cases. Systemic antifungal therapy is
ruptured hydatid cyst. An aspergilloma may co-exist with ineffective in treating these lesions. The antifungal drugs
any of these conditions also. cannot penetrate into the intra­cavitary fungi (32). Attempts
The initial suspicion of a fungus ball is raised from the are made to instil local intrabronchial intra­c avitary or
chest radiograph. Sputum culture may confirm the presence inhalational antifungal agents [amphotericin B, nystatin,
of fungus, but may be negative in about 50% of cases (30). sodium iodide] with varying success (33-35). Systemic
The serum precipitins [IgG antibodies] to Aspergillus antifungal therapy using intravenous amphotericin-B has no
are positive in almost 100% of cases except in cases of effect (36). Itraconazole therapy has been tried with varying

A B

C D
Figure 31.5: CT of the chest [lung window, supine position] showing a cavity in the left upper lobe [A and B] containing a radio-opaque shadow
with a semicircular air crescent around it [arrow] suggestive of a fungal ball [asterisk]. When the CT is repeated with the patient in the prone
position [C and D], the fungal ball can be seen to have changed its position
 Complications of Pulmonary Tuberculosis 423

success (37). Bronchial artery embolisation rarely controls Although TB and sarcoidosis were the most prevalent
haemo­ptysis because of extensive collateral blood vessels. predisposing diseases, a history of Pneumocystis jirovecii
This procedure may, however, be used as a temporary pneumonia and the consequent cavitation was found to be
measure to control massive, life-threatening haemoptysis (38). a risk factor for pulmonary aspergilloma in HIV-infected
Some advocate routine surgery because of the fear of individuals. In HIV-seropositive patients with a CD4+ count
haemoptysis in future. However, the clinical approach of less than or equal to 100 cells/μL, the disease progressed
should be individualised. In some cases the severity of the despite treatment. Compared with HIV-seropositive patients,
underlying lung disease will not allow surgical resection, significant haemoptysis requiring intervention was more
even in the presence of life-threatening haemoptysis. The likely in HIV-seronegative individuals.
surgical treatment of aspergilloma is associated with a In another study (48), Pneumocystis jirovecii pneumonia
relatively high mortality rate that ranges between 7% and was found to be a risk factor for pulmonary mycetoma in the
23% (39,40). The most common causes of death following HIV-infected individuals. These workers (48) also reported
surgery are severe underlying lung disease, pneumonia, that though the disease progressed rapidly, life-threatening
acute myocardial infarction, and invasive pulmonary haemoptysis rarely occurred in HIV-infected patients with
aspergillosis. In addition, there is a significant post-operative mycetoma. A combination of anti-fungal and antiretroviral
morbidity, including bleeding, residual pleural space, therapy [ART] may improve the clinical outcome in HIV-
bronchopleural fistula, empyema, and respiratory failure. In infected patients with pulmonary mycetoma.
younger patients with adequate lung reserve the morbidity
and mortality are lower (41,42). POST-TUBERCULOSIS BRONCHIECTASIS
The best approach seems to wait and watch and The pathogenesis of bronchiectasis in TB is multi-factorial (49).
surgery is indicated only when there is repeated and severe Caseation necrosis and granulomatous inflammation in
haemoptysis. Patients with mild infrequent haemoptysis the wall of the dilated and destroyed bronchi suggest that
or without symptoms may be observed carefully. Surgical this may represent an extension of the TB process. Scarring
approach needs to be considered in patients with massive that follows TB inflammation produces bronchial stenosis.
haemoptysis and adequate pulmonary reserve (39-43). This, when followed by mixed bacterial infection and
In a recent reported series (44) of aspergilloma [n = 35; retention of purulent bacterial secretions, leads to destruction
median age 43.4 years; 28 males] the average time to and dilatation of the bronchi as is the case with other types
consultation was 19.4 [range 1-120] months. All patients of bronchiectasis.
had a history of pulmonary TB. Haemoptysis was the most The ongoing pathological changes may be perpetuated
commonly observed symptom [54.3%]. Aspergillus serology by products of inflammation. Compression of the bronchial
was positive in 22 patients. Various surgical procedures lumen by enlarged lymph nodes produces consequences
performed including 14 lobectomies, 1 bilobectomy, similar to those of an intraluminal obstruction. This is
1 segmentectomy, 1 bisegmentectomy, 3 lobectomies with more so in the case of young children and adolescents in
segmentectomies, 1 bilobectomy with segmentectomy, and whom TB hilar lymphadenitis is more common. In both
14 pleuropneumonectomies. One patient with pulmonary these situations, inflammatory destruction of the bronchial
artery damage required repair. Complications were: wall is by and large the sequelae of secondary bacterial
empyema [n = 3], a large air-leak [n = 1], parietal suppuration infection rather than the direct effect of Mtb. Another rare,
[n = 5], and pleural effusion [n = 3]. There was no immediate but important cause of bronchial obstruction is penetration
post-operative mortality. On follow-up [median duration of the airway by a calcified TB lymph node and the
35 months], recurrence of haemoptysis was seen in one formation of broncholith. Some or all of the bronchiectatic
patient; three patients died of respiratory failure [one at cavities may represent healing or healed TB cavities that
6 months and the other two at 1 year after the surgery] (44). have been re-lined with ciliated columnar epithelium.
Cavernostomy has been found to be useful in complicated Bronchiectasis structurally resembles small/large cavities
cases (45). in the bronchial wall. Recently, it has been reported that,
M. avium-intracellulare infection of the lungs is associated
Mycetoma and Human Immunodeficiency with bronchiectasis in apparently healthy individuals, or, in
Virus Infection persons with emphysema. It seems that such an association
may either be due to a primary infection or colonisation.
Pulmonary mycetomas have also been documented in HIV- Post-TB bronchiectasis is commonly seen in the upper
seropositive individuals (24,46-48). Although life-threatening lobes, since the disease is more common at this site. It is
haemoptysis has occasionally been documented (46), a “dry” or “sicca” type of bronchiectasis because of the
it appears to be a relatively rare manifestation in HIV- effective drainage of the upper lobes by gravity. The usual
seropositive patients with pulmonary mycetoma. In a presentation is with haemoptysis or repeated episodes of
study (24) comparing the clinical presentation, disease secondary bacterial infection.
progression, treatment, and outcome of pulmonary Although the chest radiograph is important in the
mycetoma in patients with [n = 10], and without [n = 15] evaluation of a patient with suspected post-TB bronchiectasis,
HIV infection, the following observations were documented. the findings are often non-specific. Bronchography used to
 424 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

be performed earlier with a radio-opaque, iodinated lipid from rupture of a subpleural TB cavity into the pleural space.
dye for visualisation of the dilated airways. However, in Infection of pleural cavity results in pyopneumothorax.
the recent years, it has been replaced by CT. As compared Other causes of pneumothorax include rupture of an open
to the bronchography, the CT is a relatively non-invasive healed cavity or rupture of a bleb or bulla [Figure 31.7]
investigation. secondary to fibrosis and destruction of the lung (53).

TUBERCULOSIS ENDOBRONCHITIS AND

TRACHEITIS
TB endobronchitis and tracheitis are observed in about
one-third of the patients with pulmonary TB (50). These
structures can be infected by direct implantation of Mtb,
through sub­mucosal lymphatics, haematogenous spread
or from the lymph nodes. Clinical manifestations include
cough, haemoptysis, breathlessness and soreness or
constriction in the sub-sternal region. Healing can lead
to bronchostenosis. The reader is referred to the chapter
“Endobronchial tuberculosis” [Chapter 12] for more details.

SPONTANEOUS PNEUMOTHORAX
Spontaneous pneumothorax has been reported in 5%-15% of
patients with pulmonary TB (51,52). In countries where TB
is a common problem, it is an important cause of pneumo­ Figure 31.6: Chest radiograph [postero-anterior view] showing hydro­
thorax [Figure 31.6]. Spontaneous pneumothorax may result pneumothorax on the right side

A B

C D
Figure 31.7: Chest radiograph [postero-anterior view] [A], CT of the chest [coronal reconstruction, B], [C], and [D] of a patient who presented with
breathlessness showing bilateral bullous lung disease [arrows]. This patient had sputum smear-positive pulmonary tuberculosis a decade ago
and had received adequate antituberculosis treatment
 Complications of Pulmonary Tuberculosis 425

CALCIFICATION “OPEN-NEGATIVE” SYNDROME

Lung lesions of TB heal by calcification. In fact, localised Patients with “open-negative syndrome” have thin walled
or extensive calcification of the lungs is a feature of healed cavities with epithelialisation extending from bronchioles
primary TB (52). Calcification can either be microscopic or down to the inner lining of the cavity (55-57). These
macroscopic. Most often these calcifications are innocuous are observed more frequently following the advent of
and present as discrete radio-opaque shadows in patients chemotherapy. Although they are known as “isoniazid
with parenchymal disease [Figure 31.8] and sheet-like cavities”, they can also occur due to other antituberculosis
calcification in patients with pleural disease [Figure 31.9]. drugs. Complete epithelialisation prevents these cavities to
Occasionally, however, these calcified concretions may get collapse and fibrose but renders them innocuous. From a
detached from the lung tissue and erode through a bronchial clinical point of view, they are regarded as inactive cavities.
wall or blood vessel and result in massive haemoptysis. The However, histopathological examination of such cavities
patient may also give history of coughing out calcified stones may reveal incomplete epithelialisation and necrotic foci
in the sputum [broncholiths or pneumoliths]. Extensive showing Mtb. These present radiologically as “ring shadows”
calcification, may result in respiratory failure or chronic with thin walls.
cor-pulmonale. Although the cavities themselves will not produce any
symptoms, they are associated with certain hazards like
TUBERCULOSIS LARYNGITIS secondary infection, colonisation with fungi producing
fungal balls, scar carcinoma, spontaneous pneumothorax,
Involvement of larynx during the course of pulmonary TB and loss of effective volume of the lungs.
occurs in about 4%-40% of cases (54). The incidence increases
with extensive involvement of lungs and presence of cavitary SCAR CARCINOMA
disease. The usual mode of infection is by direct implantation
or through lymphatics and blood vessels. The symptoms Development of lung cancer in association with old
include soreness or pain in the throat, dry, hacking cough scars [scar carcinoma] is common in conditions, such as
and hoarseness of voice. Laryngoscopy may reveal an ulcer, progressive systemic sclerosis with lung involvement. The
granuloma, paresis or paralysis, destruction of cords, or relationship between the scars of pulmonary TB and lung
stenosis of the vocal cords. The vocal cords, arytenoids and cancer has been a matter of debate for a long time. In the
the inter-arytenoid space are most commonly affected. The series reported by Auerbach et al (58), scar cancer was
sputum is usually positive for Mtb. The reader is referred observed in 82 of the 1186 autopsied cases [1%]; 23.2% of
to the Chapter “Tuberculosis in head and neck” [Chapter 23] these had originated from TB scars. A similar association
for details. between scars of TB and lung cancer has been documented in
several other reports (59,60). However, other reports indicate
that the association between TB and lung cancer was merely
TUBERCULOSIS ENTERITIS
coincidental (61,62).
TB enteritis seldom occurs as a complication of pulmonary Impaired lung ventilation and concomitant increase
TB in the present era. The reader is referred to the chapter in pulmonary carbon dioxide levels, which in turn causes
“Abdominal tuberculosis” [Chapter 15] for further details. pronounced hyperplasia of pulmonary neuroendocrine cells

Figure 31.8: Chest radiograph [postero-anterior view] showing Figure 31.9: Chest radiograph [postero-anterior view] showing sheet-
parenchymal calcification on the left side [arrow] like pleural calcification on the right side [arrow]
426 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

have been postulated as the possible mechanisms underlying possible. Thus, in a patient with pulmonary TB, obstructive,
the genesis of lung cancer in patients with chronic lung restrictive, or a mixed type of lung function abnormality is
diseases. A receptor with sensitivity for oxygen and possible depending upon the type and extent of involvement
carbon dioxide which produce a number of autocrine or residual damage (74). A study (75) from New Delhi
growth factors is considered to be crucial in the malignant assessed the post-treatment sequelae in multidrug-resistant
transformation (63-65). A review (66) has discussed some TB [MDR-TB] patients [n = 130] who were initiated on
of these issues including TB as a cause of lung cancer and standardised treatment. Of these, 24 had died while on
simultaneous development of TB in lung cancer or TB treatment. Of the remaining 106 patients, 63 [59%] patients
developing in case of lung cancer. Various suggestions like a could be traced: 51 were currently alive and 12 had died. At
chance coincidence without any apparent relation, metastatic 24-months [range 6-63 months] of post-treatment follow-up
carcinoma developing in an old TB lesion, occurrence of TB [n = 51], 40 [78%] had persistent respiratory symptoms; 44
in a patient with cancer, chronic progressive TB in which a of the 45 tested [98%] had residual radiological sequelae
carcinoma develops and simultaneous development of both with 18/45 [40%] having far advanced involvement. On
TB and cancer (66). These issues merit further study. pulmonary function testing [n = 47] abnormal results were
In a population cohort study (67) of 716,872 insured observed in 45 [96%] patients. A predominantly mixed type
subjects, incidence of lung cancer in patients with newly of abnormality was seen in 31 [66%]; restrictive pattern in
diagnosed TB [n=4480] and the remaining non-TB subjects 9 [19%] and obstructive pattern 5 [11%] patients. None of
was compared. Patients with TB were found to have a the patients were found to be bacteriologically positive (75).
11-fold higher incidence of lung cancers compared to non- In another study (76) from Indonesia, morbidity at
TB subjects. Cox proportional hazard regression analysis baseline and during treatment, and 6-month residual
showed for the TB cohort, the hazard ratio [HR] increased disability, was assessed in 200 pulmonary patients and 40
further with co-existing chronic obstructive pulmonary volunteers. In pulmonary TB patients, the six-minute walk
disease [COPD] or other smoking-related cancers suggesting test distance, quality of life and pulmonary functions were
a strong evidence of lung cancer risk among TB patients (67). significantly lower at the baseline as well as at the end of 6
In another retrospective study (68) of 782 patients with months of anti-TB treatment compared with controls. At the
non-small cell lung cancer [NSCLC] who had undergone end of 6 months of anti-TB treatment, despite most achieving
surgical resection the association between lung cancer successful treatment outcomes, 57% TB patients still had
survival and the presence of old pulmonary TB lesions respiratory symptoms and 27% had moderate to severe
was assessed. The authors (68) reported that presence of pulmonary function impairment. More-advanced disease at
an old pulmonary TB lesion was an independent predictor baseline and HIV-seropositivity were found to be predictors
of poor survival [HR 1.72] in the subgroup of patients with of residual disability (76). Another study (77) from Gujarat,
squamous cell carcinoma. India assessed pulmonary impairment in cured pulmonary
In another surgical series (69), co-existence of TB and TB patients [n = 264]. Majority of these complained of
lung cancer in thoracic surgery was found to be fairly rare, cough [n = 224, 84%] with expectoration [n = 184, 69.7%].
being evident only in 46 cases [2.1%] out of 2218 operated Physical examination revealed rhonchi, crepitations or
lung cancer patients. Another study revealed that most of both in 178 [67.4%] patients. The chest radiograph revealed
the patients with TB and lung cancer are smokers or former varying degrees of lung destruction with a majority
smokers, and TB is diagnosed either before or simultaneously [n = 145, 38%] having involvement of two or more lobes;
with lung cancer. NSCLC, especially adenocarcinoma, was 223 of the 257 [87%] patients tested had obstructive airways
the most common histopathological type (70). disease. Electrocardiogram and echocardiography revealed
A systemic review and meta-analysis (71) evaluated pulmonary hypertension in 72 of the 76 patients tested (77).
the history of previous lung diseases as a risk factor for
lung cancer. In this meta-analysis (71), it was observed CHRONIC RESPIRATORY FAILURE
that a previous history of COPD, chronic bronchitis or
Chronic respiratory failure [type I and type II] may
emphysema, pneumonia, TB had conferred an increased risk
complicate pulmonary TB, especially if the disease had been
of lung cancer. The authors (71) reported that data from 30
extensive and the patient survived because of adequate
studies suggested that a previous history of TB conferred an
treatment. Respiratory failure develops due to extensive
increased risk of lung cancer {relative risk [RR] 1.76} and this
destruction of pulmonary parenchyma [Figures 31.10
increased risk of lung cancer was independent of smoking
and 31.11] and the resultant ventilation-perfusion [V/Q]
[RR 1.90].
mismatch.
Associated pleural thickening and fibrothorax result in
PULMONARY FUNCTION CHANGES thoracic wall malfunction and further add to the mechanical
Diffuse airway obstruction has been reported in 30%-60% disadvantage of the lung, thus contributing to the pump
of cases with pulmonary TB (72,73), which is distinct from failure (78-80). Atrophy or disuse of the respiratory
chronic bronchitis. Further, because of diffuse parenchymal muscles can also contribute to chronic respiratory failure.
fibrosis, pleural effusion and thickening, and fibrothorax, Tachypnoea, hypoxia and hypercapnia develop ultimately
a restrictive type of pulmonary function defect is also and the patient may die from these abnormalities.
 Complications of Pulmonary Tuberculosis 427

The possible causes of chronic cor-pulmonale in

pulmonary TB include abnormalities of the pulmonary
parenchyma or thoracic wall. The underlying basic
pathophysiology of chronic cor-pulmonale is an increase in
the pulmonary artery vascular resistance and pulmonary
hypertension. Mechanisms causing these changes include
occlusion or destruction of vascular bed due to lung
parenchymal destruction, vasculitis, and endarteritis
with diminished cross-sectional area of the pulmonary
circulation (81,82). Other less important causes include
hypoxia, acidosis with hypercapnia, and increased blood
viscosity due to polycythaemia. The latter may not be
important in developing nations because of a high prevalence
Figure 31.10: Chest radiograph [postero-anterior view] of a patient with
of malnutrition and anaemia. These causes also happen to
old, healed pulmonary tuberculosis showing extensive parenchymal be important in the causation of chronic cor-pulmonale in
destruction, bronchiectatic changes and pleural thickening on the left patients with COPD.
side. On the right side, compensatory emphysema and pseudobulla Normally, pulmonary circulation is a highly distensible,
formation can be seen low pressure and low-resistance circulation that transmits
the entire cardiac output without much change in pressure
because the pulmonary arteries are thin-walled with little
resting muscular tone. In adults, there is a negligible
response in terms of capacity, distensibility, or resistance
to flow following autonomic nervous system stimulation.
Many small arterioles and capillaries are non-perfused
at rest, but can be recruited when needed to expand the
pulmonary vascular bed causing a decrease in pulmonary
vascular resistance. There is no humoral counterpart of the
renin-angiotensin system that is capable of evoking sustained
pulmonary artery hypertension.
Normal mean pulmonary artery pressure is 13-14 mmHg
in a young adult and is less than 18 mmHg in 80% of
subjects of all ages. Pulmonary artery pressure of greater
than 20 mmHg signifies pulmonary hypertension. Blood flow
through the pulmonary capillaries is achieved by a pressure
drop of only 5-9 mmHg [pulmonary artery to left atrial
pressure] compared to 90 mmHg for the systemic circuit.
Figure 31.11: Chest radiograph [postero-anterior view] of a patient with Accordingly, the normal pulmonary vascular resistance is
pulmonary tuberculosis showing extensive parenchymal destruction, 10-20 times less than systemic vascular resistance.
bronchiectatic changes and pleural thickening on the left side. On the It is generally agreed that the decrease in extent of the
right side, compensatory emphysema can be seen
pulmonary vascular bed is insufficient to play a predominant
role in the pathogenesis of pulmonary hypertension unless
the reduction is extreme. The effective cross-sectional area
PULMONARY HYPERTENSION AND
of the pulmonary vascular bed must be reduced by more
CHRONIC COR-PULMONALE
than 50% before any change in pulmonary artery pressure
Chronic cor-pulmonale is defined as enlargement [dilatation can be detected at rest, although exercise will increase the
and/or hypertrophy] of the right ventricle due to increased pressure at lower levels of increased blood flow. Experiments
right ventricular afterload from intrinsic pulmonary diseases in dogs have shown that more than two-thirds of the
including those of pulmonary circulation, inadequate lungs had to be ablated before pulmonary artery pressures
function of the chest bellows or inadequate ventilatory drive approach hypertensive levels (81,82). Obliterative vascular
from the respiratory centres; when right heart abnormalities diseases increase pulmonary vascular resistance by vascular
secondary to left heart failure or congenital heart disease occlusion, while diffuse interstitial and parenchymal diseases
are excluded. Right heart failure need not be present, act primarily by compressing and obliterating small vessels.
although this is a clinical manifestation of the overloaded The diagnosis of chronic cor-pulmonale is often not
right ventricle that precedes the clinically unrecognisable made until significant right ventricular hypertrophy or
cor-pulmonale. Except in rare instances when the disease overt right ventricular failure is present. Heart failure occurs
is complicated by massive pulmonary thromboembolism, insidiously, causing further impairment of lung function and
cor-pulmonale is usually chronic. is frequently misinterpreted as worsening of the underlying
428 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

lung disease. Episodes of leg oedema, atypical chest pain, AMYLOIDOSIS

exertional dyspnoea, exercise-induced cyanosis in the
periphery, prior respiratory failure, and excessive daytime Secondary amyloidosis is known to occur in a wide variety
sleepiness are non-specific but important historical clues of clinical situations and is characterised by the deposition
suggesting the possibility of cor-pulmonale. of an extracellular eosinophilic substance in various organs.
General physical examination reveals distended neck Although the name suggests carbohydrate deposition, in fact,
veins, peripheral oedema, and cyanosis. Oedema in chronic the substance is predominantly, if not exclusively, protein in
cor-pulmonale may not be necessarily due to overt heart origin (86). Several cytokines including interleukin-1 [IL-1],
failure. Signs and symptoms suggestive of heart failure interleukin-6 [IL-6] and tumour necrosis factor-α [TNF]-α
like dyspnoea, orthopnoea, oedema, hepatomegaly, and stimulate hepatic synthesis of serum amyloid A precursor
raised jugular venous pressure [JVP] can also occur due during TB inflammation. The incidence of renal amyloidosis
to chronic obstructive airways disease without right heart in TB has been reported to range from 8%-33% (87-91).
failure. However, the raised JVP is present in both phases Differences in the method used to detect amyloidosis could
of respiration in right heart failure. also have contributed to this wide variation. The incidence
The apical impulse and the right ventricular lift are often of amyloidosis was 1.01% of 6431 postmortems and 8.4% of
not palpable. The second heart sound may be palpable 1980 renal biopsies at the Postgraduate Institute of Medical
in the pulmonary area. The earliest sign of pulmonary Education and Research, Chandigarh (90). While 87.1% had
hypertension is an accentuated pulmonic component of secondary amyloidosis, 3.5% had primary amyloidosis and
the second heart sound. A right ventricular S3 gallop is the remaining had multiple myeloma. TB of various organs
heard in the epigastrium along the sternum. With advanced was the most common predisposing cause accounting
pulmonary artery hypertension, characteristic diastolic for 59.1% of secondary amyloidosis, followed by chronic
murmur of pulmonary regurgitation and pansystolic suppurative lung diseases (90). Pulmonary TB was the
murmur of tricuspid regurgitation which accentuates during leading cause in 81.6% of cases followed by glandular
inspiration can be heard along with a systolic ejection sound. and abdominal TB. The interval between the onset of the
Right ventricular failure is usually precipitated by some predisposing disease and the first evidence of secondary
acute episode like pneumonia. Associated clinical features renal amyloidosis varied from 1 year-30 years with a mean
of the underlying basic disease will be present. of 6.9 years in this study. The interval was greater than
Cor-pulmonale due to restricted vascular bed is 5 years in 67% of patients. However, other reports suggest
manifested by a strikingly high pulmonary arterial pressure that this interval varies widely and may be as short as
associated with a low cardiac output. Hypoxaemia is often 6 months or as long as 43 years (91). Nonetheless, TB is still
mild. Tachypnoea which persists even during sleep is the the most common cause of secondary amyloidosis in Indian
rule, particularly with multiple pulmonary emboli. Chest patients (90). Abdominal fat pad, rectal, mucosal, liver,
pain is common. Enlargement of right ventricle in its pure or kidney biopsy specimens are useful in confirming the
form is manifested in these disorders. Prominent “a” and diagnosis of secondary amyloidosis. Secondary amyloidosis
“v” waves appear in the jugular veins. can occur even in adequately treated patients with
The classic radiographic evidence of right ventricular pulmonary TB (92). A study from Tunisia concluded that
enlargement [crossing the right vertebral border] will be renal amyloidosis is an important complication of TB (93).
present. This is manifested by enlargement of the outflow
tract of the right ventricle, the main pulmonary arteries, CHRONIC EMPYEMA, BRONCHOPLEURAL
and their central branches, in association with attenuated FISTULA, FIBROTHORAX/DESTROYED LUNG
peripheral branches of the pulmonary arterial tree.
Enlargement of the pulmonary artery is considered to exist Chronic empyema and bronchopleural fistula are some of the
when the diameter of the right descending pulmonary artery important complications of pulmonary TB, particularly if the
is greater than 16 mm and the left descending pulmonary disease is chronic. These may be due to active TB when occur
artery is greater than 18 mm, although the true sensitivity for the first time or can occur as complications and persist
and specificity of these measurements are not known. even after the disease is inactive after full treatment and
The “suggestive” indices of pulmonary hypertension bacteriological cure. These bring about significant amount
[right ventricular enlargement] in the electrocardiogram of morbidity and frequent causes of repeated infections by
include: p pulmonale in leads II, III, aVF, S1Q3, or S1-S2-S3 bacteria other than mycobacteria. The patient may require
patterns, right axis deviation, R:S ratio in V6 of 1.0, rSR prolonged chest tubes with frozen shoulders, protein loss
pattern in the right precordial leads, and partial or complete and respiratory and physical disability. Surgical intervention
right bundle branch block (83-85). Dominant R or R’ in lead will often be required (94-104).
V1 or V3R in association with inverted T waves in the right Destroyed lung or fibrothorax is a term which is used to
precordial leads in combination with “suggestive” criteria, denote a condition when all the three important components
are more definite indices. Non-invasive investigations such of the lung – the parenchyma, bronchi and pleura are often
as Doppler and 2-D transthoracic echocardiography may be involved. The lung is grossed shrunken, fibrosed, and
used periodically to monitor pulmonary artery pressure and the mediastinum is pulled to the same side. Most often there
right ventricular function. will be features of cavity, crepitations and can complicate
 Complications of Pulmonary Tuberculosis 429

with repeated infections and haemoptysis. The patient can 17. Zizzo G, Castriota-Scanderbeg A, Zarrelli N, Nardella G, Daly J,
be a respiratory cripple and in advanced stages, go on to Cammisa M. Pulmonary aspergillosis complicating ankylosing
spondylitis. Radiol Med [Torino] 1996;91:817-8.
respiratory failure and cor-pulmonale. The reader is referred
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19. Rosenheim SH, Schwartz J. Cavitary pulmonary cryptococcosis
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549-53.
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TB. The clinical relevance of colonisation versus active NTM
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disease needs to be ascertained by the treating physician. The Imaging 1992;7:56-74.
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nonoperative treatment. Ann Thorac Surg 1978;25:389-92.
23. Tomee JF, van der Werf TS, Latge JP, Koeter GH, Dubois AE,
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 32
Tuberculosis and Acute Respiratory
Distress Syndrome
DR Karnad, KK Guntupalli

INTRODUCTION DEFINITION
Acute respiratory distress syndrome [ARDS] is a disorder The term acute lung injury [ALI] has been loosely used until
characterised by inflammatory damage to the alveolar the 1994 American-European Consensus Conference [AECC]
capillary membrane producing severe derangement of laid down a specific definition for ALI and ARDS in order to
gas exchange, which could result from a variety of insults, ensure uniformity in diagnosis, research and management (1,6).
ultimately resulting in severe hypoxaemia, non-cardiogenic This definition was widely used in ARDS research for more
pulmonary oedema (1). In general, abnormalities of gas than 15 years since then. However, issues concerning the
exchange are uncommon in pulmonary tuberculosis [TB] limitations, reliability and validity of the AECC definition
because concomitant involvement of ventilation and had emerged. Addressing these issues, recently, the Berlin
perfusion results in maintenance of the normal ventilation- definition criteria [Table 32.1] have been described for the
perfusion relationship (2). However, severe hypoxic diagnosis of ARDS (7).
respiratory failure due can sometimes complicate severe
forms of pulmonary and miliary TB (3-5). This complication
PATHOGENESIS
is associated with a very high mortality despite treatment.
Hence, early recognition and appropriate management of ARDS occurs in approximately 40% of patients with sepsis
this uncommon complication is of utmost importance. and the systemic inflammatory response syndrome (6).

Table 32.1: The Berlin definition criteria for the diagnosis of ARDS
Variable Criteria for diagnosis
Timing Timing: within 1 week of a known clinical insult or new or worsening respiratory symptoms
Chest imaging* Bilateral opacities—not fully explained by effusions, lobar/lung collapse, or nodules
Origin of oedema Respiratory failure not fully explained by cardiac failure or fluid overload
Need objective assessment [e.g. echocardiography] to exclude hydrostatic oedema if no risk factor present
Oxygenation†
Mild 200 mmHg < PaO2/FiO2 ≤ 300 mmHg with PEEP or CPAP ≥ 5 cm H2O‡
Moderate 100 mmHg < PaO2/FiO2 ≤ 200 mmHg with PEEP ≥ 5 cm H2O
Severe PaO2/FiO2 < 100 mmHg with PEEP ≥ 5 cm H2O
* Chest radiograph or computed tomography
† If altitude is higher than 1000 m, the correction factor should be calculated as follows: {PaO2/FiO2 × [barometric pressure/760]}
‡ This may be delivered noninvasively in the mild acute respiratory distress syndrome group
ARDS = acute respiratory distress syndrome; PaO2 = arterial oxygen tension; FiO2 = fraction of inspired oxygen; PEEP = peak end-expiratory
pressure; CPAP = continuous positive airway pressure
Source: reference 7
 Tuberculosis and Acute Respiratory Distress Syndrome 433

Initially, there is inflammatory damage to the pulmonary damages the alveolar epithelial cells [Figures 32.1 and 32.2].
endothelial cell barrier, resulting in increased pulmonary Damage to the Type I cells further worsens alveolar
capillary permeability. This produces leakage of protein- flooding and gas-exchange. Type II cuboidal cells, which
rich pulmonary oedema at normal pulmonary artery produce surfactant, too are damaged in later stages of the
wedge pressure. A series of inflammatory events then disease resulting in collapse of the more severely affected

Figure 32.1: The healthy lung and the exudative phase of ARDS. The healthy lung is shown on the left, and the exudative phase of ARDS is shown
on the right. Injury is initiated by either direct or indirect insults to the delicate alveolar structure of the distal lung and associated microvasculature.
In the exudative phase, resident alveolar macrophages are activated, leading to the release of potent proinflammatory mediators and chemokines
that promote the accumulation of neutrophils and monocytes. Activated neutrophils further contribute to injury by releasing toxic mediators. The
resultant injury leads to loss of barrier function, as well as interstitial and intra-alveolar flooding. Tumour necrosis factor [TNF]–mediated expression
of tissue factor promotes platelet aggregation and microthrombus formation, as well as intra-alveolar coagulation and hyaline-membrane formation
ARDS = acute respiratory distress syndrome; AECI = type I alveolar epithelial cell; AECII = type II alveolar epithelial cell; Ang-2 = angiopoietin-2;
APC = activated protein C; CC-16 = club cell [formerly Clara cell] secretory protein 16; CCL = chemokine [CC motif] ligand; DAMP = damage-
associated molecular pattern; ENaC = epithelial sodium channel; GAG = glycosaminoglycan; HMGB1 = high-mobility group box 1 protein; KL-6 =
Krebs von den Lungen 6; LPS = lipopolysaccharide; LTB4 = leukotriene B4; MMP = matrix metalloproteinase; MPO = myeloperoxidase; mtDNA
= mitochondrial DNA; Na+/K+ ATPase = sodium–potassium ATPase pump; NF-κB = nuclear factor kappa light-chain enhancer of activated
B-cells; NET = neutrophil extracellular trap; PAMP = pathogen-associated molecular pattern; PRR = pattern recognition receptor; ROS = reactive
oxygen species; sICAM = soluble intercellular adhesion molecule; SP = surfactant protein; sRAGE = soluble receptor for advanced glycation end
products; VEGF = vascular endothelial growth factor; vWF = von Willebrand factor
Reproduced with permission from “Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017;377:562-72
(reference 6).” Copyright [2000] Massachusetts Medical Society. All rights reserved
 434 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 32.2: The proliferative and fibrotic phases of ARDS. The proliferative phase [Panel A] aims to restore tissue homeostasis and is
characterised by the transient expansion of resident fibroblasts and the formation of a provisional matrix, as well as proliferation of airway
progenitor cells and type II alveolar epithelial cells [AECII], with differentiation into type I alveolar epithelial cells [AECI]. During the fibrotic
phase of ARDS [Panel B], which is strongly associated with the need for mechanical ventilation, extensive basement membrane damage and
inadequate or delayed reepithelialisation lead to the development of interstitial and intra-alveolar fibrosis
ARDS = acute respiratory distress syndrome; AQP5 = aquaporin 5; CFTR = cystic fibrosis transmembrane conductance regulator; GMCSF =
granulocyte–macrophage colony stimulating factor; HGF = hepatocyte growth factor; IGFI = insulin like growth factor I; IRF4 = interferon regulatory
factor 4; KGF = keratinocyte growth factor; MR = mannose receptor; PDGF = platelet derived growth factor; TGFβ = transforming growth factor β
Reproduced with permission from “Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017;377:562-72
(reference 6).” Copyright [2000] Massachusetts Medical Society. All rights reserved

alveoli during end-expiration. Pro-inflammatory cytokines substances like soluble interleukin-1 receptor antagonist
interleukin-1 [IL-1], interleukin-6 [IL-6], interleukin-8 [IL-8], [sIL-1RA], soluble tumour necrosis factor receptor [sTNF-R]
and tumour necrosis factor-a [TNF-a] attract and activate and anti-inflammatory cytokines, interleukin-10 [IL-10] and
inflammatory cells like neutrophils, macrophages. These interleukin-11 [IL-11] too are present in the alveoli, but their
cells release other inflammatory substances like elastases, role in the pathogenesis of ARDS is not clear (6).
other proteases, oxygen free radicals, leukotrienes and The inflammatory process is not limited to the lung (8,9).
platelet activating factor. Endogenous anti-inflammatory Activation of coagulation is common and frank disseminated
 Tuberculosis and Acute Respiratory Distress Syndrome 435

intravascular coagulation [DIC] may develop in some epidemiological data are available on this entity. Burden of
patients. Inflammatory mediators arising from the lung may ARDS as reported in some of the clinical studies is shown
also play a role in the development of the multiple organ in Table 32.2 (3,5,17-23). Varying denominators have been
dysfunction syndrome in these patients (8). used in the published studies because of which meaningful
In patients with TB, ARDS is believed to result from the comparison of these data is not possible. The incidence of
release of mycobacteria or their products into the pulmonary TB-ARDS has been observed to increase with any delay in
circulation (10,11). This classical situation is present in severe diagnosis and institution of appropriate therapy for miliary
miliary TB where widespread distribution of the bacterial TB (24). In an autopsy study (25) from Chandigarh, 10 of the
load may result in diffuse lung injury and ARDS (12). 196 cases [5.1%] with disseminated TB, 10 met the clinical
Mycobacterial cell wall component lipoarabinomannan criteria for ARDS; in 60% of these, histopathological evidence
[LAM] and mycobacterial cytosolic heat-shock protein-65kD of diffuse alveolar damage was present.
[HSP-65] have been shown to induce release of inflammatory
cytokines (13). LAM binds to CD14 receptors on human PREDISPOSING FACTORS
mononuclear macrophages and induces the production and
release of cytokines including interleukin-1b [IL-1b], TNF-a, Acute lung injury invariably occurs in patients with severe
interleukin-1a [IL-1a], IL-6, IL-8, IL-10, and granulocyte TB, such as miliary TB, or TB bronchopneumonia (10,11).
macrophage colony-stimulating factor [GM-CSF]. Heat-shock A number of predisposing factors have been described.
protein-65kD too induces the release of cytokines, but to a Malnutrition is the most common predisposing factor seen
lesser extent than LAM, and by a mechanism that does not in patients with pulmonary TB developing acute respiratory
involve the CD14 receptor (12). Mycobacteria also induce failure (12,17,26). Other factors include alcoholism, diabetes
expression of the intercellular adhesion molecule-1 [ICAM-1] mellitus, immunosuppressive therapy with corticosteroids
on endothelial cells, which facilitates adhesion of activated or other drugs, HIV infection, drug addiction, chronic
neutrophils to capillary walls (12). Another compound, liver disease and pregnancy (2,12,14,26,27). Independent
muramyl dipeptide, stimulates chemotaxis, and enhances predictors of TB-ARDS development documented in recent
phagocytosis and release of inflammatory mediators (14). studies are shown in Table 32.3 (5,20,22).
The subsequent series of events are probably similar to those
seen in gram-negative bacterial sepsis (10,11,13). CLINICAL SYNDROMES
Some authors have also suggested that ARDS may
be partly due to a cell-mediated immune response to Acute Respiratory Distress Syndrome in
mycobacterial antigens (14). This could result either from Miliary Tuberculosis
an enhancement of the delayed hypersensitivity response In patients with miliary TB, ARDS can occur at all ages
or from a decrease in suppressor mechanisms (14,15). This and the youngest patient reported is a seven months old
may probably play an important role in ARDS that develops child (28). Fever, non-productive cough, chest discomfort
in some patients after institution of anti-TB drug therapy and dyspnoea are the common symptoms and the average
and in patients with human immunodeficiency virus [HIV] interval between onset of symptoms and diagnosis is 14
infection receiving antiretroviral drugs (12-16). days (17,26). In more than 50% of patients the diagnosis of
TB is not known at the time of admission with respiratory
EPIDEMIOLOGY failure (12). In these patients, radiological features of ARDS
Eventhough ARDS is a well recognised complication usually mask the typical miliary mottling (10). The interval
in patients with pulmonary and miliary TB, sparse between admission and diagnosis in a large series was one

Table 32.2: Burden of TB-ARDS in published clinical studies

Study [year] (reference) Incidence of TB-ARDS
Maartens et al [1990] (17) 8 of the 109 patients [7.3%] with miliary TB
Sharma et al [1995] (3) 5 of the 100 patients [5%] with miliary TB
Choi et al [1999] (18) 17 of 1010 [1.7%] patients with pulmonary TB had acute respiratory failure
Parikh and Karnad [1999] (19) 1.7% of admissions to the medical intensive care unit [ICU] in Mumbai had TB-ARDS
Kim et al [2003] (20) 8 of the 34 patients [23.5%] patients with miliary TB developed ARDS
Agarwal et al [2005] (21) 9 of the 187 patients [4.8%] admitted to the respiratory ICU at a tertiary care teaching hospital in Chandigarh,
had TB-ARDS
Sharma et al [2006] (5) 29 of the 2733 [1.06%] TB patients seen during the period 1980-2003 at two tertiary care teaching hospitals
in north and south India developed TB-ARDS
Deng et al [2012] (22) 85 of the 466 patients with miliary TB developed TB-ARDS
Sharma et al [2016] (23) 5 of the 64 [7.8%] patients with ARDS admitted to a medical ICU at a tertiary care teaching hospital in north
India had TB-ARDS
TB-ARDS = tuberculosis-acute respiratory distress syndrome
436 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 32.3: Predictors of development of TB-ARDS in various published studies

Study [year] (reference) Predictors of development of TB-ARDS
Kim et al [2003] (20) Lower WBC count and platelet count, lower serum albumin, elevated serum AST, ALT and ALP levels at the time
of admission*
Sharma et al [2006] (5) Presence of miliary TB, duration of illness beyond 30 days at presentation, absolute lymphocyte count less than
1625/mm3 and serum ALT > 100 IU/L
Deng et al [2012] (22) Presence of diabetes mellitus, ALT [70-100U/L], AST > 94 U/L, D-dimer >1.6 mg/L, haemoglobin < 9 g/dL,
serum albumin < 2.5 g/dL*
* in patients with miliary TB
TB = tuberculosis; ARDS = acute respiratory distress syndrome; WBC = white blood cell; AST = aspartate aminotransferase; ALT = alanine
aminotransferase; ALP = alkaline phosphatase

to twenty days (12). In up to 10% of patients with ARDS, [Figures 32.5 and 32.6] (3,12). High-resolution computed
miliary TB may be cryptic with systemic dissemination and tomography [HRCT] shows bronchogenic dissemination
a normal chest radiograph (24,26,29,30). A large proportion with ground glass attenuation (10). The classical tree-in-bud
of these patients may harbour HIV infection (24). Other appearance is seen on computed tomography [CT] in less
clinical findings include hepatosplenomegaly, mild hepatic than 50% of cases (18).
dysfunction and pancytopenia (26). In a patient with
unexplained ARDS, a history of fever of more than 15 days Acute Respiratory Distress Syndrome in
duration and elevation of serum alkaline phosphatase should Cavitary Pulmonary Tuberculosis
arouse the suspicion of disseminated TB as the underlying
cause (26). In a retrospective analysis of patients with TB and acute
ARDS may also develop in diagnosed patients with respiratory failure, Zahar et al (24) found that 11% of
miliary TB after anti-TB treatment is initiated (12). In patients patients had an isolated apical cavity on chest radiograph
with miliary TB, auscultation of the chest is generally normal. preceding the onset of acute respiratory failure. Choi et al (18)
Tachypnoea and presence of diffuse rales while on drug found cavities in HRCT of 45% of patients with acute
therapy is are ominous signs of early ARDS. respiratory failure. Extensive endobronchial spread of TB
Mortality in patients with ARDS due to miliary TB is following rupture of a cavity into the bronchus is thought
between 40%-80%, despite use of mechanical ventilation and to initiate ARDS (34). The initial symptoms of TB in these
corticosteroids (10,12,20,31). At autopsy, alveoli may show patients are fever and cough, which are followed after
intense perifocal inflammation, interstitial granulomas and two weeks to two months by acute onset of dyspnoea
obliterative endarteritis [Figures 32.3 and 32.4], characteristic and severe hypoxaemia (34). The chest radiograph shows
of miliary TB (32). In addition, other changes of ARDS may diffuse bilateral alveolar infiltrates as in ARDS, but unlike
be present, in the form of diffuse alveolar damage [DAD], in miliary TB complicated by ARDS, these patients tend to
increased vascularity, presence of dense exudates in the have unilateral preponderance of the infiltrates and physical
alveoli, and hyaline membrane formation (25,32,33). signs (34). They may have systemic manifestations, like DIC
and hypotension. Mycobacteria are easily demonstrable in
Acute Respiratory Distress Syndrome in tracheal aspirates in almost all cases.
Tuberculosis Pneumonia
Acute Respiratory Distress Syndrome after
Nodular lesions resulting from air-space consolidation due
Initiation of Anti-tuberculosis Treatment
to endobronchial spread to lobar or multilobar locations
is termed TB pneumonia (12). The development of acute In 1986, Onwubalili et al (14) described two alcoholic,
respiratory failure due to TB pneumonia was first reported malnourished patients, with bilateral extensive sputum
in 1977 by Agarwal et al (2). They reported 16 patients with smear-positive pulmonary TB, who developed paradoxical
acute respiratory failure, 10 of whom required mechanical worsening of the disease resulting in ARDS during the
ventilation. Alcoholism and chronic liver disease were the second week of anti-TB treatment. One patient had TB
predisposing factors in almost all cases. In a 10-year review bronchopneumonia. Baseline tests of immune function
of patients with TB requiring mechanical ventilation for revealed a negative tuberculin skin test [TST] with 10
ARDS, Penner et al (12) found that six of the 13 patients tuberculin units [TU] of purified protein derivative [PPD],
with respiratory failure requiring mechanical ventilation lymphopenia, failure of peripheral blood mononuclear cells
had TB pneumonia. The mean interval between the onset to respond to stimulation with PPD and severely depressed
of symptoms of TB and treatment was 45 days. Seven of natural killer cell activity. This patients experienced severe
the 29 patients in the series reported by Sharma et al (5) had breathlessness severe hypoxaemia 11 days after starting anti-
pulmonary TB. Chest radiographs show nodular lesions, TB therapy, along with worsening of the radiological lesions.
with mixed consolidation and ground-glass opacities At this time, the erythrocyte sedimentation rate [ESR] had
 Tuberculosis and Acute Respiratory Distress Syndrome 437

Figure 32.3: Tuberculosis pneumonia presenting as acute respiratory Figure 32.4: Acute respiratory distress syndrome in tuberculosis.
distress syndrome. Epithelioid cells are identified within the alveoli There is an inflammatory exudate in the alveolus and fibrin deposition
[Haematoxylin and eosin, × 100] [arrows] along the alveoli [Haematoxylin and eosin, × 400]

Figure 32.5: Chest radiograph [done bedside, with a portable machine] Figure 32.6: Chest radiograph [postero-anterior view] of the same
showing consolidation with air-bronchogram patient in Figure 32.5 showing classical miliary shadows evolving after
Reproduced with permission from “Sharma SK, Mohan A, Pande a few days
JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory Reproduced with permission from “Sharma SK, Mohan A, Pande
characteristics and outcome in miliary tuberculosis. QJM 1995;88: JN, Prasad KL, Gupta AK, Khilnani GC. Clinical profile, laboratory
29-37 (reference 3)” characteristics and outcome in miliary tuberculosis. QJM 1995;88:
29-37 (reference 3)”

increased to 110 mm at the end of first hour, TST [1 TU of alcohol consumption and the severe infection itself. On
PPD] revealed an induration of eight mm, and there was treatment, there was a progressive reversal of the immune
considerable improvement in the tests of immune function. deficiency and the acute respiratory failure may have been
The second patient had fibrocavitary disease and a TST due to an exaggerated delayed hypersensitivity reaction to
[1 TU of PPD] reading of 7 mm. His condition deteriorated mycobacterial antigens released by the dying organisms.
eight days after starting treatment; ESR increased to Tuberculoprotein and muramyl dipeptide have been
100 mm at the end of first hour and there was an increase implicated as possible immunogenic cell-wall components (14).
in all the parameters of immune function. He required Cell mediated damage to the pulmonary alveolar-capillary
mechanical ventilation for ARDS, and methylprednisolone membrane is believed to cause ARDS in these patients (14).
was administered to reduce pulmonary inflammation. This Akira and Sakatani (15) have reported the radiological
patient died 13 days after starting treatment. features in five patients who develop acute respiratory
The authors (14) mention that both patients had in failure due to paradoxical worsening after treatment of
vivo and in vitro anergy and depression of lymphocyte TB. All five patients had unilateral cavitary TB restricted
function, probably due to poor nutritional status, excess to one lobe. After treatment, chest radiographs revealed
438 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

progression of the original lesion, and appearance of new can cause septic shock, with increased cardiac index, and low
lesions in the other lung and other regions in the same systemic vascular resistance (38). Non-mycobacterial sepsis
lung. HRCT revealed that in addition to the segmental or due to secondary infection may supervene in approximately
lobar cavitation in the original locations, extensive areas 40% of patients receiving mechanical ventilation (12).
of ground-glass opacities were present bilaterally in all A significant number of patients also have co-existing
cases. However, a predominantly dependent distribution, DIC (17). Mortality in these patients is close to 100% (39).
which is characteristic of ARDS due to sepsis, was not seen. Up to 10% of patients may also have acute renal failure (24).
Transbronchial lung biopsy [TBLB] showed the presence of Pancytopenia has been frequently reported in ARDS due
intra-alveolar and interstitial pulmonary oedema. Two of to miliary TB (17,26). Mechanisms include bone marrow
these five patients died. infiltration by TB granulomas and cytokine-induced bone
Transient radiological worsening of pulmonary lesions marrow suppression. Pancytopenia responds well to anti-TB
has been reported in 3%-14% of patients receiving anti- treatment, but these patients have poor survival rates (26).
TB treatment (35). However, the patients may remain
asymptomatic in this setting. In 0.6% of cases, the process DIAGNOSIS
may be severe enough to cause acute respiratory failure (15).
Paradoxical worsening is more frequent and also more Acute respiratory failure is suspected in patients with
severe in patients with HIV infection, especially those severe hypoxaemia, bilateral extensive rales on auscultation,
also receiving antiretroviral drugs due to the immune presence of bilateral confluent alveolar opacities on chest
reconstitution inflammatory syndrome [IRIS] (16,36). radiograph in patients with proven pulmonary TB or
However, Wendel et al (36) showed that 11% of patients prolonged fever (10,11,37,40). Arterial blood gas will
with HIV infection receiving antiretroviral drugs along with reveal a significant alveolar-arterial oxygen gradient. Type I
anti-TB treatment developed clinically relevant paradoxical respiratory failure with normal or low arterial carbon dioxide
worsening compared to 7% receiving anti-TB treatment tension [PaCO2] is usually seen (8,11,32,37). The diagnosis is
alone; the difference was not statistically significant (31). made by the Berlin definition diagnostic criteria mentioned
Increase in severity of fever and a rising ESR may help earlier (7).
identify patients who are likely to develop severe paradoxical The diagnosis of TB in patients presenting with ARDS
worsening (14,15). Injectable methylprednisolone or oral is difficult [Figure 32.7] (30), and needs a high index of
prednisolone [1-2 mg/kg body weight, daily for one to two suspicion. Early diagnosis is important as delay in treatment
weeks which is gradually tapered] are recommended in may worsen the respiratory failure and increase mortality.
patients with paradoxical worsening, although there are no Radiographic changes of ARDS may mask underlying TB
randomised controlled studies to prove their benefit (16). and alveolar infiltrates that are more organised or appear
more nodular than usual should arouse suspicion (33).
Choi et al (18) systematically reviewed the chest radiographic
Other Manifestations
and HRCT findings in 17 patients with acute respiratory
As in severe systemic sepsis, dysfunction of other organs is failure due to TB [Table 32.4]. During resolution, HRCT
seen in 35% of patients with acute respiratory failure due to may reveal bilateral extensive thin-walled cystic lesions.
TB even in the absence of other bacterial infections (24,27,37). Whether these represent parenchymal damage due to TB
These manifestations are encountered more often in miliary or ventilator-induced lung injury is not clear. These cysts
TB than in TB pneumonia (12). Mycobacterial infection itself resolve completely over several months (18).

Table 32.4: Radiological findings in patients with acute respiratory failure due to pulmonary tuberculosis
Plain radiograph High-resolution computed tomography
Findings % Findings %
Small [<10 mm] nodular lesions 96 Nodular lesions 100
Air-space consolidation 76 Ground-glass opacities 91
Ground-glass opacities 70 Air-space consolidation 73
Reticular lesions 24 Septal thickening 73
Cavitary lesions 24 Tree-in-bud appearance 45
Cavities 45
Mediastinal lymphadenopathy 27
Pleural effusion 27
Pericardial effusion 27
Spontaneous pneumothorax 9
Adapted from reference 16
 Tuberculosis and Acute Respiratory Distress Syndrome 439

A B

C D

E F

Figure 32.7: Chest radiograph [postero-anterior view] of a pregnant woman who presented with prolonged pyrexia showing a classical miliary
pattern [A]. Fundus examination following mydriatic administration in both the eyes revealed choroid tubercles and had raised the suspicion of
miliary TB. The patient developed ARDS during the course of her illness. Chest radiograph [antero-posterior view], obtained with a portable X-ray
machine, bed-side showing bilateral frontal opacities suggestive of ARDS [B]. CT chest obtained at the same time reveals air-space consolidation
[C and D]; air-bronchogram [arrows] [D]. While assisted ventilation was being administered, the patient developed pneumothorax on the right side;
collapsed lung border is also evident [arrow] [E]. The patient required tube thoracostomy and underwater seal drainage. Eventually the patient
was weaned off the ventilator and the intercostal tube was removed following resolution of the pneumothorax. The chest radiograph obtained
thereafter shows significant improvement in the lesions [F]. The patient survived the turbulent in-hospital course, went on to complete full-term of
pregnancy and was successfully delivered a live baby
TB = tuberculosis; ARDS = acute respiratory distress syndrome; CT = computed tomography
Reproduced with permission from “Sharma SK, Mohan A, Sharma A. Challenges in the diagnosis & treatment of miliary tuberculosis. Indian J
Med Res 2012;135:703-30” (reference 30)
440 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The TST is often negative (10,26). The yield of acid- Anti-TB Drugs
fast bacilli [AFB] in the tracheal secretions depends on the
Anti-TB treatment should be instituted as soon as possible.
type of underlying pulmonary TB lesion. In fibro-cavitary
Enteral therapy may not be possible in all patients. In these
TB, TB pneumonia and endobronchial spread leading to
cases, parenteral therapy with streptomycin, isoniazid
bronchopneumonia, endotracheal aspirate will be positive
should be initiated. Injectable rifampicin may be added
for Mycobacterium tuberculosis [Mtb] in over 60% of cases
where available.
(5,24). In miliary TB the yield is much lower at approximately
33% (17). Fiberoptic bronchoscopy with TBLB or broncho­
Corticosteroids
alveolar lavage [BAL] may increase the yield to 88% (17). In
many cases, especially those with cryptic miliary TB who do Corticosteroids have been used in TB-ARDS in various
not have miliary mottling on chest radiograph, the diagnosis dosages (10,14,16,17,31,43). In addition to their immuno­
is invariably established by demonstration of TB granulomas suppressive effects, corticosteroids also inhibit synthesis of
in the liver biopsy specimen (26,29,30). several mediators of inflammation including cytokines like,
IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-a and GM-CSF (43).
MANAGEMENT They also prevent induction of the inducible forms of nitric
The basic principles of management of TB-ARDS are oxide synthase [iNOS] and cyclo-oxygenase [COX-2] (43).
the same as for ARDS due to other causes: treatment of Most workers recommend that corticosteroids be give to
basic cause, maintenance of optimum oxygen delivery, all patients with TB-ARDS along with anti-TB drugs, since
provision of adequate nutrition [preferably by the enteral up to 10% of these patients also have adrenal TB leading
route] and prevention of complications like nosocomial to adrenal insufficiency (16,17,44). The increased risk or
infections, upper gastrointestinal haemorrhage and deep upper gastrointestinal bleeding and secondary bacterial
vein thrombosis (6,41). sepsis must be weighed before instituting corticosteroid
therapy (44).
Oxygen Therapy
PROGNOSIS
Initial treatment of hypocapnic acute respiratory failure
consists of oxygen administration. The aim of therapy is to Overall mortality in TB-ARDS is between 40%-80%.
maintain arterial PaO2 above 60 mmHg and arterial oxygen Non-survivors of ARDS, regardless of the cause, die of
saturation measure by pulse oximetry [SpO2] above 90%. respiratory failure in less than 20% of cases (45). Most
Using an oxygen mask can increase fraction of inspired deaths are primarily related to the underlying disease, the
oxygen [FiO2] to 50%-60%. Pulse oximetry helps in rapidly severity of the acute illness, and the degree of dysfunction
adjusting the FiO2 to provide adequate oxygenation. If the of other organs (45). Sharma et al (5) reported that acute
desired SpO2 cannot be achieved, oxygen administered by physiology and chronic health evaluation II [APACHE II]
a non-rebreathing mask with a reservoir bag may help. score greater than 18; APACHE II score less than 18 in the
If these measures fail, or respiratory distress is severe, or presence of hyponatraemia and PaO2/FiO2 ratio less than
patient appears fatigued, tracheal intubation and mechanical 108.5 were predictors of death in patients with TB-ARDS.
ventilation may be needed (3,6,11,37,41). Zahar et al (24) have shown that patients receiving treatment
more than one month after onset of symptoms have a
Mechanical Ventilation 3.5 times higher risk of death than those in whom treatment
is started early. Deng et al (22) have observed that in miliary
The initial ventilatory strategy in patients with ARDS is
TB patients with TB-ARDS, compared to non-survivors,
to deliver tidal volumes of 6 mL/kg of ideal body weight,
survivors had a significantly shorter duration of time to
using 100% FiO2 with positive end-expiratory pressure
diagnosis, time-lag from diagnosis to institution of assisted
[PEEP] (6). After PaO 2/FiO 2 ratio reaches the desired
mechanical ventilation and time to anti-TB treatment.
levels, the FiO2 can be reduced gradually to less than 60%,
provided SpO 2 remains above 90%. Most patients will
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 33
Haematological Manifestations
of Tuberculosis
Shaji Kumar

INTRODUCTION to be more frequent and profound among patients with

disseminated TB compared to localised disease.
The interactions between the mycobacteria and the haemato­
poietic system have been a major focus of interest for
haematologists and mycobacteriologists alike for several
ANAEMIA
decades. Patients with mycobacterial infections can present Anaemia is the most common haematological manifestation
with myriad different, often puzzling, haematological of TB, and is seen in 16%-94% of patients with pulmonary
abnormalities (1,2) [Table 33.1] and different mycobacterial or extra-pulmonary TB [EPTB]. The prevalence of anaemia
infections often afflict patients with haematological disorders. is likely to be higher in the developing nations, given the
Though haematological abnormalities associated with high rates of nutritional deficiencies as well as other causes
tuberculosis [TB] have been well recognised, few studies of iron deficiency anaemia, such as worm infestations. Morris
have carefully evaluated their prevalence and relationship et al (4) observed anaemia in 60% of patients with pulmonary
with disease severity. Haematological changes have been TB, males being more frequently affected than females. In
observed with focal as well as disseminated TB and are this study (4) there was a correlation between the degree of
usually reversible with anti-TB treatment. Haematological anaemia and the presence of acid-fast bacilli [AFB] in the
manifestations of TB can be due to direct effect of the sputum and failure to correct anaemia was associated with
infectious process itself or may be a consequence of anti-TB persistence of AFB in the sputum. The anaemia observed
treatment. While haematological changes are also commonly with TB is multifactorial in aetiology [Table 33.2] and tends
seen in children with TB, a study (3) from a developing to be mostly normocytic, normochromic and less often
nation suggested that these may not be significantly different microcytic anaemia. The peripheral blood picture and the
compared to a matched group of children without TB. In haematological indices usually indicate anaemia of chronic
general, the reported haematological changes in TB appear disease. The inflammatory response seen in TB leads to
increased secretion of cytokines, such as, tumour necrosis
Table 33.1: Haematological changes in tuberculosis factor-a [TNF-a] from the monocytes, which result in a
blunted response to erythropoietin and decreased ability
Anaemia
to utilise the marrow iron stores. Morris et al (4) found
Leucocyte changes
that 81% of patients with pulmonary TB had increased
Leucopenia or leucocytosis
Lymphocytopenia iron stores, suggesting decreased release of marrow iron
Neutropenia or neutrophilia stores and suppression of erythropoiesis by inflammatory
Monocytopenia or monocytosis response mediators. However, the bone marrow iron was
Thrombocytopenia or thrombocytosis found to be decreased in another study (5). Similarly, serum
Pancytopenia iron and total iron binding capacity have been observed to
be decreased in patients with pulmonary TB and anaemia
Deep vein thrombosis
compared to those without anaemia. In addition, erythro­
Disseminated intravascular coagulation poietin level itself has been noted to be low in patients with
 Haematological Manifestations of Tuberculosis 443

Table 33.2: Aetiological factors for anaemia in TB severity or anaemia. The authors (10) concluded that
tuberculosis anaemia in patients with active pulmonary TB was probably
due to inflammation and not to iron deficiency.
Anaemia of chronic disease
Recent evidence is emerging regarding the role of
Iron deficiency hepcidin, an acute-phase reactant peptide that is the central
Nutritional deficiency
Secondary to chronic blood loss
regulator of iron homeostasis in the innate immune response
to Mycobacterium tuberculosis [Mtb] infection (11-14). Hepcidin
Folate deficiency
concentrations have been found to be strongly associated
Vitamin B12 deficiency with mycobacterial burden and disseminated TB (15).
Myelophthisic anaemia Among patients with TB, hepcidin concentrations were also
Haemolytic anaemia positively associated with greater anaemia severity.
Hypoplastic or aplastic anaemia Macrocytic anaemia is less frequently associated with
TB and is usually unrelated to folate or vitamin B12 defi­
Pure red cell aplasia
ciency (4,16). In a study of 138 patients with megaloblastic
Sideroblastic anaemia
haematopoiesis, who were also life-long vegetarians,
Drug-induced anaemia [includes marrow aplasia and haemo­lysis] 17 patients were found to have TB (16). However, Morris
Primary haematological disorder with tuberculosis disease et al (4) found that the serum vitamin B 12 levels were
elevated in over half of the patients with pulmonary TB,
while serum and red cell folate levels were normal in most
TB (6). Ebrahim et al (6) using an in vitro system of hepato­ of them. The vitamin B12 levels were higher in patients
cellular carcinoma cell lines demonstrated suppression of with leucocytosis possibly because of the elevated levels
erythropoietin secretion by monocyte supernatants from of R-binders which lead to increased concentration of
patients with pulmonary TB. The levels of TNF-a were vitamin B 12. In a study (17) of Nigerian patients with
higher in these sera and addition of neutralising antibodies TB, the cobalamin status did not appear to influence the
to TNF-a reversed some of these effects. Serum ferritin severity of anaemia seen in pulmonary or disseminated
levels have been found to be an unreliable marker for iron TB. Administration of vitamin B12 does not correct the
deficiency in patients with TB (4,7). The inflammatory anaemia in these patients. Low serum folate levels have
process in TB results in increased ferritin synthesis and high been observed in a study (5), while no relationship between
levels of ferritin in spite of decrease in iron stores. Ferritin folate levels and megaloblastic haematopoiesis was found
acts as an acute phase reactant and the levels correlate with in another study (4). Autoimmune haemolytic anaemia
C-reactive protein [CRP] concentration. In patients with TB, has been reported in association with both pulmonary and
raising the cut-off values of serum ferritin to 30 μg/L or disseminated TB and may disappear with treatment (17-19).
less, correctly diagnosed 88% patients with iron deficiency Pure red cell aplasia [PRCA] has been seen in association
compared with a figure of 61% when a cut-off value of with TB in children (20,21). Sideroblastic changes have
10 μg/L or less was used (8). A higher red blood cell volume been reported in the marrow of patients with localised or
distribution width [RDW] similar to that observed in iron disseminated TB and the anaemia has been reported to
deficiency anaemia has been reported in untreated anaemic respond to pyridoxine administration (22). There are only
patients with TB. The RDW values tended to become limited studies on the haematological changes in patients
normal with anti-TB treatment (9). In a study (10) from with disseminated and miliary TB (23-28). In a study (25)
Indonesia, the distribution of three polymorphisms in the comparing patients with disseminated and miliary TB
solute carrier family 11 member 1 gene [SLC11A1], previously and those with pulmonary TB, normocytic, normochromic
known as natural resistance-associated macrophage anaemia was the most common abnormality observed in
protein 1 [NRAMP1], including INT4, D543N and 3’UTR both the groups. Moderate degree of anaemia has been
was examined for a possible association with susceptibility observed in 52%-72% of the patients in most series (26,27,29).
to TB. The authors (10) studied 378 patients with active The anaemia is predominantly normocytic and normo­
pulmonary TB and 436 healthy control subjects from the chromic (30). Autoimmune haemolytic anaemia [AIHA] and
same neighbourhood with the same socio-economic status. PRCA have been reported in association with disseminated
Anaemia was present in 63.2% of the patients with active TB (31-33). Anaemia can be a prominent finding in patients
pulmonary TB compared with 6.8% of the control subjects. with gastrointestinal TB, where blood loss can complicate
Anaemia was more pronounced in female patients and those the anaemia of chronic disease (34).
with extensive disease as assessed by the chest radiograph. Recent studies have shown that presence of anaemia
Patients with active pulmonary TB and anaemia had lower at the time of diagnosis of TB was associated with a poor
plasma iron levels, iron binding capacity and higher ferritin prognosis and an increased risk of death (35,36). Isanaka
levels. Even without iron supplementation, anti-TB treatment et al (37) analysed data from a randomised clinical trial of
resulted in normalisation of the plasma iron, iron binding micronutrient supplementation in patients with pulmonary
capacity and ferritin levels. However, NRAMP1 gene poly­ TB in Tanzania. The authors (37) reported that anaemia
morphisms were not associated with TB susceptibility, without iron deficiency was associated with an independent,
444 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

four-fold increased risk of TB recurrence. Iron deficiency, in patients with disseminated TB (39). Hypereosinophilic
anaemia with and without iron deficiency were associated syndrome with organ damage (51) as well as isolated
with a greater than two-fold independent increase in the risk eosinophilia (52,53) have also been reported in association
of death. with TB.

LEUCOCYTE CHANGES PLATELET ABNORMALITIES

Mild leucocytosis and a left shift with increased myelocytes Patients with pulmonary or disseminated TB usually have
and metamyelocytes, in the peripheral blood is the most mild thrombocytosis, probably due to increased thrombo­
common finding in most of the studies and has been seen in poiesis reflecting an acute phase reaction (38,54). The increased
6%-22% of patients (38). Patients with pulmonary TB more thrombopoiesis may be in part be driven by inflam­matory
frequently have leucocytosis whereas leucopenia is rare. TB cytokines, such as IL-6. The IL-6 is known to increase the
can result in increased myelopoiesis and the bone marrow and megakaryocytes in vitro (55). In a study comparing patients
peripheral blood may show a leukaemoid reaction (39-41). with pulmonary TB with healthy volunteers, the median
Patients with advanced TB often have higher counts than IL-6 concentrations were higher among those patients with
those with minimal disease. Mild leucopenia with counts thrombocytosis compared to those with normal platelet
less than 4 × 109/L has been documented in 1.5%-4% of counts (56). The IL-6 concentrations were significantly
patients (4). Prevalence of leucopenia in most studies is correlated with acid-fast bacilli [AFB] positivity. Hence, it
either equal to or higher than leucocytosis (38). Leucopenia appears that IL-6 might play a contributory part in reactive
and neutropenia were significantly higher in patients with thrombocytosis and acute phase response in TB.
disseminated TB. Neutrophilia has been observed in 20%- Thrombocytopenia is more common in patients with
60% of patients while leucopenia has been documented in disseminated TB, whereas, thrombocytosis is more common
10%-30% patients with miliary TB (23,24,42). Neutropenia in pulmonary TB. However, isolated thrombocytopenia
has been observed in patients with disseminated TB (38). has occasionally been described in pulmonary TB and its
The mechanisms of neutropenia may include hypersplenism, pathogenesis is believed to be immune mediated (38,57-60).
increased neutrophil demand, or excessive margination of Anti-platelet antibodies and platelet associated immuno­
neutrophils. Cell-mediated autoimmune mechanisms may globulin G [IgG] have been demonstrated in some patients.
be responsible for neutropenia in some of the patients (43). Boots et al (57) reported a case of immune thrombocytopenia
Presence of Pelger-Huet anomaly [two symmetric, usually with pulmonary TB, where additional studies showed
rounded nuclear lobes joined by a thin-strand formed by presence of platelet bound IgG antibodies without any
hypercondensation of nuclear chromatin that creates a circulating anti-platelet anti- bodies. In contrast to antibodies
spectacle-like appearance] has been described in TB (44). in patients with idiopathic thrombocytopenic purpura,
Decrease in the peripheral blood CD4+ subset of the antibodies in this patient did not react with normal
T-lymphocytes has also been documented and may be seen donor platelets and the thrombocytopenia resolved with
in up to 15% of patients and is more common in disseminated intravenous immunoglobulin therapy (57,58). There is an
and miliary TB (45,46). Lymphopenia appear to be more inverse correlation between platelet count and the mean
common than lymphocytosis in patients with pulmonary platelet volume, and increased numbers of small platelets
TB (38,46,47). The decreased count usually returns to the have been described in these patients which have a
normal level following effective therapy (48). While the shortened survival (61). Thrombocytopenia is more common
reasons behind the lymphopenia in TB are not entirely clear, in patients with disseminated TB and has been reported in
it may reflect continued recruitment of CD4+ T-lymphocytes 23%-43% of patients (24,62,63). Majority of these patients,
to the sites of granuloma formation (48). In a study (49) however, does not have any significant bleeding. Thrombotic
of lymphocyte populations in peripheral blood, pleural thrombocytopenic purpura has been seen with lymph node
fluid, and ascites during TB infection, recent infection was as well as pulmonary TB and has been hypothesized to
associated with peripheral blood lymphocytosis involving be due to an increased procoagulant activity of IL-1 on
both CD4+ and CD8+ cells compared to no changes in endothelial cells (64,65).
previously diagnosed patients. No changes were found in
the numbers of B-lymphocytes or natural killer [NK] cells
PANCYTOPENIA
in either recently infected or previously diagnosed patients.
The pleural effusion and ascitic fluid samples contained Pancytopenia is infrequent and has been observed in only
T-lymphocytes, the majority of which were CD4+ cells. These 3%-12% of cases (66). Pancytopenia is rare in patients with
lymphocytes also showed an inverted CD45RA-to-CD45RO pulmonary TB and may occur occasionally as a result of drug
ratio, and had high-level expression of the interleukin-2 toxicity in these patients (62,66-70). It is mostly associated
[IL-2] receptor [CD25] in some patients. with an underlying haematological disease although cases
Both monocytosis and monocytopenia have been associated with severe miliary TB alone have been described.
documented in patients with TB (4). Monocytopenia has been Patients with disseminated TB may have splenomegaly as
reported in as many as 50% of the patients and may correlate a result of the disease process, underlying haematological
with the disease severity (50). Basophilia has been reported disease or both. Splenomegaly may contribute to the
 Haematological Manifestations of Tuberculosis 445

haematological abnormalities including pancytopenia in in patients with miliary TB (86). Budd-Chiari syndrome has
some of these patients (71). The pancytopenia may resolve been reported in a child with hepatic TB (87). Portal vein
after splenectomy in some of these patients, suggesting that thrombosis has been reported in association with abdominal
hypersplenism may be one of the mechanisms of pancytopenia TB (88).
in these patients. Pancytopenia in disseminated TB has
also been attributed to haemophagocytosis, even though BONE MARROW CHANGES IN TUBERCULOSIS
hypocellularity of the marrow has also been reported (71-73).
All these haematological abnormalities including pancyto­ Both localised and disseminated TB, can lead to a
penia often reverse with effective therapy (70). spectrum of histopathological changes in the bone marrow
[Table 33.3]. These changes include typical caseating
granuloma formation, non-caseating granulomas, marrow
COAGULATION ABNORMALITIES
hypoplasia, red cell aplasia, megaloblastosis, haemophago­
Various coagulation abnormalities have been described cytosis, and necrosis of the marrow (28,89). In majority of
in patients with pulmonary as well as disseminated TB. the patients, the bone marrow shows normal to increased
Disseminated intravascular coagulation [DIC] has been cellularity and myeloid hyperplasia (75). In most patients
documented in disseminated as well as pulmonary TB and with pulmonary TB, the marrow shows “reactive changes”
often is accompanied by a high mortality rate (68,74-79). with increased granulocytic hyperplasia with mild to
In these patients activated partial thromboplastin time moderate plasmacytosis (4). Bone marrow plasmacytosis
and thrombin time are increased and the antithrombin-III is seen less frequently in miliary TB and can be a helpful
[AT-III] activity is often reduced. In a retrospective study differentiating feature (4,28,90).
of 833 culture-proven TB patients with DIC were evaluated Bone marrow granulomas [Figures 33.1 and 33.2] are
before starting anti-TB treatment (80). Nearly 3.2% of them present in 50%-100% of patients with miliary TB and are
had TB induced DIC with a mortality rate of 63%. Seven usually absent in pulmonary TB (91). In a study (92) of 6,988
of the 27 patients with DIC [25.9%] had disseminated bone marrow biopsies, 6% of patients in whom granulomas
TB. An early institution of anti-TB treatment significantly were present in the bone marrow had TB as the inciting
improved survival in this study. Acquired Factor V cause. Patients with peripheral blood abnormalities are
deficiency with variable bleeding manifestations has been
described in patients with pulmonary TB. This abnormality
disappears with anti-TB treatment (81). Sarode et al (80) Table 33.3: Bone marrow changes in tuberculosis
reported the presence of platelet hyperaggregation in 88% Myeloid hyperplasia
patients with intestinal TB. Serum and plasma from 15 Plasmacytosis
of these patients, when incubated with normal platelets Megaloblastoid maturation
caused hyperaggregation as well (80). This abnormality
Hypoplasia or aplasia
may be related to increased levels of CRP in these patients.
Haemophagocytosis
Transient thrombasthenia has been reported in patients with
TB (82). Transient protein S deficiency has been reported Caseating and non-caseating granulomas
in association with TB and deep vein thrombosis [DVT]; Bone marrow necrosis
however, a direct pathological relationship could not be Myelofibrosis
established.
Deep vein thrombosis confirmed by venography has
been observed in 3%-4% of patients with pulmonary TB (83).
In a group of patients with active pulmonary TB, thrombo­
cytosis, elevations in plasma fibrinogen, fibrin degradation
products [FDP], tissue plasminogen activator [t-PA] and
inhibitor [PAI-1] with depressed AT-III levels were seen (84).
In another study (85) comparing 45 patients of active pulmo­
nary TB with healthy volunteers, elevated levels of plasma
fibrinogen, Factor VIII, PAI-1 and depressed AT-III and
protein C levels were observed. Following treatment,
fibrinogen and Factor VIII, protein C and AT-III levels
normalized. There was no evidence of activated protein
C resistance. Platelet aggregation studies demonstrated
increased platelet activation. Age, gender and disease
matched individuals with venographically proven DVT had
higher FDP, t-PA, and functional PAI-1 activity. Fibrinogen
levels in all patients rose during the first-two weeks of Figure 33.1: Bone biopsy showing a well-defined tuberculosis
therapy and, together with related disturbances, corrected granuloma composed of epithelioid cells and Langhans’ giant cells
within 12 weeks. Bone marrow emboli have been reported [arrow] [Haematoxylin and eosin, × 100]
 446 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B

Figure 33.2: Bone biopsy showing a tuberculosis granuloma composed

of epithelioid cells and Langhans’ giant cells [arrows] [Haematoxylin
and eosin, × 400]

more likely to have granulomas in the bone marrow (42). TB

granulomas usually show the presence of Langhans’ giant
cells and caseation necrosis in 60%-70% of cases (24,28).
Caseation necrosis and the presence of AFB in the granulomas
is diagnostic of TB. It has been observed that near these
granulomas the marrow cellularity is often greater or lower,
and there may be an increase in reticulin fibres and in severe
cases myelofibrosis may occur (93). Reticuloendothelial cells
in the bone marrow may show phagocytosis of erythrocytes,
leucocytes and platelets, commonly referred to as haemo­
C
phagocytosis. It is more often seen in disseminated TB and
disappears with treatment (94,95). Figure 33.3: Primary HLH. A 19-year-old male who presented with fever,
pancytopenia and splenomegaly. Photomicrograph of bone marrow
Bone marrow necrosis has been described in patients
aspirate showed increased cellularity [Giemsa, × 100] [A], [Giemsa,
with disseminated TB (96-99). The bone marrow in patients × 400] [B], histiocyte with ingested red blood cells and lymphocytes
with untreated TB may show megaloblastic changes in as [arrows] [Giemsa, × 1000] [C] suggestive of HLH. Collagen vascular
many as 60% of patients with disseminated TB, but this disease profile was negative. Further diagnostic work-up confirmed the
does not reflect vitamin B12 or folate deficiency in these diagnosis of primary HLH
patients (28). Bone marrow aspirate iron stores are usually HLH = haemophagocytic lymphohistiocytosis
increased reflecting poor iron usage, though these may be
decreased in some patients. Patients with poor nutritional
status may have decreased iron status on bone marrow haemophagocytosis, in which activated macrophages engulf
examination (31). blood cells or their precursors and cytokine storm (101).
Bone marrow examination is often a helpful diagnostic Primary [Figure 33.3] and secondary HLH have been
tool in TB. The AFB may be demonstrated in the bone described. The wrevised diagnostic criteria for HLH are
marrow morphologically within the granulomas or by shown in Table 33.4 (102). Macrophage activation syndrome
mycobacterial culture. In a study of patients with pulmonary [MAS] (102) is a clinical syndrome characterised by
TB (100), AFB were detected in 55% cases in the buffy coat, pancytopenia, elevated serum triglyceride levels, and/
and in 48.3% cases in the bone marrow. In 38.3% cases, or hypofibrinogenaemia, evidence of haemophagocytosis
the AFB could be demonstrated both in the buffy coat as in bone marrow, spleen or lymph nodes [Figure 33.4].
well as the bone marrow. It is possible to use polymerase Other associated laboratory abnormalities include hyper­
chain reaction [PCR] to detect Mtb in bone marrow aspirate ferritinaemia and elevated blood levels of lactate dehydro­
material and this technique may be more sensitive than the
genase. Presently several workers classify MAS as a category
conventional culture methods (53).
of secondary HLH and efforts are underway to streamline
the contemporary classification of histiocytic disorders.
HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS,
Secondary HLH, MAS due to TB [Figure 33.4] has
MACROPHAGE ACTIVATION SYNDROME been described in some of the recently published
Haemophagocytic lymphohistiocytosis [HLH] is an under- reports (96,97,103-106). Shea et al (107) recently reported
recognised hyperinflammatory disorder characterised by two cases and reviewed the published literature regarding
 Haematological Manifestations of Tuberculosis 447

Table 33.4: Revised diagnostic guidelines for HLH* 55 cases and suggested that TB is an important treatable
cause of secondary HLH which can be fatal if untreated.
Fever
Splenomegaly
Cytopenias in blood ≥2 cell lineages in the peripheral blood
NONTUBERCULOUS MYCOBACTERIAL
Haemoglobin < 9 g/dL [in infants <4 weeks < 10 g/dL] INFECTION
Platelets < 100 × 109/L
Neutrophils < 1.0 × 109/L Haematological abnormalities are commonly observed in
Hypertriglyceridemia and/or hypofibrinogenemia: patients with localised or disseminated infection caused by
Fasting triglycerides ≥ 265 mg/dL nontuberculous mycobacteria [NTM], but a causal relation­
Fibrinogen ≤ 1.5 g/L ship is often difficult to confirm given the usual immuno­
Haemophagocytosis in bone marrow or spleen or lymph nodes compromised status of the typical host and other predisposing
No evidence of malignancy illnesses. NTM infections are on the rise globally, especially
Low or absent NK-cell activity [according to local laboratory due to the ongoing acquired immunodeficiency syndrome
reference] [AIDS] epidemic. Anaemia can be seen in almost all patients
Ferritin ≥ 500 mg/L with NTM (108). Leucopenia, thrombocytopenia and
Soluble CD25 [i.e., soluble IL-2 receptor] ≥ 2,400 U/mL pancytopenia have been observed in nearly half of the
*Diagnosis requires a molecular diagnosis of primary HLH or the patients (109). Plasmacytosis and granulocytic hyperplasia
presence of ≥ 5 of 8 diagnostic criteria are common findings in the bone marrow (108). Granulomas
HLH = haemophagocytic lymphohistiocytosis; NK-cell = natural can be found in approximately half of the patients and
killer-cell; IL-2 = interleukin-2 range from small and lymphohistiocytic aggregates to larger
Source: reference 102
lymphohistiocytic lesions and clusters of epithelioid cells

A B

C D E
Figure 33.4: Secondary HLH due to TB. A 29-year-old male presented with fever, abdominal lymphadenopathy and pancytopenia. Photomicrograph
of the peripheral blood smear showing pancytopenia [Giemsa, × 100] [A]. Photomicrograph of the bone marrow aspirate showed increased cellularity
[Giemsa, × 100] [B], haemophagocytic lymphohistiocytosis [arrows] [Giemsa, × 400] [C]. Photomicrograph of the bone marrow trephine biopsy
showed aggregates of epithelioid cells forming granulomas [circle] [Haematoxylin and eosin, × 400] [D], necrosis and multinucleate giant cells
[circle] [Haematoxylin and eosin × 400] [E] suggestive of necrotising granulomatous inflammation. The patient responded well to anti-TB treatment
HLH = haemophagocytic lymphohistiocytosis; TB = tuberculosis
448 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and lymphocytes (108). Unlike the granulomas associated reverses on withdrawal of the drug (116). Aplastic anaemia
with TB, necrosis is not commonly seen in these granulomas. has been documented with disseminated bacille Calmette-
Usually, few bacteria are demonstrable in the bone marrow Guérin [BCG] infection (117). Treatment with PAS may
biopsy in patients with TB, whereas numerous AFB can be cause malabsorption and result in vitamin B12 deficient
seen in patients with disease due to M. avium intracellulare megaloblastic anaemia (118).
complex [MAIC]. Farhi et al (108) found granulomas in the Leucopenia, agranulocytosis and aplastic anaemia have
bone marrow in 12 of 24 patients with disseminated MAIC been observed following isoniazid, rifampicin and PAS
infection. administration (86,119-123). Anti-TB treatment induced
leucopenia appears to be more commonly seen in elderly
DRUG-INDUCED HAEMATOLOGICAL CHANGES patients (124). Leucopenia is rare with ethambutol use (120).
Para-aminosalicylic acid can produce atypical lymphocytosis
Many of the abnormalities seen with TB can also be induced by simulating infectious mononucleosis. Eosinophilia can occur
the anti-TB drugs and often makes the diagnosis difficult in a with rifampicin therapy (125) and also has been reported
patient initiated on therapy [Table 33.5]. Drug-induced AIHA with ethambutol (126).
can be precipitated by isoniazid, rifampicin, streptomycin The use of rifampicin may produce immune-mediated
as well as para- aminosalicyclic acid [PAS] (110-112). In thrombocytopenia and the antibodies may be directed against
patients receiving rifampicin, a flu-like prodrome may precede the glycoprotein Ib/IX complex (127-130). Antibodies of IgG
the onset of the intravascular haemolysis. In many of these and immunoglobulin M [IgM] type have been demonstrated
patients, direct Coomb’s test will become positive. Sidero­ in many of these patients. Thrombocytopenia has been
blastic anaemia is a well-documented adverse effect of more frequently observed when twice weekly regimen of
isoniazid therapy and usually occurs after several weeks of 900 mg rifampicin was used and it resolves with reduction
therapy (113,114). The bone marrow usually shows normo­ of dose to 150-300 mg/day. Isoniazid, pyrazinamide (131),
blastic hyperplasia with ring sideroblasts and the indices streptomycin, ethambutol (132,133), and PAS (134) may also
of iron metabolism are usually within normal range. The produce thrombocytopenia. Thrombotic thrombocytopenic
anaemia reverses on withdrawal of the drug and admini­ purpura has been reported in association with rifampicin (135).
stration of pyridoxine. Sideroblastic anaemia has also been Coagulation abnormalities are rare with anti-TB drugs.
occasionally reported with pyrazinamide (115). Isoniazid Rarely, DIC following isoniazid and rifampicin therapy has
may also produce an immune-mediated PRCA which been documented (136). Acquired Factor XIII deficiency due
to inhibitors has been reported with isoniazid therapy (137).
Table 33.5: Haematological changes due to In most cases, the inhibitors have been shown to be IgG
anti-TB treatment antibodies and these patients may present with severe
subcutaneous and retroperitoneal bleeding. The pathogenesis
Autoimmune haemolytic anaemia
Rifampicin
of isoniazid associated Factor XIII inhibitor is not fully
Para-aminosalicylic acid understood. Lorand et al (138) have proposed that isoniazid
Isoniazid binds to Factor XIII or one of its substrates and antigenically
Megaloblastic anaemia
modifies the protein resulting in autoantibody production.
Para-aminosalicylic acid PAS can produce hypothrombinemia (4). Increased incidence
of DVT has been reported among patients with TB receiving
Sideroblastic anaemia
Isoniazid
rifampicin (4). This may be related to the induction of
Cycloserine enzyme cytochrome P-450 system by rifampicin which alters
Pyrazinamide the balance between anticoagulant and coagulant proteins
Pure red cell aplasia resulting in a state of hypercoagulability. A relationship
Isoniazid between administration of isoniazid alone or in combination
with rifampicin and fibrinogen as well as AT-III blood levels
Agranulocytosis
Streptomycin has been seen in one study (139). These observations indicate
Thioacetazone a protective effect of the synchronous administration of
Para-aminosalicylic acid rifampicin in the preservation of fibrinogen blood levels by
Autoimmune thrombocytopenia enzyme induction mechanisms.
Rifampicin
Para-aminosalicylic acid ACQUIRED IMMUNODEFICIENCY SYNDROME
Isoniazid
Various haematological abnormalities have been described
Aplastic anaemia
Streptomycin
in patients with human immunodeficiency virus [HIV]
Para-aminosalicylic acid infection and AIDS (140-143). In patients with AIDS, isolated
thrombocytopenia has been observed during early part of
Disseminated intravascular coagulation
Isoniazid the disease (144); severe degree of anaemia, leucopenia
and pancytopenia are more often observed in advanced
TB = tuberculosis
disease (145,146). Leucocytosis is more often observed in
 Haematological Manifestations of Tuberculosis 449

patients with extra-pulmonary TB without HIV infection 7. Baynes RD, Flax H, Bothwell TH, Bezwoda WR, MacPhail AP,
than in patients with AIDS (147). Hill et al (148) have Atkinson P, et al. Haematological and iron-related measurements
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 34
Endocrine Implications
of Tuberculosis
CV Harinarayan, Shalini Joshi, SP Munigoti

INTRODUCTION Clinical Presentation

Tuberculosis [TB] can affect various endocrine glands in Clinical presentation of patients with hypothalamo-pituitary
the body. Endocrine involvement has been observed in involvement would depend on the extent of central nervous
pulmonary TB, extra-pulmonary TB [EPTB], disseminated TB system [CNS] involvement. Meningeal symptoms, such as,
and miliary TB. Further, anti-TB drugs induce cytochrome headache are the most common amongst those reported.
P-450 oxidase enzymes which can enhance the catabolism Sellar lesions themselves tend to be asymptomatic and
of hormones. The present chapter provides an overview get diagnosed radiologically but could manifest with
regarding the endocrine implications of TB. endocrine abnormalities. Involvement of posterior pituitary
could result in polydipsia and polyuria secondary to
TUBERCULOSIS AND HYPOTHALAMUS, diabetes insipidus. A review of 54 cases (1), revealed
PITUITARY INVOLVEMENT female preponderance [females: males ratio 2:1]. Majority
of patients were found to be young [< 45 years] and
Pituitary and Tuberculosis headache appeared to be the most common symptom [91%].
Epidemiology Suprasellar involvement was found in 74% of the cases
while sellar enlargement was seen in 95% of the cases on
Pituitary involvement in TB remains rare. TB is responsible neuroradiology imaging. In this study (1), non-preferential
for 20% of the intracranial space occupying lesions in India anterior pituitary involvement was described in more than
and tuberculomas of the sellar and suprasellar region half the cases and hyperprolactinaemia was observed in a
comprise 1% of all intracranial tuberculomas (1). Studies quarter of the cases. Posterior pituitary involvement leading
documenting hypothalamo-pituitary involvement in TB to diabetes insipidus was seen in 11% of the cases. Others
published from India are summarised in Table 34.1 (2-8). reported growth hormone and gonadotropin deficiency
In the western countries the reported frequency of sellar
as more common endocrine abnormalities (12-18). Less
tuberculomas is 0.25%-4% (4).
common endocrine abnormalities are those of corticotropic
and thyrotropic hormones manifesting as secondary
Pathogenesis adrenocortical insufficiency or hypothyroidism. In children,
TB hypophysitis can occur as a localised sellar/suprasellar the presentation could be either anterior or posterior
lesion or can be a part of a widespread disease involving pituitary dysfunction with compressive features. Clinical
the either rest of the brain parenchyma and/or meninges. manifestations are those of short stature or hypogonadism.
Intra-sellar tuberculomas may present as apoplexy. The Isolated diabetes insipidus has been reported in a young
usual mode of spread of infection to the pituitary is via male with supra-sellar involvement (15). Though pituitary
haematogenous route or direct spread from the paranasal hypofunction is more common, hormonal over activity
sinus (9-11). presenting as central precocious puberty has been reported in
454 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 34.1: Studies documenting hypothalamo-pituitary involvement in TB published from India

Study [year] (reference) Clinical manifestations Remarks
Sunil et al [2007] (1) A patient with prostatic TB on treatment developed diabetes mellitus, Case presentation and review of 54
loss of libido and headache. While on treatment for diabetes previous reported cases with sellar/
mellitus with insulin he gradually developed hypo­glycaemia. Anti- suprasellar TB
diabetic medication was stopped; evaluation for hypoglycaemia
revealed hypocorticism and pituitary mass, which on excision and
histopathological examination revealed epithelioid granulomas, giant
cell and caseation necrosis suggestive of TB
Ranjan et al [2011] (2) Young lady presented with progressive headache, found to have Sellar abscess diagnosed after culture
with hypothyroidism, hyperprolactinaemia. She responded to anti-TB of purulent discharge grew Mtb
treatment and was symptom free at follow-up
Mageshkumar et al Patient presented with sellar and suprasellar lesions with widespread Widespread inflammation resulted in
[2011] (3) CNS TB needing decompression for hydrocephalus with a shunt and hypopituitarism
also full hormone replacement therapy along with anti-TB treatment
Mittal et al [2010] (4) Full resolution of a sellar mass presenting as visual loss following Tuberculoma with apoplexy and sellar
haemorrhage that resolved completely with surgery and anti-TB haemorrhage causing compression of
treatment optic chiasma
Furtado et al [2011] (5) Panhypopituitarism Isolated tuberculoma presenting with
hypopituitarism
Hussain et al [2008] (6) Hypopituitarism Granulomatous hypophysitis diagnosed
as TB after CSF PCR tested positive
Satyarthee and Mahapatra Diabetes insipidus Rare presentation of sellar-suprasellar
[2003] (7) tuberculoma
Dutta et al [2006] (8) Patient presented with visual disturbances, diabetes insipidus with Pituitary TB abscess presenting with
panhypopituitarism. Diagnosis of TB confirmed on histopathological compressive features and endocrine
examination that revealed granulomas and tested positive for acid-fast dysfunction
bacilli
TB = tuberculosis; Mtb = Mycobacterium tuberculosis; CNS = central nervous system; CSF = cerebrospinal fluid; PCR = polymerase chain
reaction

children with preceding history of TB meningitis in as many erosion of the sellar floor (11) are some other findings
as 31% girls and 27% boys (16). Hyperprolactinaemia as a described on the MRI.
result of stalk compression and release of anterior pituitary
from inhibiting effect of dopamine due to tuberculoma have Surgery
also been recorded (14). Transsphenoidal surgery is the only way to establish
definitive diagnosis. Other than TB, histopathologically,
Diagnosis the differential diagnosis of granulomatous hypophysitis
includes sarcoidosis, mycotic infection, hypophysitis due
Imaging Studies Pituitary lesions in a patient with or without to ruptured intrasellar Rathke cleft cyst, histiocytosis
background TB would be evident after neuroradiological X and idiopathic causes (19-23). Granulomas in TB are
imaging including computed tomography [CT] and magnetic typically described to be characterised by a central area
resonance imaging [MRI]. Pituitary tuberculomas are of caseous necrosis surrounded by epithelioid cells,
isointense on T1 weighted MRI images and usually exhibit macrophages, lymphocytes and plasma cells. Identification
intense post-contrast enhancement on MRI and CT. Contrast of Mycobacterium tuberculosis [Mtb] itself is clearly diagnostic.
MRI [Figure 34.1] demonstrates thickening of the stalk Sometimes diagnosis is made after the culture results of
thought to be due to chronic inflammatory scarring (17). suspected cases turn positive. In cases of further ambiguity,
But, this thickening of the stalk is non-specific and is molecular diagnostic testing in cerebrospinal fluid could also
described in other diverse clinical conditions, such as be helpful (6).
neoplasms, sarcoidosis, syphilis, lymphocytic hypophysitis,
granulomatous hypophysitis and eosinophilic granuloma. Treatment
More so, suprasellar extension could make stalk evaluation Standard anti-TB treatment as for other forms of EPTB is
difficult on neuroimaging. Peripheral ring enhancement reported to result in good response. However, in some
of the mass, enhancement of the adjacent dural and basal patients, full functional recovery remains uncertain in
enhancing exudates due to meningitis, isolated stalk spite of adequate anti-TB treatment and patients may need
thickening, sellar/suprasellar calcification, apoplexy and hormone replacement therapy for life (1).
 Endocrine Implications of Tuberculosis 455

A B

C D
Figure 34.1: Post-contrast MRI of sella showing enlarged pituitary gland [A], thickened pituitary stalk [arrow] [B]; thickened dura [thick arrow],
pituitary stalk along with enlarged pituitary gland [thin arrow] [C]. Photomicrograph [D] of the pituitary gland showing Langhans’ giant cells
[arrows], a small focus of caseation necrosis [thick arrow] and epithelioid cells [arrow heads]. No normal pituitary tissue is identified [Haematoxylin
and eosin, × 45]
MRI = magnetic resonance imaging

Tuberculosis and Altered Water and pituitary as a stimulus for increased AVP (33-35) are some of
Electrolyte Metabolism the other postulates put forward to explain hyponatraemia.
Clinical presentation of hyponatraemia is usually mild,
In patients with pulmonary TB, hyponatraemia unexplained asymptomatic and self limiting. Water restriction as a
by primary renal and adrenal abnormality has been conservative therapy should be restricted to patients with
described (24). This was described as syndrome of serum sodium levels less than <125 mEq/L (25,34,35).
inappropriate antidiuretic hormone [SIADH] secretion by SIADH in TB meningitis carries a poor prognosis.
Schwartz et al (25). In the presence of subnormal plasma Prompt recognition of this condition and management is
osmolarity and no volume depletion, there is incomplete important (36).
suppression of peripheral arginine vasopressin [AVP].
This syndrome presents as hyponatraemia, elevated
Tuberculosis and Adrenal Gland
urinary sodium concentration and urine osmolarity.
This syndrome is seen mostly in EPTB such as TB Thomas Addison described chronic adrenocortical
meningitis (26-28), miliary TB (29) and TB epididymo- insufficiency in 1855. The term “Addison’s Disease” refers
orchitis (30). Increased adsorption of the AVP in the to chronic primary adrenocortical insufficiency. Ethnic
lung tissue is one of the postulated mechanisms (31). variations in the aetiology of chronic adrenal insufficiency
Disturbed or down set osmoregulatory mechanisms due have been described (37). While 92% of Caucasians have
to active TB (32) and circulating mediators of acute phase hypoadrenalism due to autoimmune disease, TB is the
reaction, such as, inflammatory cytokines, acting on posterior cause of hypoaderenalism 63% of Polynesians (37). TB is
456 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

still the most common cause of primary hypoadrenalism in cortisol before, 30 and 60 minutes after an intramuscular
developing countries (38,39) unlike western world where injection of 250 μg of cosyntropin (46,47).
autoimmune adrenalitis dominates the picture. Basal serum cortisol is either normal or increased (48,49).
In up to 6% of patients with active pulmonary TB, adrenal An autopsy series demonstrated that high basal serum
gland involvement has been observed. Adrenal glands are cortisol was evident in patients with adrenal granulomas
a good nidus for mycobacterium not only because of rich (50). Basal serum cortisol has been observed to be inversely
vascular supply but also due to the fact that high levels proportional to duration of symptoms (51). A direct
of local corticosteroids suppress cell mediated immune correlation between the sputum smear-positivity for acid-
response. Corticosteroid hormones have most pronounced fast bacilli [AFB], extent of disease, pyrexia and elevated
effect on lymphocyte blast transformation with mitogens erythrocyte sedimentation rate and adrenal reserve has been
persisting even after discontinuation of their use (40). The documented (51). Hyperfunctioning of the adrenal glands in
most common sites in order of involvement are liver, spleen, response to stress and infection is thought to be the cause of
kidneys and bones. Primary isolated TB adrenalitis is very increased basal serum cortisol. The ACTH stimulation tests
rare and should be considered in any patient with fever in patients with TB have shown normal or compromised to
and enlargement of adrenals (41). Similarly adrenal TB in a significant extent (48,52).
Cushing’s disease with bilateral macronodular adrenocortical
hyperplasia has been documented as an incidental diagnosis Adrenal Imaging
on histopathological examination post-surgery (42).
In the active stage of the disease, TB adrenalitis shows
Whereas release of adrenal corticosteroids is elevated in
features of enlarged adrenals associated with large,
acute infections (43), adrenal reserves in chronic infections hypoattenuating necrotic areas, with or without dot like
like TB is a subject of controversy. Overt adrenal insufficiency calcification [Figure 34.2], In the chronic stage the adrenal
occurs when more than 80%-90% of both the adrenal glands glands are typically shrunken and calcified, (44,53-55).
are destroyed. But subclinical adrenal insufficiency can Patients with enlarged adrenal gland have longer duration
occur without any evidence and can manifest when there is of disease.
an increased [supra] physiological requirement of adrenal Table 34.2 (51,56-58) summarises some of the studies from
hormones to meet heightened metabolic demands. India on adrenocortical reserve in various forms of TB.

Pathogenesis Treatment
Adrenal damage caused by TB is thought to be immune Subjects already receiving corticosteroids need to increase
mediated. Increased cortisol secretion secondary to the corticosteroid dose following anti-TB therapy. Reversal
activation of hypothalamo-pituitary axis thereby shifting of adrenal function after anti-TB therapy is controversial.
Th1/Th2 balance towards Th2 T-cell dysfunction is one of Reversibility has been seen as early as two weeks after the
the proposed mechanisms to explain TB adrenalitis and beginning of anti-TB therapy (48,59). There is a report (48)
subsequent hypoadrenalism (44). Anti-TB therapy with that rifampicin possibly prevents improvement of adrenal
rifampicin [a potent hepatic microsomal enzyme inducer] reserve with anti-TB therapy; however, observations from
reduces the half-life of corticosteroids which may unmask another study do not support this view (48,49). In a study of
the subclinical adrenal reserve and lead to Addisonian adrenal reserve in patients in 105 human immunodeficiency
crisis (45). There are reports of sudden death and rapid virus [HIV] seronegative patients with various forms TB
deterioration of clinical condition with anti-TB therapy. [72 pulmonary TB, 33 EPTB] Sharma et al (59) reported that
49.5% of the subjects had compromised adrenal reserve at
Clinical Presentation baseline. At six months of therapy the responders increased
Acute abdominal pain, vomiting, severe hypotension or to 71% and at 24 months of therapy 97% demonstrated
hypovolaemic shock and fever are presenting features of normal adrenal reserve. This fact has clinical relevance in
acute adrenal insufficiency. Fatigue, irritability, asthenia, acute stressful setting. Interestingly in this study (59), with
anti-TB treatment the adrenal insufficiency reversed in
loss of muscle strength, weight loss, nausea, anorexia, hyper­
majority of the patients.
pigmentation, salt craving and failure to thrive [in children]
There is sparse literature of adrenal reserve in patients
are features of chronic adrenal insufficiency. If these
co-infected with HIV and TB. The adrenal reserve was
symptoms appear after the initiation of anti-TB therapy,
compromised in nearly 50% of patients with both HIV-
it should raise the suspicion of hypocortisolism.
seropositive and seronegative patients with active TB (60,61).
Investigations Tuberculosis and Thyroid
Estimation of paired sample for morning [8 AM] cortisol along
Epidemiology and Pathogenesis
with adrenocorticotrophic hormone [ACTH] differentiates
primary and secondary adrenal insufficiency. Adrenal TB affecting thyroid gland is very rare. The first case of TB
reserve is most reliably estimated by estimating serum of thyroid was described by Lebret, in 1862, in a patient
 Endocrine Implications of Tuberculosis 457

A B

C D
Figure 34.2: Post-contrast MRI of adrenal gland showing enlarged adrenals with calcification [arrows] [A]; shrunken adrenal with more calcification
[arrows] [B]; bilateral shrunken and calcified [totally destroyed] adrenals [arrows] [C]; and clinical photograph showing hyperpigmentation of hands
and palms in Addison’s disease [D]
MRI = magnetic resonance imaging

Table 34.2: Studies from India on adrenocortical reserve in various forms of TB

No. of patients
Study [year] (reference) studied Basal cortisol Post-ACTH stimulation Comments
Srivastava et al [1980] 84 PTB Elevated in all patients Not described Sputum smear-positive patients had
(51) higher cortisol. Patients with longer
duration of symptoms had lower
serum cortisol
Behera and Dash 28 PTB Basal values comparable Mean delta peak, mean and There is functional impairment of
[1992] (56) 10 controls area under the response adrenal cortical reserve in patients
curve were significantly with PTB
lower in PTB patients
Prasad et al [2000] (57) 30 PTB; Mean cortisol lower Adrenal reserve Adrenal reserve compromised in
33 DTB/MTB compared to controls compromised in 45% of TB drug-sensitive TB and DR-TB
34 DR-TB Difference did not attain patients
statistical significance
Zargar et al [2001] (58) 28 PTB,12 EPTB, Comparable among 35% had sub-optimal Radiological severity and chronicity
10 control subjects controls and patients cortisol reserve of PTB inversely related to adrenal
reserve
TB = tuberculosis; ACTH = adrenocorticotrophic hormone; PTB = pulmonary tuberculosis; DTB = disseminated tuberculosis; MTB = miliary
tuberculosis; DR-TB = drug-resistant TB; EPTB = extra-pulmonary TB

with disseminated TB (62). In 1893, Burns described primary series suggests prevalence to be around 0.2% in specimens
TB of the thyroid gland even with no clinical evidence of reported as chronic thyroiditis, it is reported to be as high
pulmonary TB (63). Although estimates based on short case as 14% in patients with miliary TB (64-66). There is a female
458 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

preponderance with a male: female ratio of 1:2. Das et al (67)

have reported the prevalence of TB of thyroid to be 0.6%
among the 1283 thyroid lesions subjected to fine needle
aspiration cytology [FNAC] (67). Association of TB of the
thyroid with with papillary carcinoma thyroid has been
reported (68).
The true incidence of this condition remains unknown
as most cases reported in the literature are retrospectively
diagnosed. Asymptomatic nature of the disease, absence of
systemic TB and difficulty in demonstrating TB bacilli and/or
typical lesion in histopathological examination in most of
the cases are some of the reasons to explain the difficulties
in estimating the true incidence. The reason for rarity of
this clinical entity even in endemic areas is not known but
a number of possible mechanisms, such as, rich blood flow,
pattern of lymphatic drainage from the thyroid gland, excess A B
iodine in stored form and possible anti-tubercular nature of
stored thyroid hormone are proposed to explain this (64,65).
The protective fibrous capsule surrounding the thyroid that
separates it from other structures of the neck is thought to
prevent the spread of infection to and from the gland.

Clinical Presentation
Most cases present on pre-existing multinodular goiter, solitary
nodule, or even as an abscess [Figure 34.3]. Functionally,
cases of patients presenting with hyperthyroidism secondary
to thyroiditis and hypothyroidism secondary to total
glandular destruction have been reported (69-79). It is usually
a painless thyromegaly, with or without lymphadenopathy.
Diagnosis of TB as a cause of clinical presentation in most
cases is retrospective after histopathological demonstration
C
of either the characteristic necrotic granuloma or TB bacilli.
A cost-effective approach for diagnosis of TB of thyroid is
by FNAC. If the FNAC smear is negative for AFB, molecular
diagnostic methods may be helpful (80,81).

Effect of Anti-TB Treatment on Thyroid

Anti-TB drugs para-amino salicylic acid [PAS] and
ethionamide are known to produce goitre (82). Usually
there is complete resolution of goitre after these drugs are
discontinued.

TB and Sick Euthyroid Syndrome

Serum thyroid hormones in patient with TB show low
or normal serum total T4, low serum total T3, increase in
reverse T3, and normal TSH, a profile consistent with sick
euthyroid syndrome. Chow et al (83) have reported the D
prevalence of this syndrome in TB patients to be 63%. Low Figure 34.3: Cold abscess of the neck masquerading as a thyroid
serum total T3 predicts higher mortality. nodule. The swelling was soft, non-tender, fluctuant, and not trans­
illuminant [A and B]. CT of the neck showed cold abscess of thyroid [C].
Photomicrograph of the fine-needle aspiration cytology from the
Treatment swelling showing a moderate to richly cellular, mild haemorrhagic smear
showing many neutrophils admixed with eosinophils, lymphocytes,
Given the rarity of the clinical entity, prospective clinical
and epithelioid looking cellular clusters [C]; and acid-fast bacilli [Ziehl-
trials evaluating the efficacy of the anti-TB therapy in treating Neelsen, × 1000] [D]
thyroid TB are not available. The general consensus seems THY = thyroid gland; CT = computed tomography
to favour a full course of anti-TB treatment as for other Reproduced with permission from reference 75
 Endocrine Implications of Tuberculosis 459

forms of EPTB (64,65). Thyroid binding globulin levels macrophages and lymphocytes, chemotaxis, phagocytosis
have been demonstrated to increase with the initiation of and antigen presentation in response to mycobacterial
anti-TB treatment. Surgical intervention such as lobectomy infection. Interferon-alpha [IFN-α] production by T-cells, the
or partial thyroidectomy may be necessary in cases where growth, function and proliferation of T-cells are adversely
FNAC does not clarify the diagnosis of nodular presentation affected by DM (102). DM patients with poor glycaemic
and also in drainage of a TB abscess. In those rare cases control with TB have lower production of interleukin 1-beta
of hypothyroidism secondary to widespread glandular [IL-1b] and tumour necrosis factor-beta [TNF-b] (103).
destruction, patient would need thyroid replacement therapy Thickened alveolar epithelium and pulmonary basal lamina,
for life. altered diffusion capacity of the lungs and lung volume,
along with reduced elastic recoil of the lungs are known
Diabetes Mellitus and Tuberculosis to increase the susceptibility to TB in DM patients. Non-
enzymatic glycosylation of tissue proteins and alteration
Epidemiology in connective tissue in DM patients is thought to be the
The association between diabetes mellitus [DM] and TB pathogenetic mechanism underlying these aforementioned
has been recognised for centuries. The discovery of insulin changes in the lung causing increased susceptibility to
in 1920 and streptomycin in 1940 had lowered the fatality TB (104). Further, autonomic neuropathy causing changes in
rates of individuals with TB and DM. The incidence of TB the basal airway tone leading to reduced bronchial activity
is high in countries with high rates of infection with HIV, and dilated bronchus potentially increase the susceptibility
malnutrition and crowded living conditions. It is estimated to TB (105). The genetic predisposition towards pulmo­
that two-thirds of the 440 million persons with DM by nary TB is increased in the presence of DRB[1]*09 allele,
2030 will be from low income countries (84). TB Co-morbid while DQB[1]*05 is observed to be protective for TB in
patients with DM (106).
conditions like DM further complicate TB. In pulmonary TB,
DM is the most common co-morbid condition.
The risk of acquiring TB in a patient with DM is 4.8% Clinical and Radiographic Presentation
compared to 0.8% in general population (85). The relative The symptomatology and presentation of TB in patients
risk of developing pulmonary TB is 3.5 times higher in DM with and without DM are similar. Radiologically, lower
patients compared to matched controls; in type 1 diabetes lung field involvement is commonly observed in DM
patients under 40 years of age, the risk is 24% (86). India patients with TB compared to persons without DM in whom,
Tuberculosis-Diabetes Study Group screened patients with upper lung involvement is more common (107,108). This
DM for TB in India. Of the 7218 patients with DM screened assumes significance as such radiological lesion could easily
for TB, 254 patients were identified positive for the disease be misdiagnosed as community acquired pneumonia or
and 46% were sputum smear-positive (87). malignancy, thereby delaying the diagnosis. Elderly patients
Patients with poorly controlled DM are more prone to with DM are particularly prone for this and oxygen tension
be affected by TB. It has been shown in large studies (88,89) variability preferably involving lower lobe is thought to
that DM is a moderate to strong risk for development of be the reason for increased lower lung field predilection.
TB. Patients with DM who require more than 40 units Multilobar disease with multiple cavities [Figure 34.4] is
of insulin per day are two-times more likely to develop also more common in patients with DM with TB (109,110).
TB (90). Both type 1 and type 2 DM patients with high insulin
requirements are at increased risk of developing TB (91-93).
The evidence for association of DM with drug-resistant
TB is equivocal. While some studies have documented an
increased association (94,95), no such association was evident
in other studies (96,97). Interestingly, Bashar et al (95) have
shown that multidrug-resistant TB was more common
[36% vs 10%] in patients with DM compared with those
without DM (95). DM patients have also been found to
have a higher baseline mycobacterial burden; longer time for
sputum conversion and higher treatment failure and relapse
rate (97-100). Mortality is higher in DM patients with TB
probably because of increased severity of TB or co-existing
co-morbid conditions (101).

Pathogenesis
Figure 34.4: Chest radiograph [postero-anterior view] of a patient with
Hyperglycaemia and cellular insulinopenia directly diabetes mellitus with TB showing bilateral parenchymal infiltrates and
increases the susceptibility to the disease caused by Mtb. left pleural effusion
Hyperglycaemia has indirect effects on the functioning of TB = tuberculosis
460 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Issues in Management Pathogenesis

In the co-management of DM and TB, several issues are of TB involvement of pancreas commonly involves the head
concern to clinicians. TB is known to worsen diabetes control. of the pancreas because of its rich vasculature including
Overlapping toxicities like peripheral neuropathy due to lymphatic drainage. Haematogenous spread of the primary
isoniazid treatment and poor glycaemic control must be infection is usually the cause. Rarely, TB of the duodenum
kept in mind. Rifampicin is known to cause hyperglycaemia is said to be the cause of spread to pancreas due to reflux
either by direct action by or interaction with oral antidiabetic of duodenal material and bile into the pancreas due to
drugs (111). Rifampicin induces cytochrome P450 enzyme ampulary incompetence [commonly due to submucosal
which leads to accelerated metabolism of sulphonylureas, fibrosis] or by lymphatic spread.
like glyburide and glipizide. The concentration of these
drugs may reduced by 39% and 22% respectively (112).
Clinical Presentation
Netaglinide is metabolised by oxidative transformation by
cytochrome CYP2C9 and CYP3A4 and has no appreciable In published literature, various clinical presentations of
hypoglycaemic effect when given with rifampicin. In patients pancreatic TB have been documented. These include,
with type 1 DM the insulin requirements will increase with obstructive jaundice mimicking pancreatic cancer,
rifampicin use. Careful monitoring of glycaemic status gastrointestinal bleeding, acute or chronic pancreatitis,
because of direct and indirect effect of rifampicin is a must. pancreatic abscess, portal venous thrombosis causing portal
DM can change the effect of anti-TB drugs by decreased hypertension and colonic perforation, among others (129,131).
protein binding, renal insufficiency or fatty liver with Other findings of abdominal TB like lymphadenopathy,
impaired drug clearance (113). ascites, thickening of ileoceacal region of intestines and focal
hepatic and splenic lesions when present are helpful pointers
Tuberculosis and its Influence on to TB as the aetiological cause. Co-existence of pancreatic TB
Glucose Metabolism and pancreatic carcinoma is rare (132).
There are several studies documenting impaired glucose Miliary involvement of the pancreas may be asymptomatic
tolerance [IGT] in patients with TB (114-118). India initially, the caseous or nodular involvement of the pancreas
Tuberculosis-Diabetes Study Group screened for DM in may present as neoplasm. TB of pancreas presenting as
patients with TB [n = 8269]. Of the 8109 patients assessed, pancreatic abscess is very rare.
13% were found to have DM {8% [682] were previously
known to have DM and 5% were newly detected to have Diagnosis
DM}. The prevalence of DM in patients with TB was
significantly higher in tertiary care hospitals compared Ante-mortem diagnosis of pancreatic TB remains challenging.
to a TB unit [16% vs 9%]. In south India the prevalence Liver function testing may show features suggestive of
was signifi­cantly higher compared to north India [20% vs obstructive jaundice; non-specific elevation of tumour
10%] (119). Various postulates have been made to explain marker CA 125 is reported (129-134). Ultrasonography of the
the prevalence of DM in TB. These include: [i] reciprocal abdomen reveals a solitary hypoechoic lesion with a cystic
relationship between both the diseases (120); [ii] occult component in the head of pancreas. CT of the abdomen
IGT predisposing to TB infection (121); [iii] low body reveals either a sharply delineated mass with irregular
mass index [BMI, kg/m2] and malnutrition in developing margins in the pancreatic head, diffuse enlargement of
countries (122-126); and [iv] TB affecting the endocrine the pancreas or peripancreatic lymphadenopathy. On MRI
function of pancreas (118), among others. Persistent focal involvement appears as hypointese on fat suppressed
hyperglycemia in TB patients may be due to transient changes T1-weighted images and hypo/hyperintese on T2-weighted
in carbohydrate metabolism (118). These abnormalities images (133). Although helpful, none of these radiological
improve with commencement of anti-TB therapy. Despite features are pathognomonic of TB of the pancreas.
well documented association between TB and diabetes, the Evaluation of a pancreatic mass should be done
causative link needs further scientific exploration. diligently keeping in mind the possibility of pancreatic TB
so that unnecessary extensive surgery can be avoided. After
Tuberculosis and Endocrine Pancreas reviewing the laboratory findings, imaging modalities and
Pancreatic TB is a rare entity in spite of other forms of ultrasonography, CT guided biopsy, if the histopathology
abdominal TB being common, especially in the developing is consistent with malignancy standard Whipple’s
countries (127). In a large autopsy study (128) which pancreaticoduodenectomy should be carried out. In cases
dates back to 1944, miliary TB was noted in 297 of the where the work up is inconclusive, laparotomy with frozen
1656 autopsies of patients with TB, of which only 14 had section of pancreatic mass/or lymph nodes is indicated
pancreatic involvement (128). In a post-mortem study from which would help in clinching the diagnosis either way.
India [n = 300] spanning over a period of 12 years, none were Demonstration of caseating granulomas, AFB or a positive
found to have pancreatic TB (129). It is hypothesised that the molecular diagnostic test on specimens collected by either
pancreatic enzymes could interfere with the seeding of Mtb, endoscopic ultrasonography or CT-guided biopsy is helpful
and hence, it is biologically protected (130). in ascertaining the diagnosis.
 Endocrine Implications of Tuberculosis 461

Treatment variation in the clinical presentation (150,153). Shek et al (150)

observed it is the sixth common cause and second common
Standard anti-TB treatment for 6-9 months is considered
cause of hypercalcaemia after malignancy. There are
adequate for pancreatic TB. Prognosis is excellent with
number of factors that are thought to be responsible for
complete clinical resolution. Radiologic regression of
hypercalcaemia in patients with TB. Abnormal vitamin
the pancreatic mass on follow-up is often evident. If no
D metabolism appears to be the prime factor. The
improvement is noted, pancreatic excision is warranted (132).
hypercalcaemia observed in these cases is not influenced
by negative feedback loop involving 1α hydroxylase as
Vitamin D and Tuberculosis the serum parathyroid hormone is suppressed and serum
Attention has now focussed on the non-classical actions of phosphorous tends to be on the higher side of normal (154).
vitamin D, especially innate and adaptive immunity. In the The main factors regulating the 1α hydroxylase in the
pre-antibiotic era vitamin D was utilised as a therapy for granulomatous tissue is the locally or systemically produced
TB (135). Williams used cod-liver oil in patients with lymphokines similar to sarcoidosis (155,156). The CD4+
pulmonary TB (136). Until the introduction of antimicrobial T-lymphocytes recovered from bronchoalveolar lavage in
therapy in 1950s, cod liver oil was used in the treatment and patients with active pulmonary TB express 1,25[OH]2D3. The
prevention of TB. It is believed to be an effective treatment antimycobacterial products within the granulomatous tissue
for TB of the skin (137,138). It was shown by Liu that with could be regulating 1,25[OH]2D3 production independent
the sensing of Mtb by toll-like receptor 2/1[TLR2/1], the of parathyroid hormone and 25[OH]2D3. Hypercalcaemia
expression of vitamin D receptors [VDR] and CYP27B1 may be masked in initial presentation because of low serum
in monocytes is increased (139). Vitamin D 3 promotes albumin levels. Lung is the extra renal site of synthesis of
VDR mediated transactivation of cathelicidin. There is 1,25[OH]2D3. High concentration of 1,25[OH]2D3 is detected
direct antimicrobial function of cathelicidin which kills in patients with TB pleuritis (157). Serum 1,25[OH] 2D 3
the intracellular Mtb. Vitamin D promotes phagolysosome levels are reported to be higher in TB patients compared to
formation playing a crucial role in immune response to controls (158-161) and even in patients with end stage renal
Mtb (140). failure and TB (162). It has been shown in in vitro studies
Vitamin D deficiency is pandemic in India (141). that 1,25[OH]2D3 is produced by alveolar macrophages and
There are studies linking development of pulmonary TB lymphocytes (163,164). Studies have shown the calcium
in Asian Indians (142-145). Higher levels of 25-hydroxy absorption is high due to high 1,25[OH]2D3 levels (165-167).
vitamin D3 {25[OH]2D3} levels were associated with less Anti-TB drugs are known to adversely affect the calcium and
extensive radiological lesions (146). In the Asian Gujarati phosphate metabolism; rifampicin and isoniazid both reduce
community living in London post-primary pulmonary TB is the 25[OH]2D3 levels (168-170). This is further aggravated in
associated with Vitamin D deficiency and single nucleotide vitamin D deficient population like in India (171).
polymorphism [SNP] in VDR (147). This study revealed
association between T allele related to Taql SNP of VDR Tuberculosis of Female Reproductive
gene and vitamin D deficiency (147). In a cross-sectional Endocrine System
study done in 897 participants in north India {MDR-TB 354, The reader is referred to the chapter “Female genital
drug-susceptible pulmonary TB [DS-PTB] 338, controls 205}, tuberculosis” [Chapter 26] for details.
25[OH]2D3, serum calcium and parathyroid hormone were
measured and Genotypic and allelic frequencies of FokI, BsmI Tuberculosis of Male Reproductive
and TaqI VDR polymorphisms evaluated. MDR-TB correlated Endocrine System
positively with FokI Ff genotype and TaqI t allele. In both
MDR-TB and DS-PTB groups ff genotype and f allele of FokI The reader is referred to the chapter “Genitourinary
frequency were higher. MDR-TB correlated inversely with tuberculosis” [Chapter 27] for details.
BsmI Bb genotype. MDR-TB had the lowest serum 25[OH]2D3
concentrations and correlated inversely with time to sputum REFERENCES
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and VDR gene polymorphisms predispose to MDR-TB. Time Pituitary tuberculosis. J Assoc Physicians India 2007;55:453-56.
to MDR-TB sputum smear negativity was increased with 2. Ranjan R, Agarwal P, Ranjan S. Primary pituitary tubercular
lower serum 25[OH]2D3 levels (148). The exact mechanism abscess mimicking as pituitary adenoma. Indian J Endocrinol
Metab 2011;15 Suppl 3:S263-6.
liking the VDR polymorphism with TB is not known.
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as an unusual sequelae to central nervous system tuberculosis.
Tuberculosis and Hypercalcaemia Indian J Endocrinol Metab 2011;15 Suppl 3:S259-62.
4. Mittal P, Dua S, Saggar K, Gupta K. Magnetic resonance findings
About 50% of adult patients with TB manifest hyper­ in sellar and suprasellar tuberculoma with hemorrhage. Surg
calcaemia (149-151). Presence of hypercalcaemia has been Neurol Int 2010;1:73.
reported in abdominal TB too (152). Regional differences in 5. Furtado SV, Venkatesh PK, Ghosal N, Hegde AS. Isolated sellar
dietary calcium intake and vitamin D status account for wide tuberculoma presenting with panhypopituitarism: clinical,
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25[OH]D. Int J Tuberc Lung Dis 2012;16:1522-8. 166. Brodie MJ, Boobis AR, Hillyard CJ, Abeyasekera G, Stevenson JC,
149. Need AG, Philips PJ, Chiu F, Prisk HM. Hypercalcaemia Macintyre I, et al. Effect of rifampicin and isoniazide on vitamin
associated with tuberculosis. Br Med J 1980;282:831. D metabolism. Clin Pharmacol Ther 1982;32:525-30.
150. Shek CC, Natkunam A, Tsang V, Cockram CS, Swaminathan R. 167. Brodie MJ, Boobis AR, Dollery CT, Hillyard CJ, Brown DJ,
Incidence, causes and mechanism of hypercalcaemia in a hospital Macintyre I, et al. Rifampin and vitamin D metabolism. Clin
population in Hong Kong. QJM 1990;284:1277-85. Pharmacol Ther 1980;27:810-4.
151. Abbasi AA, Chemplavil JK, Farah S, Muller BF, Arnstein AR. 168. Davies PD, Brown RC, Church HA, Woodhead JJ. The effect
Hypercalcaemia in active pulmonary tuberculosis. Ann Intern of antituberculous chemotherapy on vitamin D and calcium
Med 1979;90:324-8. metabolism. Tubercle 1987;38:261-6.
152. Ramanathan M, Abdullah AD, Sivadas T. Hypercalcaemic crisis 169. Tebben PJ, Singh RJ, Kumar R. Vitamin D-mediated
as the presenting manifestation of abdominal tuberculosis: a case hypercalcemia: mechanisms, diagnosis, and treatment. Endocr
report. Med J Malaysia 1998;53:432-4. Rev 2016;37:521-47.
153. Chan TY. Differences in vitamin D status and calcium intake: 170. Rajendra A, Mishra AK, Francis NR, Carey RA. Severe
possible explanations for the regional variation in the prevalence hypercalcemia in a patient with pulmonary tuberculosis. J Family
of hypercalcaemia in tuberculosis. Calcif Tissue Int 1997;60:91-3. Med Prim Care 2016;5:509-11.
154. Singhellakis PN, Kitrou MP, Demertzi FD, Tzannes SE, Alevizaki 171. Harinarayan CV, Ramalakshmi T, Prasad UV, Sudhakar D,
CC, Mountokalkis TD, et al. Serum parathyroid hormone levels in Srinivasarao PV, Sarma KV, et al. High prevalence of low dietary
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 35
Tuberculosis and Human Immunodeficiency
Virus Infection
BB Rewari, Amitabh Kumar, Srikanth Tripathy, Jai P Narain

INTRODUCTION appropriate anti-TB treatment, ART, and co-trimoxazole

[trimethoprim-sulphamethoxazole] preventive therapy [CPT]
Human immunodeficiency virus [HIV] infection and to prevent other OIs (8). ART reduces mortality by 64%-95%
tuberculosis [TB] are two major public health problems in in patients with drug-susceptible TB (9), and CPT halves the
most of developing countries including India. TB is also mortality risk (10).
the most common opportunistic infection [OI] seen in HIV To maximise the benefits of ART and anti-TB treatment,
infected patients in India (1,2). In the pre-antiretroviral
it is essential that HIV-TB co-infected patients are identified
therapy [ART] era, nearly one-third of HIV-acquired
well in time, initiated on appropriate treatments and
immunedeficiency syndrome [AIDS] related deaths have
monitored closely for better treatment outcomes. Hence, it is
been reported to be due to TB (3). With the wider availability
of utmost importance to have a close coordination between
of ART, though the mortality of HIV-associated TB has
Revised National TB Control Programme [RNTCP] and
reduced significantly; it is still higher compared to HIV-
National AIDS Control Programme [NACP]. Some newer
uninfected individuals (4). HIV-TB co-infection carries a high
initiatives taken under this initiative include innovative
mortality risk and accounts for approximately 25% of global
HIV/AIDS deaths each year (5). intensified case finding using cartridge based nucleic acid
In HIV-infected individuals, presentation of TB may be amplification test [CBNAAT], daily anti-TB treatment, single
very different from that in a HIV-seronegative individual. window service for anti-TB treatment and ART, isoniazid
Extra-pulmonary TB [EPTB] accounts for up to 20% of cases preventive therapy [IPT], pharmacovigilance of anti-TB
of TB in immunocompetent, HIV-seronegative persons. and anti-retroviral drugs, information and communication
However, observations from India suggest that, EPTB technology [ICT] based adherence support and air borne
constituted 45%-56% of all the cases of TB in persons with infection control practices, among others.
HIV/AIDS (6). It is not only the HIV infection that increases This chapter provides an overview regarding the
the incidence, dissemination and severity of TB infection but different HIV-TB coordination activities recommended
TB has also been implicated to advance the progression of globally by WHO to end TB and their implementation in
the HIV disease and subsequent immunosuppression. Thus, India at national, state and district levels.
it has been rightly called the ‘deadly duet’ with one disease
fuelling the other. EPIDEMIOLOGY
The Central TB Division [CTD], Ministry of Health and
Family Welfare, Government of India and WHO India As per the WHO report 2018 (2), in 2017, there were an
laid down the “Standards of Care for TB in India” [SCTI] estimated 10 million new TB cases globally. People living
in 2014 (6). The management of active TB disease in HIV- with HIV [PLHIV] accounted for 10% of all new TB cases.
infected persons is essentially the same as in HIV-negative In 2017, there were an estimated 1.3 million TB deaths;
persons, with a few additional considerations. In addition an additional 0.3 million deaths resulted from TB disease
to anti-TB treatment, the ART must be initiated early during in PLHIV (2). TB deaths among HIV-positive people are
TB treatment for all co-infected patients to reduce the risk classified as HIV deaths in International Classification of
of death (7). Case management requires a combination of Diseases-10 [ICD-10] (2,11).
 Tuberculosis and Human Immunodeficiency Virus Infection 467

India has the third highest number of estimated PLHIV 110,000 HIV-associated TB patients emerging annually. In
in the world. In 2015, in India, the number of PLHIV was general, HIV prevalence rates are higher in southern India
estimated to be 2,117,000; national adult [15-49 years] while TB rates are higher in northern India (13).
prevalence of HIV was estimated to be 0.26% [Figure 35.1] (12). Occurrence of HIV-TB co-infection is a fatal combination
An overall reduction of 66% in the annual new HIV with extremely high death rates ranging from 15%-18%
infections over last 15 years [Figure 35.2]. As of now, around reported among HIV-infected TB cases notified under the
86,000 new infections occur every year. The trend of annual RNTCP. In terms of absolute numbers, 42,000 HIV-TB
AIDS deaths is showing a steady decline since roll out of the co-infected people die every year (14).
free ART programme in 2004 [Figure 35.3]. It is estimated
that around 450,000 lives have been saved due to ART till NATIONAL PROGRAMMES FOR TB AND HIV
2014 (12).
In terms of numbers, India accounts for about 9% of Revised National Tuberculosis
the global burden of HIV-associated TB making it second Control Programmes
highest globally. However, HIV prevalence among incident
The reader is referred to the Chapter “Revised National TB
TB patients in India is estimated to be around 5% with a
Control Programme” [Chapter 53] for details on this topic.
range of 0%-45% across the country. There are an estimated
National AIDS Control Programme
The Government of India established National AIDS Control
Organisation [NACO] and launched the NACP in 1992 with
phase-wise implementation; and currently, Phase IV of the
NACP is being implemented with focus on capacity building,
consolidating preventive services and comprehensive care,
support and treatment [Table 35.1] (13).
The Government of India launched the free ART
programme on 1 April 2004, under phase II of the NACP,
starting with 8 tertiary-level government hospitals in the
6 high prevalence states of Andhra Pradesh, Karnataka,
Maharashtra, Tamil Nadu, Manipur and Nagaland, as well
as the NCT of Delhi. As on Dec 2015, nearly 911,000 PLHIV
Figure 35.1: PLHIV and adult HIV prevalence in India 2007-2015 are receiving free ART at more than 1500 ART delivery
Lakh = 100,000; PLHIV = people living with HIV; HIV = human sites (12). The programme also provides second line ART to
immunodeficiency virus 12,500 PLHIV and is planning to introduce third line ART
Source: reference 12 shortly.

Figure 35.2: Estimated new HIV-infected persons in India, 1998-2015

Lakh = 100,000; HIV = human immunodeficiency virus
Reproduced with permission from reference 12
 468 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 35.3: Annual AIDS-related deaths and ART scale-up, India, 2000-2014
PLHIV = people living with HIV; ARD = AIDS-related deaths; Lakh = 100,000; AIDS = acquired immunodeficiency syndrome; ART = anti-retroviral
therapy
Reproduced with permission from reference 12

Table 35.1: NACP: Phase-wise implementation

NACP phase Salient features

Phase I [1992-1999] Objective of slowing down the spread of HIV infections

Reduce morbidity, mortality and impact of AIDS in the country
NACO set up for project implementation

Phase II [1999-2007] Focus shifted from raising awareness to changing behaviour

Decentralisation of programme implementation to the state level
Greater involvement of NGOs
ART provision introduced in 2004

Phase III [2007-2012] Scaling-up prevention efforts among high-risk group and general population
Integrating preventive strategy with CST services
Target of reducing new infections by 50% by 2012, achieved well in advance

Phase IV [2012-2017] Aims to consolidating the gains till NACP III

Accelerate the process of epidemic reversal
Further strengthen the epidemic response in India through a cautious and well-defined integration process
Intensifying and consolidating prevention services with a focus on high-risk groups and vulnerable population
Increasing access and promoting comprehensive care, support and treatment services

NACO = National AIDS Control Organisation; NACP = National AIDS Control Programme; HIV = human immunodeficiency virus;
AIDS = acquired immunodeficiency syndrome; NGOs = non-governmental organisations; ART = anti-retroviral therapy; CST = Care, Support
and Treatment
Source: reference 13

HUMAN IMMUNODEFICIENCY VIRUS- infection increases the risk of subsequent episodes of TB

TUBERCULOSIS: PATHOGENESIS from exogenous re-infection and it also increases the chance
of relapse. The estimated annual risk of reactivation among
HIV is the strongest of all known risk factors for the those co-infected with HIV and TB is about 5%-8% with a
development of TB and is known to affect Th-1 cell- cumulative lifetime risk of 50%-60%, which is very high
mediated immune responses that are the central immune when compared to a cumulative lifetime risk of 5%-10% in
defences against Mycobacterium tuberculosis [Mtb] in the HIV-seronegative adult patients.
body. HIV-infected persons are at markedly increased risk The interaction between HIV and TB infections is bi-
for progressive disease following primary TB infection, directional. HIV infection increases the risk of both primary
as well as reactivation of latent TB infection [LTBI]. HIV and reactivation TB (15), and this risk increases markedly
 Tuberculosis and Human Immunodeficiency Virus Infection 469

with advancing HIV disease (15). At the time of TB diagnosis, system, central nervous system, soft tissue, bone marrow,
most patients with co-infection have advanced HIV disease liver, spleen and other viscera may also occur. There is an
[Table 35.2] with low CD4+ T-cell counts and high viral loads increased frequency of lymph nodes involvement, pleural
or WHO clinical stage 3 and 4 disease [Table 35.3] (15,16). effusion, TB of the brain, abscesses of the chest wall, testes,
The development of active TB is also associated with spleen or elsewhere. In a study of HIV associated TB among
increases in HIV viral load locally and systemically (16,17). PLHIV in New Delhi, it was observed that pulmonary TB
There is consequently an increased risk of progression to in isolation was seen only in 38.4% patients while 39.7%
AIDS and death (18,19). patients had only EPTB and 21.9% had both pulmonary as
In patients of TB there is evidence of immune activation well as EPTB at diagnosis (4).
and several studies have suggested a role of persistently
activated immune system in pathogenesis of persistently DIAGNOSIS
elevated plasma viraemia in HIV-TB co-infection. It is
proposed that immune activation leads to increased Diagnosis of pulmonary TB in HIV-seronegative patient
expression of chemokine receptors CXCR4 and CCR5, as is relatively easy as sputum smear for AFB is frequently
well as their chemokine ligands. As CXCR4 and CCR5 positive. There has been a huge emphasis on sputum for
being the two major co-receptors used by HIV for cell entry, AFB examination in the RNTCP as the goal is also to cut the
increased expression leads to increased viral entry into the chain of transmission and halt the spread of TB. Published
immune cells and subsequent high replication and viraemia. evidence suggests that sputum smears reveal AFB less
It has also been observed that there is an associated increase frequently in HIV-seropositive patients with pulmonary
in plasma level of chemokines along with an increased TB, especially in late HIV disease (23). Diagnosis of such
expression of markers of immune activation (20,21). cases would, thus, require additional radiological and other
relevant investigations. The reader is referred to the chapter
“Laboratory diagnosis” [Chapter 8] for details.
CLINICAL PRESENTATION
Smear-negative pulmonary TB, EPTB, disseminated and
The clinical presentation of HIV-associated TB is diverse and miliary TB may require mycobacterial culture, nucleic acid
often atypical posing a diagnostic challenge. In HIV-positive amplification tests [NAAT] and gene probe-based tests,
cases, TB can occur at any CD4+ count (22). However, among others. Samples obtained from extrapulmonary sites
as the immunosuppression increases the likelihood of such as bone marrow, lymph node, pleural/ascitic fluid,
developing TB increases. In immunocompetent adult brain tissue, cerebrospinal fluid, urine, stool or blood should
patients, pulmonary TB is the most common form of TB be tested by conventional and rapid molecular diagnostic
encountered, often with focal infiltrates and cavities. As the tests.
CD4+ count goes down, the presentation of TB becomes Cartridge based nucleic acid amplification test [CBNAAT],
more atypical. While extra-pulmonary TB [EPTB] accounts Xpert MTB/RIF, has shown very high sensitivity and
for only 20% in HIV-negative persons, it accounts for 45%- specificity for diagnosis of both smear-positive and smear-
56% in HIV-positive individuals (22). negative pulmonary TB cases with high rates of detection
Even with the pulmonary form of TB, the presentation is of rifampicin resistance and greater concordance with
atypical. Patients are more likely to have diffuse pulmonary gene sequencing for rifampicin resistance when compared
disease without cavitation often involving the lower lobes with mycobacterial culture (24). It is designed to extract,
and prominent mediastinal or paratracheal adenopathies are amplify and identify targeted rpoB nucleic acid sequences
often seen. Such patients are less likely to be sputum positive automatically with minimal specimen handling. From the
for acid-fast bacilli [AFB]. There is also a high probability patient management perspective, it provides results within
of having miliary TB [Table 35.2]. TB of the lymphatic 2 hours that enables same day diagnosis and prompt

Table 35.2: Clinical presentation of TB in early and late HIV infection

Stage of HIV Infection
Features Early Late
Clinical presentation Often resembles post-primary TB Often resembles primary TB
Sputum smear Often positive Often negative
Radiological appearance Upper lobe involvement Lower lung-field involvement
Cavitatory lesions Cavitation rare
Intra-thoracic lymph node TB
Disseminated/miliary TB more common
Pleural/pericardial effusions
TB = tuberculosis; HIV = human immunodeficiency virus
470 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

treatment initiation with higher retention rates. This is the HIV-associated TB; the protective effect of ART was seen at
fastest turn around time as compared to 72 hours with line all stages of HIV disease, but was greatest in symptomatic
probe assay [LPA], nearly 2 months with liquid culture and patients and those with advanced disease (31,32). Concurrent
drug-susceptibility testing [DST] and four months in solid use of ART during TB treatment has been found to be
culture and DST. Xpert MTB/RIF is now the standard of associated with reduced mortality (32,33).
care for confirmation of TB among TB suspects, especially Treatment of HIV-TB is challenging, often it is difficult
those who are HIV infected. This has also been proven to identify the optimum time to start ART for patients on
to be of promising value in diagnosis of EPTB (25). Its TB treatment. This is associated with a complex series of
usefulness in paediatric TB and drug-resistant TB has also competing risks that may vary between different settings and
been well documented (26). CBNAAT based testing has patient populations (33,34). However, it is clear that delays in
now been adopted by RNTCP and is being provided at 125 ART initiation are associated with increased risk of mortality
sites presently with plans to expand to 950 sites during the among patients with TB (34-39). WHO has revised the
National Strategic Plan [NSP] period by 2017. ART guidelines for resource-limited settings several times
between 2002 and 2016, recommending progressively earlier
TREATMENT initiation of ART during TB treatment. The revision of these
guidelines, published in 2016, recommended that ART be
Treatment of HIV-TB Co-infected Persons given to all patients with TB regardless of CD4+ T-cell count,
TB is considered as WHO clinical stage 3 [pulmonary] or 4 should be started as soon as possible after TB treatment is
[extra-pulmonary] disease [Table 35.3] (27). The estimated tolerated, and should definitely be initiated maximum by
aggregate case fatality rate of HIV-infected TB is high at 8 weeks of initiating anti-TB treatment (40,41). In India,
about 40%, and may be over 50% in many developing it was seen that the median time between the start of TB
countries. While deaths in the first month of TB treatment treatment and ART was 23 days and nearly 80% imitated
may be due to TB, late deaths in co-infected persons are ART within 8 weeks of anti-TB treatment [Table 35.4] (42).
attributable to HIV disease progression (28). Immediate As new data emerge from trials being conducted all over the
treatment of TB is the central priority in management of globe these guidelines may be further refined (34). In India,
TB-HIV co-infected persons. The patient must be started on NACO recommends starting ART after 2 weeks of patients
anti-TB treatment without any delay, on the diagnosis of TB. being put on anti-TB treatment and not later than 8 weeks of
The principles of management of TB in PLHIV are essentially treatment. The programme is considering for simultaneous
the same. Standards for TB Care in India lays down uniform initiation of anti-TB treatment and ART for all co-infected
standards for TB care for all stakeholders in the country (6). patients with CD4+ count less than 50 cells/mm3 in order
The patients should be started on RNTCP Category I or to reduce mortality among those who are severely immune
Category II regimens, as per guidelines immediately. compromised.
Several issues in the management of the two diseases
together, like, pill burden, poor tolerance, poor drug
Antiretroviral Therapy
absorption, poor adherence, substance abuse, drug
interactions, overlapping toxicities, stigmatisation and The currently available antiretroviral drugs cannot eradicate
discrimination may have a bearing on the eventual outcome the HIV infection as the viruses hides in ‘immunological
of the treatment, both for TB and HIV. Outcomes of HIV-TB sanctuaries’ in the body from where it is difficult to wipe
co-infected patients continue to be poor with less than 80% it off. A pool of latently infected CD4+ cells is established
success rate amongst the new patients (29). A project has during the earliest stages of acute HIV infection and
recently been launched by WHO-NACO-CTD at 30 high persists within the organs/cells and fluids [e.g., liver and
burden ART centres across the countries where in HIV-TB lymphoid tissue] despite adequate treatment. Hence, the
co-infected persons will be initiated on daily anti-TB regimen goals of ART are to achieve suppression of viral replication
as well as IPT to improve their outcomes (14). A decision for extended period with recovery of immune system and
has now been taken by the Government of India to provide eventual prolongation of life and improving quality of life
daily anti-TB treatment for all TB patients starting with HIV- [Table 35.5] (7).
TB co-infected to begin with at all ART centres across the There are six major classes of drugs used to treat HIV/
country. AIDS termed as antiretroviral drugs [ARV]. These drugs are
Morbidity and mortality due to TB in areas of high grouped by way these interfere with steps in HIV replication
prevalence may not be singly contained by the current [Table 35.6] (7). The current standard of care for the
global TB control strategy using the WHO recommended treatment of HIV-1 infection is “triple-drug therapy” with
DOTS (30). Good quality supervised treatment for TB two nucleoside reverse transcriptase inhibitors [NRTI] or
under this strategy may take care of the TB, but its role in nucleotide reverse transcriptase inhibitors [NtRTI] backbones
slowing or reversing HIV disease progression is doubtful. in combination with a non-nucleoside reverse transcriptase
Antiretroviral treatment will reduce both the incidence of TB inhibitor [NNRTI] (40,41). Over the years there has been a
and mortality. The use of ART in TB-endemic areas has been shift towards earlier initiation of ART with simplified less
associated with more than 80% reduction in the incidence of toxic more robust ART regimen [Figure 35.4]. The guidelines
 Tuberculosis and Human Immunodeficiency Virus Infection 471

Table 35.3: WHO clinical staging of HIV disease in adults, adolescents and children
Adults and adolescents Children
Clinical stage 1 Clinical stage 1
Asymptomatic Asymptomatic
Persistent generalised lymphadenopathy Persistent generalised lymphadenopathy
Clinical stage 2 Clinical stage 2
Moderate unexplained weight loss [<10% of presumed or measured Unexplained persistent hepatosplenomegaly
body weight]
Recurrent respiratory tract infections [sinusitis, tonsillitis, otitis media, Recurrent or chronic upper respiratory tract infections [otitis media,
pharyngitis] otorrhoea, sinusitis, tonsillitis]
Herpes zoster Herpes zoster
Angular cheilitis Lineal gingival erythema
Recurrent oral ulceration Recurrent oral ulceration
Papular pruritic eruption Papular pruritic eruption
Fungal nail infections Fungal nail infections
Seborrhoeic dermatitis Extensive wart virus infection
Extensive molluscum contagiosum
Clinical stage 3 Clinical stage 3
Unexplained severe weight loss [>10% of presumed or measured Unexplained moderate malnutrition not adequately responding to
body weight] standard therapy
Unexplained chronic diarrhoea for longer than 1 month Unexplained persistent diarrhoea [14 days or more]
Unexplained persistent fever [intermittent or constant for longer than Unexplained persistent fever [above 37.5 °C, intermittent or constant,
1 month] for longer than 1 month]
Persistent oral candidiasis Persistent oral candidiasis [after first 6 weeks of life]
Oral hairy leukoplakia Oral hairy leukoplakia
Lymph node TB
Pulmonary TB Pulmonary TB
Severe bacterial infections [such as pneumonia, empyema, Severe recurrent bacterial pneumonia
pyomyositis, bone or joint infection, meningitis, bacteraemia]
Acute necrotising ulcerative stomatitis, gingivitis or periodontitis Acute necrotising ulcerative gingivitis or periodontitis
Unexplained anaemia [<8 g/dL], neutropaenia [< 0.5 × 109/L] and/or Unexplained anaemia [<8 g/dL], neutropaenia [< 0.5 × 109/L] and/or
chronic thrombocytopaenia [<50 × 109/L] chronic thrombocytopaenia [<50 × 109/L]
Symptomatic lymphoid interstitial pneumonitis
Chronic HIV-associated lung disease, including bronchiectasis
Clinical stage 4 Clinical stage 4
HIV wasting syndrome Unexplained severe wasting, stunting or severe malnutrition not
responding to standard therapy
Pneumocystis jiroveci pneumonia Pneumocystis jiroveci pneumonia
Recurrent severe bacterial pneumonia Recurrent severe bacterial infections [such as, empyema,
pyomyositis, bone or joint infection, meningitis, but excluding
pneumonia]
Chronic herpes simplex infection [orolabial, genital or anorectal of Chronic herpes simplex infection [orolabial or cutaneous of more than
more than 1 month's duration or visceral at any site] 1 month’s duration or visceral at any site]
Oesophageal candidiasis [or candidiasis of trachea, bronchi or lungs] Oesophageal candidiasis [or candidiasis of trachea, bronchi or lungs]
Extra-pulmonary TB Extra-pulmonary TB
Kaposi sarcoma Kaposi sarcoma
Cytomegalovirus infection [retinitis or infection of other organs] Cytomegalovirus infection [retinitis or infection of other organs with
onset at age more than 1 month]
Central nervous system toxoplasmosis Central nervous system toxoplasmosis [after the neonatal period]
HIV encephalopathy HIV encephalopathy
Extrapulmonary cryptococcosis, including meningitis Extrapulmonary cryptococcosis, including meningitis
Disseminated nontuberculous mycobacterial infection Disseminated nontuberculous mycobacterial infection
Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy
Chronic cryptosporidiosis Chronic cryptosporidiosis [with diarrhoea]
Chronic isosporiasis Chronic isosporiasis
Disseminated mycosis [extra-pulmonary histoplasmosis, Disseminated endemic mycosis [extrapulmonary histoplasmosis,
coccidioidomycosis] coccidioidomycosis, penicilliosis]
Lymphoma [cerebral or B-cell non-Hodgkin] Lymphoma [cerebral or B-cell non-Hodgkin]
Symptomatic HIV-associated nephropathy or cardiomyopathy HIV-associated nephropathy or cardiomyopathy
Recurrent septicaemia [including non-typhoidal Salmonella]
Invasive cervical carcinoma
Atypical disseminated leishmaniasis
WHO = World Health Organization; HIV = human immunodeficiency virus; TB = tuberculosis
Source: Adapted from reference 27
472 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 35.4: Initiation on ART for HIV-positive TB Table 35.6: Classification of anti-retroviral drugs
patients in 62 facilities in India, October-November Drug class Drugs
2014 Nucleoside reverse Zidovudine [AZT], Lamivudine [3TC],
Study cohort [adults, n= 9468] Observations transcriptase inhibitors Stavudine [d4T], Didanosine [ddl],
Patients diagnosed with TB [No.] 1871 [NRTI] Zalcitabine [ddC], Abacavir [ABC],
Tenofovir [TDF], Emtricitabine [FTC]
Patients already on ART at the
time of TB diagnosis [No.] 362
Non-nucleoside reverse Nevirapine [NVP], Efavirenz [EFV],
Time between start of TB treatment and ART transcriptase inhibitors Delavirdine [DLV]
initiation, for the 1429 HIV-positive TB patients who [NNRTI]
were not already on ART {No. [%]}
<2 weeks 200 [14%] Protease inhibitors Indinavir [IDV], Nelfinavir [NFV],
2-8 weeks 933 [65%] Saquinavir [SQV], Ritonavir [RTV],
Atazanavir [ATV], Lopinavir [LPV],
>8 weeks 296 [21%]
Fosamprenavir, Darunavir.[TMC114]
Median 23 days
ART = anti-retroviral therapy; HIV = human immunodeficiency virus; CCR5 co-receptor Maraviroc
TB = tuberculosis antagonist
Source: reference 42

Fusion inhibitors Enfuvirtide

Table 35.5: Goals of anti-retroviral therapy Integrase inhibitors Raltegravir, Elvitegravir

Goal Observations Source: reference 7
Clinical goals Prolongation of life and improvement in quality
of life
Virological goals Maximum reduction in viral load for as long as
possible with HIV-TB co-infection. The first-line, second-line and
Immunological Reconstitution of immunity
proposed third-line regimen used in the programme are
goals listed in [Table 35.8] (7).
Adverse drug reaction are a major challenge while
Therapeutic goals Rational sequencing of drugs in a way
to achieve clinical, virological and managing HIV because of the number of drugs used.
immunological goals while maintaining Common side effects of major drugs used in the program
treatment options, limiting drug toxicity and are enlisted in Table 35.9 (7). Drug toxicity can lead to
facilitating adherence patient often discontinuing ART (44). Some ARVs may have
Reduction of HIV Reduction of HIV transmission by suppression overlapping or additive toxicities with anti-TB treatment
transmission in of viral load [Table 35.10] (45). The drugs like stavudine and didanosine
individuals which were used earlier have now been phased out due to
HIV = human immunodeficiency virus their long-term toxicities. Once the patient is started on first-
Source: reference 7 line ART, it is important to monitor the CD4+ count and viral
load to identify treatment failure and switch to second line
ART. The criteria for identifying treatment failure are listed
on when to initiate ART have been progressively moving in [Table 35.11] (7).
from CD4+ count less than 200/mm3 in the year 2004 to Rifampicin, the mainstay drug in treatment of TB has
“treat all” irrespective of CD based on trials like CIPHRA major interactions with NNRTIs and the PIs. The PIs and
HT 001, SMART trial, HPTN 052 and the recent START trial NNRTIs are metabolised mainly through the cytochrome
[Figure 35.5]. The current NACO guidelines now provide for P450 [CYP] 3A4 enzymes. Rifampicin induces the expression
a simple harmonised ART in form of a single tablet of fixed of CYP3A4 isoenzyme in the liver and intestines (46),
dose combination of tenofovir, lamivudine and efavirenz decreasing the plasma concentration of PIs and the NNRTIs
to all newly diagnosed PLHIV including pregnant women, when co-administered (47). Rifampicin also increases the
those co-infected with TB or hepatitis [Table 35.7] (7). activity of the efflux multidrug transporter P-glycoprotein
This simplification is helpful for HIV-TB patients as [P-gp], which contributes to the elimination of the
efavirenz has minimal drug-drug interaction with anti-TB PIs (48,49). Rifampicin reduces the area under the curve
drugs. Efavirenz which was earlier supposed to be avoided [AUC] of efavirenz by 22%-26% (50), and nevirapine by up
during first trimester of pregnancy is now considered safe to 31% (51,52); hence, rifampicin can be co-administered
to administer (43). The eligibility for initiation of ART in with efavirenz.
asymptomatic patients has been revised to CD4+ cut off of Rifampicin reduces the AUC of available PIs by 35%-
500 and irrespective of CD4+ count for WHO stages 3 and 4 92%, and the reduction by rifabutin is in the range of
 Tuberculosis and Human Immunodeficiency Virus Infection 473

Figure 35.4: Evolution of global ARV guidelines

ARV = antiretroviral; TB = tuberculosis; HBV = hepatitis B virus; PW = pregnant women; SDC = sero-discordant couple; AZT = zidovudine;
TDF = tenofovir ;d4T = stavudine; FDCs = fixed-dose combinations; EFV = efavirenz; IDV/r = indinavir/ritonavir; LPV/r = lopinavir/ritonavir; SQV/r
= saquinavir/ritonavir; ATV/r = atazanavir/ritonavir; DRV/r = darunavir/ritonavir; DTV = dolutegravir; NRTI = nucleoside reverse transcriptase
inhibitors; ART = anti-retroviral treatment; HIV DR = human immunodeficiency virus drug-resistance; RAL = raltegravir; ETV = etravirine; VL =
viral load

Figure 35.5: Evidence-based earlier initiation of ART

ACTG = AIDS Clinical Trials Group; CPCRA = Community Programs for Clinical Research on AIDS; HAART = highly active anti-retroviral
therapy; ART = anti-retroviral therapy; AIDS = acquired immunodeficiency syndrome; TEMPRANO = A Trial of Early Antiretrovirals and Isoniazid
Preventive Therapy in Africa; START = Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection; HIV = human immunodeficiency
virus; CIPRA = Comprehensive International Program of Research on AIDS; SMART = Strategies for Management of Antiretroviral Therapy;
HPTN = HIV Prevention Trials Network; OIs = opportunistic infections
474 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 35.7: Initiation of ART based on CD4+ count and WHO clinical staging in HIV infected persons
Situation Recommendations Regimen
WHO clinical stage
Clinical stage I and II Start ART if CD4+ <500 cells/mm3
Clinical stage III and IV Start ART regardless of CD4+ count
All pregnant and breast feeding women Start ART regardless of CD4+ count
All HIV infected children below 5 years of age Start ART regardless of CD4+ count
For HIV and TB co-infected patients
 Patients with HIV and TB co-infection Start ART regardless of CD4+ count and type of TB FDC of
[PTB or EPTB] [start ani-TB treatment first, initiate ART as early as TDF 300 mg +
possible between 2 weeks and 3TC 300 mg +
2 months when TB treatment is tolerated] EFV 600 mg
[Single pill at bed time]
For HIV and hepatitis B and C co-infected patients
HIV and HBV/HCV co-infection–without any evidence of Start ART if CD4+ <500 cells/mm3
severe/chronic liver disease
HIV and HBV/HCV co-infection–with documented Start ART regardless of CD4+ count
evidence of severe/chronic liver disease
ART = anti-retroviral therapy; WHO = World Health Organization; HIV = human immunodeficiency virus; TB = tuberculosis; PTB = pulmonary
TB; EPTB = extra-pulmonary TB; HBV = hepatitis B virus; HCV = hepatitis C virus; FDC = fixed-dose combination; TDF = Tenofovir; 3TC =
Lamivudine; EFV = efavirenz
Source: reference 7

Table 35.8: ARV regimens used in the National AIDS Control Programme
Regimen Dosage
First-line ARV regimen
Tenofovir 300 mg + Lamivudine 300 mg + Efavirenz 600 mg 1 tab OD
Zidovudine 300 mg + Lamivudine 150 mg + Nevirapine 200 mg 1 tab BD
Zidovudine 300 mg + Lamivudine 150 mg/Efavirenz 600 mg 1 tab ZL BD + 1 tab EFV HS
Tenofovir 300 mg + Lamivudine 300 mg/Nevirapine 200 mg 1 tab TL OD + 1 tab NVP BD

Alternate first-line ARV regimen

Stavudine 30 mg + Lamivudine 150 mg + Nevirapine 200 mg 1 tab BD
Stavudine 30 mg + Lamivudine 150 mg/Efavirenz 600 mg 1 tab SL BD + 1 tab EFV HS
Abacavir 600 mg + Lamivudine 300 mg/Nevirapine 200 mg 1 tab AL OD + 1 tab NVP BD
Abacavir 600 + Lamivudine 300 mg/Efavirenz 600 mg 1 tab AL OD + 1 tab EFV HS

Second-line ARV regimen

Tenofovir 300 mg + Lamivudine 300 mg/Atazanavir 300 mg/Ritonavir 100 mg 1 tab TL OD + 1 tab ATV OD + 1 tab RTV OD
Tenofovir 300 mg + Lamivudine 300 mg/Lopinavir 200 mg + Ritonavir 50 mg 1 tab TL OD + 2 tab LPV/r BD
Zidovudine 300 mg + Lamivudine 150 mg/Atazanavir 300 mg/Ritonavir 100 mg 1 tab ZL BD + 1 tab ATV OD + 1 tab RTV OD
Zidovudine 300 mg + Lamivudine 150 mg/Lopinavir 250 mg + Ritonavir 50 mg 1 tab ZL BD + 2 tab LPV/r BD
Stavudine 30 mg + Lamivudine 150 mg/Atazanavir 300 mg/Ritonavir 100 mg 1 tab SL BD + 1 tab ATV OD + 1 tab RTV OD
Stavudine 30 mg + Lamivudine 150 mg/Lopinavir 250 mg + Ritonavir 50 mg 1 tab SL BD + 2 tab LPV/r BD
Abacavir 600 mg + Lamivudine 300 mg/Atazanavir 300 mg/Ritonavir 100 mg 1 tab AL OD + 1 tab ATV OD + 1 tab RTV OD
Abacavir 600 mg + Lamivudine 300 mg/Lopinavir 250 mg + Ritonavir 50 mg 1 tab AL OD + 2 tab LPV/r BD
Proposed third-line ARV regimen
Raltegravir 400 mg/Darunavir 600 mg/Ritonavir 100 mg 1 tab RAL BD + 1 tab DRV BD + 1 tab RTV OD
Source: reference 7

15%-45% (42,47). In general, co-administration of rifampicin IMMUNE RECONSTITUTION

with PIs is contra­indicated (47,51-53). Rifabutin is a much INFLAMMATORY SYNDROME
less potent inducer of the CYP3A4 isoenzyme and is used
when using PI based second-line ART for those who have Starting ART in patients having HIV infection leads to rapid
failed first-line ART and needs TB treatment as well. suppression of the virus and consequently a rapid recovery
 Tuberculosis and Human Immunodeficiency Virus Infection 475

Table 35.9: Common side effects of ARV drugs

Timing Side effects and toxicities Common causes
Short-term [the first few weeks] Gastrointestinal toxicities, including nausea, vomiting, diarrhoea, AZT,TDF,PIs
anaemia and neutropenia
Rash [most rashes occur within the first 2-3 weeks] NVP, EFV, ABC, PIs [rarely]
Hepatotoxicity [more common in hepatitis B or C co-infection] NVP, EFV, PIs
Drowsiness, dizziness, confusion and vivid dreams [normally self- EFV
resolving but can take weeks to months]
Medium-term [the first few months] Anaemia and neutropaenia, sudden and acute bone marrow suppression AZT
can occur within the first weeks of therapy or present as a slow onset of
progressive anaemia over months
Hyperpigmentation of skin, nails and mucous membranes AZT
Lactic acidosis [more common after the first few months, most commonly d4T, ddI, AZT
associated with d4T]
Peripheral neuropathy [more common after the first few months] d4T, ddI
Pancreatitis [can occur at any time] ddI
Long-term [after 6-18 months] Lipodystrophy and lipoatrophy d4T, ddl, AZT, PIs
Dyslipidaemia d4T, EFV, PIs
Diabetes mellitus IDV
Skin, hair and nail abnormalities PIs especially IDV
Renal tubular dysfunction TDF
Bone mineral toxicity TDF
ARV = anti-retroviral; AZT = zidovudine; TDF = tenofovir; PIs = protease inhibitors; NVP = nevirapine; EFV = efavirenz; ABC = abacavir;
d4T = stavudine; ddl = didanosine; IDV = indinavir
Source: reference 7

Table 35.10: Overlapping or additive toxicities due to ARV drugs and first-line anti-TB drugs
Toxicity Antiretroviral agents Anti-TB drugs
Peripheral neuropathy Stavudine, didanosine, zalcitabine Isoniazid, ethambutol
Gastrointestinal intolerance All All
Hepatotoxicity NVP, EFV, all NRTIs and PIs Isoniazid, rifampicin, rifabutin, pyrazinamide
Central nervous system EFV Isoniazid
Bone marrow suppression AZT Rifabutin, rifampicin
Skin rash ABC, amprenavir, NVP, EFV and Isoniazid, rifampicin and pyrazinamide
fosamprenavir
Ocular effects ddl Ethambutol, rifabutin
ARV = anti-retroviral; TB = tuberculosis; NVP = nevirapine; EFV = efavirenz; NRTIs = nucleoside reverse transcriptase inhibitors;
PIs = protease inhibitors; AZT = zidovudine; ABC = abacavir; ddl = didanosine
Source: reference 45

of the immune system. The immune reconstitution, however,

Table 35.11: Criteria for identifying treatment failure
can lead to an acute inflammatory reaction against infectious
Types of failure Criteria and non-infectious agents (54). Symptomatic disease is most
Clinical failure New or recurrent WHO stage 4 condition common in patients starting treatment with low CD4+
after at least 6 months of ART T-cell counts and is attributed to poor regulation of the
Immunological failure Fall of CD4 count to pre-therapy
restored immune system (55). Mtb infection accounts for
50% fall from the on-treatment peak value probably one-third of [HIV] related immune reconstitution
Persistent CD4 levels below 100 cells/mL inflammatory syndrome [IRIS] events, particularly in
Virological failure Plasma viral load >1,000 copies/mL after at
developing countries where HIV and TB co-infection is very
least 6 months of ART common. Up to 7%-43% of patients with HIV-TB coinfection
may develop IRIS (56,57). TB-associated IRIS has a wide
Source: reference 7
spectrum of presentations, ranging from mild lymph node
476 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

inflammation to potentially fatal disease of the central HIV-TB activities which outlined broad activities in the
nervous system. policy. The major collaborative activities recommended
IRIS can be of two types [in TB]: “paradoxical” transient by WHO are listed in Table 35.12 (66,67). India has been
clinical deterioration after clinical improvement [paradoxical implementing HIV/TB collaborative activities since 2001 in
IRIS]; and the uncovering of active TB disease in patients increasing the universal access to prevention, early diagnosis,
with unrecognised “occult” TB [“unmasking IRIS]”. In a and treatment services in combating the threat of HIV/TB.
clinical setting, TB-IRIS must be differentiated from anti-TB In 2008-2009, NACO and CTD jointly developed a National
treatment failure. IRIS is usually accompanied by an increase Framework for HIV/TB collaborative activities to address
in CD4+ T-cell count and/or a rapid decrease in viral load
the two intersecting epidemics. The framework called
while treatment failure is associated with increasing viral
“Intensified TB-HIV package” emphasised increased HIV
load and decline in CD4+ count. TB-IRIS can occur as early
as 5 days after starting ART; however, most patients develop testing of TB patients, TB screening for PLHIV and prompt
symptoms within the first 2-6 weeks (58,59), though cases treatment for persons affected with HIV/TB.
may occur even later. A low baseline CD4+ T-cell count, a To further strengthen the HIV/TB collaborative activities
shorter interval between TB diagnosis and ART initiation, in the country during 2012-2017, the ‘National Framework
and disseminated or EPTB have been proposed as risk factors for Joint HIV/TB Collaborative Activities’ was revised in
for TB-IRIS (56,60). November, 2013, based on updated WHO HIV/TB policy
IRIS in a TB patient may present as prolonged, high grade recommendations and vision documents of both the National
fever or the reappearance of fever, worsening pulmonary Programmes, NACP-IV and RNTCP National Strategic
infiltrates, new pleural effusions, or increased or new Plan (68). This document is a guidance tool for policy
lymphadenopathy (61). Many patients initially treated for
pulmonary TB develop additional manifestations of IRIS at
extrapulmonary sites (59). Hepatomegaly, lymphadenopathy
[mediastinal, cervical, or abdominal], splenic abscesses, Table 35.12: WHO-recommended collaborative
terminal ileitis leading to perforation, arthropathy, and TB/HIV activities
cutaneous lesions may be manifestations of TB-IRIS, with Establish and strengthen the mechanisms for delivering integrated
or without exacerbation of existing TB disease (57,59,62). TB and HIV services
Neurological disease following initiation of ART may have Set up and strengthen a coordinating body for collaborative TB/HIV
a poor outcome (63). activities functional at all levels
Most cases of TB-IRIS are self-limiting (59), and may
Determine HIV prevalence among TB patients and TB prevalence
require no change or only minor changes in treatment. among people living with HIV
Mild cases may just require symptomatic management with
non-steroidal anti-inflammatory drugs [NSAIDs]. Moderate Carry out joint TB/HIV planning to integrate the delivery of TB and
HIV services
to severe cases usually respond to corticosteroids, and
occasionally interruption of ART may be needed. Rarely, Monitor and evaluate collaborative TB/HIV activities
needle aspiration, surgical drainage, or laparotomy may be Reduce the burden the TB in people living with HIV and initiate
required for severe manifestations. early antiretroviral therapy [the Three I’s for HIV/TB]
Intensify TB case-finding and ensure high quality antituberculosis
Human Immunodeficiency Virus and treatment
Multidrug Resistant-Tuberculosis Initiate TB prevention with isoniazid preventive therapy and early
antiretroviral therapy
Human immunodeficiency virus per se does not predispose
a person to development of multidrug-resistant TB [MDR- Ensure control of TB infection in health-care facilities and
congregate settings.
TB] (64,65). However, several factors during co-treatment
of HIV-TB like poor drug absorption, pill burden and Reduce the burden of HIV in patients with presumptive and
overlapping toxicities leading to poor compliance, drug diagnosed TB
interactions leading to sub-therapeutic drug levels, etc. may Provide HIV testing and counselling to patients with presumptive
lead to emergence of drug resistance to anti-TB drugs as well and diagnosed TB
as resistance to ARVs. Second line anti-TB drugs are with Provide HIV prevention interventions for patients with presumptive
more toxic and often difficult to tolerate. Combining it with and diagnosed TB
ARV makes it even more difficult. Treatment of MDR-TB and Provide co-trimoxazole preventive therapy for TB patients living with
HIV together is challenging and often with poor outcomes. HIV
Ensure HIV prevention interventions, treatment and care for TB
HIV/TB COLLABORATIVE ACTIVITIES patients living with HIV

Considering the evidence that TB and HIV duo form the Provide antiretroviral therapy for TB patients living with HIV
deadly synergy and the co-infected patients with these WHO = World Health Organization; TB = tuberculosis; HIV = human
diseases more often have unfavourable treatment outcomes, immunodeficiency virus
WHO in 2012 released a policy document on collaborative Source: references 66,67
 Tuberculosis and Human Immunodeficiency Virus Infection 477

Figure 35.6: Framework of TB/HIV co-ordination activities in India to reduce mortality

TB = tuberculosis; HIV = human immunodeficiency virus; PITC = provider initiated testing and counselling; ART = anti-retroviral therapy;
DR-TB = drug-resistant TB; ICTC = Integrated Counselling and Testing Centres; PLHIV = people living with HIV; PI = protease inhibitor;
ICF = intensified case-finding; LAC = Link ART Centre; TI = treatment initiation
Source: reference 7

makers, programme managers, professionals at health SERVICE DELIVERY

facilities, health-care workers and partners.
The joint framework was developed to maintain close National AIDS Control Programme—Revised
coordination between RNTCP and NACP at national, state National TB Control Programme Coordination
and district levels, to decrease morbidity and mortality Activities
due to TB among persons living with HIV/AIDS, to decrease
impact of HIV in TB patients and provide access to HIV- A ‘four pronged strategy’ has been formulated to ensure
related care and support to HIV-infected TB patients, and strong collaboration and good coordination between
to significantly reduce morbidity and mortality due to NACP and RNTCP. It involves early detection of TB/HIV,
HIV-TB through prevention, early detection and prompt prevention, prompt treatment, and management of special
management of HIV and TB together. A four pronged TB/HIV cases. The Three I's used under this strategy
strategy for strong collaboration between NACP and for prevention of TB/HIV include: [i] intensified case
RNTCP has been formulated in the revised framework finding [ICF]; [ii] isoniazid preventive therapy [IPT]; and
[Figure 35.6] (7). [iii] infection control activities [IC].
The programme has formulated four important
National AIDS Control Programme—Revised strategies to ensure early diagnosis of HIV and TB at
all service delivery sites, namely [i] provider initiated
National TB Control Programme Coordination
testing and counselling [PITC] in TB patients; [ii] PITC in
Mechanisms at Various Levels
presumptive TB cases; [iii] rapid diagnostics for detection
A National TB-HIV Coordination Committee [NTCC] of TB and DR-TB in PLHIV; and [iv] ICF activities
has been constituted at the national level headed by the at all HIV settings, namely, Integrated Counselling and
administrative heads from both the programmes. The Testing Centre [ICTC], ART, Link ART Centre [LAC]
National Technical Working Group [NTWG] comprising settings.
of key officials from NACO, CTD and other stakeholders,
helps in identifying bottlenecks in policy, programme Human Immunodeficiency Virus Testing
design and service delivery, explore solutions to address the
of Tuberculosis Patients
bottlenecks and provides oversight for joint implementation
of activities. Similarly at the state and district levels, PITC for HIV among TB patients is implemented across
state level coordination committees [SCC], state technical the country as a part of the intensified HIV/TB package
working group [SWG] and district level coordination [DCC] so as to ensure early detection of HIV and linkage to
committees are in place to ensure smooth implementation care and support. HIV testing of TB patients is presently
and regular review of TB-HIV collaborative activities. done at integrated counselling and testing centres [ICTC]
There are well laid defined terms of references and meeting which many a times leads to referral loss. It is planned that
schedules for all these groups and joint field visits by RNTCP all designated microscopy centres [DMC] conducting quality
and NACO staff are conducted regularly for looking into assured sputum microscopy, will have a co-located HIV
implementation of collaborative activities in the facilities. testing facility to minimise linkage loss. At present there are
 478 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

more than 13,500 DMCs of which out more than 7,500 have effects of drugs through pharmacovigilance programme of
co-located HIV/TB testing. India [PvPI]; [iv] treatment adherence support to patient
Under ICF, all ICTC clients are screened by ICTC including support through use of ICT; [v] provision of IPT
counsellors for presence of four TB symptom score to HIV- infected individuals; and [vi] minimisation of risk
[current cough, weight loss, fever, nigh sweats] at every of acquiring TB in HIV-seropositive individuals through
encounter [pre-, post-, or follow-up counselling]. Further, implementation of airborne infection control measures at
that all patients coming to ART centres are actively these ART centres.
screened for opportunistic infections [OIs], particularly There is the risk of transmission of TB in health care
TB. The presumptive TB cases identified at ART centres facilities including laboratories. Early diagnosis and
are prioritised and “fast-tracked” for evaluation by Senior immediate initiation and adherence to RNTCP treatment
Medical Officer/Medical Officer to minimise opportunities regimens will make infectious TB patients rapidly non-
for airborne transmission of infection to other PLHIV. All infectious and breaks the chain of transmission. Ensuring
TB co-infected PLHIV are initiated on ART irrespective of various administrative, environmental and personal
CD4+ count (67). protective measures as recommended in the airborne
infection control guidelines is crucial in reducing the risk of
Innovative Intensified Tuberculosis Case Finding transmission of TB at HIV-TB care settings. The assessment
and Appropriate Treatment at High Burden of these centres has been completed recently and these
Antiretroviral Treatment Centres in India activities will soon be expended to all ART centres across
There exists a gap in early identification, screening and the country.
referral of TB among PLHIV, resulting in delayed diagnosis
of TB and poor outcomes of subsequent treatment. Achievements under Human Immunodeficiency
Considering the challenges, there is a felt need to implement Virus/Tuberculosis Collaborative Activities in India
the comprehensive strategy to reduce the burden of TB
among PLHIV. With support from WCO-India, NACO- The NACO and RNTCP have been successful in increasing
CTD have jointly launched “Innovative, intensified TB case access and uptake of HIV testing and counselling for all TB
finding and appropriate treatment at selected 30 high burden patients. The trend of known HIV status among TB patients
ART centres in India” in March 2015, aimed at reducing the is increasing and in 2015, 78% of TB patients knew their
burden of TB among PLHIV. HIV status [Figure 35.7]. The linkage of TB HIV co-infected
The key features of this project are single window patients to CPT and ART is showing increasing trend in
service delivery to HIV-seropositive individuals through India; 95% of co-infected patients received CPT in 2015
provision of TB services at ART centres which include [Figure 35.8] and 31% of co-infected patients received ART
[i] intensified TB case finding by deployment of rapid in 2014 [Figure 35.9]. All these achievements have higher
molecular diagnostics [CBNAAT]; [ii] daily anti-TB averages in India compared to global achievement on each
treatment; [iii] identification and management of side indicator.

Figure 35.7: Trends in Number [%] of registered TB patients with known HIV status, 4q08- 2q15
TB = tuberculosis; HIV = human immunodeficiency virus; q = quarter
Source: Data from Basic Services Division, National AIDS Control Organisation
 Tuberculosis and Human Immunodeficiency Virus Infection 479

Figure 35.8: State-wise [%] of HIV patients with TB receiving CPT, 2q14
TB = tuberculosis; HIV = human immunodeficiency virus; CPT = co-trimoxazole preventive therapy; q = quarter; pts = patients
Source: Data from Basic Services Division, National AIDS Control Organisation

Figure 35.9: State-wise status of ART in TB-HIV co-infected patients reg. in 2q14
TB = tuberculosis; HIV = human immunodeficiency virus; ART = anti-retroviral therapy; reg. = registered in; q = quarter; pts = patients
Source: Data from Basic Services Division, National AIDS Control Organisation
480 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

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53. Centers for Disease Control and Prevention. Updated guidelines
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 36
Tuberculosis in Children
SK Kabra, Rakesh Lodha

INTRODUCTION data linking the incidence of TB to the proportion of the TB

caseload represented by children suggest an exponential
Tuberculosis [TB] is one of the major infections affecting rise in the proportion of the TB caseload caused by children.
children worldwide. It causes significant morbidity and With rise in the incidence of TB; children may constitute
mortality, especially in infants and young children as TB nearly 40% of the caseload in certain high incidence
infection can progress rapidly to the disease, particularly communities (3).
in this group. TB in children reflects the prevalence of the TB infection and disease among children are much
disease in adults as well as current transmission rates. more prevalent in developing countries, where resources
Developing countries in Africa and South-east Asia have for control are scarce (4). It is estimated that in developing
the largest number of TB cases and the situation there has countries the annual risk of TB infection in children is
been worsened by the human immunodeficiency virus [HIV] 2%-5%. The estimated lifetime risk of developing TB
epidemic. Children born to HIV-infected parents, whether disease for a young child infected with Mtb as indicated by
infected or not, are at high risk of developing TB because positive tuberculin test is about 10% (5). About 5% of those
of the increased risk of exposure to the disease. TB is more infected are likely to develop disease in the first year after
common among the disadvantaged and vulnerable groups in infection and another 5% in rest of their lifetime. These rates
each society and the impact of overcrowding, undernutrition increase in HIV-infected individuals. Nearly 8%-20% of the
and poverty is particularly severe on children. Mycobacterium deaths caused by TB occur in children (6). The age of the
tuberculosis [Mtb] infects millions of children worldwide child at acquisition of TB infection has a great effect on the
every year, yet accurate information on the extent and occurrence of TB disease. Approximately, 40% of infected
distribution of the disease in children is not available for children less than 1 year of age, if left untreated, develop
most of the world. In a recent meta-analysis (1), it was radiologically significant lymphadenopathy or segmental
observed that without adequate treatment, children with lesions compared with 24% of children between 1-10 years
TB, especially those under five years of age, are at high risk and 16% of children 11-15 years of age (7). As per the Global
of death. HIV-coinfected children have an increased risk of TB Report, 2017 (8), in the year 2016, 6.9% of the 10.4 million
mortality even when receiving anti-TB treatment (1). estimated new TB cases were among children.

EPIDEMIOLOGY TRANSMISSION
Since most children acquire the organism from adults in their Transmission of Mtb generally is person-to-person and
surroundings, the epidemiology of childhood TB follows occurs via inhalation of mucous droplets that become
that in adults. The burden of childhood TB in the world is airborne when an individual with pulmonary or laryngeal
unclear. This is because of the difficulty of confirming the TB coughs, sneezes, speaks, laughs, or sings. After drying,
diagnosis of childhood TB. The other important reason is that the droplet nuclei can remain suspended in the air for hours.
children do not make a significant contribution to the spread Only small droplets [<5 µ in diameter] can reach alveoli.
of TB. Several estimates make use of an arbitrary calculation Droplet nuclei also can be produced by aerosol treatments,
assigning 10% of the TB burden to children (2). Available by sputum induction, and through manipulation of lesions.
484 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Numerous factors are associated with the risk of acquiring find their way into blood stream through lymph nodes.
Mtb infection (9). The risk has been associated consistently This may result in foci of infection in various organs.
with the extent of contact with the index case, the burden If the host immune system is good, then these foci are
of organisms in the sputum, and the frequency of cough contained and disease does not occur. Seeding of apex of
in the index case. Patients with smear-positive pulmonary lungs leads to development of Simon’s focus. Lowering of
TB are more likely to transmit infection. Markers of close host immunity may lead to activation of these metastatic
contact such as urban living, overcrowding, and lower foci and development of disease. This is especially seen in
socioeconomic status all are correlated with the acquisition young infants, severely malnourished children, and children
of infection. An increased risk-developing infection has been with immunodeficiency [including HIV infection]. Massive
demonstrated in multiple institutional settings, including seeding of blood stream with Mtb leads to miliary TB, where
nursing homes, correctional institutions, and homeless all lesions are of similar size. This usually occurs within three
shelters. The risk of acquiring infection increases with to six months after initial infection.
age from infancy to early adulthood, likely attributable to Pulmonary TB resulting from endogenous reactivation of
increasing contact with other persons. foci of infection is uncommon in children; but may be seen
in adolescents. The most common site for this type of disease
NATURAL HISTORY is the apex of the lung [Puhl’s lesion], because the blood flow
is sluggish at apex. Regional lymph nodes are usually not
The natural history of TB infection is covered in detail in the involved in this type of TB (19).
chapter “Pulmonary tuberculosis” [Chapter 10]. Progressive
primary disease is a serious complication of the pulmonary
CLINICAL FEATURES
primary complex [PPC], in which the PPC instead of
resolving or calcifying, enlarges steadily and develops a Childhood TB can be divided into two broad classifications:
large caseous center. The center then liquefies; this may intra- and extrathoracic TB. Most children with TB will
empty into an adjacent bronchus leading to formation of a develop pulmonary TB. Nonetheless, the recognition of
cavity with a large numbers of tubercle bacilli (10). From extrathoracic TB is equally important because of its great
this stage, the bacilli may spread to other parts of the lobe potential for causing morbidity.
or the entire lung. This may lead to consolidation of area of
lung or bronchopneumonia. Cavitary disease is relatively Intrathoracic Tuberculosis
uncommon in children. It may be difficult to differentiate
progressive primary disease from a simple TB focus with Diagnosis of TB in a child is often difficult because of absence
superimposed acute bacterial pneumonia. Appearance of typical symptoms, signs and of microbiologic evidence
of a segmental lesion is fan shaped on a roentgenogram, in the majority of children with pulmonary TB. The onset
representing mainly atelectasis and almost always involves of symptoms is generally insidious, but may be relatively
that very segment occupied by the primary pulmonary acute in miliary TB.
focus (11,12). Primary infection usually passes off unrecognized.
Some of the events may occur because of involvement Asymptomatic infection is defined as infection associated
of lymph nodes (13,14). The enlarged lymph nodes may with tuberculin hypersensitivity and a positive tuberculin
compress the neighbouring airway (15,16). Ball-valve effect skin test [TST] but with no striking clinical or radiographic
due to incomplete obstruction may lead to trapping of manifestations. Most symptoms in children with primary
air distal to obstruction [emphysema] (17,18). Enlarged complex are constitutional in the form of mild fever,
paratracheal nodes may cause stridor and respiratory anorexia, weight loss, decreased activity. Cough is an
distress. Subcarinal nodes may impinge on the esophagus inconsistent symptom and may be absent even in advanced
and may cause dysphagia. If the obstruction of bronchus is disease. Irritating dry cough can be a symptom of bronchial
complete, atelectasis occurs. and tracheal compression due to enlarged lymph nodes. In
some children, the lymph nodes continue to enlarge even
after resolutions of parenachymal infiltrate (20,21). This may
Outcome of Bronchial Obstruction
lead to compression of neighbouring regional bronchus. The
Bronchial obstruction may resolve in several ways, including: PPC is the most commonly encountered presentation in the
[i] complete expansion and resolution of the chest radiograph outpatient setting. In a community setting, often primary
findings; [ii] disappearance of the segmental lesions; and [iii] infection occurs without sufficient constitutional symptoms
scarring and progressive compression of the lobe or segment to warrant medical advice. The PPC may be picked up
leading to bronchiectasis. A caseous lymph node may erode accidentally during evaluation of intercurrent infections (22).
through the wall of the bronchus, leading to TB bronchitis Progressive primary disease is the result of progression of
or endobronchial TB. Fibrosis and bronchiectatic changes primary disease. Children with progressive primary disease
may supervene. Discharge of Mtb into the lumen may lead may present with high-grade fever and cough. Expectoration
to bronchial dissemination of infection. of sputum and haemoptysis are usually associated with
Haematogenous disemination of Mtb occurs early in advanced disease and development of cavity or ulceration
the course of the disease; this results when the bacilli of the bronchus. Physical findings of consolidation or
 Tuberculosis in Children 485

cavitation depend on the extent of the disease. Abnormal In some instances, acute secondary bacterial infection
chest signs consist mainly of dullness, decreased air entry, occurs, presenting with high fever, cough and crepitations.
and crepitations. Cavitating pulmonary TB is uncommon The symptoms and signs respond partially to the conventional
in children. However, Maniar (23) reported a series of 75 antibiotics, but the chest radiographic findings due to
children, less than two years of age presenting with primary underlying TB persist. Calcification of the primary complex
cavitatory pulmonary TB suggesting variability of clinical occurs more commonly in children.
presentation of TB in different setting.
Children with endobronchial TB may present with Extrathoracic Tuberculosis
fever, troublesome cough [with or without expectoration]. A detailed description of extrathoracic TB is beyond the scope
Dyspnoea, wheezing and cyanosis may be present. of this chapter, but clinicians must consider this possibility
Occasionally, the child may be misdiagnosed as asthma. In when evaluating children with a history of persistent fevers.
a wheezing child less than two years of age, the possibility The most common forms of extrathoracic disease in children
of endobronchial TB should always be considered, especially include TB of the peripheral lymph nodes and the central
if there is poor response to asthma medications. Partial nervous system. Other rare forms of extrathoracic disease in
compression of the airway can lead to emphysema. Features children include osteoarticular, abdominal, gastrointestinal,
of collapse may be present if a large airway is completely genitourinary, cutaneous, and congenital disease.
compressed (21,22). TB of the peripheral lymph nodes involves the supra­
Miliary TB is an illness characterised by heavy clavicular, anterior cervical, tonsillar, and submandibular
haematogenous spread and progressive development of nodes. Although lymph nodes may become fixed to
innumerable small foci throughout the body. The disease is surrounding tissues, low-grade fever may be the only
most common in infants and young children. The onset of systemic symptom. A primary focus is visible radiologically
illness is often sudden. The clinical manifestations depend only 30%-70% of the time. TST is usually positive. Although
on the numbers of disseminated organisms and the involved
spontaneous resolution may occur, untreated lymphadenitis
organs. The child may have high-grade fever, which is
frequently progresses to caseating necrosis, capsular
quite unlike in other forms of TB. The child may also have
rupture, and spread to adjacent nodes and overlying skin,
dyspnoea and cyanosis. There are hardly any pulmonary
resulting in a draining sinus tract that may require surgical
findings but fine crepitations and rhonchi may be present.
removal (24).
These findings may occasionally be confused with other
Central nervous system disease is the most serious
acute respiratory infections of childhood. The illness may
complication of TB in children and arises from the formation
be severe, with the child having high fever, rigors and
of a caseous lesion in the cerebral cortex or meninges that
alteration of sensorium. In addition, these children may
results from early occult lymphohaematogenous spread.
have lymphadenopathy and hepatosplenomegaly. The
Infants and young children are more likely to experience
other presentation of miliary TB may be insidious with the
a rapid progression to hydrocephalus, seizures, and
child appearing unwell, febrile and losing weight. Choroid
cerebral oedema. In older children, signs and symptoms
tubercles may be seen in about 50% children. TB meningitis
progress over the course of several weeks, beginning non-
may occur in 20%-30% of cases (21,22).
specifically with fever, headache, irritability, and drowsiness.
The rupture of a subpleural focus into the pleural
Disease abruptly advances with symptoms of lethargy,
cavity may result in pleural effusion. The pleura may also
be involved by haematogenous spread from the primary vomiting, nuchal rigidity, seizures, hypertonia, and focal
focus. The effusion usually occurs due to hypersensitivity neurologic signs. The final stage of disease is marked by
to tuberculoprotein[s]. If the sensitivity is high, there is coma, hypertension, decerebrate and decorticate posturing,
significant pleural effusion along with fever and chest and eventually death. Rapid confirmation of tuberculous
pain on affected side. Minor effusions associated with the meningitis can be extremely difficult to establish because of
rupture of primary foci are usually not detected. TB effusion the wide variability in cerebrospinal characteristics, negative
is uncommon in children under five years of age, is more TST in 40% of cases, and normal chest radiographs in 50% of
common in boys, and is rarely associated with segmental cases. Because improved outcomes are associated with early
lesion and miliary TB (19). The onset may be insidious or treatment, empiric anti-TB therapy should be considered
acute with rise in temperature, cough, dyspnoea and pleuritic for any child with basilar meningitis and hydrocephalus
pain on the affected side. There is usually no expectoration. or cranial nerve involvement that has no other apparent
The pleuritic pain may disappear once the fluid separates cause (25).
the inflamed pleural surfaces; and a vague discomfort may
then be felt. Increase in effusion may make breathing shallow DIAGNOSIS
and difficult. The clinical findings depend on the amount of
Laboratory Tests
fluid in the pleural sac. In early stages, a pleural rub may be
present. Early signs include decreased chest wall movement, The diagnostic tests for pulmonary TB can be broadly
impairment of percussion note and diminished air entry on divided into two categories: [i] demonstration/isolation
the affected side. As the fluid collection increases, the signs of Mtb or one of its components; and [ii] demonstration of
of pleural effusion become more definite. host’s response to exposure to Mtb.
486 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Conventional Diagnostic Methods of Smear and [EBUS] commonly used in adults, has also been shown to be
Mycobacterial Culture useful in children with mediastinal nodes on imaging (34).
The yield of mycobacterial culture in gastric aspirate
In children with suspected pulmonary TB, spontaneously specimens varies from 30%-50% in children with TB (35,36).
expectorated or induced sputum, gastric aspirate, A higher yield [up to 70%] has been reported in infants and
bronchoscopic secretions are subjected to smear examination, children with extensive disease (15). The long period required
mycobacterial culture and molecular diagnostic testing. for isolation of Mtb by conventional culture techniques has
Ziehl Neelsen [ZN] stain reveals acid-fast bacilli [AFB] if led to the develop­ment of other techniques for culture such
the number of Mtb is more than 104/mL of specimen (26). as BACTEC radiometric assay, Septichek AFB system, and
The best specimen for demonstration of AFB in children mycobacterial growth indicator tube system [MGIT] (37-41).
is the early morning gastric aspirate obtained by using
a nasogastric tube before the child arises and peristalsis
Serodiagnostic Methods
empties the stomach of the respiratory secretions swallowed
overnight (27). The yield of Mtb on ZN stain is less than 20% Serodiagnostic methods have been banned and should not
and depends on extent of pulmonary disease and number of be used for diagnosis of TB in children.
specimen tested (28). To avoid hospitalisation, an ambulatory
gastric lavage specimen has been shown to yield good Molecular Methods
results. Children are asked to come on an empty stomach
Conventional polymerase chain reaction [PCR] is not
for six hours and nasogastric tube is inserted to aspirate
recommended for diagnosis of TB in children (42). Cartridge-
the gastric contents for smear and culture examination. If
based nucleic acid amplification tests [CBNAAT] are a major
gastric contents are less, gastric lavage may be done with
advance in diagnosis of TB in adults. The sensitivity of the
10-20 mL sterile saline. Samples obtained on two consecutive
CBNAAT, Xpert MTB/RIF in identifying intrathoracic TB
days may provide smear positivity between 5%-10% (29).
in children using two gastric aspirate specimens or induced
Neutralisation of gastric aspirate by sodabicarb is not
sputum has been reported to be between 60% and 70% and
recommended as it does not improve yield and may cause
specificity is more than 90% (43-45a,45b). The evidence-based
contamination (30).
recommendations regarding the use of Xpert MTB/RIF in
When adequate sputum specimen is not being produced,
the diagnosis of TB in children as described in the recently
sputum induction is attempted. Three mL of hypertonic
published World Health Organization [WHO] guidelines (46)
saline [3%] is nebulised after priming with salbutamol.
are shown in Table 36.1. The recently published evidence-
Older children may directly cough out expectoration while
based guidelines for Extrapulmonary TB for India [INDEX-
in younger children and infants, nasopharyngeal secretions
TB guidelines] (47) provide current evidence for use of Xpert
are secured by placing a small tube in nasopharynx and
MTB/RIF in the diagnosis of extrapulmonary TB.
applying slow suction (29).
For further details on the laboratory diagnostic methods,
In childhood TB, the yield of gastric aspirate is superior
including those used for the diagnosis of latent TB infection,
to bronchoalveolar lavage [BAL] fluid in detecting
the reader is referred to the chapter “Laboratory diagnosis”
AFB (27,31). Bronchoscopy would allow visualisation
[Chapter 8] for more details.
of the tracheobronchial tree and use of BAL fluid may
improve the diagnostic yield over gastric aspirate by 17%-
26%. Detection of external compression by lymph nodes
Imaging Studies
and endobronchial spread may help in diagnosis of TB in Primary TB is the most common form encountered in
children (32,33). Endobronchial ultrasound-guided sampling children. On the chest radiograph, the PPC manifests as

Table 36.1: Evidence-based recommendations for use of Xpert MTB/RIF for the diagnosis of TB in children
Recommendation Evidence
Xpert MTB/RIF should be used rather than conventional microscopy Strong recommendation, very low quality of evidence
and culture as the initial diagnostic test Conditional recommendation acknowledging resource implications,
in children suspected to have MDR-TB or HIV-associated TB very low quality of evidence
in all children suspected of having TB
Xpert MTB/RIF may be used as a replacement test for usual practice Conditional recommendation, very low quality of evidence
[including conventional microscopy, culture, and/or histopathology] for
testing of specific non-respiratory specimens [lymph nodes and other
tissues] from children suspected to have EPTB
Xpert MTB/RIF should be used in preference to conventional Strong recommendation given the urgency of rapid diagnosis, very
microscopy and culture as the initial diagnostic test in testing CSF low quality of evidence
specimens from children suspected of having TBM
TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis; HIV = human immunodeficiency virus; EPTB = extra-pulmonary tuberculosis;
TBM = tuberculosis meningitis
Source: reference 46
 Tuberculosis in Children 487

an area of airspace consolidation of varying sizes, usually Occasionally, the chest radiograph may be normal
unifocal, and homogeneous [Figure 36.1]. Enlarged lymph and lymphadenopathy may be evident only on computed
nodes may be seen in the hilar, or right paratracheal region. tomography [CT]. In addition, CT features, such as, low
Sometimes, lymphadenopathy alone may be present in attenuation of lymph nodes with peripheral enhancement,
children with primary TB. calcification, branching centrilobular nodules and miliary
Consolidation in progressive primary disease is usually nodules are helpful in suggesting the diagnosis in cases
heterogeneous, poorly marginated with predilection of where the radiograph is normal or equivocal. Other features
involvement of apical or posterior segments of the upper such as segmental or lobar consolidation and atelectasis are
lobe or superior segment of the lower lobe [Figure 36.2]. non-specific (48). In a study by Kim et al (49), CT including
Features of collapse may be present as well [Figure 36.3]. high-resolution CT [HRCT] revealed lymphadenopathy,
Bronchiectasis may occur in a progressive primary disease and parenchymal lesions that were not evident in 21% and
because of: [i] destruction and fibrosis of lung parenchyma 35% of the chest radiographs, respectively. The HRCT is
resulting in retraction and irreversible bronchial dilatation; more sensitive than chest radiograph for the detection of
and [ii] cicatricial bronchostenosis secondary to localised miliary TB and shows randomly distributed multiple, small
endobronchial infection resulting in obstructive pneumonitis [< 2 mm diameter] nodules (50). The nodules may be so
and distal bronchiectasis. In children, cavitary disease is numerous that these coalesce to form larger nodules greater
uncommon [Figure 36.4]. Pleural effusion may occur with or than 2 mm in diameter and at times areas of consolidation
without lung lesions [Figure 36.5]. In miliary TB, the lesions with air bronchograms may be seen. Thickening of the
are less than 2 mm in diameter [Figure 36.6]. interlobular septa may also be a feature. Mediastinal and

Figure 36.1: Chest radiograph [postero-anterior view] in a child with Figure 36.2: Chest radiograph [postero-anterior view] in a child with
progressive primary complex showing left-sided hilar adenopathy and progressive primary disease showing consolidation in the right mid-
an ill-defined parenchymal lesion zone

Figure 36.3: Chest radiograph [postero-anterior view] showing collapse Figure 36.4: Chest radiograph [postero-anterior view] showing a cavity
consolidation of the right upper lobe [arrow] in the right mid-zone
 488 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 36.5: Chest radiograph [postero-anterior view] showing massive Figure 36.6: Chest radiograph [postero-anterior view] showing miliary
pleural effusion on the left side mottling and right-sided paratracheal adenopathy

hilar lymphadenopathy may also be present. Cavitation is Table 36.2: Diagnostic criteria for pulmonary
reported to be rare on the chest radiograph in children with tuberculosis in children in countries where
TB. However, children co-infected with HIV and TB may mycobacterial culture facilities are not available
manifest atypical radiographic features (51,52). In children co-
Gastric washings positive for AFB
infected with HIV and TB, CT may show areas of cavitation or
that are not apparent on the chest radiograph (51,52). Two or more of the following criteria
The HRCT and colour Doppler ultrasonography have History of contact with a TB adult
been found to be useful in the diagnosis of cervical  Symptoms suggestive of pulmonary TB [cough for more than
lymphadenopathy (53). 2 weeks]
TB of the spine is the most common site of osseous 2 TU PPD reaction positive
   > 10 mm in unvaccinated BCG patients
involvement and has a higher prevalence in developing    > 15 mm in vaccinated BCG patients
nations with an increasing incidence in developed nations. Radiological findings compatible with pulmonary TB
Magnetic resonance imaging [MRI] findings include:  Response to treatment [body weight increase > 10% after
contiguous involvement of two or more vertebral bodies, 2 months of treatment, plus clinical improvement]
intraspinal or paraspinal soft tissue mass or abscess, AFB = acid-fast bacilli; TB = tuberculosis; TU = tuberculin units;
subligamentous extension, and ring enhancement of the soft PPD = purified protein derivative; BCG = Bacille Calmette-Guérin
tissue mass (54). Contrast-enhanced MRI is emerging as a Source: reference 58
very useful technique for diagnosing neurological TB, as it
demonstrates the localised lesions, meningeal enhancement of AFB, tubercles in biopsy, suggestive radiology and TST
and the brain stem lesions (55). greater than 10 mm induration. These scoring systems
need validation in individual countries. The criteria for
Scoring Systems for Predicting
diagnosis of pulmonary TB in children in countries where
Childhood Tuberculosis mycobacterial culture is not available proposed by Migliori
Diagnosis of TB in children is usually based on clinical signs et al (58) is shown in Table 36.2.
and symptoms, chest radiograph, TST and history of contact
with adult patients. Clinical features may be non-specific DIAGNOSTIC ALGORITHM
and chest radiograph and TST are difficult to interpret and
The new diagnostic algorithm is prepared jointly by the
do not provide conclusive evidence for the disease. Though
Indian Academy of Paediatrics and Revised National
demonstration of Mtb in various clinical specimens remains
Tuberculosis Control Programme [RNTCP] of Government of
gold standard, this is often not possible in children due to
India for paediatric pulmonary TB and lymph node TB (59,60)
the pauci-bacillary nature of the illness.
are shown in Figures 36.7A, 36.7B and 36.7C.
To overcome the problem of diagnosis in children;
combination of clinical features, history of exposure to adult
patient with TB, result of TST and radiological finding have DRUG-RESISTANT TUBERCULOSIS
been evaluated by various workers. Several scoring systems Pattern of drug resistance among children with TB tends to
have been developed after giving different weightage reflect the same found among adults in the same population.
to these variables (56,57). In these scoring system, more A four-year prospective study in the Western Cape province
weightage is given to laboratory test, i.e. demonstration of South Africa evaluated 149-child contacts of 80-adult
 Tuberculosis in Children 489

Figure 36.7A: Diagnostic algorithm for paediatric pulmonary TB

TB = tuberculosis; CXR = chest X-ray; TST = tuberculin skin test
Source: reference 59

multidrug-resistant [MDR] pulmonary TB cases (61). Culture the view that majority of the childhood contacts of adults
for Mtb was obtained from both the adult source cases as with MDR-TB are likely to be infected by these source cases.
and the child contacts. Isolates were compared by drug Childhood contacts of adults with MDR-TB should,
susceptibility testing [DST] and restriction fragment length therefore, be treated according to the drug susceptibility
polymorphism [RFLP] analysis. Six adult–child pairs with patterns of Mtb strains of the likely source cases unless the
cultures positive for Mtb were identified. DST and RFLP susceptibility pattern of the strain isolated from the child
analyses were identical for five adult-child pairs. The strain indicates otherwise. In another report from South Africa (62),
isolated from a child, in whom a source case was not evident, of the 306 mycobacterial culture and sensitivity results
was different from that isolated from the source cases. available from 338 children [under 13 years of age], the
However, the strain isolated from this child was prevalent in prevalence of isoniazid resistance and multidrug-resistance
the community in which he resided. This study (61) supports [defined as isolates resistant to isoniazid and rifampicin
 490 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 36.7B: Diagnostic algorithm for further investigations in pediatric pulmonary TB suspect who has persistent symptoms and does not
have a suggestive chest radiograph
TB = tuberculosis; CXR = chest X-ray; TST = tuberculin skin test; GL = gastric lavage; IS = induced sputum; BAL = bronchoalveolar lavage
Source: reference 59

Figure 36.7C: Diagnostic algorithm for paediatric lymph node TB

*The INDEX-TB guidelines (47) recommend use of Xpert MTB/RIF for diagnosis of lymph node TB
TB = tuberculosis; AFB = acid-fast bacilli; ZN = Ziehl Neelsen; FNAC = fine needle aspiration cytology; TST = tuberculin skin test
Source: reference 59
 Tuberculosis in Children 491

with or without resistance to other anti-TB drugs] were 6.9% Table 36.3: Recommended daily dosages of first-line
and 2.3%, respectively (62). Clinical features were similar in anti-TB drugs in children
children with drug-susceptible and drug resistant TB (62).
Dosage and range Maximum dose
Drug [mg/kg body weight] [mg]
TREATMENT Isoniazid 10 [7-15]* 300
The principles of therapy in children with TB are similar to Rifampicin 15 [10-20] 600
that of adults. Short-course anti-TB treatment is presently Pyrazinamide 35 [30-40] –
the standard of care for paediatric TB. It has been observed
Ethambutol 20 [15-25] –
that conventional doses used in childhood TB fail to
achieve serum concentrations above minimal inhibitory *higher end of the dosage range for isoniazid applies to younger
children. As the children grow older, the lower end of the dosage
concentrations [MICs] (63). The recently revised anti-TB range becomes more appropriate
drug dosages as per the WHO guidelines are shown in TB = tuberculosis
Table 36.3 (46). The WHO recommended daily treatment Source: reference 46
regimens for new TB cases in children are listed in
Table 36.4 (46). The WHO guidelines (46) advocate daily
anti-TB treatment for paediatric TB. Table 36.4: Recommended daily treatment regimens
In India, children with TB get treated under the RNTCP of for new TB cases in children
the Government of India. The treatment categories advocated Anti-TB treatment regimen
in the recently updated National Guidelines for Diagnosis Intensive Continuation
and Treatment of Paediatric TB (59,60); and the treatment Diagnostic category phase phase
regimens used are described in the chapter “Revised National HIV-negative children in low HIV
Tuberculosis Control Programme” [Chapter 53]. The reader prevalence and low H resistance
is also referred to the chapter “Endobronchial tuberculosis” settings
[Chapter 12] for details on airway stent placement. Smear-negative pulmonary TB 2HRZ 4HR
Intrathoracic lymph node TB 2HRZ 4HR
Corticosteroids TB peripheral lymphadenitis 2HRZ 4HR
Corticosteroids, in addition to anti-TB drugs, are useful in Extensive pulmonary disease 2HRZE 4HR
the treatment of children with neurological TB and in some Smear-positive pulmonary TB 2HRZE 4HR
children with pulmonary TB. These are mainly useful in Severe forms of EPTB [other than 2HRZE 4HR
settings where the host inflammatory reaction contributes TBM/osteoarticular TB]
significantly to tissue damage. Short-courses of corticosteroids High HIV prevalence or high H
are indicated in children with endobronchial TB that causes resistance or both
localised emphysema, segmental pulmonary lesions or Smear-positive pulmonary TB 2HRZE 4HR
respiratory distress. Some children with severe miliary TB
Smear-negative pulmonary TB with or 2HRZE 4HR
may show dramatic improvement with corticosteroids, if without extensive parenchymal disease
alveolo-capillary block is present.
Severe forms of EPTB [other than 2HRZE 4HR
TBM/osteoarticular TB]
Management of an Infant Born All regions
to a Mother with Tuberculosis TBM and osteoarticular TB 2HRZE 10HR
The foetus may be infected either haematogenously through MDR-TB Individualised
umbilical vessels or through ingestion of the infected treatment
amniotic fluid. In the former situation, there will be primary regimens
focus in liver and in the latter it will be in the lungs. It is The number preceding the treatment regimen indicates the duration
difficult to find the route of transmission in a newborn of that phase in months; drug treatment is daily
TB = tuberculosis; H = isoniazid; R= rifampicin; Z = pyrazinamide;
with multiple foci of infection. It is difficult to differentiate
E = ethambutol; EPTB = extrapulmonary tuberculosis; TBM =
between congenital and postnatally acquired TB (64). tuberculosis meningitis; MDR-TB = multidrug-resistant tuberculosis
According to the criteria proposed by Cantwell et al (65) Source: reference 46
in 1994, congenital TB is diagnosed if the infant has proven
TB lesion[s] and at least one of the following criteria: [i]
appearance of lesions in the first week of life; [ii] a primary All infants born to mothers with active TB should be
hepatic complex or caseating hepatic granulomas; [iii] TB screened for evidence of disease by doing a good physical
infection of the placenta or the maternal genital tract; and examination, TST and chest radiograph. If physical
[iv] exclusion of the possibility of postnatal transmission by examination and investigations are negative for TB disease,
a thorough investigation of contacts including the infant’s the infant should be started on isoniazid prophylaxis
hospital attendants or birth attendant. [10 mg/kg/day] for six months.
492 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Infants with congenital TB should be treated with four Radiological Criteria

drugs [isoniazid, rifampicin, pyrazinamide, ethambutol]
Clinical improvement precedes clearance of lesion on
in the intensive phase followed by two drugs [isoniazid,
chest radiographs. The optimal frequency of radiological
rifampicin] during the continuation phase for next four
monitoring in children with pulmonary TB is unclear. A
months (60).
chest radiograph may be obtained after completing six
months of treatment if the child is showing satisfactory
Management of a Child in Contact with improvement on clinical monitoring. If the child shows
an Adult with Tuberculosis worsening of clinical features at any time or no improvement
after two months of intensive phase, a repeat chest
In a prospective observational study (66), nearly one-third radiograph may be obtained (59,60). Children who show
of children [aged < 5 years] in contact with adults with poor or no response at the end of intensive phase should be
active TB disease had evidence of TB infection. The infection given benefit of extension of intensive phase for one more
was more commonly associated with younger age, severe month. The child, if better, should be shifted to continuation
malnutrition, absence of Bacilli Calmette-Guérin [BCG] phase; else, the child is investigated for failure of treatment
vaccination, contact with an adult who was sputum-positive, and drug-resistance.
and exposure to environmental tobacco smoke (66). It is
suggested that children below six years of age in contact
Microbiological Criteria
with adult patients with sputum positive TB should receive
six months of isoniazid prophylaxis. It is mandatory to Most of the childhood pulmonary TB is paucibacillary. In
screen all children in the household of an adult patient with children, where isolation of Mtb was possible at the time
sputum-positive TB. of diagnosis, every effort should be made to document
disappearance of bacilli during therapy.
Monitoring of Therapy
Other Measures
Response to treatment can be judged by using the following
Although an elevated erythrocyte sedimentation rate [ESR]
criteria: clinical, radiological, bacteriological, and laboratory
may be expected in children with TB, a recent study found
test results.
that one-third of children with TB had a normal ESR at the
time of diagnosis, suggesting little value in using ESR as a
Clinical Criteria diagnostic and monitoring test for childhood TB (70).
Clinical improvement in a child on anti-TB treatment is the
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 37
Surgical Aspects of Childhood Tuberculosis
Minu Bajpai, Alisha Gupta, Manisha Jana, Arun K Gupta

INTRODUCTION TB of the genitourinary tract must be suspected if a child

presents with chronic or recurrent urinary tract infection
Diagnosis of tuberculosis [TB] in children poses a major
[cystitis] not responding to adequate standard antibiotic
problem and a high degree of suspicion is warranted to therapy for recommended duration. The clinical suspicion
make an early diagnosis even in endemic regions. Currently, is enhanced when pus cells are found without bacteria in
surgery has a minimal role in treatment of childhood TB, an acidic urine or on methylene blue staining of the urine
because anti-TB treatment remains the mainstay in the sediment. Gross or microscopic haematuria; an enlarged,
management. Surgery is generally performed to secure tissue non-tender epididymis with a thickened, beaded vas; a
for diagnosis confirmation. With the increasing application chronic, draining scrotal sinus in the setting of history of TB
of cartridge-based nucleic acid amplification tests [CBNAAT] elsewhere in the body or definite history of contact, further
like Xpert MTB/RIF for the diagnosis of TB in children, support the diagnosis of genitourinary TB.
surgical intervention is being resorted to more frequently for Urinary frequency is the earliest symptom which is
procuring tissue for confirmation of diagnosis of TB (1-3). diurnal and progressive in nature (5). Frequency is secondary
Surgery has a role in managing sequelae or complications of to vesical irritation, decreased bladder capacity and rarely
TB. Sometimes, resectional surgery is carried out in children as a result of polyuria with tubular dysfunction. The urine
with drug-resistant active TB. In this chapter, the surgical may be opalescent. Occasionally, patients may present with
aspects of TB in children will be discussed laying emphasis pyuria. The child may initially complain of suprapubic pain
on the clinical, diagnostic and surgical principles involved. with a moderately full bladder which gradually progresses to
dysuria and strangury. Renal pain is usually absent but some
GENITOURINARY TUBERCULOSIS patients may have a dull flank ache. Painless haematuria may
result because of ulcers at the renal papilla in 5% cases (4-7).
As there is a time lag of about four to twenty years between
the initial infection and occurrence of genitourinary involve­
ment, paediatric genitourinary TB presents usually in the Table 37.1: Clinical features of genitourinary
adolescent period. The time lag noted is more than five years tuberculosis
in two-thirds of the patients and is greater than 15 years in Symptoms
a quarter of the cases (4). Progressive, diurnal urinary frequency
Dysuria
Clinical Presentation Macroscopic haematuria with back and flank pain
Renal colic
TB of the genital tract is uncommon before puberty. Systemic symptoms [fever, anorexia, night sweats, weight loss]
Majority of the young children with genitourinary TB are Hypertension
asymptomatic. Symptoms are seen in the more advanced Chronic epididymitis
stages and usually after vesical involvement. Symptoms and Other symptoms
signs commonly observed in children with genitourinary TB Polyuria, hyponatraemia [with adrenal tuberculosis]
Chronic renal insufficiency
are listed in Table 37.1.
 496 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Renal and ureteric colic may occur due to passage of a blood tract, urinary bladder, urethra. Algorithm for the surgical
clot, secondary calculi or debris. There is usually no renal management of children with genitourinary TB is shown
enlargement or tenderness. Rarely, the contralateral kidney in Figure 37.1. Surgery should be preceded by at least three
may show compensatory enlargement. Symptomatic chronic weeks and preferably four months of anti-TB treatment with
renal failure occurs rarely but subclinical impairment of renal constant clinical and radiological monitoring. The principles
functions may be seen more often. Hypertension may be of surgery for urogenital TB in children are same as those for
evident in 5%-10% children with renal TB (4-7). Ocon et al (6) adults. The reader is referred to the chapter “Genitourinary
have shown that in most patients, the hypertension is not tuberculosis” [Chapter 27] for more details.
mediated by the renin-angiotensin system, and is therefore,
not cured by nephrectomy. Genitourinary TB may present
with other complications, such as perinephric abscess, renal
ABDOMINAL TUBERCULOSIS
calculi, secondary amyloidosis and adenocarcinoma of the The clinical manifestations of abdominal TB are protean
renal pelvis. [Figures 37.2, 37.3, 37.4, 37.5 and 37.6]. All age groups are at
TB of the genital tract most often manifests as epididymitis risk, and children between six and fourteen years of age are
in boys. Fever is seldom present. Enlarged epididymis may often affected (8,9). Clinical presentation of abdominal TB in
be felt as a hard, nodular swelling. A chronic draining scrotal
children can be acute, sub-acute or with other manifestations.
sinus should suggest TB aetiology unless proved otherwise.
The reader is referred to the chapters “Tuberculosis in children”
A secondary hydrocoele may accompany epididymitis. The
[Chapter 36] and “Abdominal tuberculosis” [Chapter 15] for more
testis may be fixed by an extension of an epididymal abscess.
details regarding the clinical presentation, diagnosis and
The prostate may be nodular or indurated and the seminal
medical management of this condition.
vesicle is similarly involved. In the presence of prostatitis, TB
may spread via the semen. Genital TB may be a manifestation
of sexual abuse and there are reports of urethral involvement Role of Surgery
and penile lesions following ritual circumcision. In girls, Anti-TB treatment is the mainstay of management (4-9).
lower abdominal pain and amenorrhoea may be presenting Surgical intervention is helpful in procuring tissue for
symptoms of genital TB. Constitutional symptoms are rare. confirmation of aetiological diagnosis in children with
Free peritoneal fluid and lower abdominal mass may be peritoneal and mesenteric lymph node TB (8-12). An
evident.
algorithm for assessment of suspected abdominal TB is
shown in Figure 37.7 (13). Surgery is also helpful in the
Role of Surgery management of complications of intestinal TB, such as
Surgery is reserved for the management of local complications, perforation of intestinal ulcer and intestinal obstruction.
such as ureteral strictures, perinephric abscesses, non- The possible role of surgical intervention in children with
functioning kidneys and reconstruction of upper urinary abdominal TB is shown in Figures 37.8A and 37.8B.

Figure 37.1: Algorithm for the surgical management of children with genitourinary TB
IVP = intravenous pyelography; TB = tuberculosis
Adapted and reproduced with permission from reference 7
 Surgical Aspects of Childhood Tuberculosis 497

Figure 37.2: Barium meal follow through examination showing Figure 37.3: Barium meal follow through examination showing short
ileocaecal tuberculosis [stricture marked by arrows] segment tuberculosis stricture [arrow] in the small bowel with proximal
dilatation

A B
Figure 37.4: Ultrasonography of the abdomen showing ascites [A] and multiple hypoechoic masses in the prevertebral location [B] suggestive
of lymphadenopathy

A B
Figure 37.5: Gastrointestinal tuberculosis in an 8-year-old girl. CECT abdomen axial [A] and coronal reformatted [B] images showing wall
thickening of the terminal ileum [arrow] and adjacent mesenteric lymphadenopathy
CECT = contrast-enhanced computed tomography
 498 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 37.6: Peritoneal tuberculosis. CECT abdomen axial [A] and coronal reformatted [B] image reveal ascites [asterisk] with peritoneal
thickening [arrow] and clumped bowel loops in the central abdomen
CECT = contrast-enhanced computed tomography

Figure 37.7: Algorithm for assessment of suspected abdominal TB

*Confirmatory investigations: [i] culture for Mycobacterium tuberculosis from accessible source; [ii] peripheral lymph node biopsy for histopathology
and culture; [iii] adenosine deaminase levels in ascitic fluid; and [iv] CT of the abdomen if ultrasonography is inconclusive
TB = tuberculosis; AFB = acid-fast bacilli; TST = tuberculin skin test; CT = computed tomography
Adapted from reference 13
 Surgical Aspects of Childhood Tuberculosis 499

Ileum is the most common site of TB perforation and

is associated with distal stricture formation. Resection and
anastomosis are preferred because simple closure of the
perforation is associated with a high incidence of leakage and
fistula formation, and thus, higher mortality (17). Emergency
surgery for intestinal obstruction is best avoided as it is
associated with a high mortality (18).

PERIPHERAL LYMPH NODE TUBERCULOSIS

Figure 37.8A: Surgical intervention in patients with peritoneal TB TB accounts for a high proportion of lymphadenopathy
TB = tuberculosis in children. Classically, the cervical nodes are involved in
Adapted from reference 12
67%-90% of cases (19,20). The exact incidence may vary
in childhood but has been reported in up to 55% in a
cohort of 223 children under six years of age (21). Painless
enlargement, matting, fluctuant neck mass or a discharging
sinus may be evident. Multifocal [> 3 sites] or generalised
lymphadenopathy is uncommon without co-existent dis­
seminated or miliary TB. Associated extralymphatic TB has
been described in 5%-15% cases. Such presentation is more
frequently seen in human immunodeficiency virus [HIV]
infection (19-22). Isolated TB lymphadenitis at sites other
than cervical region has been reported rarely.
Selective preauricular and intraparotid lymph nodal TB
with or without parotid parenchymal involvement may,
sometimes, be seen (23). The lower pole is usually involved
presenting as a swelling antero-inferior to the ear and in
front of the mastoid attachment of the sternocleidomastoid
Figure 37.8B: Surgical intervention in patients with intestinal TB muscle. The dense parotid fascia limits the spread of
TB = tuberculosis infection and the resultant swelling may mimic a tumour
Adapted from reference 6
on physical examination.

Nontuberculous Mycobacterial
The role of laparoscopy has been promising in procuring
tissue for histopathological diagnosis (14). It has brought Lymphadenitis in Children
down the rate of unnecessary laparotomies in children and In lymphadenitis caused by nontuberculous mycobacteria
with experience, its role may also be extended to therapeutic [NTM], females are mostly affected and lymph node
purposes [stricturoplasty, adhesiolysis]. Surgery for abdo­ involvement is unilateral (24,25). High cervical lymph
minal TB must be cautious and minimal as the risk of nodes near the mandible are characteristically involved
inadvertent bowel injury with subsequent entero-cutaneous and the enlarged lymph nodes are firm, rubbery and non-
fistulae is high. Procedures commonly adopted include tender. These may not manifest the signs of inflammation
closure of perforation, exteriorisation of bowel, adhesiolysis and matting is exceedingly rare. Systemic symptoms
and resection-anastomosis of the bowel. The choice of are uncommon and history of exposure to TB is rarely
surgery is dependent on several factors. TB perforations obtained.
carry a high mortality [30%-40%] despite surgery (15). The reader is referred to the chapters “Lymph node
Stricturoplasty is preferred to multiple resection anastomoses tuberculosis” [Chapter 22], “Nontuberculous mycobacterial
in multiple strictures as it conserves the bowel and obviates infections” [Chapter 41] for more details.
the occurrence of blind loop syndromes.
Abdominal cocoon is a rare disease in which intestinal Role of Surgery
obstruction results from the encasement of variable lengths
of the bowel by a dense fibrocollagenous membrane that Anti-TB treatment is the mainstay in management of
gives the appearance of a cocoon. Patients with tuberculous lymph node TB. The surgeon aids in obtaining tissue for
cocoon usually complain of recurrent attacks of subacute the confirmation of diagnosis [e.g., in performing excision
intestinal obstruction or abdominal lump, and some patients biopsy of the lymph node]. The indications for the lymph
may be asymptomatic. An accurate diagnosis is difficult node sampling are listed in Table 37.2. NTM lymphadenitis
to make preoperatively. Surgical exploration with release is treated primarily by surgical excision (19). Parotid
of gut from the encasement membrane is the treatment of lymph nodal TB may mandate superficial extirpation of an
choice (16). The typical finding at surgery is a conglomeration encapsulated mass with a 1 cm margin (23). Aspiration of
of small bowel loops encased in a dense white membrane. fluctuant lesions may also be required in some patients.
500 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 37.2: Indications for lymph node sampling

Difficulty in clinical diagnosis and/or non-diagnostic fine needle
aspiration cytology
Abscess formation
History of rapid increase in size
Further significant increase in size on treatment
Supraclavicular lymph nodes
Hard or matted lymph nodes
Fixation to surrounding structures
Development of new signs and symptoms [fever, weight loss, night
sweats]
Significant lymph node [> 2 cm] not responding to antibiotic therapy
in 4 to 6 weeks Figure 37.9: Chest radiograph [postero-anterior view] showing right
Non-resolution of the lymphadenopathy in 8 weeks paratracheal lymphadenopathy [thick arrow] and left upper zone patchy
consolidation [thin arrow]

PULMONARY TUBERCULOSIS
In children with primary pulmonary TB disease [Figures 37.9
and 37.10], compression of the relatively narrow and com­
pliant airways by the enlarged intrathoracic lymph nodes
can result in atelectasis, obstructive emphysema, pulmonary
infection and even asphyxia (26-28). The enlarged media­
stinal lymph nodes can also cause perforation of the tracheo­
bronchial tree. The aim of effective surgical treatment in
childhood pulmonary TB includes restoring lung function
to normal and managing complications. The indications for
surgery are listed in Table 37.3 (26-30).

Role of Surgery
Major Airways Obstruction A

When there is an obstruction of the major airways and

acute respiratory distress, administration of prednisolone
[2 mg/kg/day] along with anti-TB treatment and nebulised
bronchodilator therapy is indicated. Lack of improvement
within 48-72 hours is an indication for operative intervention.
Following a pre-operative bronchoscopic assessment of
the airway, usually a right thoracotomy is performed. An
attempt to resect the entire nodal mass is hazardous and can
lead to damage of the airway wall. Most of the nodes can be
evacuated by incising the capsule and removing the caseous
material or by removing the calcified contents piecemeal.
When there is chronic compromise, these patients may
be asymptomatic. Superinfection by pyogenic organisms can
result in an acute presentation. Also, the distal atelectatic
or collapsed lung can undergo progressive damage despite B
effective medical therapy [Figure 37.11]. Figure 37.10: Intrathoracic lymph node involvement in TB in a child.
Recent evidence suggests that the early surgical decom­ Chest radiograph [A] shows superior mediastinal widening, lobulated
soft tissue density shadows in right paratracheal and hilar regions
pression prevents irreversible pulmonary parenchymal
[arrows]. CECT chest [B] shows central non-enhancing areas [asterisk]
damage. The risk of airway damage during evacuation of indicating caseation necrosis and peripheral thin rim enhancement
lymph nodes is higher in this group. Nodal incision and [arrow] indicating inflammation in the lymph nodes
curettage of the mass is recommended. TB = tuberculosis; CECT = contrast-enhanced computed tomography
 Surgical Aspects of Childhood Tuberculosis 501

Table 37.3: Indications of surgery in childhood

pulmonary TB
Major airway obstruction by extraluminal lymph node compression
or intraluminal tissue
Post-TB pulmonary destruction
TB pleural disease
Other indications
Drainage of active TB lung abscess
Repair of broncho-oesophageal and bronchopleural fistula using
vascularised muscle flaps
Resection of persistently discharging chest wall sinuses
TB = tuberculosis

B
Figure 37.11: Chest radiograph [postero-anterior view] showing
collapse of left lower lobe which can be seen as a triangular radiodensity
[arrow] in the left retrocardiac region

When the obstruction is due to intraluminal tissue

[endobron­chial TB], the collapsed lung is at high risk of being
permanently damaged by infection. Bronchoscopic suction
and removal of granulomatous tissue with biopsy forceps
results in re-inflation of the lobe or lung in more than 50%
of the cases. This usually requires multiple attempts which
are repeated every five to seven days. Haemorrhage during
removal of the granulation tissue is a possible complication.
This procedure decreases the incidence of pulmonary
resection and salvages lungs or lobes which are collapsed
secondary to obstruction but are otherwise normal.
C
Figure 37.12: Extensive lung parenchymal involvement in a child with
Post-tuberculosis Pulmonary Destruction pulmonary TB. CT topogram [A] showing an opaque left hemithorax
Patients with post-TB pulmonary destruction present with areas of cavitation and bronchiectasis. CECT chest [mediastinal
window] [B] and lung window [C] bilateral consolidation and areas of
with definite evidence of extensive pulmonary damage
breakdown in left upper lobe
[Figures 37.11, 37.12 and 37.13] and are usually symptomatic. TB = tuberculosis; CT = computed tomography; CECT = contrast-
Decision making regarding pulmonary resection is primarily enhanced computed tomography
based on symptomatology rather than the radiological
findings. The risk to the remaining pulmonary tissue This regimen is continued till the sputum production is
should be kept in mind while planning for surgery. Intensive reduced to a minimum. One lung ventilation and prone
pre-operative preparation involving physiotherapy and position with head end lowered is recommended during
use of broad-spectrum antibiotic treatment is mandatory. surgery to avoid contamination of the normal lung.
 502 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A A

B B
Figure 37.13: Destroyed left lung secondary to TB in an adolescent
male. Chest radiograph [postero-anterior view] [A] shows opaque
left hemithorax with ipsilateral mediastinal shift. CECT chest [lung
window] [B] shows complete destruction of left lung parenchyma and
compensatory hyperinflation of the right lung
TB = tuberculosis; CECT = contrast-enhanced computed tomography

Tuberculosis Pleural Disease

In children, TB of the pleura can, sometimes, present with
associated chest wall abscess and bone involvement as well
[Figure 37.14]. Late pleural fibrosis after a TB empyema
requires decortication [Figures 37.15 and 37.16]. Patients with
minimal or no respiratory symptoms despite radiographic
evidence of pleural fibrosis do not require decortication
unless there is a significant postural problem [scoliosis]. C
Patients with minimal symptoms cope well with pleural Figure 37.14: Pleural thickening and TB osteomyelitis in a 13-year-
fibrosis which tends to regress with age and activity. It old girl. CECT chest axial images [A and B] show right-sided pleural
is also important to ensure that the underlying lung is thickening [arrow head] and anterior chest wall abscess [thick arrow],
and destruction of the angle of right scapula [thin arrow]. Coronal
not bronchiectatic and unsalvageable before undertaking reformatted image [bone window] [C] shows the destruction of right
decortication. Video-assisted thoracoscopic surgery [VATS] scapula [arrow]
is also finding increasing use in the treatment of pleuro­ TB = tuberculosis; CECT = contrast-enhanced computed tomography
pulmonary TB (31-33). VATS is a safe approach and avoids
the morbidity associated with conventional thoracotomy. The
current role of VATS in the management of pleuropulmonary achieving the diagnosis of TB through pleural biopsies or
TB is unclear but VATS has been found to be useful in the wedge lung resection of indeterminate pulmonary nodules;
following situations (31-33): [i] VATS is safe and effective in it is particularly useful for those patients who are debilitated,
 Surgical Aspects of Childhood Tuberculosis 503

Figure 37.15: CECT of the chest showing loculated encysted empyema Figure 37.16: Chest radiograph [postero-anterior view] of a 12-year-
in right hemithorax with enhancing walls. Thickening of extrapleural soft old boy with left-sided TB empyema. The left hemithorax shows volume
tissues can also be seen loss, rib crowding and pleural thickening
CECT = contrast-enhanced computed tomography TB = tuberculosis

thus making them poor candidates for conventional open Surgical Therapy
surgery; and [ii] in patients with trapped lung or TB
Intrathecal hyaluronidase has been used in children
empyema, VATS could achieve full lung re-expansion with
with thick basal exudates. Besides clearing up meningeal
minimal morbidity. However, therapeutic lung resection
adhesions hyaluronidase helps in better diffusion of drugs
using VATS in patients with TB is technically demanding
and reverses or reduces vasculitis. A weekly dose of
and potentially hazardous. Its role is, at present, limited.
1000-1500 units for five to ten weeks has been recommended
The reader is also referred to the chapter “Surgery for
as treatment (34).
pleuropulmonary tuberculosis” [Chapter 46] for more details.
In 50% or more cases, there is established hydrocephalus
[Figure 37.17] requiring treatment. Meningeal exudates not
NEUROLOGICAL TUBERCULOSIS
only obstruct cerebrospinal fluid [CSF] pathways but can
Neurological TB constitutes almost half the cases of child­ occlude large vessels in the circle of Willis, the middle cerebral
hood TB. The reader is referred to the chapter “Neurological artery in the Sylvian fissure and the lenticulostriate vessels
tuberculosis” [Chapter 17] and “Tuberculosis in children” causing infarction. The aetiopathogenesis of hydrocephalus
[Chapter 36] for more details. in TBM involves blockage of the basal cisterns by the TB

A B
Figure 37.17: NCCT of the head showing obscured suprasellar cisterns [A] which manifest intense enhancement with intravenous contrast.
Communicating hydrocephalus with periventricular ooze [arrow] is also seen [B]
NCCT = non-contrast computed tomography
504 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

exudates in the acute stage and adhesive leptomeningitis in

the chronic stage resulting in communicating hydrocephalus.
The aqueduct of sylvius may be blocked by circumferential
compression of the brainstem by the meningeal exudates
leading to non-communicating hydrocephalus. Rarely,
an intraluminal subependymal tuberculoma or a plug of
ependymal exudate may block the aqueduct.
In patients with hydrocephalus due to TBM, surgical
management is indicated if the signs and symptoms
suggestive of raised intracranial pressure persist despite
adequate medical therapy. Increasing ventriculomegaly
with periventricular ooze, recent onset papilloedema and
signs and symptoms of raised intracranial pressure like
vomiting, hypertonia, gaze palsies and bradycardia are
indications for shunt surgery (35-40). Ventriculoperitoneal
shunts are preferred over ventriculoatrial shunts unless the Figure 37.19: CECT of the head showing contrast-enhancing granuloma
peritoneal cavity is involved in the disease. Various shunt with lobulated outline and surrounding oedema. Tuberculoma is difficult
to differentiate reliably from other inflammatory granulomas on the
systems are available and all of them involve a one-way basis of CT alone
pressure regulated valve. CSF examination is mandatory CECT = contrast-enhanced computed tomography; CT = computed
before shunt placement. The presence of persistent infection tomography
in the CSF can lead to a low-grade peritoneal inflammation
and pseudocyst formation. Further, the high protein content
COMPLICATIONS OF SURGERY FOR
of the CSF has been implicated in the higher incidence of
TUBERCULOSIS IN CHILDREN
shunt blockage seen in this setting. Intraventricular septae
and ependymal adhesions complicate the picture and cause Complications of surgery in childhood TB are shown in
incomplete decompression of ventricles. Ventriculoscopy and Table 37.4. The surgical complications or post-operative
adhesiolysis may be required to break the loculations and sequelae may be due to an ongoing process of cicatrisation
allow free CSF drainage. It must be remembered that CSF as a result of healing. Hence, emphasis should be on initial
shunting has definite serious complications and, therefore, adequate drug therapy, meticulous surgery and regular
the decision to place a shunt must be individualised and follow-up. Follow-up of at least 12 months after completion
based on definite indications. of therapy and life-long follow-up is suggested in cases with
Intracranial tuberculomas can be multiple [Figure 37.18]. calcification.
If the tuberculoma is large or is located in the pathway of
CSF circulation, surgical removal is essential [Figure 37.19].
Table 37.4: Some of the complications of surgery in
However, in majority of the patients, tuberculomas respond
childhood TB
well to anti-TB treatment and corticosteroids.
Pulmonary TB Contralateral spread of disease
Retention of secretions
Nonspecific pneumonia
Symptomatic air space
Infarction of middle lobe
Postoperative haemorrhage
Empyema
Abdominal Inadvertent bowel injury
Entero-cutaneous fistulae
Genitourinary TB Following reconstructive surgery
TB = tuberculosis

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 38
Tuberculosis in the Elderly
Surendran Deepanjali, Tamilarasu Kadhiravan

INTRODUCTION trend continues to hold (2). As a result, the age-structure of

populations is undergoing a marked change [Figure 38.1] (3).
The past century had witnessed an impressive improvement Globally, in a few years’ time, elderly people will outnumber
in human survival across the globe brought about by children. The elderly population [aged ≥ 65 years] is
advances in modern medicine. Average life-expectancy projected to grow from an estimated 524 million in 2010 to
at birth had improved from 48 years to 65 years over the nearly 1.5 billion in 2050 (4). Notably, most of this increase
period of 1955-1995, and is expected to improve further to would happen in the developing countries [250% versus 71%
73 years by 2025 (1). This increase had been observed in increase] (4). In India, the average life-expectancy improved
all regions of the world. On the other hand, fertility rates from 56.3 years in early 1980s to 66.3 years by 2011;
had steadily declined all around the globe, and this secular simultaneously, the fertility rate declined from 4.47 births

Figure 38.1: Population pyramids illustrating the age-composition of population during 1950 to 2025 [projected] in the world [top panels] and
India [bottom panels]
Reproduced with permission from “http://populationpyramid.net/ Courtesy: Martin De Wulf ”
 Tuberculosis in the Elderly 507

in early 1980s to 2.5 births per woman in 2011 (5,6).

While the elderly [aged ≥ 60 years] constituted 5.3% of
Indian population in 1960, the contribution is expected to
rise to 11% by 2025 (7).
Alongside this demographic transition, the relative
burden of human illnesses is also witnessing a substantial
change. The Global Burden of Disease Study 2010 (8)
found that ageing of the world’s population contributed
to a 11.2% decrease in mortality due to communicable,
maternal, neonatal, and nutritional disorders over the
period 1990-2010; on the other hand, ageing contributed
to a 39.2% increase in deaths due to non-communicable
diseases. During this period, mortality due to tuberculosis
[TB] saw a relative decrease of 18.7%. As a result, TB fell
from 6th to 10th position among the top 25 causes of global
deaths and likewise dropped to the 11th position from its
previous ninth position among the top 25 causes of years of
life lost globally (8). Notwithstanding this general decline
in infectious diseases, TB continues to be a public health
burden in developing countries (9). It has been recognised Figure 38.2: Time trends in age-specific TB incidence in the United
States during 1993 to 2011
since long that ageing is a risk factor for TB, and that age
Based on data from reference 13
is closely linked to the treatment outcome in patients with
TB. The profound change in the demographic structure of
populations, is thus, likely to alter the epidemiology of TB
Population-based studies from India, a high burden
both in endemic as well as non-endemic countries.
country, had found increased prevalence as well as incidence
of both latent TB infection [LTBI] and active TB as the age
EPIDEMIOLOGY OF TUBERCULOSIS IN increases, especially among people aged 55 years or more. A
THE ELDERLY population-based survey in southern India during 1961-1968
The generally accepted concept is that in low-burden, found that the average annual incidence of TB among those
developed countries, TB is a disease of elderly native-born aged 55 years or more was 327 per 100,000 population while
and the immigrant populations while it commonly affects it was 153 per 100,000 among those aged 35-54 years (16).
young adults in high-burden, developing countries (10-12). Similarly, more contemporary [1999-2006] population-based
However, this is a simplistic supposition since the surveys from south India also confirm a substantially
epidemiology of TB is influenced by the interplay of multiple higher prevalence of culture-positive TB in the 55-64 and
factors, some of which might be context specific such as above 65 years age-groups compared to the rest of the
the prevalence of human immunodeficiency virus [HIV] population (17,18).
infection in the population. In the United States, persons A modest over-representation of elderly is observed
aged 65 years and above constituted 21% of all TB cases among TB patients in India; 8.3% of all smear-positive
notified in the year 2011. Interestingly, this proportion has pulmonary TB cases notified in the year 2011 were aged
remained fairly the same over time, despite a progressive 65 years or above, while they constituted only about 5.1%
decline in the risk of TB across all age-groups during the of the total Indian population in 2010 (7). Thus, it is
period 1993-2011 (13). Over this period, the incidence rates in reasonable to believe that the elderly are at a higher risk
elderly have consistently remained higher than the rest of the of TB even in high-burden settings. In fact, nearly 10% of
population [Figure 38.2]. Moreover, the higher risk among all new smear-positive pulmonary TB notified in the year
elderly was apparent in all ethnic groups such as Whites, 2011 from the 22 high-burden countries was among the
African, Americans, Asians, Hispanics, Pacific islanders, elderly aged 65 years or more (9). There exists a possibility
and American Indians or Alaskans (13). In contrast, a study that these figures might, in fact underestimate the actual
from Switzerland found that TB among the foreign-born burden of TB among the elderly, as sick elderly people do
most commonly affected the younger ages with less than not always seek care and are largely dependent on others
5% of patients aged 65 years and above, whereas among for their health care needs. On the other hand, in the World
the native-born nearly 50% of patients were aged 65 years Health Organization [WHO] African region, just about 4%
and above. Further, the native-born TB patients had a of smear-positive TB cases notified in 2011 were among the
bimodal age distribution—the other peak in the younger age elderly (9). In African countries like South Africa, the major
group was attributable to HIV infection (14). In the United burden of TB is borne by young adults aged 20-50 years,
Kingdom, where 74% of all cases reported in 2011 were attributable to the influence of the HIV epidemic (19).
among the foreign-born, elderly [≥ 65 years] constituted It emerges that the contribution of elderly to the total
14% of all cases (15). number of TB cases depends on the relative contribution
 508 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

of elderly to the total population as well as the differential described by some as a sign of successful TB control (24).
decline/increase in the incidence of TB in the younger However, with a substantially lesser selection pressure due
age-groups. For example, a burgeoning elderly population to decreasing transmission and the availability of curative
would increase the relative contribution of elderly to the treatment, more and more susceptible persons might survive
total number of TB cases. Likewise, decreasing transmission to old age in the future as compared to the past. As a result
in the community brought about by effective TB control of this easing selection pressure, the cohort-contour that
programmes with a resultant decline among the younger was described to be constant across generations based on
ages would also increase the relative contribution of elderly. data from the pre-chemotherapy era [1851-1930] might get
It should be noted that both these factors are currently distorted (22).
influencing the epidemiology of TB. On the other hand, any On the other hand, some authors have contested the
increase in the risk of TB among the younger ages and a notion that the actual risk of TB is less among the elderly,
decrease in life expectancy, as it happened in some African based on more contemporaneous data (25). Davies (25)
countries with the advent of the HIV epidemic, would reported that the decline in the risk of after adulthood
attenuate the contribution of elderly to the TB burden. has started reversing since 1978 in Hong Kong during the
period 1953-1993 (26). Another study (27) from the same
Ageing and Risk of Tuberculosis population covering the time period 1961-2005, employing
a robust age-period-cohort modelling approach, found
Leaving aside the issue of the relative contribution of the that after adjusting for the effects of birth cohort and time
elderly to the total TB burden, an entirely different question period, “the relative risk of age began to rise in both men and
that needs to be answered is, whether the elderly are women in the 5-9 year age group, peaked at 20-24 years, then
intrinsically at a higher risk of TB. The absolute risk of TB in quickly declined to a nadir in the 45-49 year age group, and finally
elderly is influenced mainly by two factors—prevalence of showed an upturn during the eighth decade for women which
LTBI and the risk of reactivation. In light of the contribution was not apparent for men. Whereas both sexes [female more so
of reinfection [detailed below], the risk of progression than male] showed an upward inflection as they approached their
following a reinfection should also be considered as the 70s, this effect was only observed for people born later [1911-56]
third factor. In any population, irrespective of the level of but not earlier [1876-1906]”. It is really remarkable that the
endemicity, the prevalence of LTBI increases with age. The cohort-contour described by Andvord continues to hold true
gradient in the prevalence of LTBI between the young and even today, barring the upturn in the later part of life. This
elderly sections of the population is more pronounced in upturn in the risk of TB case-notifications among the elderly
countries with a currently low burden of TB. Historically, is possibly an early indication of the easing selection pressure
however, these countries had witnessed a high burden of TB at younger ages as a result of successful TB control. While
several decades ago in the past. Most of the elderly people such a conclusion is entirely speculative, it is not biologically
presently living in the low-burden countries were born implausible given the fact that ample evidence exists to attest
during this era. Thus, the majority of the elderly in these the fact that humans and Mycobacterium tuberculosis [Mtb]
countries is supposed to have got infected several decades have co-evolved over a long period of time pre-dating the
ago when the annual risk of TB infection was high and Neolithic period (28). Thus, at the end of this convoluted
effective anti-TB treatment was unavailable. In fact, early series of arguments, it emerges that the contemporary elderly
epidemiological studies concluded that the higher risk of are perhaps at a higher risk of TB, especially in populations
TB in this population was just a reflection of a high burden where there has been a sustained improvement in control.
of LTBI among them. This phenomenon is known as the
“generation or birth cohort effect” (10,20). Frost described RE-INFECTION VERSUS RE-ACTIVATION
this as “the peak of [tuberculosis related] mortality in late life does
not represent postponement of maximum risk to a later period, but The higher risk of TB among the elderly is attributable to
rather would seem to indicate that the present high rates in old age a higher risk of reactivation of LTBI. The majority of TB
are the residuals of higher rates in earlier life” (21). disease in the elderly is believed to be caused by re-activation
Seminal epidemiological studies (21-23) have demon­ of endogenous infection rather than by exogenous new
strated that the apparently higher risk of TB mortality among infection/re-infection (29). In one of the earliest population-
the elderly seen in cross-sectional studies of populations based molecular epidemiological studies from San Francisco,
is actually a fallacy. Rather when the populations were USA [1991-1992], clustering of isolates was seen much
studied as birth cohorts, the risk of TB death peaked among less frequently among the elderly compared to the rest
children [0-5 years] and young adults [20-30 years] and the [24% versus 46%], indicating that the majority of cases
risk was comparatively less among the elderly (22,23). The were not attributable to recent infection (30). A subsequent
counterintuitive finding that the risk was lower among molecular epidemiological analysis of all TB cases reported
elderly is fascinating and was attributed by Frost (21), over a 13-year period [1991-2003] in San Francisco also
Andord et al (23) to host resistance. Possibly, it represents confirmed the finding that cases aged over 55 years were
a healthy survivor bias as a result of natural selection significantly less likely to be in a cluster (31). In Norway,
operating at younger ages. In fact, the phenomenon of higher 213 of 418 Mtb isolates during 1998-2005 from persons
incidence in the elderly compared to the young has been born before 1950 were attributed to re-activation (32).
 Tuberculosis in the Elderly 509

In a population-based study from Florida, USA, HIV-seronega­ and evidence of more haematogenous dissemination to the
tive persons aged over 50 years had a four-fold higher risk of liver (46-48). A low antigen-specific CD4+ T-cell proliferative
re-activation (33). In another study from New York, USA, capacity and a decline in natural killer [NK] cell activity have
75 [76%] of 98 TB patients aged over 60 years had a unique also been demonstrated in the elderly (46,49). The gamut of
IS6110 deoxyribonucleic acid [DNA] fingerprint, while immune system changes due to ageing is quite similar to that
only 210 [47%] of 448 patients younger than 60 years had a of HIV infection (50). Although these factors may potentially
unique isolate (34). Thus, multiple molecular epidemiological predispose to re-activation of LTBI or development of
studies done in low-burden countries have shown decreased disease after exogenous infection in the elderly, conclusive
‘clustering’ of cases in the elderly population, which suggests evidence for the purported role of immunosenescence in
endogenous re-activation, rather than exogenous infection. humans is still not available.
Another study from the USA which examined TB among
foreign-born US residents found that the elderly immigrants RISK FACTORS
with TB had a 4.5-fold higher odds of reactivation TB
compared to younger immigrants [< 15 years] with TB (35). The various risk factors known to predispose otherwise
A population-based molecular epidemiologic study on a healthy adults to TB, increase the risk of TB among the
rural southern Indian population found that 38% of patients elderly also (51). Many studies have found a preponderance
were in clusters suggesting recent transmission (36). In of men among the elderly TB patients. The lower prevalence
contrast to other studies, among patients detected by house- of TB in women is often attributed to poor care-seeking
to-house survey, patients in clusters were significantly older behaviour and barriers to access healthcare. But, population-
than those with unique isolates [55 versus 43 years]. While based studies from India have also found a consistently
the reason for this aberrant observation is unclear, it is lower prevalence of TB among women of all age-groups
possible that an elderly patient with endogenous reactivation compared to men (16,18). Diabetes mellitus is another
could be the original source of infection in such clusters (36). well-recognised risk factor that increases the risk for TB
From the data discussed earlier, it also emerges that even by 2- to 3-fold (52,53). Globally, about 10% of TB cases are
in low-burden settings, at least a fourth of cases among the attributable to diabetes mellitus (54,55). A burgeoning elderly
elderly could be the result of recent infection. Of late, an population in the low- and middle-income countries is set to
important role for exogenous re-infection has been proposed increase the burden of diabetes in these countries, thereby
based on epidemiological and experimental evidence (37). posing a challenge to TB control (56,57). Likewise, tobacco
This is particularly important in high-burden countries like smoking is another risk factor for TB whose significance is
India with high rates going on of TB transmission in the being increasingly recognised (58). Notwithstanding the fact
community (38). On the other hand, in low-burden countries that the prevalence of active smoking declines with ageing,
like the USA, clustering of cases due to spread of infection a population-based study from southern India found that at
has been reported among elderly residing in nursing homes least 45% of TB deaths among the urban living and at least
and long-term care facilities (11,39). The risk of active TB 28% of TB deaths among the rural living elderly men aged
among them is almost two- to three-fold higher compared 65 years or more were attributable to smoking (59). In
to community-dwelling elders. addition to these risk factors, poor socio-economic condi­
tions, such as, poverty, malnutrition, and overcrowding and
AGEING AND IMMUNOSENESCENCE other co-morbidities, like chronic renal failure, malig­nancy,
silicosis, post-gastrectomy status, and use of immuno­
In general, the elderly are considered to be more susceptible
suppressive drugs render the elderly population more
to infectious diseases (40). ‘Immunosenescence’—a decline
vulnerable to TB (60).
in immunity with ageing—is characterised by defects in
the haematopoietic bone marrow, impaired peripheral
lymphocyte migration, maturation and function, and chronic CLINICAL FEATURES OF TUBERCULOSIS
involution of the thymus gland (41). The age-related decline IN THE ELDERLY
in output of T-cells from thymus is compensated by an Pulmonary Tuberculosis
increase in the lifespan of naïve CD4+ T-cells mediated
by decreased levels of the proapoptotic molecule (42,43). In general, TB among the elderly is characterised by a higher
However, these naïve T-cells with increased lifespan are frequency of atypical clinical presentations. Pulmonary TB
functionally defective (44,45). A robust antigen-specific CD4+ in the elderly may also present with typical clinical and
T-cell response and production of T-helper 1 [Th1]-associated radiographic features. However, atypical presentations are
cytokines, such as, interferon gamma [IFN-γ], interleukin-12 often encountered in the elderly, leading to the premise
[IL-12], and tumour necrosis factor-alpha [TNF-a] are whether it is a different disease altogether (61). A number
necessary for immunity against TB (46). Paradoxically, in of studies in the past had compared the clinical features
murine experiments with aerosol delivery of Mtb to the of pulmonary TB in the elderly with younger patients,
lungs, old mice exhibit some early resistance to infection that and their findings were variable and sometimes even
is mediated by CD8+ T-cells, but they subsequently have discordant (62-66). Differences that were observed in
a higher bacterial load in the lungs than the younger ones these studies include more frequent mid- and lower-zone
510 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

infiltrates, miliary shadows, post-mortem diagnosis, and the southern state of Tamil Nadu during the second quarter
concomitant comorbidities; and a comparatively infrequent of 2011 (78). However, since the study involved a review of
occurrence of fever, weight loss, night sweats, expectoration, data collected by the programme, detailed information on
haemoptysis, positive tuberculin skin test [TST], cavitating the differences in clinical presentation between elderly
lung infiltrates, and alcoholism among elderly TB patients. and the rest was not available. Notwithstanding, there
In a pooled analysis of 12 studies that together had was no excess of sputum-smear negative pulmonary cases
compared 859 elderly with 1,801 young pulmonary TB among the newly treated elderly compared to the rest
patients, male preponderance was similar among both [34% versus 32%]. However, extra-pulmonary TB [EPTB] was
younger and elderly TB patients (67). Similarly, there was much less common among the elderly [12% versus 23%] (78).
no difference between young and older patients with respect
to evolution time before diagnosis, frequency of cough or Fever of Unknown Origin
sputum production, weight loss, and fatigue. But, fever,
Sometimes, symptoms such as anorexia, fatigue, change in
night sweats, and haemoptysis were less frequent among the
cognitive state, mental dullness, or simply ‘failure to thrive’
elderly. Interestingly, there was no significant difference in
may be the sole manifestation of TB in an elderly patient
the frequency of radiographic upper lobe lesions and sputum-
[Figure 38.3]. As noted above, fever may not be a prominent
smear positivity, even though cavitation was significantly
feature. However, TB does present sometimes as fever of
less common among the elderly (67). Other studies have
unknown origin [FUO] in the elderly, as it often does in
also found that ageing does not drastically influence the
the young. In two large case series from China covering the
frequency of upper lobe involvement in pulmonary TB; but,
years 2000-2008, TB was the most frequent infectious cause
it definitely increases the concomitant involvement of lower
of FUO among patients aged 60 years or more – 103 of 397
lobes (68-70). The frequent involvement of lower lobes in
patients and 13 of 87 patients had TB in these studies (79,80).
elderly has been traditionally ascribed to poor immunity and
Further, contrary to the earlier assertion that extrapulmonary
disease caused by re-infection. However, age-related changes
disease is comparatively infrequent among the elderly,
in lung ventilation–perfusion are thought to predominantly
a high proportion of elderly patients with presenting as
affect the lower lobes leading to a higher alveolar oxygen
FUO had EPTB (79,80). Similarly, vintage studies from
tension in the lower lobes, which favours the multiplication
developed countries also found that TB was an important
of Mtb (69).
cause of FUO in the elderly (81,82). In fact, 11 of the 100 cases
Diabetes mellitus exhibits a complex interaction with
of FUO originally studied by Petersdorf and Beeson in the
ageing to influence the clinical and radiographic findings 1950s were due to TB; three of their 11 TB patients were aged
of pulmonary—[i] patients with diabetes and TB are more than 60 years (83). However, TB is much less common
comparatively older; [ii] the male preponderance of TB is in more contemporary studies from developed countries.
not observed among patients with diabetes mellitus; [iii] in
elderly diabetes mellitus increases the chances of lower lobe
lesions [synergism] as well as cavitation [antagonism]; and,
diabetes mellitus modestly decreases the frequency of upper
lobe involvement (69,71,72). Rarely, pulmo­nary TB in the
elderly may present as organising pneumonia. Parenchymal
pseudotumoural variant of pulmonary TB does not seem to
have a predilection for the elderly.
Perez-Guzman et al (67) also found that elderly TB
patients had lower serum albumin levels, and a negative
tuberculin skin test was more common. Dyspnoea was
more commonly seen in the elderly, attributable to a
greater prevalence of concomitant medical conditions, like
cardiovascular diseases, chronic obstructive pulmonary
disease, diabetes, and cancers among the elderly. On the
contrary, alcoholism was more common among younger TB
patients. Most of these differences could be because of the
physiological changes associated with ageing (67).
After the publication of this meta-analysis, several Figure 38.3: Atypical clinical presentation of TB in the elderly. Chest
small-sized studies from India had compared the clinical radiograph [postero-anterior view] of an 80-year-old man with no
presentation of TB in the elderly, and their obser­ known comorbidities who presented with anorexia, dysphagia, and
vations were largely similar to the findings of this meta- inanition since 20 days; symptoms were preceded by a low-grade
fever for 2 days. Treating physician did not suspect TB; but, a routinely
analysis (73-77). To date, the largest study of TB among the
performed chest radiograph revealed miliary mottling, after which anti-
elderly from India is a retrospective population-based study TB treatment was started presumptively. However, patient succumbed
of 1,485 TB patients aged 60 years or more who were treated 15 days later. TB was confirmed on post-mortem examination.
under the national programme in 12 of the 32 districts of TB = tuberculosis
 Tuberculosis in the Elderly 511

But, it continues to be one of the causes of FUO, and its series of 254 deaths due to miliary TB confirmed at autopsy
diagnosis is often delayed (84-86). Apart from a general in Finland during 1974-1993, the mean age of the patients
decline in the incidence of TB, another potential reason for a was more than 75 years; the average age of 140 patients
decline in TB as a cause of FUO is the widespread availability with cryptic form of the disease was 78 years (92). This
of non-invasive imaging modalities such as computed finding is possibly attributable to a decline in childhood
tomography and magnetic resonance imaging (86). miliary TB as a result of improved TB control, while miliary
TB in elderly increased due to re-activation in an ageing
Cryptic Miliary Tuberculosis population (94). On the other hand, very few studies have
been published on cryptic miliary TB during the past two
A related clinical entity was described in 1969 by Proudfoot
decades. Presumably, the widespread availability of non-
and colleagues (87) as ‘cryptic military TB’. They reported
invasive imaging seems to have led to a decline in missed
a series of 16 patients that “did not present the clinical and
diagnoses. However, occasional cases of cryptic miliary TB
radiographic features associated with classical miliary TB” (87).
in elderly continue to be recognised only at necropsy even
Most of these patients (11 of 16) were elderly that presented
in resource-replete settings (95). Hence, one must bear in
with malaise, weight loss, and fever that remained un­
mind another important observation by these studies that
explained despite detailed investigation. Typically, these
the cryptic variety in the elderly was as common as the overt
patients had a paucity of respiratory symptoms, and their
classical miliary TB (87,90,92,93).
chest radiographs showed no diagnostic abnormalities. In
sharp contrast to other studies where the diagnosis was
made only at necropsy, in this series a diagnosis of TB was Extrapulmonary Tuberculosis
suspected during life in all except two patients. Indeed, As mentioned earlier, the relative frequency of extrapulmo­
10 patients showed a clinical response to a therapeutic trial nary involvement is considerably less in elderly with TB.
of isoniazid and para-aminosalicylic acid (87). Proudfoot In Poland, extrapulmonary TB constituted 8.5% of all
et al (87) concluded that, “Cryptic miliary TB is a difficult TB notifications in elderly aged 60 years or more during
diagnostic problem and should be suspected in any elderly patient, the period 1974-2010, while it was 18.6% in those aged
particularly a woman, who has an unexplained pyrexia, pancyto­ 0-19 years (96). The most common forms among the elderly
penia, or leukaemoid reaction”. Such a clinical presentation were pleural effusion [34%], peripheral lymphadenitis
was not entirely unknown before this seminal report. In [20%], genitourinary [13%], and osteoarticular TB [12%]. In
1962, several years ahead of Proudfoot’s report, Bottiger et contrast, intrathoracic lymphadenitis [44%], pleural effusion
al (88) had described a series of 5 patients with miliary TB [22%], and peripheral lymphadenitis [11%] were common
diagnosed at necropsy. They wrote, “The disease resembles in the 0-19 years age-group (96). In an analysis of TB cases
malignant neoplasia with weight loss, fever, and much-increased reported to the Centers for Disease Control and Prevention,
erythrocyte-sedimentation rate but without local signs” (88). But, USA, during 1993-2008, extrapulmonary disease was slightly
it was the legacy of Proudfoot et al (87) that popularised less common among the elderly compared to younger adults
cryptic miliary TB as a distinct clinical entity. aged 21-64 years [17.5% versus 18.9%] (97). However, 27% of
When miliary TB manifests in a cryptic fashion, choroid all extrapulmonary notifications were among elderly aged
tubercles are absent; enlargement of liver and spleen is fre­ over 60 years (98). Particularly, elderly contributed to about
quently seen; and serosal cavity effusions are uncommon (89). 35% of osteoarticular and genitourinary TB cases. Common
Often, although not invariable, these patients have a non- forms of EPTB which may present differently in elderly are
reactive type of TB—described as “Microscopically there is an discussed here.
abundance of small caseaeous [sic] necrotic lesions, especially in the
liver and spleen, but characteristically no giant or epitheliod [sic] Pleural Tuberculosis
cells are found. The lesions generally contain enormous amounts
of tubercle bacilli” (88,90,91). A broad range of haematological Pleural effusion occurs early during the natural history
abnormalities such as neutropenia, pancytopenia, leukaemoid of Mtb infection. Most instances of TB pleural effusion
reaction, and myelofibrosis have been described in such develop 3-7 months following primary infection (99). Thus,
patients (91). Other laboratory abnormalities, such as, understandably, TB pleural effusion is typically a disease of
elevated alkaline phosphatase, hyponatraemia due to adrenal adolescents and young adults in high-burden settings. In a
involvement, and hypokalaemia may also be seen (89). recently published large multicentric study of TB pleural
Nearly half the patients have associated co-morbidities such as effusions from India, elderly constituted less than 5%
diabetes, solid organ or haematologic cancers, and auto­ of patients (100). Similarly, of the 254 patients with
immune diseases, that often distract the attention of the tubercular pleural effusion treated at a Spanish University
clinician (89,92). Hospital during 1989-1997, just 12% of patients were
As originally noted by Proudfoot et al (87), subsequent aged over 60 years (101). In another study from the
studies (90,92,93) also found that the age of patients with same setting, it was also observed that 70% of pleural
miliary TB [both overt and cryptic] had progressively effusions in patients aged under 40 years were tubercular
increased over the years, while the number of cases actually in origin (102). Whereas, only 10% of pleural effusions in
showed a declining trend or remained stable. In a large those aged over 40 years were due to TB; malignancy and
512 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

congestive heart failure were the most common causes in this of all patients were foreign-born (111). It clearly emerges that
age-group. Understanding this pre-test probability is very irrespective of the epidemiologic setting, elderly contribute
important from a diagnostic point of view [detailed below]. to a considerable burden of tubercular meningitis and other
On the other hand, pleural effusion can also occur forms of CNS TB. However, it is unclear whether CNS
following re-activation of remote infection, especially involvement in the elderly is the result of reactivation or
in the elderly. Moudgil et al (103) observed that most else follows fresh infection at a later age.
cases of TB pleural effusion notified in Edinburgh during TB meningitis in the elderly may just present as
1980-1991 were attributable to reactivation rather than unexplained obtundation, confusion, or irritability (112).
primary infection; most of the pleural effusions due to Typical symptoms of a meningitic illness such as fever,
re-activation were seen in persons aged 40 years or more. headache, vomiting, and nuchal rigidity are often absent.
Similarly, in a study of 548 TB effusions from Spain, Hyponatraemia caused by inappropriate secretion of
Sahn et al (104) noted that the mean age of patients had antidiuretic hormone may be present contributing to the
increased from 34 years to 43 years over the period that altered sensorium. Infrequently, TB meningitis in the elderly
spanned two decades from 1991 to 2011, possibly indicating might present with cognitive defects clinically mimicking a
an increasing contribution of re-activation. The annual dementia (113). In a series of 124 elderly patients evaluated
incidence of TB had fallen from 72 cases to 28 cases per for dementia at a teaching hospital in northern India, 10 were
100,000 population in the study region over the period of found to have CNS TB, which is potentially reversible with
1996 to 2010. In Taiwan, which has a large and fast-growing prompt treatment (114).
elderly population and declining TB incidence, the mean
age of patients with TB pleural effusion was 62 years (105). Other Forms of Extra-pulmonary Tuberculosis
Similarly, in a series of 106 consecutive patients from
South Korea, 41% were aged 60 years or more; 74% of all TB lymphadenitis is uncommon in the elderly population (115).
patients had computed tomographic features suggestive of But, it may be encountered in specialist practices due to referral
re-activation TB, and such patients were about two decades bias (116,117). In endemic regions, TB lymphadenitis may
older than those with features of primary infection (106). be incidentally found in nodes suspected to have meta­static
Pleural effusions occurring in the setting of sputum culture- cancers (118). Rarely, TB and malignancy might be present
positive TB indicating parenchymal disease is more common in the same lymph node (119). On the other hand, tubercular
among the elderly [23% versus 9%] compared to the rest (70). lymph nodes may closely mimic metastatic malignancy on
Chest pain might be less frequent in elderly patients with TB fluorodeoxy glucose—positron emission tomography [FDG-
pleural effusion; pleural thickening and calcification might PET] evaluation showing very high standardised uptake
be more frequently seen (107). values (120). Paradoxical reaction, commonly encountered
during treatment of tubercular lymphadenitis in the young,
Tuberculosis Meningitis has also been reported in elderly patients (121).
Typically, genitourinary and skeletal TB clinically manifest
Classically, the risk of meningitis is maximal during the a long time after the primary infection. Thus, a consider­
initial 1-3 months following the primary infection when able proportion of these forms of TB will be in the elderly
haematogenous seeding of the central nervous system [CNS] population. The mean age of patients with bone/joint TB
occurs (99). Thus, the risk of meningitis is disproportionately and genitourinary TB in the USA was 50 years and 52 years
borne by children and young adults. However, empirical respectively (98). Interestingly, in low-burden settings,
data from high-incidence settings suggest that tubercular genitourinary TB is more common among the native-born
meningitis is not confined to the younger ages. In a large elderly than foreign-born immigrants (122). This is attri­
clinical trial on tubercular meningitis in adolescents and buted to confounding by age rather than a true difference.
adults aged over 14 years from Vietnam, about 13% of Similarly, 82% of bone/joint TB in Denmark was among the
patients were elderly aged over 65 years, and almost 40% native-born; the median age at diagnosis was 72 years (123).
of all patients had chest radiographic features of active non- Spine and hip are the most commonly affected sites. Isolated
miliary TB, that may suggest the possibility of reactivation involvement of a peripheral joint is not uncommon in the
rather than primary infection as the proximate cause in many elderly, and when it presents so, the diagnosis is often
of them (108). In Turkey, a moderate incidence setting, a delayed (124). Apart from symptoms referable to the local
sizeable proportion of patients with tubercular meningitis site of involvement, genitourinary and bone/joint TB may
diagnosed between 1985 and 1997 at 12 university hospitals, also present as FUO.
was elderly (109). The findings from low-incidence settings Comparison of clinical presentation of TB in the young
were also largely similar. In a nationwide study from and the elderly patients is shown in Table 38.1 (125).
Denmark, 18% of all adult TB meningitis patients were over
60 years of age; 45% of the cases were ethnic Danes (110).
DIAGNOSIS
Danish natives with TB meningitis were more likely to be
elderly compared to immigrants [28% versus 10%]. Similarly, The diagnostic tools for TB in the elderly do not differ from
in Houston, Texas, USA, 5% of all CNS TB diagnosed over a the rest. However, a diagnosis of TB in the elderly is often
10-year period [1995-2004] was among the elderly; only 27% delayed and sometimes totally missed. Elderly contribute
 Tuberculosis in the Elderly 513

Table 38.1: Comparison of clinical presentation of TB the sensitivity and specificity of pleural fluid adenosine
in the young and the elderly patients deaminase [ADA] level to detect a TB pleural effusion are
100% and 95% respectively, at a disease frequency of 10%,
Variable Young Elderly
the corresponding positive predictive value would still be
Constitutional symptoms just 70%, i.e., 30% of such effusions would actually be non-
Fever + − TB (101,131). The implication of this observation is that, an
Night sweats + − exudate with elevated ADA cannot be considered diagnostic
Non-specific symptoms* + − of tubercular aetiology in elderly patients and further
investigations such as pleural fluid cytology, pleural biopsy,
Respiratory symptoms
and a contrast-enhanced computed tomographic imaging
Cough + −
of the chest should always be done to rule out malignancy.
Haemoptysis + − Lymphoma is a common condition in the elderly that closely
Dyspnoea − + mimics tubercular pleural effusion in its clinical, radiological,
Comorbid conditions† − + and laboratory characteristics including a high ADA level
Hypoalbuminaemia − + in the pleural fluid (132). Drug-induced pleural effusion
caused by tyrosine kinase inhibitors such as dasatinib may
Tuberculin positivity + –
resemble TB effusion in its characteristics (133). Uraemic
Adverse drug reactions − + pleurisy is another condition in which it is often difficult to
* = dizziness, mental dullness rule out the possibility of TB aetiology (134). The diagnostic
† = chronic obstructive pulmonary disease, diabetes mellitus, utility of pleural fluid ADA in elderly is further complicated
bronchiectasis, stroke
TB = tuberculosis; + = more frequent; – = less frequent
by issues surrounding its sensitivity. Recently, it has been
Reproduced with permission from “van Cleeff M , Gondrie PCFM, recognised that elderly patients with TB pleural effusion
Veen J. Tuberculosis in elderly. In: Sharma SK, Mohan A, editors. have significantly lower levels of ADA in the pleural fluid,
Tuberculosis. Second edition. New Delhi: Jaypee Brothers Medical necessitating a lower cut-off which would further com­
Publishers; 2009.p.625-33” (reference 125) promise its specificity (135,136). Likewise, ageing might
influence the pleural fluid protein and lactate dehydrogenase
levels causing difficulty in the identification of exudative
to about 50% of all such missed opportunities for TB treat­ pleural effusions (137). This is important, because the
ment (126). In the USA during 1985-1988, about 12% of pleural fluid may be classified as a transudate in about 1% of
TB cases among the elderly aged 65 years or more were otherwise proven cases of tubercular pleural effusion (104).
diagnosed only at death; the figure was much higher among But, the factors responsible for these aberrant transudates
those aged over 85 years (126). Similarly, 8% of elderly with in TB are unknown; advanced age might be responsible in
pulmonary TB diagnosed in Taipei city, Taiwan during some of them. On the same note, the proportion of patients
2005-2010 died before treatment could be initiated (127). with lymphocyte predominance [>50%] on pleural fluid
Two factors that are responsible for a delay in diagnosis analysis may be considerably less among the elderly – 17%
are lack of suspicion and atypical clinical presentations. of patients had lymphocyte count less than 50% in a study
TB should always figure among the differentials in elderly of predominantly elderly (105) as opposed to 7% in another
presenting with lung infiltrates, pleural effusion, unexplained study of predominantly younger patients (101).
weight loss, FUO, failure to thrive, etc. A careful physical exami­ It is often difficult to differentiate spinal TB from
nation to look for lymphadenopathy and choroid tubercles metastatic cancer and myeloma, especially in early stages.
is often rewarding in an elderly patient with FUO. The chest In such situations, where the diagnosis of TB warrants an
radiograph should be carefully looked at for miliary nodules. invasive procedure on an elderly patient, clinicians often
Biopsy of the bone marrow or liver may be considered, resort to a trial of treatment with anti-TB treatment. Such
especially in the presence of cytopenias, hepatosplenic focal decisions are only to be made on a case-by-case basis taking
lesions, or elevated serum alkaline phosphatase. into consideration the various factors, such as, availability
While the sputum smear examination remains a useful of sampling and laboratory testing facility, safety of the
diagnostic tool for pulmonary TB in the elderly (67), some­ diagnostic procedure in a given patient, acuity of the
times patients may not expectorate sputum due to frailty. In clinical condition, turnaround time, limitations in sensitivity,
such circumstances, sputum induction and gastric washings risk of adverse drug reactions, possibility of promoting
might obviate the need for invasive procedures such as bron­ drug-resistance, and the dangers of missing an alternative
choscopic sampling (128). While a high degree of suspicion is diagnosis.
needed, entities like cryptogenic organising pneumonia are
often misdiagnosed as pulmonary TB in endemic regions (129). TREATMENT
High-resolution computed tomography could be of help in
General Principles and Adverse Effects
such situations (130).
Considerable caution is warranted while diagnosing TB The principles of treatment of TB in the elderly are
pleural effusion in the elderly. Even if one assumes that no different from that of other patient groups. But, as
514 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

noted earlier, many of these patients have other medical Drug-resistance, Human Immunodeficiency
comorbidities that might complicate the issue. They might be Virus Co-infection in the Elderly
on drugs like oral hypoglycaemic agents, antihypertensives,
While multidrug-resistant-TB [MDR-TB] and HIV-associated
digoxin, or theophylline, some of which might have clinically
TB threaten to destabilise the global TB control, the situation
significant drug–drug interactions with rifampicin (12).
is better in the elderly. Since most of the TB among the elderly
Problems like cognitive impairment or dementia may lead
is caused by re-activation of infection often acquired in the
to difficulty in comprehending how to take the medicines.
pre-chemotherapy era, primary drug-resistance including
Poor eyesight, poor memory, and lack of determination to MDR is believed to be uncommon among the elderly (11).
complete 6-month long therapy may result in default (12). In the USA, during the period 1993-2007, the frequency of
Elderly often depend on others to access health care and to MDR-TB, including extensively drug-resistant TB [XDR-TB]
take the drugs regularly. In countries like India, where a among the elderly was 0.8% while it was 2.5% in the 25-44
considerable fraction of people aged >60 years still work for years age group (147). Similarly, in the European Union and
livelihood, loss of wages might adversely affect adherence the European Economic Area, the frequency of MDR-TB
with directly observed therapy. [including XDR-TB] reported in 2012 was 2.1% among the
The risk of anti-TB drug-induced hepatotoxicity is at elderly, while it was 5.4% in the 25-44 years age group (148).
least two-fold higher in the elderly (138,139). Malnutrition In the update to the fourth report of the WHO/International
and hypoalbuminaemia prevalent among the elderly Union Against Tuberculosis and Lung Disease [IUATLD]
may add to the risk (140). Ethambutol can cause optic global project on anti-TB drug resistance surveillance, in
neuritis in the presence of renal failure, and hence dose countries reporting continuous drug-resistance surveillance
adjustment is needed. Advanced age is a risk factor for both data, the frequency of MDR-TB decreased linearly with age
nephrotoxicity and ototoxicity with aminoglycosides. The and was lowest in persons aged 65 years or over (149). Even
dose of streptomycin should not exceed 500-750 mg/day. in the central and eastern European countries with a very
The symptoms of toxicity might be presumed by patients high the frequency of MDR, it was still lowest in persons
as age-related and may not be reported early. aged 65 years or more (150). But, it needs to be appreciated
that the elderly are not completely protected against drug-
Treatment Outcome in the Elderly resistant TB, and the treatment of MDR-TB, XDR-TB in an
elderly patient is challenging.
Despite timely diagnosis and treatment, the outcomes As with MDR-TB, the problem of HIV-associated TB
in elderly TB patients are often worse. Only 73% of 812 is largely confined to the younger ages even in high HIV
elderly patients treated at a chest clinic in Delhi, India, prevalence settings. While 6.5% of all TB patients tested
over the period of 2005-2010 had a favourable outcome in 2011 had HIV co-infection in India (9), in a study from
compared to 86% in the non-elderly (141). Rates of death southern India only 1.5% of TB patients aged 60 years or
[7.6% versus 1.5%] and loss to follow-up [9.9% versus 6.5%] more were HIV-infected (78). Interestingly, an age cut-off
were higher among the elderly. Likewise, aggregated of over 50 years is customarily used to denote elderly in
unfavourable outcome [death, failure, or default] was more the context of HIV infection. At present, 7% of people living
common among the elderly [16% versus 11%] treated under with HIV in India are aged over 50 years (150). But, with
programme conditions in south India (78). Particularly, the widespread availability of life-saving antiretroviral
those aged over 70 years fared much worse than those aged treatment, a large number of HIV-infected persons will
60-70 years [22% versus 14%]. Death during treatment largely survive into their 60s and beyond. It is estimated that by
accounted for these differences. Multiple studies from 2015, half the people living with HIV would be aged over
disparate epidemiologic settings have consistently found 50 years in the USA; a similar transition is expected in
that elderly patients with TB are more likely to die compared African countries as well (151). Although limited data indicate
to younger patients (126,142-144). The risk of death in that TB is not more common in elderly with HIV (152),
elderly remains elevated even after the intensive phase of how this transition would impact the interaction between
treatment (126,143). Further, the standardised mortality rate ageing, TB, and HIV is currently unknown.
[SMR] in elderly TB patients aged 60 years or more was
only 2.2 compared to an SMR of 15.1 in the 15-44 years LATENT TUBERCULOSIS INFECTION IN THE
age group (145). Both these observations clearly indicate ELDERLY
that TB per se does not account for a substantial part of Despite being an important clinical issue, TB in the elderly
this mortality risk in the elderly. Rather, the excess risk is is not considered a problem that warrants population-level
largely attributable to the frailty and multiple comorbidities prevention, for various reasons. The present thinking is
which are often present in these patients. Very recently, it has that elderly age per se is not an indication for targeting TB
been found that TB is independently associated with a 40% prevention. But, when elderly persons reside in settings
higher risk of acute coronary syndrome (146). Apart from favouring transmission to others such as elderly homes,
treating early, it remains unclear at present how to mitigate homeless shelters, nursing homes, and other long-term care
the excess mortality among elderly with TB. facilities, testing and treatment of LTBI is recommended in
 Tuberculosis in the Elderly 515

some developed countries (153). In resource-limited high 8. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V,
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present. for 20 age groups in 1990 and 2010: a systematic analysis for the
Global Burden of Disease Study 2010. Lancet 2012;380:2095-128.
While a robust body of evidence from randomised
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controlled trials supports the efficacy isoniazid for preventing Geneva: World Health Organization; 2012.
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 39
Tuberculosis in Health Care Workers
SK Jindal

INTRODUCTION medical literature of the past 100 years (3). It was perhaps
in 1938 when a high incidence of TB among nurses was
The contagious nature of tuberculosis [TB] was recognised
demonstrated for the first time (4). Several other reports had
long before the bacteriological aetiology was identified (1).
appeared thereafter (5-8). Quite aptly, it had been termed as
Historically, there are innumerable examples of relatives and
“the battle of a century” (9).
close contacts of patients with TB themselves developing
There is a paucity of data on this subject from this country
the disease. Similarly, the risk of TB is high in health care
in spite of the fact that India accounts for about one-third
workers [HCWs] looking after patients suffering from an
of the total global TB burden and that most disease indices
active infectious disease. This is particularly so since the
are alarmingly high (10). A study from a teaching hospital in
infection is air-borne and the presentation of the disease
Chandigarh (11) revealed that, among resident doctors, the
after acquisition of infection is generally delayed. It seems
overall risk of developing TB was estimated as 11.2 cases per
quite appropriate to consider TB as an occupational disease
1000 person-years of exposure; the overall incidence of TB
as suggested in the recent medical literature (2).
was found to be 17.3 per 1000. Several of the recent reports
corroborate the observation of an increased risk in HCW
TUBERCULOSIS CARE AS AN
[Table 39.1] (12-16). In a systematic review of published
OCCUPATIONAL HAZARD studies, the median prevalence of latent TB infection
There is a large body of data to suggest that looking after [LTBI] in HCWs was reported as 63% on an average with
patients of TB is an occupational hazard. This belief was median annual risk of 5.8% in lower and middle income
traced to the 1950s in an elegant historical review of the countries (17). In another recent systematic review the pooled

Table 39.1: Some of the recent reports from different countries showing a higher risk of TB among HCWs
Study [year] (reference) Place Type of study Study population TB risk
Naidoo and Jinabhai South Africa Retrospective study HCWs [n = 583] TB incidence 1133/100,000
[2006] (12) HCWs
Lopes et al [2008] (13) Central Brazil Prospective cohort study Nurses [n = 128] 11.5 new TST
conversions/100 person years
Christopher et al [2010] (14) India Prospective cohort study Nursing trainees [n = 436] 50.2% tested TST positive
He et al [2010] (15) China Cross-sectional survey HCWs [n = 3746] TB prevalence 6.7 TB/1000
medical staff; 2.5/1000
administrative/ logistic staff
Claasens et al [2010] (16) South Africa Retrospective study Community-based health TB incidence 4.39
care researchers [n = 180] TB/100 person years of
follow-up
TB = tuberculosis; HCWs = health care workers; TST = tuberculin skin test
 Tuberculosis in Health Care Workers 521

prevalence of LTBI in HCWs in high TB burden countries in the HCWs. The incidence seems to have declined in the
was reported to be 47% (18). developed countries in the recent studies (23,29,33-36).
Studies from the developing countries, however, continue to
RECOGNITION OF TRANSMISSION OF report a high transmission risk (12-17). Both the TB infection
TUBERCULOSIS and the disease are reported to be significantly higher in
most studies among HCWs. The criteria used for assessment
Diagnosis of clinical TB is made on the basis of clinical picture of TB risk are diverse in different studies. In the Western
and microbiological positivity of sputum or other biological European countries, USA, Canada and Australia where the
specimens. The presence of infection, however, is established TB prevalence is rather low, the positive TST and/or TST
long before the onset of disease symptoms. Based on the conversion are the most frequently employed tests to detect
circumstantial evidence, it is somewhat easy to attribute the presence of infection. In a large study (37) involving 4070
the occurrence of new clinical symptoms and aetiology in HCWs and 4298 non-HCWs, a positive TST was observed
an HCW to their exposure to TB. This, however, cannot be in 19.3% HCWs compared with 13.7% in non- HCWs; the
definitely said unless the mycobacterial transmission can be significant differences were not explained by the employees
traced to the specific source in a health care setting. This can characteristics, such as age, country of birth and the past
be done with the help of molecular techniques, such as, the BCG status (37).
deoxyribonucleic acid [DNA] fingerprinting. Besides the transmission of TB infection, there are
several reports on occurrence of active TB disease amongst
Tuberculin Skin Test physicians and other HCWs from India (38,39). In a short
report, TB was diagnosed to develop in 4 of 23 resident
A positive tuberculin skin test [TST] result is the most
doctors during their residency period at the author’s
frequently used marker of TB infection. There are several institute (11). A 10-year review of hospital records from
difficulties in interpreting TST results and estimating TST Vellore reported the incidence of TB among HCWs to
conversion rates. This is generally attributed to factors such as be 0.3-1.57 per 1000 pulmonary TB and 0.34-1.57 per
the prior Bacille Calmette-Guérin [BCG] vaccination and/or 1000 extra-pulmonary tuberculosis [EPTB] cases (40).
previous exposure to environmental mycobacteria. It is
difficult to attribute the presence of TB infection in HCWs DETERMINANTS OF RISK OF INFECTION
to occupational exposure merely from the presence of TST
positivity unless the pre-exposure status is known to be TST The risk of infection amongst HCWs depends upon a
negative. In a study (19) from Chandigarh, a cut-off of 10 mm large number of factors. Some of the important risk factors
was found to be useful in supporting the diagnosis in patients [Table 39.2] are discussed below.
with strong clinical suspicion of TB; in other patients, the
15 mm cut-off was more suitable. From retrospective Category of HCW
analyses, it is perhaps more pertinent to compare the number Higher infection rates are reported in almost all categories
of TB patients among HCWs versus general population in of HCWs including the doctors, nurses and other ancillary
these areas, provided reliable data are available.
Table 39.2: Factors influencing nosocomial
Interferon-gamma Release Assays transmission of TB among HCWs
The interferon-gamma release assays [IGRAs] are now being Related to HCW type
extensively used for diagnosis of LTBI in HCWs (20-29). The Related to the health facility
test has been employed in both low and high TB prevalence
Level of exposure
settings. However, there is no distinct advantage of IGRAs High versus low exposure areas
over TST. Therefore, in view of the higher costs as well as Inadequate isolation of infected patients
the requirement of a blood sample for IGRAs, the TST is a Environmental
preferred method for contact screening in high TB burden Inadequate sanitation
settings. Inappropriate disposal of excreta
Crowding in the wards
RISK OF INFECTION Poor ventilation
Host factors related to HCWs
The annual risk of TB infection [ARI] assessed using Immune status of an individual
TST in HCW had varied from 0.09% to 10% in different Comorbidities
populations in various studies published in the 1980s and BCG vaccination status
1990s (7-9,30-32). This was up to a hundred times higher than General clinical factors
the estimated ARI in the general population of the Western Delayed suspicion and diagnosis
Europe and the United States during this period. The Delayed initiation of treatment
Self-administration of drug
calculated risk for the home staff and the pulmo­nary fellows
versus general population was probably highest. Similarly, TB = tuberculosis; HCWs = health care workers; BCG = bacille
the annual incidence of TB disease was considerably more Calmette-Guérin
522 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

staff (11,13,17,41-44). Those HCWs who are in direct care Immune Status and Comorbidities
with the patients [such as nurses and doctors] are at higher
The presence of diseases, which predispose to TB and the
risk of contacting infection. The risk is also high amongst
nursing trainees who spend a significant amount of time status of immunity are important factors which determine
in patient-care (14). A higher risk has also been reported in the prevalence of TB in HCWs. Prevalence of diseases such as
the community setting in health care researchers working diabetes mellitus, as well as many other conditions requiring
in an area with high prevalence of TB and human immuno­ use of corticosteroids or other immunosuppressive drugs,
deficiency virus [HIV] infections in South Africa (16). among HCWs, is at least similar to their prevalence in the
community. Their presence in HCW is likely to augment
their predisposition to TB.
Level of Exposure
Intrinsic immune status of an individual HCW is a parti­
The risk of transmission of infection is greater when the cular point of interest. Immunodeficiency is an independent
level of exposure is high. Patients with pulmonary TB, risk factor for TB. In a study on occupational transmission
especially those who are sputum smear positive are more in a haemodialysis unit, the TB isolates from different
likely to infect HCWs. Data from several studies indicate that sources showed the strains to be unrelated when tested
medical and nursing personnel [especially chest physicians with restriction fragment length polymorphism [RFLP] (52).
and HCWs working in chest diseases wards] have higher Presence of HIV infection in HCWs is an important risk
risk ratios of TST conversion and development of active factor for TB (12,53-56). The impact of HIV infection on
TB (2,42,45-47). On the other hand, smear-negative TB increase in number of TB patients was demonstrated in a
appears to be less contagious to HCWs (34). South African district hospital where the incidence rate of
Nosocomial transmission, however, is also known to TB among HCWs and ancillary staff was not significantly
occur from non-pulmonary sites (48). Twelve [13%] of different from the age-specific rate in the community. But
95 HCWs who were initial non-reactive to tuberculin there was a five-fold increase in annualised incidence rate
developed a positive TST after exposure to an index patient from 1991 to 1992 and 1993 to 1996 which was directly
with TB prostatic abscess who had undergone abscess attributable to HIV infection (57). In another study, strains
drainage and bilateral orchiectomy and had died after of TB bacilli infect­ing eight of nine HIV-seropositive HCWs
27 days of hospitalisation (48). Such transmission is more had a clustered RFLP pattern, implying a common source,
likely to happen in the presence of other risk factors, such i.e., an unrecognised occu­pational transmission (58). The
as altered host immunity, environmental conditions and HIV-seropositive HCWs who developed TB following a
inadequate infection control measures. The level of exposure hospital outbreak of MDR-TB had more severe disease and
is also high in medical wards and microbiology laboratories. had died (59).
In a case-control study from India, the risk was over five Overall 14% of 1627 HCWs with TB were found to be
times higher among laboratory workers and over 12 times co-infected with HIV infection in an analysis of surveillance
higher for HCWs in the medical wards (49). data on HIV-TB co-infection in England and Wales (60).
High TST positivity has been recorded among phy­ This had increased from 8% in 1999 to 14% in 2005, mostly
sicians [45.9%] than the general Canadian population (41).
amongst non-UK born HCWs. The authors (60) had also
Similarly, physicians in USA had a high rate of tuberculin
recommended voluntary HIV testing for new HCWs for an
reactivity [7%] although the TST conversion rate was low (42).
early diagnosis.
A TST conversion rate of 1.7% over a 12 months period was
also seen in dental HCWs (43).
A strong association has also been shown with type and
Bacille Calmette-Guérin Vaccination
duration of work; for example people working in respiratory BCG vaccination is administered at birth or in early child­
therapy, physiotherapy and housekeeping have greater hood as a general vaccination policy in countries with high
risks (9). TB prevalence, including in India. It is unclear if the BCG
vaccination in childhood affects the incidence of risk in
Environmental Factors HCWs.
Environment of hospital wards and the methods employed
Clinical Factors
for sanitation and disposal of waste materials and excreta
affect the disease transmission. The TST conversion rate Besides factors related to the host, i.e., the type of HCWs
has been shown to be strongly associated with inadequate and the environment in which HCWs work, factors related
ventilation of the general patient rooms (50). Room size to awareness of occupational transmission, preventive
was the major determi­nant in a report from Italy where steps being used, clinical suspicion and diagnosis of an
8% of HCWs developed TST conversion after a workplace early disease are important in influencing the occurrence
exposure to a highly infectious multidrug-resistant TB of disease. There was an inadequacy of knowledge on TB
[MDR-TB] patient (51). Some of these factors are of particular transmission and infection control measures among HCWs
importance in this country where the wards are rather in the USA in a questionnaire survey (61). The situation is
overcrowded and poorly ventilated. likely to be worse in most hospitals of the developing world.
 Tuberculosis in Health Care Workers 523

Many HCWs are likely to be more negligent in adopting While HCWs are better placed to seek early interventions,
routine measures while working in the hospitals and tend they also tend to ignore early symptoms, more than the
to ignore precautionary practices generally recommended people in the community. It is a common observation
for attendants and care providers of patients. Attitudinal that hospital personnel including doctors and nurses rely
desensitisation to follow guidelines is common unless greatly on self-administered symptomatic treatments before
repeatedly enforced. seeking appropriate medical advice. This is particularly
so in developing countries where medicines are relatively
RISK ASSESSMENT easily accessible and available to medical, nursing and
paramedical personnel. These factors are likely to delay
It is known that an untreated patient with active TB transmits
the early diagnosis. A careful approach to diagnosis among
acid-fast bacilli [AFB] and infects other individuals. This
symptomatic individuals and routine screening programmes
risk is likely to be significant in the hospital surroundings
among HCWs are, therefore, important for success.
with a larger number of patients staying in a closed-door
An early and aggressive approach is important for
environment. HCW in the in-patient and out-patient
diagnosis and treatment considering the hospital work as a
facilities and history of TB exposure in the previous year
risk factor and the fact that more specialised expertise and
were found to be significant predictors for TST conversion
care is available in a hospital setting. A simplified algorithm
in a study on 624 HCWs in Thailand (62). More than the
[Figure 39.1] for diagnosis and treatment of TB, may be
close personal contact, it is the inhalational route which is
useful in the evaluation of HCWs who are TB suspects.
important in spreading TB. This was amply shown following
The suggested definition of a TB suspect among HCWs is
a sharp outbreak of TB abroad the naval vessel “Richard E
different from that used in the Revised National TB Control
Byrd” (63). It was concluded that the rate of infection was
Programme [RNTCP] in India. It is worthwhile to introduce
proportional to the amount of contaminated air.
a standardised symptoms questionnaire as an instrument for
The mathematical model for quantitative assessment
active case finding for screening of all HCWs on a regular
of air-borne infection vis-a-vis room ventilation developed
basis. Any individual who reports with respiratory and/or
for measles epidemic has been also used for TB (64).
general constitutional symptoms of even one week’s duration
The probability curve of TB infection clearly showed the
[unless explained by a definite alternative aetiology] should
diminishing effectiveness of high level of ventilation. A
be considered as a TB-suspect and investigated with the help
similar curve was drawn for TB outbreak from a brief
of both sputum microscopy for AFB and a chest radiograph
but intense exposure during bronchoscopy (65). It can
examination. In case sputum smear is positive for AFB, anti-
be, therefore, concluded that TB transmission can be
TB treatment is given accordingly. In case, sputum smear is
quantitatively assessed fairly well from the amount of room
negative for AFB, and the chest radiograph findings suggest
ventilation (66).
TB, treatment for smear-negative TB should be instituted
and an attempt should be made to demonstrate AFB in the
CONTROLLING OCCUPATIONAL TUBERCULOSIS
bronchoalveolar lavage [BAL] fluid and/or other appropriate
An increased occurrence of TB in HCWs has more serious investigations. In case the chest radiograph is clearly normal
rami­fications than a mere addition to the total pool of TB or negative for TB, other diagnoses should be considered
patients. There is the fear of spreading panic among the and appropriate investigations done. Treatment regimens
employees as well as the community. It is, therefore, an in HCWs do not differ from those recommended for TB in
issue of great public and social importance. It is important other groups.
to adopt strategies to prevent and control TB in HCWs.
Implementation of protection guidelines has been shown to Preventive Strategies
effectively reduce the TB risk in HCWs (35,67-69). Therefore,
Different strategies are employed in different countries
there is a clear need to implement infection control policies
to prevent infection and mycobacterial transmission. The
in all health care settings (13,33,35,67-70).
differences in approach in India reflect the difficulties due
There are two important strategies to control occupational
to the enormity of the burden and the inadequacy of the
TB among HCWs: [i] early diagnosis and treatment; and
existing health care infrastructure. Nonetheless, the infection
[ii] prevention of infection and disease.
control measures which are recommended anywhere are
generally similar [Table 39.3].
Early Diagnosis and Treatment
The Centers for Disease Control [CDC], “Guidelines for
It is important to make diagnosis and institute anti-TB pre­venting the transmission of Mycobacterium tuberculosis
treatment at the earliest. Hospital employees have the in health care settings” uses a broader term “health care
advantage of an easy availability of medical advice and setting” to include not only the hospital-related scenario
investigations. It is, therefore, simpler to make an early [e.g., in-patient and out-patient settings, TB clinics], but
diagnosis in a symptomatic individual. In fact, early also correctional facilities in which health care is delivered,
documentation of detection and notification of cases of TB settings in which home-based health care and emergency
among HCWs may partly account for some of the increased medical services are provided, and laboratories handling
risk among them. clinical specimens that might contain Mtb (33). The recently
 524 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 39.1: Suggested algorithm for early detection of TB in HCWs in resource-limited settings
HCWs = health care workers; TB = tuberculosis; AFB = acid-fast bacilli; TST = tuberculin skin test; IGRAs = interferon-gamma release assays;
BAL = bronchoalveolar lavage; BCG = bacille Calmette-Guérin

Table 39.3: General measures used for control of a comprehensive framework on important preventive
tuberculosis transmission in HCWs measures [Table 39.4]. The recommendation includes the
adoption of administrative, environmental and personal
General Infection Control Measures
Reduction of environmental load by reducing the release of
protection measures (71).
mycobacteria
Use of masks for patients Infection Control Measures
Isolation rooms
Preventing environmental spread The most important source of mycobacteria in the environ­
Negative pressure rooms ment is an open patient with pulmonary TB who is excreting
Use of HEPA filters bacilli in the sputum. Bacteria are released during coughing,
Use of ultra violet radiation laughing and talking, and transmitted to others through
Individual protection measures air-borne droplets. Infection control measures are, therefore,
Inhalational prevention strategies designed to focus on reduction of environmental load of
Use of simple masks
mycobacteria by one or more of the following steps in
Use of respirators: HEPA filters/PAPR
BCG vaccination transmission of infection.
Chemoprophylaxis Reducing the release of mycobacteria and preventing
Early detection and treatment
environ­mental distribution The most efficient method to
HCWs = health care workers; HEPA = high-efficiency particulate air; prevent dispersion of infectious particles from a patient in a
PAPR = powered air-purifying respirator; BCG = bacille Calmette-
hospital room is to trap the particles at the patient’s mouth.
Guérin
This can be achieved by the masks covering the mouth
and nose. In resource-limited settings, simple gauze masks
framed guidelines on “Airborne infection control in health or a piece of cloth are commonly used for this purpose.
care and other settings” published by Ministry of Health The respiratory droplets released on coughing are impinged
and Family Welfare, Government of India (71) provide on the mask. A mask is fairly effective but is not convenient
 Tuberculosis in Health Care Workers 525

Table 39.4: Recommended control measures to prevent dispersal. Separate cubicles/booths should be made
reduce risk of transmission of respiratory pathogens available in the wards and laboratories for performance of
procedures requiring coughing, such as induced sputum
Administrative controls
Decompression of crowded areas
induction. Similarly, bronchoscopic examination in suspected
Segregation of patients with respiratory symptoms TB patients should be performed in well-equipped areas
Fast tracking through health care facility fitted with HEPA filters.
Minimise hospitalisation
Infection control training of HCWs Air filtration and disinfection The air-cleaning technologies
Regular assessment of TB in all HCWs are common for prevention of all airborne infections
Procedures for standard precautions including TB. Some of these methods include in-room
Hand hygiene air cleaners, HEPA and ultraviolet germicidal irradiation
Personal protection [gloves, gowns, masks, shields] [UVGI] air technologies. No health technology assessment
Respiratory hygiene and cough etiquette on air cleaning technology was found on literature review in
Prevention of injury from needles or other sharp objects an evidence-based analysis of studies on air (74). Cleaning
Cleaning and disinfecting medical equipments
technologies in Ontario, Canada (74), HEPA filters, perma­
Cleaning the patient care environments
Linen and waste management nently fixed for room ventilation remove droplet nuclei
carrying tubercle bacilli from the air. They are capable
Biomedical waste management protocol
of removing almost 100% of particles of over 0.3 mm in
Environmental controls diameter (75). The filter units are fitted with blowers to
Effective ventilation
Mechanically aided means
recirculate air. The filtered air from the room or the booth
Natural can also be re-circulated through a duct to create a negative
Ultraviolet germicidal irradiation pressure within. This type of HEPA filtered self-contained
Personal protection booths for some specified purposes as listed earlier, are
already available commercially.
TB = tuberculosis; HCWs = health care workers
Ultraviolet radiation has some advantages over HEPA
air disinfection. The resistance to airflow is much less than
with an HEPA filter. Therefore, the blowers used are smaller
for constant use. It gets wet very soon and cumbersome and quieter. But the main disadvantage is the possibility of
for use in a patient with persistent cough and sputum causing excessive exposure to the germicidal UV causing
production. The use is, therefore, restricted to specific painful superficial irritation of skin and eyes although there
situations for limited time periods. are no serious long-term effects (75). There is no evidence
Adequate ventilation is useful to dilute the environmental of systemic immune-suppression from UV germicidal
concentration of mycobacteria. While the indoor load within irradiation employed for room disinfection (76). To prevent
a hospital is reduced, the method may prove to be counter- personal exposure, the germicidal UV is directed at the air
productive by spreading infectious, airborne droplets in in the upper part of the room. The mixing of lower air with
the surrounding areas. This poses a risk of infection to upper air permits disinfection of all indoor air. This mixing
a larger number of employees and other people in the is promoted by convection and forced air movement by
building. Such incidents of infection in the entire building supplemental fans. But when the ceilings are low, the upper
spread through mechanical ventilating systems have been air UV radiation gets deflected downwards posing a greater
reported in the literature, such as the TB outbreak through risk to the occupants. Ultraviolet radiation can also be used
ventilation in two adjoining compartments, in the naval in the ventilating ducts to make the re-circulated air germ-
vessel “Richard E Byrd” and the other outbreak, where one free. Generally, the upper air disinfection in each room is
worker with undiagnosed TB infected 27 of 67 colleagues more effective than central duct irradiation but it requires a
over a four-week period (63,72). Similarly, it was shown that more elaborate setting.
the exposure in the hospital building treating HIV patients
with TB infection was universal and a sojourn of 40 or more
Individual Protection
hours per week was enough to get infection (73). This was
attributable to recirculation of air from the infected source Inhalational prevention strategies Protective measures
to the entire building. It is, therefore, more useful to contain which can be employed by an individual working in a health
the infection within, rather than ventilating it out. Internal care facility include the use of devices to prevent inhalation
containment includes the prevention of dissemination of of infectious droplet nuclei. Unfortunately, most of these
infectious droplets in the air by entrapment procedures as methods have their fallacies and failures. The risk of infection
well as the air disinfection. in HCWs is minimal from paediatric patients with primary
Complete isolation of a TB patient is not feasible. As TB (77).
per current practice and recommendations in India, a Historically, surgical facemasks have been employed
sputum smear-positive patient need not be admitted in the by visitors and HCW attending upon TB patients. It is
hospital. If the medical indication for admission is strong, difficult to comment upon the usefulness of this method
separate areas should be earmarked for such patients. The in the absence of any efficacy-study on their use. There is
use of high-efficiency particle air [HEPA] filter is useful to a complete lack of standardisation, besides the difficulties
526 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

involved in wearing of a well-fitted facemask all the Preventive isoniazid therapy after exposure is advisable
time. in persons younger than 35 years of age, those with HIV
More effective than a simple mask is a respirator infection or receiving any kind of immunosuppressive
which removes the infectious particles through impaction therapy. Several regimens have been used for the treatment
by filtration and/or electrostatic attraction. If properly of LTBI (87). The WHO guidelines for LTBI treatment in
worn, a respirator can prevent up to 80% of exposure. high income countries have recently been published (88,89).
It is cumbersome to wear respirators continuously in all There is no consensus on these recommendations as yet in
situations. These are generally recommended for personnel India and other resource-limited settings. It is perhaps fair
attending upon sputum-smear positive patients and during to conclude that, as of today, there is sparse evidence to
cough induction and bronchoscopic procedures (33). Leakage advocate treatment of LTBI in HCWs irrespective of their
of droplet nuclei from a filter depends upon the filtration contact with sputum-smear positive patients. Personal
efficiency and facial seal. The CDC (33) recommends that a protective measures and close supervision are important
respirator should meet the following criteria: [i] it should be to detect an early disease and treat them immediately. The
able to filter particles of 1 mm in size with 95% efficiency; BCG vaccination policy also needs to be re-examined.
[ii] it should have a face seal leakage of 10% or less; [iii] it
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 40
Nutrition and Tuberculosis
Ramnath Subbaraman, Jason Andrews

INTRODUCTION Evidence from Animal Models

Research has established clear connections between malnutri­ Animal models have helped to characterised connections
tion and impairment of immune defense, including decreased between malnutrition, immunosuppression, and the risk
cell-mediated protection, abnormal phagocytic function, and of active TB disease. In these models, protein malnutrition
reduced immunoglobulin production (1). Among infectious plays a more significant role in modulating TB risk than do
diseases, tuberculosis [TB] has a particularly powerful his­ micronutrient deficiencies. In a guinea pig model, vitamin
torical association with malnutrition: its name has been D and zinc deficiencies were not associated with increased
linked to its wasting effect on the body since at least the TB risk (2,3). In contrast, protein-malnourished guinea pigs
time of Hippocrates in the 5th Century BC. exhibited absolute and relative deficiencies in a variety of
Despite this millenia-old association, several issues
T-lymphocyte subsets, including CD2+, CD4+, and CD8+
complicate our understanding of the relationship between TB
cells (4-6). After bacille Calmette-Guérin [BCG] vaccination,
and malnutrition. These include the probable bi-directional
these protein-deficient guinea pigs had markedly decreased
influence of one on the other [in which malnutrition pre­
tuberculin skin test and interferon-g assay responses, as
disposes to active TB even as TB causes wasting], the co-
occurrence of malnutrition with other poverty-associated compared to protein-replete animals (7,8).
risk factors for TB, and the high incidence of TB in patients Lymphocyte transfer experiments in both guinea pig and
co-infected with the human immunodeficiency virus [HIV], mouse models have helped to shed further light on the role
which itself causes wasting. In this chapter, we discuss the protein malnutrition plays in blunting the immune response
relationship between nutrition and TB from a scientific, to TB. Lymphocytes transferred from TB-infected, protein-
epidemiologic, and clinical perspective, including a review of deficient animals to syngeneic, well-nourished animals did
recent trials of various forms of nutritional supplementation not protect the well-nourished animals from subsequent
for patients with active TB. TB infection. However, the reverse was true: lymphocytes
from TB-infected, well-nourished animals transferred into
IMPACT OF NUTRITION ON THE RISK protein-deficient animals protected the protein-deficient
OF ACTIVE TUBERCULOSIS animals against TB infection, suggesting that protein-related
Like HIV, severe malnutrition can cause profound immuno­ nutritional status has a major impact on the lymphocytic
suppression, compromising the body’s ability to control immune response to TB (9,10). Moreover, these animal
mycobacterial infection. The mechanisms of immunological models showed a significant reduction in the risk of
dysfunction that predispose to TB have been elucidated active TB infection with improvement in protein-related
mostly in animal models, while the impact of malnutrition on nutritional status, suggesting that some recovery of the
the risk of TB at the population level has been demonstrated TB-specific immune response is possible with reversal of
in epidemiological studies. malnutrition.
530 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Epidemiological Evidence born inside the settlement [where adequate nutrition and
housing conditions were ensured].
While several studies describe the diverse macro- and micro- The most compelling evidence from India regarding the
nutrient deficiencies present in TB patients (11-17), most influence of malnutrition on TB risk comes from a recent
of these cross-sectional studies are unable to differentiate prospective cohort study in Mumbai of 148,173 adults
whether these nutritional deficits are an underlying cause followed for six years, with 13,261 deaths recorded during
of TB disease or an effect of nutritional wasting resulting the study period (21). After controlling for other risk factors,
from TB. Other prevalent poverty-associated risk factors— for severely underweight individuals with a body mass
including living environments with high population density, index [BMI] of less than 16, the adjusted relative risks of
poor sanitation, and concurrent social crises—also confound death from TB compared to individuals with normal BMI
these analyses. were 7 and 14 in men and women, respectively. Mildly and
A couple of classic studies from the mid-20th century moderately underweight individuals also had a markedly
provide unique insight into the role of malnutrition as a risk increased risk of death from TB, and overweight and obese
factor for the development of TB. One study was performed individuals had a significantly decreased risk of death from
while the author himself was a British prisoner-of-war in TB. In a subsequent analysis, the authors found tobacco use
a German camp during World War II (18). Two groups of to be a major effect modifier of the role malnutrition plays
prisoners-of-war [Russian and British] were held in the camp in increasing TB risk (22). Of the TB-related deaths in the
in very similar living conditions. The Germans provided cohort study, among non-tobacco users, 9% and 12% were
both groups the same meager rations, vividly described by attributable to being underweight [BMI <18.5] for men and
the author as meat “with high percentage of bone,” potatoes women respectively. However, among tobacco users, 27%
“largely frost-bitten and inedible,” and a stew “full of small and 37% of TB deaths were attributable to being underweight
particles of grit and often containing large stones.” The in men and women, respectively.
British soldiers, however, also received extra food rations A similar analysis of the prospective National Health and
from the Red Cross, adding 1300 extra calories to their daily Nutrition Examination Survey [NHANES] collected from
diet and nearly doubling their protein intake. The Russians, 1971-1992 in the US found that underweight individuals
by contrast, underwent a process of slow starvation on [BMI <18.5] had an adjusted hazard ratio for developing TB
the German rations, as was evident by their higher rate of of 12.4, when compared to normal weight individuals (23).
anemia and lower plasma protein levels. Being overweight or obese was protective against developing
Nineteen per cent of the Russian soldiers developed TB. A systematic review of six prospective cohort studies
pulmonary TB, as compared to only 1.2% of the relatively found a consistent inverse log-linear relationship between
well-fed British soldiers. This suggested a 16 times increased TB incidence and BMI, in which each unit increase in
relative risk of developing TB that was largely attributable BMI is associated with a 13.8% average reduction in TB
to undernourishment. Moreover, the character of the disease incidence (24).
was different in the two populations. The Russians had A few studies have attempted to identify specific diets
rapidly progressive, highly fatal infection with massive and micronutrient deficiencies that may increase TB risk.
tissue breakdown but little granuloma formation, while Two studies examining Hindu vegetarian versus Muslim
infection in the British soldiers followed a normal chronic omnivore South Asian immigrants in Britain found that
course with good granuloma formation. Furthermore, the vegetarianism correlated with a three- to four-fold increased
prevalence of malaria, dysentery, and other infections was risk of developing active TB (25,26). There was a notable
similar between the two groups, suggesting that TB had dose-response relationship, in which decreasing meat
the strongest association with malnutrition of any of the consumption correlated with increasing TB risk (26). Another
common infectious diseases affecting soldiers in the prisoner- study found that increased fruit, vegetable, and berry intake
of-war camp. decreases the risk of developing active TB (27).
Another classic study was carried out in Norway in While the data showing that malnutrition at the
the 1940s, where the high rate of TB among naval recruits population level predisposes to active TB is persuasive,
was initially believed to result from the young men’s these findings have yet to be translated into public health
interventions aimed at curbing the epidemic. Given TB’s
overcrowded and unhygienic living conditions (19).
position as a major cause of morbidity and mortality in India,
However, improvements in hygiene and housing failed
our knowledge regarding malnutrition as a central TB risk
to reduce TB rates, however. Authorities then heavily
factor should be a consideration when designing policies
supplemented the recruits’ diets with milk, cod liver oil,
and interventions addressing food security.
fruits, and vegetables, after which TB rates quickly declined.
A similar conclusion was reached from a recent re-evaluation
of the incidence of active TB among children in the classic
Diabetes Mellitus and Tuberculosis
1918-1943 Papworth Village Settlement experiment in While undernutrition has historically been a primary driver
England (20). Children born outside of the settlement [who of TB in India, a rise in obesity has sparked recognition of
presumably experienced very poor nutrition and housing the role that diabetes mellitus may be playing in increasing
conditions] had a much higher incidence of TB than children TB risk. Most prospective cohort and case-control studies
 Nutrition and Tuberculosis 531

suggest that diabetes mellitus is associated with an approxi­ in more affluent countries such as the USA, weight loss
mately two times increased odds of developing active is a presenting complaint in nearly 50% of patients (39).
TB, (28-30) though some studies suggest as much as a five The little research that has compared weight changes in
to seven times increased odds (31,32). pulmonary versus extra-pulmonary TB suggest that—at least
Despite the recent rise in the prevalence of diabetes in as a subjective complaint—the loss is similar (40). The bulk
India, it probably remains a relatively smaller contributor to of weight loss in patients with TB is fat mass, though the fat-
the TB epidemic in India when compared to undernutrition. free component, which is also lost in significant amounts, has
A recent analysis estimated that 34% of the TB burden more of an effect on the physical functioning of the patient.
among the poorest one-third of the Indian population was Protein deficiency has been well described in the context
attributable to low BMI, while only 1.3% was attributable to of TB, and albumin and prealbumin have been found to be
diabetes mellitus. Even among the richest Indians, only 4% useful markers both for the diagnosis of deficiency as well as
of TB was estimated to be attributable to diabetes mellitus, the monitoring of its reversal (15,36,41,42). The predominant
while 20% was attributable to low BMI (31). However, this biochemical source of wasting is believed to be an increase
analysis was limited by the fact that the National Family in tumor necrosis factor-a [TNF-α], which causes a net
Health Survey-3 [NFHS-3], which was the dataset used for catabolic state (42). While some have further described an
this analysis, captured diabetes mellitus data based on self- “anabolic block”, or decrease in protein synthesis, in the
report, which likely resulted in significant underestimation context of TB (43), other research has failed to demonstrate
of actual diabetes prevalence. Indeed, when the analysis this abnormal metabolism (44).
was repeated using a higher estimated diabetes mellitus The physiologic basis of TB-associated wasting is poorly
prevalence, the authors estimated that as much as 20% of understood. Leptin, a well-known cytokine involved in
the TB burden in India may be attributable to diabetes energy metabolism, appears not to be involved in the wasting
mellitus (31). process (45-47). There are conflicting reports regarding the
Recent surveys of TB patients in Tamil Nadu and role of other hormones such as ghrelin (46,47), and a recent
Kerala suggest that, at least in the South Indian context, TB study suggests that plasma peptide YY may modulate
and diabetes frequently occur as comorbid conditions. In appetite suppression and be associated with poor prognosis
two districts in Tamil Nadu, among 827 TB patients who in TB patients (47).
were screened, 25% were found to have diabetes and 25%
were found to have pre-diabetes by oral glucose tolerance Micronutrient Deficiencies
testing (33). Notably, 37% of these diabetes cases were newly
detected based on screening at these TB centers. A similar Several vitamin deficiencies have been found to be common
survey performed using a state-wide representative sample in TB patients and may be a result of TB wasting; however,
of TB patients in Kerala, found a remark­able 44% prevalence most of these studies are cross-sectional, making it difficult
of diabetes, based on haemoglobin A1C testing (34). Forty- to distinguish those results from the disease from those
seven per cent of these patients with diabetes mellitus were that predispose to it. Vitamin A deficiency is perhaps the
newly diagnosed based on testing in the TB clinic, and the best studied micronutrient deficiency in TB, with several
majority of these patients had poorly controlled diabetes. studies demonstrating greatly decreased serum levels in
Only four TB patients needed to be screened to identify one TB patients (14,15,36,38,48-50). In a study in India, serum
new case of diabetes, which suggests that universal screening vitamin A levels in TB patients were found to be half that
of TB patients for diabetes [as is already recommended for of household contacts, who presumably had a similar diet,
HIV] may be a highly beneficial policy in TB clinics and suggesting that the deficiency resulted from the disease (35).
hospitals in India. Multiple studies have also consistently described a high
prevalence of vitamin D deficiency in TB patients (51-56),
and a recent meta-analysis of studies that compared TB
IMPACT OF ACTIVE TUBERCULOSIS
patients to healthy controls found that TB patients have a
ON NUTRITION much higher probability of being vitamin D deficient (57).
TB has been understood as a disease of wasting since its
earliest descriptions, and we now know that it causes Wasting in HIV/TB Co-infected Individuals
significant deficiencies in nearly every nutritional marker.
Given the significant role that HIV has played in fanning the
Body mass index [BMI, kg/m2], skin-fold thickness, mid-
TB epidemic globally, the impact of HIV-TB co-infection on
upper arm circumference, grip strength, body fat percent­
nutrition merits special mention. Like TB, HIV often leads
age, calorie stores, muscle mass, serum albumin, blood
to clinical wasting, particularly in its later stages (58,59).
haemoglobin, plasma retinol, plasma zinc, selenium, iron,
“Acquired immunodeficiency syndrome [AIDS] cachexia”
and vitamins A, C, D and E have all been found to be
and “HIV wasting” are well-characterised phenomena,
depressed in TB patients (11-14,17,35-38).
with the latter carrying precise clinical definitions. While
untreated HIV disease is, like TB, a net catabolic state,
Weight Loss and Protein–Energy Malnutrition evidence has suggested that, in regions in which it is
Weight loss has long been identified as one of the most endemic, TB is the predominant cause of severe wasting in
common presenting complaints of patients with TB; even patients with HIV (60).
 532 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The combination of these two diseases produces a pro­ Nutritional Recovery

found cachexia, rapidly obliterating a patient’s nutritional
Chemotherapeutic treatment of TB interrupts the progressive
stores (61). The resulting deficiencies are more severe
wasting that is part of the natural history of the disease.
than that of usually the case for patients with either HIV
A few studies have evaluated this process of nutritional
or TB alone, for a wide variety of nutritional indicators—
recovery. Initiation of therapy and reduction in the burden
including BMI, arm circumference, waist circumference, of TB bacilli was associated in one study with a decline
albumin, and vitamin A levels (35,62-64). The two diseases in plasma peptide YY and ghrelin (47). Decline in these
also act synergistically to cause anemia, which can have a hormone levels was followed by a rise in appetite and a
major impact on functional status and mortality (65,66). If subsequent increase in body fat and BMI. Despite general
untreated, data suggest that HIV infection may blunt certain improvement in nutritional indicators, many TB patients
aspects of nutritional recuperation that normally takes place may never fully recover back to their baseline nutritional
during TB treatment (61,64). status. A study from Chennai found that more than 80% of
HIV-TB co-infected patients remained underweight even
NUTRITION AND THE NATURAL HISTORY after the completion of anti-TB therapy (63).
OF TUBERCULOSIS In addition, “nutritional partitioning” may occur, in
which patients experience disproportionate recovery of fat
Disease Manifestations and Mortality stores as compared to protein stores. In one study, patients
on an average, gained 10% in body weight during the
Severely malnourished patients are more likely to have
first six months of TB treatment; however, this increase
atypical symptoms, signs, and radiographic presentations in weight was mostly attributable to recovery of body fat.
of pulmonary TB. They are less likely to have symptoms There was minimal improvement in protein stores or bone
of haemoptysis and more likely to have dyspnoea and mineralisation (83). Diabetes may blunt nutritional recovery
diarrhoea (18,67). On chest imaging, upper lobe cavitation further. One prospective cohort study in Tanzania found
is less common than in well-nourished patients, while that diabetics had a significantly lower increase in body
atypical findings of lower lobe consoli­d ation, miliary weight, mid-upper arm circumference, and hemoglobin
nodules, and mediastinal lymphadenopathy are more after five months of TB treatment, compared to non-diabetic
common (68). In general, these findings parallel the pre­ TB patients (84). All these findings suggest that, despite
sentation of TB in patients with AIDS. T-lymphocyte- some nutritional recovery with TB treatment, TB-associated
associated immunodeficiency may be a common pathway malnutrition may still exert a long-term toll on patients’
for these manifestations (68). functional status and quality-of-life.
Malnutrition in patients with active TB has been
independently associated with increased mortality, as well NUTRITIONAL STATUS AND THE TUBERCULIN
as higher rates of treatment failure and relapse (69-71). Poor SKIN TEST, INTERFERON GAMMA RELEASE
nutritional status results in similar outcomes in patients with ASSAYS, AND BACILLE CALMETTE-GUÉRIN
multidrug-resistant TB (72). Indeed, multiple studies have VACCINE
shown initial body weight or BMI at the time of TB diagnosis
to be a good prognostic indicator, at times predicting Malnutrition likely decreases the sensitivity of the TST.
survival better than more complicated outcome instruments Studies in humans and animal models have suggested that
such as the acute physiology and chronic health evaluation low biometric nutritional indicators, low serum albumin,
and deficiencies of vitamin D and zinc are associated with
[APACHE] score (41,73). Other studies have found that
decreased size of the TST reaction, which may result in false
measuring lean tissue mass (74), assessing for iron deficiency (75)
negative tests (85-90).These findings parallel TST studies in
and calculating a composite nutrition score [based on multiple
HIV patients, suggesting that clinicians should err on the
indicators] can add further prognostic value for predicting
side of liberally interpreting borderline TST reactions in
mortality and other adverse outcomes, such as, respiratory
undernourished patients. IGRAs are increasingly being used
failure, treatment failure, and relapse (76-79). Nutrition may for detection of latent TB infection, and studies suggest that
also alter the effects of TB medications, as undernourished the sensitivity of these tests is also decreased significantly in
patients may be more likely to have sub-therapeutic drug malnourished patients (90-93).
levels and drug-induced hepatotoxicity (80-89). Malnutrition may compromise the efficacy of the BCG
Diabetes may also alter the natural history of TB. A meta- vaccine in two different ways. First, maintenance of good
analysis of several studies found that diabetes increased the nutrition is critical for continuing vaccine-induced immune
risk of the combined outcome of treatment failure and death, protection. Deteriorating nutritional status between serial
with a mildly increased pooled relative risk of 1.69 (89). TSTs after BCG vaccination resulted in a marked decrease
Interestingly, four studies which looked at the out­come in the size of induration (94). Children with even mild levels
of death alone and adjusted for age and other covariates of malnutrition in this study also had fewer positive TSTs
showed that diabetes was associated with a much higher after vaccination. These results suggest that vaccine-induced
five times increased pooled odds of death in TB patients (82). immune protection may be a function of nutritional status at
 Nutrition and Tuberculosis 533

any given time. Similar findings in animal models support supplements, and individual vitamins. The outcomes
these data (6,9,95). measured in these studies have variably included mortality,
Second, severe malnutrition at the time of BCG adminis­ sputum smear or culture conversion, weight gain, treatment
tration can permanently affect vaccine-induced immune adherence, functional status, and quality-of-life. Table 40.1
protection. Children who had kwashiorkor at the time of summarises the critical nutritional considerations in the
BCG administration had very high rates of negative TSTs, prevention and management of TB. We review below a
despite much better nutrition between the time of vaccine few of the more interesting studies that may guide more
administration and TST placement (96). This implies definitive research in the future on the question of nutritional
severe protein malnutrition prevented the vaccine from supplementation for TB patients.
“registering” with the immune system in the first place.
Severely protein malnourished children may, therefore, Macronutrient Interventions
derive greater benefit from being vaccinated with the BCG
after improvement of nutrition status, if such delay is feasible. In a classic randomised trial performed in Chennai in the
late 1950s, 193 patients were randomised to treatment at
home or in a TB sanatorium (98). The sanatorium provided
NUTRITIONAL INTERVENTIONS FOR PATIENTS
nutritional supplementation so that these patients had
WITH TUBERCULOSIS significantly increased caloric, protein, carbohydrate, and
While it is difficult to sort out the predisposing nutrient micronutrient intake as compared to patients treated at
deficiencies from those caused by TB, it is probably best home. Patients were followed for six months, after which
to understand them as a spiraling force, with nutritional response to therapy was assessed using time to culture-
deficiencies compromising the immune system, which negative sputum and improvement in chest radiograph. In
enables TB to strengthen its hold on the body; this spite of a markedly poorer diet and substantially less weight
proliferation of TB leads to further nutritional deterioration. gain in the patients who received treatment at home, the
The challenge for clinicians is to interrupt this cycle, with TB overall response to therapy was similar in the two groups.
chemotherapy serving as the most potent tool for doing so. In a multivariate analysis, none of the dietary factors
It would seem intuitive that adjunctive nutritional support studied [calories, carbohydrates, proteins, fats, minerals, and
might also serve a key role in decreasing TB-associated vitamins] were found to influence the time to attainment of
malnutrition, morbidity, and mortality. The scientific con­ quiescent disease.
sensus regarding this question is not clear, however. A recent Since the time of the classic Chennai sanatorium study, a
meta-analysis of randomised trials evaluating nutritional handful of studies have re-evaluated the benefits of different
supplementation in TB patient highlights the fact that this types of macronutrient supplements, through provision of
field is limited by poor-quality studies with small sample additional cereals and lentils (99), high-calorie nuts and
sizes and varied methodologies (97). Interventions have ghee (100), high-calorie packaged supplements (101,102),
included provision of daily cooked meals, high energy peanuts high in arginine (103), and a more comprehensive
macronutrient supplements, combinations micronutrient nutritional meal (104). Notably, none of the studies has

Table 40.1: Critical nutritional considerations in the prevention and management of TB

Prevention
Reduction of protein-energy malnutrition is critical to controlling and reducing rates of TB
BCG vaccine efficacy may be compromised in malnourished recipients
Protein and nutritional repletion prior to BCG vaccine administration should be considered, if possible, in severely protein malnourished
children
Diagnosis
Borderline TST in malnourished patients should be interpreted liberally, erring on the side of a positive read
Severe malnutrition is associated with atypical presentations of TB, paralleling patterns in AIDS patients
Treatment
It is unclear whether macronutrient supplementation in patients with active TB decreases mortality or improves treatment outcomes, but it
may help improve weight gain and quality-of-life
Combination micronutrient (i.e., multivitamin) supplementation may help decrease recurrence rates in patients with active TB
High-dose vitamin D supplementation may improve treatment outcomes in TB patients with certain vitamin D receptor genotypes, though
further research is needed
Supplementation with 25-50 mg of pyridoxine daily during TB treatment should be considered for malnourished individuals, the elderly,
pregnant women, cancer patients, chronic liver disease patients, children, and individuals with preexisting risk factors for peripheral
neuropathy
Repletion of tissue mass in TB patients probably requires greater-than-normal levels of nutritional intake, including protein and high energy
supplementation
Improvements of serum albumin may be the earliest sign of improving nutritional status in patients being treated for TB
TB = tuberculosis; BCG = bacille Calmette-Guérin; TST = tuberculin skin test; AIDS = acquired immunodeficiency syndrome
534 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

followed patients long enough or had been adequately Trials of vitamin D supplementation as adjunctive
powered to evaluate for differences in mortality. With therapy for patients with active TB have produced mixed
regard to TB treatment outcomes, the studies have been results, though interpretation of these studies is limited
mixed, with some showing improvements in sputum smear by highly varied dosing of vitamin D. Studies evaluating
clearance, treatment completion rates, and treatment failure lower dose daily supplementation [e.g., 5,000 IU daily] or
rates (99,100,103); while others showed trends towards intermittent high-dose supplementation [e.g., 100,000 IU
these favorable outcomes that did not reach statistical signifi­ every few months] did not show improvements in mortality
cance (104). Nearly all of the studies showed increased or sputum smear conversion rates (111,112). In contrast, a
weight gain in the intervention group, and some also study that administered a higher dose of 10,000 IU a day
captured significant increases in lean body mass (101), grip showed a statistically significant improvement in the rate
strength (100,101), and quality-of-life scores (100,101). Given of sputum smear conversion (113).
the possible long-term toll of TB-associated malnutrition, In a more recent double-blind randomised controlled
these improvements in weight gain, physical functioning, trial, 100,000 IU of vitamin D was administered every two
and quality-of-life may provide benefits to patients that weeks for the first six weeks of TB therapy (114). While
are meaningful enough to justify provision of adjunctive vitamin D supplementation did not significantly affect the
nutritional supplementation on a wider scale. time to sputum culture conversion for the overall study
In the few studies where caloric intake was measured, population, it did improve sputum culture conversion times
even with the adjunctive nutritional supplementation, the in patients with the VDR TaqI receptor polymorphism tt
intervention groups were not able to meet the minimum genotype. This trial suggests the possibility that therapeutic
caloric intake of 2500 kcal/day that is recommended for responses to vitamin D supplementation may be modulated
the general population. TB patients may need even higher by VDR receptor genotype. If confirmed in future studies,
levels of caloric intake than the general population, given the this finding may have significant implications for the
profound catabolic state and possible anabolic block induced individualised use of high-dose vitamin D supplementation
by TB. As such, future studies might focus on providing as adjunctive TB therapy based on a patient’s genotype—a
even higher levels of nutritional supplementation, though strategy that may be of increasing importance in the era of
caloric intake may ultimately be limited in these patients by multidrug-resistant and extensively drug-resistant TB, where
the profound decrease in appetite caused by TB disease. other chemotherapeutic options are limited.

Vitamin D Other Micronutrients

Indirectly, vitamin D has long been used to treat TB. In A randomised trial performed among 194 families in Harlem
the mid-1800s, cod-liver oil, which contains high levels in New York City in the 1940s suggested that regular
of vitamin D, was reported to be effective in improving supplementation with a combination of micronutrients may
outcomes for patients with TB (105,106). In 1895, Niels help protect against the development of active TB (115).
Finsen found sunlight exposure to be effective in treating The micronutrient supplement, which included vitamins
lupus vulgaris [cutaneous TB], a discovery for which he won [niacin, thiamine, riboflavin, vitamin A, and vitamin C] and
the Nobel Prize (107). More recently, several observational minerals [calcium and iron], was provided to families in
studies and a meta-analysis have found vitamin D deficiency the intervention arm for five years. There was a statistically
to be associated with an increased risk of TB (51-55,57). significant lower incidence of active TB among those receiving
Basic science research suggests that when Mtb activates micronutrient supplementation [0.16 cases/100 person-
toll-like receptors on macrophages [a key component of years] compared to those not receiving supplementation
the innate immune response], this results in upregulation [0.91 cases/100 person-years], though notably this was not
of the vitamin D receptor [VDR]. In turn, activation of an intent-to-treat analysis. No further studies have been
VDR by vitamin D may enhance killing of M. tuberculosis performed evaluating the role of combination micronutrient
[Mtb] by increasing the phagocytic activity of macrophages supplementation for TB prevention, and, to our knowledge,
and by inducing production of the antimicrobial peptide this intervention has never been implemented on a wider
cathelicidin (108). scale.
Individual risk for TB infection and therapeutic res­ Subsequent studies have evaluated the role of combination
ponses to vitamin D administration may vary due to VDR micronutrient supplementation as an adjuvant therapy for
gene polymorphisms. The FokI, BsmI, TaqI, and ApaI poly­ patients with active TB. A high-quality randomised, placebo-
morphisms have been of particular research interest. A recent controlled trial of combination micronutrient supple­
meta-analysis suggests that the effect of these polymorphisms mentation was performed among 887 Tanzanian TB patients,
on TB risk may be especially pronounced in Asian popula­ about half of whom were co-infected with HIV (116).
tions, including Indians (109). Notably, there is a high The study found a statistically significant decreases in
diversity of VDR gene poly­morphisms within the Indian TB recurrence of 45% and 63% in the overall intervention
population, with major differences in the distribution of group and the subset of HIV-infected patients, respectively.
the polymorphisms among Hindus, Muslims, and tribal Moreover, there was a 64% reduction in mortality in the
populations (110). HIV-negative intervention group that did not reach statistical
 Nutrition and Tuberculosis 535

significance. Rates of peripheral neuropathy were greatly FEAST AND FAMINE: NUTRITION’S CENTRAL
decreased among those who received the micronutrient ROLE IN INDIA’S TB EPIDEMIC
supplement. Other studies of combination micronutrient
supplementation have not found evidence of improved TB Contemporary India is in a unique moment in the epidemio­
treatment outcomes (117-121), though some of these studies logical transition, in which the country is facing both
did find evidence of increased grip strength (120) and weight pervasive and persistent under-nutrition, as well as rapidly
gain (117-120) in the interventions groups. rising rates of obesity—as one author puts it, a state of
Several other studies have evaluated provision of TB being both “stuffed and starved” (130). Remarkably, the
patients with vitamin A or zinc supplementation, either Indian population is at historic lows in terms of daily calorie
individually (15,117,122,123) or in combination (48,122-125). consumption (131). While the decline in calorie consumption
Notably, none of the studies showed improvements in may partly reflect a decline in calorie expenditure due to
mortality or treatment completion rates in the interventions sedentary lifestyles resulting from increased urbanisation,
groups, though one study found that patients receiving it is also clear that the average BMI has actually decreased
vitamin A and zinc had more rapid conversion of sputum in recent years among already undernourished sub-sections
cultures. Concerningly, two studies found a higher risk of of the population, such as rural men (132). A recent
mortality in HIV-infected patients who received vitamin study estimated that, between 1998 and 2008, India likely
A and zinc supplementation (123,125). Finally, one study experienced a rise in the number of TB cases that was
from Odisha has suggested that iron supplementation may disproportionate to population growth (132). The majority
accelerate improvement of anemia during the first month of of this rise in TB incidence was attributable to nutritional
TB treatment; however, these benefits largely disappeared factors—predominantly worsening under nourishment
after the second month of treatment (126). among rural men, but also the rising prevalence of diabetes.
Amartya Sen and Jean Dreze have argued that hunger in
Isoniazid and Vitamin B6 Deficiency the modern world is a crisis of both food security and health
care (133). Clinicians treating TB are in an ideal position to
Isoniazid-induced peripheral neuropathy is a well-recognised confront this combined entity of hunger and disease. They
adverse effect of TB treatment mediated by nutritional can do this not only by optimising nutritional status in those
deficiency of pyridoxine, or vitamin B6. Anti-TB therapy with active TB [thereby improving quality of life for these
has been shown to cause significant reductions in plasma patients], but also by addressing malnutrition in all their
pyridoxine levels within one week of therapy (127), and patients as a method of TB prevention. Specific interventions
isoniazid may also compete with pyridoxine in its role as a might include encouraging increased protein intake, targeted
co-factor for synthesis of neuro­transmitters, such as gamma- micronutrient supplementation, and diabetes screening, as
aminobutyric acid [GABA]. The result is a dose-dependent well as aggressively treating intestinal parasites and anemia.
toxicity of numbness and tingling in the extremities in a Perhaps the most powerful way doctors can confront
glove and stocking distribution, though it can also present as TB is by moving beyond the purely medical approach and
ataxia or muscle weakness. Central nervous symptoms such stepping outside of their hospitals into the realm of public
as seizures and confusion are less frequent presentations of action. Even as malnutrition is a medical problem, so is TB
B6 deficiency from isoniazid. inseparable from hunger. By advocating for public policies
Studies in Chennai in the 1960s first identified the role of
that ensure food security for the poor, doctors can confront
low dose pyridoxine supplementation in protecting against
TB as it needs to be confronted— at both the social and
isoniazid-induced peripheral neuropathy (128). Current
medical levels.
guidelines for pyridoxine supplementation are based on
the patient’s risk for isoniazid toxicity. Malnourished
individuals, the elderly, pregnant women, cancer patients, ACKNOWLEDGEMENTS
chronic alcoholics, chronic liver disease patients, and Ramnath Subbaraman is supported by a Harvard T32
children [especially adolescent females] are at higher risk for post-doctoral HIV Clinical Research Fellowship [NIAID AI
pre-existing pyridoxine deficiency even before TB treatment. 007433].
In addition, isoniazid peripheral neuropathy occurs more
frequently in those already at risk for neuropathy from other
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Micronutrient status and immune function in tuberculosis. Ann
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 41
Nontuberculous
Mycobacterial Infections
VM Katoch, T Mohan Kumar, Babban Jee

INTRODUCTION infections in immunocompromised individuals and cervical

lymphadenitis in children (3-8,11,12). Of the approximately
Nontuberculous mycobacteria [NTM] in the past were known
200 known species and 13 subspecies of NTM so far (13), only
by various names such as ‘anonymous’, ‘environmental’,
one-fourth is found to be associated with disease in humans.
‘opportunistic’ mycobacteria and mycobacteria other than
The important NTM species are listed in Tables 41.1A
Mycobacterium tuberculosis [Mtb] complex [MOTT] (1-14).
and 41.1B. Most of these NTM exhibit in vitro resistance to
None of these terms has become universally acceptable
many drugs that are used for the treatment of Mtb (14,15).
and the name NTM seems to have better consensus and
Some species, like M. genavense (16), M. celatum (17), M.
is also endorsed by the American Thoracic Society [ATS]
conspicuum (18) and M. colombiense (19) were reported for
and the Infectious Diseases Society of America [IDSA]
the first time from people living with HIV/AIDS [PLHA].
statement (11,14).
M. paratuberculosis also appears to be the likely causative
These mycobacteria mainly exist in the environment as
organism for Crohn’s disease.
saprophytes. First such mycobacterium was recognised as
a cause of human disease in 1908 (1). These organisms in
DISTRIBUTION IN THE ENVIRONMENT
the past were called “atypical mycobacteria”, the term first
coined by Pinner (2). Diseases caused by these organisms Most of the NTM are ubiquitous in distribution and have
are uncommon compared with tuberculosis [TB], but been isolated from a wide variety of environmental sources
there has been a significant increase in pulmonary and including water (20), soil (21), swamp (22), biofilms (23),
non-pulmonary infections due to these mycobacteria ice-machine (24), cigarette (25), biocide-treated metal-
during the last two to three decades (3-8). This increase working fluid (26), gentian violet solution (27), moisture-
can be partly explained by the increase in the number of damaged buildings (28), food stuffs (29) and protozoa (30).
susceptible and immunocompromised individuals but can Generally, domestic, municipal and hospital water supply
also be attributed to the availability of better technology systems, swimming pools and whirlpools, coastal areas,
and increased reporting worldwide. While the infections hot tubs, aquaria, water and sewage treatment plants are
caused by Mtb, M. bovis, M. leprae are definite clinical entities, considered main reservoirs of NTM (31). Further, NTM have
the diseases caused by NTM have varied manifestations, extraordinary ability to survive in very odd physio­logical
are usually not transmitted from man-to-man except and environmental conditions and continue their life cycle
M. abscessus in cystic fibrosis patients. Even though these even in extreme nutritional starvation and temperature
mycobacteria have been present in the environment, the fluctuations (32-35).
emergence of human immunodeficiency virus infection M. avium complex [MAC] organisms have been isolated
[HIV] and acquired immunodeficiency syndrome [AIDS] from natural water sources, M. kansasii from tap water; and
has significantly increased the risk of TB and disease due rapidly growing mycobacteria are found in soil and natural
to NTM (9-11). In these individuals the NTM disease has water sources as well as in tap water, water used for dialysis
been a major cause of morbidity and mortality in western or even in surgical solution (3). Man-made changes in
countries (11). The NTM cause pulmonary and disseminated the environment may also have altered the risks from
 Nontuberculous Mycobacterial Infections 541

Table 41.1A: NTM species these mycobacteria. For example, hot water systems are
growth nidus for some of these mycobacteria, such as
M. arupense M. malmoense
M. xenopi, in the hospital environment and use of showers
M. aubaganense M. marinum may result in droplet inhalation of the mycobacteria.
M. avium M. mucogenicum
M. avium intracellulare M. neoaurum EPIDEMIOLOGY
complex
M. boenickei M. neworleansese
The distribution of NTM, incidence and prevalence of
diseases caused by them are difficult to determine since
M. bohemicum M. nonchromogenicum
systems of notification vary from country to country. In the
M. bolletti M. palustre
HIV-era, the United States and European countries appeared
M. brisbanense M. parascrofulaceum to be most affected regions of the world with NTM-associated
M. canariasense [closely M. paratuberculosis infections. While MAC, M. kansasii, M. abscessus, M. chelonae
related to M. diernhoferi] and M. fortuitum were most frequently isolated NTM species
M. celatum M. parmense in USA; M. malmoense, M. xenopi, M. kansasii, M. abscessus
M. conspicuum M. phocaicum were predominant in Europe [particularly northern Europe].
M. elephantis M. porcinum M. xenopi, M. kansasii and M. ulcerans were much common
M. fortuitum- M. chelonae M. pseudoshottii in Canada, South Africa, Australia respectively (14,36).
complex M. marinum, a common cause of skin and tendon infections,
M. fortuitum third biovariant M. scrofulaceum occurs in people living in coastal areas and those exposed to
complex fish tanks or swimming pools. Recent data suggest that Asia
M. genavense M. septicum is also becoming hot-spot of infections due to both slowly
M. goodii M. shottsii and rapidly growing NTM species. Like America, MAC
was a common isolates in north-eastern Asia, especially in
M. gordonae M. simiae
Japan and South Korea during 1971-2007. During this period
M. habana M. smegmatis
in India, MAC, M. terrae, M. scrofulaceum, M. flavescens,
M. haemophilum M. szulgai M. gordonae were frequently encountered species. Interestingly,
M. heckeshornense M. terrae complex M. fortuitum was found to be common NTM isolate from
M. houstonense M. thermoresistibile pulmonary infections in India followed by M. kansasii,
M. immunogenum M. ulcerans M. triviale and M. szulgai (37). There are several other important
M. interjectum M. vaccae reports of NTM infections from India (38-45). Although Mtb
M. intracellulare M. wolinskyi has always been found as the major cause of mycobacterial
infections and the proportion of NTM has varied (46-52).
M. kansasii M. xenopi
As the mycobacterial culture with strict criteria is still not
Timpe and Runyon Classification (4) based on NTM growth rate routinely performed in most parts of India, and there is
and pigment production: growth rate >7 days; slowly growing
mycobacteria [SGM]: Type I [photochromogens: M. kansasii, a tendency to ignore such isolates and in the absence of
M. marinum, M. asiaticum, M. simiae]; Type II [scotochromogens: clear-cut guidelines followed in the country it is difficult to
M. scrofulaceum, M. szulgai, M. gordonae, M. flavescens]; Type III comment on the exact NTM disease burden. Moreover, NTM
[non-photochromogens: MAC, M. xenopi, M. ulcerans, M. terrae, disease is not notifiable in India. Mtb has been observed to
M. haemophilum]; growth rate < 7 days: Type IV [rapidly growing be the most common cause of TB especially EPTB in Indian
mycobacteria: M. fortuitum, M. abscessus, M. chelonae]
patients with HIV/AIDS (52). It is emphasised that over-
NTM = nontuberculous mycobacteria
reliance on smear microscopy should be substituted with

Table 41.1B: Species of NTM causing infections in humans

M. abscessus complex M. elephantis M. marinum M. septicum
M. arupense M. fortuitum M. neourum M. shottsii
M. aubaganense M. genavense M. neworleanense M. simiae
M. avium M. goodii M. nonchromogenicum M. smegmatis
M. boenickei M. gordonae M. palustre M. szulgai
M. bohemicum M. haemophilum M. parascrofulaceum M. thermoresistibile
M. brisbanense M. heckeshornense M. paratuberculosis M. terrae
M. canariense M. houstonense M. parmense M. triviale
M. celatum M. immunogenum M. phocaicum M. ulcerans
M. chelonae M. interjectum M. porcinum M. vaccae
M. conspicuum M. intracellulare M. pseudoshottsii M. wolinskyi
M. diernhoferi M. kansasii M. scrofulaceum M. xenopi
M. malmoense
NTM = nontuberculous mycobacteria
542 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

identification, speciation including subspeciation of NTM subjects but little is known how host counters the attack of
isolates at the international level. M. avium at immune level. It is assumed that M. avium
Source of NTM infections is usually from environmental enters macrophage using similar complement receptors
reservoirs (53-56). Transmission of NTM from human- CR1, CR3, CR4 and mannose receptors used by Mtb (65-67)
to-human is rare except outbreaks of infections due to and thereafter promotes recruitment of naïve monocytes
M. massiliense in cystic fibrosis centres. Transmission of NTM to the site of infection by upregulating the expression of
from animal to human is also rare but, the possibility of some prominent chemoattractants including interleukin
person-to-person transmission cannot be ruled out (57). It [IL]-8, macrophage-inflammatory protein [MIP]1β, MIP1α,
was thought that NTM do not lead to latent infection but a MIP2α, Regulated on Activation, Normal T-cell Expressed
study has shown that NTM can also undergo dormancy and and Secreted [RANTES] protein, monocyte chemoattractant
eventually may develop latent infections similar to Mtb (58). protein [MCP]-1 (68,69). Once phagocytosed, M. avium tries
Exposure to NTM results in sensitisation which can to adapt in the hostile environments of macrophage while
be detected by skin test to NTM antigens and differential host activates killing cascades. In this course, enhanced
tuberculin testing with antigens prepared from other production of cytokines, like tumour necrosis factor-
mycobacteria, e.g., purified protein derivative [PPD]-A alpha [TNF-α], IL-1β, small inducible cytokine A5, trans­
[M. avium] or PPD-Y [M. kansasii] has been considered as a forming growth factor [TGF]-β2, IL-15, IL-9, IL-3, IL-6, IL-10,
satisfactory method of distinguishing sensitisation due to TGF-β1 (68,70), appearance of granuloma (71-75) and
NTM from Mtb. subsequent cell death (76-79) were thought to be the major
steps in the control of infections. However, unaltered levels
PREDISPOSING FACTORS of iNOS, IL-12p40 and interferon-gamma [IFN-γ] during the
exposure of M. avium to macrophage are intriguing (68).
It is well known that these environmental mycobacteria Cell death of M. avium infected macrophages has been
cause disease in individuals who offer some opportunity shown to be under the control of Th1 immunity. Increasing
due to altered local or systemic immunity (3,4,11,59-63). amount of evidences suggests the central role of TNF-α in
While the reasons may be less clear in children with cervical the apoptosis of M. avium infected macrophages (77,80)
lymphadenitis such factors may be quite obvious in patients whereas IFN-γ appears to be major driving force behind
with bronchiectasis, surgical procedures, injections, break granuloma necrosis (81). It has been reported that addition
in skin surface due to wounds and generalised immune of exogenous hydrogen peroxide to macrophage culture also
deficiency states, like AIDS and use of immunosuppressive initiates apoptosis (82). Engulfment of apoptotic macrophage
agents in transplant patients (11). However, mechanisms containing M. avium by healthy macrophages may be
of pathogenesis of NTM infections are not very clear and an additional strategy of host to limit the intracellular
have not been adequately investigated. The lipid-rich outer infection (77). Interestingly, M. avium, in some studies,
envelope of the organisms may be important as the first has been observed to inhibit the apoptosis of infected
defense of these organism but specific moieties on the surface macrophages (69,83,84).
may also be important factors. Some NTM species, such Like M. avium, M. avium subsp. paratuberculosis [MAP] is
as M. avium and M. simiae have been reported in patients also a multiple host pathogen causing deadly granulomatous
with AIDS in India (60). Very low CD4+ T-cell counts in enteritis [Johne’s disease] in ruminants as well as possibly
patients with AIDS and defective cytokine response[s] inflammatory bowel syndrome known as Crohn’s disease
have been linked to development of severe infections due in humans (85). Experimental data gathered from some in
to M. avium from the common sources, such as potable vitro and animal studies showed a clear shift in host immune
water (64). Chronic obstructive pulmonary disease [COPD], responses during the infection of MAP. It was found that
emphysema, pneumoconiosis, bronchiectasis, cystic fibrosis, in early phase of pathogenesis, major pro-inflammatory
thoracic scoliosis, aspiration due to oesophageal disease, cytokines are produced in larger quantity but this host action
previous gastrectomy and chronic alcoholism are some of is not sustained for longer period. As infection progresses,
the conditions which have been linked to disease due to the production of pro-inflammatory cytokines is replaced
NTM. Table 41.2 provides a list of predisposing conditions with abundant secretion of anti-inflammatory cytokines (86).
to NTM infections. A recent study using pan-genomic analysis of gene
expression of MAP infected bovine monocyte derived
HOST IMMUNE RESPONSE TO NTM INFECTIONS macrophage provided a time-related picture of host’s
immune response. In this study, it was observed that just
Due to increasing number of NTM species identified 2 hours after infection, MAP induced several-fold increase in
to be associated with human infections, inadequate expression of TNF-α, IL-1β, IL-1β, IL-6, CXCL2 and CCL20
information is available on species specific host immune genes and after 6 hours of infection, IL-1β, TNF-α, CXCL2,
response. The knowledge about the immunoregulation CCL4, CCL5, CCL20, CD40 and the complement factor B
in NTM infections is growing. From the risk point, [CFB] genes were among the differentially expressed genes
M. avium is a most successful pathogen after Mtb causing showing relatively higher level of expression as compared
a wide spectrum of diseases both in birds and human to those observed at two hours post-infection (87). In other
 Nontuberculous Mycobacterial Infections 543

Table 41.2: Important host-related predisposing conditions

Association with host-related predisposing factors [NTM-PD]
Bronchiectasis [especially middle lobe and lingual]
Bronchiectasis due to cystic fibrosis-CFTR gene polymorphism
Chronic obstructive pulmonary disease
Destroyed lungs due to TB or other diseases like pneumoconiosis
Pulmonary alveolar proteinosis
Primary ciliary dyskinesia
Alpha 1 antitrypsin deficiency
Thoracic skeletal abnormalities [kyphoscoliosis]
Gastroesophageal reflux disease
Lady Windermere syndrome*
Immunodeficiency states
Primary†
Anti-interferon γ-antibodies [blocking of interferon γ–interleukin-12 pathway]
Anti-GM-CSF antibodies [impaired local immunity]
NEMO mutations [impaired signal transduction from Toll-like receptors, interleukin-1, and TNF-α]
STAT1 deficiency [weakened systemic immunity]
IL12 mutations [reduced T-cells and natural killer cells stimulation]
CYBB mutations [decreased bactericidal activity]
GATA2 gene mutations [impaired hematopoietic, lymphatic, and vascular development]
Acquired
HIV status [CD4 counts <50 cells/µ]
Use of biologics [anti-TNF agents and TNF receptor blockers]
Use of immunosuppressive agents and steroids in organ transplantation and other autoimmune diseases
Lung cancer
Environmental factors
Individual factors
Indoor swimming pool use [in past 4 months]
Swimming pool use at least once a month
Soil exposure
Climatic factors
Proportion of areas as surface water
Mean daily potential evapotranspiration
Higher copper soil levels [helps mycobacteria to form biofilms]
Higher sodium soil levels [more nutrition for mycobacteria]
Lower manganese soil levels [manganese inhibits mycobacterial growth]
Lower top soil depth [high nutrition for mycobacteria due to low vegetation]
* Non-smoking post-menopausal white women who are taller and leaner with scoliosis, pectus excavatum and mitral valve prolapse
syndrome than their peers
† These mutations are rare and associated with disseminated NTM disease
NTM-PD = NTM pulmonary disease; BMI = body mass index; CFTR = cystic fibrosis transmembrane receptor; GM-CSF = granulocyte
macrophage colony stimulating factor; NEMO = nuclear factor κB essential modulator; STAT1 = signal transducer and activator of transcription 1
[for disseminated infection]; IL-12 = interleukin-12; TNF = tumour necrosis factor; CYBB = cytochrome b-245 beta

study (88), a marked upregulation of anti-inflammatory regulatory T-cells [Treg] cells (94) have been implicated
cytokine IL-10 gene at all the experimental time-points in the breakdown of host protective immunity. Further,
[6, 24 and 72 hours] and concomitant downregulation of polymorphism in IL-18 gene has also been associated with
IFN-γ and TNF-α [at 6 hours] and IL-12 [at 72 hours] was increased risk of Crohn’s disease (95).
noticed suggesting that development of true clinical form Studies carried out with murine model infected with M.
of disease is largely concerned with the dysregulation of abscessus [MAB] have shown that early neutrophilic response
host’s effective defense mechanisms against this facultative was an important factor in limiting the intracellular spread of
pathogen. Not only in this but in many subsequent this pathogen (96). Interaction of toll-like receptor-2 [TLR-2]
molecular studies carried out either with patients or animal with dectin-1 resulted in the enhanced production of TNF-α,
monocytes/macrophages, higher expression of IL-10 and IL-6 and p40 subunit of IL-12 in murine macrophages (97).
other important anti-inflammatory cytokine genes [IL-6 Further study demonstrated that control of MAB infection
and TGF-β] six hours of post-infection emphasised the role in mice spleen was primarily dependent on T-cell while in
of IL-10 in progression of disease (89-92). Interleukin-23 liver, it was both T-cell and B-cell driven (98). It has been
[IL-23] (93) and an imbalance in the ratio of Th17 cells and reported that an early influx of IFN-g-producing CD4+ and
 544 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

CD8+ T-cells into the lungs of C57BL/6 mice might play a CLINICALLY IMPORTANT MYCOBACTERIA
pivotal role in clearing the invading agents from the host
Among the known 200 species and 13 subspecies of NTM,
body (96). In an in vitro study carried out with MAB infected
only one-fourth have been associated with localised and
human cells, it was found that production of TNF-α was
or disseminated diseases in humans [Tables 41.3 and 41.4].
dependent on TLR-2 and mitogen-activated protein kinase
[MAPK] p38 pathways and is a property shared with
Mycobacterium avium Complex
M. avium (99).
Prior to 2010, it was only a hypothesis that person having Members of MAC group have gained a major prominence
genetic defects in IFN-γ/IL-12 co-stimulatory axis may be in the west, especially after an increased frequency of
more prone to NTM infections. But recent clinical data have infections produced by these organisms in patients with
provided evidence that such hypothesis is correct, it has AIDS (105-108). However, in western countries these
been observed that production of anti-IFN-γ autoantibodies organisms were also an important cause of pulmonary and
in patient’s body, IFN-γ associated first-line defence other infections in the pre-AIDS era (11,109,110) as well due
machinery was not able to counter the attack of exogenous to TB becoming rarer in these countries long back.
pathogens resulting in establishment of infections (100-103).
Based on analysis of different studies during 1979 to 2015, M. avium subsp. Avium
Wu and Holland (104) have proposed mechanism[s] linking M. avium subsp. avium has been isolated from environment as
certain genetic/immunological defects with susceptibility well as clinical specimens including sputum from India (51,111).
to disseminated NTM disease [Figure 41.1] and have Certain specific serotypes of M. avium (11,62), plasmid
also suggested an algorithm to investigate these defects containing M. avium (112) and in some European and African
[Figure 41.2]. Further studies will be required to validate countries certain restriction fragment length polymorphism
the same and adopt the strategy for clinical use in different [RFLP] types of M. avium have been found to be more
geographical settings. commonly isolated from patients with AIDS (62,108).

Figure 41.1: Host defence mechanisms against NTM. Defects leading to disseminated nontuberculous mycobacterial infection are shown in red
ISG15 = interferon-stimulated gene 15; IFNGR = interferon-gamma receptor; TYK = tyrosine kinase; JAK = Janus kinase; STAT = signal transducer
and activator of transcription; IRF = interferon regulatory factor; GATA = transcription factor implicated in early haemopoietic, lymphatic, and
vascular development; NEMO = nuclear factor kappa-light-chain-enhancer of activated B cells essential modulator; IL = interleukin; TNF = tumour
necrosis factor; TLR = toll-like receptors.
Reproduced with permission from “Wu UI, Holland SM. Host susceptibility to non-tuberculous mycobacterial infections. Lancet Infect Dis
2015;15:968-80 (reference 104)”
 Nontuberculous Mycobacterial Infections 545

Figure 41.2: Stepwise approach to diagnosis of patients with DNTM infection

DNTM = disseminated nontuberculous mycobacterial; IFN = interferon; IL = interleukin; CBC = complete blood count; NK = natural killer;
IFNGR = interferon gamma receptor; IKBKG = X-linked IKK-γ gene; CYBB = encodes the gp91pox submit of the phagocyte nadph oxidase;
pSTAT1 = phosphorylated STAT1; NADPH = nicotinamide adenine dinucleotide phosphate; STAT = signal transducer and activator of
transcription; Reproduced with permission from “Wu UI, Holland SM. Host susceptibility to nontuberculous mycobacterial infections. Lancet Infect
Dis 2015;15:968-80 (reference 104)”

Table 41.3: Localised clinical diseases due to NTM

Type of lesion Species
Pulmonary disease Common: M. avium complex, M. abscessus, M. kansasii, M. malmoense, M. xenopi
Uncommon: M. chelonae, M. fortuitum, M. haemophilum, M. celatum*, M. asiaticum*, M. scrofulaceum,
M. shimoidei*, M. simiae, M. smegmatis, M. szulgai
Lymphadenopathy Common: M. avium complex, M. scrofulaceum, M. malmoense
Uncommon: M. genavense, M. haemophilum, M. chelonae, M. abscessus, M. fortuitum, M. kansasii, M. szulgai
Skin, soft tissue, Common: M. marinum, M. ulcerans, M. chelonae, M. fortuitum, M. abscessus
wound infections, bone Uncommon: M. avium complex, M. haemophilum, M. mucogenicum, M. nonchromogenicum, M. kansasii,
disease M. malmoense, M. smegmatis, M. szulgai, M. terrae complex, M. immunogenum
Specimen contaminant M. gordonae, M. haemophilum, M. mucogenicum, M. nonchromogenicum, M. terrae complex
Crohn’s disease M. avium subsp. paratuberculosis
* Details regarding these species are available in the online supplement to reference
NTM = nontuberculous mycobacteria

Table 41.4: Disseminated disease due to NTM

Condition Species
Disseminated disease Common: M. avium complex, M. chelonae, M. haemophilum, M. kansasii*
Uncommon: M. abscessus, M. celatum†, M. conspicuum†, M. fortuitum, M. genavense, M. immunogenum,
M. malmoense, M. marinum, M. mucogenicum, M. scrofulaceum, M. simiae, M. szulgai, M. xenopi
Without AIDS [usually M. avium complex, M. kansasii, M. chelonae, M. scrofulaceum, M. fortuitum including members of M. fortuitum
transplant patients, third biovariant complex-M. boenickei, M. houstonense, M. neworleansese, M. brisbanense, M. porcinum and
leukaemia, etc.] M. parascrofulaceum, M. septicum, M. canariasense closely related to M. diernhoferi, M. haemophilum
With AIDS M. avium complex, M. haemophilum, M. simiae, M. xenopi, M. kansasii, M. fortuitum-chelonae complex,
M. genavense, M. malmoense, M. celatum, M. conspicuum
* M. kansasii lung disease is similar to that caused by Mtb and responds to rifampicin, isoniazid and ethambutol
† Details regarding these species are available in the online supplement to reference
NTM = nontuberculous mycobacteria; AIDS = acquired immunodeficiency syndrome; Mtb = Mycobacterium tuberculosis
546 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

As compared to M. intracellulare, M. avium appears to have to determine the presence of this slowly growing pathogen
a greater predilection for causing disease in patients with in clinical samples by various molecular techniques even
AIDS (62). Further, these organisms may cause mixed in a small laboratory setting. Literature suggests that like
infections along with other NTM, such as M. kansasii (106) M. avium, this pathogen is an established aetiological agent
and M. simiae (107), among others. of pulmonary disease (125-127), further its involvement in
Infections caused by MAC were commonly observed in pathogenesis of cutaneous infection (128), thymoma (129)
chronic bronchitis, bronchiectasis and chronic obstructive and disseminated disease (130) has been reported.
air-ways disease in the pre-AIDS era in geriatric patients.
In non-HIV patients, M. avium has been associated with M. colombiense
pulmonary disease, lymphadenitis and joint involvement (11). M. colombiense, a slowly growing NTM species developing
Unlike Mtb, the MAC strains have a low virulence and pigmentation over two weeks of incubation (131), is a new
despite being commonly found in the environment rarely member of MAC which has been identified to be a human
cause disease (64,113). These usually produce clinical disease pathogen. After the first report of infection by this species
only when the CD4+ T-cell count is very low [< 50 cells/mm3] in HIV-seropositive individuals in Colombia (19), it has also
towards the end of natural history of disease, seen in 4%-5% been isolated from an immunocompetent patient suffering
of HIV/AIDS patients (61). MAC strains isolated from with lymphadenitis (120). Recently, it was associated with
patients with AIDS in Africa have been shown to be different the outcome of defects in IFN-γ/IL-12 costimulatory axis
as compared with western strains (62). In AIDS patients, the of a 49-year-old Canadian woman who died due to fatal
portal of entry is thought to be mainly through the gut (64) pneumonia and disseminated infection. Perhaps, this was the
and the most common presenting features include persistent first report that showed the role of anti-IFN-γ autoantibodies
high-grade fever, night sweats, anaemia and weight loss in the NTM-associated death (132).
in addition to non-specific symptoms of malaise, anorexia,
diarrhoea, myalgia and occasional painful adenopathy. M. chimaera
On examination, there may be hepatomegaly and chest
radiograph as well as computed tomography [CT] of the M. chimaera is another potential human pathogen recently
chest and abdomen may show a widespread intrathoracic included as a species in MAC by virtue of its greater
and intra-abdominal lymphadenopathy. The diagnosis is genetic similarity with M. avium. It shows full resistance
generally not difficult as clinical specimens yield numerous to ethambutol and can easily be differentiated from
acid–fast bacilli [AFB] which can be cultured and identified. other members of MAC by high-performance liquid
chromatography [HPLC]-mycolic acid patterns and other
M. avium subsp. paratuberculosis molecular markers (133). The clinical data revealed its
greater occurrence in respiratory as well as non-respiratory
MAP subspecies is closely related to M. avium and has samples taken from elderly people suffering with a wide
characteristic property of dependence on mycobactin J. This range of underlying diseases including bronchiectasis,
organism has been reported to be causative organisms of COPD, pulmonary cavitation, diabetes and non-Hodgkin’s
enteritis [Johne’s disease] in cattle, goats and sheep and can lymphoma (133-135). In addition, isolation of this slowly
be characterised rapidly with molecular techniques (114,115). growing and unpigmented bacillus from respiratory tract
With the help of gene probes, strains belonging to this of children with underlying cystic fibrosis highlights its
subspecies have been linked to aetiology of Crohn’s disease expanding clinical domain (136). M. chimaera infection has
in man (115). Demonstration of specific sequences in tissue also been reported to be the possible cause of death of
sections by in situ hybridisation has provided a strong patients suffering with prosthetic valve endocarditis and
evidence of an aetiological relationship of this mycobacterium bloodstream infection (137). A retrospective hospital-based
with Crohn’s disease (116). study (138) from Germany showed that M. chimaera was the
most frequent isolate in MAC-positive clinical specimens
M. avium subsp. hominissuis analysed between the years 2002 and 2006. Overall data
regarding the isolation of M. chimaera from environmental
M. avium subsp. hominissuis is a new opportunistic myco­ sources and animals are very limited.
bacterial pathogen (117) found to be associated with lympha­
denitis in children (118-120), pulmonary disease (121,122) Mycobacterium kansasii
and AIDS (123). Pigs and slaughtered cattle are considered
the potential sources of this NTM species in addition to M. kansasii are found in water and consequently in
human (124). some sputum samples as non-significant commensals.
Nevertheless, when repeatedly isolated from sputum they
could be associated with pulmonary disease (11). Since
M. intracellulare
long time, M. kansasii has been considered an important
Before molecular era, the clinical disease caused by this cause of pulmonary disease (3,11) and has become even
NTM pathogen was possibly wrongly estimated due to close more important in AIDS era (106,139-142). Although
phenotypic similarity with M. avium. But, now it is possible in vitro susceptibility tests suggest that members of these
 Nontuberculous Mycobacterial Infections 547

species are more resistant to antimicrobial agents than Mtb, samples, however, not all clinical isolates had association
M. kansasii disease frequently responds well to multiple with disease. Southwestern United States and Middle East
drug therapy (6,141,142). New biotypes of M. kansasii have were thought to be most affected parts of the world with
been isolated from patients with AIDS (140). As with MAC this pathogen although its fatal clinical consequence was
infections, these patients may present with advanced AIDS reported around the globe (164-170).
with very low CD4+ T cell count [< 50 cells/mm3].
M. triplex
M. scrofulaceum
Before being recognised as a separate taxon, M. triplex was a
The distribution of these pigmented organisms in nature member of “simiae-avium group”[SAV] (171). The first case
is similar to that of M. avium and MAC (143). The most of its pathologic involvement was reported in 2000 when
common disease caused by these organisms is cervical M. triplex associated disseminated disease was reported in
lymphadenitis in children as well as chronic ulcerative and a 40-year-old HIV-seropositive individual (172). M. triplex
nodular lesions (11). It may cause adult pulmonary disease has been found to be a cause of both disseminated (172,173)
and disseminated infections in patients with AIDS (11,143). and pulmonary disease (174) in both immunodeficient and
immunocompetent people.
M. interjectum
The first report on pathogenic behaviour of M. interjectum M. genavense
appeared in 1993 when a German group isolated this M. genavense was isolated for the first time from patients with
organism from an 18 months old boy with chronic lympha­ AIDS (16). Later, these have been emerged as major cause of
denitis (144). Later on, this scotochromogenic and smooth disseminated infections in AIDS survivors (175-177). These
colony-forming NTM has been found to be causative organisms are grown with difficulty and need enrichment
agent of disease involving lung (145,146), intestine (147), with mycobactin J. It grows in liquid media, often after
skin (148) and brain (149) of both immunocompetent prolonged incubation periods (16,178,179). Patients are
and immunocompromised AIDS individuals. This micro­ usually in advanced stage of AIDS and present with weight
organism has been found to be a major cause of lympha­ loss, fever, abdominal pain and diarrhoea. This organism has
denitis of cervical and submandibular glands mainly in
been found to be sensitive to clarithromycin.
children (150,151).
M. lentiflavum
M. xenopi
M. lentiflavum was first recovered from a panel of clinical
M. xenopi is an unusual bacterium with optimal growth
samples in 1996 (180) and later characterised as a potential
temperature at 45oC. It has been reported as a pathogen
human pathogen causing lung infection (181), lympha-
in patients with other underlying lung diseases (152-154).
denitis (182,183) and disseminated infections (184).
It has been isolated from hot water reservoirs of hospitals
and has been found to be associated with various clinical
problems (11,152,153). Clinical manifestations are similar
M. heidelbergense
to MAC in patients with advanced AIDS. An outbreak of M. heidelbergense has been recognised as an aetiological agent
pulmonary disease due to this organism from hot water of cervical lymphadenitis in children (185). Its association
supply of a hospital has been reported (11). with lung disease has also been documented (186).

M. simiae Complex M. parascrofulaceum

M. simiae complex is a fast-expanding NTM group and M. parascrofulaceum is a rare opportunistic pathogen and as
so far comprises nine genetically close species M. simiae, of now limited information about its clinical relevance is
M. triplex, M. genavense, M. lentiflavum, M. heidelbergense, available. It has been isolated from AIDS patients as well as
M. parascrofulaceum, M. florentinum, M. europaeum and some other forms of pulmonary disease in non-AIDS patients
M. stomatepiae. with underlying bronchiectasis, epidermoid carcinoma,
COPD and emphysema (187,188). This species has also been
M. simiae considered as an agent of cutaneous (189) and chronic pelvic
pain (190) in normal individuals. This mycobacterium was
M. simiae, a niacin-positive mycobacterium, was initially
isolated for the first time from an Indian woman with a past
isolated from a monkey in 1965 (155) and later recognised
history of TB who had immigrated to Canada in 1999 (191).
as a causative agent of pulmonary infection (156-159),
lymphadenitis (160) and disseminated disease (161-163). This
M. florentinum
has been reported to be a causative agent in AIDS as well as
non-AIDS patients. Like other NTM, it is less prevalent in M. florentinum first described in 2005, has been isolated from
environment and most of its isolation occurred from clinical various clinical specimens like sputa, stool and lymph node
 548 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

derived from patients with known respiratory diseases and about its pathogenic behaviour in human subjects, so far
lymphadenopathy (192). There are only two recent reports this has been found to be causative organism of chronic
which described its opportunistic nature in developing the osteomyelitis in a 71-year-old man (222).
human infections (193,194).
M. senuense
M. europaeum
M. senuense is a new inclusion in M. terrae complex. It was
M. europaeum is a recently discovered mycobacterium added isolated from a Korean patient with symptomatic pulmonary
to the M. simiae complex (195). This mycobacterium has infections (223).
been associated with pulmonary infection in people with
underlying AIDS and cystic fibrosis (196). M. arupense
M. arupense is an emerging human pathogen with varied
M. terrae Complex
clinical manifestations. It has been reported to cause infec­
In classifications dating back to the 1970s, M. terrae complex tions not only in immunocompromised AIDS patients (224)
included three species M. terrae, M. nonchromogenicum and but also osteomyelitis (225), tenosynovitis (226) and lung
M. triviale. After addition of eight new members namely disease (227) with or without underlying complications in
M. longobardum, M. engbaekii, M. heraklionense, M. algericum, immunocompetent individuals.
M. senuense, M. arupense, M. kumamotonense and M. hiberniae
to this complex, the total number of species included in M. kumamotonense
M. terrae complex has now reached 11.
M. kumamotonense was initially isolated from Japanese
patients (228) but subsequently it was isolated from a
M. terrae
Paraguayan HIV-positive patient with established extra­
M. terrae was initially considered as an environmental pulmonary disease (229).
saprophyte (197). However, over the years, this mycobactin-
dependent Runyon group III species has appeared as a M. marinum
significant cause of number of infections including lung
infection (198,199), tenosynovitis (200,201), knee arthritis (202), M. marinum has been recognised as a causative organism
knee sepsis (203), occurrence of sepsis during sickle of “swimming pool granuloma” or fish tank granuloma.
cell disease (204), recurrent skin abscesses (205), lympha­ It causes papular lesions in the extremities and may be
denitis (206) and disseminated disease (207). Infection confused with sporotrichosis (3,4,230-232). This has also been
in renal transplant recipients has also been found to be reported as a cause of infections of hands and wrist (231)
associated with this organism (208). During in vitro testing, and bones, joints and tendon sheaths, especially in patients
the organism was susceptible to rifampin (209). with AIDS (232).

M. nonchromogenicum M. szulgai
M. nonchromogenicum was first isolated from Japanese M. szulgai species has been isolated on several occasions
soil (210). The characteristic features of this NTM entity from patients with pulmonary disease. It is confused often
include intermediate growth on solid media and lack of with some of the scotochromogenic mycobacteria. This
pigmentation. This is usually a harmless microorganism but organism is also been associated with disseminated disease
in some cases it was found to be pathogenic and associated and also involves skin, joint and lymph nodes (233). These
with infections of intestine (211), tendons of hand and mycobacteria have been isolated from India also (48,49).
wrist (212,213), lung (214,215) and eye (216).
M. haemophilum
M. triviale During the recent years this mycobacterium has emerged as an
M. triviale was isolated from normal individuals in 1970s (217) important human pathogen (234-238). This slowly growing
and till that time this species was not reported to be asso­ organism has been recognised as a cause of life-threatening
ciated with disease. Subsequently, this has been reported infections in immunocompromised individuals, like AIDS,
from a few clinical cases, including septic arthritis (218,219), bone marrow transplant recipients. The organism has been
peritonitis (220) and keratitis (216). isolated from the skin lesions, lymph nodes, synovial fluid,
vitreous fluid, bronchoalveolar lavage [BAL] fluid, bone
marrow aspirate and blood. Recovery of this organism
M. longobardum
requires cultivation in enriched chocolate agar or haemin
M. longobardum is recently described NTM species isolated or ferric ammonium citrate supplement and incubation at
from clinical samples, showing rough and unpigmented 30°C up to eight weeks. Information about its environmental
colony at solid media during 7-14 days culture period and reservoirs and spread is limited. Despite aggressive therapy
negative niacin tests (221). There is insufficient clinical data with multiple anti-TB drugs, the recurrence is common.
 Nontuberculous Mycobacterial Infections 549

M. fortuitum Group post-mammaplasty infections (283) and postoperative sternal

osteomyelitis (284).
M. fortuitum group is a cluster of total 13 genetically
close rapidly growing NTM species including members
M. septicum
of a M. fortuitum third biovariant complex, M. fortuitum,
M. peregrinum, M. senegalense, M. mageritense and This rapidly growing mycobacterium has been found to be
M. conceptionense. M. fortuitum third biovariant complex associated with pulmonary disease (285), pneumonia (286)
con­sists of M. boenickei, M. houstonense, M. neworleansense, and central line sepsis (287).
M. brisbanense, M. porcinum and M. septicum.
M. conceptionense
M. fortuitum
M. conceptionense has been isolated for the first time
M. fortuitum is a widely distributed NTM species first from a 31-year-old woman having post-traumatic osteitis
isolated from a human abscess in 1938 by da Costa Cruz (15). infection (288) and later this NTM has been associated
With very high frequency of recovery from clinical samples with pulmonary and extrapulmonary infections (289,290),
studied so far, this human pathogen is ubiquitous in nature subcutaneous abscess (291) and postoperative sepsis (292).
and found usually in water, soil and dust (15). This has
emerged as an important cause of community acquired or M. mucogenicum
health-care associated diseases and outbreaks (239-243). This
M. mucogenicum is a non-pigmented rapidly growing
has been associated with localised cutaneous and soft tissue
mycobacterium showing higher degree of susceptibility to
infections (244-249), lymphadenitis (250,251), peritonitis (252),
a number of antibiotics, such as, amikacin, clarithromycin,
keratitis (253,254), endocarditis (255,256), meningitis/ imipenem, trimethoprim-sulfamethoxazole, linezolid,
meningoencephalitis (257,258), hepatitis (259,260) and cefoxitin, ciprofloxacin and doxycycline. This mycobacterium
catheter-related infection (261,262) has also been reported. has emerged as an important human pathogen and causes
Disseminated infections due to this opportunistic pathogen varied types of opportunistic infections mostly due to
are uncommon (263). After M. abscessus, it is the second contaminated hospital water and health-care products. Its
most common species recovered from pulmonary infections frequent isolation has been reported from the patients having
caused due to rapidly growing mycobacteria (47,264-266). post-organ transplantation (293), post-cosmetic surgery (294),
Pulmonary infection usually occurs secondary to aspiration. bloodstream infections (295-298), peritonitis (299), pulmonary
disease (168), cutaneous infection (300), catheter-related
M. peregrinum infection (301), central nervous system infection (302),
M. peregrinum was first described in 1962. It is a rare cause Münchausen syndrome (303) and disseminated infection (304).
of disseminated infections and only two cases of its kind
have been reported so far (267,268). This pathogen has M. senegalense
been associated with infections of lung (269,270), skin M. senegalense has been associated with catheter-related
and soft tissue (271,272) and cervical lymph node (273) in sepsis (305) as well as tissue infection (306).
addition to health care-related injection site and post-surgical
infections (274,275). M. mageritense
M. fortuitum Third Biovariant Complex M. mageritense, a non-pigmented mycobacterium, is an
occasional cause of infections in human. There are some
M. fortuitum third biovariant complex came into existence by reports which showed the association of this pathogen
the work of Bönicke in 1966 (276). Members of this complex to meningitis (307), bloodstream infection (308) and
are clinically important and mainly associated with skin furunculosis (309).
and soft tissues infections, traumatic injuries (277) and post-
surgical infections (278). Currently, very little data regarding M. abscessus
clinical significance of newly added members of this complex
except M. porcinum and M. septicum are available. M. abscessus is a rapidly growing and non-chromogenic
environmental mycobacteria dwelling primarily in domestic,
municipal and hospital water supply systems, soil and
M. porcinum
decaying vegetations. Its initial isolation was reported from
M. porcinum has been isolated from a variety of clinical a patient’s knee abscess in 1953 (310). In subsequent years,
samples, such as sputum, thigh and leg wound, inguinal this organism has been considered as a life-threatening
node and lung biopsy derived from Australian and American pathogen with worldwide occurrence. To date, this organism
peoples (279). This pathogen has been reported as a cause has been linked with a wide variety of diseases producing
of pulmonary infections (280,281) in AIDS and non-AIDS serious to moderate clinical consequences and many
patients with some underlying conditions, such as, prior TB global outbreaks mainly in the United States (39,311-318).
and bronchiectasis. In some cases, it causes peritonitis (282), By virtue of its ability to grow at normal human body
550 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

temperature, it causes deadly pulmonary disease not only EMERGING NEW MYCOBACTERIAL PATHOGENS
in immunocompromised AIDS patients (319) but also
Several species of NTM have been isolated from AIDS
in immunocompetent people (320,321) with underlying
patients over several years. Besides M. genavense (16), other
diseases, such as, bronchiectasis, cystic fibrosis and prior
species isolated for the first time from AIDS patients include:
granulomatous diseases, such as TB. Clinical data showed
M. celatum (17), M. conspicuum (18) and M. colombiense (19).
that this pathogen is responsible for major proportion
Other mycobacteria rarely associated with disease are:
of rapidly growing mycobacterial [RGM] pulmonary
M. smegmatis (363-365), M. thermoresistibile (366-369),
disease (322) and after MAC, it is second most common NTM
M. neoaurum (370,371) and M. vaccae (372). Due to wider
species isolated from pulmonary patients suffering with
use of gene sequencing using 16S ribosomal ribonucleic
cystic fibrosis (323). Clinical findings also revealed that about
acid [rRNA], rpoB, these days several new species have
20% of MAB-infected people may also develop MAC diseases
been identified which were earlier missed as variants of
in their whole lifespan (322). Moreover, its frequent recovery
known species. Within one decade (2,13) the number of
from almost all clinical samples made this pathogen second
identifiable distinct species has doubled. Some of them
most common NTM pathogen reported after M. fortuitum (15).
have been found to be the cause pronounced human
Besides, this mycobacterial species has largely been
infections. These newly identified pathogens have been
associated with many other community acquired, health
isolated from a variety of conditions such as cutaneous, soft
care- and hygiene-associated diseases which involve skin,
tissue and wound infections, from patients with pulmonary
soft tissue, bone, eye and heart (14,15,324,325). This species
disease, lymphadenitis, bacteraemia, febrile conditions
has been reported to be responsible for outbreaks mainly
and disseminated disease. The exact importance of these
associated with interventions like injections (313,315,316).
potential pathogens in the causation of diseases will be
Studies from India (39,44,326-329) have also reported the
better known with routine use of modern techniques for
isolation of this pathogen from a wide variety of clinical
molecular characterisation in different parts of the world.
samples. It also shows complete resistance to all common
The emerging human NTM pathogens are described in
anti-TB drugs.
Table 41.5. Several among them, namely, M. phlei, M. asiaticum,
M. aurum, M. gordonae, M. gastri, etc. have been taxonomically
M. chelonae
identified long back but were considered as saprophytes.
M. chelonae is an established cause of localised infections in Most others have been identified in recent past. It would be
both immunocompetent and immunosuppressed humans important to carefully analyse the pathogenic importance
and has largely been associated with skin and soft tissue of all of these species in the context of emerging evidence
infections (330-335). Additionally, it has caused a wide variety of their association with disease. It would be appropriate to
of infections including disseminated disease (336), cardio­ adopt and open but careful approach.
vascular infections (337,338), parotitis (339), osteomyelitis
(340,341), keratitis (342), peritonitis (343), arthritis (344), CLINICAL MANIFESTATIONS
nodular lymphangitis (345) and catheter-related bacter-
aemia (346). This pathogen has also been recovered from NTM have been reported to be associated with varied
patients with multiple clinical presentations (332,347,348). clinical manifestations (3,4-8,11). In non-HIV patients,
M. chelonae is occasionally associated with NTM pulmonary NTM has been established to be responsible for pulmonary
infection (349,350) and solitary rectal ulcer (351). disease usually with some local predisposing conditions,
lymphadenitis, soft tissue infections, infections of joints
and bones, bursae, skin ulcers and generalised disease in
M. malmoense
individuals like leukaemia, transplant patients, among
M. malmoense (352-359) has emerged as another important others (3,4,11,373). In patients with AIDS the spectrum
pathogen which has not been isolated from the environ- of clinical involvement may depend upon the degree of
ment (113). This Mycobacterium has been associated with immune deficiency and the manifestations may range
disease in HIV (353), chronic granulocytic leukaemia (354), from localised pulmonary to intestinal and disseminated
skin disease (355), pulmonary disease (356), cervical disease (11,374-376). Most of the NTM can be associated with
abscess (357), bursitis (358) and disseminated disease. both the localised and generalised disease depending upon
Some of these infections occurred in immunocompetent degree of immune deficiency or local favourable conditions
individuals (355,357,359). for their establishment and growth.

M. ulcerans DIAGNOSIS
M. ulcerans has been established as an important skin Diagnosis of the disease due to NTM depends upon the
pathogen for a long time (3,4,360-362). This pathogen degree of suspicion and strict laboratory practices [Table 41.6].
was well known as a cause of Buruli ulcer in Africa (3,4), The algorithm for the diagnosis of NTM infections is
however, the skin infections caused by it are now being shown in Figure 41.3. Due to ubiquitous presence of these
reported from other countries such as Japan (361). organisms in the environment, it is extremely important to
 Nontuberculous Mycobacterial Infections 551

Table 41.5: The emerging human nontuberculous rule out contamination. At present, most of the experience
mycobacterial pathogens is based on published findings from western countries and
there is a general tendency of discarding these isolates as
M. abscessus subsp. abscessus M. heckeshornense
contaminants. These issues have been extensively debated
M. abscessus subsp. bolletii M. hodleri
and some broad guidelines have emerged (11,12,14).
M. abscessus subsp. massiliense M. holsaticum
M. alvei M. intermedium Pulmonary Disease
M. arosiense M. iranicum
Clinical presentation of the disease due to NTM may be
M. asiaticum M. kyorinense
like TB and pulmonary infections may present as chronic
M. aurum M. llatzerense
cough and infiltrates in the chest radiographs [Figures 41.4A
M. austroafricanum M. mantenii
and 41.4B]. Infection due to NTM should be suspected,
M. bacteremicum M. monacense especially in patients in whom initial anti-TB treatment has
M. bohemicum M. nebraskense not produced clinical, radiographic and microbiological
M. branderi M. novocastrense response. Sputum should always be sent for smear and myco­
M. brisbanense M. palustre bacterial culture examination. If the cough is non-productive,
M. brumae M. paraffinicum bronchoscopy, and diagnostic testing of bronchial brushings,
M. canariasense M. parakoreense
washings, aspirate, BAL and bronchoscopic biopsy material
is indicated. NTM infection may be asymptomatic or may
M. celatum M. phlei
present as a subacute or chronic illness. Symptoms include
M. cosmeticum M. phocaicum
cough, sputum production, weight loss, haemoptysis,
M. doricum M. poriferae shortness of breath, malaise, pleuritic chest pain, low-grade
M. farcinogenes M. rhodesiae fever and night sweats. Radiographic appearances are similar
M. flavescens M. riyadhense to TB with cavities and infiltrates; though the upper lobes
M. fortuitum subsp. acetamidolyticum M. saskatchewanense are more involved and the distribution is more variable
M. frederiksbergense M. setense than TB. Thin-walled cavities with lesser parenchymal
M. gastri M. sherrisii infiltrates have been described as a suggestive feature (11).
M. goodii M. shimoidei
The changes may be unilateral or bilateral and more than
one lobe may be involved. In high-resolution computed
M. gordonae M. shinjukuense
tomography [HRCT], clusters of small nodules associated
M. hassiacum M. tokaiense
with areas of bronchiectasis in the lower and middle zones

Table 41.6: Clinical and microbiological criteria for diagnosing NTM lung disease*
Clinical [both required]
i. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows
multifocal bronchiectasis with multiple small nodules [A, I]* and
ii. Appropriate exclusion of other diagnoses [A, I]*
Microbiologic
i. Positive culture results from at least two separate expectorated sputum samples [A, II]*. If the results from [i] are non-diagnostic,
consider repeat sputum AFB smears and cultures [C, III]* or
ii. Positive culture result from at least one bronchial wash or lavage [C, III]* or
iii. Transbronchial or other lung biopsy with mycobacterial histopathologic features [granulomatous inflammation or AFB] and positive
culture for NTM or biopsy showing mycobacterial histopathologic features [granulomatous inflammation or AFB] and one or more sputum
or bronchial washings that are culture positive for NTM [A, II]*
iv. Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent
environmental contamination [C, III]*
v. Patients who are suspected of having NTM lung disease but do not meet the diagnostic criteria should be followed until the diagnosis is
firmly established or excluded [C, III]*
vi. Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential
risks and benefits of therapy for individual patients [C, III]*
* Evidence quality as stated in online supplement of reference 14
NTM = nontuberculous mycobacteria; AFB = acid-fast bacilli
Reprinted with permissions of The American Thoracic Society. Copyright © 2019 American Thoracic Society, Griffith DE, Aksamit T, Brown-
Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An Official ATS/IDSA Statement: Diagnosis, treatment, and prevention of nontuberculous
mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416. An official Journal of The American Thoracic Society.
 552
Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 41.3: Diagnostic algorithm for NTM disease

* Three consecutive sputum samples are obtained; positive results from at least two separate expectorated sputum samples confirm the diagnosis (reference 14). They may appear as Gram-
positive beaded rods [if organism burden is high]
† While sputum collection, the patient should not rinse mouth with municipal or untreated water. Spontaneous sputum should be collected or sputum should be induced if no sputum is produced
by patient
‡ Common mycobacteria and additional species [CM/AS] is a strip-based reverse hybridisation technique in which 17 common mycobacterial and 17 additional mycobacterial species can be
identified
§ These are target genes proposed for taxonomic identification of NTM due to their conserved nucleotide sequences. The sequencing hsp65 and ITS genes has been widely accepted but for
accurate identification multigene target approach has been recommended
NTM = nontuberculous mycobacteria; HRCT = high-resolution computed tomography; CSF = cerebrospinal fluid; ICA = immunochromatographic assay; CBNAAT = cartridge based nucleic
acid amplification test; LJ = Lowenstein–Jensen media; HPLC: high performance liquid chromatography; SGM: slowly growing mycobacteria: RGM: rapidly growing mycobacteria; DST: drug
susceptibility testing; LPA: line probe Assay; PNB: para-nitro benzoic acid; PCR/PRA: polymerase chain reaction/restriction endonuclease assay; MAC: mycobacterium avium complex; MALDI-
TOF MS: matrix-assisted laser desorption ionization- time of flight mass spectrometry
 Nontuberculous Mycobacterial Infections 553

A1 A2
Figure 41.4A: Chest radiograph [postero-anterior view] [A1], CT chest [A2] showing destroyed left upper lobe.Sputum culture grew M. intracellulare
CT = computed tomography

B1 B2
Figure 41.4B: Chest radiograph [postero-anterior view] [B1] showing bilateral parenchymal lesions in the paracardiac region. CECT chest [lung
window] [B2] of the same patient showing parenchymal lesions in the medial segment of the middle lobe on the right side and lingula on the left
side. Sputum culture from two separate specimens grew Mycobacterium intracellulare. The patient was successfully treated with drug regimen
consisting of clarithromycin, rifampicin and ethambutol
CECT = contrast-enhanced computed tomography

are common. Asymptomatic solitary nodules due to MAC mycobacteria and, if required, determine their sensitivity
have been documented. Pleural thickening and effusion are profile.
not common. The gold standard for NTM disease compared
to colonisation is a tissue biopsy showing granulomatous Specimens
inflammation, which may or may not contain AFB and a
positive culture, even if the sample is smear-negative. Because NTM are widely distributed in the environment
and may be merely present as colonising agents on the skin
and mucous membranes, proper sample collection is very
Other Clinical Forms
important. In patients with suspicion of NTM pulmonary
Most of other manifestations should be considered in the disease, the sputum collection should be done very carefully
differential diagnosis of any chronic infection, pyrexia of avoiding any environmental contamination. Prior to sputum
unknown origin and localised clinical disease [abscess, collection, patients should not rinse mouth with municipal
ulcers, nodules, infiltrates, etc.] not responding to antibiotics or untreated water and if the rinsing is required, sterilised
[Figures 41.5, 41.6, 41.7, 41.8, 41.9A, 41.9B and 41.10]. water should be used. The specimen should be obtained
Attempts should be made to demonstrate and isolate the directly from the lesion or organ concerned (11). It is
NTM from such lesions using most stringent criteria and recommended to attempt repeated isolation in significant
precautions. numbers to firmly link the isolate with the aetiology. Further,
As most of the NTM are not sensitive to routine anti-TB the decontamination has to be gentler than Mtb. In case
drugs, it is imperative to correctly identify the causative of disseminated infections, such as in patients with AIDS,
 554 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 41.5: Clinical photograph [A], MRI [B] showing discharging sinus in the abdominal wall [arrow] in a patient following left inguinal hernia
repair with mesh. Culture grew M. abscessus
MRI = magnetic resonance imaging

Culture
There has been a considerable progress in developing
and evaluation of methods for isolation of NTM from
environment as well as clinical specimens (11,379-388). As
these mycobacteria may be susceptible to decontaminating
procedures like sodium hydroxide [NaOH] treatment (379),
approaches like paraffin bating such as paraffin-coated
slides become attractive option (380,381). Most of these
mycobacteria are easy to cultivate and these can be grown
on ordinary media for mycobacteria like Lowenstein-Jensen,
Middle- brook and Dubos Broth, and Agar (11,380,384).
Organisms like M. haemophilum may have special
requirements like haemin for which blood containing
A B media-chocolate agar or supplement of ferric ammonium
Figure 41.6: Clinical photograph [A] showing sinuses over the left
citrate may be required. Various radiometric systems
knee joint and lateral aspect of upper left thigh. [B] MRI of the same [e.g., BACTEC] (382,383,386); non-radiometric methods
patient showing intramedullary collection [thick arrows] suggestive of like mycobacteria growth inhibitor tube [MGIT] and
chronic osteomyelitis of left femur, soft tissue collection [thin arrow]. MB/BacT (387,388) or liquid media like 13A or BACTEC 12B
Left sided hip and knee joint involvement is also evident. Pus culture broth medium (60) as well as agar-based isolation systems
grew M. abscessus
MRI = magnetic resonance imaging
have been described to be highly sensitive [up to 96%-98%]
for MAC and other NTM (3,4,11,110,377,378,382-388).
Pyruvate-containing medium may be necessary for growth
of M. bovis or bacille Calmette-Guerin [BCG] (385).
blood cultures have been shown to yield positive cultures.
Diagnosis of MAC disease is established by growing the M. genavense, M. paratuberculosis will require supplementa­
mycobacteria from the peripheral blood or bone marrow tion with mycobactin J. Different incubation temperatures
sample (377,378). such as 30°C for M. ulcerans and M. marinum, 37°C for most
pathogens, 45°C for M. xenopi, etc. will have to be selected
Histopathology depending upon the suspected organisms.

Histopathological examination of bone marrow, liver or Identification of Isolates

lymph nodes [aspirates or biopsy] showing granuloma may
be helpful in the diagnosis, the greatest advantage of this The first scheme for identification and grouping of cultivable
approach over the culture being the speed (105). It may be mycobacteria was based on growth rates and colony
advisable to include some in situ methods [antigen detection pigmentation. Since the days of Runyon, it is conventional
and gene probes] to confirm the histological diagnosis to initially classify the organisms as rapid and slow
straightaway. growers (384).
 Nontuberculous Mycobacterial Infections

A B
Figure 41.7: FDG PET-CT images of the same patient in Figure 41.6, showing increased tracer accumulation in the head of left femur [A] and along the
entire length of femur extending up to the condyles [B] suggesting osteomyelitis of the entire left femur
FDG = 18F labelled 2-deoxy-D-glucose; PET = positron emission tomography; CT = computed tomography
555
 556 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

A B
Figure 41.8: Clinical photograph [A], MRI [B] [arrow] showing right-sided post-injection gluteal abscess in a patient with NTM infection
MRI = magnetic resonance imaging; NTM = nontuberculous mycobacteria

Figure 41.9A: Transaxial fused FDG PET-CT image of the same patient in Figure 41.7, at the level of acetabulum showing FDG accumulation
in the subcutaneous thickening and stranding [arrow] involving the underlying right gluteus muscle superficially in right gluteal region
FDG = 18F labelled 2-deoxy-D-glucose; PET = positron emission tomography; CT = computed tomography

Biochemical Tests tests can usually identify a strain to clinical satisfaction.

These common tests are: niacin production, nitrate reduction,
After classifying the mycobacteria on the basis of growth and tween-80 hydrolysis, arylsulphatase, urease, and catalase
pigmentation, most of the mycobacteria can be identified by [qualitative and quantitative] production, tellurite reduction,
biochemical tests (384). A few simple biochemical and culture thiophene-2-carboxylic acid hydrazide sensitivity, growth on
 Nontuberculous Mycobacterial Infections 557

Figure 41.9B: Clinical photograph showing left-sided orbital cellulitis, cavernous sinus thrombosis [upper panel left] and pinna involvement
[upper panel right]. MRI head of the same patient showing left-sided seventh nerve involvement, mastoiditis, apex of the petrous bone involvement
[arrow] [lower panel left]; and meningitis [lower panel right]
MRI = magnetic resonance imaging

MacConkey agar, para-nitrobenzoic acid Lowenstein-Jensen to serotypes. Some serotypes (11,377) of M. avium have been
medium [PNB-LJ] medium, sodium chloride tolerance, shown to be preferentially associated with disease in patients
among others (384). with AIDS.
Isoenzyme and protein electropherograms Simple electro­
Lipid Patterns phoretic techniques and schemes based on electrophoretic
Mycobacteria can be characterised at group and species from mobilities of proteins and isoenzymes for the characterisation
analysis of their cell wall lipids by thin layer chromatography of strains of Mtb and NTM have been developed which can
and HPLC. These techniques are simple and have been be used to confirm identity of the isolate rapidly (390-392).
developed along with easy software programmes for rapid These patterns may be used both for rapid identification and
analysis (385,386) by which isolates from liquid and solid characterisation of these mycobacteria (392).
media can be rapidly identified.
Measurements of immunological relatedness Based on
divergences in the structure of certain enzymes, such as,
Identification Techniques for Established, catalase (393) and superoxide dismutases (394), various
Reference Laboratories clinically relevant mycobacterial species can be identified.
Alternative methods for identification of mycobacteria This approach may also be evaluated in future studies.
which would require special laboratories and expertise are
described below: New Molecular Methods for Identification
and Characterisation
Serotyping These methods have been well developed for
the members of MAC (377,389). Based on serotype specific Recent years have witnessed many advances in the molecular
sera, these strains can be correctly identified and assigned genetics of various organisms including mycobacteria.
 558 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

B
Figure 41.10: Clinical photograph [A] of a patient with NTM breast abscess. Nipple discharge can be seen. FDG PET-CT images [B] of the same
patient showing FDG-avid right breast lesion [thick arrow] and right axillary lymphadenopathy [thin arrow]
FDG = 18F labelled 2-deoxy-D-glucose; PET = positron emission tomography; CT = computed tomography
 Nontuberculous Mycobacterial Infections 559

As these are based on the complementarity of gene random amplified polymorphic DNA [RAPD]—arbitrary
sequences, these techniques can achieve maximum sensiti­ PCR (414), rRNA probes (415-417) and different insertion and
vity and specificity. repeat elements have been described for characterisation of
By hybridisation of isolated RNA, deoxyribonucleic acid NTM (237,418,420,421). Insertion elements have been described
[DNA] from growth or tissue with specific probes, identity to be useful for characterisation of M. haemophilum (237),
of isolates is rapidly established. Based on new knowledge M. avium (418,419,423,424), M. scrofulaceum (421,423) as
about the gene sequences many gene probes for the well as M. kansasii (420). Using these probes and finger­
identification of isolates as well as amplification of specific printing systems, the aetiology of Crohn’s disease due to M.
gene fragments from the lesions and mycobacterial culture paratuberculosis has been established to a large extent (114,116).
isolates have been developed and are described below. Further, some specific RFLP types of M. avium have been
shown to be closely linked with disease in Europe and
Gene probes During the last 20 years, a number of gene Africa (62,108). The IS1245-based RFLP analysis of Indian
probes for the identification of important NTM have isolates of M. avium suggested birds as origin of most of
been developed and some are also being commercially human isolates (419).
marketed (383,395-397). With the help of these probes,
growth from solid slants and even liquid cultures [e.g., Matrix associated laser desorption/ionisation-time of flight
BACTEC] can be identified and these have been found to mass spectrometry [MALDI-TOF] mass spectrometry
be fairly reliable and rapid. This technique has been found to be useful in identifying
NTM species by analysing protein sequences.
Gene amplification methods Advances in gene amplification
methods, especially polymerase chain reaction [PCR] Determination of sensitivity profiles The NTM tend to be
technology have influenced almost every discipline of generally resistant to low concentrations of various anti-TB
medicine. Several PCR techniques for rapid detection and drugs (11). However, at high concentrations [within the
identification of various clinically relevant mycobacteria have therapeutic limits], these organisms may be drug sensitive.
been developed (398-411). These include different types of Except for a limited number of drugs for some NTM drug
PCR assays for detection of M. avium, M. intracellulare (400-402) susceptibility profiles have not been found to be clinically
and M. paratuberculosis (114,398) from the clinical specimens. relevant (14). The media usually recommended for sensitivity
The PCR assays using genus and group specific amplification screening of Mtb are also used for NTM. However, due to
followed by RFLP analysis have been developed for regions differences in the levels of sensitivity in broth (11), a caution
like 65 kD for Mtb, M. avium, etc. (399), rRNA gene region for is required. Other media, like chocolate agar supplemented
M. avium, M. chelonae, M. xenopi and early secretory antigen-6 with ferric ammonium salts and mycobactins, etc. will
[ESAT-6] for Mtb and M. kansasii, etc. (407-412). A new PCR be required for sensitivity screening of other fastidious
technique appears to be potentially useful for characterising species. While newer techniques like BACTEC, MGIT and
various pathogenic NTM (411). Another PCR strategy using MB/BacT (387,388) have been quite promising in early
amplification followed by capture plate hybridisation has detection of growth of NTM from clinical specimens,
been reported to be useful for M. ulcerans (403) and M. avium, only BACTEC and E-test have been found to be useful for
M. chelonae, M. scrofulaceum (404). A reverse hybridisation sensitivity determination of rapid as well as slowly growing
line probe assay [LipA][e.g., INNO-LiPA, Innogenetics, NTM (425-427). Expert Group of American Thoracic Society
Ghent, Belgium] has been described to be quite useful for [ATS] (14) has suggested that there is no use of testing of
rapid identification of mycobacteria (405). The PCR targeting sensitivity for rifampicin and isoniazid for rapid growers
certain regions on rRNA has been observed to be useful as they are usually resistant to these drugs and other drugs
for quick identification of various NTM (408). These PCR such as sulphones, clarithromycin, cefoxitin, amikacin,
methods can be used for rapid identification of clinical etc. should be considered for the treatment of NTM
isolates (399,400,402,403,407,408,411) as well direct detection disease. Likewise, higher cut-off values for determination
of pathogens from the clinical specimens (401,406). Keeping of sensitivity should be considered for organisms, like M.
in view the diversity of these organisms present in different avium. Recombinant strain of M. avium expressing beta
geographical locations, it would be important to evaluate the galactosidase has been reported to be useful for screening
usefulness of these techniques. Further, contamination from of activity of antimycobacterial compounds (428a).
Laboratories with different levels of infrastructure and
the environment will have to be carefully ruled out.
financial commitment can follow different strategies to deal
DNA fingerprinting and probes for strain differentiation with diagnosis and characterisation of NTM for management
Due to almost universal presence of these organisms in [Table 41.7].
the environment, there has been interest in identifying the A recent study from India (428b) in pulmonary and
strains which would be more commonly associated with extrapulmonary specimens suggested that all mycobacterial
disease. Further, such identification would be important to culture positive specimens when found negative by rapid
investigate hospital infections as well other sources of such molecular testing for Mtb should be considered as NTM
infections (413-424). The DNA fingerprinting techniques using suspects and require further confirmation and NTM
procedures such as pulsed-field gel electrophoresis (413,422), speciation by DNA sequencing.
560 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 41.7: Recommended techniques for the diagnosis and characterisation

Low-resource settings Moderate-resource settings Reference laboratories
Repeated isolation on conventional Repeated isolation on conventional media and Repeated isolation on conventional media
media and identification by identification by selected biochemical tests and identification by selected biochemical
selected biochemical tests tests
Growth in any liquid medium and Growth in any standard liquid medium system like Growth in any liquid medium BACTEC/
identification by lipid patterns BACTEC/MGIT/MB-BACTEC and identification by MGIT/MB-BACT and identification by probe
probe hybridisation/lipid patterns hybridisation/lipid patterns
Histopathology Histopathology; plus immunohistochemistry, in situ Histopathology; plus immunohistochemistry,
hybridisation, etc. in situ hybridisation, in situ PCR, etc.
PCR-RFLP PCR-RFLP PCR-RFLP
[if PCR available]
DST DST
DNA sequencing
DNA fingerprinting
MALDI-TOF mass spectrometry
Fluorochrome-staining technique is preferred for NTM. Routine DST of M. avium complex isolates is recommended for clarithromycin only.
Routine DST of M. kansasii is recommended for rifampicin only. Routine DST of rapid-growing mycobacteria [M, fortuitum, M. chelonae
and M. abscessus] should be with clarithromycin, cefoxitin, doxycycline, fluorinated quinolones, amikacin, a sulphonamide or trimethoprim-
sulfamethoxazole, linezolid, imipenem [M. fortuitum only] and tobramycin [M. chelonae only]. For species and subspecies identification multi-
locus DNA sequencing of specific target genes such as 16S rRNA, hsp65, rpoB, 16S-23S rRNA internal transcribed region, gyrB, danA, recA
and sec A has been recommended and considered as a gold satndard. Recently MALDI-TOF mass spectrometry has been considered as
method of choice for NTM species identification.
NTM = nontuberculous mycobacteria; PCR = polymerase chain reaction; RFLP = restriction fragment length polymorphism;
MGIT = mycobacteria growth indicator tube; DST = drug-susceptibility testing; DNA = deoxyribonucleic acid; MALDI-TOF= matrix associated
laser desorption/ionization-time of flight

MANAGEMENT Treatment
Prevention Treatment of NTM disease is generally difficult. The
decision for treatment of NTM patients should be based on
NTM infections, especially those due to contamination
patient’s characteristic, radiographic features and species and
of disinfectants, ice, wounds, injection sites, catheters,
subspecies of the isolated NTM. There are multiple potential
endoscopes etc. can be prevented by proper sterilisation.
impediments which can affect the treatment outcomes in
Avoiding the use of tap water is considered a key step to
patients and the treating clinician should keep a record of
prevent hospital infections due to NTM. Further, patients
it. These impediments include [i] constitutive [innate] and
undergoing cardiac surgery and transplants should
additional [during treatment] antibiotic resistance of NTM;
receive extra attention. Besides different drug regimens,
[ii] prolonged treatment for conversion; [iii] adverse events
certain non-pharmacological options are available which
can help in improvement of NTM disease patient. Chest [AEs] and serious adverse events [SAEs]; [iv] co-infection
physiotherapy, especially in cystic fibrosis and bronchiectasis with other agents like Mtb, fungi and other bacteria;
can be helpful to improve lung functions and mucociliary [v] potential of permanent underlying diseases such as
clearance. Exercises including aerobic activity such as destroyed lungs and immunodeficiency states for their
Yoga, are generally believed to be helpful in pulmonary persistence.
rehabilitation. Apart from drugs therapy, avoidance to NTM Response to anti-TB drug regimens is poor which
exposure is necessary, specifically from household plumbing on many occasions serves as a lead towards diagnosis
and water sources. Increasing hot water temperature to as well. As compare to Mtb, drug-susceptibility testing
more than or equal to 54oC [130oF] and changing of shower [DST] usually is not recommended as a routine except in
heads at regular intervals can be beneficial to prevent NTM certain situations and for certain drugs like rifampin for
transmission. Nutrition is also important and one should M. kansasii (429), clarithromycin and amikacin for MAC
maintain adequate calorie intake and BMI especially in case particularly when response is not good and several drugs
of surgical intervention. Monitoring pre-albumin level can for rapidly growing mycobacteria (14). Drug susceptibility
be used as a marker of nutrition. In some individuals along testing for amikacin and imipenem is recommended for
with antibiotic regimen, probiotic therapy can be helpful. M. fortuitum and for doxycycline, sulphonamides, quino­
Chemoprophylaxis with azithromycin, clarithromycin lones and tobramycin for M. chelonae (14). It has been
and rifabutin in HIV-AIDS cases with severe immuno­defi­ suggested that routine susceptibility testing for amikacin,
ciency [CD4+ T-lymphocyte count < 50 cells/mm3] is recom­ imipenem, doxycycline, fluroquinolones, sulphonamides
mended (14). Prevention of NTM is detailed in Table 41.8. [trimethoprim-sulphamethoxazole], cefoxitin, clarithromycin,
 Nontuberculous Mycobacterial Infections 561

Table 41.8: Prevention of NTM disease

Health care- and hygiene-associated NTM disease
Avoid the following:
Exposure of injection sites, intravenous catheters and surgical wounds to tap water and tap water-derived fluids
Cleaning of endoscopes with tap water
Contamination of clinical specimens with tap water and ice
Use of benzalkonium chloride as a skin disinfectant prior to local injections
Household and personal measures
Avoid using saunas, hot tubs or any water with an aerator. Hot water usage should be done in proper ventilation
Replacement of shower heads at regular intervals; temperature of water heater should be ≥ 54.4°C
Sterilised water should be used in humidifiers; avoid ultrasonic humidifiers
Household plumbing systems should be cleaned and sterilized regularly to avoid NTM biofilm formation
 Take steps to reduce gastroesophageal reflux disease [GERD]; avoid foods that may trigger it and avoid vulnerable body positions that may
cause aspiration
NTM-associated hypersensitivity lung disease
Ensure regular cleaning of indoor pools, hot tubs and hot water pipes
Chemoprophylaxis for PLHA* with CD4+ T-lymphocyte count <50 cells/µL
Azithromycin† 1200 mg PO weekly
or
Clarithromycin‡ 500 mg PO twice-daily
or
Rifabutin 300 mg/day {dose needs to be modified based on drug-drug interaction [s]}
* Preventive treatment may be stopped if CD4+ T-lymphocyte count is >100/µL for more than 3 months
† First preference [in some countries where azithromycin is available as 250/500 mg preparation, the dosage is 1250 mg]
‡ Role of macrolide prophylaxis in susceptible/immunodeficient [such as, IFN-γ/IL-12 axis defect] is not clear
NTM = nontuberculous mycobacteria; PLHA = people living with human immunodeficiency virus infection/acquired immunodeficiency
syndrome; PO = per orally; IFN-γ = interferon-gamma; IL = interleukin
Adapted with permissions of The American Thoracic Society. Copyright © 2019 American Thoracic Society, Griffith DE, Aksamit T, Brown-
Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An Official ATS/IDSA Statement: Diagnosis, treatment, and prevention of nontuberculous
mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367-416. An official Journal of The American Thoracic Society.

linezolid and tobramycin would be useful for taxonomic infected with organisms that contain an inducible erm 41
identification and also treatment of infections due to gene, namely, M. abscessus subsp. abscessus and M. fortuitum.
rapidly growing mycobacteria such as M. fortuitum, M. During treatment of NTM disease, treating clinicians should
chelonae and M. abscessus. Rifampicin, rifabutin, ethambutol, monitor the peak levels of drugs weekly and keep a check
clofazimine, amikacin, linezolid, new generation macro­ on conventional microbiological outcomes such as smear
lides such as clarithromycin/azithromycin and quino­ status, culture conversion and relapse [detailed below] for
lones like ciprofloxacin/moxifloxacin are part of regimens further disease management.
to treat NTM infections. Treatment of important NTM MAC infections are considered most important because
infections is summarised in Table 41.9 (14,430a). Tetra­ of morbidity and mortality associated with them. Different
cyclines [doxycycline, minocycline], sulphonamides and regimens tried for the treatment of MAC infections include
cephalosporins such as cefoxitin are useful against rapidly combinations of rifampin, isoniazid, ethambutol and
growing mycobacteria. Imipenem has been reported to streptomycin (9,430b); ansamycins, clofazimine, ethambutol
be useful against M. abscessus and M. chelonae infections. and isoniazid (431), amikacin, ethambutol, rifampicin and
Cases having significant hypersensitivity component ciprofloxacin (432), rifabutin, ethambutol, clofazimine
such as hot tub disease may require additional steroid and isoniazid (433), rifampicin, ethambutol, clofazimine
treatment (14). While macrolide clarithromycin, is considered and ciprofloxacin (434). Over the years, clarithromycin
to be the backbone of treatment of NTM disease, species and and azithromycin have emerged important drugs for
subspecies identification is important to know the presence treating these infections (14,435-438). A combination of
of an active erythromycin ribosomal methylase [erm] 41 clarithromycin or azithromycin with ethambutol and
gene. When the organism is incubated in the presence of rifabutin for one year has been recommended by ATS and
clarithromycin, the erm 41 gene is induced and the organism IDSA (14) for the treatment of nodular or bronchiectatic
rapidly acquires resistance to macrolides. M. abscessus subsp. pulmonary infections and also disseminated forms and for
abscessus, M. abscessus subsp. bolletii and M. fortuitum have an severe nodular and extensive disease additional amikacin
inducible erm 41 gene while M. abscessus subsp. massiliense or streptomycin has been suggested (14). According to some
and M. chelonae have a non-functional copy of erm 41 recent studies, fluoroquinolones have been found ineffective
gene. Therefore, patients infected with organisms having in MAC disease and certain authors have not recommended
non-functional erm 41 gene [M. abscessus subsp. massilense, its use. Further, it is critical to prevent the emergence of
M. chelonae] are more likely to improve clinically than those macrolide resistance as the chances of successful treatments
562 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

weakens when the minimum inhibitory concentration is recommended for 12 months during which time sputum
[MIC] of macrolides for MAC is greater than 16 μg/mL. In culture should remain negative (439). Although, the role
addition, the administration of inhaled amikacin, specifically of isoniazid is not defined and it is not recommended by
an inhaled liposomal amikacin preparation is promising in group of authors. For rifampicin-resistant disease, regimen
case of advanced or recalcitrant MAC pulmonary disease. comprising sulphonamides has been found to be effective.
Although, a recent study has shown that MAC isolates Any three-drug combination—clarithromycin/azithromycin,
having amikacin MICs greater than 64 μg/mL were found moxifloxacin, sulphonamides, streptomycin after DST is
to have amikacin resistance associated with mutated 16S suggested for such cases (14).
rRNA gene. Surgical debridement is of paramount importance treat­
M. simiae, another slowly growing NTM which is ment of M. marinum infections in addition combinations
commonly isolated but rarely indicative of true infection. of sulphamethoxazole-trimethoprim and doxycycline (12);
The clinical manifestations of M. simiae infection are similar clarithromycin and ethambutol or ethambutol and clarithro­
to MAC pulmonary disease. But, when clinical disease mycin have been reported to be useful (14,440-443).
occurs, M. simiae is very challenging to treat and requires The rapidly growing NTM, M. fortuitum and M. chelonae
expert consultation. With no established drug regimen, the are also among frequently isolated NTM rarely cause
M. simiae disease has been treated similar to MAC disease pulmonary disease except in patients with gastrointestinal
and multidrug DST is recommended. In few countries, disorders, M. fortuitium has been found to be associated
M. szulgai is often associated with active pulmonary disease with active pulmonary disease. For the management of
and treatment is similar to the MAC disease. M. fortuitum and M. chelonae infections besides the
M. xenopi pulmonary disease are associated with high all- surgical drainage/debridement, treatment with clarithro­
cause mortality with low overall survival rates. According to mycin or azithromycin, amikacin and doxycycline is
some recent literatures, severity of M. xenopi disease should recommended (444-446).
be accounted and treated accordingly [Table 41.10] (430a). M. abscessus Surgical resection of localised disease along
Despite unclear role in treatment, inclusion of isoniazid in with treatment with multidrug-regimens that include macro­
drug regimen to treat M. xenopi is recommended. Similar lides, especially clarithromycin is the line of manage­ment
approach as M. xenopi should be adopted to treat M. of infections due to this pathogen. Linezolid has also been
malmoense disease as well [Table 41.11] (430a). found to be effective in nearly half of the infections (14).
For the treatment of M. kansasii infections, a regimen M. abscessus is considered as “an antibiotic nightmare”
comprising rifampicin, isoniazid, ethambutol and pyridoxine due to resistance shown towards macrolides. The in vitro

Table 41.9: Treatment of important/selected NTM disease conditions

Disease Drugs and surgery Dose and frequency Duration
MAC pulmonary disease
Nodular/bronchiectatic Clarithromycin 1000 mg TWI For one year after culture
disease or conversion
Azithromycin 500 mg TWI
Rifampicin 600 mg TWI
Ethambutol 25 mg/kg TWI
 Fibrocavitary lung disease or Clarithromycin 1000 mg/day [lower dose if body For one year after culture
severe nodular/ bronchiectatic or weight < 50 kg] conversion
disease Azithromycin 250-350 mg/day
and
Rifampicin 450-600 mg/day [lower dosage if
or body weight < 50 kg]
Rifabutin 150-300 mg/day
Ethambutol 15 mg/kg/day
Amikacin* 15-25 mg/kg TWI during initial
or 3 months of therapy
Streptomycin†
 Recalcitrant/macrolide- Rifampicin 600 mg daily For one year after culture
resistant MAC-pulmonary and and conversion
disease Ethambutol 15 mg/kg daily
and and
Isoniazid 300 mg [plus pyridoxine 10 mg] daily
or or
Moxifloxacin 400 mg daily
and and
Amikacin* intravenous amikacin for up to
3 months
Contd...
 Nontuberculous Mycobacterial Infections 563

Contd...
Disease Drugs and surgery Dose and frequency Duration
 Extensive or previously Clarithromycin 1000 mg daily
treated disease or
Azithromycin and 250-300 mg daily
Ethambutol and 15 mg/kg daily
Rifabutin 150-300 mg daily
or
Rifampicin 450-600 mg daily [lower dosage if
and body weight < 50 kg]
Streptomycin or amikacin* 15-25 mg/kg TWI during initial
3 months of therapy
Disseminated MAC disease‡ Clarithromycin 500 mg orally twice daily Until resolution
or of symptoms and
Azithromycin [alternative] 500 mg orally daily reconstitution of cell-
Ethambutol 15 mg/kg orally daily mediated immune
plus function
Rifabutin§ 300-450 mg orally daily
M. kansasii pulmonary disease║ A regimen consisting of For one year following
Isoniazid 300 mg daily negative sputum culture
Rifampicin and 450-600 mg [lower dosage if body
weight < 50 kg]
Ethambutol 15 mg/kg/day
Pyridoxine 50 mg daily
M. abscessus pulmonary disease For one year following
negative sputum culture
Clarithromycin sensitive
 
isolates Initial phase [≥1 month]
Amikacin Intravenous 15 mg/kg/day or TIW
and
Tigecycline 100 mg intravenous loading dose
followed by intravenous 50 mg twice
daily

Imipenem Intravenous 1g twice daily

[when tolerated]
Clarithromycin 500 mg orally twice daily
or
Azithromycin 250-500 mg orally daily
[when tolerated]
Continuation phase
Nebulised amikacin¶ 500 mg nebulisation twice daily
and
Clarithromycin 500 mg orally twice daily
or or
Azithromycin 250-500mg daily
and
1-3 of the following drugs orally as per
DST and patient’s tolerance:
Clofazimine 50-100 mg daily
Linezolid 600 mg once daily
Minocycline 100 mg twice daily
Moxifloxacin 400 mg once daily
Co-trimoxazole 960 mg twice daily

 Constitutive macrolide-
resistant isolates
Initial phase [≥1 month]
Amikacin Intravenous 15 mg/kg/day or TIW
and
Tigecycline 100 mg [intravenous] loading dose
followed by intravenous 50 mg twice
daily
Imipenem Intravenous 1g twice daily
[when tolerated]
Contd...
 564 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Contd...
Disease Drugs and surgery Dose and frequency Duration
Continuation phase
Nebulised amikacin¶
and
2-4 of the following drugs orally as per
DST and patient’s tolerance:
Clofazimine 50-100 mg daily
Linezolid 600 mg once daily
Minocycline 100 mg twice daily
Moxifloxacin 400 mg once daily
Co-trimoxazole 960 mg twice daily
NTM cervical lymphadenitis‡ Surgical excision is the treatment of
choice for single site involvement [usually
in children]. Multiple sites involvement
should be ruled out by appropriate imaging
techniques including PET-CT or PET- MRI
if available

 Patient with extensive MAC Macrolide-based drug regimen

lymphadenitis or poor Drug regimen[s] to be based on in vitro DST
response to surgical treatment

 Non-pulmonary disease due Surgical debridement is an essential

to rapidly growing NTM component of treatment. A macrolide-based
drug regimen is frequently used for
M. abscessus
* Liposomal amikacin is the drug of choice for nebulization, however, nebulized amikacin 500 mg twice daily may be administered in patients
with macrolide resistance, fibrocavitary and treatment failure MAC pulmonary disease
† Dosage depending upon age, weight and renal function
‡ When disease is due to MAC, multiple sites involvement has to be ruled out by appropriate imaging such as CT, abdominal and pelvic
ultrasonography or whole body PET-CT or PET-MRI, if available
§ Rifabutin preferred over rifampicin especially in PLHA to avoid drug–drug interactions
║ There is no recommended prophylaxis or suppressive regimen for disseminated M. kansasii disease. Treatment for disseminated and
pulmonary disease is similar to disease due to Mtb. Since MICs of isoniazid are higher as compared to Mtb, clarithromycin is preferred over
isoniazid for treatment of M. kansasii. Due to resistance to pyrazinamide, the drug is not recommended for M. kansasii treatment. For patients
with rifampicin-resistant M. kansasii disease, a 3-drug regimen [based on in vitro susceptibility] clarithromycin or azithromycin, moxifloxacin,
ethambutol, sulphamethoxazole or streptomycin
¶ Amikacin for nebulisation may be re-constituted by adding injectable amikacin [250 mg/mL] to only 0.9% sodium chloride and made up to
4 mL. This should not be mixed with nebulised bronchodilator solutions or other nebulised antibiotics. Prior use of aerosolised bronchodilator
[nebulised or inhaler] can be made to prevent coughing or bronchospasm
TWI = thrice-weekly intermittent; NTM = nontuberculous mycobacteria; MAC = M. avium complex; DST = drug-susceptibility testing;
CT= computed tomography; PET = positron emission tomography; MRI = magnetic resonance imaging; PLHA = people living with human
immunodeficiency virus infection/acquired immunodeficiency syndrome
Adapted from the following:
The American Thoracic Society. Copyright © 2019 American Thoracic Society, Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C,
Gordin F, et al. An Official ATS/IDSA Statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir
Crit Care Med 2007; 175:367-416. An Official Journal of The American Thoracic Society.
The BMJ Publishing Group Ltd., Copyright © 2015, British Medical Journal Publishing Group Haworth CS, Banks J, Capstick T, et al, British
Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease [NTM-PD], Thorax 2017;72:ii1-ii64.
Philley JV, Griffith DE. Medical Management of Pulmonary Nontuberculous Mycobacterial Disease. Thorac Surg Clin 2019;29:65-76.

susceptibilities towards macrolides should be determined Lymphadenitis Surgical removal of lymph glands in case
for M. abscessus [Table 41.12] and based on that the combi­ of lymphadenitis has been found to be effective in achieving
nation of drugs should be used for a successful treatment full cure in majority of cases [provided imaging has ruled
outcome (430a). out multiple site involvement]. However, additional chemo­
therapy depending upon NTM species has also been found
Cystic fibrosis Patients should be regularly screened for
to be beneficial (14).
NTM infections and macrolide monotherapy for commonly
occurring infections should be given only after screening for Hypersensitivity like disease The measures that are to be
NTM. After diagnostic confirmation, NTM disease should be under­taken for the management and prevention of such
treated according to particular mycobacterial pathogen (14). cases are provided in Table 41.8 (14).
 Nontuberculous Mycobacterial Infections 565

Definitions for clinical and microbiological outcomes have good pulmonary function reserve without having
are listed in Table 41.13 (14,430a). impaired gas exchange. For a successful surgical outcome,
role of pulmonary and/or infectious disease specialist,
Surgical Intervention respiratory therapist and nutrition expert is crucial. It is
frequently reported that surgery improves the chances
Surgical intervention is considered necessary in certain of success of prolonged NTM disease treatment. In
individuals with NTM pulmonary disease. These patients extrapulmonary NTM disease, surgical intervention may
should have localised underlying lung disease and should be required through aggressive debridement or removal
of implanted material. In patients with peripheral solitary
lymph node involvement, surgical excision is the treatment
Table 41.10: Suggested antibiotic regimens for adults of choice.
with M. xenopi pulmonary disease
M.xenopi-pulmonary
disease Antibiotic regimen Table 41.11: Suggested antibiotic-regimens for adults
Non-severe M. xenopi Treatment with a four-drug regimen with M. malmoense-pulmonary disease
pulmonary disease consisting of:
M.malmoense-pulmonary
[i.e., AFB smear-negative Rifampicin 600 mg daily
disease Antibiotic regimens
respiratory tract samples, and
no radiological evidence Ethambutol 15 mg/kg daily Non-severe Treatment with a daily oral three-
of lung cavitation or and M.malmoense- drug regimen consisting of:
severe infection, mild- either Azithromycin 250 mg/daily or pulmonary disease Rifampicin 600 mg daily
moderate symptoms, no clarithromycin 500 mg twice daily [i.e., AFB smear-negative and
signs of systemic illness] and respiratory tract samples, Ethambutol 15 mg/kg daily
Moxifloxacin 400 mg daily or isoniazid no radiological evidence and
300 mg [plus pyridoxine 10 mg] daily of lung cavitation or Azithromycin 250 mg/daily or
Antibiotic treatment should continue for severe infection, mild- clarithromycin 500 mg twice daily
a minimum of 12 months after culture moderate symptoms, no Antibiotic treatment should continue for
conversion signs of systemic illness] a minimum of 12 months after culture
Severe M. xenopi Rifampicin 600 mg daily conversion
pulmonary disease and
[i.e., AFB smear-positive Ethambutol 15 mg/kg daily Severe M.malmoense- Rifampicin 600 mg daily
respiratory tract samples, and pulmonary disease and
radiological evidence or Azithromycin 250 mg/daily or [i.e., AFB smear-positive Ethambutol 15 mg/kg daily
lung cavitation/severe clarithromycin 500 mg twice daily respiratory tract sample, and
infection, or severe Moxifloxacin 400 mg daily or isoniazid radiological evidence Azithromycin 250 mg/daily or
symptoms/signs of 300 mg [plus pyridoxine 10 mg] daily of lung cavitation/ clarithromycin 500 mg twice daily
systemic illness] and consider intravenous or nebulised severe infection or sever and consider intravenous amikacin for
amikacin for up to 3 months symptoms/signs of up to 3 months or nebulised amikacin
Antibiotic treatment should continue for systemic illness] Antibiotic treatment should continue for
a minimum of 12 months after culture a minimum of 12 months after culture
conversion conversion
AFB = acid-fast bacilli AFB = acid-fast bacilli
Reproduced with permission of the BMJ Publishing Group Ltd., Reproduced with permission of the BMJ Publishing Group Ltd.,
Copyright © 2015, British Medical Journal Publishing Group Copyright © 2015, British Medical Journal Publishing Group
Haworth CS, Banks J, Capstick T, et al, British Thoracic Society Haworth CS, Banks J, Capstick T, et al, British Thoracic Society
guidelines for the management of non-tuberculous mycobacterial guidelines for the management of non-tuberculous mycobacterial
pulmonary disease [NTM-PD], Thorax 2017;72:ii1-ii64. pulmonary disease [NTM-PD], horax 2017;72:ii1-ii64.

Table 41.12: Interpretation of extended clarithromycin susceptibility results for M. abscessus

Clarithromycin Clarithromycin Macrolide susceptibility
susceptibility days 3-5 susceptibility day 14 Genetic implication M. abscessus subspecies phenotype
Susceptible Susceptible Dysfunctional erm (41) gene M.a.massiliense Macrolide susceptible
Susceptible Resistant Functional erm (41) gene M.a.abscessus Inducible macrolide
M.a.bolletii resistance
Resistant Resistant 23S ribosomal RNA point Any High-level constitutive
mutation macrolide resistance
Reproduced with permission of the BMJ Publishing Group Ltd., Copyright © 2015, British Medical Journal Publishing Group Haworth CS,
Banks J, Capstick T, et al, British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease
[NTM-PD], Thorax 2017;72:ii1-ii64.
566 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

2. Pinner M. Atypical acid-fast microorganisms. Am Rev Tuberc

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 42
Drug-resistant Tuberculosis
Keertan Dheda, Grant Theron, Gregory Calligaro, Jason Limberis,
Malika Davids, Alisgar Esmail, Rodney Dawson

INTRODUCTION NTP are of paramount importance, further research and

understanding into the underlying genesis of drug resistance
Although the global incidence of tuberculosis [TB] has
is critical if the development of drug resistance in the future
been slowly declining, TB remains out of control in many
is to be minimised.
parts of the world (1). Some of the early gains made in
several parts of the world, including in Africa and Asia, are
CLINICAL EPIDEMIOLOGY
now being threatened by the emergence of drug-resistant
TB [DR-TB]. Although multidrug-resistant TB [MDR-TB] The causes of DR-TB are complex. While programmatic
defined as resistance to rifampicin and isoniazid comprises conditions are often responsible for promulgating MDR-TB
only 6%-7% of the total burden of TB it deserves public epidemics [through, for example, frequent drug shortages
health prioritisation and is important for several reasons. and poor drug quality, inadequate drug-susceptibility
First, DR-TB is associated with longer time to diagnosis testing [DST], poor training, and non-standardised treatment
and considerable pulmonary morbidity including chronic regimens] (3,4) certain patient-specific factors are associated
lung fibrosis, bronchiectasis, Aspergillus-associated a lung with an increased likelihood of MDR-TB. Traditionally,
disease, etc. Secondly, DR-TB is associated with considerable previous TB treatment [including number of episodes,
mortality and substantial a global reduction in TB mortality irregular treatment, and frequency of default] (5-10) has
will not be achievable unless the problem of DR-TB is been considered the single biggest risk factor for MDR-TB.
addressed. MDR-TB and extensively drug-resistant TB [XDR- However, other factors, such as age, male sex, alcohol abuse,
TB] [defined as MDR-TB plus resistance to at least one drug poverty, HIV infection (7), smoking (8), substance abuse (11),
in the following classes of medicines used in the treatment a history of imprisonment (8), hospitalisation (5,12) or recent
of MDR-TB, namely, fluoroquinolones and second-line immigration (13), or infection with certain strains [such as,
injectable agents] is also associated with substantial cost. For atypical Beijing] (14-16) all increase the probability of DR-TB.
example, in South Africa, despite X/MDR-TB comprising For XDR-TB, the previous use of second-line drugs [SLDs]
less than 4% of the total TB burden, it is already consuming is the single biggest risk factor (5,6,17). However, although
close to 40% of all TB-related healthcare resources, a situation there are several risk factors for MDR-TB it should be noted
that is unsustainable. Therefore, DR-TB has a capacity that almost two-thirds of MDR-TB cases have never been
to destabilise well-functioning national TB programmes previously been treated for TB or have none of these asso­
[NTPs] (2). X/MDR-TB and resistance beyond XDR-TB ciated risk factors. Thus, it is not practical nor useful to risk
has become a burgeoning problem in many countries. stratify patients to guide DST, and every case of TB should,
Several issues are critical to the control of DR-TB including therefore undergo DST for at least rifampicin resistance.
reducing global levels of poverty and overcrowding, and As per the Global TB Report 2018 (1), in 2017, there were
addressing drivers like human immunodeficiency virus approximately 558,000 estimated new cases of MDR-TB/
[HIV], cigarette smoking, alcohol and substance abuse, rifampicin resistant-TB [RR-TB] globally (1), and MDR-TB
biomass fuel exposure and diabetes. Indeed, reduction in was found in approximately 3.6% of new cases and approxi­
the total burden of TB will also reduce the prevalence of mately 17% of retreated cases [Figures 42.1A and 42.1B] (1).
DR-TB. Whilst capacity development and strengthening of More than half the MDR-TB burden lies in India, China and
 580 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 42.1A: Percentage of new TB cases with MDR/RR-TB

TB = tuberculosis; MDR = multidrug-resistant; RR = rifampicin resistant
Reproduced with permission from “World Health Organization. Global tuberculosis report. Geneva: World Health Organization; 2018”
(reference 1)
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/

Figure 42.1B: Percentage of previously TB cases with MDR/RR-TB

TB = tuberculosis; MDR = multidrug-resistant; RR = rifampicin resistant
Reproduced with permission from “World Health Organization. Global tuberculosis report. Geneva: World Health Organization; 2018”
(reference 1)
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/

the Russian Federation. In sub-Saharan Africa and about There are several worrying trends with regard to DR-TB.
half of the MDR-TB patients are HIV co-infected. MDR-TB The global average isoniazid mono-resistance rate was 7.1%
is also prevalent in children roughly mirroring the MDR-TB in new and 7.9% in previously treated TB (1). Although,
prevalence in adults (1). the global burden of MDR-TB remained unchanged over
 Drug-resistant Tuberculosis 581

Figure 42.2: Number of patients with laboratory confirmed XDR-TB started on treatment in 2016
XDR-TB = extensively drug-resistant tuberculosis
Reproduced with permission from “World Health Organization. Multidrug-/rifampicin-resistant TB[MDR/RR-TB]: Update 2017. Available at URL:
http://www.who.int/tb/areas-of-work/drug-resistant-tb/MDR_TB_2017.pdf?ua=1. Accessed on August 29, 2018.” (reference 18a)
The World Health Organization updates these data annually. The reader can access the updated information from the WHO report of the current
year available at the URL: http://www.who.int/topics/tuberculosis/en/

the period 2008 to 2017, in several countries [China, India, Sparse published data are available on drug-resistance in
Pakistan, Nigeria, South Africa, Indonesia, Bangladesh, and extra-pulmonary tuberculosis [EPTB]. In a study (26) from
the Democratic Republic of Congo, amongst others] the New Delhi, 2553 extra-pulmonary specimens from 2468
number of RR-TB cases over the period 2009 to 2017 has patients, mycobacterial culture was positive in 18.9%. MDR-
increased substantially. Worryingly, in 2017 the proportion TB was evident in 8.1% of the specimens; pre-XDR-TB and
of MDR-TB cases with any fluoroquinolone resistance XDR-TB were evident in 17.9% and 2.6% extra-pulmonary
was 22%, and disturbingly 51% of MDR-TB patients had specimens respectively. The sensitivity and specificity of
resistance to either a fluoroquinolone, or a second-line genotypic DST using both Xpert MTB/RIF and line probe
injectable drugs [SLIDs], or both. The average proportion assay [LPA] for detection of rifampicin resistance was 92.7%
of MDR-TB cases with XDR-TB was 8.5% [Figure 42.2] an and 99.3% with 100% concordance between the two tests (26).
increase from 6.2% in 2016 (1,18a).
In India, the estimated percentage of new and retreatment MOLECULAR EPIDEMIOLOGY AND
cases with MDR/RR-TB was 2.2% and 18%, respectively (1). TRANSMISSION DYNAMICS OF DRUG-
It has been estimated that, in 2017 there were an estimated RESISTANT TUBERCULOSIS
135,000 incident MDR/RR-TB cases in India. Data from
different parts of India are variable. Recent studies have A basic understanding of the molecular epidemiology of
reported alarmingly high levels of MDR-TB in several wards DR-TB is crucial for clinicians and scientists, because not
of Mumbai [24% in previously untreated cases] (18b) and only does it enable them to identify patients at a high risk of
in Lucknow [20% of isolates] (19). A report from Mumbai DR-TB, but it also permits them to identify potential out­
documented a 11% prevalence of XDR-TB in 326 patients breaks of DR-TB. Drug-resistant TB may be acquired endo­
with MDR-TB (20). Other studies from India reported an genously during the course of treatment or by primary
XDR-TB prevalence ranging between 1.5% and 7.4% (21,22). [person-to-person] spread (27). DR-TB is increasingly
One study (23) reported that 4 out of 12 HIV, MDR-TB co- being seen in patients who have no history of previous TB,
infected patients had XDR-TB. In a study from New Delhi, suggesting that these cases are mostly caused by primary
Sharma and colleagues (24) reported that approximately transmission (1,27). Although some DR strains may be less
2.4% of MDR-TB cases had XDR-TB. An alarming report fit [and hence may be less transmissible] (28), the fact that
from Udwadia and co-workers drew attention to the problem many patients with MDR-TB are not detected or started
of resistance beyond XDR-TB, i.e., totally drug-resistant TB on treatment, and that the duration of infectiousness is
[TDR-TB] in India (25). longer for MDR-TB than drug-susceptible TB [DS-TB] once
582 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

treatment is started (29), means that there is a large pool of small. The traditional view holds that erratic therapy either
infectious DR-TB cases in many high burden TB countries. due to programme-related or patient-related factors results
Evidence of this ongoing transmission is provided by in the killing off of susceptible bacterial sub-populations
molecular tools, such as, spoligotyping (30), IS6110 deoxyri­ but allows the pre-existing DR populations to continue
bonucleic acid [DNA] fingerprinting (31) or Mycobacterial to replicate, thus eventually resulting in a predominant
interspersed repetitive unit-variable number tandem population of DR organisms. Thus, the traditional view
repeat [MIRU-VNTR] typing (32)] that identify clusters of holds that DR mutants are selected out because of a lack of
genotypically similar strains, which can be used to trace adherence due to several factors. However, newer findings
an epidemic or deter­mine whether a patient’s DR-TB is have challenged this traditional understanding.
acquired [genetically similar to earlier episode] or trans­mitted
[genetically similar to other strains in the community]. Using Pharmacokinetic Variability at Population Level
these techniques, researchers have shown that 80%–90% of and Induction of Efflux Pumps
MDR-TB cases in settings, such as, South Africa (33) and
China (9) are likely caused by primary spread (34a), and It is now well-appreciated that drug resistance can develop
that primary transmission is likely responsible for outbreaks even when adherence to treatment is excellent (47). In some
of XDR-TB, such as that seen in Tugela Ferry (34b). Whole cases, pharmacokinetic [PK] mismatch occurs where a
genome sequencing, where all the DNA in the Mtb cell is drug with a long half-life [e.g., bedaquiline or clofazimine]
sequenced, has recently started to move beyond being just effectively is available to act as monotherapy. Studies using
a useful research tool to one where, for example, it can be the hollowing fibre system have shown that a acquired drug
used to simultaneously detect DR mutations, investigate resistance is strongly associated with the area under the
and track outbreaks with more resolution than traditional curve and peak drug concentrations indexed to minimum
molecular techniques (35-37), and discriminate between inhibitory concentration [MIC], and there is, therefore
relapse or rein­fection more accurately (38,39). facilitated at concentrations below which drug resistance
Whole genome sequencing [WGS] has recently been is amplified and microbial killing fails. The acquired drug
success­fully used to trace epidemics of XDR-TB in South resistance is often accompanied or preceded by very early
Africa, showing that most transmission events occur due induction of many low-level resistance efflux pumps, which
to casual contacts in the community and that patients who confers resistance or tolerance (48,49). These efflux pumps
are highly drug-resistant and on inadequate treatment still are thought to protect bacilli during several rounds of
transmit the disease (34a,34b,40a). replication and act as a gateway for the eventual generation
Importantly, epidemics of DR-TB driven by primary of chromosomal mutations associated with high level
transmission appear to largely be caused by a highly acquired resistance. This process is termed the antibiotic
infectious minority of patients [the “super-spreading” pheno- resistance arrow of time (50). Several studies report the
menon] (40b-43). Although we currently have a limited co-existence of genetic mutations and multi-drug efflux
understanding of why only some patients with DR-TB are pumps (51,52). However, WGS-related studies may not
highly infectious and others are not (44,45) [which is likely a show this effect because efflux pumps are already encoded
result of different bacterial, behavioural, and environmental by the TB genome and induction is epigenetic. Furthermore,
factors], research on this phenomenon is needed to facilitate conventional susceptibility testing using breakpoints will
clinical interventions [e.g., inhaled antibiotics, triage for not detect low-level resistance. Other low level mutations
specialised infection control] that can target this minority have been described that may act as a gateway for resistance
of patients in order to halt transmission. amplification (53). The clinical relevance of such mutations
require further study.
PATHOGENESIS The hollow fibre model further showed that although
therapeutic failure occurred when more than 60% of the
Traditional Understanding of how doses were missed there was no generation of MDR-TB.
Drug-resistance Develops More importantly, however, is the PK variability occurring
The underlying pathogenesis of DR-TB has been summarised in individuals and populations. In a population simulation
in Figure 42.3 (27). It is known that acquisition of resistance model using PK data, it is estimated that MDR-TB would
in Mtb is characterised by a low rate of spontaneous still occur in 0.68 of patients during the first 2 months of
mutation, and not by horizontal gene transfer [for example treatment despite 100% adherence because of between
~2.6 isoniazid-specific mutations per 10 8 Mtb bacteria patient PK variability of isoniazid and rifampicin. Thus, there
per generation occurs] (46). Thus, Mtb resistance arises would effectively be monotherapy for long periods of time.
spontaneously but at a low and predictable de novo rate, A similar situation occurs in the intensive phase of short-
and in a patient with a large bacterial burden of up to 109 course treatment of patients who are still culture positive
organisms, a small number of bacteria may be resistant but have underlying isoniazid mono-resistance. The PK
to a single drug. However, the probability of pre-existing variability in individuals and populations is driven mainly
resistance to two or three drugs [calculated by multiplying by genetic poly­morphisms in genes coding for metabolism
the mutation rates for the specific drugs] is infinitesimally and drug transporters.
 Drug-resistant Tuberculosis 583

Figure 42.3: The pathogenesis of DR-TB. The traditional interpretation of resistance development is that sequential drug resistance develops through
fragmented treatment [A], which can be fuelled by several programmatic and socioeconomic factors. However, resistance can develop despite
excellent adherence. Several factors, including efflux pumps [B], between-person pharmacokinetic variability [C], and extensive immunopathology
in the lung resulting in differential drug penetration into granulomas and cavities [D] might all drive site-specific drug concentrations below minimum
inhibitory concentrations, thus probably enabling drug resistance. After acquired drug-resistance develops, person-to-person transmission might
constitute the major route of spread [E]. Strain-specific genotype, newly acquired drug-encoding mutations, and compensatory mutations that can
affect fitness cost [and hence transmission] might also interact [F]. Compensatory mutations could be associated with changes in structure and
physiological pathways, which could affect host immune response and thereby potentially subvert protective responses and drive progressive
disease [G].
DR-TB = drug-resistant tuberculosis; INH = isoniazid; RIF = rifampicin; PZA = pyrazinamide; MDR-TB = multidrug-resistant tuberculosis
Reproduced with permission from “Dheda K, Gumbo T, Gandhi NR, Murray M, Theron G, Udwadia Z, et al. Global control of tuberculosis: from
extensively drug-resistant to untreatable tuberculosis. Lancet Respir Med 2014;2:321-38” (reference 27)

Differential Drug Penetration into finding of different susceptibility profiles of isolates from
Lung Micro Compartments different lesions [obtained through biopsies from the cavity
wall versus the per-fibrotic margin versus apparently normal
Local PK variability can also be caused by differential lung] in the same patient [also termed hetro-resistance] lend
penetration of drugs into the lung micro compartments. The support to this hypothesis [Lenders and Dheda; unpublished
584 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

observations]. The immunopathology in the lung may, poorly character­ised and is currently under study by the
therefore, drive considerable within-person PK variability, authors’ group using cough aerosol sampling [CASS] techno­
which is a key factor in the genesis of MDR-TB (27). logy. The high transmissibility and virulence, characterised
There are several implications of these findings. Future by high mortality and transmission of highly DR strains
studies are required to: [i] evaluate the impact of therapeutic in South Africa and elsewhere, suggest that in many cases
drug monitoring to minimise amplification of drug-resis­ compensatory mutations may result in normal or possibly
tance; [ii] use of a pharmaco-genomic approach where even enhance evolutionary fitness levels (58). Epistatic
certain patient genotypes would be associated with more interactions may modulate fitness cost associated with drug
rapid or modulated drug metabolism, thus mandating resistance (61,62).
therapeutic monitoring; and [iii] improved targeting of drugs In summary, several newer concepts have challenged the
to the disease site by dosage adjustments or targeting of drug traditional view about the pathogenesis of drug resistance.
to the lung through the inhalation route (54). There are several clinical implications of these findings
including the use of therapeutic drug monitoring, pharma­
Genotype and Compensatory Mutations cogenomics, new methods of dosing and drug delivery
depending on low versus high level mutations, selection
Certain strains may have a higher in vivo mutation rates of drugs and regimens least likely to induce low fitness
than other strains making the emergence of drug-resistance cost mutations, the potential use of immunomodulatory
more likely (55). Mutation rates also vary between strains therapies, use of rapid diagnostic techniques to characterise
of the same genotype. There is limited evidence to support super spreaders, and newer diagnostic approaches that
the hypothesis that some strains are more likely to mutate can interrogate multiple samples and colonies for drug
as a result of dysfunctional DNA repair mechanisms (56,57). resistance. These aspects will need to be addressed to prevent
Furthermore, the genetic background of different strains the future emergence of TB-specific drug resistance.
results in differing fitness costs associated with particular
DR mutations (28). There may also be synergistic interaction
DIAGNOSIS OF DRUG-RESISTANT
between hyper mutable bacterial lineages and patients who
rapidly metabolise first-line drugs [high PK variability], thus,
TUBERCULOSIS
accounting for the high rates of MDR-TB reported in some Improving the diagnosis of DR-TB is potentially the single
settings despite directly observed therapy. most effective intervention that can enhance the clinical
Findings from WGS-related studies have shown that outcome of patients and limit the emergence of new cases.
resistance-encoding mutations are associated with compensa­ However, only two-thirds of the estimated 9 million cases
tory mutations elsewhere in the TB genome (58-60). It is of TB are diagnosed each year, and less than half of these
known that compensatory mutations in Pseudomonas species undergo DST. The net effect of this phenomenon, which is
can modulate virulence and transmissibility (27), and com­ due in part to the limited availability of DST methods [which
pensatory mutations in Mtb can be associated with physio­ themselves are often slow], is that the majority of DR-TB
logical and structural changes (27). Collectively, these cases remain untreated and continue to transmit disease. If
findings raise the possibility that drug resistance could affect we are to enhance the diagnosis of DR-TB, which we know
mycobacterial structure and antigen specificity, and hence, results in improved treatment initiation (63,64), clinical
perhaps even the T-cell immune responses. The underlying outcomes (65-67), and long-term TB incidence (41,68), we
immunology in patients with DR-TB is poorly understood and need to not only ensure that every patient diagnosed with
few data are available (27). Nevertheless, several immuno- TB also undergoes DST, but also understand the strengths
therapeutic interventions have been proposed for the treat­ and limitations of different diagnostic technologies. Current
ment of DR-TB, e.g., M. vaccae, vitamin D, and intravenous state-of-the-art methods for diagnosing DR-TB are described
immuno­globulin [IVIG], though their effectiveness remains in Figure 42.4 and Table 42.1A. Table 42.1B (69-93) provides
to be proven across different settings (60). a comprehensive list, together with their mode of operation,
and commercial manufacturers.
Fitness Cost
Culture-based Tests
Transmission is driven by clinical, bacterial, behavioural,
and environmental factors. However, as already outlined, Phenotypic testing involves incubating a bacterial isolate
transmission dynamics plays a critical role in the patho­ [grown from a clinical specimen] in the presence of a specific
genesis of DR-TB in terms of total case burden. For drug. As this method directly measures bacterial growth
example, in South Africa, over 80% of new MDR-TB cases [and is not reliant on proxies of resistance, such as genetic
are due to person-to-person spread rather than by acquired mutations], it is the most sensitive and most specific form of
resistance. Thus, over time, transmission becomes the DST, and is often the benchmark against which other tests
predomi­nant mode of acquisition of drug resistance. It is are measured. Although optimised, more rapid versions
also well-recognised that a small percentage of individuals are available, such as, microscopic observation direct
[< 10%–20%] are responsible for most of the disease trans­ susceptibility [MODS], phenotypic testing will always be
mis­sion. The determinants of the ‘super spreader’ status are constrained by the relatively slow growth of Mtb. This limits
 Drug-resistant Tuberculosis 585

C
Figure 42.4: New rapid tests for detecting mutations associated with DR-TB. The MODS kit [Hardy Diagnostics], where bacilli are cultured in a
micro titre well plate format, and inspected using light microscopy for distinctive cording patterns, which are indicative of Mtb growth. MODS is
primary used for drug susceptibility testing [A]. The Xpert MTB/RIF test [Cepheid, Sunnyvale, USA], detects rifampicin resistance simultaneously
with Mtb. The test is largely automated and endorsed by the World Health Organization. Sputum treated with sample buffer is added to a single-
use MTB/RIF cartridge [left panel], prior to loading into a GeneXpert machine [middle panel; a four module GeneXpert machine is depicted],
before the reading of the result about 2 hours later [right panel; information regarding the TB status, bacterial load, and rifampicin susceptibility
is shown] [B]. The Genotype MTBDRsl assay, which detects mutations in the rrs, gyrA and embB genes [associated with resistance to the
aminoglycosides, flusroquinolones, and ethambutol, respectively], shown. Nucleic acid amplification products are separated via lateral flow onto a
strip containing probes corresponding to specific mutations. Upon binding to a probe, a colorimetric reaction occurs and the presence or absence
of a mutation is visualised [C]. Images are courtesy of the respective manufacturers
DR-TB = drug-resistant TB; TB = tuberculosis; MODS = microscopic observation drug-susceptibility; Mtb = Mycobacterium tuberculosis
Reproduced with permission from “Dheda K, Gumbo T, Gandhi NR, Murray M, Theron G, Udwadia Z, et al. Global control of tuberculosis: from
extensively drug-resistant to untreatable tuberculosis. Lancet Respir Med 2014;2:321-38” (reference 27)
586 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 42.1A: Time-to-result and lower limit of bacilli detection for various diagnostic tests for TB
Diagnostic test Time-to-result Lower limit of bacilli detection
AFB Microscopy
Z-N stain 45 minutes 104 bacilli/mL
LED-FM 30 minutes 104 bacilli/mL
Mycobacterial growth detection
Solid [L-J medium] Up to 6-8 weeks 10-100 bacilli/mL
culture [average 3-4 weeks]
Solid [L-J medium] 6 weeks after detection of growth All positive cultures
culture DST
Liquid culture [MGIT-960] Up to 6-8 weeks 10-100 bacilli/mL
[average 10-14 days]
Liquid culture DST 1-2 weeks after detection of growth All positive cultures
ICA 15 minutes
LPA
FL-LPA 48 hours 104 bacilli/mL
SL-LPA 24-48 hours 104 bacilli/mL
GeneXpert
Xpert MTB/RIF 90 minutes 131 CFU/mL
Xpert MTB/RIF Ultra 90 minutes 16 CFU/mL
TB = tuberculosis; AFB = acid-fast bacilli; Z-N = Ziehl-Neelsen; LED-FM = light emitting diode-fluorescent microscopy;
L-J = Lowenstein-Jensen; DST = drug-susceptibility testing; MGIT = mycobacterial growth inhibitor tube; ICA =
immunochromatographic assay; LPA = line probe assay; FL = first-line; SL = second-line

the utility of currently commercially available platforms, and specificity of the assay for rifampicin resistance to be
such as the BACTEC MGIT 960 System [Becton-Dickinson], 95% and 98%, respectively (101). The Xpert MTB/RIF will
for patient management [time to result can range from not detect isoniazid mono-resistance, which is in one in
1–4 weeks after a culture isolate has grown, which itself can seven TB cases worldwide [and in half of TB cases in
take 1–6 weeks] (94-96) and result in patients with DR-TB Eastern Europe] (102). Another concern is Xpert MTB/
being ‘lost’ by the system. This, coupled with demanding RIF’s suboptimal false-positivity for rifampicin resistance,
technical and infrastructural requirements, means that for which data are conflicting. For example, in settings such
molecular tests, which are potentially deployable close to the as India, where the MDR-TB/RR-TB prevalence is 2.2%
patient, are better for the rapid diagnosis of drug-resistance. amongst new cases (1), it is projected that half of those with
a positive Xpert MTB/RIF result will be phenotypically
Nucleic Acid Amplification Tests susceptible [only 1 in 10 will be “false-positive” amongst
retreatment cases] (103). However, in settings such as Brazil,
Nucleic acid amplification tests [NAATs] detect DNA muta­ which also have a low MDR-TB prevalence [~1%], empiric
tions associated with drug resistance. They are inherently evidence has suggested the false-positive rate to be low
rapid because they do not rely on mycobacterial growth, [< 1 in 10] (104). In South Africa [MDR-TB prevalence of
and can go from “specimen in” to “result out” in a few 2% in new cases], the false-positivity rate has been shown
hours, meaning that patients could theoretically present to to be very low [less than 1 in 100] (105). A new version of
the clinic, be correctly diagnosed, and started on effective the Xpert MTB/RIF assay cartridge called the Xpert MTB/
treatment in a single clinical encounter. Critically, simulta­ RIF Ultra has been released in 2016. This assay includes
neous NAAT-based DST for at least one of the first-line multicopy insertion sequence targets [IS6110 and IS1081]
drugs is increasingly being incorporated into initial which allow improved sensitivity in the detection and the
diagnostic tests for TB, the best example of which is Xpert differentiation of the Mtb complex. The new cartridges have
MTB/RIF [Cepheid, Sunnyvale, USA]. decreased run-time, improved chemistry and, improved
Xpert MTB/RIF is a quantitative real-time NAAT that probes which target the 81bp-rifampicin resistance “hotspot”
diagnoses TB and rifampicin resistance in less than two of the Mtb genome. These cartridges have improved
hours (97). It is an automated, cartridge-based system that sensitivity of the assay as compared to that of the Xpert
can be performed in well-resourced decentralised locations, G4 version by 5% but with a loss of 3% specificity when
outside of reference laboratories by staff with minimal “trace” results were considered positive (106a). In addition,
laboratory training (98). It has been widely validated, a new version of the GeneXpert system, which allows for
endorsed by the World Health Organization [WHO] (99) one cartridge to be run at a time has been released. This
and the US Federal Drug Administration [FDA], (100) for device can be battery operated and is point-of-care, allowing
the initial diagnosis of TB and for the diagnosis of MDR- for the detection of Mtb and determination of rifampicin
TB, and is increasingly being deployed in high burden in remote locations. In South Africa, second-line treatment
countries. A meta-analysis has reported the sensitivity is initiated based on an Xpert MTB/RIF result; however,
Table 42.1B: Available and in-development phenotypic and molecular-based tests for detecting drug resistance in
Mycobacterium tuberculosis
Test Description Advantages Limitations Commercial versions
Culture methods
Solid agar Bacilli are grown in the Highly sensitive and specific [considered the ‘gold Slow time-to-result [2-4 months] requires Typically done using in house
[Middlebrook presence or absence of standard’ of DST] an isolate and cannot be performed directly methods
or Lowenstein each drug. An isolate is Relatively inexpensive from the specimen
Jensen media] resistant when the agar Standardisation challenges [e.g., drug
plate containing the drug critical concentration, reproducibility,
has ≥1% the number of inoculum size, media and drug pH]
colony forming units as the Technically challenging and requires strong
media without the drug laboratory biosafety infrastructure
Unreliable for drugs with close MICs and
critical concentrations [e.g., ethambutol]
Automated Decontaminated sputum is Highly sensitive and specific [like the solid agar Similar limitations to solid agar methods Bactec MGIT960 system and
liquid inoculated into a liquid- method is also considered the ‘gold standard’ of DST] Higher rates of contamination than solid SIRE and PZA kits [Becton–
techniques media containing tube, Faster than solid agar DST agar DST Dickinson]
which is automatically and WHO approved (1) VersaTrek/ESP [Thermo Fisher
continuously monitored for Scientific]
growth BacT/Alert3D [bioMerieux]
Microcolony Drug-free or drug- Highly sensitive and specific (1) Limited evidence for second-line drugs TB MODS Kit [Hardy
culture containing media is Generally rapid [mean turnaround time for MODS May not be suited to high NTM settings Diagnostics]
techniques inoculated with specimens and TLA of 10 and 11 days, respectively] Require significant technical expertise Sensititre system
from patients and Can be performed directly on specimens but less infrastructure than other culture [Thermoscientific, TREK
Drug-resistant Tuberculosis

examined microscopically Relatively inexpensive and non-proprietary methods Diagnostic Systems]

for growth, frequently in MODS is approved by the WHO No commercial versions of the NRA or TLA In development: B-SMART
closed micro-well plates assays exist [Sequelae]
NAATs
Fully or For Xpert MTB/RIF which Rapid [potentially same day results] Xpert MTB/RIF only detects rifampicin Xpert MTB/RIF, Xpert MTB/RIF
partially is the only commercially Can be performed directly on specimens resistance [not isoniazid] Ultra [Cepheid]
automated available test in this DST may occurs simultaneously with TB detection Patients with a low pre-test probability of In development: Xpert XDR-
nucleic acid category, liquefied sputum Closed cartridge system which minimises cross- MDR-TB who are positive for rifampicin TB cartridge [isoniazid and
amplification is added to a cartridge and contamination and the technical expertise required resistance require confirmatory testing second-line drugs], m2000
assay inserted into the machine. Xpert MTB/RIF is WHO and FDA approved and Relatively costly and requires expensive RealTime MTB DST reflex
A run is completed within widely available instruments assay [Abbott], AlereQ relex
2 hours. Several fast Can provide quantitative information about bacterial DST test [Alere], Fluorocycler
followers are expected load, which can predict infectiousness [Hain Lifescience]
Contd...
587
 588

Contd...

Test Description Advantages Limitations Commercial versions

LPAs Polymerase chain reaction Good sensitivity and high specificity and can detect Sensitivity generally lower when performed MTBDRplus and MTBDRsl
amplicons are passed multiple targets in parallel on smear-negative samples [Hain Lifesciences]
over a lateral flow strip Rapid [time to result of 2 days] Phenotypic DST required in specimens or INNO LiPA RifTB
containing probes for MTBDRplus and the next iteration of the MTBDRsl isolates with a susceptible DST result in [Innogenetics]
specific mutations. Bound assay can be performed directly on specimens order to rule-out second-line resistance TB Resistance Module [AID]
amplicons and mutations Information about specific mutations [e.g., in inhA Generally open system with manual steps AdvanSure MDR TB GenoBlot
are subsequently detected and katG] can inform dosing that is vulnerable to cross-contamination assay [LG Life Sciences]
colourmetrically Some LPAs are WHO approved Limited performance data [expect for the MDR-TB, INH, PZA and FLQ
Low instrumentation costs Hain Lifesciences LPAs] LPAs [NIPRO Co.]
Performance depends on the local genetic MolecuTech REBA MTB-
epidemiology of drug-resistant TB strains. MDR – FQ, -KM, -XDR [YD
Mutations in drug-susceptible strains Diagnostics]
can cause false positive results in some
regions (1)
Manual NAATs These generally require Highly multiplexed and amenable to high throughput Very limited performance data Anyplex plus MTB/NTM/MDR
manual DNA extraction and DST often occurs in conjunction with TB detection Can only be viably performed at high level TB and Anyplex II MTB/MDR/
real-time [or isothermal] reference laboratory due to the manual XDR [Seegene]
PCR instrumentation processing steps and non-automated MeltPro Drug Resistant TB
testing procedure testing kits [Xiamen Zeesan
Biotech] (1)
B-SMART NASBA-based test
[Sequella Inc.]
Other tests This category includes Highly multiplexed and amenable to high throughput Very limited performance data INFINITI MDR-TB assay
microarray platforms and Several technologies are FDA-endorsed or CE- Only suited to well-resourced reference [AutoGenomics]
mass spectrophotometry marked [e.g., INFINITI MDR-TB assay] laboratories, however some tools currently M. tuberculosis Drug
systems. They are not in development show promise for POC use Resistance Detection Array Kit
widely used and have [e.g., HYDRA 1K] Limited availability in the [CapitalBio Corp.]
limited evidence to support high burden TB countries Ibis Mass Spectrometry
their use Expensive platform [Abbott]
In development: VerePLEX
Biosystem and VEreMTB
Detection Kit [Veredus
Laboratories], TruArray MDR-
TB assays [Akonni Biosystems,
Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

MYCO assay [iCubate],

HYDRA 1K [Insilixa Inc.].
DST = drug-susceptibility testing; MIC = minimum inhibitory concentration; WHO = World Health Organization; PZA = pyrazinamide; TB = tuberculosis; MODS = microscopic obser­
vation drug-susceptibility; TLA, = thin layer agar; NRA = nitrate reductase assay; NAATs = nucleic acid amplification tests; FDA = Federal Drug Administration; MDR-TB = multidrug-
resistant tuberculosis; LPAs = line probe assays; DNA = deoxyribonucleic acid; PCR = polymerase chain reaction; POC = point-of-care; NTM = nontuberculosis mycobacteria
Data from references 69-93
 Drug-resistant Tuberculosis 589

confirmatory testing is subsequently done using a LPA, the the diagnosis of DR-TB (110), as the cost of sequencing has
most widely available example of which is the MTBDRplus declined dramatically. Although not as rapid as molecular
test [Hain Lifesciences], which can be performed directly on DST, the turn-around-time of sequencing methods is reduced
the specimen with high sensitivity and specificity (106b,107). by the use of “early positive” cultures [2–7 days] (111). As
With a vision to offer DST at the earliest time in the sequencing provides a comprehensive genotypic DST, it
diagnostic process, the Guidelines on management of DR- permits patients to have individualised treatment regimens,
TB in India (108a), integrated DR-TB diagnostic algorithm which is more likely to result in cure (112). However, the
has been recommended. This algo­rithm [Figures 42.5A and clinical impact of this strategy in different settings remains
42.5B] facilitates risk assessment for DR-TB and DST-guided to be established. Next generation sequencing also allows
treatment for at least rifampicin resistance at the time of for the detection of minority populations and information
diagnosis [“universal DST”]. on compensatory mutations. Furthermore, it provides infor­
NAAT are often unable to target all resistance causing mation on transmission and allows for tracking of outbreaks,
mutations. For example, resistance to the SLIDs is, in and it can be used to identify novel mutations to newly
addition to being caused by mutations in rrs, also caused by introduced anti-TB drugs. This is of particular importance in
mutations in tlyA, the eis promoter and gibB, the frequency high burden settings, where transmission can quickly drive
distribution of which differs according to geographical resistance to these new drugs.
region (108b). Thus, confirmatory phenotypic testing is still
required in patients who have a susceptible result according Importance of Healthcare Systems and
to, for example, the MTBDRsl [Hain Lifesciences] LPA, Linkage to Care
which only targets rrs for SLID DST (109). This also applies Lastly, it should be noted that the impact of a test for DR-TB
to new tests in development, such as the Xpert XDR assay will always be undermined by the quality of the healthcare
[Cepheid, Sunnyvale, USA], which targets only rrs and eis for system. Healthcare workers should do everything they can
the SLIDs, and new molecular assays for new drugs, such to make sure diagnostic specimens arrive at laboratories
as bedaquiline and delamanid, for which we have an incom­ timeously, are processed quickly, the result is rapidly sent
plete understanding of the genetic associates of resistance. back, and that drugs are readily available to rapidly start
patients on treatment. For example, a study (113) in Cape
Targeted and Whole Genome Sequencing Town found that Xpert MTB/RIF reduced time to MDR-TB
Next generation sequencing [which can be performed on the treatment from 25 days to 17 days, however, this is nowhere
entire genome or pre-specified regions] offers promise for near what it should be for a test that takes two hours.

Figure 42.5A: Integrated DR-TB diagnostic algorithm in adults

*States to advance in phased manner as per PMDT scale up plan for universal DST based on lab capacity and policy on use of diagnostics
† LC DST [Mfx 2.0, Km, Cm, Lzd] will be done only for patients with any resistance on baseline SL-LPA. DST to Z, Cfz, Bdq and Dlm would be
considered for policy in future, whenever available, standardised and WHO endorsed.
‡ Molecular testing is offered for H-mono/poly resistance to TB patients prioritised by risk as per the available laboratory capacity
TB = tuberculosis; DR-TB = drug-resistant TB; CBNAAT = cartridge-based nucleic acid amplification tests; HIV = human immunodeficiency
virus; EPTB = extra-pulmonary TB; NA = not available; RR-TB = rifampicin resistant TB; RS-TB = rifampicin-sensitive TB; SL-LPA = second-
line line probe assay; FL-LPA = first-line line probe assay; PMDT = programmatic management of drug-resistant TB; DST = drug-susceptibility
testing; LC = liquid culture; Mfx 2.0 = moxifloxacin break-point concentration 2 mg/L; Km = kanamycin; Cm = capreomycin; Z = pyrazinamide;
Cfz = clofazimine; Bdq = bedaquiline; Dlm = delaminid; WHO = World Health Organization
Reproduced with permission from “Revised National Tuberculosis Control Programme, Directorate General of Health Services, Ministry of Health
and Family Welfare, Government of India. Guidelines on programmatic management of drug-resistant tuberculosis in India 2017. New Delhi:
World Health Organization, Country Office for India; 2017” (reference 108a)
 590 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 42.5B: Integrated DR-TB diagnostic algorithm in children

TB = tuberculosis; DRT = drug-resistance testing; DST = drug-susceptibility testing; DR-TB = drug-resistant TB; DS-TB = drug-sensitive TB
Reproduced with permission from “Revised National Tuberculosis Control Programme, Directorate General of Health Services, Ministry of Health
and Family Welfare, Government of India. Guidelines on programmatic management of drug-resistant tuberculosis in India 2017. New Delhi:
World Health Organization, Country Office for India; 2017” (reference 108a)

In summary, molecular DST is accurate and feasible in two-thirds of patients with MDR-TB globally have not
high incidence countries and should always be performed previously been treated for TB, and thus, DR-TB should
as the initial test for drug resistance; however, due to always be excluded.
suboptimal rule-out value for drug resistance, culture-based
phenotypic DST should always also be performed. Good PRINCIPLES OF DRUG-RESISTANT
infrastructure and training to support the use of DST results TUBERCULOSIS TREATMENT
for rapid patient management are critical.
Treatment of Multidrug-resistant and
CLINICAL PRESENTATION Extensively Drug-resistant Tuberculosis
The clinical features of DR-TB are indistinguishable from The updated 2016 WHO guidelines (115) recommended a
those of DS-TB and include cough, fever, weight loss, stan­dardised regimen with an intensive phase of treatment
haemoptysis and night sweats. The traditional culture-based containing kanamycin [an injectable agent], moxifloxacin,
laboratory diagnosis of DR-TB results in long delays [usually prothionamide, clofazimine, isoniazid, pyrazinamide and
several weeks] in obtaining DST results, and as a result, DR- ethambutol which are given together in an initial phase
TB is often diagnosed late when DS-TB treatment fails or of 4 months [with the possibility to extend to 6 months if
when the cultures are still positive after several months of they remain sputum smear positive at the end of month 4].
treatment. During this delay, patients may undergo clinical This is then followed by the continuation phase of treat­
worsening, and thus, are often sicker with more extensive ment for 5 months with a regimen consisting of four TB
radiological disease at the time of commencement of DR-TB. drugs: moxifloxacin, clofazimine, pyrazinamide, and
The NAATs promise to reduce the interval between sample ethambutol (115,116a). The suggested regimens for the
acquisition and DST result from weeks to hours. Previous programmatic management of drug-resistant TB in India
treatment for TB, local rates of drug resistance, or contact are listed in Figure 42.6 (108a).
with a patient with DR-TB may raise the suspicion that the In 2018 August, December the WHO rapid communication
current episode is DR. Some studies have identified HIV regarding key changes to treatment of MDR/RR-TB (117a)
infection, homelessness and a history of alcohol abuse as and pre-final text ahead of a fully edited version scheduled
additional predictors of risk (114), but this has not been for publication in early 2019 as part of consolidated WHO
consistent across different countries. Nevertheless, almost treatment guidelines on DR-TB (117b) were published.
 Drug-resistant Tuberculosis 591

Figure 42.6: Treatment regimens for programmatic management of DR-TB in India

*States to advance in phased manner as per PMDT Scale up plan for universal DST based on lab capacity and policy on use of diagnostics
† Conventional MDR-TB regimen [24 months] for pregnant women or for EPTB patients who are not eligible for shorter regimen
‡ LC DST [Mfx 2.0, Km, Cm, Lzd] will be done only for patients with any resistance on baseline SL-LPA. DST to Z, Cfz, Bdq and Dlm would be
considered for policy in future, whenever available, standardised and WHO endorsed
§ Molecular testing and treatment for H-mono/poly resistance is offered to TB patients prioritised by risk as per the available lab capacity
TB = tuberculosis; CBNAAT = cartridge-based nucleic acid amplification tests; HIV = human immunodeficiency virus; EPTB = extra-pulmonary TB;
NA = not available; RR-TB = rifampicin resistant TB; RS-TB = rifampicin-sensitive TB; MDR-TB = multidrug-resistant TB; SL-LPA = second-line
line probe assay; FL-LPA = first-line line probe assay; FQ = fluoroquinolones; SLI = second-line injectable drugs; H = isoniazid; PMDT = programmatic
management of drug-resistant TB; DST = drug-susceptibility testing; LC = liquid culture; Mfx 2.0 = moxifloxacin break-point concentration 2 mg/L;
Km = kanamycin; Cm = capreomycin; Z = pyrazinamide; Cfz = clofazimine; Bdq = bedaquiline; Dlm = delaminid; WHO = World Health Organization
Reproduced with permission from “Revised National Tuberculosis Control Programme, Directorate General of Health Services, Ministry of Health
and Family Welfare, Government of India. Guidelines on programmatic management of drug-resistant tuberculosis in India 2017. New Delhi:
World Health Organization, Country Office for India; 2017” (reference 108a)

Tables 42.2A, 42.2B and 42.2C (116b,117a,117b) depict the especially in patients who are to be started on the shorter
revised grouping of anti-TB medicines recommended for MDR-TB regimen [defined as a course of treatment for
use in longer MDR-TB regimens. The anti-TB medicines MDR/RR-TB lasting 9 to 12 months]. The WHO 2018
that were grouped into four groups as per the WHO 2016 guidelines (117a) also address issues concerning need for
guidelines (115) have regrouped into three categories close monitoring of patient safety and treatment response;
[Table 42.2C] in the WHO 2018 guidelines (117a,117b) a low threshold is recommended for switching non-
and have been ranked based on the latest evidence as per responding patients or those experiencing drug intolerance
the effectiveness and safety. As per the WHO 2018 guide­ to alternative medicines and/or new regimens. Options for
lines (117a), Group A includes anti-TB medicines to be the choice of agents for the intensive and continuation phases and
prioritized; Group B includes anti-TB medicines to be more detailed guidance is expected to be provided at the time of
added next; and anti-TB medicines that are to be included release of the final WHO guidelines later in 2019.
to complete the regimens and when anti-TB medicines from In South Africa, approximately half of the MDR-TB
Groups A and B cannot be used are listed under Group C. patients receiving kanamycin develop some degree of
Kanamycin and capreomycin are no longer recommended. ototoxicity and nephrotoxicity prompting substitution of
Based on the currently available published evidence, kanamycin with bedaquiline. Additionally, a retrospective
the WHO 2018 rapid communication (117a) recommend cohort analysis con­ducted by the South African Department
implementing effective and fully oral treatment regimens for of Health showed that, in rifampicin-resistant TB, bedaquiline
most patients. The guidelines (117a) also suggest the need resulted in a 41% increase in treatment success and a three-
to ensure that drug- resistance is excluded [at least to the fold reduction in mortality, compared with those that did not
fluoroquinolones and injectables] before initiating treatment, receive bedaquiline (118,119). Thus, based on the superior
 592

Table 42.2A: Characteristics of drugs* used for drug-resistant TB

Group Dosage Special precautions Adverse events
Group A
Include all three
medicines [unless they
cannot be used]
Levofloxacin [Lfx] 500 mg-1000 mg daily Dose adjustment required in CKD In advanced CKD, class effect of fluoroquinolones may
Cr cl 30-50 mL/min = 750-1000 mg daily pose a higher risk of neuro-psychiatric adverse events and
<30 mL/min = 750-1000 mg thrice weekly tendinopathy; QTc prolongation on ECG more with Mfx
   or than Lfx, a combination of Bdq, Cfz and Lfx [rather Mfx]
preferred
Moxifloxacin [Mfx] 400 mg daily No dose adjustment in CKD; predominantly hepatobiliary
excretion; may increase liver enzymes; has good
CNS penetration; avoid concomitant administration of
antacids, phosphate binders, calcium, iron, or aluminium
containing medications to avoid malabsorption

Bedaquiline [Bdq] 400 mg daily for initial 2 weeks Administration with meal increases bio-availability; no QTc prolongation, arthralgias, hepatitis, headache,
and subsequently 200 mg thrice dose adjustment with renal or liver disease; ECG should anorexia, nausea
weekly for next 22 weeks [can be be done to monitor QTc prolongation at baseline, 2,12
given longer] and 24 weeks and stop the drug if QTc >500 ms, serum
serum potassium, magnesium and calcium monitoring
required for QTc prolongation; QTc monitoring required
when co-administered with clarithromycin, Cfz, Lfx/Mfx
Linezolid [Lzd] 600 mg once daily; the dose can Main route of excretion is hepatic with some renal Haematological toxicity, lactic acidosis, peripheral and
be decreased to 300 mg after clearance. No dose adjustment is required in CKD; optic neuropathy and serotonin syndrome. Drug toxicity is
3-6 months; linezolid should careful monitoring of haematological toxicity, lactic related to dose and duration of linezolid. Haematological
be discontinued in case toxicity acidosis, peripheral and optic neuropathy [often toxicity and lactic acidosis occur in few weeks to months
occurs and can be re-introduced reversible] required. Pyridoxine 100 mg daily can be while neurological toxicity occurs after 3-4 months
at a lower [300 mg daily] dose administered to prevent haematological toxicity. Avoid
following recovery concomitant use of food items rich in tyramine and
medications [SSRIs and other medicines] known to
Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

increase serotonin production to prevent development of

serotonin syndrome
Contd...
Contd...
Group Dosage Special precautions Adverse events
Group B
Add both medicines [unless
they cannot be used]
Clofazimine [Cfz]
100 mg daily QTc monitoring on ECG is required when co- Ichthyosis and dry skin, sunburn, pink-brownish-
administered with Bdq, Lfx/Mfx; serum potassium, black discoloration of skin, cornea, retina and
magnesium and calcium monitoring required for QTc urine; acne flare
prolongation. Not to be used in pregnancy and severe
hepatic insufficiency. Skin problems can be prevented by
application of sunscreen and lubricants
Cycloserine [Cs] 10-15 mg/kg/day in divided Cr cl ≥ 30 mL/min: no dose adjustment required; Dizziness, slurred speech, convulsions, headache,
doses < 30 mL/min: 250 mg daily or 500 mg on alternate days; tremor, insomnia, confusion, depression, and
or therapeutic drug monitoring is recommended if facility is altered behaviour, suicidal tendency, generalised
250 mg morning available; avoid if possible in renal disease as the main hypersensitivity reaction or hepatitis
OR 500 mg evening route of excretion is renal.
Cs[and Trd] should be avoided in patients with a history
Terizidone [Trd] of epilepsy, psychiatric illness or alcoholism, to prevent
300 mg morning minor adverse reactions like insomnia administration
300 mg evening of small dose of a tranquiliser is recommended or
pyridoxine 50 mg/250 mg of administered cycloserine
can be given to prevent neurotoxicity
Group C
Add to complete the regimen
and when medicines from
Group A and B cannot be used
Drug-resistant Tuberculosis

Ethambutol [E] 15-25 mg/kg/day Cr cl ≥ 30 mL/min, no dose adjustment required; Dose dependent optic [retrobulbar] neuropathy
< 30 mL/min: 15-25 mg/kg thrice weekly. [> 30 mg/kg/day or
Patients should be monitored at baseline and regularly 15-25 mg/kg in CKD]; generally reverses on prompt
thereafter for visual acuity and red-green colour discontinuation;
discrimination hyperuricemia
Uncommon: interstitial nephritis, cholestatic
jaundice, neutropenia and thrombocytopenia,
reversible cutaneous hypersensitivity disappearing
on desensitisation
Delamanid [Dlm] 100 mg twice weekly for six QTc monitoring at baseline, 2, 12 and 24 weeks. Stop if > QTc prolongation, nausea vomiting and abdominal
months [can be administered QTc 500 ms; monitor serum potassium, magnesium and pain, dizziness
longer] calcium
Pyrazinamide [Z] 25-30 mg/kg/day Cr cl ≥ 30 mL/min: no dose adjustment required; GI upset, hyperuricemia, arthralgia, hepatotoxicity
[1.5 g for 50 kg, < 30 mL/min: 25-30 mg/kg three times/week [not dose related]
2 g for > 50 kg]
Contd...
593
 594

Contd...
Group Dosage Special precautions Adverse events
Imipenem - cilastatin [Ipm-Cln] 1 g IV every 12 h Dose adjustment required in CKD
OR
Meropenem Amoxycillin
Clavulanate [Mpm/Amx/Clv] 1 g every 8-12 h IV administered Dose adjustment required in CKD GI upset, transaminitis
with clavulanate [as amoxycillin
clavulanate 250/125 mg
every 8-12h]
Amikacin [Am] 15 mg/kg-maximum 1 g; five to Baseline audiogram and renal functions. Dose Vestibular, auditory and renal toxicities
seven times weekly or adjustment required in CKD; prefer to avoid if possible.
20-25 mg/kg 2-3 times/week Periodic monitoring of audiogram and renal functions
every 2-4 weeks
Ethionamide [Eto] 15-20 mg/kg/day Should not be administered in pregnancy [teratogenicity Pto is generally considered to be less unpleasant
or in divided doses. in animals]. Careful monitoring is required if administered and better tolerated than Eto. However, profile of
Prothionamide [Pto] The usual dose is 250-1000 mg/ in patients with diabetes mellitus, liver disease, adverse events is similar.
day. alcoholism or mental instability. GI disturbances, metallic taste and sulphurous
Most patients should be started No dose adjustment required in CKD. belching; psychotic reactions, hypoglycaemia
on 250 mg doses daily or twice Serum TSH monitoring required periodically especially [especially in diabetes mellitus patients]; hepatitis;
daily and gradually increased when co-administered with PAS other rare side-effects include gynaecomastia
over several days to 750 or menstrual disturbance, impotence, acne, alopecia
1000 mg total daily dose and peripheral neuropathy
p-amino salicyclic acid [PAS] 150 mg/kg or 10-12 g daily Although no dose adjustment required in CKD. GI disturbances [diarrhoea is self-limiting],
In 2-3 divided doses However, caution should be exercised, since main route hypothyroidism [more chances if given along
of excretion is renal. with ethionamide], hypokalemia, hepatitis,
Serum TSH monitoring required periodically especially thrombocytopenia, increased acidosis in patients
when co-administered with ethionamide with renal failure
* All are bactericidal except Cs and PAS which are bacteriostatic; Cfz and Eto are weak bactericidal
TB = tuberculosis; CKD = chronic kidney disease; Cr Cl = creatinine clearance; CKD = chronic kidney disease; ECG = electrocardiogram; SSRIs = selective serotonin reuptake
Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

inhibitors; TSH = thyroid stimulating hormone

Data from references 116b,117a,117b
Table 42.2B: Principles underpinning the management of drug-resistant TB
Principles underpinning the medical management of MDR-TB
A regimen is based, when possible, on proven or likely susceptibility to at least 5 drugs
A backbone of a later generation fluoroquinolone [moxifloxacin or levofloxacin], and bedaquiline and any drugs such as clofazamine, ethionamide, high dose isoniazid are
recommended, such that at least 5 drugs to which the isolate is likely to be susceptible are being used is recommended. Use of an injectable in a frontline MDR-TB regimen is not
recommended given the proven efficacy of bedaquiline and the toxicity of SLIDs. This proposed approach is synonymous with using bedaquiline in place of the SLID in the WHO
shorter course regimen
Where toxicity, intolerance or resistance precludes use of one of the standard MDR-TB drugs, delamanid and/or linezolid may also be added to the regimen
Bedaquiline is usually used for a minimum duration of 6 months in the absence of adverse events, and longer in certain cases.
The total recommended duration of treatment using the 2016 standardised WHO shorter treatment regimen is between 9 months and 12 months [depending on culture conversion],
recommend a 12 month duration of treatment if bedaquiline is included in the regimen
   If the patient has previously been on treatment with a specific drug for 3 or more months, then that drug is generally avoided
   Addressing psychological and social factors to ensure adherence is critical
   Patients should be monitored for adverse drug reactions, which are common
   A single drug should not be added to a failing regimen
Principles underpinning the medical management of pre-XDR-TB and XDR-TB
   Regimens should be constructed based on prevailing DST patterns
  A regimen is usually based on a backbone of bedaquiline, linezolid, PAS [and cycloserine]. Other drugs such as delamanid and meropenem/clavulanate are added depending
on availability.
   In patients with FQ-resistant pre-XDR-TB a SLID may be considered
  Given the high degree of resistance, any drug that the isolate is [potentially] susceptible to from Table 42.2A are added such that at least 4-5 effective drugs are included in
Drug-resistant Tuberculosis

the regimen
   Patients should be carefully monitored for adverse drug reactions [Table 42.2A]
  Attention should be given to correcting risk factors for renal failure [dehydration, nausea, vomiting and diarrhea, avoidance of other nephrotoxic drugs [cotrimoxazole and
nevirapine], and early identification of underlying renal disease [diabetes and HIV-associated nephropathy]
  Patients on linezolid should be monitored for the development of myelosuppression [usually develops with in 2-3 months of treatment], peripheral neuropathy [usually develops
between 1 month and 4 months of treatment] and optic neuropathy [usually develops after 5 months of treatment]
  Patients on bedaquiline and delamanid [especially when used with other QT prolonging drugs] should have a baseline ECG, with follow-up ECG at least 2, 6, 12, and 24 weeks
after starting therapy to monitor for QT prolongation. Serum calcium, potassium, and magnesium should be measured prior to starting treatment and corrected if needed
  Bedaquiline should be discontinued in patients who develop QTc interval >500 ms or a significant ventricular arrhythmia. Liver function testing should also be performed prior
to initiation of treatment and repeated monthly
TB = tuberculosis; MDR-TB = multidrug-resistant tuberculosis; XDR-TB = extensively drug-resistant TB; PAS = para-amino salicylic acid; DST = drug-susceptibility testing;
ECG = electrocardiogram
595
 596 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 42.2C: WHO 2018 rapid communication: grouping of medicines recommended for use in
longer MDR-TB regimens
Group Medicine [abbreviation]
Group A: Include all three medicines [unless they cannot be used] Levofloxacin [Lfx] OR moxifloxacin [Mfx]
Bedaquiline [Bdq], linezolid [Lzd]

Group B: Add both medicines [unless they cannot be used] Clofazimine [Cfz]
Cycloserine [Cs] OR terizidone [Trd]
Group C: Add to complete the regimen and when medicines from Ethambutol [E]
Groups A and B cannot be used Delamanid [Dlm]
Pyrazinamide [Z]
Imipenem-cilastatin [Ipm-Cln] OR meropenem [Mpm]
Amikacin [Am] [OR streptomycin {S}]
Ethionamide [Eto] OR prothionamide [Pto]
p-amino salicylic acid [PAS]
*Longer MDR-TB regimens usually last 18-20 months and may be standardized or individualised. These regimens are usually designed to
include at least 5 medicines considered to be effective
WHO = World Health Organization; MDR-TB = multidrug-resistant tuberculosis
Adapted from “World Health organization. Rapid Communication. Key changes to treatment of multidrug- and rifampicin-resistant
tuberculosis [MDR/RR-TB]. WHO/CDS/TB/2018.18. Geneva: World Health organization; 2018” (reference 117a)

outcomes and better adverse event profile, the South African Long-term outcome data for linezolid in patients with
Department of Health has recently recommended the use XDR-TB, especially when combined with other effective
of bedaquiline for all MDR-TB patients [with kanamycin drugs such bedaquiline, is encouraging with reported
being substituted for bedaqualine in the shorter course treatment success rates approaching ~70% (119,128).
WHO regimen] (118,119). In patients who fail to respond to However, linezolid toxi­city, specifically myelosuppression
treatment the following must be considered: poor adherence, and peripheral neuro­pathy, is a major concern that prompts
incorrect dosage, poor penetration of drugs in lung cavities, treatment withdrawal in up to 1/3 of patients receiving
hetero-resistance, and malabsorption of anti-TB drugs. linezolid (129-134).
The treatment regimen for XDR-TB is more complex.
The current XDR-TB regimen consists of a backbone of Adverse Effects
bedaquiline, linezolid, and para-amino salicylic acid [PAS]. Treatment for DR-TB involves the use of toxic medications and
Other drugs [Table 42.2A] may be added depending on drug-associated adverse effects [AEs] are common (135-137).
availability [e.g., delamanid and meropenem plus clavulanic They impact compliance, cause drug suspension and
acid] and to which susceptibility has been demonstrated, treatment interruption, and may result in serious morbidity
or at the discretion of the attending clinician (115,116a). and even death. A study (138) from South Africa in patients
Many patients with XDR-TB have been pre­viously treated with XDR-TB found that 58% of patients experienced a drug-
for MDR-TB (120,121), and prior exposure to drugs like related AEs during their treatment, and culture-conversion
ethionamide, isoniazid and clofazamine usually excludes and survival were significantly lower in those patients
their use in a new regimen. who had experienced severe AEs. In this study, 5% of all
Moxifloxacin has been shown to be effective against AEs resulted in death, and the second-line injectable drugs
isolates phenotypically resistant to ofloxacin or cipro­ [in particular, capreomycin] were associated with all of
floxacin (122), and may be associated with improved these deaths. It is thus essential to monitor renal function
outcomes for patients with XDR-TB (123). In isolates where and potassium at least monthly during the intensive phase
lack of isoniazid susceptibility results from mutations in of treatment involving an injectable. Ototoxic hearing loss is
the promoter region of the InhA gene (124,125), low-level common in patients with DR-TB: another study from South
resistance can likely be overcome by increased doses of Africa found that 57% of patients had developed high-
the isoniazid [“high-dose isoniazid”] (126). This pattern frequency hearing loss after three months of aminoglycoside
of resistance is often accompanied with cross-resistance to treatment (139), and this complication may be more common
other second-line anti-TB agents, specifically ethionamide, as in patients with HIV infection. All patients should be
it has a structural similarity to isoniazid (127). In recent years, screened monthly with audiometry during the intensive
linezolid has been used to treat patients with X/MDR-TB, phase of treatment. Thyroid function should be monitored
although there have been no fully controlled trials of line­ between six and nine months of treatment with ethionamide,
zolid in a regimen for this indication. Linezolid added to prothionamide or PAS, and a full blood count, neurological
the regimen of patients failing standard XDR-TB treat­ exam and assessment of visual acuity should be checked
ment has been shown to improve culture-conversion (130). regularly in patients taking linezolid.
 Drug-resistant Tuberculosis 597

Adjuvant Surgical Management hope for the successful treatment of MDR-TB (130,165).
It should be noted that co-administration of bedaquiline
The rationale behind surgery for DR-TB is that excision of
with efavirenz has the potential of reducing serum levels
cavities [along with “debulking” of any necrotic or non-viable
of bedaquiline (166). It is, therefore, recommended that
lung tissue] will dramatically reduce the overall organism
bedaquiline be co-administered with two nucleoside
burden in the lung while simultaneously removing the sites
reverse transcriptase inhibitors [NRTIs] and nevirapine
of high concentrations of DR bacilli. This is hoped to enhance
or two NRTIs and a protease inhibitor [PI]. However, it
the sterilising properties of post-surgical chemotherapy and
should be noted that both nevirapine and certain PIs can
increase the likelihood of treatment success (140,141).
increase bedaquiline levels by 10%–20% but the significance
Reported outcomes for surgery in DR-TB are unavoidably
of this remains unclear (167). A potential alternative is an
skewed by selection bias, as sicker patients with bilateral
integrase inhibitor. However, this is not widely available in
disease and other comorbidities are generally not considered
resource-limited settings. Other toxicity-related drug-drug
operative candidates. However, a recent systematic review
interactions are described in Table 42.3.
and meta-analysis of 24 comparison studies of MDR- and
XDR-TB [involving more than 5000 patients] found a signifi­
MANAGING DRUG-RESISTANT TUBERCULOSIS
cant association between surgical intervention and success­
ful outcome when compared to non-surgical treatment IN SPECIAL SITUATIONS INCLUDING
alone {odds ratio [OR] 2.24, 95% confidence intervals [CI] PREGNANCY, RENAL FAILURE, LIVER DISEASE
1.68-2.97} (142). Sub-group analyses of studies involving AND IN THE INTENSIVE CARE UNIT
XDR-TB patients revealed an even more pronounced Management of DR-TB in special situations including
treatment effect [OR 4.55, 95% CI 1.32-15.7], which would pregnancy, renal failure, liver disease and in the intensive
the view that surgery is a viable therapeutic option in care unit necessitates a change in either the selection of
carefully selected patients who remain culture positive drugs, dosage, or duration of therapy. The reader is referred
despite receiving an effective regimen for drug-resistant TB, to the chapters “Tuberculosis in pregnancy” [Chapter 25],
or are deemed to have a high risk of relapse. Surgery as a “Tuberculosis in chronic kidney disease” [Chapter 28],
treatment modality for drug-resistant TB must be used in “Hepatotoxicity associated with anti-tuberculosis treatment”
conjunction with an effective salvage regimen consisting of [Chapter 45] and “Tuberculosis and acute lung injury” [Chapter 32]
at least 4-5 drugs. for details.

HUMAN IMMUNODEFICIENCY VIRUS AND NEW DRUGS AND TREATMENT REGIMENS FOR
DRUG-RESISTANT TUBERCULOSIS DRUG-RESISTANT TUBERCULOSIS
The management of TB in HIV-infected individuals is It is clear that the current available treatment regimen for
complex. The management of DR-TB in HIV-infected persons MDR-TB is inadequate. Issues with current treatments
is even more challenging, specifically due to the shared toxi­ include multiple drug toxicities, prolonged treatment dura­
city between anti-HIV and TB drugs [Table 42.3], (143-156), tion, development of acquired resistance, ART interactions
in addition to other factors such as greater potential for and the on-going use of injectable agents. A promising
increased drug toxicity, HIV-related organ disease such as pipeline of new drugs is emerging and at least 10 new studies
nephropathy, pharmacokinetic drug-to-drug interactions, are planned or underway to address this problem (168-188).
and immune reconstitution inflammatory syndrome [IRIS]. Key questions that will need to be addressed are listed below.
All these factors ultimately translate into increased com­ Bedaquiline is a diarylquinoline and the first new anti-TB
plexity and potentially mortality in MDR-TB-HIV co-infected drug on the market in over 40 years. This orally administrated
patients (157). agent acts via a novel mechanism that selectively inhibits
Antiretroviral therapy [ART] improves survival in mycobacterial adenosine triphosphate synthase (189). It
patients with MDR-TB (157-159). The WHO recommends that is well tolerated (166), and has demonstrated both safety
MDR-TB patients who are not already on ART should start and efficacy in HIV co-infected patients (165,170). XDR-TB
ART within the first eight weeks of starting effective MDR-TB patients receiving a backbone of bedaquiline and linezolid
treatment irrespective of CD4 count (160). Patients with low had substantially better favourable outcomes compared
CD4+ counts [<50/mm3] should have expedited initiation to those not using these drugs [66.2% versus 13.2%;
of treatment with anti-retrovirals [ARVs] usually within p < 0.001] (119). Bedaquiline is known to cause joint pains
two weeks of starting MDR-TB treatment (115,161-163), and prolongation of the QTc interval , which warrants regular
similar to the recommendation for DS-TB. ECG monitoring especially when using it in conjunction
Initiating ART together with MDR-TB drugs is challenging with fluoroquinolones [drug of choice is levofloxacin] and
because of overlapping adverse events, high pill burden, clofazamine.
IRIS, and potential drug-drug interaction [Table 42.3]. In Delamanid is an orally administered agent that acts by
recent times introduction of new drugs such as bedaquiline, inhibiting mycolic acid synthesis in the mycobacterial cell
shown to be both safe and efficacious even in a high HIV wall (179). It has demonstrated increased rates of sputum culture
prevalence settings (164), and linezolid have renewed conversion and improved clinical outcomes (181,190-192).
Table 42.3: Important drug co-toxicity and drug-drug interactions in patients with HIV/DR-TB co-infection
598
Responsible ARV Responsible anti-TB
Description drugs drugs Considerations
Renal toxicity TDF Aminoglycosides, Cm TDF causes renal failure with hypophosphatemia and proteinuria
Avoid TDF in patients receiving aminoglycosides and Cm
Serum creatinine should be checked before switching patients onto TDF after completion of aminoglycoside
Caution is advised when administering TDF or aminoglycosides in patients with underlying co-morbidities, such
as, diabetes mellitus or in patients who are receiving concomitant nephrotoxic agents such as NSAIDs and
amphotericin B
If TDF is necessary, close monitoring of serum creatinine is required
Electrolyte TDF Aminoglycosides, Cm Exclude exacerbating factors, such vomiting, diarrhoea, dehydration, diuretics, etc.
derangement
Hepatitis/ NVP, EFV, PI Z, Bdq, PAS, FQ When severe stop both ARVs and anti-TB agents, restart TB drugs first
hepatotoxicity [especially RTV], Assess for other contributing factors such as alcohol abuse, viral aetiologies and other drugs like co-trimoxazole
NRTI Avoid concomitant use of NVP and Z
The risk of NVP hepatotoxicity is highest in the first 3 months of starting therapy with higher risk in patients with
CD4+ >250/mm3, the risk of NVP hepatotoxicity is lower if VL is suppressed
Myelosuppression AZT Lzd, H Stop Lzd if myelosuppression occurs. Blood transfusion is indicated if haemoglobin falls below 8 g/dL
Avoid co-administration of AZT and Lzd
Adverse events should be managed with a combination of temporary suspension of linezolid, dose reduction
and/or symptom management
Reduction dose of 300 mg daily may be associated with fewer neuropathic effects but is not supported by
pharmacokinetic data
Consider stopping cotrimoxazole
Peripheral ddI, d4T Lzd, Cs, H, Eto, E Avoid use of D4T or ddI in combination with Cs or Lzd
neuropathy Use pyridoxine as prophylaxis in patients receiving Cs, H and Lzd
QT prolongation BDQ, Mfx, Cfz Lfx, Ofx Close monitoring of QTc is recommended when using these agents in combination
Central nervous EFV Cs, H, Eto/Pto, FQ EFV toxicity occurs in first 2–3 weeks of treatment
system toxicity Concurrent use of EFV with CS needs close monitoring
Headache AZT, EFV Cs, BDQ Headaches may be self-limited in case of AZT, EFV and Cs
Advice analgesia and hydration
Nausea and RTV, d4T, NVP Eto, PAS, H, BDQ, Most drugs will cause some degree of nausea
vomiting E, Z If persistent consider drug-induced pancreatitis, hepatitis
Lactic acidosis d4T, ddI, AZT, 3TC Lzd High index of suspicion needed to detect hyperlactatemia to prevent overt symptoms of lactic acidosis
Pancreatitis d4T, ddI Lzd Avoid co-administration where possible
If pancreatitis occurs discontinue the ARVs completely
Diarrhoea PI, ddI PAS, FQ, Eto For mild diarrhoea anti-motility drugs can be used
May be self-limited. Exclude opportunistic infections
Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Optic neuritis ddI E, Lzd, Eto Stop all suspected agents causing optic neuritis
Screen patients using the Snellen chart and Ishihara chart
Hypothyroidism d4T Eto, PAS Monitor TSH for patients receiving these agents
Joint pain PI [Indinavir] Z, BDQ Mild symptoms can be managed by simple analgesia
HIV = human immunodeficiency virus; DR-TB = drug-resistant tuberculosis; TDF = tenofovir disoproxil fumarate; Cm = capreomycin; NSAIDs = nonsteroidal anti-inflammatory
drugs; NVP = nevirapine; EFV = efavirenz; PI = protease inhibitor; RTV = ritonavir; NRTI = nucleoside reverse transcriptase inhibitors; ARVs = anti-retroviral drugs;
Z = pyrazinamide; Bdq = bedaquiline; PAS = para-amino salicylic acid; FQ = fluoroquinolones; ARV = anti-retroviral drugs; TB = tuberculosis; VL = viral load; AZT = zidovudine;
Lzd = linezolid; H = isoniazid; ddl = didanosine; d4T = stavudine; Cs = cycloserine; Eto = ethionamide; Pto = prothionamide; E = ethambutol; Mfx = moxifloxacin; Cfz = clofazimine;
Gfx = gatifloxacin; Lfx = levofloxacin; Ofx = ofloxacin; TSH = thyroid stimulating hormone
Based on references 143-156
 Drug-resistant Tuberculosis 599

Delamanid is known to cause prolongation of the QT interval trials. This step is key and harmonisation is required on
mainly via the DM-6705 metabolite which is regulated by definitions of treatment failure, unfavourable outcomes, and
serum albumin. Therefore, delamanid is contraindicated understanding loss to follow up and minimum acceptable
in patients with hypoalbuminemia, [albumin < 28 g/L], adherence. Culture conversion should be clearly defined
which is a frequent finding in HIV-infected individuals. This with uniformity on dealing with missed or contaminated
may limit its use in the HIV co-infected population despite samples and on documenting treatment modification across
having a safe drug-drug interaction profile with first-line studies. Key to understanding treatment shortening is
antiretroviral medications (193). Additionally, delamanid defining cure and length of follow-up particularly for agents
is administered twice daily, 30 minutes after a standard with long half-lives such as Bedaquiline. Over all, a 6-month
meal (194). This dosing schedule may affect adherence (195). negative culture may be a reliable predictor of relapse-free
It seems that delamanid is potentially efficacious and well cure in patients with drug-resistant TB (200).
tolerated in children aged 6 years and older (196), however,
data from controlled studies are scarce in the paediatric Evolution to an all Oral, Injection Free,
population. MDR-TB Regimen

How can Novel Agents Safely be South Africa is the first country to implement a standardized, all
oral injection free regimen for the treatment of MDR-TB (118).
Used in Combination?
This policy change is based on the observed superior
The novel agents, most advanced in MDR-TB development treatment success rates and better adverse events profile
include, the nitroimidazoles [pretonamid and delamanid] (194), of the bedaquiline-based shorter MDR-TB regimen when
the adenosine triphosphate [ATP]-synthase inhibitor beda­ compared to the kanamycin-based regimen. However, the
quiline and the oxazolidinone, sutezolid (197). Murine data long-term impact of this policy change on the emergence of
and Phase II early bactericidal activity studies [EBA] inform resistance to bedaquiline is unknown.
the use of novel agents in combination. Both Bedaquiline and Several clinical trials including STREAM II, endTB,
Delamanid have conditional regulatory approval and these TB-Practecal and MDR-END are evaluating novel injection
two drugs may represent a feasible alternative to injectable free regimen for M/XDR-TB. One such study is the
agents, such as, the aminoglycosides. Bedaquiline, however, randomised controlled trial New and Emerging Treatments
while promising impressive superiority to a standardised for MDR-TB [NExT] (201) which is a prospective open-
background regimen after two months of treatment for MDR-
labelled randomised controlled trial that seeks to further
TB was associated with increased mortality, and concerns for
reduce treatment duration by evaluating a completely
reduced activity in combination with pretomanid will need
new, injection-free, short-course regimen for MDR-TB.
to be addressed (197,198). Sutezolid, whilst showing activity
With over 100 patients randomised, this study seeks to
against MDR-TB strains has not yet been clinically tested in
compare a six-month five-drug regimen consisting of
combination with other novel agents and may be a more
bedaqualine, linezolid, levofloxacin, pyrazinamide and either
suitable agent than Linezolid which has been associated with
bone marrow and neurotoxicity with longer term use (199). ethionamide, high-dose isoniazid or terizadone, depending
on the presence of mutations in the inhA or katG genes
[as determined by a LPA] with the conventional injection-
How can Existing Agents be Effectively
based WHO shorter MDR-TB regimen of 12 months.
Integrated into Novel Regimens?
Each existing agent needs to be assessed in terms of toxicity How can we Protect Novel Agents Against
in combination with novel agents. Fluoroquinolones and Developing Resistance?
clofazimine potentially prolong the QT interval, as can novel
agents beda­quiline and delamanid. While it is accepted that It is clear that newer agents need to be introduced with a
a FQ-containing regimens improve outcomes in MDR-TB robust stewardship programme to prevent the development
optimal risk assessment with other novel combinations will of acquired resistance. As MDR-TB treatment already
need to be better understood. has a high rate of treatment non-compliance there needs
On-going questions related to including nitroimidazoles to be a renewed focus on psychosocial measures such as
into regimens will need to address several key factors motivational interviewing and counselling for substance
including identification of the correct patient population abuse and default. Measures such as tightened drug accoun­
[MDR-TB versus XDR-TB], understanding the effect of food tability, resistance monitoring and population PK monitoring
intake on absorption, and the ideal method of constituting of multiple agents needs to continue once novel regimens
a regimen [individualised versus standardised] to prevent have attained regulatory approval.
emergence of resistance (199).
PROGNOSIS
Treatment Shortening Surrogates
Globally, survival and treatment outcomes of DR-TB vary
There is no current consensus on endpoints that would widely depending on geographical location, regimen choice,
allow easy comparability between different MDR-TB clinical duration of treatment, and background prevalence of TB
600 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and HIV, but in general, correlate with the degree of drug Active Case Finding for Drug-resistant
resistance. The overall treatment outcomes are far from Tuberculosis
satisfactory: the WHO reports that of the estimated half a
million MDR-TB patients started globally on treatment in Active case finding in DR-TB, when using culture, poses
an added challenge in that the results of DST only become
2009, only 48% were treated successfully (202). Treatment
known 3–4 months after the initial sputum sample is taken.
outcomes in XDR-TB are even worse; while the overall
Polymerase chain reaction [PCR]-based diagnostic tests
success rate for XDR-TB in a meta-analysis was reported to
can shorten the delay and are cost effective when used in
be 44% (123), additional resistance to second- and third-line
specific settings, such as, prisons in some countries (208).
TB medications beyond the minimum definition of XDR-TB
A strategy of screening communities at large using point
was associated with further reductions in the likelihood of
of care GeneXpert MTB/RIF that is mounted in vehicles is
success. The cure rate in high-burden countries may be even
currently being evaluated in ongoing studies. Modelling
lower: in South Africa, less than 20% of patients with XDR- studies suggesting that point-of-care [POC] diagnostics could
TB, using non-bedaquiline and linezolid regimens culture- have transformative impact only if deployed in the context
converted within six months of initiation of treatment, and of targeted screening (209). However, little is known about
this poor outcome was independent of HIV status (120). the optimal strategies and utility of newer tools to screen
Lung function impairment and residual radiological sequelae for DR-TB.
are also more common in patients completing DR-TB
treatment compared to those with DS-TB (203,204). These Contact Tracing
sequelae, together with other post-TB complications, like
massive haemoptysis, aspergilloma, bronchiectasis, pneumo­ General indications for contact tracing include sputum smear
thorax, bronchopleural fistula, tracheal or bronchial stenosis positive TB, and exposure involving persons living with HIV,
and empyema, are important contributors to chronic pulmo­ and children under the age of 5 years (210). Studies have
nary disability due to TB. shown that contact tracing has an appreciable yield of about
4.5% [95% CI 4.3-4.8] for bacteriologically and clinically
PREVENTION diagnosed TB in low- to middle-income countries (211). The
progression to active TB among household contacts exposed
Active Case Finding and Contact Tracing to DS and MDR-TB cases have been shown to be comparable
in previous studies, despite a longer duration of exposure
In countries with well performing TB programmes, it
with MDR-TB (212). Screening of household contacts of
has been shown that patients with TB, even those who
MDR and XDR-TB index cases in South Africa resulted in
are smear positive, may be asymptomatic or minimally
a MDR-TB and XDR-TB detection rate of nearly 2% in the
symptomatic and so do not seek medical attention (205). It,
contacts screened, in keeping with estimates for DS-TB (213).
therefore, makes sense to reach out to high-risk patients to
However, this is likely an under estimate since this study
systematically look for TB. Active case finding [ACF] strives
excluded enrollment of children who are more likely to
to ensure that active TB is detected as early as possible to
progress to active TB. In countries with a high prevalence
reduce poor treatment outcomes and spread of disease. of HIV such as South Africa, the incidence rate of DR-TB
However, there is limited or poor quality evidence was greater than 1700/100,000 individuals screened versus
that smear-microscopy-based active case finding detects a community based rate of 45–65 cases/100000 (214). These
earlier or less severe disease, or impacts disease burden or high rates highlight the need to include ACF as part of the
outcomes (206). Improved tools and approaches for active national TB control strategy as it provides an opportunity
case finding are urgently required to minimise transmission to prevent transmission. WHO recommends contact tracing
and close the detection gap (207). for all close contacts of patients with DR-TB irrespective
Several studies have suggested that mass population of smear status (210).
screening is expensive with an unfavourable risk benefit ratio The general likelihood of transmission to contacts is
and that it is much more cost effective to perform targeted dependent on several factors including smear positivity,
screening of high-risk groups, e.g. close contacts in the home, cavitary disease, the closeness and intensity of the exposure,
school or workplace, HIV-infected persons, prisoners, miners and the immune status of the host, amongst others (210).
especially silica-related, those with untreated fibrotic chest Thus, contacts should be risk stratified and screened using
radiograph lesions, in high prevalence settings [>1%] those a combination of symptoms, chest radiograph and sputum
passively seeking health care, and actively in persons in culture/DST and/or Xpert MTB/RIF depending on local
shelters, slums and shanty towns where several risk factors availability of these diagnostic tests. Those patients who are
predominate (206). The goal is to provide treatment to found to have active TB should be started on treatment based
patients with active TB and chemoprophylaxis to those with on their GeneXpert MTB/RIF or LPA results, if available.
latent TB infection [LTBI]. The main tools used for active If immediate DST is unavailable and illness is severe then
case finding are symptom and radiographic screening (207). a case could be made for commencing the symptomatic
The predictive values of different screening algorithms have contacts on treatment based on the DST pattern of the index
been published recently (207). patient (212). However, a study conducted in New Delhi
 Drug-resistant Tuberculosis 601

showed that a majority of the contacts of MDR-TB actually the global reduction of the key driver of TB, including
had DS-TB (214). In settings where only conventional DST poverty, overcrowding, smoking, diabetes, exposure to
is available it is, therefore important to balance the risk of biomass fuels, and HIV the problem of DR-TB will not be
waiting for results [morbidity and mortality] to the potential circumvented. Thus, like with DS-TB, control of DR-TB will
toxicity from MDR-TB drugs (215,216). Symptomatic contacts only occur through global reductions in the level of poverty,
whose work-up for TB is negative may be empirically treated overcrowding, increase funding for research and capacity
for lower respiratory tract infection [LRTI], if indicated, development, strengthening of NTP, and political will.
with antibiotic that does not have efficacy against TB.
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 43
Antituberculosis Drug Resistance Surveillance
CN Paramasivan, VH Balasangameshwara

INTRODUCTION levels of drug resistance over the years in various parts of

the country would be of great value.
With the discovery of streptomycin in the 1940s and
Vigorous implementation of a multi-pronged approach
isoniazid in the 1950s, chemotherapy became the standard
in the treatment of TB resulted in a decline in the percentage
method of treatment of tuberculosis [TB]. In the early years
of drug resistance in Korea (4) and New York city (5). But
of the chemotherapy era, it was found that treatment with a
the information on drug resistance in India is available
single drug resulted in the development of drug resistance
from well-conducted studies for only a small proportion
in a high proportion of the patients, with a consequent loss
of population; the percentages of drug resistance in these
of efficacy of treatment. Hence, combined chemotherapy
settings have remained almost static. In many of the drug
with two or more drugs given together became the standard
practice. At present fixed-dose combinations, where two or resistance surveys conducted earlier in India, small or non-
three drugs are incorporated in a single tablet or capsule, representative samples have been studied. Also, there has
are also widely available. Despite all these advancements, in been no clear distinction between primary and acquired
most of the disease endemic countries there was a dramatic resistance, as the history of previous chemotherapy was not
increase in the level of initial drug resistance. obtained. Despite such limitations, an attempt has been made
The response to treatment in patients with multidrug- to give an overview of the prevalence of drug resistance in
resistant TB [MDR-TB] [defined as resistance to rifampicin India over the last three decades.
and isoniazid, with or without resistance to other anti- For the purpose of drug resistance surveillance [DRS]
TB drugs] is poor and the mortality rate is high. Since in TB, the definitions of primary drug resistance and
these patients have to be treated with several toxic and acquired drug resistance have been revised by the World
expensive second-line anti-TB drugs, and may need pro­ Health Organization [WHO] and International Union
longed hospitalisation to manage drug toxicity and other Against Tuberculosis and Lung Diseases [IUATLD; now
complications, they account for a significant proportion of called “The Union”] as ‘resistance among new cases’ and
the health care resources (1). ‘resistance in previously treated patients’ (6). ‘Resistance
In recent years, the incidence of human immunodeficiency among new cases’ is defined as ‘the presence of resistant
virus [HIV] infection has increased enormously all over strains of Mycobacterium tuberculosis [Mtb] in a patient who,
the world. Patients with HIV infection are known to have in response to direct questioning, denies having had any
an increased risk of developing TB. The case fatality rate prior anti-TB treatment, [for more than one month], and, in
is high in patients with the acquired immunodeficiency countries where adequate documentation is available, for
syndrome [AIDS], who have associated MDR-TB (2). whom there is no evidence of such history’. For the purpose
The level of initial drug resistance is said to provide an of surveillance, ‘resistance in a previously treated patient’ is
epidemiological indicator to assess the amount of resistant defined as the presence of resistant strains of Mtb in a patient
bacterial transmission in a community, as well as the success who, in response to direct questioning, admits having been
or otherwise of the National Tuberculosis Programme [NTP]. treated for TB for one month or more, or, in countries where
Further, this influences the design of therapeutic regimens, adequate documentation is available, in a patient for whom
as well as policy decision (3). Hence, reliable data on the there is evidence of such history.
610 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Since 1994, several countries have established National regions surveyed and resistance to isoniazid or streptomycin
Tuberculosis DRS projects. These projects have adopted a was most common.
standardised methodology for susceptibility testing with Despite high rates of HIV co-infection in African
the assistance of the Supranational Reference Laboratories countries, the prevalence of drug resistance was generally
[SRLs]. Establishing surveillance of drug resistance at the low (8,9). The low level of MDR may be attributed to the
country level requires strict adherence to three principles: unavailability of control programmes and the relatively late
[i] the sample of specimens should be representative of the introduction of rifampicin.
TB patients in the country/geographical setting under study In Western European countries, where TB notification
and the sample size should be determined to permit standard rates were low (10), the median prevalence of primary MDR
epidemiological analysis. It was recommended that anti-TB was less than 1%. Despite 28% of patients with TB having
DRS should cover the entire country/geographical area and co-infection with HIV in Barcelona, Spain, the prevalence
that the sample size is derived from the total number of rate of MDR was only 0.5%. Reversal of previously declining
new sputum-positive cases in that country; [ii] the patient’s rates of TB has been observed in Eastern Europe particularly
history should be carefully obtained and available medical in the former Soviet Union (11,12). This has been attributed
records reviewed to clearly determine whether the patient to an irregular supply of drugs, non-standardised regimens,
has previously received anti-TB drugs. This was felt essential nosocomial infections and the occurrence of outbreaks in
to distinguish between drug resistance among newly prisons (8,9). The prevalence of MDR-TB was observed to be
diagnosed cases and drug resistance among previously higher in the Baltic states than in any of the other countries
treated cases; and [iii] the laboratory methods for anti-TB surveyed.
drug susceptibility testing [DST] should be selected from Following the publication of the first global report on
among those that are internationally recommended. Four anti-TB drug resistance by the WHO in 1997 with results
DST methods have been standardised and are widely used from surveys conducted in 35 countries (8,9), by 2010, a total
throughout the world (7). These are: [i] proportion method of five global reports (13-16) had been published. Thereafter,
and its economic and standard variants; [ii] resistance surveillance data have been published annually in the WHO
ratio method; [iii] absolute concentration method; and Global Tuberculosis Report.
[iv] radiometric method [e.g. BACTEC 460]. Comparability These surveillance results suggest link between the
of data resulting from any of the above four methods is quality of TB control programmes and levels of drug
assured by the quality assurance [QA] and proficiency resistance. However, this relationship is complex (18).
testing performed by the SRL network. Immigration is considered to be an important contributor
to drug resistance rates (19-21).
GLOBAL PREVALENCE OF
DRUG-RESISTANT TUBERCULOSIS Extensively Drug-resistant Tuberculosis
The worldwide magnitude of the problem of resistance to The Centers for Disease Control and Prevention [CDC],
anti-TB drugs is not known. The literature search suggests Atlanta, in March 2006 reported the extensively drug-
high levels of resistance in some areas. However, many of resistant TB [XDR-TB] (22). The XDR-TB was initially defined
these studies were not based on representative samples and as cases in persons with TB whose isolates were resistant to
failed to distinguish between patients who had received anti- isoniazid and rifampicin and at least three of the six main
TB treatment in the past and those who had not. Further, classes of second-line drugs [SLDs] such as aminoglycosides,
there was no consensus on definitions and laboratory results polypeptides, fluoroquinolones, thioamides, cycloserine,
were not standardised. The major limitation for the adequate and para-aminosalicyclic acid (22-24). Subsequently, this
assessment of drug resistance was the inadequate culture definition had been modified and XDR-TB is presently
and DST facilities in many parts of the world. All these defined as isolates of Mtb resistant to at least rifampicin
limitations prevented an exact assessment of the magnitude and isoniazid [which is the definition of MDR-TB], any
of the problem worldwide and meaningful comparisons fluoroquinolone, and at least one of the three following
among various countries. injectable drugs, namely, capreomycin, kanamycin and
Global project on anti-TB DRS represents a coordinated amikacin (25-27). The XDR-TB has emerged worldwide as
international effort (8). It serves as a model for surveillances a threat to public health and TB control, raising concerns of
of drug resistance in other diseases resulted in the establish­ a future epidemic of virtually untreatable TB.
ment of multinational system for the surveillance of drug WHO surveillance of TB drug resistance over the last
resistance. Yield of reliable results in this surveillance report two decades has provided evidence on the response to the
comes from laboratory standardisation and QA. MDR-TB epidemic, and recent innovations in molecular
The World Health Organization [WHO] and IUATLD diagnostics allow a definitive shift to routine surveillance
Working Group on anti-TB DRS published report on compared to special surveys hitherto being conducted.
the prevalence of resistance to four first-line drugs in 35 As a pathfinder with two decades of experience to draw
countries between 1994 and 1997 (8,9). As per this report (8,9) upon, the global project on anti-TB DRS is a model for
resistance to anti-TB drugs was found in all 35 countries and scaling up surveillance of antimicrobial resistance [AMR] to
 Antituberculosis Drug Resistance Surveillance 611

other infectious diseases. The available data indicates that The global TB Supranational Reference Laboratory
considerable progress in the global and national response Network [SRLN] which included 14 laboratories in 1994
to the MDR-TB epidemic is evident, particularly since has grown to 33 laboratories in 2014, covering all six
2009 when the World Health Assembly [WHA] called for WHO regions. These laboratories are entrusted with the
universal access to diagnosis and treatment of MDR-TB. The responsibility to conduct quality assurance, coordinate
response, however, still remains insufficient. The percentage technical assistance to strengthen laboratory networks in all
of new TB cases that have MDR-TB globally has remained high TB and MDR-TB burden countries, and are the entry
unchanged. Some countries have severe epidemics and in point for the introduction of new TB diagnostics. Since
many settings the treatment success rate is alarmingly low. 2013, the SRLN has expanded its membership to include
WHO has suggested five priority actions [Figure 43.1], from a new category of TB laboratory designated as ‘Centres of
prevention to cure to address the global MDR-TB crisis. Excellence’ in large low- and middle-income countries that
Health system barriers, diagnostic and treatment challenges works specifically to build in-country laboratory capacity (28).
and inadequate funding for care and research and these must Surveillance data compiled since 1994 has been essential
be urgently addressed (17). to inform and guide the response to MDR-TB. The first
guidance on MDR-TB treatment and care was issued in 1996.
Since then updated guidance has been issued, including
guidelines on laboratories, diagnostics and infection
control (29).
In the earlier published previous global TB reports,
estimates of the burden of DR-TB have focussed on MDR-TB.
Since May 2016, the WHO issued guidance that rifampicin-
resistant TB [RR-TB] with or without resistance to other
anti-TB drugs, should be treated with an MDR-TB treatment
regimen. This included patients with MDR-TB as well as
any other patient with RR-TB. As per the global TB
report 2018 (17), worldwide in 2017, an estimated 3.6%
{95% confidence interval [CI] 2.6%-4.8%} of new cases and
17% [95% CI 5.6%-33%] of previously treated cases had
MDR/RR-TB [Table 43.1]. In 2017, there were an estimated
58,000 [range 483,000–639,000] incident cases of MDR/RR-
TB, with cases of MDR-TB accounting for 83% of the total
cases. The largest numbers of MDR/RR-TB cases [47% of the
global total] had occurred in China, India and the Russian
Federation. There were nearly 230,000 [range 140,000-
310,000] deaths from MDR/RR-TB in 2017 (17). Unpublished
observations from the National Institute for Research in
Tuberculosis [NIRT, earlier called Tuberculosis Research
Figure 43.1: Five priority actions to address the global MDR-TB crisis
Reproduced with permission from “Drug-resistant TB; surveillance Centre], Chennai, has indicated that XDR-TB was detected in
and response Supplement to the Global Tuberculosis Report [2014]” approximately 4% of 3173 isolates received during the period
(reference 28) 2001 to 2004 from chronically ill patients with a prolonged

Table 43.1: Estimated incidence of MDR/RR-TB in 2017 for WHO regions and globally
Estimated % of new cases with Estimated % of previously treated cases
WHO region MDR/RR-TB* with MDR/RR-TB* Incidence of MDR/RR-TB†
Africa 2.4 [1.4-3.7] 15 [0.81-43] 8.6 [7.2-0]
The Americas 1.9 [0.89-3.2] 14 [5.0-25] 1.1 [0.99-1.3]
Eastern Mediterranean 3.8 [2.6-5.3] 21 [4.9-4.5] 6 [4.5-7.7]
Europe 7.1 [5.9-8.4] 21 [15-29] 12 [9.4-15]
South-East Asia 3.4 [2.5-4.4] 19 [9.6-3.1] 9.7 [6.7-13]
Western Pacific 2.1 [0.99-3.6] 14 [3.9-30] 6.0 [4.7-7.5]
Global 3.6 [2.6-4.8] 17 [5.6-33] 7.4 [6.4-8.5]
* Data are presented as best estimate [uncertainity level]
† Rate/100,000 population [uncertainity level]

MDR = multidrug-resistant; RR = rifampicin resistant; TB = tuberculosis; WHO = World Health Organization

Source: reference 17
612 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and varying treatment history. As per Global TB Report enablers and social support] through patient follow-up
2018 (17), in 2017, XDR-TB was estimated to be present in and remains important activity to improve treatment
8.5% [95% CI 6.2%-11%] cases with MDR-TB. outcomes.
Among the 40 countries with a high TB or MDR-TB WHO has identified TB infection control as an essential
burden [or both], only 20 had repeated a survey at least activity to minimise the risk of disease transmission which
once. Of these, eight countries, namely, Belarus, Kazakhstan, has remained one of the most neglected components of TB
Myanmar, Peru, Republic of Moldova, Tomsk Oblast in the prevention and care”. The evidence for this inference is
Russian Federation, Thailand and Viet Nam had at least 3 that in 2013, more than 50% of new cases of MDR-TB were
years of data. There appears to be a slight trend for cases of among people never before treated for TB, highlighting
MDR-TB to increase as a proportion of all TB cases in these the importance of transmission and the lack of appropriate
countries (17). infection control measures, particularly at community
The tripling of MDR-TB detection between 2009 and 2013 level. MDR-TB transmission in health care facilities and
is thought to be the result of concerted efforts to strengthen in congregate settings such as prisons is a well-known
laboratories and roll out rapid tests. Expanding Access to public health threat. As this transmission can be effectively
New Diagnostics for TB [EXPAND-TB], the largest multi- addressed by appropriate infection control measures, it is
partner global project has focused on accelerating access to necessary to implement them. They are a mix of environ­
modern diagnostics for TB and MDR-TB, and is supporting mental, personal protection and administrative measures,
27 low- and middle-income countries. Between the start rapid identification of drug resistance, and prompt,
of the project in 2009 and the end of June 2014; 89,261 appropriate treatment of MDR-TB patients.
people with MDR-TB were detected in the 97 state-of-the- In view of the fact that MDR-TB is a global health security
art laboratories supported by EXPAND-TB partners. Since risk and carries grave consequences for those affected, WHO
2010, when WHO approved the Xpert MTB/RIF assay [for has called for MDR-TB to be addressed as a public health
the simultaneous detection of TB and rifampicin resistance], crisis in 2013. The WHO has recommended the following
global roll out of the technology has been impressive. five actions needed on all fronts from prevention to cure;
An important addition to DRS is incorporation of rapid priority actions that are crucial to accelerate the response
molecular tests such as the Xpert MTB/RIF assay, which against the MDR-TB epidemic are; prevent MDR-TB as a first
provides results much faster than conventional methods priority, scale up rapid testing and detection of all MDR-TB
[culture and phenotypic DST]. It also does not require cases, ensure prompt access to appropriate MDR-TB care,
sophisticated laboratory infrastructure, which greatly including adequate supplies of quality drugs and scaled-up
reduces and simplifies laboratory work and decrease costs. country capacity to deliver services, prevent transmission
Being a molecular test, it does not suffer from some of the of MDR-TB through appropriate infection control, and
limitations observed in conventional methods, such as those underpin and sustain the MDR-TB response through high
requiring timely and refrigerated transportation of sputum level political commitment, strong leadership across multiple
samples with live bacteria, growing in laboratories prior to governmental sectors, ever-broadening partnerships, and
testing, the need to decontaminate to isolate TB bacteria and financing for care and research.
prevent the growth of other organisms, resulting in the risk WHO has reiterated that adequate treatment of drug
of killing TB bacilli [through too harsh decontamination] susceptible TB remains the cornerstone of efforts to prevent
or contamination from other organisms. As a result rapid the emergence and spread of DR-TB. This is supported by the
molecular methods may detect TB [including drug-resistant fact that globally, more than 95% of people who develop TB
cases] that would have been missed by conventional for the first time do not have rifampicin resistance or MDR-
methods. TB and can thus be treated successfully using a standard,
The Global Drug Facility [GDF] of the Stop TB Partnership inexpensive, six-month course of treatment. The encouraging
has increased its supplier base for second-line anti-TB drugs observation is that globally in 2012, the treatment success
from 10 to 19 between 2009 and 2014, which has resulted rate for drug-susceptible TB was 86%, a level that has
in an increase in the available number of second-line drugs been maintained for several years (28). The definitions
[12-23] and also price reductions. Country progress to improve for monitoring of drug resistance-TB and MDR-TB and
delivery of MDR-TB treatment through new appro­aches treatment outcomes were revised in 2013 (30) to enhance
such as a shift away from hospitalization to ambulatory the monitoring of patients. One of the Global Plan targets
care in Central Asian countries; worldwide expansion of is for all 27 high MDR-TB countries to manage their data
treatment of XDR-TB patients; and pioneering efforts of on treatment of MDR-TB patients electronically by 2015. By
several countries in use of shorter regimens for MDR-TB 2013, 16 of these countries reported that national electronic
under operational research conditions. However, health databases were in place for TB patients and another five had
service capacity to treat patients has to increase with the systems for MDR-TB patients only. Guidance on the design
pace of diagnosis to reduce the “waiting lists” for MDR- and implementation of electronic systems for recording
TB treatment in several countries. In addition, a major and reporting data was produced by WHO and technical
health service constraint is patient-centered care [including partners in 2011 (31).
 Antituberculosis Drug Resistance Surveillance 613

The WHO and MDR-TB global stakeholders Consultation A Historical Account of Burden of
meeting of NTP staff, donors, and all other major stakeholders Drug-resistant Tuberculosis in India
during meeting recommendations of October 2013 in Paris,
on indicator[s] to use and purpose were subsequently Drug Resistance in Newly Diagnosed Cases
discussed and endorsed by WHO’s Strategic and Technical Though drug resistance in newly diagnosed cases is found
Advisory Group for TB [STAG-TB] in June 2014 (32). to be low in developed countries, it is common in India
Consensus was reached on the following five indicators and varies widely from area to area. The South-East Asia
and their application: [i] the indicator “estimated number region is a major contributor, accounting for almost 40% of
of MDR-TB cases among notified cases of pulmonary TB” the global burden of MDR-TB among new cases. The data
should be used for assessing programmatic performance in on drug resistance in newly diagnosed cases estimated by
diagnostic and treatment coverage, at country and global different investigators during the period 1964-1991 are listed
levels. It is also appropriate for planning and budgeting
in Table 43.2 (33-42).
purposes; [ii] a global estimate of MDR-TB incidence is
In the 1960s, Indian Council of Medical Research
useful for global advocacy; [iii] a global estimate of MDR-
[ICMR] conducted two nationwide surveys at nine urban
TB prevalence is also useful for advocacy; [iv] a global
chest clinics in India (33,34). The results of the first survey
estimate of MDR-TB mortality is useful for global advocacy;
showed resistance level of 8.2% to isoniazid alone, 5.8%
[v] proportion of new and previously treated TB cases with
to streptomycin alone and 6.5% to both the drugs. The
MDR-TB is useful for monitoring trends in levels of drug
resistance levels among new cases seen respectively in these
resistance at global and country levels.
two surveys were 14.7% and 15.5%, respectively to isoniazid
and 12.5% and 13.8%, respectively to streptomycin.
Global Surveillance of Drug Resistance:
A decade later, a study was conducted to assess the
Status in 2018 prevalence of resistance among new cases in Government
Since the launch of the Global Project on Antituberculosis Chest Institute and Chest [Tuberculosis] Clinic of Government
Drug Resistance Surveillance in 1994 (8,9,13-16), global data Stanley Hospital, Chennai (35). The results of this study were
on anti-TB drug-resistance have been systematically collected almost similar to the earlier ICMR surveys and the authors
and analysed from 82% of the 194 WHO Member States reported that the prevalence of resistance among new cases
[160 countries] (17). This includes 91 countries that have has not risen during the span of 10 years.
continuous surveillance systems based on routine diagnostic During the 1980s among five reports on primary drug
DST of Mtb isolates obtained from all TB patients, and resistance, while the levels of resistance among new cases
69 countries that rely on epidemiological surveys of bacterial to isoniazid and streptomycin were similar to that reported
isolates collected from representative samples of patients. in earlier studies. Rifampicin resistance started appearing in
In resource limited setting, when routine diagnostic DST is North Arcot, Puducherry, Bengaluru and Jaipur but not in
not possible, surveys conducted about once in every 5 years Gujarat (36-41). The reason for the emergence of rifampicin
represent the most common approach to investigating the resistance during this period may be the introduction of
burden of drug resistance. Of the 40 countries with a high TB short-course chemotherapy [SCC] regimens containing
burden [n = 30] and high MDR-TB burden [n = 30], 37 have rifampicin.
data on levels of drug resistance. Of these, Congo and Liberia Further, a higher level of resistance among new cases
never conducted a drug-resistance survey and Angola has to isoniazid was observed among the rural population in
initiated a national survey in 2018. Brazil, Central African Kolar (40) compared to the urban patients contradicting a
Republic, Democratic People’s Republic of Korea and Papua Korean study where a much higher level of initial resistance
New Guinea rely on DRS data gathered from subnational was seen among urban patients giving the reason of easy
areas only. access to the anti-TB drugs (4), There was also an increase in
In Eritrea, Indonesia and Lao People’s Democratic the proportion of resistance among new cases to rifampicin
Republic, the first-ever national drug-resistance surveys were [4.4%] encountered in this rural population. In the early
completed and repeat surveys were completed in Eswatini, 1990s, a retrospective study done at New Delhi (42) showed a
Sri Lanka, Togo and the United Republic of Tanzania during high level of resistance among new cases to isoniazid [18.5%]
2016-2017. During the period 2017-2018, drug-resistance
and a low level of rifampicin resistance.
surveys were ongoing in 12 countries [first nationwide
Overall, the prevalence of resistance among new cases to
surveys in Angola, Burundi, Haiti, Mali and Timor-Leste;
isoniazid as a single agent ranged from 6% to 13% (33-38, 40-42)
and repeat surveys Bangladesh, Cambodia, Ethiopia,
except among the rural population in Kolar, Karnataka (39)
Malawi, the Philippines, Thailand and Turkmenistan] (17).
where a high rate has been reported. Prevalence of resis­
tance in newly diagnosed cases to streptomycin as a single
DRUG-RESISTANT TUBERCULOSIS IN INDIA agent ranged from 1% to 5.8% and to rifampicin from
DR-TB has frequently been encountered in India and its 0% to 1.9% (33-42). In many of these surveys, ethambutol
presence has been known from the time anti-TB drugs were susceptibility was not performed. In a study conducted in
introduced. Bengaluru (40), the resistance in newly detected cases was
614 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

13.7% to isoniazid, 22.5% to streptomycin; and 2.2% had reference laboratories [NRLs] of India between 1985-2003,
MDR-TB. namely Tuberculosis Research Center [TRC], Chennai and
For a correct evaluation of primary drug resistance, National Tuberculosis Institute [NTI], Bengaluru is shown
standardised methodology should have been used taking in Figure 43.2 (40,48-50). The resistance varied from 0.5%
care of the following namely; eliciting patient history, to 3.4%. The level of MDR-TB in previously treated cases
adequate sample size, uniform laboratory methods, external was less than 13% except in Gujarat where a high level
and internal quality control, reliable drugs for setting was observed [11.4% to 18.5%] [Table 43.3]. In the report
up drug susceptibility media, standard chemicals in the from the Institute of Thoracic Medicine, Chennai (44) on
preparation of media, etc. Many Indian studies may have the prevalence of MDR-TB among patients undergoing
limitations related to these methodological issues. treatment for varying periods of time at four District
Tuberculosis Centres in Tamil Nadu, 20.3% were found
Resistance in Previously Treated Tuberculosis Cases to be harbouring MDR strains. Majority of these patients
had irregular and interrupted treatment owing to the non-
The rates of resistance in previously treated patients are
availability of drugs (44). Data documented at the TRC,
invariably higher than the rates of resistance in newly
Chennai (51) from 443 Category II patients from the model
diagnosed cases, though data on resistance in previously
treated patients are limited. Studies on resistance in DOTS area in Tiruvallur district of Tamil Nadu [1999-2003]
previously treated patients during the period 1980-2000 revealed that the prevalence of MDR-TB was 11.7%. In the
are shown in Table 43.3 (36,42-44). The longitudinal trend study (52) carried out in patients co-infected with HIV-TB
of drug resistance in Gujarat between 1980 and 1986 (41) [n = 37], during the period 2000-2002, the incidence of MDR-
showed that in treatment failure or relapsed patients, TB in new and previously treated patients was 5.9%.
resistance to rifampicin increased from 2.8% in 1980 to 37.3%
in 1986 and to isoniazid from 34.5% to 55.8%. From this DRUG-RESISTANT TUBERCULOSIS IN INDIA:
study (41), it was presumed that high level of rifampicin CURRENT SITUATION
resistance was almost entirely acquired. A study was Data documented from early 1980s during clinical trials
conducted by the ICMR (43) to compare the efficacy of SCC conducted at the National Institute for Research in
with the conventional [non-SCC] chemotherapy in North Tuberculosis [NIRT], Chennai [earlier called Tuberculosis
Arcot district, Tamil Nadu. The population was examined Research Centre] have shown that MDR-TB has been
during their follow-up period to confirm the bacterial increasing from less than 1% in the early 1990s to 2.0% in
quiescence, and in turn, the efficacy of SCC. It was found 2006 [Figure 43.3] (53). The burden of MDR-TB, MDR-TB/
that there was an increase in the frequency of resistance in
rifampicin-resistant TB among new and previously treated
previously treated patients with 67% resistance to isoniazid,
TB patients in India documented in studies between 1997
26% to streptomycin and 12% to rifampicin. In addition,
and 2016 are shown in Table 43.4 (53,54).
6% of the strains tested were resistant to both isoniazid and
rifampicin (43). A study from New Delhi in the 1990s (42)
also showed a higher level of resistance in previously treated
National Anti-TB Drug Resistance
patients to isoniazid and rifampicin, which is almost similar Survey 2014-2016
to that of the Gujarat report (36). A study conducted by The Government of India conducted a National Anti-TB
the Institute of Thoracic Medicine, Chennai (45) aimed at Drug Resistance Survey 2014-2016 [NDRS 2014-2016] (53) to
finding out the prevalence of TB resistance in four District know the prevalence of drug resistance among TB patients
Tuberculosis Centres of Tamil Nadu, showed that acquired among both new and previously treated TB patients. The
resistance was 63%, out of which 23.5% were resistant to NDRS 2014-2016 is the largest ever conducted by any
single drug and 39.5% resistant to more than one drug. In country in the world and the first ever survey having DST
a recently conducted study in Bengaluru (44), the MDR in for 13 anti-TB drugs using the automated liquid culture
previously treated cases was found to be 12.8% and ranged system, mycobacteria growth indicator tube [MGIT] 960®. In
from 8.4% to 17.2%. The proportion of 12% MDR-TB in the NDRS 2014-2016, 5280 sputum smear-positive pulmonary
previously treated patients appears to be similar in other TB patients. This included 3240 new [DST available for 3065,
DOTS implemented areas such as Hong Kong (46) and 94.6%] and 2040 previously treated patients [DST available
Nepal (47). The overall rates of resistance in previously for 1893, 92.8%] diagnosed at the designated microscopy
treated patients to isoniazid ranged from 34.5% to 67%, for
centres [DMCs] of RNTCP were enrolled. The key findings
streptomycin from 26% to 26.9% and for rifampicin from
of the NDRS 2014-2016 are listed in Tables 43.5 and 43.6.
2.8% to 37.3% (33-42).
In the NDRS 2014-2016 (54) MDR-TB was evident in 2.8%
new and 11.6% previously treated TB patients. Among MDR-
Multidrug Resistance TB patients, additional resistance to any fluoroquinolones
The rate of MDR-TB in new cases in India has been low, and to any second-line injectable drugs was seen in 21.8%
ranging from 0% to 3% [Table 43.2]. The drug resistance 3.6% respectively. Among MDR-TB patients, XDR-TB was
in various DRS sites in India conducted by two national evident in 1.3% cases.
Table 43.2: Summary of studies on resistance among new cases in Mycobacterium tuberculosis isolates from India
Resistance to multiple Total
No. of isolates Resistance to single drug [%] drugs [%] resistance
Study (reference) Year tested H S R E T SH HR SHR [%] Location
9 Urban Centres India (33) 1964-65 1838 8.2 [14.7] 5.8 [12.5] ND ND – 6.5 – – 20.4 Urban
9 Urban Centres India (34) 1965-67 851 15.5 13.8 ND ND – – – 22 Urban

Government Chest Institute and

1976 254 10.6 9.5 ND ND ND 4.7 – – – Urban
Stanley Hospital Chennai (35)

Gujarat* (36) 1983-86 570 7.9 [13.9] 3.2 [7.4] 0 2.5 [4] 0.5 [1.5] 3.3 0 – 20
North Arcot (37) 1985-89 2779 13 4 0.07 [2] ND ND 7 0.7 0.9 26 Rural
Pondicherry (37) 1985-91 2127 6 4 0.2 [0.9] ND ND 3 0.4 0.3 13.9
Bangalore† (38) 1980s 436 12.1 [17.4] 1.8 [5.7] 1.8 [3] 0 [0.5] ND 3.6 0.9 0.2 21.1 Urban
Bangalore‡ (39) 1985-86 588 12.6 [17.4] 1.7 [4.8] 1.5 [2.3] 0 [0.5] ND 2.9 1.2 0.2 20.5 Urban
Bangalore (40) 1999 271 13.7 22.5 2.6 1.8 ND 6.6 2.2 1.1 27.7 Urban
Kolar§ (39) 1987-89 292 26.7 [32.8] 1 [5.1] 1 [4.4] 0 [1.7] ND 2.4 3.2 0.7 34.9 Rural
Jaipur¶ (41) 1988-91 1009 7.6 [10.1] 5.2 [7.6] 1.9 [3] 2 [2.6] ND 1.6 0.7 0.1 19.9 –

New Delhi (42) 1990-91 324 18.5 – 0.6 – – – – – Urban

Figures in parentheses indicate percentage of isolates resistant to a drug along with other drugs. [H] = H+SH+HR+SHR; [S] = S+SH+SR+SHR; [R] = R+SR+HR+SHR;
[E] = E+HE+SE+SHE+HRE; [T] = T+HT
* Multiple resistances were also reported for HT [1.0%]; HE [0.7%]; SHE [0.9%]
† Multiple resistances were also reported for HE [0.5%]
‡ Multiple resistances were also reported for HE [0.6%]
§ Multiple resistances were also reported for HE [0.3%]; SHE [1.0%]; HRE [0.3%]
¶ Multiple resistances% were also reported for SR [0.2%]; SE [0.5%]; SHE [0.1%]
H = isoniazid; S = streptomycin; R = rifampicin; E = ethambutol; T = thiacetazone; ND = not done
Antituberculosis Drug Resistance Surveillance

Table 43.3: Summary of studies on resistance in prevwiously treated patients in Mycobacterium tuberculosis isolates from India
Number of Resistance [%]
Study (reference) Year isolates H S R SH HR SR SHR Location
Gujarat (36) 1980-86 1574 34.5-55.8 26.3-26.9 2.8-37.3 – – – – –
Gujarat (36) 1983-86 1267 – – – – 11.4-18.5 1.2-3.5 14.5-15.3 –
North Arcot (43) 1988-89 560 67.0 26.0 12.0 19.0 6.0 – – Rural
New Delhi (42) 1990-91 81 50.7 – 33.7 – – – – Urban
Bangalore (44) 1999-2000 226 4.7-12.1 5.4-13.2 0-3.6 0-1.3 8.4-17.2 0.2-1 0.2-4.2 Urban
615

H = isoniazid; S = streptomycin; R = rifampicin

 616 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 43.2: Drug-resistance data from some surveillance sites in India [1985-2003]. Figures in square brackets indicate prevalence of
multidrug-resistant tuberculosis

Figure 43.3: Trend of prevalence of drug resistance in newly diagnosed cases of tuberculosis in various studies conducted at National Institute
for Research in Tuberculosis [NIRT, earlier called Tuberculosis Research Centre], Chennai
H = isoniazid; S = streptomycin; R = rifampcin
Reproduced with permission from reference 53

PROGRAMMATIC MANAGEMENT OF patients who remained smear-positive during follow-up;

DRUG-RESISTANT TUBERCULOSIS IN INDIA: to “previously treated patients”; HIV-seropositive persons;
CURRENT STATUS and persons who had contact with a known DR-TB patient
with a plan to achieve universal DST, to all diagnosed and
Following the successful national coverage of RNTCP
services across the country in 2006, the Programmatic notified TB patients (55,56).
Management of Drug-resistant TB [PMDT] services were Capacity building for DST then ensued from a few
introduced in 2007 and the whole country was covered 2013. national reference laboratories [NRLs], and state level
Initially, DR-TB services were offered to TB patients with Intermediate reference laboratories [IRLs] with solid or
the highest risk to develop drug resistance, i.e., treatment liquid culture and DST facilities, a wide network of state
failure cases. A horizontal and vertical scale-up ensured and regional level IRLs with solid and liquid culture
thereafter. Definite criteria were defined to assess the risk DST and line probe assay [LPA] facilities and district
and eligibility for DST. The DST was then offered to TB level network of laboratories capable of cartridge based
 Antituberculosis Drug Resistance Surveillance 617

Table 43.4: MDR-TB among new and previously treated TB patients in India
Previously treated
Study New TB patients % TB patients %
Tamil Nadu State, 3.4 25
1997-1998 [n = 60 million]
Gujarat State, 2007-2008 [n = 56 million] 2.4 17.4
Maharashtra State, 2008 [n = 108 million] 2.7 14
Undivided Andhra Pradesh State, 2009 [n = 86 million] 1.8 11.8
Tamil Nadu State, 2011 [n = 77 million] 1.8 13.2
MDR-TB/RR-TB reported under RNTCP India’s routine surveillance data
2007-2012 [n = 144,326] NA 19
2013-2015 [n = 779,300] 5 11
2016 [n = 580,438] 4 9
n = no. studied; MDR-TB = multidrug-resistant TB; TB = tuberculosis; RR-TB = rifampicin resistant-TB; RNTCP = Revised National TB
Control Programme; NA = not available
Source: references 53,54

Table 43.5: MDR-TB/XDR-TB among new and previously treated TB patients

New TB patients Previously treated All patients
[n = 3065] patients [n = 1893] [n = 4958]
DST results % [95% CI] % [95% CI] % [95% CI]
Susceptible 77.5 [75.9-78.9] 63.2 [61-65.3] 72 [70.7-73.3]
Any drug-resistance 22.5 [21.1-24.1] 36.8 [34.6-39] 28 [26.8-29.3]
MDR-TB 2.8 [2.3-3.5] 11.6 [10.2-13.1] 6.2 [5.5-6.9]
MDR-TB + any SLI resistance 6.9 [2.6-14.4] 2.3 [0.7-5.2] 3.6 [1.8-6.3]
MDR-TB + any FQ resistance 24.1 [15.6-34.5] 20.9 [15.7-26.9] 21.8 [17.3-26.9]
XDR-TB 2.3 [0.3-8.1] 0.91 [0.1-3.3] 1.3 [0.4-3.3]
MDR-TB = multidrug-resistant TB; XDR-TB = extensively drug-resistant TB; TB = tuberculosis; CI = confidence intervals; DST = drug-
susceptibility testing; SLI = second-line injectable drugs; FQ = fluoroquinolones
Source: reference 53

nucleic acid tests [CBNAAT]. Diagnostic algorithm has release of the revised Technical and Operational Guidelines
also undergone revision wherein CBNAAT is offered to cases in 2016, regimens to treat other forms of drug resistance,
who are smear-negative but have a chest X-ray suggestive such as mono and poly resistance to first and second-line
of TB, as well as for new TB cases. Initially, only MDR-TB drugs were also included. This has been further updated
patients were offered treatment with a standard second- and consolidated in the Guidelines for PMDT in India
line regimen. Later, treatment with standard regimen was 2017 (55,56). The Guidelines for PMDT in India 2017 (55)
offered to XDR-TB patients and MDR-TB with additional integrates use of the shorter MDR-TB regimen and newer
resistance to quinolone or second-line injectables (55,56). containing regimen under RNTCP with a DST guided
During 2011-12, there was a massive scale-up of regimen design. The reader is referred to the chapters
procurement and supply chain management of second- “Drug-resistant tuberculosis” [Chapter 42] and “Revised National
line drugs with concerted efforts of multiple stakeholders, Tuberculosis Control Programme” [Chapter 53] for further
resulting in countrywide coverage by 2013. During the details.
subsequent period, detection and management of DR-TB Key challenges envisaged in the MDR-TB response
through RNTCP progressively increased. DR-TB case finding include; growing gaps between numbers detected and
and treatment initiation efforts 2007-2017 are shown in numbers started on treatment; poor treatment outcomes due
Figure 43.4 (56). to health system weaknesses; lack of effective regimens; and
In 2016, new drug bedaquiline [Bdq] was made accessible insufficient funding including for research. These barriers
to DR-TB patients through a conditional access programme need to be urgently addressed. Further, novel drug regimens
[CAP] under RNTCP. In 2017, conditional approval was for shortened treatment of drug-susceptible and/or DR-TB,
accorded for use of delamanid under RNTCP. With the including new or re-purposed drugs, are under investigation.
 618 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 43.6: Individual drug resistance patterns

New patients Previously treated patients
% any resistance % mono-resistance % any resistance % mono-resistance
Drug [95% CI] [95% CI] [95% CI] [95% CI]
Streptomycin 6.88 2.22 13.26 2.48
[6.01-7.84] [1.73-2.81] [11.76-14.87] [1.83-3.29]
Isoniazid 11.06 3.85 25.09 7.61
[9.97-12.22] [3.20-4.60] [23.15-27.11] [6.45-8.89]
Rifampicin 2.84 0 11.67 0.05
[2.28-3.49] [0.0] [10.26-13.21] [0.001-0.29]
Ethambutol 2.28 0.23 7.03 0.21
[1.78-2.88] [0.092-0.47] [5.92-8.27] [0.06-0.54]
Pyrazinamide 6.95 4.11 8.77 4.07
[6.07-7.91] [3.44-4.88] [7.53-10.13] [3.22-5.06]
Kanamycin 1.01 0.03 1.01 0
[0.69-1.43] [0.0-0.18] [0.61-1.56] [0.0]
Amikacin 0.98 0.07 1.01 0.05
[0.66-1.39] [0.01-0.24] [0.61-1.56] [0.001-0.29]
Capreomycin 1.04 0.03 0.85 0
[0.72-1.47] [0.02-0.18] [0.48-1.37] [0.0]
Levofloxacin 2.71 0.1 3.75 0
[2.16-3.35] [0.02-0.29] [2.94-4.71] [0.0]
Moxifloxacin 2.58 0.07 4.01 0
[2.04-3.20] [0.01-0.24] [3.18-4.99] [0.0]
PAS 2.32 0.33 2.38 0.42
[1.81-2.91] [0.16-0.60] [1.74-3.17] [0.18-0.83]
Ethionamide 2.54 0.33 3.06 0.26
[2.02-3.17] [0.16-0.60] [2.33-3.94] [0.09-0.62]
CI = confidence intervals; PAS = para-amino salicylic acid
Source: reference 53

Figure 43.4: DR-TB, case-finding and treatment initiation effort, in India 2007-2017.
DR-TB = drug-resistant TB; MDR/RR TB = multidrug-resistant/rifampicin-resistant tuberculosis; Rx = treatment; XDR-TB = extensively drug-
resistant tuberculosis; CBNAAT = cartridge-based nucleic acid amplification tests
Reproduced with permission from “Revised National Tuberculosis Control Programme, Directorate General of Health Services, Ministry of Health
and Family Welfare, Government of India. India TB Report 2018. New Delhi: Revised National Tuberculosis Control Programme, Directorate General
of Health Services, Ministry of Health and Family Welfare, Government of India; 2018” (reference 56)
 Antituberculosis Drug Resistance Surveillance 619

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treatment. Indian J Tuberc 1992; 39:121-4. in/showfile.php?lid=3315. Accessed on June 26, 2018.
43. Datta M, Radhamani MP, Selvaraj R, Paramasivan CN, 54. Ramachandran R, Nalini S, Chandrasekar V, Dave PV,
Gopalan BN, et al. Critical assessment of smear-positive pulmo­ Sanghvi AS, Wares F, et al. Surveillance of drug-resistant
nary tuberculosis patients after chemotherapy under the district tuberculosis in the state of Gujarat, India. Int J Tuberc Lung Dis
tuberculosis programme. Tuber Lung Dis 1993;74:180-6. 2009;13:1154-60.
44. Sophia V, Balasangameshwara VH, Jagannatha PS, Saoja VN, 55. Revised National Tuberculosis Control Programme, Directorate
Shivashankar B, Jagota P, Re-treatment outcome of smear positive General of Health Services, Ministry of Health and Family
tuberculosis cases under DOTS in Bangalore City. Indian J Tuber Welfare, Government of India. Guidelines on programmatic
C 2002;49:195-204. management of drug-resistant tuberculosis in India 2017. New
45. Vasanthakumari R, Jagannath K. Multidrug resistant tuberculosis: Delhi: World Health Organization, Country Office for India;
a Tamil Nadu study. Lung India 1997;15:178-80. 2017.
46. Kam KM, Yip CW. Surveillance of Mycobacterium tuberculosis 56. Revised National Tuberculosis Control Programme, Directorate
drug resistance in Hong Kong, 1986-1999, after the implementation General of Health Services, Ministry of Health and Family
of directly observed treatment. Int J Tuberc Lung Dis 2001;5: Welfare, Government of India. India TB Report 2018. New Delhi:
815-23. Revised National Tuberculosis Control Programme, Directorate
47. Malla P, Bam DS, Shrestha B, Drug resistance surveillance of TB General of Health Services, Ministry of Health and Family
cases in Nepal. Int J Tuberc Lung Dis 2001;5:S 84. Welfare, Government of India; 2018.
 44
Treatment of Tuberculosis
Rupak Singla, Sanjay Gupta, Amit Sharma

INTRODUCTION show short burst of metabolic activity; [iii] their ability to

prevent the emergence of acquired resistance by suppressing
Tuberculosis [TB] has been a scourge of mankind for
drug-resistant [DR] mutants which may be present in large
thousands of years and remains one of the deadliest diseases
bacterial populations [Figure 44.1, Table 44.4] (14).
in the world today. Nevertheless, TB can be cured in nearly
The drugs with bactericidal action will lead to early
all cases. The only way to stop the spread of disease in the
sputum conversion and higher cure rates. The drugs with
community is to cure all smear-positive cases by treatment
ability to prevent the emergence of acquired resistance will
with appropriate chemotherapeutic regimens. The major
prevent failures to occur. The drugs with sterilising action
landmarks in the evolution of modern anti-TB treatment are
will reduce the relapse rates and are very vital for reducing
given in Table 44.1 (1-11).
the treatment duration.

ANTI-TUBERCULOSIS DRUGS Bacteriological Factors

Isoniazid, rifampicin, pyrazinamide, streptomycin and
ethambutol are the principal first-line anti-TB drugs used in The Numerical Factor
short-course treatment. Isoniazid and rifampicin are bacteri­ The number of tubercle bacilli varies widely with the type
cidal drugs. Pyrazinamide is bactericidal in acidic medium of lesion. While in an encapsulated medium sized nodular
while streptomycin is bactericidal in alkaline medium. lesion with no bronchial communication, the number of
Ethambutol is generally considered bacteriostatic, although bacilli can be as low as 100, the number in a cavity of same
it is bactericidal in vitro. The mechanism of action and size communicating with the bronchi is about 108 (15).
classification of anti-TB drugs are shown in Tables 44.2 and Resistant mutants are likely to be present even before treat­
44.3 (12,13). The reader is referred to Tables 42.2A and 42.2C ment is started if the bacterial population is larger.
for the current [year 2018] classification of anti-TB drugs.
The Metabolic Factor
SCIENTIFIC BASIS OF TUBERCULOSIS
Anti-TB drugs kill tubercle bacilli that are metabolically active
TREATMENT
and are multiplying continuously. However, in each bacterial
Mycobacterium tuberculosis [Mtb] is a slow-growing aerobic population there are bacilli with a very low metabolic rate
organism with a generation doubling-time of 18 hours and [Figure 44.1]. Some are inhibited due to low pH, while others
can remain dormant for a long period. Therefore, prolonged remain dormant most of the time and multiply only for short
treatment is required to ensure relapse-free cure. periods. These bacilli are called “persisters” and “spurters”.
In any drug regimen the anti-TB drugs act by three Only pyrazinamide and rifampicin are effective against them
ways: [i] their bactericidal action, defined as their ability to under certain conditions. This phenomenon explains to some
kill rapidly large numbers of actively multiplying bacilli; extent why all bacilli are not killed during treatment, and
[ii] their sterilising action, defined as their capacity to kill all why drug-susceptible bacilli are coughed up for some time
the bacilli including semi-dormant bacilli and bacilli which thereafter. Further, endogenous reactivation and relapse
622 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 44.1: Evolution of modern chemotherapy for TB

Year Major events
1940 Bacteriostatic effect of sulphonamides and dapsone was demonstrated in guinea-pigs infected with tubercle bacilli, However,
results in humans were disappointing
1944 Streptomycin showed striking therapeutic effect on experimental TB in guinea-pigs. Soon afterwards, it was used for the first
time in human patients
1946 Clinical use of streptomycin, monotherapy leads to resistance
1949 PAS prevented the emergence of drug resistance if given in combination with streptomycin
1952 Anti-TB activity of isoniazid was discovered though synthesized 40 years earlier. Since then it has been an important
component of all primary drug regimens as it is highly effective, inexpensive, and has low toxicity
1952-1955 Introduction of isoniazid and two drug regimens [PH and SH]
1958 Data from India suggests that supervised administration of treatment [DOT] is essential
1959 Ambulatory chemotherapy as effective as sanatorium treatment. No additional risk of disease to close contacts
1964 Intermittent regimens demonstrated to be as effective as daily regimens. Efficacy of twice weekly SH intermittent regimen
[S2H2] proved
1969 Twice weekly PH as effective as daily PH
1958-1967 Emergence of daily administered 3 drug regimens [STH/TH, SPH/PH]
1970 Rifampicin introduced as the most effective medication for TB. It led to the emergence of effective short-course regimens
1970 Inclusion of rifampicin or pyrazinamide in SH regimen substantially reduced the relapse rate
1972-1974 Treatment duration shortened to 6 months by the inclusion of rifampicin and pyrazinamide in the regimen
1976 Modern SCC regimens delineated. It was shown that the sterilizing activity of pyrazinamide was confined to the first 2 months of
treatment during IP, whereas the sterilising activity of rifampicin persisted throughout the CP
1977 Demonstration of the value of intermittency in short-course regimens, particularly that three times weekly treatment throughout
onwards was as effective as, and less toxic and expensive than daily regimens
1980s 6-month fully intermittent effective SCC regimens evolved
1980s Treatment duration of less than 6 months demonstrated high relapse rates [11%-40%]
Standardised and simplified regimens using fully intermittent, directly observed 6-month treatment shown to be effective on a
mass basis
TB = tuberculosis; S = streptomycin, P = para-aminosalicylic acid; H = isoniazid; T = thiacetazone; IP = intensive Phase; CP = continuation
phase; SCC = short-course chemotherapy
Source: references 1-11

Table 44.2: Mechanism of action of first-line anti-TB drugs

Drug Mechanism of action Genes involved in drug resistance
Streptomycin Inhibition of protein synthesis by binding tightly to the conserved A Ribosomal protein subunit 12 [rpsL]
site of 16S rRNA in the 30S ribosomal subunit 16S ribosomal RNA [rrs]
Isoniazid Exact mechanism of action is not known. It probably acts by its Catalase-peroxidase [katG]
effect on nucleic acid biosynthesis, lipids and glycolysis, leading to NADH-specific enoyl acyl carrier protein [acp]
the inhibition of the synthesis of mycolic acid of mycobacteria reductase [inhA]
Alkyl hydroperoxide reductase [ahpC]
NADH dehydrogenase [ndh]
Oxidative stress regulator [oxyR]
Beta-ketocyl acyl carrier protein synthase [kasA]
Rifampicin Inhibition of the beta-subunit of the enzyme DNA dependent RNA RNA polymerase subunit B [rpoB]
polymerase, thus suppressing the initiation of chain formation in
RNA synthesis
Pyrazinamide Exact mechanism of action is not known. It is postulated that Pyrazinamidase [pncA]
the acidic pH and intracellular environment induce a component
necessary for the action of pyrazinamide. However, the target is
not known. Pyrazinoic acid, an active moiety of pyrazinamide has
been shown to inhibit various functions at acid pH in Mtb
Ethambutol The exact mode of action of the drug is not known. Inhibits Arabinosyl transferase [emb A, emb B, and
arabinosyl transferases involved in cell-wall biosynthesis emb C]
TB = tuberculosis; RNA = ribonucleic acid; NADH = nicotinamide adenine dinucleotide; DNA = deoxyribonucleic acid; Mtb = Mycobacterium tuberculosis
Source: references 12,13
 Treatment of Tuberculosis 623

Table 44.3: Classification of anti-TB drugs

First-line drugs
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
Streptomycin
Second-line drugs
Broad spectrum agents
Cycloserine
Fluoroquinolones
Ciprofloxacin
Ofloxacin
Levofloxacin
Moxifloxacin Figure 44.1: Theoretical basis of chemotherapy of tuberculosis.
Gatifloxacin Three populations of Mycobacterium tuberculosis are postulated to
Rifamycins [other than rifampicin] exist in a tuberculosis cavity, based on their anatomic and metabolic
Rifabutin characteristics. Population A refers to rapidly multiplying bacteria found
Rifapentene in caseous debris in pulmonary cavities. Compared with streptomycin
Macrolides [S], rifampicin [R], and ethambutol [E], isoniazid [H] is most active
Azithromycin against this population. Slowly multiplying bacteria because of local
Clarithromycin acidic conditions are referred to as population B. Pyrazinamide [Z] is the
Narrow spectrum agents most effective antituberculosis drug active against this group followed
Capreomycin by rifampicin [R] and isoniazid [H]. “Elimination” of populations “A”
Kanamycin and “B” results in negative sputum cultures, typically after two months
Amikacin of treatment. Bacilli in the host tissue capable of sporadic bursts of
Viomycin metabolism, multiplication constitute population “C”. This population is
Ethionamide a potential source for relapses. Rifampicin [R] plays a major role in
Prothionamide eliminating these organisms followed by H. Another population of bacilli
Clofazimine designated as population “D” are dormant non-replicating bacilli that
Para-aminosalicylic acid are not vulnerable to antimicrobial action and are also considered to be
Thioacetazone a potential source for relapse.
TB = tuberculosis Reproduced with permission from “Balasubramanian R, Ramachandran
Source: reference 13 R. Evolution of chemotherapeutic regimens in the treatment of TB and
their scientific rationale. In: Sharma SK, Mohan A, editors. Tuberculosis,
Second Edition. New Delhi: Jaypee Brothers Medical Publishers;
2009.p.734-50” (reference 14)
with drug-susceptible organisms after being “cured” may
occur due to bacilli that have persisted in residual lesions
in a dormant state for a long time. Table 44.4: Grading of activities of anti-TB drugs
Extent of Prevention of
Environmental Factors activity resistance Early bactericidal Sterilising
High Isoniazid Isoniazid Rifampicin
The Anatomical Factors Rifampicin Pyrazinamide
All drugs are not able to penetrate into all tissues and cells Moderate Ethambutol Ethambutol Isoniazid
Streptomycin Rifampicin
or permeate biological membranes, including the normal
blood-brain barrier. Isoniazid, rifampicin and pyrazinamide Low Pyrazinamide Streptomycin Streptomycin
readily cross biological membranes, whereas streptomycin Thiacetazone Pyrazinamide Thiacetazone
Thiacetazone Ethambutol
fails to enter many cells and is much less effective against
intracellular bacilli (16). TB = tuberculosis

The Biochemical Factors bronchus] where pH is usually acidic and PaO2 is decreased.
Environmental pH and arterial oxygen tension [PaO2] are the Presence of small number of bacilli in closed extrapulmonary
important biochemical factors that influence the antimicrobial lesions also shows that the PaO2 is an important factor.
effect of a drug. At a neutral pH, as in cavity walls, all the
anti-TB drugs are highly effective. Streptomycin, however, is Pharmacological Factors
most active in a slightly alkaline [extracellular] environment,
Dosage
whereas pyrazinamide acts largely in acidic medium such
as that found inside cells. Further, it is suggested that Drugs must be given in a dosage adequate enough to
dormant organisms survive within cells or in necrotic areas produce an inhibitory concentration at the site where bacilli
of old encapsulated lesions [that do not communicate with a are present, but it is not necessary to keep this concentration
624 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

at a constant level. Studies on the role of dosage and Table 44.5: Lag in growth of Mycobacterium
serum levels of isoniazid shows that it is both, the peak tuberculosis after temporary exposure to drugs
level and the total exposure to the drug that are important
Concentration Lag [days] after exposure for
for the response to the drug. Thus, 400 mg of isoniazid
given once daily is therapeutically superior to the same Drug [mg/L] 6 hours 24 hours
dose divided into two parts and administered at 12 hours Isoniazid 1 0 6-9
intervals (17). Rifampicin 0.2 2-3 2-3
Pyrazinamide 50 5-40 40*
Combinations of Drugs Ethambutol 10 0 4-5
Treatment regimens should contain a combination of three Streptomycin 5 8-10 8-10
or more bactericidal drugs, particularly in the initial phase of Ethionamide 5 0 10
treatment so that both the susceptible and bacilli resistant to Cycloserine 100 0 4-8
one drug are killed rapidly. For patients who have received
Thiacetazone 10 0 0
anti-TB drugs earlier, regimen should include at least three
new drugs to which the bacilli are likely to be susceptible. * Depending on the pH of the medium
Source: references 17-19
Sometimes drugs are successively substituted or added,
one at a time, to a failing regimen with the result that these
people eventually became chronic patients with organisms
resistant to all the drugs they had received. Thus, treatment
Evolution of Short-course Chemotherapeutic
of TB should never be attempted with a single drug nor
Regimens
should a single drug be added to a failing regimen.
The monumental advances in the chemotherapy of TB
The “Lag Period” Factor in the last three decades has been the development of
short course chemotherapy [SCC] regimens of six to eight
In vitro experiments have shown that, when tubercle bacilli
months duration as against 12–24 months of conventional
are exposed to a drug for a short-time [6-24 hours] and are
chemotherapy. Animal studies had shown high sterilising
transferred to a drug-free medium, the surviving bacilli
activities of pyrazinamide and rifampicin resulting in low
start to grow again after an interval of several days. This
relapse rates. The chances of failure due to initial drug
interval, called the “lag period”, varies with the type and resistance are greatly decreased because of the multiplicity
concentration of the drug and with the length of exposure. and potency of the drugs used in the intensive phase [IP].
All anti-TB drugs have been tested for their ability to Sputum conversion occurred rapidly. This led to evolution
produce a lag period, in order to determine whether they of highly effective SCC regimens consisting of rifampicin,
are suitable for intermittent regimens (18,19). isoniazid, and pyrazinamide with streptomycin/ethambutol
for a period of two months followed by two or three drugs
THE SCIENTIFIC BASIS OF like rifampicin plus isoniazid with or without ethambutol
INTERMITTENT TREATMENT or a non-rifampicin continuation phase [CP] consisting of
streptomycin or thiacetazone plus isoniazid. These regimens
Intermittent regimens are those in which the individual
were found to be highly effective with no failures among
drugs are given at intervals of more than one day, e.g.,
patients with sensitive tubercle bacilli. The relapse rates
three or two times a week. Originally, it was believed that
were less than 5% during a two-year period of follow-up.
anti-TB drugs require daily administration to maintain drug
In contrast, 12 months non-rifampicin conventional regimens
concentrations at inhibitory levels continuously. The two
had an overall failure [failure plus relapse] rate of maximum
main reasons why intermittent dosage was thought likely to
of 18%.
be effective included the observation that a dose of 200 mg
isoniazid given daily was more effective than the same
STANDARD ANTI-TUBERCULOSIS
total dosage given in divided doses twice daily, and the lag
period [post-antibiotic effect] factor. Table 44.5 shows the TREATMENT REGIMENS
lag period in the growth of Mtb after exposure to different Standardised treatment means that all patients in a defined
drugs for varying times. For each bactericidal drug there is group receive the same treatment regimen. Standard
a maximum lag period that seems to indicate the practical regimens have the following advantages over individualised
limit beyond which the interval between two doses should treatment: [i] reduced errors in prescription [and thus, less
not be extended. Thiacetazone is not suitable for intermittent risk of development of DR-TB]; [ii] facilitating the estimation
treatment as it does not produce any lag period even after of drug needs, purchasing, distribution and monitoring;
exposure for 24 hours. A series of experiments in animal [iii] staff training is facilitated; [iv] reduced costs; [v] main­
models demonstrated that intermittent administration of taining a regular drug supply when patients move from one
isoniazid, rifampicin and pyrazinamide actually increased area to another is made easier; and [vi] outcome evaluation
the efficacy of treatment (18,19). is convenient and results are comparable.
 Treatment of Tuberculosis 625

For assigning standard regimens, patients are grouped by Table 44.6: Standard treatment regimens for “new”
the same patient registration groups used for recording and TB patients [presumed, or known, to have drug-
reporting, which differentiate new patients from those who susceptible TB]
have had prior treatment. Registration groups for previously
Intensive Continuation
treated patients are based on the outcome of their prior phase* phase Comment
treatment course, i.e., failure, relapse and default.
2HRZE 4HR Optimal regimen
All TB treatment regimens comprise of two phases, an
initial IP of four or five bactericidal drugs and a CP of two or 2HRZE 4HRE Applicable in countries/settings where the
level of H resistance among new cases
three drugs. The initial IP is designed to kill actively growing is high and H susceptibility testing is not
and semi-dormant bacilli. This means a shorter duration of done, or results are not available, before
infectivity with a rapid smear conversion [80%-90%] after the continuation phase begins
two to three months of treatment. It usually comprises of * In TB meningitis, E should be replaced by S
four drugs for new patients, and five drugs for patients H = isoniazid; R= rifampicin; Z = pyrazinamide; E= ethambutol; S =
who had taken anti-TB treatment for more than one month streptomycin
in the past. Use of three drugs in the initial IP has the risk Source: references 20a,20b
of selecting DR mutants in the smear-positive pulmonary
TB patients with high bacillary loads, especially if initial DR
rates are high in the area. A four-drug regimen decreases the
Table 44.7: Recommended doses of first-line anti-TB
risk of developing DR and reduces failure and relapse rates.
drugs for adults
The multiplication of susceptible organisms stops during the
first few days of effective treatment, and the total number of Daily
bacilli in the sputum decreases rapidly, especially within the Dose and range [mg/kg body Maximum [mg]
first two weeks of effective treatment. This will prevent early Drug weight]
deterioration and death in the initial weeks of treatment. Isoniazid 5 [4-6] 300
The CP eliminates most residual bacilli and reduces Rifampicin 10 [8-12] 600
failures and relapses. Because of a small number of bacilli Pyrazinamide 25 [20-30] -
at the beginning of the CP, fewer drugs are required as Ethambutol 15 [15-20] -
the chance of emergence of DR mutants is low. It usually
Streptomycin* 15 [12-18] 1000
comprises of two or three drugs given for four to five
months. *Patients aged over 60 years may not be able to tolerate more than
500-750 mg daily, so some guidelines recommend reduction of the
World Health Organization [WHO] had revised the dose to 10 mg/kg per day in patients in this age group. Patients
inter­national guidelines for treatment of TB in 2010 (20a) in weighing less than 50 kg may not tolerate doses above 500-750 mg
view of new evidence that became available (21-24). These daily
guidelines (20a) were further updated in 2017 (20b). Standard TB = tuberculosis
treatment regimens for “new” TB patients [presumed, Source: references 20a,20b
or known, to have drug-susceptible TB] as per the WHO
guidelines (20a,20b) is shown in Table 44.6. Thrice-weekly
intermittent treatment has been discontinued. Drug dosages negative during this period. In the CP usually two drugs,
are presented in Table 44.7. In these guidelines the emphasis namely isoniazid and rifampicin, are required for a period
has been placed on the role of drug-susceptibility testing of four months. The CP should include drugs with sterilising
[DST] in the management of retreatment group keeping in effect so that all the bacilli including semi-dormant bacilli
mind the laboratory infrastructure in a given country. and bacilli which show short burst of metabolic activity are
For deciding the treatment regimen, earlier, patients killed. This will prevent the recurrence of TB. The WHO has
used to be categorised into two groups: [i] treatment naive recommended (20a,20b) that in populations with known or
patients [new patients or patients who have received less suspected high levels of isoniazid resistance, new TB patients
than 1 month of treatment]; and [ii] retreatment cases can receive ethambutol along with isoniazid and rifampicin
which includes treatment failure, patients returning after in the CP (20a,20b).
loss to follow-up or relapsing from their first treatment In 2014, India Government released document for
course treatment and a few other less defined groups. With Standards for TB care in India (25). As per this document the
availability of “universal DST”, this paradigm is not in use CP should consist of three drugs [isoniazid, rifampicin and
presently. ethambutol] given for at least four months. The Standards for
For patients with drug-susceptible TB, treatment regimens TB care in India (25) also states that in special situations like
have an initial IP for two months and a CP lasting for four bone and joint TB, spinal TB with neurological involvement
months. During the initial IP of therapy four drugs, namely and neurological TB, the duration of CP may be extended
isoniazid, rifampicin, ethambutol and pyrazinamide, are by three to six months. The Presently, as per the Revised
administered which lead to rapid killing of bacilli. Majority National TB Control Programme [RNTCP] Technical and
of cases with sputum smear-positive TB will become sputum Operational Guidelines for Tuberculosis Control in India (26)
626 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

the CP consists of three drugs [isoniazid, rifampicin and Treatment of Smear-negative Tuberculosis
ethambutol] given for at least four months. The reader is
In a trial done in Hong Kong (37) the patients received daily
referred to the chapter “Revised National Tuberculosis Control
or thrice weekly treatment with four drugs [streptomycin,
Programme” [Chapter 53] for details.
isoniazid, rifampicin and pyrazinamide] for 3-4 months for
With availability of “universal DST”, molecular testing
smear- and culture-negative patients. The smear negative and
for drug resistance is done and treatment is administered as
culture positive patients received 4-6 months of treatment.
per the category of DR-TB. The new diagnostic algorithm
The follow-up of over 60 months showed a combined relapse
in adults and children is shown in Figures 42.5A and 42.5B.
rate of 7% and 3% for patients who received 3 months and
The treatment algorithm as per the “universal DST” results
4 months of treatment. The WHO guidelines (20a,20b)
is shown in Figure 42.6. The reader is referred to the chapter
recommend six months treatment even for smear-negative
“Drug-resistant tuberculosis” [Chapter 42] for details.
and culture-negative patients for consistency and to allow
a margin of safety.
Short-course Chemotherapy Regimens of less
than Six Months Using First-line Drugs Only Adverse Drug Reactions
In a study (27) conducted at Chennai, a five month regimen
The important adverse reactions to anti-TB drugs are
consisting of rifampicin, streptomycin, isoniazid and pyrazi­
listed in Table 44.8. The reader is referred to the chapter
namide daily for two months, followed by streptomycin,
“Hepatotoxicity associated with anti-tuberculosis treatment”
isoniazid and pyrazinamide twice weekly for three months
[Chapter 45] for details on this topic. Arthralgia due to
was found to be effective and had a low relapse rate [7.1%
pyrazinamide is due to inhibition of renal tubular secretion
of patients with organisms initially sensitive to streptomycin
of uric acid by pyrazinoic acid, the main metabolite of
and isoniazid] (27). The efficacy of a three-month regimen
pyrazinamide. It can be treated with non-steriodal anti-
[90 doses of RHZS] during the follow-up period of five
inflammatory drugs [NSAIDs]. High serum concentration
years (28,29) has been studied in patients with pulmonary
of uric acid may uncommonly precipitate gout.
TB. Though this regimen achieved a near 100% culture
There are certain adverse reactions with rifampicin
conversion rate at the end of treatment, 20% of patients had
which occurs when it is given intermittently. These include
bacteriologically confirmed relapse during the follow-up
“flu-like” syndrome, shortness of breath and shock, thrombo­
period of five years. In contrast, when fewer doses were
cytopenia, acute haemolytic anaemia and acute tubular
administered over a longer duration [thrice-weekly for
2 months; followed by twice-weekly for 4 months, making
up a total of 63 doses in 6 months], relapse rates were Table 44.8: Adverse drug reactions to anti-
only 4%-6%. Thus, the duration for which the drugs are tuberculosis drugs
administered appears to be of prime importance and not Adverse drug reactions
the number of doses (30-32). Similarly, four months SCC Drug Common Uncommon
regimens investigated in Singapore also had high relapse
Isoniazid Asymptomatic elevation Giddiness, convulsions,
rates [8%-16%] (32). of serum hepatic psychosis, haemolytic
enzymes, cutaneous anaemia, aplastic
Optimum Duration of Standard, Non-rifampicin hypersensitivity, hepatitis, anaemia, lupoid
Containing Regimens peripheral neuropathy reactions, arthralgias,
gynaecomastia, optic
There are situations where rifampicin is either not available neuritis
or rifampicin and pyrazinamide cannot be given to a patient. Rifampicin Hepatitis, gastrointestinal Shortness of breath,
For patients with initially sputum smear-positive TB, reactions, thrombocyto­ shock, haemolytic
practically all-effective regimens reach the potential of penia, febrile reaction, anaemia, acute kidney
bacteriological quiescence within six months of the start flu syndrome, cutaneous injury, thrombotic
hypersensitivity thrombocytopenic
of treatment. However, relapse occurs in about one-fourth
purpura
of patients treated with streptomycin, isoniazid and
Pyrazinamide Hepatititis, arthralgia, Sideroblastic anaemia,
thiacetazone daily for six months (33). Hence, if rifampicin
anorexia, nausea, gout
and pyrazinamide are not used the total duration should be vomiting, flushing,
at least 12 months. photosensitivity,
With reference to study the optimum duration of initial cutaneous reactions
supple­ment of streptomycin or the initial IP in long-term Ethambutol Retrobulbar neuritis, Peripheral neuropathy
treatment, studies in East Africa had shown that two or cutaneous reactions
four weeks are less effective and optimum duration of IP Streptomycin Giddiness, numbness, Renal failure, aplastic
is eight weeks (32,34,35). There is satisfactory evidence that tinnitus, vertigo, anaemia
more than 18 months of good treatment produces little ataxia, deafness,
additional benefit, if any, in terms of treatment success or nephrotoxicity, cutaneous
hypersensitivity
prevention of relapse (36).
 Treatment of Tuberculosis 627

necrosis (38). In last four situations the rifampicin should Management of anti-TB drug-induced hepatotoxicity
not be given again. With current intermittent treatment their is covered in “Hepatotoxicity associated with anti-tuberculosis
incidence is quite low (39,40). treatment” [Chapter 45]. Management of TB in patients with
Isoniazid is acetylated in the liver. Europeans and renal impair­ment is covered in “Tuberculosis in chronic kidney
southern Indians are predominantly slow acetylators; disease” [Chapter 28].
while the Japanese, Korean and Eskimo populations are
predominantly rapid acetylators. The acetylator status Bacteriological Monitoring of Patients
neither affects the efficacy of isoniazid nor the risk of during Anti-tuberculosis Treatment
isoniazid induced hepatitis (41-43).
Peripheral neuropathy with isoniazid is more common In new patients, sputum smear examination for acid-fast
in malnourished, elderly, patients with chronic liver disease, bacilli [AFB] should be done at the end of two months, and
slow acetylators and in pregnancy. It can be prevented by if positive, should be repeated at the end of three months.
simultaneous administration of 10 mg of pyridoxine to Usually at the end of two months more than 80% of positive
high risk group of patients (2). Larger doses of pyridoxine sputum smears would have converted to negative. By the
[100-200 mg per day] are needed to treat established end of three months, virtually all patients [> 90%] would be
neuropathy. smear negative. Before the programmatic management of
Streptomycin is toxic to eighth cranial nerve, with vesti­ DR-TB was launched in India there were significant delays
bular damage more common than auditory damage. The in diagnosis of multidrug-resistant TB [MDR-TB] as well as
risk increases with the dose of drug and with age. in the initiation of subsequent treatment of such cases (44).
These delays could lead to increased defaults and deaths of
Management of Cutaneous Reactions MDR-TB cases.

Anti-TB treatment may be associated with cutaneous

reactions in the form of itching, rash etc. The rash is erythe­
Table 44.9: Challenge doses for detecting cutaneous
matous, macular or papular and is pruritic. In the majority
or generalised hypersensitivity to anti-tuberculosis
of patients the treatment should be stopped until the rash
drugs
has subsided to prevent the progression of reaction. Only
Challenge dose [mg]
symptomatic treatment with oral anti-histamines and local
soothing lotions may be required. In serious cases exfoliative Drug Day 1 Day 2
dermatitis, Stevens Johnson’ syndrome and anaphylaxis Isoniazid 50 300
may occur resulting rarely in death. Here systemic steroid Rifampicin 75 300
therapy is required. For patients requiring desensitisation Pyrazinamide 250 1000
the sequence and doses of the challenged regimen to be
Ethionamide, prothionamide 125 375
used to identify the responsible drug is shown in Table 44.9.
When other effective drugs are available one may substitute Cycloserine 125 250
the offending drug with another effective drug rather than Ethambutol 100 500
attempting desensitisation. Presently desensitisation is Para-aminosalicylic acid 1000 5000
rarely required in clinical practice. Hyperpigmentation of Thiacetazone 25 50
skin and gums induced by second-line drug clofazimine
Streptomycin or other aminoglycosides 125 500
used in the treatment of MDR-TB [Figure 44.2] is frequently
Source: reference 20a
encountered.

A B
Figure 44.2: Clofazimine-induced hyperpigmentation of skin and gums
628 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The Standards for TB Care in India (25) recommend Treatment of Drug-resistant Tuberculosis
that, if the sputum smear is positive at any time during the
MDR-TB is defined as isolates of Mtb resistant to at least
follow-up period, a rapid molecular DST [as the first choice]
isonizid and rifampicin. Treatment of MDR-TB is difficult
or culture-DST [at least for rifampicin and if possible for
and has higher failure rates and relapse rates. It requires the
isoniazid, kanamycin and ofloxacin, if rifampicin-resistant/
use of second line anti-TB drugs.
MDR-TB] should be performed as laboratory facilities
DR-TB is a man made problem. It is always preferable
become available.
that national programmes should invest their resources to
Rapid genotypic/molecular methods can help in early
prevent the development of DR-TB rather than for treating
detec­tion of MDR-TB leading to early start of appropriate
it. Also it is important that the suspected MDR-TB cases
treatment with second line drugs. In India there has been a
are diagnosed early and are initiated on treatment as early
rapid scale up of laboratory services under programmatic
as possible. In India programmatic management of DR-TB
management of DR-TB national programme (18) introducing
was launched in 2007 (18). Since then, there has been a rapid
use of rapid molecular methods, Xpert MTB/RIF and
scale up of the programme and rapid genotypic laboratory
line probe assay [LPA] and “universal DST” is being offered
methods are being used for early detection and early
to all patients presently under the RNTCP [Figures 42.5A
initiation of appropriate treatment of DR patients. The reader
and 42.5B].
is also referred to the chapter “Drug-resistant tuberculosis”
[Chapter 42] for further details.
Clinical and Radiographic Monitoring of Patients
during Anti-tuberculosis Treatment
Treatment of Extra-pulmonary Tuberculosis
Usually after one to two months of treatment the patients
Extra-pulmonary TB [EPTB] accounts for about 20% of all
start feeling better, are free from fever, cough and sputum.
cases of TB in immunocompetent persons (20a). Lymph
Chest radiograph also shows improvement. They continue
node TB, TB pleural effusion, bone or joint TB are the most
to improve over next several months eventually leaving
common types of EPTB (55,56). Meningeal, miliary, and
residual fibrotic/cavitary changes. Routinely monitoring
pericardial TB are more likely to result in a fatal outcome (55).
of response to treatment by serial chest radiographs is not
Sparse evidence is available from controlled clinical trials
recommended as they are non-specific. However, they
regarding the treatment of EPTB. The WHO 2010 guide­
may be of use to look for some suspected complications
lines (20a) recommend that most of the EPTB should be
such as pneumothorax, pleural effusion/empyema and in
treated with six months standard short-course regimen.
cases with haemoptysis. Also, the chest radiograph may
Studies in India have demonstrated that six months intermit­
be done at the end of treatment for future follow-up of
tent short course chemotherapy under national programme
the patient. If patients do not show clinical improvement
is adequate and effective for TB pleural effusion (57) and
after two or three months of treatment it should alert the
lymph node TB (58,59).
clinician regarding treatment compliance and/or drug-
Some authorities recommend that for miliary TB and some
resistant TB.
cases with bone and joint TB the treatment may be extended
to nine months (13,60). For TB meningitis 9-12 months
Infectivity during Treatment
of treatment has been recommended (13,60). The Standards
Currently ambulatory treatment of TB is recommended (45-47). for TB Care in India (25) recommend that in bone and joint
Hospitalisation is necessary only for some specific situations TB, spinal TB with neurological involvement and neuro­
such as serious disease, compliance problems, and associated logical TB the duration of CP may be extended by three to
complications such as pneumothorax, empyema or haemo­ six months.
ptysis. Usually after two weeks of treatment the patients The evidence-based Guidelines for Extrapulmonary
are considered non-infectious and may return to work TB for India [INDEX-TB Guidelines] have recently been
thereafter (48-54). Generally it is preferable to keep sputum published. When TBM is present, the evidence-based
positive patients off the work for at least four weeks. INDEX-TB guidelines (61) recommend treatment for at least
nine 9 months. The INDEX-TB guidelines (61) recommend
Laboratory Monitoring during Treatment that when spinal TB and other forms of bone and joint TB are
present, a total treatment duration of 12 months [extendable
Most of the patients complete anti-TB treatment without
to 18 months on a case-by-case basis] is indicated.
any significant treatment-related ADRs. Patients should be
Details regarding treatment of various forms of EPTB
monitored clinically and counselled to inform the treating
have been covered in the respective chapters in the book.
physicians in case they have any symptoms sugges­tive of
ADRs. Except in high risk groups, such as, elderly, mal­
nourished, patients with underlying liver disease, alcoholics,
Ensuring Compliance during Treatment
pregnant women, it is recommended that the routine Many patients do not adhere to anti-TB treatment. Certain
laboratory monitoring is not considered necessary (20a). factors such as homelessness, alcohol or drug abuse,
 Treatment of Tuberculosis 629

behavioural problems, mental retardation, lack of family/ Table 44.10 lists the clinical situations where TDM may
social support, among others could be responsible for non- be useful (70-73). TDM is not being used in developing
compliance (60). Directly observed treatment [DOT] was countries due to high cost involved and the requirement
shown to be very efficacious in ensuring patients adherence of specialised technologies. Lack of awareness about the
by experience at Chennai and Hong Kong (62). In 1993 utility of TDM may also be a contributing factor for it’s
WHO announced the new global strategy for TB control under utilisation. For accessing the peak serum concentration
called DOTS (63). This strategy is regarded as the most cost for most of anti-TB drugs, blood should be collected after
effective intervention in the control of TB (63). The reader is two hours of ingestion of drug (71). For evaluating delay
referred to the chapter “DOTS: the strategy that ensures cure in absorption a second sample should be collected six
of tuberculosis” [Chapter 47] for further details. hours after the drug ingestion (71). However, TDM results
should always be correlated with clinical scenarios and
Fixed-dose Combination Formulations bacteriological data (71).
The use of fixed-dose combination [FDC] formulations,
NEWER ANTI-TUBERCULOSIS DRUGS
comprising of two, three or even four drugs in the same
formulation, is thought to improve the treatment compliance, There is a need for newer anti-TB drugs which are safer,
lead to ease of prescription for the physician, thus, reducing low in cost, easier to deliver and above all could reduce the
in medication errors. FDCs also have the potential to duration of chemotherapy. Place of new anti-TB drugs has
simplify the drug procurement and supply under national been extensively reviewed (74-78).
tuberculosis programmes (64). The use of FDCs may also As on date, several new or repurposed anti-TB drugs
reduce the chances of developing DR-TB. However, the are under clinical investigation. There has been progress in
majority of clinical studies did not document the superiority repurposing or redosing of known anti-TB drugs such as
of FDC formulations over the use of individual drugs rifamycins [rifapentine, rifampicin], fluoroquinolones [gati­
regarding sputum smear-conversion, frequency of ADRs floxacin, moxifloxacin] and riminophenazines [clofazimine].
and occurrence of relapse (65,66). Many of the drugs have entered in advanced Phase 3
While using FDCs it is important to ensure quality studies. Results of three major Phase 3 trials looking at treat­
and bio-availability of their component drugs (67,68). ment shortening for drug-sensitive TB are summarised in
Only FDC formulations of proven good quality should be Table 44.11 (79-81).
used. Otherwise the bio-availability of some of the drugs, Bedaquiline [TMC-207], linezolid, sutezolid [PNU-
especially rifampicin, may be significantly reduced. Now 100480], PA-824, SQ-109 and AZD-5847, delamanid [OPC-
FDCs are included in the list of essential drugs (69). 67683] have shown encouraging results (82,83a). Bedaquiline
has been found to be effective against drug-sensitive and
Surgery DR strains of Mtb and has shown significant improve­ment
in sputum culture conversion at two months (82). Since
The reader is referred to the chapter “Surgery for pleuro­
December 2012 bedaquiline has been approved for
pulmonary tuberculosis” [Chapter 46] for details on this topic.
conditional use in USA and is the first new TB drug to be
approved for use in last more than 40 years. It was recom­
Therapeutic Drug Monitoring
mended conditional authorisation by US-FDA for use in
Measuring blood levels of anti-TB drugs during treat­ difficult X/MDR-TB patients in combination with other
ment is referred to as therapeutic drug monitoring [TDM]. medicines when an effective treatment regimen cannot be

Table 44.10: Clinical situations where TDM may be useful

Patients showing unsatisfactory treatment response despite a good compliance and absence of anti-TB drug resistance to assess
malabsorption of drugs
In HIV-seropositive patients with poor response [as HIV infected patients may have low levels of anti-TB drugs]
To optimise scheduling of administration and dosing of anti-tuberculous treatment in specific clinical setting such as tuberculous meningitis or
some patients with MDR-TB
For evaluation and management of pharmaco-kinetic drug interaction with anti-TB drugs specially rifampicin
In presence of associated renal dysfunction, TDM to drugs such as aminoglycosides, ethambutol, ofloxacin and cyclocerine to guide optimum
doses to be used without increased risk of adverse reactions and improved efficacy
For evaluation of new drug formulation such as FDC, as the bio-equivalence of individual drugs, especially rifampicin, may be affected in
these
For monitoring the drug-adherence
For evaluating the influence of food or anti-ulcer medication on bio-availability of anti-TB drugs
TDM = therapeutic drug monitoring; TB = tuberculosis; HIV = human immunodeficiency virus; MDR-TB = multidrug-resistant tuberculosis;
FDC = fixed-dose combination
630 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 44.11: Phase 3 trials for treatment shortening in patients with drug-sensitive TB
Trial Name Method Result
OFLOTUB trial (79) Trial evaluated 4-month combination regimens in which a At two months and end of treatment, patients in
gatifloxacin was substituted for ethambutol in test arm. In the the intervention arm fared better. However,
intervention arm, 917 patients received 400 mg of gatifloxacin, after 24 months of completion of treatment
six days a week, in place of ethambutol for two months, patients in the gatifloxacin arm showed higher
followed by two months of treatment with gatifloxacin, isoniazid frequency of TB recurrence [14.6% vs 6.9%]
and rifampicin. In the control arm patients received 6 months of compared to control arm
conventional WHO recommended regimen
REMox TB trial (80) Trial evaluated 4-month combination regimens in which The two moxifloxacin arms had higher relapses
moxifloxacin was substituted for either ethambutol or isoniazid. compared to the control arm, but an earlier
This was compared with standard six months conventional conversion to culture-negative sputum was
WHO recommended regimen observed in moxifloxacin containing arms. However,
both of moxifloxacin-containing regimens were safe,
with comparable incidence of grade 3 and 4 adverse
events. Also there was no evidence of increased
hepatic dysfunction. There was no clinical evidence
of cardiac toxicity in moxifloxacin containing arms
Rifaquin Trial (81) Trial evaluated the safety and efficacy of two regimens for The study concluded that the 6-month study
patients with drug-susceptible TB. The control arm was regimen was non-inferior, safe and well tolerated.
standard 6 months WHO regimen. One study arm included The 4-month study regimen was safe and well
2 months of daily ethambutol, moxifloxacin, rifampicin and tolerated but its efficacy was inferior to the control
pyrazinamide followed by 2 months of twice weekly
moxifloxacin [500 mg] and rifapentine [900 mg]. Second study
arm included 2 months of daily ethambutol, moxifloxacin,
rifampicin and pyrazinamide followed by 4 months of once
weekly moxifloxacin [500 mg] and rifapentine [1200 mg]
TB = tuberculosis; WHO = World Health Organization

devised due to resistance or tolerability. It is administered isoniazid, pyrazinamide and ethambutol during the first-two
in a dosage 400 mg once daily for two weeks, followed by months of treatment are being investigated. Early results
200 mg thrice-weekly for 22 weeks. The drug is to be taken demonstrated that rifapentine has good tolerability and good
with food. Generally it is well tolerated. However, it can antimicrobial activity. A study has shown that two weeks of
cause QT prolongation in the electrocardiogram. Therefore, rifampicin up to 35 mg/kg was safe and well tolerated (84).
one has to be careful in using it with other anti-TB drugs The effects of high doses of rifampicin, 600 mg and 900 mg,
which can cause QT prolongation such as clofazimine, in combination with other standard regimen drugs over
moxifloxacin, etc. 2 months [HIGHRIF2] are also being tried (76).
In 2013, another new drug, delamanid, was recommended In a meta-analysis (85), linezolid, an oxazolidinone anti­
conditional authorisation with similar conditions for limited. biotic class of drugs was found to be promising in MDR-TB.
Delamanid also appears to be a promising molecule and has However, it has potential toxicity including anaemia, thrombo­
also been found to be effective against drug-sensitive and cytopenia, peripheral neuropathy and optic neuritis (85).
DR strains of Mtb. Delamanid has shown increased sputum In India, linezolid has been found to be cheap, effective and
culture conversion at 2 months in MDR-TB cases and also relatively safe (86).
shown to reduce mortality in difficult to treat cases of DR. A Sutezolid [PNU-100480] is an oxazolidinone and an
Phase 3 trial [NCT01424670] is underway where delamanid analogue of linezolid. Sutezolid at a dosage of either 600 mg
with optimised background regimen for MDR-TB patients is twice a day or 1200 mg once a day led to a significant reduc­
being compared to a regimen with only background regimen tion in log colony forming units [CFU] counts after 14 days
with placebo. The enrolment of around 500 patients has of treatment. SQ-109, originally synthesised as deriva­tive
been completed and the results of the trial are awaited (76). of ethambutol, is also being tested as part of combination
Bedaquiline and delamanid are available for use through regimen.
conditional access under Programmatic Management of Recently there are attempts towards novel anti-TB drugs
Drug-resistant Tuberculosis [PMDT] in India (83b,83c,83d). regimen which could transform therapy by shortening
The reader is referred to chapters “Drug-resistant tuberculosis” and simplifying the treatment of both drug-sensitive and
[Chapter 42] and “Revised National Tuberculosis Control DR-TB with the same oral regimen. NC-001, also known
Programme” [Chapter 53] for details. as new combination 1 [PaMZ], is one such regimen where
In a Phase 2b trial [TBTC trial 29X] tolerability, safety drug candidate PA-824 is combined with moxifloxacin plus
and antimicrobial activity of different doses of rifapentine pyrazinamide. The early bactericidal activity of this regimen
[at 10, 15 and 20 mg/kg body weight] in combination with is found to be good (82). The testing of NC-001 advanced
 Treatment of Tuberculosis 631

to a two months trial [called NC-002] in March, 2012 where whereas poor countries, whose main objective is to cut-
in PaMZ was tested for drug-sensitive patients and patients down TB transmission by primarily treating active cases,
with DR-TB who are sensitive to drugs included in the new may have as much as 50% of the population infected,
regimen (87). The results showed that this combination making LTBI treatment practically impossible. Yet, targeted
was effective for both drug sensitive as well as for MDR-TB testing of high risk populations may prove useful as
patients. The ADRs were similar to standard regimen (88). shown by the successful treatment of LTBI in HIV infected
A second trial, NC-003 is testing the early bactericidal action individuals (94,95).
of various combi­nations of bedaquiline, PA-824, clofazimine In patients with LTBI, use of potentially toxic drugs for
and pyrazinamide in drug susceptible patients (89). extended intervals of time poses difficulty both to patients
There are attempts at reducing the treatment duration for [mostly asymptomatic] and providers. Evidence is available
MDR-TB patients also. In Bangladesh regimen, 515 MDR-TB demonstrating that isoniazid taken for at least six months
patients were given minimum nine months of treatment in persons with LTBI reduced subsequent TB incidence by
regimen and followed up for 2 years. It showed 84% 25%-92%, the differences in effectiveness largely explained
relapse free successful outcomes at 24 months (90). Under by differences in treatment completion (96). Use of isoniazid
the umbrella of “Standardised Treatment Regimen of Anti- in LTBI treatment, however, is fraught with difficulties.
tuberculosis Drugs for Patients with Multi-drug-Resistant Long duration of administration [6-12 months] coupled with
Tuberculosis [STREAM]” trials, a trial is being carried out potentially lethal albeit uncommon adverse effects, such as,
with nine months treatment duration for MDR-TB patients drug-induced hepatotoxicity reduce its acceptability both to
with moxifloxacin replacing gatifloxacin in Bangladesh trial. patients and providers alike (97,98).
The results will be compared with WHO recommended The International Union Against Tuberculosis [IUAT]
standard of care treatment for MDR-TB (91). Under the same trial (99), conducted in Eastern Europe, showed that
participants, who completed six and 12 months of isoniazid,
umbrella a nine months and six months oral-only regimen
had 69% and 93% reduction in active TB, respectively (99).
using bedaquiline have been planned (91).
However, completion of the 12 months regimen was much
A recent systematic review (92) identified six drugs,
less than the 6 months regimen. The American Thoracic
which are not in the list of WHO guidelines for treatment
Society [ATS] in 2000 recommended 9 months isoniazid with
of MDR-TB, but have potential for the management of
estimated efficacy of 90% as the accept­able regimen (100).
MDR-TB. These include phenothiazines [thioridazine], co-
Adverse effects, especially hepatitis, may be difficult to
trimoxazole, metronidazole, doxycycline, disulfiram and
detect and can lead to fatality which may be as high as 1%
tigecycline. For actively replicating TB bacilli co-trimoxazole in older patients (101).
may be very effective. For dormant bacilli thioridazine The problems with isoniazid have stimulated develop­
appeared promising as an adjuvant drug (92). ment and evaluation of several shorter regimens. Several
Among new drugs some are predicted have activity randomised trials conducted to compare six to 12 months
against persisters populations in TB. These include clofazi­ isoniazid with two months of rifampicin and pyrazinamide in
mine, bedaquiline and oxazolidinones [sutezolid and AZD- HIV infected patients demonstrated equivalent efficacy (102).
5847] (78). Nitroimidazopyrans [delamanid and PA-824], In 2000, ATS recommended use of rifampicin and pyrazina­
and benzothiazinones [BTZ-043] also have activity against mide for two months along with a strong recommendation
persister populations. for use in HIV infected persons and a conditional recom­
However, despite the advancements in new drugs the mendation for non-HIV infected persons (100). This led to
search for drugs which could significantly reduce the duration widespread use of this regimen, but was quickly followed
of treatment for drug sensitive and DR-TB, especially by reports of serious hepatotoxicity and death, leading to
avoiding the need for prolonged use of injections is still on. revision of recommendations that advocated cautious use
in HIV infected individuals (103,104).
Corticosteroids in Tuberculosis The WHO has published detailed guidelines for manage­
ment of LTBI (105). There was consensus of the WHO Panel
Cortiosteroids should be judiciously used in the treatment
on the equivalence of six-month isoniazid, nine-month
of TB. The reader is referred to the chapters covering the
isoniazid, and three-month rifpentine plus isoniazid (105).
concerned organ systems for details regarding the evidence The recent 2018 WHO guidelines (106) for testing and
and rationale for use and of corticosteroids in patients with treat­ment of LTBI in adults and adolescents are shown in
active TB. Tables 44.12A and 44.12B.

Treatment of Latent Tuberculosis Infection Newer Regimens for Latent Tuberculosis Infection
The term latent TB infection [LTBI] refers to the presence of One of the promising new drugs being tested for the
Mtb in the body without signs and symptoms, radiographic treatment of LTBI is rifapentine, a cyclopentyl-substituted
or bacteriologic evidence of active TB disease. Approximately rifamycin that is as effective as rifampicin, but whose serum
one-third of the world’s population is infected with Mtb (93). half-life is five times that of rifampicin, thus permitting
Developed countries have been successful in lowering down weekly dosing. The isoniazid-rifapentine regime was
TB incidence by targeted testing of high risk population, investigated (107) and once-weekly, three months regimen
632 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 44.12A: Treatment options for LTBI Table 44.12B: Treatment regimens and dosages of
Risk group category Recommendation for treatment of LTBI drugs for LTBI
Adults in countries Isoniazid monotherapy for 6 months Regimen Dosage
with high and low TB Isoniazid alone, Adults 5 mg/kg body weight
incidence daily for 6 or 9 Children 10 mg/kg body weight [range 7-15 mg]
Isoniazid monotherapy for 6 months months Maximum dose 300 mg
Adults in countries with Alternative regimen: rifapentine and
high TB incidence isoniazid weekly for 3 months Rifampicin alone, Adults 10 mg/kg body weight
daily for 3-4 Children 15 mg/kg body weight
Adults in countries with Isoniazid monotherapy for 6 months months [range 10-20 mg]
a low TB incidence Alternative regimens: Isoniazid Maximum dose 600 mg
monotherapy for 9 months; or a 3-month Isoniazid + Isoniazid
regimen of weekly rifapentine plus rifampicin daily Adults 5 mg/kg body weight
isoniazid; or 3-4 months of isoniazid plus for 3-4 months Children 10 mg/kg body weight [range 7-15 mg]
rifampicin; or 3-4 months of rifampicin Maximum dose 300 mg
alone Rifampicin
Adults 10 mg/kg body weight
Adults and adolescent At least 36 months of IPT, regardless Children 15 mg/kg body weight
PLHW who have an of whether they are receiving ART. IPT [range 10-20 mg]
unknown or a positive should also be given irrespective of the Maximum dose 600 mg
TST and are unlikely to degree of immunosuppression, history of
have active TB disease previous TB treatment and pregnancy Rifapentine + Isoniazid
isoniazid weekly Age 12 years = 15 mg/kg body weight
LTBI = latent TB infection; TB = tuberculosis; PLWH = people living for 3 months Age 2-11 years = 5 mg/kg body weight
with HIV; HIV = human immunodeficiency virus; TST = tuberculin [12 doses] Maximum dose = 900 mg
skin test; IPT = isoniazid preventive therapy; ART = antiretroviral Rifapentene
treatment 10-14 kg = 300 mg
Source: reference 3 14.1-25 kg = 450 mg
25.1-32 kg = 600 mg
32.1-50 kg = 750 mg
of isoniazid-rifapentine [900 mg each] was found to be as >50 kg = 900 mg
effective as nine months of isoniazid alone in preventing TB Maximum dose = 900 mg
and had a higher treatment-completion rate. LTBI = latent tuberculosis infection
Rifabutin may be substituted for rifampicin in HIV- Source: reference 106
seropositive patients at risk for isoniazid-resistant TB
owing to its lower interaction with anti-retroviral drugs as
compared to RIF. The six months regimen of pyrazinamide risk of infection being 1.5% (113,114). The priority in India
and a fluoroquinolone, recommended for LTBI treatment has been to treat sputum smear-positive TB patients in order
of MDR-TB contacts, has been shown to have very poor to interrupt the transmission in TB. Treating 40% of the
completion rates due to high toxicity. This has prompted population for LTBI is neither rational nor practicable, thus
the use of monotherapy with levofloxacin or moxifloxacin, emphasising the need for a focussed approach. The most
the latter showing special promise on account of published obvious target groups for LTBI treatment would include
literature showing its equivalence to isoniazid (108,109). high-risk patients, such as, those receiving corticosteroids,
Shorter Regimens for Treatment of Latent Tuberculosis immunosuppressants, HIV-infected and juvenile contacts of
Infection In their meta-analysis of 10 randomised controlled sputum-positive index cases, showing recent tuberculin skin
trials consisting of 10,717 HIV-negative adults and children, test [TST] conversion.
Sharma et al (110) concluded that shortened prophylactic Another major concern in LTBI treatment is development
regimens using rifampicin alone did not demonstrate higher of drug-resistance. The most likely reason for development
rates of active TB when compared to longer regimens with of drug-resistance with LTBI treatment is improper dosing
isoniazid. A weekly regimen of rifapentine plus isoniazid and/or administration, which can be prevented by strict
had higher comple­tion rates with less liver toxicity but more monitoring, good education and rigorous follow-up. The
treatment discontinua­tion due to adverse events than with second reason for the development of drug-resistance could
isoniazid (110). Further, data suggest that, treatment with be partial treatment of active TB masquerading as LTBI. This
four months of rifampicin had similar rates of safety and should be avoided by a thorough clinical assessment, based
efficacy but a better adherence compared with nine months on sound history and appropriate investigations such as
of treatment with isoniazid (111,112). chest radiograph and sputum testing, before starting LTBI
treatment.
Finally, it is the responsibility of the health care provider
Treatment of Latent Tuberculosis Infection in India
team to ensure that patient complies with treatment once the
India is home to nearly one-fourth of the global burden of decision to treat LTBI with a suitable regime on an individual
TB. In India, 40% of the population are infected, the annual basis has been taken.
 Treatment of Tuberculosis 633

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 45
Hepatotoxicity Associated with
Anti-tuberculosis Treatment
Divya Reddy, Jussi Saukkonen

INTRODUCTION the drug. Stress on the liver, generally in the form of an

administered drug or toxin, induces minor hepatocellular
The treatment of both latent tuberculosis infection [LTBI]
injury, an array of hepatic enzymes, and can be manifested
and active tuberculosis [TB] has long been challenged by
as aminotransferase elevation (1). On the other hand, a
effects on the liver. While isoniazid is a prototypical drug
progressive rise in liver transaminases, generally accom­
for causing hepatic dysfunction, other first and second-line
panied by hepatitis symptoms of nausea, vomiting, abdo­
antibiotics in TB treatment may also affect the liver. The
minal pain, or unexplained fatigue, and eventual jaundice
extended treatment duration, the often-challenging lives,
are indicative of DILI (2).
and co-morbidities of patients with TB pose unique issues
The pathogenesis of anti-TB DILI is not well characterised.
of potential hepatotoxicity. There are frequent challenges in
For isoniazid, for which the capacity for hepatotoxicity
evaluating, diagnosing and determining whether observed
is better described and understood, DILI occurrence is
liver abnormalities are related to TB treatment or another
idiosyncratic, and not entirely predictable, while hepatic
confounding cause. Strategies have evolved to try to prevent,
adaptation is known to occur in up to 20% of those
evaluate, diagnose and manage hepatotoxicity related to
taking the medication. In contrast, some drugs can cause
TB medications from occurring and to such hepatotoxicity.
a dose-related hepatotoxicity that is at least somewhat
Such strategies for preventing and monitoring drug-induced
predictable. Pyrazinamide is thought to cause both dose-
liver injury [DILI] have not been systematically developed,
related and idiosyncratic hepatotoxicity (3,4). Isoniazid can
but have evolved from practice. Co-morbidities such as
induce oxidative stress, unleashing several mechanisms
alcohol abuse, human immunodeficiency virus [HIV], and
of injury, including a cytokine-mediated inflammation,
the burgeoning epidemics of viral hepatitis, complicate
with a Th1 and Th2 imbalance. Covalent binding of drug
treatment and the potential for hepatotoxicity. The use of
or metabolites to hepatic proteins can induce potent
new regimens for latent and active TB treatment, as well
immune and other cytotoxic responses. These oxidative
as the spate of new medications is introducing both new
and inflammatory insults lead to hepatocyte apoptosis and
concerns and potential opportunities for less hepatotoxicity.
necrosis. Transaminase elevations signify hepatocellular
injury of varying degrees. Concomitant development of
MECHANISM OF ANTI-TUBERCULOSIS
jaundice or hyperbilirubinemia indicates widespread hepato­
DRUG-INDUCED LIVER INJURY cellular injury with resulting bile ductile obstruction by
A broad range of hepatic abnormalities may occur during oedematous and necrotic tissue (2,5).
anti-TB treatment, related or unrelated to the medications Drug metabolism, influenced by gene polymorphisms
used. Liver dysfunction associated with anti-TB treatment of several key enzymes, plays a role in susceptibility to
ranges from asymptomatic elevation of transaminases potential DILI. Considerable evidence has accrued impli­
to rare, fulminant liver failure. Low-grade transaminase cating specific N-acetyl transferase 2 [NAT2] genotypes
elevations due to a particular medication and that do not associated with slow acetylation of isoniazid as a factor
progress to severe injury constitute hepatic adaptation to predisposing to varying degrees of transaminase elevation
638 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

and liver injury (6-8). There are differences in prevalence of mani­festations of hepatotoxicity, based on expert opinion,
slow acetylation phenotypes that may account for reported in order to prevent those patients who might progress to
variations in the occurrence of hepatotoxicity (9). Gene severe liver injury. Unfortunately, this interrupts treatment
polymorphisms in cytochrome p450 2E have also been for many patients who are experiencing either transaminase
implicated in hepatotoxicity during TB treatment (10). elevation unrelated to TB treatment or hepatic adaptation
Glutathione S-transferase [GST] gene polymorphisms at without progression to DILI. Evaluation of the possible
loci and alleles have also been shown to be associated with causes of the hepatic event is imperative. In most cases,
hepatotoxicity (11), likely through increased generation of treatment may be resumed with the same or similar regimen,
free radicals. Hepatic injury is accompanied by decreased suggesting most of these cases of hepatotoxicity were those
glutathione [GSH] and thiols, with increased lipid peroxi­ with hepatic adaption. However, the more severe the event,
dation, resulting in hepatocellular injury. N-acetylcysteine particularly if jaundice or hyperbilirubinemia accompanies
has been shown to be protective in an animal model of significant transaminase elevation, more caution should be
INH/Rif oxidative hepatic injury (12), and in one small used in reintroducing some or all of the same medications.
clinical trial (13). Several other anti-oxidants appear to
exert hepatoprotective effects in models of TB DILI (14,15), CLINICAL MANIFESTATIONS OF
and curcumin when given to patients treated for TB (16). HEPATOTOXICITY
However, a recent study from India has shown that GSTM1
‘null’ mutation is not independently associated with DILI Many patients found to have high-grade transaminase
development in subjects receiving anti-TB treatment (17). elevation have few or no symptoms. Constitutional sym­
A recent study has reported that higher concentration of ptoms may occur early, lasting often for days to weeks. In
plasma rifampicin is associated with subsequent develop­ patients with severe hepatotoxicity, nausea, vomiting and
ment of DILI (18). abdominal pain occur in 50%-75%, while fever is noted in
10% and rash in 5%. Jaundice, dark urine and clay-coloured
CLINICAL SIGNIFICANCE OF HEPATIC stools are generally late signs of severe hepatotoxicity.
Coagulopathy, hypoalbuminaemia and hypoglycaemia are
ADAPTATION
signs of hepatic failure. Most individuals recover with prompt
There are several essential points for the clinician regarding discontinuation of isoniazid, but resolution usually takes
hepatic adaptation and true DILI. First, transaminase weeks (20).
elevation during TB treatment should be evaluated for
other causes and not immediately assumed to be related INCIDENCE OF HEPATOTOXICITY WITH
to anti-TB treatment. The serum alanine amino transferase ANTI-TUBERCULOSIS THERAPY
[ALT] level is more specific for the liver then is aspartate
amino transferase [AST], which may be elevated from other Among the first-line drugs used for treatment of TB, isoniazid,
tissues. Thus, the former should be used for assessment rifampicin and pyrazinamide can cause hepatotoxicity.
for potential hepatotoxicity. Second, the association with Most clinical trials until more recent years were not designed
the level of transaminase elevation for DILI has not been to systematically capture hepatotoxicity data.
established. This seems to vary from drug to drug, with DILI During treatment of TB with first-line therapy, hepato­
from methotrexate appearing at ALT elevations of 3 times toxicity has been reported to occur in 3%-25% of those treated
the upper limit of normal [ULN], on liver biopsy. Whereas in studies that used differing regimens and definitions of
with other drugs elevations of ALT that exceed even 10 hepatotoxicity (2). Using American Thoracic Society [ATS]
the ULN, have not correlated with DILI (2). Similarly, for criteria, approximately 3% of treated individuals experience
anti-TB treatment, the amplitude of ALT elevation that hepatotoxicity during treatment of TB (21).
occurs during treatment has not been established. Third, For LTBI, several regimens are available with varying
the most concerning DILI is manifested by the development hepatotoxicity. These regimens include isoniazid for six
of jaundice or total bilirubin elevation more than twice to nine months, rifampicin for four months, isoniazid and
the ULN. With this development, the risk of liver failure rifampicin, and isoniazid with rifapentine for three months.
is escalated to about 10%, known as “Hy’s law’” after the The regimen of rifampicin and pyrazinamide given for
distinguished hepatologist Hyman Zimmerman (2,19). two months is not recommended due to severe and fatal
For the TB provider the mandate is to effectively treat hepatotoxicity (22,23).
TB and to avoid or mitigate adverse events [AEs], especially During treatment of LTBI, the incidence of hepatotoxicity
DILI, for each patient. Simply put, the transition from due to isoniazid has been estimated to occur in the range
transaminase elevation from hepatic adaptation to DILI from 0.1% to 0.56% of those treated with isoniazid (24-27). In
is not clearly defined. The development of jaundice or a recent large multi-centre LTBI treatment trial hepatotoxicity
hyperbilirubinemia with significant transaminase elevation attributed to isoniazid was 2.7% (28). Treatment of LTBI
is a comparatively late manifestation of liver injury with with rifampicin is associated with less hepatotoxicity,
a potentially unacceptably high-risk of progression to from 0.08% to 2% (29-31). A systematic review found less
fulminant liver failure. Thus, a strategy of interrupting treat­ hepatotoxicity with rifampicin than with isoniazid in four
ment has evolved, using preset stopping rules for potential trials, although the quality of evidence from these trials
 Hepatotoxicity Associated with Anti-tuberculosis Treatment 639

was low (32). Hepatotoxicity from the combination of isoniazid Risk Factors for Hepatotoxicity during Treatment
and rifampicin has been assessed in a meta-analysis and for Active Tuberculosis Disease
rifampicin was found to potentiate the hepato­toxicity of
Several risk factors for either increased incidence of or
isoniazid (33), while another systematic review assessing
more severe liver injury include hypoalbuminemia, female
two trials that yielded relatively low quality evidence (34).
gender, increasing age, pregnancy, elevated baseline trans­
In a large study, isoniazid and rifapentine administered
aminase (2,21). Variable data have been reported for alcohol
once weekly for three months was less hepatotoxic than
consumption, but most consider it a risk factor. Similarly,
isoniazid given daily for nine months, 0.4% versus 2.4%,
concomitant ingestion of other potentially hepatotoxic drugs
respectively (28a). In the recent REMoxTB clinical trial (28b) is also considered a risk factor.
patients [n = 1928] received either standard anti-TB treatment Viral hepatitis co-infection often complicates treatment of
[2 months of ethambutol, isoniazid, rifampicin, pyrazinamide patients with TB. Several studies in patients co-infected with
followed by 4 months of isoniazid and rifampicin; n = 639], hepatitis B indicate no increased risk, unless the baseline
or a 4-month regimen in which moxifloxacin replaced either ALT is abnormal (36-39), with some caveats about design.
ethambutol [isoniazid arm, 2MHRZ/2MHR; n = 654] or However, two studies suggest increased incidence and
isoniazid [ethambutol arm, 2EMRZ/2MR; n = 635]. DILI, severity risks (40,41).
[defined as peak ALT more than or equal to 5 times the Hepatitis C was reported to be associated with a higher
ULN or ALT more than or equal to 3 time the ULN with risk of hepatotoxicity in three studies (36,42,43), but not
total bilirubin greater than 2 times the ULN] occurred in in others (6,35,44). These viral hepatitis’ are considered
58 of the 1928 [3%] at a median time of 28 days. hepatotoxi­city risk factors, particularly if transaminases are
abnormal prior to TB treatment.
ASSESSMENT OF ANTI-TUBERCULOSIS Assessment of cohorts of human immunodeficiency virus
TREATMENT BENEFITS, RISKS AND [HIV] infected individuals for hepato­toxicity during TB is
difficult due to potential confounding factors, including
MITIGATION OF RISKS
concomitant hepatotoxic medications, substance abuse,
A risk-benefit analysis is appropriate in all medical and viral hepatitis. Several studies indicate a higher risk
interventions, although for some clinical conditions the of hepatotoxicity associated with HIV infection (35,42,44),
therapeutic path is clear. For patients with active disease, including an additive effect between hepatitis C and HIV
the benefits are clear and treatment should proceed, most infection (42) [Table 45.2].
commonly with a (35) standard regimen, but assessment of
the risks for hepatotoxicity, other AEs and drug interactions Risk Factors for Hepatotoxicity during Treatment
should be done. This may, in some cases, inform the choice of for Latent Tuberculosis Infection
regimen, monitoring strategy, and subsequent management Risk for hepatotoxicity during treatment for LTBI increases
decisions, should there be indications of DILI. For patients progressively with age (45,46). Several studies with methodo­
with LTBI, the risk/benefit analysis is less stark. In most logic limitations suggest that the severity of isoniazid-
cases, treatment of LTBI in those at high-risk for progressing induced hepatotoxicity, when it does occur, may be worse in
to TB disease is beneficial in those whose risk of liver injury women, but incidence is not clearly increased (2). Elevated
is not high. Thus, in the circumstance of LTBI the benefits of baseline transaminases are a risk factor for hepatotoxicity
treatment are weighed more closely in relation to the risks during treatment of LTBI (25,47). Other hepatotoxicity risk
for that individual patient. Since the patient is healthy from factors include alcohol consumption (48), active but not
the standpoint of TB, i.e., does not have disease, the tragic quiescent hepatitis B (49,50). Hepatitis C infection alone,
circumstance of a healthy individual sustaining a serious or
permanent liver injury is to be avoided [Table 45.1].
Table 45.2: Potential risk factors for hepatotoxicity*
Increasing age
Table 45.1: Pre-treatment clinical evaluation and plan Malnutrition or hypoalbuminemia
A standardised history form is recommended, which includes risk Pyrazinamide in regimen
factors for hepatotoxicity Other hepatotoxic agents
The physical examination should include evaluation for signs of liver Alcohol
disease, such as, liver tenderness, hepatosplenomegaly, jaundice,
caput medusae, spider angiomata, ascites, and oedema Elevated baseline alanine aminotransferase

Treatment indication: latent vs active TB Pre-existing chronic liver disease

Consider regimen and educate patient regarding adherence and Viral hepatitis
adverse effects Human immunodeficiency virus infection
Decide upon and discuss monitoring plan with patient Pregnancy or post-partum
TB = tuberculosis *Evidence base for each is variable
640 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

in limited data, was not associated with hepatotoxicity during evaluate for potential drug interactions if a rifamycin is
treatment of LTBI (47,51). Malnutrition, prior isoniazid- being considered.
related hepatotoxicity, and continued use of isoniazid while
symptomatic have been described to contribute to higher- HEPATOTOXIC RISK MITIGATION AND
grade isoniazid hepatotoxicity (20). HIV infection alone MONITORING DURING TUBERCULOSIS
does not appear to increase risk for hepatotoxicity (52,53), TREATMENT
although infected patients often have other risk factors,
including anti-retroviral [ARV] medications. Steps to try to prevent and recognise early the occurrence
The risk-benefit analysis for treatment of LTBI should of hepatotoxicity include patient education, discontinuation
include the benefit at the patient’s age, co-morbidities, and of other potentially hepatotoxic substances, modified
baseline transaminases. Concomitant medications, drug regimens, intensive monitoring, daily directly observed
interactions, drug and alcohol use, capacity to understand therapy [DOT], and clear and prompt communication among
instructions and communicate with staff, and ability to avoid patients and staff. Alcohol intake should be stopped, as
hepatotoxic agents. well as any potentially hepatotoxic drugs, illicit or over the
counter, such as acetaminophen or related drugs. Prescribed
PATIENT AND REGIMEN SELECTION concomitant medications with hepatotoxic potential that
cannot be replaced or discontinued are indications for close
Tuberculosis Treatment monitoring.
Most patients with TB can be successfully treated with first- Patient education about hepatotoxicity should not jeopar­
line anti-TB therapy. Treatment of patients with pre-existing dise adherence to the regimen, but should point out that
significant liver disease creates substantial challenges. Serum most patients do not experience hepatotoxicity. Nevertheless,
transaminases and total bilirubin may vary as a result of the patients should be educated about symptoms and signs of
underlying liver disease, complicating monitoring for DILI. liver injury and to immediately notify the clinic or DOT
TB involving the liver may also cause elevated baseline worker. For abdominal pain, vomiting, nausea or jaundice
transaminases, which improve with treatment. the patient should halt ingestion of anti-TB treatment,
For patients with significant liver disease or baseline any relevant concomitant medications and promptly com­
transaminase exceed 3 times the ULN [not thought to be municate with TB programme staff.
related to tuberculous involvement of the liver], regimens A monitoring plan should be established to assess
with less potentially hepatotoxic drugs should be selected. adherence, response to therapy, and for AEs. Clinical moni­
Efforts should be made to try to retain isoniazid and parti­ toring for symptoms and signs of hepatotoxicity by trained
cularly rifampicin, if possible, due to their high efficacy. TB programme staff is complemented by biochemical
Expert consultation is recommended and adjustments during monitoring, preferably of serum ALT, for those with specific
treatment are likely. Alternative regimens in the face of risk factors for hepatotoxicity, usually every four weeks. For
liver disease include treatment with first-line drugs without patients with cirrhosis, liver transplant, or who are otherwise
either pyrazinamide for a nine-month course or isoniazid clinically deemed at very high hepatotoxic risk, monitoring
[potentially with a fluoroquinolone] for at least six months. more at least every two weeks is recommended, and if
Treatment that leaves out both isoniazid and pyrazinamide the patient develops symptoms compatible with hepatitis.
entails treatment with rifampicin and ethambutol with a Adjustments of this regime based on local epidemiology and
fluoroquinolone, injectable, or cycloserine for 12-18 months. hepatotoxicity risk factors may be appropriate (2).
A regimen that leaves out the first-line potentially hepatotoxic Hepatotoxicity tends to occur early in therapy. During
drugs for patients with severe, unstable liver disease patients treat­ment of TB most hepatotoxicity occurs during the four
includes ethambutol, a fluoroquinolone, cycloserine, and drug, intensive phase, but may occur subsequently (55).
second-line injectable for 18-24 months. Some experts Several studies of LTBI treatment have shown that
avoid amino­glycosides due to concerns about causing renal
about 50%-60% of hepato­t oxicity occurred in the first
insufficiency or causing bleeding from injection sites due to
three months of treatment and up to about 80% in the first
thrombocytopenia and/or coagulopathy (2).
six months (25,26,48,56).
The benefits of scheduled as opposed to symptom-
Latent TB Infection triggered biochemical monitoring have not been well
The clinician and patient decide on treatment of LTBI, based studied. Rather, current monitoring practices have histori­
on the expected benefits of treatment relative to the risks for cally evolved to try to prevent the development of liver
that patient, as well as likely adherence. For patients with injury. A retrospective study suggested that scheduled
ALT elevation more than 2.5 to 3 times the ULN, chronic monitoring reduced hospitalisations (57). An observational
high level of alcohol consumption, or cirrhosis the risks of study of a uniform baseline and two weeks serum trans­
treatment for LTBI may outweigh benefits. If LTBI treatment aminase monitoring strategy had low sensitivity but high
is undertaken in such individuals, they should have close specificity for hepatotoxicity. Sensitivity and specificity for
monitoring and a lower risk regimen should be selected, hepatotoxicity risk factor based strategy for monitoring
such as 3HP or rifampicin alone (54). The clinician should were 66.7% and 65.6% (58).
 Hepatotoxicity Associated with Anti-tuberculosis Treatment 641

TREATMENT INTERRUPTION, EVALUATION, returned to a first-line regimen. This is probably a reflection

AND SUBSEQUENT MANAGEMENT that most cases of presumed hepatotoxicity are actually
experiencing hepatic adaptation or even occasionally that
Patients who develop symptoms of nausea, vomiting, and extraneous factors were responsible for the hepatic event.
abdo­m inal pain, or who develop jaundice should stop
medication and be evaluated for possible hepatotoxicity as
RESEARCH ISSUES
soon as possible. A careful history should be obtained for
ingestion of the proper doses of TB medications, concomitant Clearly, better approaches are needed for identifying those at
prescribed or over the counter hepatotoxic medications, risk for or progression to TB DILI with improved sensitivity
alcohol and illicit drug consumption, and for risk factors and specificity. This can include better epidemiologic
for viral hepatitis. Serum transaminase and total bilirubin understanding of patients, their co-morbidities, potential
levels should be measured, as well as any other laboratory co-factors for hepatotoxicity, and the biomarkers for DILI.
tests pertinent to the patient. Much work can be done with existing clinical information
If the symptomatic patient has transaminases elevated and technology to try to improve strategies for monitoring
beyond 3 times ULN, TB and other hepatotoxic medications for adverse events. However, research into prediction,
should be held. For asymptomatic patients who are found susceptibility factors, novel biomarkers, prevention strategies,
through scheduled monitoring to have ALT at least 5 times hepatoprotective agents, and therapeutic drugs for hepato­
ULN, TB medications should be held. The liver enzymes toxicity are needed. Interdisciplinary collaboration between
should be repeated and viral hepatitis serologies should clinicians and bench researchers is needed.
be obtained to assess for coincidental infection. Other Anti-TB medications commonly cause transaminase
confounding hepatic insults or disease should be excluded elevations that reflect hepatic adaptation. Rarely is there
as clinically indicated. If the transaminases are markedly progression to severe TB DILI, reflected by significant
elevated with or without total bilirubin elevation beyond transaminase elevation with jaundice or hyperbilirubinemia.
twice the ULN or if the patient is deteriorating, tests of blood Risk factors and gene polymorphisms have been associated
coagulation and complete blood and platelet counts should with hepatic events during treatment of TB. A risk-benefit
be obtained, as well. In patients with high-burden or severe assessment should be employed when evaluating patients
TB disease in which it is felt that treatment should not be for treatment of both LTBI and TB treatment. Patient
interrupted, a hepatic sparing regimen may be substituted, education; clinical and selective ALT monitoring; and
often temporarily. regimen selection may help drug safety. Stopping rules have
For patients with severe liver injury thought to be TB been historically implemented to allow interim evaluation of
DILI, particularly the Hy’s law patient with hepatocellular potential hepatic events and to prevent the development of
injury [ALT elevation] and total bilirubin elevation or severe DILI. Confounding causes of hepatic events should
jaundice, evaluation by a hepatologist experienced in be excluded when such events occur. Optimal approaches
evaluating and caring for such patients is needed promptly. for hepatotoxicity prevention, monitoring, and management
The role of therapeutic N-acetylcysteine in severe isoniazid are needed. The approach and rapidity of reintroducing TB
DILI has not been studied. Supportive care is indicated. For treatment is likely to be guided by the severity of the hepatic
patients with fulminant liver failure, evaluation for urgent event and of TB disease. Considerable research is needed
liver transplant may be indicated. to find better predictors, biomarkers, protective agents, and
The evidence base for management of hepatotoxic events therapeutic drugs for DILI.
is lacking. Management is often driven by the severity
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 46
Surgery for Pleuropulmonary Tuberculosis
Abha Chandra

INTRODUCTION study (2), pulmonary tuberculoma was confirmed as the

histopathological diagnosis in 36 patients presenting with
Till the time effective anti-tuberculosis [anti-TB] treatment
a solitary pulmonary nodule on the chest radiograph who
was available in the middle of the twentieth century, surgery
underwent surgery for the confirmation of diagnosis.
was the only therapeutic option for pulmonary tuberculosis
Preoperatively, lung cancer was initially suspected in 21
[TB]. Several operations were devised and practiced with
the aim of controlling spread of the disease and promoting [58%] of these patients. In another retrospective study (3)
healing of the lesions. With the advent of effective anti-TB where thoracotomy was performed to ascertain the aetio­
treatment, there has been a gradual decline in the need for logical diagnosis and rule out malignancy, 24 of 31 patients
surgical intervention in patients with pulmonary and pleural [77%] were found to have pulmonary TB. At the Sri
TB. The human immunodeficiency virus [HIV] infection and Venkateswara Institute of Medical Sciences [SVIMS], Tirupati,
acquired immunodeficiency syndrome [AIDS] pandemic during the period 1996 to 2000, 23 patients with a solitary
has resulted in the resurgence of TB worldwide. Further­ lung lesion in whom TB was suspected preoperatively
more, extensively drug-resistant/multidrug-resistant TB but diagnostic work-up did not reveal an aetiological clue
[X/MDR-TB] have emerged as a major public health problem underwent thoracotomy for the confirmation of diagnosis (4).
in several parts of the world. Because of all these factors, Of these patients, 15 [65%] were found to have TB, five
there has been renewed interest in surgery. Presently, there were found to have bronchogenic carcinoma and three were
has been an increase in the number of patients with pulmo­ found to have a fungal ball [aspergilloma] and definitive
nary and pleural TB requiring surgical intervention for treatment could be instituted in all these patients. In another
diagnostic or therapeutic purposes (1). retrospective study (5) from Romania, of the 144 patients who
This chapter deals with the role of surgery in the manage­ underwent pleuropulmonary surgery, TB was confirmed
ment of pleuropulmonary TB. TB of the vertebra and the as the aetiological diagnosis in 21% patients with pleural
oesophagus belongs to the domain of orthopaedics and effusion; 54% with empyema and pachypleuritis; 10% with
gastrointestinal surgery and will not be discussed here. pneumothorax; 11% with mediastinal lymphadenopathy;
The reader is referred to the chapters “Skeletal tuberculosis” and 27% patients with pulmonary nodules.
[Chapter 19] and “Abdominal tuberculosis” [Chapter 15] for
more details. Video-assisted Thoracoscopic Surgery

SURGERY IN THE DIAGNOSIS OF In a study reported from the All India Institute of Medical
Sciences [AIIMS], New Delhi (6), video-assisted thoracoscopic
PLEUROPULMONARY TUBERCULOSIS
surgery [VATS] was helpful in confirming the diagnosis of
Inspite of the advances in modern methods of imaging and TB in five of the 18 patients with pulmonary pathology,
diagnosis, a definitive diagnosis of pleural and pulmonary three of the eight patients with mediastinal pathology and
TB is not possible in several patients. In this setting, surgery one of the five patients with pleural pathology. Importantly,
is often performed to obtain tissue specimen to confirm VATS was helpful in providing a definitive diagnosis in
the diagnosis and exclude underlying malignancy. In one all 18 patients with lung pathology, seven of the eight
 Surgery for Pleuropulmonary Tuberculosis 645

patients with mediastinal lesions and five of the six patients pulmonary TB, most physicians, however, consider the use
with pleural pathology who would have otherwise under­ of surgical methods appropriate in the situations outlined
gone diagnostic thoracotomy (6). In another study from in Table 46.1 (14-18). The presence of a cavitary disease in
Switzerland (7), VATS was useful in confirming TB as the itself is not an indication for surgery unless it is associated
aetiological diagnosis in 10 of the 96 patients [10.4%] in with one of these complications. The relative indications for
whom the pre-operative diagnoses were lung cancer [n = 4], resection are listed in Table 46.2.
empyema [n = 2], Pancoast tumour, pericardial effusion,
pleural mesothelioma, and mediastinal lymphoma [one Preoperative Work-up
patient each]. Similar observations were also reported
The patients to be taken up for surgery for chest TB should
from Japan (8), and Romania (5). Thus, VATS, a minimally
have reasonably localised disease amenable to surgical
invasive procedure has been found to be of great assistance
resection and they should have adequate cardiopulmonary
in confirming the diagnosis of TB in recent times.
reserve to undergo the operation safely. The preoperative
work-up apart from a chest radiograph includes computed
SURGERY IN THE TREATMENT OF ACTIVE tomography [CT] of the chest, pulmonary function tests and
PULMONARY TUBERCULOSIS if possible, arterial blood gas analysis. It has been suggested
Several surgical procedures have been used for the treatment that ventilation perfusion scan should also be done on all
of active pulmonary TB in the era before the advent of these patients as it is useful in determining the extent and
effective anti-TB treatment. These include cavernostomy, the type of resection to be performed. The primary role of the
collapse therapy, use of phrenic nerve paralysis, artificial ventilation perfusion scan is to confirm that the regions to be
pneumothorax, pneumoperitoneum, extrapleural pneumo­ resected are physiologically inert and contributed minimally
nolysis and thoracoplasty. The reader is referred to the to the patient’s respiratory capacity. In addition, sometimes,
earlier editions of this textbook (4,9) for details regarding an area which appears normal on chest radiograph and CT
these procedures. It is likely that several of these so called may actually have no function on ventilation scan and is
“historical” procedures may have relevance in the current best removed than left inside.
scenario as well. These patients should also have frequent sputum analysis
A new modality of collapse therapy which uses percuta­ for smear and culture of mycobacteria. The patients should
neous tissue expanders [the Perthes tissue expander] has be reviewed jointly by the physician and the surgeon and
been described (10). Classical thoracoplasty consists of they should be started on an intensive drug regimen to
extraperiosteal resection of seven ribs in three stages at achieve sputum negativity or at least reduce the bacterial
two to three weeks intervals [Figure 46.1]. There is some load to the minimum possible extent before surgery. Ideally,
deformity with thoracoplasty but not as much as might be surgery should be performed when the smears and culture
imagined [Figure 46.2]. Compared with the classical extra­ have become negative as it has a direct bearing on the inci­
pleural thoracoplasty, long-term complications such as dence of bronchial stump related complications after surgery.
erosion of major vessels, infection, and migration are likely Pomerantz et al (14) have reported 65% success in
to be less with this technique (10). A modified thoracoplasty achieving sputum conversion after an average of two and
with the use of a breast implant to obliterate the residual a half months of intensive anti-TB treatment. Treasure and
pleural space without any distortion of the chest wall has Seaworth (18) also used intensive preoperative chemothera­
been found to be useful as an alternative to traditional peutic regimen but reported success in turning sputum
thoracoplasty (11). nega­tive in much higher number of patients [17 of 19
patients; 90%]. They reported that patients with persistent
cavities, or disease affecting multiple segments or a lobe or
Current Status of Surgery
with total lung destruction were candidates who benefited
Anti-TB treatment sometimes proves ineffective or of little from surgery. Surgical removal of destroyed lung tissue
benefit in controlling the disease. This lack of response may harbouring a large number of bacilli protected from anti­
vary from as low as 5% of all patients to as high as 40%-55% biotics by poor blood supply assists in converting the
patients (12). This happens in patients with resistant forms sputum negative and helps prevent relapse.
of infection or in the treatment of certain forms of TB and It is also recommended that bronchoscopy be performed at
its complications or sequelae which are associated with or before operation to exclude the presence of endobronchial
irreversible morphological changes in organs and tissues. disease at the proposed bronchial resection margin, as its
Surgery is indispensable in such patients. In combination presence will greatly increase the risk of bronchopleural
with chemotherapy, surgery can ensure sufficiently radical fistula [BPF] after resection.
removal of localised lesions and save the patients life, halt
progression of the disease, create better conditions for Preoperative Preparation
reparative processes, restore organ functions and promote
complete recovery (12,13). Nutritional Build-up
Although, there are conflicting views regarding the exact Most of the patients with chest TB would have been ill for
role of surgery in the overall management of patients with a long time and are in a chronically debilitated condition
 646 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 46.1: Thoracoplasty incision [upper panel centre]. Periosteum of the third, fourth and fifth ribs being peeled off [middle panel left]. Third,
fourth and fifth ribs being excised [middle panel right, lower panel left]. The third, fourth and fifth ribs have been removed and the chest wall has
fallen into the cavity obliterating the pleural space [lower panel right]

with poor nutritional status. Before taking up for surgery, by encouraging high protein and calorie diet. Sometimes,
it is important to build up nutrition of these patients. patients may need hyperalimentation. The value of nutri­
When possible this should be achieved by enteral means tional build up needs to be emphasised as it has a direct
 Surgery for Pleuropulmonary Tuberculosis 647

Incentive Spirometry
The outcome after surgery can be improved and the
incidence of complications reduced by preoperative chest
exercises in the form of deep breathing and breath-holding
exercises and incentive spirometry. It is important to explain
the value of these simple looking exercises in improving
the postoperative outcome to the patient in detail in order
to achieve their maximum cooperation and compliance.
Several days of such “chest training” helps tremendously
in improving the outcome after surgery.

Principles of Surgery
Double lumen endotracheal tube should be used for
anaesthesia in these patients to avoid cross-contamination
of the contralateral lung. Patients with TB often have exten­
sive, dense adhesions between pleura and the lung and
it may be impossible to find a plane between the pleura
and the lung. Additionally, dissecting through the infected
material present in the pleural cavity increases the risk
Figure 46.2: Chest radiograph [postero-anterior view] showing thoraco­ of postoperative empyema several folds. Due to these
plasty on the left side reasons, an extrapleural approach for pneumonectomy
has been suggested (19) which decreases the morbidity
Table 46.1: Definite indications for surgery in patients as well as mortality of this operation. Dehiscence of the
with pleuropulmonary TB bronchial stump leading to BPF and empyema is the most
feared and the most common complication after resectional
To procure tissue material for confirmation of diagnosis of TB
lung surgery. Reinforcement of the bronchial stump by
Multidrug-resistant, extensively drug-resistant TB a vascularised tissue like intercostal muscle, pedicled
Complications of TB extrathoracic skeletal muscle [myocutaneous flap using
Haemorrhage latissimus dorsi or serratus anterior] or omentum has
Bronchopleural fistula
Empyema
been shown to significantly decrease the incidence of this
Bronchiectasis complication (12,17). These should be used in all cases of
Tracheal or bronchial stenosis resectional lung surgery for TB.
Broncholiths The aim of surgery in TB is to remove all the disease-
Pulmonary aspergilloma bearing lung tissue at the same time preserving as much of
TB = tuberculosis normal lung tissue as possible. Sometimes the amount of lung
tissue remaining after a resection may not be adequate to
fill the entire pleural cavity and may lead to space problems
Table 46.2: Relative indications for surgery in patients post-operatively. In such cases, a concomitant tailoring
with pleuropulmonary TB thoracoplasty is recommended to reduce the chances of
Destroyed lobe or lung distal to an irreversibly damaged bronchus post-operative space problems (12). The exact procedure to
and subject to repeated TB or, pyogenic infection be performed may vary from segmental or wedge resection
An open negative cavity of significant size [> 2 to 3 cm] in a young to lobectomy, pneumonectomy or pleuropneumonectomy
person with or without myoplasty.
A cavity in an immunocompromised host
Demonstrable nontuberculous mycobacteria, multidrug-resistant, Extensively Drug-resistant Tuberculosis and
extensively drug-resistant organisms in a cavitary disease that can Multidrug-resistant Tuberculosis
be resected clearly by lobectomy
Recurrent sputum positive infection in a given segment or lobe, Indications for surgery in patients with X/MDR-TB are listed
even though no macroscopic cavity can be demonstrated in Table 46.3. Various procedures performed for patients
Asymptomatic peripheral nodule with MDR-TB have ranged from segmental resection
to pleuropneumonectomy (14,18,20-32). In a systematic
TB = tuberculosis
review and meta-analysis (33) that evaluated the role of
pulmonary resection for MDR-TB [12 studies] and XDR-TB
bearing on the outcome and the complications after surgery. [3 studies] revealed substantial heterogeneity in the study
Patients with anaemia and hypoproteinaemia have uniformly characteristics. The authors (33) reported that the estimated
poor outcome after surgery. pooled treatment success rate of pulmonary resection for
648 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 46.3: Indications for surgery in patients negative status, if possible. The operative risks are acceptable
with X/MDR-TB and the long-term survival is much improved than that with
continued medical treatment alone. However, for this to be
Drug resistance so extensive that there is a high probability of
failure or relapse
achieved, the chemotherapeutic regimen needs to continue
for prolonged periods after surgery also, probably for well
Disease sufficiently localised so that the great preponderance
over a year, otherwise recrudescence of the disease with poor
of radiographically visible disease could be resected with the
expectation of adequate cardiopulmonary reserve after surgery and survival is a real possibility.
sufficient drug activity to diminish the mycobacterial burden enough
to facilitate probable healing of the bronchial stump after surgery SURGERY FOR THE COMPLICATIONS OF
X/MDR-TB = extensively drug-resistant/multidrug-resistant TUBERCULOSIS
tuberculosis
Bronchopleural Fistula
Bronchopleural fistula may develop in TB patients following
patients with MDR-TB was 84%. The rates of failure, relapse, lung resections or spontaneously in association with lung
death and default were 6%, 3%, 5% and 3%, respectively. lesions or empyema. Although the incidence of post-
In another published review (34) evaluating the role of resection fistula in patients with TB has come down from
surgery in the treatment of drug-resistant TB [DR-TB], the as high as 28%, two or three decades ago, to 3% or less in
authors reviewed a total of 26 case series and cohort studies recent years (23-25), it nevertheless, remains an important
and reported that surgical resection was beneficial in the problem for the thoracic surgeon. Also, the non-surgical,
treatment of DR-TB. In another recent meta-analysis (35) spontaneously occurring BPF continues to be a problem,
that assessed the effectiveness of surgical interventions [24 responsible for up to 27% of all TB-related BPF (36,37).
comparison studies] in the treatment of DR-TB, a significant Spontaneous BPF develops due to liquefaction necrosis
association between surgery and successful treatment and rupture of a sub-pleural TB focus. If the fistula is small
compared to non-surgical interventions [Odds ratio 2.24] was and effective chemotherapy is instituted, the leak may close
observed. Meta-analysis of 23 single-arm studies showed that spontaneously and the lung re-expands as the pleural air is
92% and 87% of surgical patients achieved successful short- absorbed. Unfortunately, such is usually not the case and
and long-term outcomes, respectively. The authors (35) the leak persists with pneumothorax leading to collapse
cautioned that insufficient evidence to recommend surgery of the underlying lung and ultimately development of an
plus chemotherapy over chemotherapy alone, to evaluate the empyema. It is generally believed that every patient with
potential harm from surgery and to determine the optimal active pulmonary TB who develops pneumothorax has a
conditions for surgery. BPF.
Based on the experience reported in the literature BPF is a serious condition with a reported mortality of
about surgery for X/MDR-TB, it can be concluded that the 23.1%, mostly due to aspiration and its complications (36,37).
operation can be performed with a low mortality. However, In post-resection BPF, the incidence of this complication
the complication rates are high with BPF and empyema is highest during the first three months after surgery,
being the major complications. Sputum positivity at the although it can occur at any time even several years after
time of surgery, previous chest irradiation, prior pulmonary surgery (38,39). The risk of aspiration pneumonia is highest
resection and extensive lung destruction with polymicrobial during these first three months and its incidence decreases
parenchymal contamination are the major factors affecting dramatically if BPF occurs later than three months after
morbidity and mortality. Over 90% of the patients achieve surgery (40).
sputum negative status postoperatively. More liberal use of Adequate dependent surgical drainage is the basic
muscle flaps to reinforce the bronchial stump and fill the principle in the treatment of BPF. Drainage alone may
residual space has helped significantly in reducing the rates result in closure of the fistula in some patients. In patients
of BPF, air leaks and residual space problems. These must be with non-surgical, spontaneously occurring BPF associated
used in patients with positive sputum, when residual post- with pulmonary TB, intercostal tube drainage should
lobectomy space is anticipated, when BPF already exists pre- be complemented with intensive chemotherapy as all of
operatively or when extensive polymicrobial contamination these patients have active, severe, often sputum positive
is present. In patients with nontuberculous mycobacterial TB infection. The pulmonary disease may vary in severity
[NTM] infection, the outcome is poorer as compared to from an isolated focus to extensive disease with cavities
patients with resistant Mycobacterium tuberculosis infection. or even bilateral disease. Continuous suction should
However, these patients should also be operated before always be applied to the tube thoracostomy and intensive
the disease causes extensive destruction of the lung or antituberculosis chemotherapy continued. These patients,
polymicrobial infection, when the incidence of complications apart from TB infection, have associated secondary
becomes very high. pyogenic infection also which is often polymicrobial and
Thus, surgery is currently recommended for patients needs antibiotics based on the culture reports. Ihm et al (41)
with X/MDR-TB whose prognosis with medical treatment is analysed 52 patients with spontaneous BPF of TB aetiology.
poor. It should be performed after minimum of three months Of these, 38 patients were treated with intercostal tube drain­
of intensive chemotherapeutic regimen, achieving sputum age with anti-TB treatment and the lung re-expanded in 28.
 Surgery for Pleuropulmonary Tuberculosis 649

On analysing the factors affecting the success or failure of Tuberculosis Empyema

intercostal tube drainage, they found that the size of the
The term “TB empyema” refers to massive, frankly purulent
BPF that gave rise to pneumothorax was the most important
involvement of the pleura with BPF and trapping of the
factor. This, in turn, was influenced by the extent of TB
lung. Some patients develop a restricting pleural peel with
disease in the lung. Patients with extensive parenchymal
or without secondary pyogenic infection of the pleural fluid.
disease, poorly controlled by drugs, had large fistulae,
It is suggested that in these patients, anti-TB treatment along
early development of a restrictive peel on the lung and with antimicrobial therapy for secondary pyogenic infection
poor outcome following tube drainage. The initial degree of [according to culture if possible] should be continued
collapse of the lung had no bearing on the outcome. A short till maximum resolution of the parenchymal disease and
time interval between the onset of pneumothorax and chest associated sepsis is achieved. At that point, an anatomical
tube insertion was a favourable factor, but not dramatically evaluation of the disease status by CT of the thorax should
so, and a long interval did not preclude success (41). be done. In case of a residual cavity with collapsed lung,
In patients failing to re-expand the lung following tube surgical intervention is indicated and decortication should be
drainage, suction and chemotherapy, thoracotomy and performed [Figures 46.3A and 46.3B]. If the underlying lung
decortication, with or without lobectomy or pneumonectomy
or pleuropneumonectomy may be required depending
upon the findings at surgery. The timing of this procedure
is crucial. It is vital to recognise the point at which no
further headway is being made with tube thoracostomy and
chemotherapy and schedule the patient for definitive surgery
straightaway. In the post-resection BPF, tube drainage alone
may close the fistula in up to 20% patients (42), otherwise
definitive surgical procedure is required. For patients with
post-lobectomy or post-pneumonectomy fistula, this may
involve dissection down to the lung or the mediastinum to
identify the fistula site and its suture ligation. Suture ligation
alone has a high failure rate. Use of pedicle muscle flaps
has been recommended to fill up the empyema cavity and
buttress the suture closure of the fistula site. This has been
reported successful in over 75% patients (36). However, it is
important that the muscle flap completely fills the empyema
cavity. The muscles that have been used include intercostals,
pectoralis major, serratus anterior, latissimus, dorsi and
sacrospinalis. Indications for myoplasty in the treatment
of BPF are listed in Table 46.4. For post-pneumonectomy Figure 46.3A: Chest radiograph [postero-anterior view] showing
fistulae, reamputation of a long bronchial stump may hydropneumothorax on the right side
sometimes affect the closure especially if the BPF has been
diagnosed early (42,43). Further resection of the residual lung
[site of BPF] or thoracoplasty of various types have also been
recommended for treating resistant post-resectional BPF but
these have the disadvantage of further compromizing the
already compensated cardio-pulmonary reserve of these
patients. On the other hand, myoplasty, can close the fistula
without excision of additional lung tissue and with the
removal of few, if any, additional ribs. Using the myoplasty
techniques, a high rate of BPF closure with a low mortality
has been reported (42-44).

Table 46.4: Indications for myoplasty in the treatment

of bronchopleural fistula
A persistent bronchopleural fistula despite an adequate drainage
and thoracoplasty
When thoracoplasty alone is not considered to be sufficient to close
the fistula [due to a large residual cavity]
In a situation where myoplasty is likely to obviate the need for a
Figure 46.3B: Chest radiograph [postero-anterior view] of the same
thoracoplasty altogether
patient after decortication on the right side
650 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

is grossly diseased or destroyed or fails to expand following that the bronchial artery embolisation is an effective method
decortication, pulmonary resection may also be needed. In of treatment for immediate control of life-threatening
these situations also, muscle flaps should be liberally used haemoptysis.
to obliterate the residual spaces and buttress the bronchial Similar experience has been reported by others (48,50,52).
stump to prevent the development of post-resection BPF. Sharma et al (50) have reported the use of an indigenous
The use of myoplasty reduces the need for thoracoplasty in coil embolisation for controlling recurrent, massive haemo­
many situations or at least reduces the number of ribs that ptysis secondary to post-TB bronchiectasis. This method is
need to be resected in the thoracoplasty. extremely cheap and highly effective. In patients with life-
threatening haemoptysis, early operation is considered when
Haemoptysis bleeding has been localised to one side and embolisation
is not available or not feasible when bleeding continues
Haemoptysis is a frequent complaint in patients with pulmo­ despite embolisation or it is associated with persistent
nary TB. Sometimes, the bleeding may be sudden and large haemodynamic and respiratory compromise. However,
in amount, threatening life of the patient. This topic has before surgery, it should be ensured that the lesion is
been dealt with in the chapter “Complications of pulmonary sufficiently localised to be resectable and the patient’s general
tuberculosis” [Chapter 31]. condition [cardiopulmonary status] does not contraindicate
The treatment of massive or life-threatening haemoptysis thoracotomy and pulmonary resection (45,46). For patients
has to be immediate and quick. Medical or expectant treat­ment in whom bleeding has ceased or decreased, emergent
is associated with an unacceptably high mortality (45,46). intervention may not be necessary. Surgery is the most
The first priority in treating patients with massive haemoptysis definitive form of therapy for patients with haemoptysis
is to maintain the airway, optimise oxygenation, and stabilise because it removes the source of bleeding. Whether to
the haemodynamic status. When indicated, the patient proceed with elective surgery in patients with a major bleed
should be intubated for better gas exchange, suctioning, that has stopped or one that is controlled angiographically
and protection from sudden cardiorespiratory arrest. If the is a difficult decision. Limited data are available to
bleeding site is known, the patient should be placed with the assist in this decision, even for specific diseases, such as
bleeding lung in the dependent position. Once stabilisation bronchiectasis. Similarly, the long-term course of patients
is accomplished, diagnostic and therapeutic interventions treated with endobronchial tamponade or topical therapy
should be promptly performed because recurrent bleeding is unknown. For patients with inoperable disease, limited
occurs unpredictably. Early bronchoscopy, preferably during cardiopulmonary reserve or bilateral progressive disease,
active bleeding, should be performed with three goals in embolisation is the mainstay of treatment and should be
mind: to lateralise the bleeding side, localise the specific pursued vigorously, even repeating it, if necessary. It
site, and identify the cause of the bleeding. In those patients frequently controls bleeding for prolonged periods. Majority
with lateralised or localised persistent bleeding, immediate of patients with life-threatening haemoptysis due to TB have
control of the airway may be obtained during the procedure bilateral disease, often with cavitation. Localisation of the
with topical therapy, endobronchial tamponade, or unilateral side and the lobe from which the bleeding is originating
intubation of the non-bleeding lung. If bleeding continues is of para- mount importance for therapy. Bronchoscopy
but the site of origin is uncertain, lung isolation or use of a performed during bleeding is able to localise it in most of
double-lumen tube is reasonable, provided that the staff is the cases. However, it needs to be performed quickly when
skilled in this procedure. If the bleeding cannot be localised the patient is actively bleeding.
because the rate of haemorrhage makes it impossible to In a retrospective study (56) [n = 89] of patients with
visualise the airway, emergent rigid bronchoscopy or massive haemoptysis caused by pulmonary TB, 36 patients
urgent arteriography is indicated. Numerous reports in the [40.4%] under­went an emergency surgery and 53 [59.6%]
recent past have outlined the value of arteriography and underwent a delayed operation. The operative morbidity
embolisation in the management of haemoptysis (47-55). rate was 31.5% [28 of 89] and mortality was 2.2% [2 of 89].
Arteriography and embolisation should be used emergently Multivariate analysis showed that patients who received
for both diagnosis and therapy in patients who continue to anti-TB treatment before surgery had a decreased risk while
bleed despite endobronchial therapy. patients who underwent an emergency operation had an
Mani et al (47) in a series of 37 patients presenting with increased risk of developing postoperative complications.
massive or recurrent haemoptysis of TB aetiology, were able
to successfully control the bleeding in all the 33 patients Tracheal or Bronchial Stenosis, Broncholiths,
where embolisation with gelfoam could be performed. In
Destroyed Lung, Bronchiectasis
two patients the bronchial artery could not be cannulated
and in the remaining two embolisation was not performed TB is a necrotising infection, and certain patients, although
because the anterior spinal artery was seen to be arising from cured of the infectious process, carry in their lungs the
the bronchial artery trunk. During six months of follow-up, residuum of this destruction (57). Patients with a destroyed
four of these 33 patients had relapse of haemoptysis. Three lobe or lung, bronchial stenosis with distal recurrent
were treated by re-embolisation of the abnormal bleeding secondary infection and atelectasis, bronchiectasis with
vessels while one died due to aspiration. They concluded chronic infection and its consequences, and other similar
 Surgery for Pleuropulmonary Tuberculosis 651

residua may be candidates for operative intervention. These complications caused by the enlarged lymph nodes. Surgical
abnormalities are doubtful indications, however, unless asso­ treatment, when performed as an adjuvant treatment for
ciated with significant symptoms that cannot be controlled tracheobronchial complications stemming from mediastinal
by current medical modalities. TB lymphadenitis, has resulted in the resolution of the
In a retrospective study (58), 172 patients with destroyed lesions and has no related morbidity (66).
lung underwent various surgical procedures, such as, total
pneumonectomy [n = 110], pleuropneumonectomy [n = 37], Surgery for Complications of Previous Surgery
BPF repair [n = 11], residual lobectomy [n = 10], total
Sometimes, plombage therapy can result in long-term post­
pneumonectomy and tracheoplasty [n = 2], lobectomy,
operative complications. The management of these late
thoracoplasty [n = 1 each], among others. The perioperative
complications is challenging and frequently requires surgical
mortality was 2.9%. The surgical complication rate was
18.6%. The sputum negative conversion rate was 87.8%, and intervention (67,68).
the clinical cure rate was 91.9%.
SURGERY FOR TUBERCULOSIS:
Pulmonary Aspergilloma INDIAN EXPERIENCE
Pulmonary aspergilloma is often produced in residual Indian experience regarding the role of surgery in the
cavities of TB origin. This topic has been covered in the treatment of TB is summarised in Table 46.5 (9,69). After the
chapter “Complications of pulmonary tuberculosis” [Chapter 31]. advent of drug treatment for pulmonary TB, the operation
The surgical treatment of aspergilloma is a much debated of thoracoplasty became rare in the developed countries.
matter. On the basis of having described its spontaneous
lysis in 5%-15% of cases (59), some authors advise an
expectant attitude for uncomplicated, asymptomatic cases Table 46.5: Indications for surgery in
of aspergilloma while others advise that it is preferable to pleuropulmonary tuberculosis: Indian experience
treat all aspergillus lesions with respect to the future risk Lahiri et al (69) SVIMS, Tirupati (9)*
of complications (60). If there are accompanying clinical [1970-1990] [1993-2015]
symptoms, and if the patient meets the conditions of [n = 1655] [n = 988]
Variable No. [%] No. [%]
operability, it is preferable to undertake surgical resection
taking into account the condition of the affected lung. Tuberculosis empyema with 1507 [91.0] 654 [66.1]
Lobectomy is preferred, although there may also be or without bronchopleural
fistula
indications for segmental resection or pneumonectomy
depending on the size of the lesion (60-62). Another ICT drainage 1507 [91.0] 654 [66.1]
surgical technique used, although only in patients with high Thoracostoma 56 [3.4] 8 [0.8]
operative risk, is simple cavernostomy and extraction of the Decortication 45 [2.7] 293 [29.7]
aspergilloma as well as myoplasty in the treated zone (63). Thoracoplasty 6 [0.4] 5 [0.5]
A surgical alternative in cases that precludes operation is
 Continuous short tube 17 [1.1] 22 [2.2]
intracavitary instillation of antifungal agents (62). In patients
drainage†
with massive haemoptysis, embolisation of the bronchial
Complicated pulmonary 78 [4.7] 279 [28.2]
arteries is indicated as a primary recourse before planned
tuberculosis
surgery. Surgical treatment for aspergilloma demands indi­
vidual, careful validation because it is a complex pathology Pneumonectomy 35 [2.1] 66 [6.7]
with high incidence of post-resection complications. Lobectomy 30 [1.8] 132 [13.4]
 Segmental wedge 3 [0.2] 6 [0.6]
Cold Abscess of the Chest Wall resection
Thoracoplasty 10 [0.6] 2 [0.2]
Cold abscesses of the chest wall, though uncommonly
encountered in industrialised countries, are common Bullectomy 0 [0] 17 [1.7]
problems in areas where TB is highly endemic (64). Because Cold abscess in the chest 54 [3.3] 7 [0.7]
fine needle aspiration remains an inaccurate diagnostic tool wall
and anti-TB treatment is not always efficient, chest wall TB Osteomyelitis of ribs, or 16 [1.0] 16 [1.6]
cold abscesses remain in most patients a surgical entity. sternum
Surgical management includes adequate debridement and Aspergilloma 0 [0] 32 [3.2]
a postoperative anti-TB treatment (65). Some patients underwent more than one procedure
* Data updated up to May 2015 from reference 9
Surgery for Complications Caused by Enlarged † The intercostal tube was cut short, fixed with a safety pin and left
open to atmosphere. This procedure was used in patients who were
Mediastinal Lymph Node Tuberculosis in Children either unfit, or could not afford major surgery
Sometimes, surgical intervention may be required in children ICT = intercostal tube; SVIMS = Sri Venkateswara Institute of
Medical Sciences
with mediastinal lymph node TB for the management of
652 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

However, this was not the case in developing countries like 13. Olcmen A, Gunluoglu MZ, Demir A, Akin H, Kara HV, Dincer SI.
India. Dewan et al (70) reported results of thoracoplasty in 139 Role and outcome of surgery for pulmonary tuberculosis. Asian
Cardiovasc Thorac Ann 2006;14:363-6.
patients. Indications of surgery were TB empyema [n = 84],
14. Pomerantz M, Madsen L, Goble M, Iseman M. Surgical
pyogenic empyema [n = 33], post-operative empyema with manage­ment of resistant Mycobacterial tuberculosis and other
BPF [n = 8], drug- resistant pulmonary TB [n = 2] and recurrent mycobacterial pulmonary infections. Ann Thorac Surg 1991;52:
haemoptysis [n = 2]. Successful outcome in the form of control 1108-12.
of sepsis, closure of BPF, sputum conversion and control 15. Pomerantz M, Brown J. The surgical management of tuberculosis.
of haemoptysis was achieved in most cases. The authors Semin Thorac Cardiovasc Surg 1995;7:108-11.
concluded that with the persisting problem of pulmonary 16. Reed CE, Parker EF, Crawford FA. Surgical resection for
complications of pulmonary tuberculosis. Ann Thorac Surg
TB in the developing countries, thoracoplasty is still an
1989;48:165.
operation of continued relevance. Resectional surgery (71) 17. Rizzi A, Rocco G, Robustellini M, Rossi G, Della-Pona S,
for pulmonary aspergilloma and its complications is also Massera F. Results of surgical management of tuberculosis:
frequently used in India [Table 46.5]. In another recent study, experience in 206 patients undergoing operation. Ann Thorac
Dewan et al (72) reported their experience with surgery in Surg 1995;59:896-900.
DR-TB. Over a period of 20 years, 107 surgical procedures 18. Treasure RL, Seaworth BJ. Current role of surgery in
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19. Brown J, Pomerantz M. Extra-pleural pneumonectomy for
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surgery, sputum smear-negativity could be achieved in Preliminary results of collapse therapy with plombage for
93 cases. At four years of follow-up, 62 patients were cured. pulmonary disease caused by multidrug-resistant mycobacteria.
Am J Respir Crit Care Med 1998;157:1609-15.
21. Kir A, Tahaoglu K, Okur E, Hatipoglu T. Role of surgery in
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 47
Stopping TB: The Role of DOTS
in Global Tuberculosis Control
Deanna Tollefson, N Sarita Shah, Andrew Vernon

INTRODUCTION TB incidence, prevalence, and mortality rates have

decreased under DOTS, yet the burden of TB remains
In April 1993, the World Health Organization [WHO] dec­
staggering. In 2015, the WHO estimated that TB developed
lared tuberculosis [TB] to be a global health emergency (1).
in 10.4 million people and 1.4 million died from TB (6).
Once considered a disease of the past, TB resurged as the
Globally, the decline in TB incidence remains slow, and the
human immunodeficiency virus [HIV] pandemic expanded,
average rate of decline in TB prevalence [3.7% per year] is
the Soviet Union collapsed, and economies stagnated (2,3).
insufficient to achieve the 2015 target of 50% reduction from
Many countries were ill-equipped to address the expanding
1990 levels, much less elimination by 2050 [≤1 active TB
epidemic as general TB control practices and the structures
case per million population per year] [Figure 47.1] (10,11).
needed to implement these practices had been neglected for
Moreover, half of the world’s 22 highest-burdened TB
decades (1,3). “The high mortality and morbidity due to TB
is often the result of inadequate control measures and neglect countries were not on track to meet the 2015 targets for
of the disease,” the WHO said in 1994 and advocated that decreases in TB incidence, prevalence, and mortality
nations adapt the directly observed therapy short-course [Figure 47.2] (12). This begets the question on the role DOTS
[DOTS] strategy to quell the sudden rise in TB (1). Three should play in the future of TB control (3,10,13-15).
years after this recommendation, the Director-General of the In this chapter, we provide an overview on the evolution
WHO praised the strategy, declaring, “The DOTS strategy of the DOTS strategy since its global introduction and
represents the most important public health breakthrough uptake, the role DOTS currently plays in TB control, and
of the decade, in terms of lives that will be saved” (4). opportunities and challenges facing the control and pre­
Since its initiation, DOTS has served as a guide for TB vention of TB in the future.
programmes in at least 182 countries (5). Between 1990 and
2013, the global TB mortality rate decreased 45% and global EVOLUTION OF DOTS
TB prevalence decreased 41%, while the global incidence of Original DOTS Frameworks
TB decreased an average of 1.5% per year from 2000-2013 (6).
In raw numbers, over 56 million people were successfully As TB rates increased and worries of drug resistance grew,
treated for TB and an estimated 22 million lives saved WHO developed and began promoting DOTS as the policy
through the programmatic implementation of DOTS between package for global TB control (1). This strategy, which
1995 and 2012 (7). In China, the implementation and scale-up was published in 1994, was based on innovative practices
of DOTS from 1990 to 2010 corresponded to a 65% decrease that successful public health programmes had used since
in smear-positive TB prevalence; the successful DOTS the mid twentieth-century, many of which had been first
scale-up is credited for China exceeding WHO’s goal to developed and tested in India [e.g., home-based, multi-drug
reduce TB prevalence by 50% by 2015 (8). Similarly, India chemotherapy] (16-19). Dr Karel Styblo, Director of Scientific
estimates that by embracing DOTS and by following their Activities at the International Union Against Tuberculosis
2012–2017 TB Control Strategy the government can avert and Lung Disease [IUATLD, now called “The Union”]
over 1.7 million TB cases and save 750,000 lives in the next from 1979-1991, used the lessons learned and research
15 years (9). on innovative practices from successful public health
 Stopping TB: The Role of DOTS in Global Tuberculosis Control 655

Figure 47.1: Current and potential rates of decline in TB incidence through 2050
TB = tuberculosis
Source: reference 11

Figure 47.2: Progress towards TB-related Millennium Development Goals and select stop TB targets, by WHO region
TB = tuberculosis; WHO = World Health Organization

programmes to develop the mutual assistance programme of as ‘DOTS’ because a shortened course of directly-observed
the IUATLD, which included the core components of DOTS: therapy was its cornerstone. However, the DOTS framework
the use of monitored, short-course treatment regimens to actually consisted of five components, each necessary for
ensure TB patients complete treatment, and thus, achieve TB control [Table 47.1]: political will to assure provision of
high TB cure rates (20-22). WHO adopted this strategy for TB adequate resources; case-finding at health facilities, primarily
control based on the understanding that this approach would through microscopic examination of sputum; a short-
increase cure rates, decrease transmission, and limit the course of anti-TB drugs provided under direct observation;
development of drug resistance. The strategy became known adequate drug supply to ensure availability of sufficient
656 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 47.1: A comparison of the original DOTS framework [1994] and the DOTS framework in the Stop TB
Strategy [2006]
Original DOTS framework [1994] (1) Updated DOTS Framework, Stop TB Strategy [2006] (5)
Government commitment Political commitment with increased and sustained financing
Case detection through predominantly passive case finding Case detection through quality-assured bacteriology
Short-course of anti-TB drugs given under direct observation Standardised treatment, with supervision and patient support
Regular drug supply An effective drug supply and management system
Monitoring system for programme supervision and evaluation Monitoring and evaluation system and impact measurement
TB = tuberculosis

medication to achieve cure for every patient; and a system Development Goals in all regions [i.e., halving TB mortality
for monitoring, with accountability for the outcome of every and prevalence by 2015], and would be insufficient to
patient diagnosed (1). reverse the global epidemic (28). The TB epidemic had
The DOTS strategy was widely and rapidly adopted, worsened in select areas in Africa, Eastern Europe, and
with WHO reporting that 148 countries had embraced Asia, as MDR-TB and TB-HIV increasingly hindered efforts
DOTS by 2000 (23). Despite this enthusiastic adoption, it to reduce the global burden of TB (3). Once again, it became
was estimated that only 27% of people with smear-positive evident that DOTS would need to expand to effectively
TB actually received treatment under DOTS and only 19% address the evolving epidemiology and global burden of TB
were effectively treated in 2000 (23). It became evident to [Figure 47.3].
public health leaders that in order to increase coverage the
framework needed to expand, especially in low resource and Stop TB Strategy
high HIV prevalence areas (3,24).
To further expand DOTS, in 2006 WHO and the Stop TB
Partnership launched a new strategy, the Global Plan to
DOTS Expansion
Stop TB 2006-2015 [commonly referred to as the “Stop TB
Expansion of the DOTS framework began when the “Stop Strategy”] (5). This plan was developed to build on the
TB Initiative” was established after the meeting of the first achievements of the prior decade while presenting a clear
Ad Hoc Committee on the Tuberculosis Epidemic in 1998. roadmap to meet the new challenges that were blocking
Two years later, the “Stop TB Initiative” produced the progress towards the Millennium Development Goals and
Amsterdam Declaration to Stop TB, which called for action related Stop TB targets. An update to the Global Plan to Stop
from ministerial delegations of 20 countries with the highest TB [2011-2015] was released in 2010 to clarify the roadmap
burden of TB. At this time, the World Health Assembly also presented in the Global Plan to Stop TB and to improve
endorsed the creation of a global partnership to improve TB the plan’s relevance in light of progress made towards
control and achieve the Millennium Development Goals (25). 2015 targets (11).
The WHO Assembly recommendation led to the formation
In the Stop TB Strategy, DOTS is placed in the larger
of the Stop TB Partnership, whose task was to lead efforts
context of global TB control. The strategy encompasses all
to extend the DOTS strategy.
elements necessary for effective TB control, ranging from
Including partners from the private, public, and non-
profit sectors, the Stop TB Partnership created the first surveillance to programme implementation and research. In
Global Plan to Stop TB [2001–2005] which emphasised DOTS addition, the strategy was designed to frame TB control as a
expansion (26). This re-visioning of DOTS was captured necessary part of poverty alleviation (5). Ultimately, the Stop
in the 2002 document, An Expanded DOTS Framework for TB Strategy was created to be a roadmap to enable national
Effective Tuberculosis Control (27), which described DOTS as TB programmes and policy makers to jointly expedite TB
a “comprehensive support strategy” that provided support control (29).
to all persons affected by TB by placing equal emphasis on The Stop TB Strategy encompasses six major elements
the technical, managerial, social, and political elements of TB for National TB Programmes [NTPs], their local and
control. This framework also led to programmatic advances international partners, and policy makers to pursue
in addressing the growing epidemics of HIV-associated TB in order to achieve TB control (5). These elements are:
[thereafter referred to as TB-HIV] and multidrug-resistant [i] pursuing high-quality DOTS expansion and enhancement;
TB [MDR-TB]. [ii] addressing TB-HIV and MDR-TB and other special
By 2004, DOTS programmes had treated more than challenges; [iii] contributing to health system strengthening;
20 million patients and cured more than 16 million (5). [iv] engaging all care providers; [v] empowering people
Nonetheless, TB control experts realised that DOTS, as with TB and communities; and [vi] enabling and promoting
designed, would not achieve the TB-related Millennium research.
 Stopping TB: The Role of DOTS in Global Tuberculosis Control 657

Figure 47.3: Major milestones in the modern era of TB control

TB = tuberculosis; HIV = human immunodeficiency virus

The pursuit of high-quality DOTS expansion is pur­ Political Commitment with Increased
posefully listed first among the Stop TB elements, as DOTS and Sustained Financing
is the foundation upon which all elements of this framework
depend (5). In other words, DOTS has an essential role in Under DOTS, provision of TB services is considered a core
successfully addressing the other five elements of the Stop government function, and treatment of patients with TB
TB Strategy. is a necessity to protect the public’s health. TB treatment
is a service not just to the individual but to all of society
Attaining “high-quality DOTS expansion and enhance­
because treatment of infectious cases interrupts transmission
ment” requires a multi-faceted and multi-sectoral approach.
of TB within the community. To ensure services are widely
The following section describes in detail what comprises
available, under the DOTS strategy TB programmes are
“high-quality” DOTS.
encouraged to provide testing, treatment, and care free
of charge to all people suspected of or diagnosed with TB
DOTS IN THE STOP TB STRATEGY
disease. In order to do so, robust mechanisms must be in
The DOTS strategy remains the cornerstone of the WHO place to fund and sustain the TB control infrastructure.
and Stop TB Partnership plan for global TB control (5,11). While TB control is a core government function, the
The strategy remains based on core principles for effective imple­m entation of a successful TB control programme
public health programme implementation and continues requires the collaborative efforts of multiple sectors in
to serve as a model for other public health programmes to society, such as public health authorities, health facilities
emulate (29,30). The first element of the Stop TB Strategy [public and private], academic or research institutions, non-
contains the five components of DOTS, which have evolved governmental organisations, and communities [Figure 47.4].
slightly from the original 1994 DOTS framework (1,5). The In other words, effective TB control requires a commitment
original 1994 core components of DOTS, and the updated to strong partnerships. There must be both local and
components expressed in the 2006 Stop TB Strategy, are national partnerships, such as, the NTPs with public and
listed in Table 47.1. private hospitals and NTP with other disease-specific
In this section we elaborate on the importance, successes, programmes, and international partnerships, such as, NTP
and challenges in implementation of each of the five with international expert bodies, or NTP with NTPs in
components of DOTS in the Stop TB Strategy. neighbouring countries. Domestic partnerships are necessary
658 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 47.4: The network of partners for DOTS implementation in high TB burden settings
TB = tuberculosis; HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome

to ensure uniform implementation of, and nationwide TB control include multilateral entities, such as, the Global
coverage with, the country’s national TB guidelines. Inter­ Fund to Fight AIDS, Tuberculosis and Malaria and the World
national partner­ships can be used by NTP leadership to Bank; bilateral organisations, such as, the US Agency for
build expertise, which helps ensure that the country’s TB International Development [USAID], the United Kingdom’s
strategy is current, efficient, and consistent with international Department for International Development [DFID], or the
standards. Canadian International Development Association [CIDA],
Although DOTS is a very cost-effective public health and large non-governmental organisations, such as, the Bill
inter­vention (31,32), the expanded DOTS strategy in the Stop and Melinda Gates Foundation, the Aga Khan Foundation,
TB framework requires significant and sustained resources and the Wellcome Trust. While there is increasing emphasis
to prevent, detect, treat, and report TB cases (29,33,34). that TB funding should come from domestic sources [i.e.,
This includes funding for diagnostics, drugs, and human local governments] (5,29), the majority of high TB burden
capital to ensure that the health care system can diagnose countries continue to rely heavily on non-domestic sources
and treat people with TB without interruption; treatment for TB funding [primarily the Global Fund] (35). Political
without interruption is essential to increase the likelihood commitment to global TB has been a source of contention as
of achieving cure and preventing drug-resistance. Beyond funding for TB has declined in recent years (13,14). Declining
ensuring there are sufficient health care workers to treat rates of TB [especially in donor countries], competing health
and manage TB cases, funding must be available to train priorities, and a poor fiscal environment are some of the
and sustain a variety of other staff, including but not limited many reasons that funding for TB control has decreased.
to TB programme managers, epidemiologists, informa­tion
technology [IT] specialists, community-health outreach Case Detection through Quality-assured
workers, administrative and other support staff. TB pro­ Bacteriology
gramme success is dependent upon staffing to ensure strong
surveillance, effective resource management, and quality To achieve global TB control, all countries are expected to
patient care and management (34). use standardised evidence-based procedures to detect TB.
Overall, the majority of funds for global TB control To ensure quality and standardisation, WHO outlines how
come from national governments and their support for their countries should detect cases and provides clear definitions
respective NTPs. Other major funders contributing to global for diagnosing TB [Table 47.2] (36). WHO guidelines specify
 Stopping TB: The Role of DOTS in Global Tuberculosis Control 659

Table 47.2: Select WHO TB reporting definitions

Case definitions
Presumptive TB
A patient who presents with symptoms or signs suggestive of TB
Bacteriologically confirmed TB case
A case from whom a biological specimen is positive by smear microscopy, culture or WHO approved rapid diagnostic methods [such as Xpert
MTB/RIF]. All cases should be notified, regardless of whether TB treatment has started
Clinically diagnosed TB case
A case that does not fulfill the criteria for bacteriological confirmation but has been diagnosed with active TB by a clinician or other medical
practitioner who has decided to give the patient a full course of TB treatment. This definition includes cases diagnosed on the basis of X-ray
abnormalities or suggestive histology and extrapulmonary cases without laboratory confirmation
Smear-positive pulmonary TB
A patient with one or more initial sputum smear examinations [direct smear microscopy] AFB-positive; or one sputum examination AFB
positive plus radiographic abnormalities consistent with active pulmonary TB as determined by a clinician. Smear-positive cases are the most
infectious, and thus, of the highest priority from a public health perspective
Smear-negative pulmonary TB
A patient with pulmonary TB who does not meet the above criteria for smear-positive disease. Diagnostic criteria should include: at least
two AFB-negative sputum smear examinations; radiographic abnormalities consistent with active pulmonary TB; no response to a course of
broad-spectrum antibiotics [except in a patient for whom there is laboratory confirmation or strong clinical evidence of HIV infection]; and a
decision by a clinician to treat with a full course of anti-TB chemotherapy. A patient with positive culture but negative AFB sputum examination
is also a smear negative case of pulmonary TB
New patient
A patient who has never been treated for TB or has taken anti-TB drugs for less than 1 month
Previously treated patient
A patient who has received 1 month or more of anti-TB drugs in the past. They are further classified by the outcome of their most recent
course of treatment:
Relapse patient
A patient previously treated for TB, who was declared cured or treatment completed at the end of their most recent course of treatment,
and are now diagnosed with a recurrent episode of TB [either a true relapse or a new episode of TB caused by reinfection]
Treatment after failure patient
A patient who has been previously treated for TB and whose treatment failed at the end of their most recent course of treatment
Treatment outcomes [excludes patients treated for RR-TB or MDR-TB]
Cured
A pulmonary TB patient with bacteriologically confirmed TB at the beginning of treatment who was smear- or culture-negative in the last
month of treatment and on at least one previous occasion
Treatment completed
A TB patient who completed treatment without evidence of failure but with no record to show that sputum smear or culture results in the
last month of treatment and on at least one previous occasion were negative, either because tests were not done or because results are
unavailable
Treatment success
The sum of ‘cured’ and ‘treatment completed’
Treatment failed
A TB patient whose sputum smear or culture is positive at month 5 or later during treatment
Died
A TB patient who dies for any reason before starting or during the course of treatment
Lost to follow-up
A TB patient who did not start treatment or whose treatment was interrupted for 2 consecutive months or more
Not evaluated
A TB patient for whom no treatment outcome is assigned. This includes cases “transferred out” to another treatment unit as well as cases for
whom the treatment outcome is unknown to the reporting unit
WHO = World Health Organization; TB = tuberculosis; AFB = acid-fast bacilli; HIV = human immunodeficiency virus; RR-TB = rifampicin
resistant TB; MDR-TB = multidrug-resistant TB
Source: reference 36
660 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

that bacteriological methods, including smear microscopy, diagnosed (48-50). Other community-based TB programmes
culture, or approved rapid diagnostic tests, such as Xpert have not necessarily been found to be effective (51,52).
MTB/RIF, should be used to diagnose all persons suspected Emerging technologies provide TB programmes staff
to have TB. In low-to-medium resource settings, persons with new tools for improving case detection both within
suspected to have TB are first tested using smear microscopy. central labs and closer to the point of care for patients.
At least two sputum samples should be submitted [one spot GeneXpert MTB/RIF machines are a rapid diagnostic
and one morning sample] and local laboratories should be option to bacteriologically confirm TB and detect rifampicin
able to process these samples within a few hours. If a patient resistance. Although culture remains the gold standard
is smear-negative or is HIV-infected, the patient’s specimens for TB diagnosis, Xpert MTB/RIF holds great promise for
should also be tested using mycobacterial culture. improving TB diagnostics in high-burden TB countries (53).
This component of DOTS highlights the importance of Because Xpert MTB/RIF is more sensitive than sputum
TB laboratories in achieving TB control (5). Successful imple­ smear, it reduces time-to-diagnosis compared to liquid or
mentation of the strategy requires that countries improve the solid culture; it is also relatively simple to use. The numbers
number and quality of their TB diagnostic labs. Expanded of Xpert MTB/RIF machines are increasing in high-burden
laboratory capacity includes decentralised TB diagnostic countries (54). India alone has purchased over 379,000
facilities, national laboratory standards, and a functional cartridges and dozens of machines, along with other high
national reference laboratory. In addition, mycobacterial burden, middle-income countries [e.g., South Africa and
culture and drug-susceptibility testing [DST] should be China]. Access to this technology is greatly increasing the
introduced into more laboratories and used for more diagnostic capacity of TB programmes in high-TB and high-
patients, including all smear-negative, HIV-infected, paedi­ MDR-TB settings.
atric, and possible drug-resistant cases. Molecular epidemiologic investigations rely upon
In reality, the quality and availability of laboratories another set of new tools that some countries are now using
differs widely between and within countries. Mycobacterial to detect TB clusters, which allows programmes to find and
culture is the gold standard for TB diagnosis, but it remains treat sources of transmission. If not available to NTPs, this
minimally available in most high-burden TB countries and technology is increasingly available to research institutions,
is not used to confirm all smear-negative or drug-resistant even in low-resource settings; through collaboration between
TB [DR-TB]. Instead, diagnoses based on clinical and chest NTPs and research institutions, molecular technology can be
radiograph findings remain frequent; these diagnostic used to inform the NTP’s case detection efforts. The reader
approaches have variable sensitivity and specificity for TB is referred to the chapter “Laboratory diagnosis” [Chapter 8]
diagnosis, and are subject to wide variability in inter- and for more details.
intra-reader agreement (37-45). Variable quality at labo­
ratories can also lead to false-positives or false-negatives (46); Standardised Treatment, with Supervision
inconsistent practices between labs may artificially decrease and Patient Support
the number of cases of smear-positive TB detected and
ultimately reported (47). Missed diagnoses can hamper The DOTS strategy includes clear standards and procedures
treatment success, breed resistance, and increase both that the WHO suggests should be followed to increase cure
transmission and mortality. The persisting challenges in rates, decrease transmission, and reduce development of
expanding access to and utilisation of appropriate TB additional drug-resistance.
diagnostics contributes to the WHO estimate that only 66%
of people estimated to have TB and less than 25% of people Standardised Treatment
estimated to have MDR-TB worldwide are actually detected
and reported to NTPs (7,12). The WHO provides guidelines for standardised treatment
In addition to improved laboratory services, the DOTS of TB, including recommendations for the management of
strategy includes an emphasis on the need for improved patients with TB and for appropriate drug regimens for each
case detection. Active case finding, or purposeful searching patient category (55). Recent guidelines (55) emphasise the
to identify undiagnosed TB disease, is an essential element importance of routine DST, where feasible, or to regularly
of the strategy. The incorporation of active case finding in evaluate the local epidemiology of DR-TB so that the
the revised DOTS strategy marks a substantial change from best standardised treatment regimen can be prescribed.
the original framework, which focused on passive case Treatment guidelines are updated as TB evolves, i.e., the
finding (1). Today, many NTPs have procedures in place for development of extensively drug-resistant TB [XDR-TB] and
active case finding, especially amongst persons living with as new TB medications become available [i.e., bedaquiline
HIV/AIDS where screening for TB is recommended at all and delanamid, which were approved for use in TB therapy
clinical encounters. Select programmes even employ cough in 2013]. By treating patients according to the WHO guide­
monitors or community health workers to actively seek lines, countries can be confident that their patients are
and refer persons with TB symptoms for testing. In some receiving evidence-based therapies, maximising the chance
places, these programmes and related efforts have been for cure and minimising chance of patients developing anti-
found to drastically increase the number of active cases TB drug resistance.
 Stopping TB: The Role of DOTS in Global Tuberculosis Control 661

Supervision during Treatment community, TB programmes must ensure treatment is

convenient and accessible for patients in their jurisdiction.
The second aspect of this element of the strategy relates to
It is the responsibility of the public health system to ensure
supervision of patients while on anti-TB treatment. This
patients complete TB therapy, but the way in which this
includes the well-known, yet controversial, directly-observed
happens will differ from place to place, and it should be
treatment [DOT]. Note that directly-observed treatment
context-specific (56).
is referred to as “DOT”, while the overarching TB control
strategy is referred to as “DOTS.” DOT continues to be recommended by WHO, but its con­
tribution to treatment completion is controversial (56,70,71).
DOT has long been one of the cornerstones of the DOTS
Recent studies have found DOT to be associated with
strategy, originating from observations and research that
improved treatment success (21,72), decreased acquisition
showed low cure rates among patients because of poor
and transmis­sion of DR-TB (69,70), and a decline in the
treatment adherence. Because even the “short course” of
prevalence of TB infection in the community (73). However,
treatment for drug-susceptible TB is lengthy [i.e., six months]
robust review of randomised trials and observational
and far exceeds the period of time a patient feels ill, experts
studies provide no assurance that direct observation of
have long understood that it is difficult to complete a full-
therapy, in comparisons to self-administered therapy [SAT],
course of treatment. Moreover, patient characteristics are
increases the rate of treatment success (71). Ethical and
not predictive of which patients will adhere, and which will
logistical issues make it difficult to demonstrate the effect of
not adhere, to treatment (56,57). Failing to finish treatment
supervision [i.e., DOT] alone, as distinct from other, related
is dangerous because it can lead to relapse and breed
aspects of case management (70,74). Consequently, SAT has
drug resistance; both of these consequences affect not only
its advocates, and it has been suggested in areas where
the patient, but also the community, by allowing further
DOT is exceptionally difficult [e.g., conflict zones, pastoralist
transmission of TB. Recognising that the consequences of
regions] (75-78). In many high burden countries, such as
incomplete treatment were dire, experts emphasised DOT
India or South Africa, the volume of cases exceeds the
for TB for all patients (34,58).
programme capacity to provide DOT, even on an intermittent
In DOT, a person trained and monitored by the health basis [e.g., thrice weekly]. Nonetheless, direct observation
system directly observes the patient as he or she takes each
of each dose of therapy [i.e., DOT] currently remains the
dose of the prescribed TB treatment. This person could
globally preferred practice for TB treatment and control.
be a clinician, a community health worker, a community
There is intense interest in the use of mobile health
volunteer, a workplace associate, a community shopkeeper,
[mHealth] technologies to support patients during treat­
a member of a non-governmental organisation, a religious
ment for TB. Short-message service [SMS] text messaging
leader, or another member of the community, who is
could be used to remind patients about appointments
trained and accountable to the health care system (57). To
or track treatment, even in low resource, high burden
improve accountability, it is generally advised that this
settings (79-84), while video chatting [e.g., Skype] could be
person should not be a family member (56,57), although in
used to replace in-person DOT in areas where such infra­
some settings this has been successful (59-62). Regardless
structure is available (85,86).
of their position, the DOT provider should do more than
simply watch patients as they take medications. The DOT
provider should encourage the patient and teach the value
Patient Support
of treatment success for both patients and their communities. The third part of this strategic element is support for patients
The DOT provider also has the opportunity to inquire about with TB. Increasingly, TB programmes are recognising the
TB symptoms in other family members and thus contribute need to provide physical, social, psychological, or economic
to active case finding efforts. Ultimately, DOT builds bonds support to patients to facilitate treatment success. In part,
between the health system and patients and is intended to this is because TB treatment, especially MDR-TB treatment,
keep patients at the center of care, further strengthening can cause extreme hardship socially [e.g., stigma], finan­
chances for treatment success (34,56,57). cially [e.g., job loss or transportation costs], and physically
There are many approaches to DOT. Some countries [e.g., illness and side effects from therapy] (87-90). Social
ensure DOT by hospitalising all patients with TB during support can be provided through establishing peer support
therapy, while others employ DOT regularly for outpatients. groups (5) or dedicated community health workers who
The most critical element for treatment success is to ensure are available to patients (49). Some programmes provide
that treatment is administered with a focus on patient- nutritional support to increase treatment adherence because
centered care (56,63,64). TB programmes have found that it can act as a behavioural incentive to continue with treat­
long-term facility-based DOT is often unsatisfactory for both ment (91). Similarly, other programmes may consider provi­
patients and programmes (65,66). TB programmes in many ding material incentives to bolster treatment adherence (92).
high-burden settings are finding DOT arrangements offered Globally, TB programmes continue to face the challenge
in the community or a location of the patient’s choosing of making TB care and treatment accessible to patients.
result in equal if not higher treatment success (59,67-69). Although the majority of TB programmes offer free treat­
Because successful TB treatment is needed to protect the ment, per DOTS guidelines, accessing TB care costs too
662 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

much money and demands too much time from patients Monitoring and Evaluation System,
in all parts of the world (93-97). TB programmes need and Impact Measurement
policies or practices that bring TB services closer to those
at high risk for TB [i.e., migrant workers, prisoners]. By The last component of the updated DOTS framework
focuses on the development and maintenance of a strong
improving access to TB services, an increased proportion
TB surveillance system, which is vital because its data are
of persons with TB disease will be able to access and
used to understand TB epidemiology and provide the basis
complete treatment, thereby reducing transmission within
for estimating national, regional, and global TB trends.
the community.
Strong surveillance systems also enable programmes to
monitor overall programme performance and to estimate
An Effective Drug Supply and TB incidence more accurately. These types of information
Management System in turn can better inform patient management practices and
In order to control and reverse the TB epidemic, an effective improve distribution of resources.
drug supply and management system is crucial. Part of the Since the 1990s, countries have adopted WHO recommen­
DOTS strategy is that anti-TB drugs are to be available free dations to use standardised recording and reporting forms
of charge to patients: TB treatment is a service not just to and registers [e.g., registers for people suspected of having
the individual but to all of society. Furthermore, these drugs TB, treatment registers, laboratory registers, and MDR-TB
must be well-managed so that stock-outs do not occur. registers] to systematically capture and report TB cases.
Lack of sustained access to effective drugs could lead to These data are collected at the facility level [i.e., at points of
increased drug resistance, prolonged transmission within treatment], and then transmitted up administrative levels
until they reach the national programme office. Within
the community, and higher mortality.
the reformed DOTS approach, countries are advised to
The drug supply can be managed using a variety of
include an expanded number of variables on their registers.
diverse, sometimes unrelated systems. TB recording and
For example, registers now regularly include diagnostic
reporting systems can be used to monitor the number of
information and HIV status to help guide patient care.
people on TB treatment, to ensure drugs can be properly
Today, TB surveillance is comprised of both paper-based
planned and stocked. Drug use can also be monitored by
and electronic systems. Traditionally, countries have used
providers. With electronic systems increasingly available,
paper treatment cards and registers to record and report
drug supplies can be monitored in real-time.
cases. However, because of expanding technology, many
Despite the options available for managing the drug
countries, including those traditionally considered to be
supply, maintaining a consistent supply of TB drugs,
low-resource countries, are converting to electronic systems.
especially of second-line drugs for MDR-TB treatment,
The DOTS strategy encourages countries to use electronic
remains a challenge for many countries. There are waiting systems, if possible, because this facilitates individual case-
lines for MDR-TB treatment in many countries because drug based surveillance. Case-based surveillance enables more in-
shortages and difficulties in procuring drugs can lead to depth data analysis, and thus, better understanding of the TB
drug stock outs (98-100). In other countries, drugs may be epidemic at the local, provincial, and national levels. Some
plentiful but waiting lines for treatment still exist because electronic, web-based surveillance systems even enable the
programmes may have difficulty accessing and distributing real-time monitoring of the TB epidemic [Figure 47.5] (104).
them (101). During 2000–2009, experts estimated that fewer Moreover, with electronic systems, multiple TB registers
than 0.5% of global MDR-TB cases had received treatment can be linked on the basis of a unique identifier to further
with “drugs of known quality” through programmes that monitor and evaluate the TB programme [e.g., to identify
were competent to deliver care (98). This is problematic patients not adhering to treatment or provide enhanced drug
both because this leads to patients failing to receive the care management].
they need and because it leads to continued transmission of In recent years, WHO has placed much emphasis on the
MDR-TB within communities. need to strengthen the quality of TB surveillance. In 2006, it
Strengthening the supply chain for second-line anti-TB developed the WHO TB Task Force for Impact Measurement
drugs could help improve treatment and save lives (98). to assess global progress towards the 2015 goals and
Indeed, countries procuring second-line drugs through the strengthen the capacity of countries to monitor and evaluate
Green Light Committee Initiative—a WHO and Stop TB their TB control efforts. The Task Force has helped develop
Partnership effort that offered reduced cost, quality assured and implement a variety of tools and procedures to measure
second-line drugs, along with continuous monitoring and this progress. For example, it created the Standards and
technical assistance—had significantly fewer MDR-TB Benchmarks for Tuberculosis Surveillance and Vital Registration
cases develop additional second-line drug resistance during Systems, which countries can use to find possible gaps in
treatment, in comparison with countries not relying on the their TB surveillance system; from this, countries can identify
initiative (102). Efforts are underway to decentralise the ways to improve the accuracy of TB case detection and
work of this initiative, in an effort to expand global access notification (105). Similarly, the Task Force has promoted
to MDR-TB care (103). the use of inventory studies and capture-recapture studies to
 Stopping TB: The Role of DOTS in Global Tuberculosis Control 663

and our ever-changing world, TB control faces many new

opportunities and challenges that must be considered in the
quest to end TB.

Opportunities
The unceasing evolution of technology brings with it new
possi­b ilities to advance global TB control. Scale-up of
access to Gene Xpert machines in high-burden countries
accelerates the diagnosis of DR-TB. As internet and mobile
networks grow in even the remotest corners of the world,
new communications technologies [i.e., Skype or SMS] offer
opportunities for TB programmes to connect to patients
who would otherwise be difficult to reach because of
limited human resources or high travel costs. Improved
access to technology also gives traditionally resource-poor
countries the possibility of real-time, electronic-based TB
surveillance systems. Eventually, this technology could allow
Figure 47.5: Flow of case-based data in Kenya’s drug-susceptible, programmes to link their multiple TB data systems [i.e., NTP,
electronic TB surveillance system, called TIBU [meaning “to treat” in laboratory, and drug-management systems], which would
Swahili language] allow for the real-time monitoring of the TB epidemic to
TB = tuberculosis improve patient management, monitor patient outcomes,
and prevent drug stock-outs.
In addition, the public health community is hopeful that
assess the level of under-reporting of TB cases (106). Finally,
treatment methods will advance. Although the development
there has been a renewed focus for NTPs to analyse their
of new TB drugs has been a slow process, in 2013 and 2014,
own surveillance data at the national and sub-national levels,
bedaquiline and delanamid received stringent regulatory
so they can understand gaps in surveillance and local trends
approval, the former in the United States and the latter in
in TB, and adjust their programmes accordingly (107). This
Europe. Bedaquiline and delanamid are the first new drugs
is crucial as TB cases continue to be under-diagnosed and
in decades to be successfully created for TB treatment,
under-reported. In both 2012 and 2013, the WHO estimated
and there remain other drugs in the pipeline (109). These
that, globally, three million TB cases were missed by national
advances provide new possibilities for TB treatment and
TB systems (6,12).
care, and thus new opportunities for DOTS. The reader is
referred to the chapter “Treatment of tuberculosis” [Chapter 44]
FUTURE OF DOTS for further details.
The Stop TB Strategy, which expanded upon the original Finally, TB control has the opportunity to evolve as
DOTS strategy, provided the framework to make tremendous the world reshapes its view of TB as both an international
strides in TB control, but with the Stop TB Strategy continued development topic and a global security threat. Rebranding
just through 2015, a new framework, called the End TB TB control as an issue of international development or
Strategy [2015-2035], now guides TB control (6,108). The End poverty alleviation can promote innovations in TB control
TB Strategy includes ambitious targets for 2035, namely 95% that address the roots of the problem (15). Meanwhile,
reduction in TB mortality and 90% reduction in TB incidence declaring TB as a global security issue can reinvigorate
compared to 2015, and no families facing catastrophic funding and resources to address TB on the global scale (110).
costs due to TB. It proposes three pillars building upon the
achievements of the DOTS framework: integrated patient- Challenges
centered care and prevention, bold policies and supportive Despite the opportunities that exist, TB control faces many
systems, and intensified research and innovation. The End challenges, which must be considered when envisioning the
TB Strategy adds to the components of the updated DOTS future of DOTS. First, the TB epidemic continues to evolve.
strategy, calling for earlier diagnosis with universal drug Secondly, DR-TB is increasing, with the rate of MDR-TB
susceptibility testing, collaborative TB/HIV activities, increasing many-fold since 1990, and XDR-TB now found
management of co-morbidities, expanded use of preventive around the world. The majority of DR-TB globally is now
therapy and vaccination, broader governmental and social the result of person-to-person transmission, not acquisition
engagement, greater attention to rational use of medications from poor adherence or poorly-designed treatment regimens.
and to infection control, and a greater engagement with Thirdly, the co-morbidities associated with TB are also
research and innovation. DOTS has enabled society to reach expanding. Although HIV continues to be the most serious
many milestones in TB control, but with this new framework co-morbidity, the increasing prevalence of diabetes and
664 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

tobacco smoking threaten progress made in TB control, 3. Lienhardt C, Glaziou P, Uplekar M, Lonnroth K, Getahun H,
as the portion of TB attributable to diabetes or smoking Raviglione M. Global tuberculosis control: lessons learnt and
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 48
The Role of Medical Colleges
in Tuberculosis Control
D Behera, MPS Kohli, Jai P Narain

INTRODUCTION involvement of medical colleges and their hospitals is of

paramount importance and their importance cannot just be
Tuberculosis [TB] continues to be a major public health
ignored. Being tertiary care medical centers, large numbers
problem throughout the world, more so in developing
of patients seek care from the medical colleges. In addition,
countries and India in particular. TB is a fatal infectious
the role of medical college faculty in TB control as key
disease with devastating and serious socio-economic con­
opinion leaders and role models for practicing physicians
sequences. India is one of the high TB burden countries
and as teachers imparting knowledge, skills and shaping
harboring the highest number of TB cases in the world (1).
the attitude of medical students cannot be underesti­
More adults die from TB than from any other infectious
mated. There is a pressing need for all medical colleges to
disease in India (2). With its commitment to reduce the
morbidity, mortality and disability due to TB and to control advocate and practice DOTS strategy and Programmatic
and eliminate it as a public health problem, the Government Management of Drug Resistant TB [PMDT] guidelines which
of India [GoI], after piloting the DOTS strategy successfully provides the best opportunity for cure of TB patients and
from 1993-1996, had initiated the Revised National TB control at large. In addition, medical colleges have the
Tuberculosis Control Programme [RNTCP] adopting the diagnostic facilities for extra-pulmonary TB [EPTB], human
DOTS strategy in 1997. Subsequently, the Programme immunodeficiency virus [HIV]-TB co-infection, multidrug-
expanded to cover the entire population of the country resistant TB and extensively drug resistant TB [M/XDR-TB]
by March 2006 (3). In India, TB patients are managed by and other forms of drug resistance like mono- or poly-
several health care providers with involvement of diverse resistant TB cases, associated co-morbidities like diabetes
sectors that include the government, non-governmental mellitus, immunosuppressed state, kidney disease and liver
organisations [NGOs], the private and corporate sectors disease, etc.
including the civil society and patients themselves. For Till the time involvement of medical colleges in
effective TB control all stakeholders need to work together the RNTCP was conceived, the interaction between the
towards a common goal of Universal access. academicians in the medical colleges and the Programme
A substantial proportion of patients with TB are managers was sparse and on many occasions discordant.
managed at medical colleges across the country because The young doctors in training seldom got an opportunity
of mere reputations of these colleges, public faith in their to practice what was preached to them. As a result, the
health care delivery mechanisms, availability of expertise facilities available under the RNTCP were seldom utilised
in the field of medical sciences and infrastructure present to the full extent possible. Keeping in mind the needs of
in these medical colleges. Therefore, from the TB control the country, a future “5-Star” doctor who would take up
point of view, medical colleges, in both the government the responsibilities as a care provider, decision maker, com­
and private sectors are recognised to occupy a key position municator, community leader, and a manager was visualised
with a unique potential for involvement with the RNTCP. so that such a future doctor would not only serve the patients
To widen access and improving the quality of TB services, and the community but would also gain their respect.
 The Role of Medical Colleges in Tuberculosis Control 669

EVOLUTION OF MEDICAL COLLEGE

INVOLVEMENT IN THE REVISED NATIONAL
TUBERCULOSIS CONTROL PROGRAMME
The involvement of medical colleges in TB control envisaged
and successfully implemented by the RNTCP for more than
a decade in India is an extraordinary effort. Since 1997,
concerted efforts have been made to involve medical colleges
and their hospitals in the Programme when the first National
Consensus Conference on TB was held in New Delhi (4-7).
This meeting was followed by two meetings in 2001 at the
National Tuberculosis Institute [NTI], Bengaluru (8) and the
All India Institute of Medical Sciences [AIIMS]-World Health
Organization, South-East Asia Regional Office [WHO-
SEARO], New Delhi Meeting on the Involvement of Medical
Colleges in TB and Sexually Transmitted Infections [STIs]/
HIV Control held at AIIMS, New Delhi (9). Professors from
over 35 prestigious medical colleges/institutes participated
in these meetings and accepted RNTCP as a control
programme with potential for a “remarkable success” in
TB control in India and expressed their commitment to the
Programme. In the meeting, recommendations were made to Figure 48.1: Structure of medical college involvement in RNTCP
consider medical colleges as an integral part of the RNTCP. CTD = Central TB Division; NTI = National Tuberculosis Institute,
As per these recommendations, it was envisaged that Bengaluru; TRC = Tuberculosis Research Centre [presently known
medical colleges will offer RNTCP diagnostic and treat­ as National Institute for Research in Tuberculosis, NIRT], Chennai;
ment services, teach and carry out advocacy about RNTCP, LRS = Lala Ram Sarup Institute of Tuberculosis and Respiratory
Diseases [presently known as the National Institute of Tuberculosis
and participate in implementation and monitoring of the
and Respiratory Diseases]; WHO = World Health Organization; STO
Programme. The October 2002 National Level Workshop of = State Tuberculosis Officer; RNTCP = Revised National Tuberculosis
Medical Colleges at AIIMS, New Delhi, was instrumental Control Programme
in developing the structure and processes required for the
effective nation-wide participation of medical colleges in the
Programme. Seven medical colleges located in the different coordinate with the CTD, and monitor the activities of the
zones of the country at New Delhi, Chandigarh [North], ZTF. The ZTF facilitated the establishment of State Task
Jaipur, Mumbai [West], Kolkata [East], Vellore [South] and Forces [STF], coordinated between the national and STF, as
Guwahati [North-East] were identified as nodal centres and well as between medical colleges and the State/District TB
were requested to lead the initiative of participating in the Centres, and monitored the activities of the STF. Because
Programme [Figures 48.1 and 48.2]. of addition and establishment of more and more Medical
Colleges in the country, the south zone has been further
MEDICAL COLLEGE INVOLVEMENT: divided in to South Zone I and South Zone II and presently
there are six zones [Table 48.1].
THE TASK FORCE MECHANISM
The implementing unit is the STF, which facilitates the
The Task Force mechanism has entrusted the responsibility establishment of Designated Microscopy Centres [DMCs]
to medical colleges to ensure their effective contribution to and directly observed therapy [DOT] centres, as well as other
the efforts of GoI in TB control. A Task Force mechanism activities, in all the medical colleges in the respective States.
at the National, Zonal and State level [Figure 48.1] was Over the years, wider interaction with medical colleges has
established. Subsequently, there were consensus workshops occurred through a series of sensitisation seminars, training
in the States with medical colleges which further detailed the of medical college faculty staff at Central TB institutes,
exact mechanisms for collaboration. This formed the basis national and zonal level workshops. Steps for involvement
for GoI’s policy of involving medical colleges in TB control. of individual medical colleges included sensitising faculty
The National Task Force [NTF] consisted of representatives members about RNTCP services, identifying a faculty
from the zonal nodal centres, Zonal Task Forces [ZTFs], member as a “Nodal Officer” for coordinating RNTCP acti­
National TB Institutes, WHO-SEARO and the Central TB vities and training of staff. Other steps included formation
Division [CTD], Directorate General of Health Services, of a “Core committee” consisting of the heads of various
Ministry of Health and Family Welfare [MoHFW], GoI was departments [Table 48.2] (10-19).
formed. The main role of the NTF was to guide, provide Core Committees, at the level of medical colleges facilitate
leadership and advocacy for the RNTCP, develop policies inter-departmental coordination for implementation of
regarding medical colleges’ involvement in the RNTCP, DOTS strategy. DMC and DOT Centres were established
 670 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 48.2: Various zones and nodal centres as per the structure of medical college involvement in RNTCP. Presently South Zone has been
further sub-divided into South I and South II
RNTCP = Revised National Tuberculosis Control Programme

Table 48.1: Zonal Task Force [ZTF] in different States in all government and private medical colleges and these
and Union Territories of India were equipped with suitably trained additional manpower
in the form of laboratory technician [LT] and TB health
Zone States
visitor [TBHV].
North Jammu and Kashmir, Himachal Pradesh, Haryana, The activities of the medical colleges at the district and
Punjab, Chandigarh, Uttar Pradesh, Uttarakhand, Delhi State level are supported through the respective Health
East Bihar, Odisha, West Bengal, Jharkhand, Chhattisgarh Societies as per approved policy of RNTCP for implementa­
West Maharashtra, Rajasthan, Gujarat, Goa, Madhya Pradesh tion of Programme activities.
South 1 Andhra Pradesh, Telangana, Karnataka The annual ZTF and NTF meetings provided an impor­
tant forum for consultation with the medical fraternity on
South 2 Tamil Nadu, Kerala, Puducherry
issues or new initiatives being considered by the Programme
North Assam, Meghalaya, Sikkim, Tripura, Manipur such as external quality assurance of sputum microscopy,
East
drug resistance surveillance, TB/HIV management and
 The Role of Medical Colleges in Tuberculosis Control 671

Table 48.2: Framework for the involvement of medical colleges in RNTCP

All teaching hospitals attached to medical colleges will have a DMC and DOT centre. The following contractual staff are provided: Laboratory
Technician [one] TB Health Visitor [one] Medical Officer [one; for Government Medical Colleges] with provision for providing more staff
depending on workload
Medical colleges would be represented in the State/District TB Society
Constitution of the “Core Committee” consisting of at least 4 members with representatives from the department of Medicine, Chest Medicine,
Microbiology, Community Medicine. Monthly conduct of Core Committee meetings
Training of medical college faculty: STF Chairman, who is a medical college faculty member [concise modular training at National level];
Faculty co-ordinator of Core Committee; Trainer of trainers, Master trainers [MO-TC modular training at National/State level]; Heads of the
departments and other senior staff [concise modular training at State level]; other interested faculty members [MO modular training at Medical
College level]; nurses, pharmacists and other paramedical staff [MPW training at Medical College level]
Recording, administration of treatment, referral for treatment, and monthly and quarterly reporting as per the format prescribed for medical
colleges
Training and teaching about RNTCP
Sensitisation of faculty members
Posting of Interns, UGs and PGs at DOT centres
Include questions on RNTCP in UG and PG examinations
Advocacy
Publish articles/ newsletters, deliver radio and TB talks
Sensitisation/ training of PPs & NGOs, IMA and other sectors
Undertake other relevant IEC activities
Operational research
Conducting thesis work on RNTCP [Rs 30,000 consolidated; at least one per medical college/year; more if appropriate]
Conducting operational research on RNTCP
Mainstreaming of management of DR-TB
 Development of requisite infrastructure [e.g., microbiology laboratories in medical colleges to apply for accreditation for carrying out
mycobacterial culture and drug-susceptibility testing]
Formation of DOTS-Plus committee and DOTS-Plus site committee.
Strengthening of the existing core committee co opting DOTS-Plus committee members
RNTCP = Revised National Tuberculosis Control Programme; TB = tuberculosis; DMC = Designated Microscopy Centre; STF = State Task
Force; MO-TC = Medical Officer Tuberculosis Centre; MO = Medical Officer; MPW = Multipurpose Worker; UG = undergraduate; PG =
postgraduate; PPs = private practitioners; NGOs = Non-governmental Organisations; IMA = Indian Medical Association; IEC = information,
education, communication; DR-TB = drug-resistant tuberculosis
Updated and reproduced with permission from reference 18

coordination, management of M/XDR-TB and DOTS CURRENT STATUS OF MEDICAL COLLEGE

Plus (10-19). INVOLVEMENT
The successful amalgamation of the public health
approach and the expertise of academicians has immensely As on 2015-16, 382 medical colleges are involved under
benefited the RNTCP and TB control in India and facilitated RNTCP with the formation of core committee, DMC and
the emergence of the “future doctor” from among the DOT Centre [Table 48.3] (4,5). STF Workshops are held once
medical students. Involvement of medical colleges in the a quarter in each State to review the activities of the previous
RNTCP is a high priority. Continuing success of RNTCP quarter and dissemination of the updates under RNTCP to
requires involvement of all large providers of health care all medical colleges. The annual ZTF continuing medical
including medical colleges. Under RNTCP Medical Colleges education [CME] lectures cum workshops are held every
play important roles in service delivery, advocacy, training year. This is an opportunity for reviewing the performance
and operational research. of STF and medical colleges and advocating the guidelines

Table 48.3: Involvement of medical colleges under RNTCP

Variable 2009-10 2010-11 2011-12 2012-13 2013-14 2014-15 2015-16
No. of medical colleges 282 291 315 320 347 363 382
PTB cases diagnosed 141859 144303 136072 136130 156858 171627 159560
EPTB cases diagnosed 81615 83824 82067 78,200 91367 110083 101434
Total cases diagnosed 223,474 225,127 218,139 214,330 252,066 281,719 260,994
RNTCP = Revised National Tuberculosis Control Programme; PTB = pulmonary tuberculosis; EPTB = extra-pulmonary tuberculosis
Source: references 4,5
672 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

of RNTCP. In all these workshops, two representatives OR is one of the important activities of Medical Colleges.
from each medical college in the zone, the state TB officers To encourage young physicians, RNTCP helps postgraduate
[STOs], STF Chairpersons, ZTF Chairpersons, Zonal thesis on TB with a contribution of Rs 30,000 per medical
operational research [OR] Committee Members and head college. Besides, individual projects are supported if they
quarter RNTCP consultants of all the states in the zone are have operational values for the programme. The mechanism
invited to participate. NTF Workshop is the event wherein also helps developing research capacity in medical faculty
all the recommendations from the ZTF are consolidated and through workshops at national, zonal and state levels.
deliberated to enable necessary policy changes. The NTF has been the voice of the collective opinion of
academicians in medical colleges and has contributed in
Impact of Medical Colleges shaping key policy issues, such as, ensuring that teaching and
training regarding RNTCP and provision of infrastructural
Medical colleges contribute about 17% of the total registered facilities like DMC and DOT Centre at medical colleges are
cases under the RNTCP [Table 48.3]. The main contribution made mandatory by the Medical Council of India [MCI];
is in terms of the sputum negative and extra-pulmonary rational use of fluoroquinolone antibiotics in the treatment of
TB [EPTB] where their contribution is above 30% of the
respiratory tract infections; airborne infection control policy,
overall cases diagnosed. More than 600 faculty members
drug regimens, ban of serological tests, rational use of anti-
from Medical Colleges are trained as master trainers who
TB drugs, taking up drug trials among others (4,18,20).
support the program beyond the academics as training and
Medical College Faculty have been a part of the Joint
facilitators for over 300 CMEs and workshops annually as
Monitoring Mission undertaken every few years to evaluate
part of advocacy efforts and also participating in Internal
the Programme. Some of the major contributions of NTF
Evaluations and appraisals of the RNTCP. Currently,
Workshop are shown in Table 48.4 (18).
382 medical colleges are involved with RNTCP. Of the
total patients notified from RNTCP, medical colleges
have contributed 16%-20% pulmonary TB and 50% EPTB
ISSUES WITH MEDICAL COLLEGE INVOLVEMENT
patients (5). IN THE REVISED NATIONAL TUBERCULOSIS
Medical colleges have DMCs and DOTS Centres and CONTROL PROGRAMME
referral for treatment, recording and reporting data, carry­ Some problems have been identified in the implementation
ing out advocacy for RNTCP and conducting operational of RNTCP activities in medical colleges, especially in the new
research relevant to RNTCP. medical colleges set up in the private sector. These include
Majority of the medical colleges are running Integrated delay in formation of Core Committees, establishment of
Counseling and Testing Centers [ICTCs] and antiretroviral DMCs in some of the medical colleges. Technical doubts
treatment [ART] centres and have established standard cross about efficacy of DOTS regimens particularly in EPTB cases
referrals between TB and HIV programs (4,5). Medical col­ have lingered on. Consequently, many patients with EPTB,
leges are contributing to diagnosis and treatment of HIV-TB especially, orthopaedic and neurological TB are being treated
co-infection and development of laboratory infrastructure for outside the programme resulting in inadequate utilisation
early diagnosis of MDR and/or XDR-TB and Programmatic of the RNTCP programme. The inadequacies in staff and
Management of Drug-Resistant TB [PMDT]. human resources shortage at all levels require rectification.
Irrespective of which medical college in the country the Issues, such as, staff vacancies in medical colleges not being
patient is diagnosed to have TB, the referral mechanisms filled up on time, and salaries to RNTCP contractual staff
for treatment have facilitated the delivery of DOTS at the not being at par with payments in the sector also need to
patient’s place of domicile. Medical colleges, by virtue be addressed.
of being referral centres with more facilities for invasive In some states, delay/non-release of funds to STFs has
procedures and histopathological and microbiological resulted in non-performance of planned activities. There
methods of diagnosis, have enhanced diagnostic yield is a need to ensure financing essential for sustenance of this
of EPTB, such as, TB pleural effusion, lymph node TB, model. In states with a large number of medical colleges,
abdominal TB, neurological TB, among others. These have, such as Karnataka, visit by the STF Chairperson has become
thus, contributed to early diagnosis of EPTB cases and a practical problem. Therefore in States with large number
facilitated institution of the standard of care, i.e., DOTS of medical colleges there is provision of having vice chairs
for these patients. Medical college involvement has also for every 10 medical colleges.
facilitated more active involvement of pediatricians in the Poor and inadequate airborne infection control practices
RNTCP and effective utilisation of RNTCP diagnostic and in most of the medical colleges, especially the overcrowded
therapeutic services for paediatric TB. government medical colleges have been another issue of
The Medical Colleges/Institutions have settled the issue concern. There is an urgent need for advocacy regarding
of efficacy of DOTS therapy in EPTB like, pleural effusion, education on cough hygiene and etiquette. Weaknesses that
lymph node TB, gastrointestinal tract TB, TB meningitis, are evident in supervision capacity and quality as well as in
genitourinary TB, and bone and joint TB. Currently many planning, monitoring and evaluation, need to be addressed.
experts from medical colleges had contributed to the recently In medical colleges, there is a need for enhanced
released INDEX-TB guidelines (19). inter-departmental sensitisation and better advocacy for
 The Role of Medical Colleges in Tuberculosis Control 673

Table 48.4: The key contributions made by medical colleges in RNTCP policy formulation and programme
implementation during the last decade
Defining the mechanisms for the involvement of medical colleges effectively under the programme [NTF recommendations 2002, 2003, 2004]
Management of TB cases presenting to a medical college hospital [NTF recommendations 2002, 2003, 2004]
Development of RNTCP operational research mechanisms: Identifying and addressing priority OR topics [NTF recommendations 2004, 2005,
2007]
RNTCP strategy for DRS/DOTS-Plus, role of medical colleges in the management of MDR-TB patients [NTF recommendations 2004, 2006]
Strategy for TB-HIV co-ordination at medical colleges [NTF recommendations 2004, 2006]
Recommendations for generation of evidence on effectiveness of RNTCP regimens in extra-pulmonary TB by developing generic operational
research protocols on pleural effusion, lymph node [NTF recommendations 2005, 2006]
Statement on rational use of second line anti-TB drugs [NTF recommendations 2006]
Adoption and endorsement of “International Standards for Tuberculosis Care” [NTF recommendations, 2006]
Adoption and endorsement of the Chennai Consensus statement on the problem, prevention, management and control of MDR-TB and
XDR-TB [NTF recommendations 2007]
Contribution to the development of RNTCP DOTS-Plus guidelines and RNTCP OR guidelines [NTF recommendations 2007]
Contribution to the development of National Airborne Infection Control Guidelines [NTF recommendations 2008]
Revision of the RNTCP Operational Research Agenda and Guidelines [NTF recommendations 2008]
Endorsed and contributed to implementation of revised diagnostic criteria of 2 weeks cough to suspect TB and 2 samples examination for
diagnosis [NTF recommendations 2008]
Endorsement of proposed revision of RNTCP treatment regimen and nomenclature [2009]
Rolling out pilot of National Guidelines on Airborne Infection Control in health care and other settings in India [2009]
Promoting involvement of Medical Colleges for implementing MDR-TB diagnostic and treatment services under RNTCP [2009]
Streamlining reporting from Medical Colleges [2009]
Endorsing the RNTCP response to WHO treatment guidelines [2010]
RNTCP = Revised National Tuberculosis Control Programme; NTF = National Task Force; TB = tuberculosis; DRS = drug-resistance
surveillance; MDR-TB = multidrug-resistant tuberculosis; HIV = human immunodeficiency virus; XDR-TB = extensively drug-resistant
tuberculosis; WHO = World Health Organization
Updated and reproduced with permission from reference 18

RNTCP and need for more contribution in pulmonary practice, senior faculty [of the rank of a professor] in medical
TB [smear-positive and smear-negative cases] and EPTB colleges will influence the practice in the private sector as
cases. There is also a need for strengthening the feedback well as the future generation of physicians thus making
for transferred out cases. This can be facilitated by holding DOTS the standard of care for TB patients in the country.
regular core committee meetings, more intense and sustained This will ensure that all TB patients, irrespective of where
sensitisation regarding the Programme and enhanced inter- they seek care, receive the best available care, free of cost.
departmental cooperation. Several issues need to be streamlined and improved
Establishment of Intermediate Reference Laboratories upon in the coming years to make this partnership between
[IRLs] and DOTS-Plus sites for M/XDR-TB in medical colleges the RNTCP and the medical colleges a truly effective
would contribute to capacity building and strengthening collaboration.
of mycobacteriology laboratory services in the department
of microbiology in medical colleges. Availability of quality THE FUTURE: THE WAY AHEAD
assured accredited laboratories in medical colleges would As the RNTCP widens the scope of services that it provides,
facilitate better management of drug-resistant TB and HIV- medical colleges will have an increasingly important role
TB co-infection. to play in areas such as TB/HIV co-infection, external
Active medical college involvement in prior planning quality assurance of the sputum microscopy network, drug-
and efficient management of drug logistics cycle will avoid resistance surveillance and management of MDR-TB patients.
shortages and will ensure timely supply of drugs. However, The RNTCP needs active support of medical colleges in
in spite of all these deterrents and shortcomings, the carrying out OR in these areas to guide the development of
landmark decision taken more than a decade ago to involve the Programme’s future policies. Recently, medical colleges
medical colleges in TB control appears to have extraordinary have also begun participation in airborne infection control
foresight. This has resulted in the establishment of DOTS as policy implementation. This will involve engineering works,
the standard of care for TB patients in all medical colleges renovation of existing infrastructure by involving medical
and their hospitals. It is expected that through their own college authorities.
674 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Medical colleges also have the potential for evaluating [C-DST] laboratories and establishing Nodal DR-TB Centres
the efficacy of isoniazid preventive treatment [IPT] in the [NDR-TBC] and District DR-TB Centres [DDR-TBC] in
field setting. Thus, by their active involvement in the “3Is”, govern­ment medical colleges as a part of PMDT in India is
namely, intensified case finding, air borne infection control laudable (21,22).
policy, and IPT medical colleges are active partners in the Although the programme has achieved a lot in TB control,
implementation of the RNTCP. there are certain lacunae still which need to be addressed.
The beginning and the progress made so far seem These include review of programme performance; and
promising. But, the need of the hour is to sustain the reorganisation, strengthening of core committees, state and
momentum gained and push medical college involvement zonal task force mechanisms. Teaching, training regarding
forward by continuing coordination and communication. RNTCP and TB control to undergraduate and postgraduate
The OR relevant to the Programme needs can be further medical students, encouraging conduct of mini-projects on
facilitated by providing attractive funding and a clear-cut TB by the medical students also needs attention. There is a
modus operandi with a specified time-line so as to attract need for involvement of various specialties in the core com­
interested faculty members from medical colleges to take up mittee. Medical college faculty have an important role to play
research studies. Identifying thrust areas relevant to current regarding the operationalisation of the recently published
needs of the Programme, and making available quality INDEX-TB guidelines (19). Private practitioner involvement,
generic protocols can facilitate OR studies to be carried out in anti-TB drug regulation, pharmacovigilance are other
medical colleges in multicentre mode. There is also a need for areas where medical colleges are expected to take a lead.
visible networking to facilitate the widespread dissemination Collaboration is desired from National Institutes/Medical
of the outcomes and results documented in the OR studies College collaboration for capacity building in research in
so that this will also enthuse and inspire more research TB. Better co-ordination is also desired between Medical
relevant to the Programme needs. The experience from colleges/STOs/DTOs regarding fund-flow mechanism.
India in involving medical colleges in national Programme
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 49
Public-Private Mix for TB Care
Mukund Uplekar, Sreenivas Achutan Nair

INTRODUCTION TB care vary greatly from country to country. Private health

sector in high TB-burden countries is an unorganised and
The Mismatch of Demand and Supply heterogeneous mix of commercial and non-commercial care
Like most public health interventions, tuberculosis [TB] con­ providers. These may include informal and formal private
trol in high TB-burden countries is planned and designed by practitioners, laboratories, pharmacies, non-governmental
governments and implemented largely through government organisations [NGOs], private hospitals and academic
facilities supervised by National Tuberculosis Programmes institutions. Large and medium-sized businesses also offer
[NTPs]. The NTPs operate through a network of public health services to employees and their families. With a
sector services with the objective of detecting and treating plethora of providers with no linkages among them, people
all people with TB. In reality, however, many people with tend to shop around for care. Government regulations on
TB, including the very poor, do not approach the network quality-assurance for laboratory services, notification of TB
of services providing TB care under the NTP. They seek cases or rational prescribing and use of anti-TB drugs may
and receive care from a wide variety of public, voluntary, exist but are rarely enforced. A study conducted based on
corporate and private health care providers (1). Public anti-TB drug sale data revealed that enough TB drugs were
sector facilities such as hospitals and medical colleges or sold in the private sector in India, Pakistan, the Philippines,
health facilities beyond the administrative control of health and Indonesia to treat 65%-117% of those countries’ TB
ministries such as mines and prison health services do not burdens with a full course of regimen (7).
always follow the guidelines of the NTP. Studies have shown There are two major impediments to TB control globally
that in urban and rural areas alike, a private provider is often and in most high TB-burden settings. First, almost every
a first contact for a large proportion of TB patients especially third case of TB goes undetected or unreported and secondly,
in Asia (1,2). The uneven quality of care provided in the among those who do get detected, there are significant delays
private sector has been widely documented (3,4). Increasing in diagnosis leading to continued disease transmission with
evidence from Africa also shows a rapidly growing private little impact on TB incidence in the community. On this
sector and its use by the people (1). Patient perceptions and background, there is increasing realisation that effective TB
preferences, convenience, stigma, gender are some of the control is not possible without active engagement of all care
factors that play a major role in determining the patient’s providers in the delivery of TB care and prevention. This
decision to first visit a private provider (5). Inconvenient concern and the need to address engagement of all care
clinic timings, long waiting times, provider attitudes, providers are reflected in the Stop TB Strategy 2006-2015
direct and indirect costs and perceptions on quality of care and also in the End TB Strategy (8,9).
at government health facilities are some of the reasons that This chapter describes the evolution of public-private
drive people away from free or subsidised care at public mix for TB care and control. The development of the concept
sector health facilities (5,6). and practice of public-private mix [PPM] is described. The
current approaches and results of PPM scale up efforts
The Need to Engage All Care Providers underway globally and the place of PPM in the new End
The burden of TB managed outside the NTPs and roles of the TB Strategy is discussed. Each country has a distinct
diverse public and private care providers in the delivery of approach in implementing and scaling up PPM and there
 Public-Private Mix for TB Care 677

is no “one size fits all” approach. An illustration of the Table 49.1: Key steps in implementing PPM and
progress and prospects of PPM for TB care and prevention practical tools to help scale it up
in India, in the context of the End TB Strategy is also
Situation assessment
provided.  Assess types of care providers and their current and potential roles
Assess NTP capacity for PPM implementation
EVOLUTION AND EXPANSION OF Assess regulatory environment
PUBLIC-PRIVATE MIX FOR TB CARE Mobilisation of human and financial resources
Development of operational guidelines incorporating
Public-Private Mix and Public-Private
Objectives of implementing PPM
Partnership for TB Care Definition of task-mix for different provider types
 Description of service delivery model[s] considering incentives
What is PPM and how it is different from public-private and enablers [based on national/International experiences] and
partnership [PPP]? PPM is nothing but PPP for delivery of use of digital technology
TB care. The label PPM helps to differentiate partnership  Modules for capacity strengthening of programme staff and
for care provision from all other types of partnerships training and certification of private providers
Mechanism for monitoring and periodic evaluation
that the TB community is engaged in, such as, resource
mobilisation, research and new technology development, Phased implementation
TB drugs procurement and distribution etc. PPM also Generic tools presented in the PPM scale-up tool-kit
conveys another meaning–a mix of mutually agreed roles Core Tools
   Tool to describe rationale and generic approach
for the public sector and diverse private providers to    National situation assessment tool
ensure TB care provision in line with national/international    Operational guidelines development tool
standards. In practising PPM, the NTP is expected always to    Tool for advocacy and communication
retain the stewardship role assuming the overall responsi­    International Standards for TB Care
bility of formulating policies and guidelines and manag­    Monitoring and evaluation tool
ing collaborations with judicious use of incentives and Specific Tools
Engaging solo private practitioners
disincentives.
Engaging large hospitals
The different types of private care providers–institutional Engaging non-governmental organisations
as well as individual–play suitable roles in the mix depend­ Engaging workplaces
ing upon their willingness and capacity. For example, a Engaging social security organisations
private non-profit or for-profit institution may take the Engagement of TB/HIV collaborative activities
Engagement for programmatic management of drug-resistant TB
responsibility of providing TB services in totality in a Engagement of pharmacies
specified area and the NTP may play only supervisory role
PPM = public-private mix; TB = tuberculosis; NTP = National
while a solo private practitioner may simply play the role Tuberculosis Programme; HIV = human immunodeficiency virus
of referring presumed TB cases to the NTP or managing Source: references 13,14
them in his/her own clinic according to programme
guidelines with or without support for free diagnosis, free
drugs and supportive supervision from the NTP. Generally,
collaborating with institutions, for-profit or non-profit, specialist chest physicians, public and private hospitals,
public or private, is much less cumbersome than working and NGOs to the NTPs have been documented (10,11). The
with a large number of unorganised, solo, qualified and World Health Organization [WHO]-based secretariat of the
non-qualified private practitioners. Much of the discourse Public-Private Mix Subgroup on TB care provides a global
on PPM is therefore centred around ways to successfully platform for sharing of experiences of PPM implementation
engage private practitioners in TB care and control in diverse among countries (12). Based on available evidence, WHO
country settings. and the PPM Subgroup have developed practical guidance
and tools to help implement and scale up PPM. Table 49.1
lists generic implementation steps described in WHO’s
Global Efforts to Promote Public-Private Mix
PPM guidance document and practical tools presented
Several PPM pilot projects were implemented successfully in the PPM scale up tool-kit (13,14). Evidence shows that
in many countries over the last decade and a half. These PPM for TB care and control is a feasible, productive and
pilots were minor variations of a typical PPM model. In a cost-effective approach to enhance TB case detection and
this model, the NTP plays the stewardship role and an improve treatment outcomes as well as to promote equity
intermediary agency such as a non-governmental organisa­ in access and save costs of care for the poor (15,16). The
tion, a professional association or a franchising agency expansion of PPM over the last decade has seen two distinct
undertakes the task of mapping, enrolling, educating and development phases: the one before and the one after the
engaging private practitioners and supporting them in application of information and communication technology
delivering TB services. Dozens of projects linking various care in care delivery and introduction of regulatory approaches
providers like non-qualified village doctors, informal and such as mandatory case notification and ensuring rational
formal private practitioners, private general practitioners, use of anti-TB drugs.
678 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

SCALING UP PUBLIC-PRIVATE MIX public-private mix approaches and that of the public sector
providers outside the purview of NTPs through PPM
Country Variations initiatives. Table 49.2 gives an indication of the progress
Approaches to engage non-NTP care providers vary accord­ selected countries have made in scaling up PPM in 2015 (18a).
ing to the country context. For example, in the Philippines, In most of these countries, PPM initiatives contributed
the national health insurance organisation has designed about 10%-40% of total notifications. Considering that
a special TB package for providers that collaborate with the private medical sector in Africa is smaller than that
the NTP. India has diverse schemes for individual and in Asia, the contribution of private for-profit and not-for-
institutional providers based on financial and non-financial profit providers in Ethiopia, Kenya, Nigeria and the United
incentives. China uses an internet-based system for Republic of Tanzania is noteworthy. Progress in parts of
mandatory reporting of TB cases by hospitals from where Asia is also noticeable–almost every third or fourth case in
most TB patients seek care. It is also noticeable that countries India, Indonesia and Myanmar was notified by non-NTP
have prioritised different types of care providers. These care providers in 2013. Large public sector hospitals have
include general public hospitals [in China], private clinics contributed sizeable proportions of cases in China [over 50%
and hospitals [in Nigeria and the Republic of Korea], medical of notified cases], Indonesia and the Philippines. In India, a
colleges [in India] and health insurance organisations that large proportion of the cases notified by non-NTP providers
also provide health services [in Egypt]. Social security were from medical colleges were 87% of notifications;
organisations and prison health services are the main non- from public non-NTP providers, 51% of notifications
NTP providers in the Region of the Americas and in Eastern were from private providers, and 76% of total [public and
Europe, respectively (17). private] notifications were from non-NTP providers. As
Every year, countries collect and report to WHO the per Global TB Report 2018 (18b), an increasing trend in the
data on the contribution of PPM to TB case notifications. contribution of public non-NTP or private sector engage­
This includes contribution from the private sector through ment to TB case notifications has been observed in countries,

Table 49.2: Contribution of PPM to TB case notifications in selected countries, 2015

No. of TB cases notified by Contribution of non-NTP public No. of TB cases notified Contribution of private sector
non-NTP public sector care sector care providers to total by private sector care care providers to total case
Country providers in 2015* case notifications in 2015 [%]* providers in 2015† notifications in 2015 [%]†
Bangladesh ND ND 60879 29
China 447148 56 ND ND
Egypt 1375 17 ND ND
Ethiopia ND ND 15195 ND
India 284636 16 184802 11
Indonesia 61183 18 30550 9.2
Iran 7196 69 3019 29
Iraq 2438 30 ND ND
Kenya ND ND 15531 19
Malawi ND ND 3049 18
Myanmar ND ND 23513 17
Nigeria 6996 7.7 13088 14
Pakistan ND ND 72144 22
Philippines 79197 28 18442 6.4
Sri Lanka 4575 48 ND ND
Swaziland 312 6.8 ND ND
Thailand 3444 5.2 ND ND
UR Tanzania ND ND 7773 13
Vietnam 6913 6.7 ND ND
* Includes all contributions from non-NTP providers of care in the public sector, including public hospitals, public medical colleges, prisons/
detention centres, military facilities, railways and public health insurance organisations
† Private sector providers include private individual and institutional providers, corporate/business sector providers, mission hospitals, NGOs
and faith-based organisations
PPM = public-private mix; TB = tuberculosis; NTP = National Tuberculosis Programme; ND = not described; NGOs = non-governmental
organisations
Source: reference 18
 Public-Private Mix for TB Care 679

such as, Bangladesh, India, Indonesia, Kenya and Pakistan, includes mandatory TB case notification, rational use of TB
that have prioritised PPM. drugs and infection control in health facilities should be in
In most countries, only a small proportion of targeted place and effectively enforced. Rapid and rational uptake of
care providers collaborate actively with NTPs and contribute new diagnostics and drugs for patients in private clinics will
to TB case notifications. Achieving early TB case detection require explicit policies and guidance. Optimising current
to minimise disease transmission will require greater PPM models and developing new and better ones will
involvement of front-line care providers such as community- require operational research. New models of scaling up PPM
based traditional healers and informal practitioners, qualified for TB care such as social franchising and social business
general practitioners and pharmacists–who are often the first models have been implemented successfully in recent years
point of contact for people with symptoms of TB (17,18a). with appropriate use of information and communications
technology tools; their suitable application and scale up
Collaboration-Regulation Mix should be encouraged (20). Finally, sustainable financing
of PPM interventions and ensuring social support to TB
Most of the country approaches to engage private care patients managed by non-NTP care providers will requires
providers have been based on collaboration that involves consideration under universal health coverage and social
sensitisation and training of care providers on the standards protection (21).
of care, support for patient care and offering financial or
non-financial incentives. The result, though encouraging The Strategy-mix to Scale up Public-Private Mix
in terms of contribution to case notifications, has been that
a large proportion of care providers do not feel obliged Large scale implementation of PPM to engage all care
to contribute to national efforts to control TB. There providers in TB care and prevention generally requires
is increasing realisation that collaborative approaches application of a mix of country-specific strategies based
alone may not help in getting all care provider to follow on a thorough national situation assessment and the status
the international standards of TB care or their national of PPM implementation in the country. The strategy-mix
adaptations (19). Looking forwards, a combination of shown in Table 49.3 should be considered in scaling up PPM
collaboration and regulation will likely elicit required actions implementation.
Useful information and resources are available to help
from most private care providers. Along with introduction
implement the strategy-mix [Table 49.1]. The important ones
of information and communication technology [mHealth and
include the national situation assessment tool and the tool on
eHealth] to enhance ease of collaboration, measures should
inventory studies to estimate the number of TB cases treated
also be put in place for certification and accreditation of
in the private sector. Documented country experiences on
collaborating providers, mandatory notification of TB cases
engaging hospitals, engaging the business sector, setting up
by all relevant care providers, and rational use of anti-TB
a certification and accreditation system and implementing
drugs effected through the engagement of pharmacies.
mandatory case notification are also available. The PPM scale
PPM IN THE ‘END TB STRATEGY’
A Great Deal Remains to be Done Table 49.3: The strategy-mix should be considered in
scaling up PPM implementation
The End TB Strategy is presented in the chapter “WHO’s new
Ensuring that the resources available–human and financial–to scale
end TB strategy” [Chapter 52]. The PPM approach cuts across up engagement of all care providers are commensurate with [i] the
all the pillars and components of the End TB Strategy (9). A magnitude of the problem of engaging all care providers; [ii] the
great deal remains to be done to make PPM integral to TB burden of TB managed outside the NTPs; and [iii] the strengthening
care and prevention in order to achieve the ambitious targets of capacity needed within the public sector
of the new Strategy. A large proportion of care providers in Optimising and expanding engagement of large hospitals, academic
most high TB-burden countries still remain unengaged. Early institutions and NGOs
diagnosis of TB requires understanding of patient pathways Sharing the burden of engaging numerous solo private practitioners
and engaging relevant informal and formal providers with “intermediary organisations” such as professional societies and
that people with symptoms of TB first approach. Even in associations; social franchising and social enterprise institutions;
countries where anti-TB drugs are not available in private and NGOs with capacity and skills to work with private practitioners
pharmacies, reducing diagnostic delays requires education Mobilising and supporting the business sector to initiate and expand
of and engagement with all care providers. TB programmes
The PPM approach should also be employed for expansion Implementing regulatory approaches, such as mandatory case
of both–collaborative TB/human immunodeficiency virus notification, rational use of TB medicines, and certification and
accreditation systems to identify and support collaborating providers
[HIV] activities and programmatic management of multi­
drug-resistant TB [MDR-TB]. Mechanisms of certification Engaging communities and civil society to create demand for quality
TB care from all public and private care providers
and accreditation of private providers need to be devised
to ensure adherence to International Standards for TB Care PPM = public-private mix; TB = tuberculosis; NTP = National
Tuberculosis Programme; NGOs = non-governmental organisations
[or their national adaptations]. A regulatory framework that
680 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

up tool kit provides all available guidelines and tools in a surveillance system collected disaggregated data from the
summary form along with an abstract of relevant country different health-care providers. Providers were involved
examples. through a systematic process of situational analysis and
listing of health-care facilities, sensitisation and training of
A COUNTRY EXAMPLE OF PUBLIC-PRIVATE practitioners on RNTCP, training of RNTCP staff on PPM-
MIX SCALE UP DOTS, identification of facilities for RNTCP service delivery,
memoranda of understanding and RNTCP service delivery.
Approaches to implementing and scaling up PPM vary The data from the intensified PPM sites have shown an
according to the country contexts. With almost a quarter overall increase in the number of TB cases notified under
of global TB burden, the largest private sector and a RNTCP (25).
plethora of different types of formal, informal, individual There have been several other positive developments
and institutional care providers, India presents a typical in the recent years. National consultations were held for
context to understand evolution and expansion of PPM in better PPM engagements and a National Technical Working
a country. The following paragraphs describe the progress Group has been established. Serological testing for TB has
and prospects of PPM implementation in India. been banned and TB has been made a notifiable disease,
The private medical sector in India accounts for nearly with a case based electronic notification [NIKSHAY] system
85% of the first contact of patients from all socioeconomic developed for the notification of cases. Standards for TB Care
groups, and at least half of those treated for TB in India (22). in India [STCI] were developed for bringing together the
Studies conducted since the 1990s have documented the right standards in diagnosis, treatment, public health and
extent to which TB is diagnosed and treated in the private social inclusion for all (26). STCI has become the yardstick
sector, as well as largely inappropriate diagnostic and in measuring quality standards in TB care including in
treatment practices.4 The Revised National Tuberculosis public and private sector. This has made the levelling of
Control Programme [RNTCP] has established itself as a the playing field for private sector also and is helping better
strong and effective way to deliver TB care in the public PPM engagement in a large way. Strategic opportunities
sector providing a firm base upon which PPM efforts are are presented by several key developments, such as the
being built. It is estimated that presently, private practi­ emergence of new diagnostic technologies and advances in
tioners contribute just 2%-3% of case-finding and less than mobile phone penetration and applications.
1% of case management under the RNTCP. The many
challenges hampering meaningful engagement of private CURRENT STATUS
providers include poor relationship between the private
providers and the state which is often characterised by a India’s national TB strategic plan aims to achieve a rapid
deep mutual mistrust. Market forces are often powerful decline in burden of TB mortality and morbidity towards
impediments to the adherence of private providers to ending TB in India by 2025 (27). To this effect, the RNTCP
government protocols. The state’s regulatory enforcement has taken steps to reach the unreached through synergising
mechanisms are too weak to control the private market, the efforts of all partners and stakeholders. This change
considering its size and fragmentation. is reflected through increased allocation of resources for
partnerships, increase in manpower through sanction of
EVOLUTION dedicated positions to focus on partnership building at
the state and district levels, greater flexibility to allow for
PPM had been well recognised as a requirement for effective innovation, capacity building through targeted training and
TB control by the TB programme. As a consequence, an enabling environment to expand new approaches. The
numerous pilot projects were set up and documented. Using RNTCP is now engaging with private sector partners in most
the experiences gained from the collaborations with NGOs of the major cities of India with primary focus on notification
and the private sector, the RNTCP published guidelines through innovative partnership mechanisms (27-32). Some
for the participation of the NGOs [2001] and private of the major PPM milestones in India include the following.
practitioners [2002] (23). These guidelines were revised
in 2008 and again in 2014. In the context of engaging all The Indian Medical Association: Revised
care providers, involvement of public and private medical National Tuberculosis Control Programme–
colleges in TB care and control has met with great success.
Public-Private Mix Project
By creating national, regional, state and medical college
task forces, the RNTCP has managed to rope in medical The Indian Medical Association [IMA]–RNTCP–PPM
colleges in expanding quality-assured TB care services. Project started in the year 2008 in five states and one union
These medical colleges alone contribute about 20% of TB territory of India, covering 177 districts. Subsequently
cases notified in the country (24). A first attempt of scaled up 10 more states were added. The objective of this project
implementation of PPM was undertaken in 14 urban sites in was to improve access to the diagnostic and treatment
India. WHO-PPM medical consultants and peripheral field services of RNTCP and thereby, improve the quality of care
supervisors were recruited and posted to these districts. for patients suffering from TB through the involvement of
An expanded version of the existing routine RNTCP Indian Medical Association. The key activities undertaken
 Public-Private Mix for TB Care 681

as part of the project include state/district level workshops, and laboratories for the required programme management
publication of quarterly TB/RNTCP newsletter, publication activities and coordination. The project has engaged large
in the Journal of Indian Medical Association, district level number of private practitioners, hospitals and laboratories
CME’s of all the IMA branches in the target states, produce and have substantially increased the TB notification. There
information, education and communication [IEC] materials, were many important factors for success of these projects
assist District TB Officers [DTOs] in training of private such as; qualified private sector providers were allowed
providers etc. (27). to manage TB patients [instead of referring them to the
RNTCP], and TB patients received free services including
Catholic Bishops Conference of India-Coalition easy digital e-vouchers for free anti-TB drugs, and laboratory
for Acquired Immunodeficiency Syndrome and tests, such as chest X-rays, sputum smears and Xpert® MTB/
Related Diseases RIF. The field staff of intermediary agencies aggregated
diverse private providers into a network, engaged, and
The Catholic Bishops Conference of India-Coalition for made frequent visits to private providers, and ensured that
Acquired Immunodeficiency Syndrome [AIDS] and Related patients were notified to the NTP and linked to care. Good
Diseases [CBCI-CARD] project worked to improve access adherence monitoring and support was offered to all TB
to TB diagnostic and treatment services within the Catholic patients to help them complete treatment, quality of care
Church Healthcare Facilities [CHFs]. Under this partnership, was monitored and targeted feedback was used to improve
across 19 states of India, field consultants visit CHFs, conduct performance over time (30).
situational analysis, liaise with programme managers and The National Strategic Plan 2017-2025 of RNTCP
other CHF personnel to participate in TB control and care (27). incorporated the learnings from the successful models
for private sector engagement to overcome the barriers of
Involvement of Pharmacists mutual mistrust, conflicting market forces and fragmentation
As community pharmacies are often the first port of call for so that the quality of TB care is improved and encompassed
patients seeking healthcare, systematic and comprehensive within the programme (31). At the national and state
engagement of pharmacists and chemists is crucial for early levels, a technical support group [TSG], to support the
diagnosis and proper treatment of patients. The Central programme for effective contract management and other
TB Division collaborated with the Indian Pharmaceutical partnership-strengthening functions Private Provider
Association [IPA], All India Organisation of Chemists and Interface Agencies [PPIAs] contracted in the states are
Druggists [AIOCD], Pharmacy Council of India [PCI] and required to manage the activities essential for engaging the
South-east Asia Region [SEAR] Pharm Forum representing private sector. An innovative strategy adapted in India that
WHO–International Pharmaceutical Federation [FIP] Forum has further stimulated TB notification is the ‘Nikshay Poshan
of National Associations in South East Asia for engaging Yojana’ in which financial incentive to TB patients is given
pharmacists in TB control in India (27). through direct beneficiary transfer mechanism (33). Other
measures for future PPM expansion include rapid uptake of
Universal Access to TB Care Project internationally approved diagnostic and treatment protocols
by the RNTCP, use of mandatory TB case notification as an
A very important milestone for PPM in India is the Universal instrument to initiate and sustain collaboration, financial and
Access to TB Care project implemented in Mumbai in other incentives to providers for TB notification, increased
Maharashtra, Patna in Bihar and Mehesana district in Gujarat use of accreditation and contracting for further outreach to
in which free anti-TB drugs for TB patients seeking care private laboratories, stronger regulations on anti TB drugs
in private sector are provided to achieve universal access and innovative use of information and communication
following Standards for TB Care in India. Once a qualified technologies.
practitioner diagnose and decide to treat a TB patient outside The guiding principles for PPM TB are well illustrated
the scope of RNTCP, s/he will notify the case using digital in the following section in the National Strategic Plan for
technology enabled mechanisms and prescription details TB Elimination in India (27): “The learnings that guide
relevant to anti-TB drugs are shared with contact centre. the efforts to invoke support from the private sector and
Based on it, a unique voucher number is generated and provide public services to its patients include the following:
shared with practitioner and patient. The voucher number [i] the government will be an enabler and not see itself as
written on prescription is carried by patient to chemist. the sole provider of TB care; [ii] “go where the patients
The voucher is validated by chemist with help of contact go” and currently around half of the TB patients go to the
centre and free anti-TB drugs are given to patients. Patient private sector. This should be true of investments to address
is contacted telephonically for confirmation of receipt of this fact as well; [iii] The cost of involving the private sector
free medicine and later at home, for extending public health is not high. It is almost the same or marginally higher than
services like contact screening, adherence and infection the cost in the public sector; [iv] Investments in involving
control counselling, HIV testing, drug-susceptibiliity testing the private sector yields significant returns in case detection,
services, etc. The project showed the importance of inter­ with doubling or even tripling of the case notification rates;
mediary agencies for engagement of private practitioners and [v] public health actions to support the private sector
682 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

provides for better outcomes related to access, notifications, 11. Dewan PK, Lal SS, Lonnroth K, Wares F, Uplekar M, Sahu S,
adherence, treatment outcomes and cost savings”. et al. Improving tuberculosis control through review public-
private collaboration in India: literature review. BMJ 2006;332;
574-8.
PROSPECTS 12. Lei X, Liu Q, Escobar E, Philogene J, Zhu H, Wang Y, et al. Public-
The main impediments to the successful execution of private mix for tuberculosis care and control: a systematic review.
the PPM strategy include a lack of capacity within the Int J Infect Dis 2015;34:20-32.
13. Subgroup on public-private mix for TB care and control.
programme in areas such as cost analysis and contract
Available at URL: http://www.who.int/tb/careproviders/
design, and protracted procurement processes. The ppm/en/. August 14, 2018.
persistent mistrust of the private sector, both in the context 14. World Health Organization. Engaging all care providers in
of the programme as well as in the broader political and TB control: guidance on implementing public-private mix
administrative context, may lead to a lack of commitment to approaches. WHO/HTM/TB/2006.360. Geneva: World Health
the new strategy in some states and districts. The success of Organization; 2006.
the strategy is to some extent dependent on developments 15. World Health Organization. Stop TB partnership public-private
outside the TB programme, such as the strengthening mix for TB care and control: a toolkit 2010. http://www.who.int/
tb/careproviders/ppm/PPMToolkit.pdf. Accessed on August
of regulatory processes and the development of digital
14, 2018.
technology systems. Strong leadership will be of the utmost 16. Floyd K, Arora VK, Murthy KJ, Lönnroth K, Singla N, Akbar Y,
importance in tackling the possible pitfalls. A new spirit of et al. Cost and cost-effectiveness of PPM-DOTS for tuberculosis
genuine partnership will be needed, sufficient resources control: evidence from India. Bull World Health Organ
will have to be allocated and accountability will have to be 2006;84:437-45.
established. 17. Lönnroth K, Aung T, Maung W, Kluge H, Uplekar M. Social
franchising of TB care through private GPs in Myanmar: an
assessment of treatment results, access, equity and financial
DISCLAIMER protection. Health Policy Plan 2007;22:156-66.
The authors are staff members of the World Health Organiza­ 18a. World Health Organization. Global tuberculosis report 2016.
tion. The views expressed in this article do not necessarily WHO/HTM/TB/2016.13. Geneva: World Health Organization;
2016.
represent the views or policies of the organization.
18b. World Health Organization. Global tuberculosis report 2018.
WHO/CDS/TB/2018.20. Geneva: World Health Organization;
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 50
Building Partnerships for Tuberculosis Control
Vineet Bhatia, Md Khurshid Alam Hyder

INTRODUCTION incorporating key elements that provided a long term vision

for the national TB control programmes [NTPs]. In May
We are in an interesting and yet challenging era of tuber­
2014, the World Health Assembly [WHA] in its resolution
culosis [TB] care and control where the goal of ending TB
WHA67.1 adopted the global strategy and targets for TB
by 2030 has been endorsed by World Health Assembly in
prevention, care and control after 2015 based on a bold vision
2014 and yet the efforts have to gain requisite momentum.
of a world without TB and targets of ending the global TB
Global success of TB control efforts can be measured by the
epidemic, elimination of asso­ciated catastrophic costs for
fact that the Millennium Development Goal [MDG] target to
TB-affected households. This lays the foundation of End TB
halt and reverse the TB epidemic by 2015 were achieved (1).
strategy (10) [Table 52.1].
Mortality and incidence rates are falling in all of World
Health Organization [WHO] six regions and in most of
the 22 high-burden countries [HBCs] that account for over OVERVIEW OF TUBERCULOSIS SITUATION
80% of the world’s TB cases. However, the global burden AND PROGRESS IN TUBERCULOSIS CONTROL
of TB remains enormous and progress towards ending TB IN THE SOUTH-EAST ASIA REGION
remains slow.
Global efforts to treat TB patients with internationally The WHO South-East Asia Region [SEAR] consists of 11
recommended, standard treatment have had a reasonable member countries, namely, Bangladesh, Bhutan, Democratic
success since the year 1993, when recognising the need Peoples’ Republic of Korea, India, Indonesia, Maldives,
for enhanced response for TB control, the WHO took an Myanmar, Nepal, Sri Lanka, Thailand and Timor Leste.
unprecedented step of declaring TB a global emergency (2). Six out of these 11 countries—Bangladesh, Democratic
To strengthen the fight against TB, WHO began to promote People’s Republic of Korea, India, Indonesia, Myanmar and
DOTS strategy during the same period (3). The package Thailand, are among the 22 global high TB burden countries.
combined key elements from early work carried out at the TB remains one of the major public health concerns in the
Tuberculosis Research Centre [TRC] – formerly known as SEAR of WHO (1,11).
the Tuberculosis Chemotherapy Centre, and now renamed In terms of progress in TB control, all 11 member states
as National Institute of Research in Tuberculosis [NIRT], have sustained country-wide access to quality treatment with
Chennai (4) and the National Tuberculosis Institute [NTI] DOTS as one of the pillars. In 2016, more than 2.9 million TB
Bengaluru (5) in India. The elements of the approach were were registered for treatment and the treatment success rate
outlined in the “Framework for effective tuberculosis among new and relapse TB cases registered in the previous
control” launched by WHO in 1994 (6,7). In its report in year was 78%. The TB mortality rate has decreased by 50%
1993, the World Bank hailed short-course chemotherapy since 1990 and SEAR has already achieved the global target
[SCC] with closely monitored walk-in treatment as one of a 50% reduction by 2015. The decline in the prevalence is
of the most cost-effective of health interventions (8). In observed in all member countries and in some countries it
2005, a comprehensive Stop TB Strategy (9) was launched is over 50% [Figure 50.1] (12).
 Building Partnerships for Tuberculosis Control 685

Figure 50.1: Projected regional trajectory of TB incidence and TB death 2015-2035 in South-East Asia. Dotted line representing the current trend,
continuous line representing needed decline to reach targets

Table 50.1: Estimated HIV prevalence among adult populations and the number of people living with HIV
infection in SEAR countries, 2013
Estimated number of people Estimated adult [15-49 years] HIV Estimated number of people
Country newly infected with HIV prevalence [%] living with HIV
Bangladesh 1300 <0.1 9 500
Bhutan <200 0.1 <1000
DPR Korea * * *
India 130,000 0.3 2,100,000
Indonesia 80,000 0.5 640,000
Maldives NA <0.1 <100
Myanmar 6700 0.6 190000
Nepal 1300 0.2 39000
Sri Lanka <500 <0.1 2900
Thailand 8,200 1.1 440,000
Timor-Leste NA NA NA
Total 230,000 0.3 3.4 million
* No reported HIV positive individual till date
HIV = human immunodeficiency virus; DPR Korea = Democratic People's Republic of Korea; NA = not available
Source: reference 14

Multidrug-resistant and Rifampicin-resistant range 105,000-130,000] among notified pulmonary TB cases

Tuberculosis accounting for nearly one-third of the global burden of
such cases in 2016 (1,11,12). Extensively drug-resistant TB
Multidrug-resistant TB [MDR-TB] is defined as TB caused by [XDR-TB] is a subclass of MDR-TB where there is resistance
Mycobaterium tuberculosis [Mtb] that shows in vitro resistance to at least isoniazid, rifampicin, any fluoroquinolone, and at
to at least isoniazid and rifampicin, the two most important least one of the three injectable drugs [amikacin, kanamycin,
first line anti-TB drugs. MDR-TB is said to be a man-made or capreomycin]. XDR-TB has been isolated in samples
phenomenon since it is caused by inadequate, irregular or from six countries in the region, namely, Bangladesh, India,
incomplete treatment with poor quality of drugs and poor Indonesia, Myanmar, Nepal and Thailand (1,11,12).
adherence to treatment by the patients.
Levels of MDR-TB in WHO SEAR in terms of propor­ Impact of Human Immunodeficiency Virus
tions are still low, at 2.8% among notified new TB cases
on Tuberculosis in the Region
[uncertainty range 2.4%-3.1%] and 13% among retreatment
TB cases [uncertainty range 10%-15%]. However, given the It is estimated that there are 3.4 million people living with
large numbers of TB cases in the SEAR, this translates to human immunodeficiency virus [HIV] infection/acquired
totally 117,000 estimated RR/MDR-TB cases [uncertainty immuno­deficiency syndrome [AIDS] {people living with
686 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

HIV/AIDS [PLHA]} in the WHO SEAR, accounting for further challenged by the increasing burden of HIV/AIDS,
nearly 10% of global PLHA. In SEAR, an estimated 210,000 DR-TB, as well as the growing burden and challenge of non-
cases [5.2%] of the 4 million incident cases were HIV- communicable diseases.
seropositive and an estimated 62,000 cases died of HIV- Access to health care including TB care in the Region is
associated TB in 2014. Five countries in the region [India, significantly funded by out-of-pocket expenditure by the
Indonesia, Myanmar, Nepal and Thailand] accounted for patients themselves. This is direct spending by households
99% of HIV cases in the region (1,11,12). The magnitude of on health services, without reimbursement of any kind
HIV infection differs greatly between countries of the region, and is considered the most regressive option for funding
and even within countries, there are marked differences health systems – funding through general taxes, and social
[Table 50.1] (11,13). insurance being the most equitable forms of health financing.
Of all health expenditures in countries of the SEAR, 66% are
Resources for Tuberculosis Control out-of-pocket, of which a substantial proportion is spent on
the purchase of drugs. And, estimates suggest that as much
In the whole Region, domestic sources continue to account as 30% of new poverty in some countries in the Region is
for just over 62% of the funding for NTPs. Ten member caused by the catastrophic cost of accessing health care.
countries currently benefit from funds mobilised through Low levels of community awareness also hamper the
the Global Fund to fight AIDS, TB and Malaria [GFATM]. uptake of services, and there is increasing recognition
In addition, nine member states benefit from funds from that attention needs to be paid to the social, economic and
other development partners and donor governments, the behavioural determinants that impact TB, if national efforts
exception being Maldives, where the only external funds to combat the disease are to succeed in the longer term.
are WHO country budgets. Maldives is in the process of There is still a limited involvement of private care providers.
obtaining GFATM support. A global study to this effect was instituted by the Global
There, however, remains a significant funding gap Alliance for TB drugs, which explored the private sector
for the overall budget of TB control programmes (14). landscape of 10 high TB burden countries [HBCs] [that
Considering the threshold of 2.28 health professionals per collectively account for 60% of the global TB burden] and
1,000 population, only five of the 11 member states have found that the private sector treatment landscape in these
sufficient human resources for health. High turnover of the countries was largely unregulated and fragmented (15). For
staff, lack of adequate training and insufficient manage­ment example, the study detected 111 different first-line TB drug
of human resources is a common challenge for most of the dosages and combinations, compared to the 14 deemed
countries in the region. necessary by the Stop TB Partnership’s Global TB Drug
Facility [GDF]. Drug misuse by the private sector is likely to
Key Challenges to Tuberculosis Control be responsible for many treatment failures and for escalating
in the South-East Asia Region the emergence of MDR-TB, which is further worsening the
Countries in the SEAR have varied socio-economic and wider TB epidemic. The impacts of these challenges are listed
demo­graphic profiles, leading to diverse challenges faced by below.
TB programmes in the respective countries. These include
uncer­tainties regarding sustainable financial and operational Inadequate Access and Delayed Diagnosis of
resources; limited technical and management capacity; weak Persons with Tuberculosis, Including Children
national laboratory networks, procurement and supply With current notification rates, almost a third of the estimated
management mechanisms which in turn are slowing the pool of TB cases in the Region are either not detected or not
planned expansion of interventions for TB-HIV and MDR- notified. Factors contributing to suboptimal case detection
TB; case detection mainly focussed on passive case finding include poor knowledge and awareness of the population;
and lack of emphasis on management of latent TB infection. geographical, social and financial barriers; suboptimal identi­
The current laboratory capacity in the region remains fication by health services of persons suspected of having TB;
inadequate to reach global and regional targets for the suboptimal diagnostic procedures, referral and notification
diagnosis of drug-resistant TB [DR-TB] and HIV-associated practices [public and private] including little attention paid
TB. Even in countries with a large number of laboratories, to children; and limited screening of high-risk groups e.g.
country-specific conditions such as geographically chal­ contacts, clinical risk groups and risk populations. Paediatric
lenging situations mean that diagnostic services are currently TB remains a neglected area as demonstrated by the very low
not available to all in need. notification rate in the age group below 15 years.
TB prevention, care and control are heavily dependent
on strong primary health care systems. Many of the con­ Slow Progress in Scaling up Programmatic
straints to effective implementation of TB prevention, care
Management of Drug-resistant Tuberculosis
and control services in the Member States are related to
underlying weak and underfinanced national health systems In May 2009, the WHA resolution 62.15 urged the Member
in general, many of which are already overstretched in terms States “to achieve universal access to diagnosis and treatment
of both infrastructure and staffing. Weak health systems are of MDR-TB and XDR-TB” (16). However, the coverage for
 Building Partnerships for Tuberculosis Control 687

MDR-TB access is far from universal access as of now with government as well as those involved in health care outside
just about 20% of the estimated incidence being notified. the government. Therefore, there is a need for partnership
if the problem of TB has to be adequately dealt with.
Slow Progress in Scaling up Tuberculosis-Human
Immunodeficiency Virus Collaborative Activities What is a Partnership?
In SEAR region, 45% of all TB cases notified in SEAR knew A partnership may be defined as agreement between indi­
their HIV status; of the TB patients known to be living viduals and organisations to work towards a common goal
with HIV, 85% were on anti-retroviral therapy [ART] in the with shared vision and responsibilities. There is generally a
region. The SEAR maintained 85% co-trimoxazole preventive consensus on issues being dealt with, and motivation levels
therapy [CPT] enrollment of all notified HIV-seropositive TB are high. In the case of TB care and control, a partnership
patients since 2003 (1,11). will have a shared vision of TB elimination, and partners
undertake joint activities to promote synergy of efforts.
Addressing the Challenges through the National TB control programmes need to continue to
World Health Organization South-East Asia engage a wide range of stakeholders both within the health
Region Strategic Plan sector and other sectors, to ensure that the distribution and
coverage of quality services is equitable across all geographic
The WHO SEAR Strategic Plan for TB Control was initially locations and reach various socioeconomic groups, especially
developed in 2006 (17) and described the future direction the marginalised and hard to access populations. Engaging
and focus of work for TB control in the region. The targets with multiple partners requires close attention to their acti­
and strategies in the document are consistent with the global vities, and providing support and guidance to ensure that
targets and strategies, but focussed on the priorities most all activities serve their intended purpose. Partners need to
relevant to the Region and built on past experience and be provided with relevant information, reports on achieve­
successes (14). ments, a forum for regular interaction, and opportunities to
The year 2015 has been a watershed moment in the battle share experiences and develop consensus on joint activities
against TB. It marks the deadline for global TB targets set towards a common goal.
in the context of the MDGs, and is a year of transitions:
from the MDGs to a new era of Sustainable Development Relevance of Partnerships for Tuberculosis
Goals [SDGs], and from the Stop TB Strategy to the End TB
Care and Control
Strategy. In this transition, paradigm shifts are expected in
all sectors, including health. To end the epidemic [defined Partnerships are an instrument to tap diverse resources—
as an incidence of fewer than 100 cases per million people] technical, financial, human and physical infrastructure—
by 2035 will require a rapid upgrade of care and managerial to fill gaps in programme implementation. In resource-
standards. constrained settings, partnerships are a mechanism to
Ending the TB epidemic will require an expansion of the induce synergies and avoid duplication. Partnerships can be
scope and reach of interventions for TB prevention, care and viewed as a means of maximising benefits. The incentives
control: the institution of systems and policies to promote an for working in a partnership are not limited to monetary
enabling environment, shared responsibilities with universal benefits; they include specific skills derived from the learning
coverage; and aggressive pursuit of research and innovation experience, greater collective capacity to respond to the
to promote development and use of new tools for TB care problem, and increased quality of solutions.
and prevention. Through partnerships, a platform is available for shared
This Regional Strategic Plan towards Ending TB in the SEAR responsibility and decision making for TB care and control,
2016-2020 (14) describes the future directions and focus of where all partners feel the needs to directly or indirectly
the work towards TB elimination aiming to support Member support the cause. A dialogue between the programme
States in the reduction in TB mortality and incidence in and other stakeholders, including the most marginalised,
line with the global targets as set in WHA resolution 67.1, will lead to a common understanding and consensus for
guiding the countries in addressing the persisting and addressing challenges. This will help create an inclusive
emerging epidemiological and demographic challenges strategy and action plan for the perceived programme needs
and advancing universal health coverage and robust health and civil society needs. This would help all partners to have
systems. The plan (14) builds on and expands the existing a shared vision and confidence in how their individual
updated Regional Strategic plan for TB Care and Control efforts are contributing to the larger goals of the programme.
2012-2015 (17) and focuses on the implementation of the Partnerships allow programmes to get diverse views and
End TB Strategy in the coming five years within the overall perspectives on challenges faced by the programme, creating
scope of the 20-year strategy covering the period from 2015 a holistic picture. By listening to various community voices
to 2035. and stakeholders, the programme can gain an idea of their
It is often beyond the capacity of NTPs alone to address needs and expectations. Gaps in service delivery will also
these and other systemic issues. All Programmes need to be highlighted. On the other hand, the community and
work in close collaboration with other sectors within the stakeholders will also get a better picture of programme
688 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

views on service delivery, existing constraints and efforts to their future potential. As government determines the
to improve service delivery. overall policies and outlines the framework of cooperation,
Through partnerships, programmes can share information government representatives are the initiators of the partner­
on their achievements. Partners can share their experience on ship and accept ownership and responsibility of the process.
a common platform. This promotes transparency and builds Based on the common goals, and guided by the priorities
trust amongst stakeholders. Thus, partnerships act as an and gaps in the Stop TB strategy implementation plan, the
interface between programme, stakeholders and community. TB programme is responsible for assessing and grading these
The partnership can carry the voice and opinion of multiple partners according to their value in tackling priority issues.
stakeholders and community members to the programme Some examples are given in the Table 50.3.
managers, and vice versa.
Partner Involvement in Helping Tuberculosis
KEYS STEPS TO BUILDING PARTNERSHIPS Care and Control
The key steps to building partnerships are listed in Improving the Quality
Table 50.2 (18).
While the national programmes strive to improve outreach,
Analysing the Potential of Various Partners the limited availability of resources may compromise
quality of services in resource constrained settings. Partners
To establish a structure and align all partners for an effective can ensure quality by pooling of resources specifically
response, it is important that a transparent assessment be by improving access and by independent evaluation and
carried out against the background of implementation of the feedback to the programme. Partners can also act as voice
Stop TB strategy in respective countries. Exploring options of community. Quality can be improved right at the stage of
for working together and building relationships requires planning by involving communities who can help envisage
that this be done in a spirit of mutual respect, commitment implementation and access challenges for those who need
to a common task, and sensitivity to the needs of various it the most.
partners. At times, mutual trust and credibility need to be
developed before partners can be expected to work together.
Improving Case Notification
To develop a common outlook it is useful for stakeholders
to explore their expectations of tackling the ambitious task Partners working in health and other development sectors
together. can quickly identify chest symptomatics in community,
Analysis of stakeholders is crucial. It will help in identi­ given their proximity and close relations. Similarly industries
fying potential partners and assessing their relevance. have captive population that can be easily approached
Questions are asked about the position, interest, influence, through peer support groups and through the in-house
interrelations, networks, and other characteristics, with medical facilities and when available. Early recognition of
reference to their past and present positions as well as symptoms will also ensure early diagnosis and hence cure.

Table 50.2: The key steps to building partnerships

 ndertake a situation analysis of the programme. Identify gaps or requirements that need to be filled and list all potential partners who can
U
contribute in these areas to fulfil the programme’s goals
Identify the strengths of potential partners. Various resources available through partnerships include:
Technical resources through technical agencies, academic institutions, professional bodies located within countries
Public and private human resources, including NGOs and other civil society organisations, health care providers, community volunteers
Financial resources, which can be harnessed through development partners, corporations and business houses
Public and private physical infrastructure, including for-profit and not-for-profit organisations, health facilities, community-based groups
Shortlist the potential partners and define their roles in the programme. Share the programme goals and vision with them
 iscuss the programme with them and explain why they should partner with the efforts of the programme. Address any concerns they may
D
have in joining the programme
Obtain consensus on a common plan: targets, objectives, areas of responsibility, use of operational guidelines, procedures and timeframes.
If required, help build the capacity of the partner
Implement agreed activities according to the plan
 ustain communication. Network and share information regularly with all partners on progress being made, any problems that need to be
S
resolved and how they may maximise their contribution
Periodically and systematically monitor and evaluate progress
 ocument lessons learned and experiences. Share these with the partners. Appreciate and praise successes and work towards accepting
D
failures jointly
Broaden the partnership and scope of work as the programme grows
NGOs = non-novernmental organisations
 Building Partnerships for Tuberculosis Control 689

Table 50.3: Responsibility of partners in tackling priority issues

Types of organisation Prime interest Value for TB care and control
Human rights groups Human rights Awareness and legal expertise
Patient associations Patients’ rights Advocacy and service monitoring
TB and lung associations TB awareness Advocacy and network
Business/corporate sectors Benefits and profits Service delivery
Professional associations Education and standards Management and training
Private practitioners, hospitals, prisons, Health care and medical Capacity building and service delivery
military services
Ministry of Finance Public finances Financial resources and expertise
International and national technical agencies Technical support Update policies and operations research
Medical Colleges Academic and tertiary level care Service delivery, operations research, policy feedback and
tertiary care for complicated cases and co-morbidities
TB = tuberculosis

Supporting Treatment Adherence durable when the commitment of individual members is

strong.
Treatment of TB is long-up to 9 months for susceptible
TB and 20 months or more for MDR-TB. Completion of Information Sharing with the Partners
treatment is important for cure. However a long treatment
may be associated with several challenges–psychological and Communication is a binding force for the partnership. It is
emotional trauma, loss of job and wages, and discrimination essential that partnership activities are regularly shared with
of various kinds. Partners can provide counselling services, all partners. To accomplish this task there is need to have a
psychological support and rehabilitation services that may focal point responsible for regular communication to which
generally be outside the purview of a government run TB all partners have a good relationship. There is also a need
control programme. to share information with all partners and the programme,
through newsletters, e-mails and meetings.
Improving Communication and Community
Awareness Regarding the Disease, Symptoms, Frequent Discussions/Meetings with Partners
Transmission and Curability and other Stakeholders
The fact that TB can be cured through a regular and compete All important decisions should be consensus-based, and it
course of treatment needs to be reinforced to reduce any is important to involve all stakeholders in discussions prior
associated stigma. to arriving at decisions.

Clarity of Roles and Responsibilities

Illustrative List of Country Stakeholders, Possible
Implementation Roles of Different Partners Partners have their own core strengths, and responsibilities
within partnership can be defined accordingly. It is also
The illustrative list of country stakeholders are listed in important to have defined governance structures that help
Table 50.4 (19). Possible implementation roles of different manage the partnership efficiently.
partners are shown in Table 50.5 (20).
Forward Thinking
Successful Partnerships: What Works Well
The partnership structure should not only be able to manage
Mutual Respect and Recognition the present but also plan for the future.
All partners come with different strengths and varied
experience. It is essential that in partnership this diversity Global and Regional Partnerships in
is recognised and respected so that everyone feels included. Tuberculosis Care and Control
Shared decision making leads to greater understanding and
Global Partnership
commitment. Commitment has many dimensions and is
related to the extent to which participating organisations In 1998, the WHO convened an “ad-hoc committee on the
have endorsed or adopted the common mission or carried TB epidemic” to analyse the reasons for the slow progress
out activities in the name of partnership. The key to success and provide recommendations to the global community
is to identify bona fide partners who could also be respected to support acceleration of progress (21,22). Among the
leaders in the effort. Partnerships are more likely to be recommendations made by the ad-hoc committee were
690 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 50.4: Illustrative list of country stakeholders

Ministry of Health
 National TB Programme, National Public Health Laboratory, National AIDS Control Council, Joint HIV-TB Committee, National
Immunisation Programme, Department of Planning, Directorate of Primary Health Care, Health Education Department, Provincial and
District Health Officers, Training Department, Medicines Regulatory Authority, Pharmacy and Essential Medicines Department
Ministry of Justice
 TB control in penitentiary system/prisons
Ministry of Finance
 Directorate of health budgets
 Planning Commission
Ministry of Education
 Academic, research and training institutions
 Medical colleges, research institutes, training institutes
World Health Organization, United Nations and International technical agencies
 Interministerial groups led by WHO or the UN, such as, the HLWG on TB in the Russian Federation
 FHI 360, MSH, MSF, KNCV, PATH, The Union—specifically when agencies have a local presence
Funding agencies
 Global Fund
 World Bank
 USAID, PEPFAR, DFID, BGMF
Professional organisations
 Medical and paediatrics associations, nurses’ association, pharmacists’ associations, national TB/lung associations, laboratory
technologists’ associations
State-owned enterprises
 Manufacturers of TB-control products
Private sector health and non-health companies
 Manufacturers of TB-control products [diagnostics, medicines, vaccines], importers and wholesalers, hospitals and clinics, clinical
diagnostic laboratories, faith-based organisations and NGOs, pharmacies and drug shops, traditional healers
 Local enterprises committed to corporate social responsibility
Decision-makers and opinion leaders
 National health policy-makers, academic and religious leaders, national “envoys” for TB [e.g., famous sportsmen, actors, etc.]
Community and patient advocacy groups
 Community-based organisations, patients’ organisations, advocacy and community-based organisations
 Civil society organisations
Communications media
 Print media and journalists, television and radio stations
TB = tuberculosis; AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus; WHO = World Health Organization;
UN = United Nations; HLWG = High Level Working Group; FSI = Family Health International; MSH = Management Sciences for Health; MSF =
Medicines Sans Frontiers; KNCV = Royal Netherlands Tuberculosis Association; PATH [from 1980 until 2014, PATH stood for Program for
Appropriate Technology in Health. Presently it is simply referred to as PATH]; USAID = United States Agency for International Development;
PEPFAR = United States President’s Emergency Plan for AIDS Relief ; DFID = United Kingdom Department for International Development;
BGMF = Bill and Melinda Gates Foundation; NGOs = non-governmental organisations

the creation of a global charter among all key partners and planning from HBCs was held in Amsterdam in March
countries with the highest burdens of disease [22 countries 2000 leading to the landmark “Amsterdam Declaration”
account for 80% of global TB burden], involvement of the to stop TB. In May 2000, the WHA endorsed the formation
private sector and communities in national TB control efforts of a global partnership for TB control and, at the same
and the creation of a global drug facility. time, considering that most countries had not reached the
In the same year, Dr Gro Harlem Brundtland, the then targets set in 1991, postponed these targets to 2005 (24).
Director-General of WHO, launched the Stop TB Initiative In 2001 a structure for a global Stop TB partnership was
founded on the principle of a global partnership to address developed and this was endorsed at first meeting of the
the lacunae pointed out by the ad-hoc committee and to Stop TB Partners forum in Washington in October 2001 (25).
accelerate action against TB control. At the first forum of the partnership, 80 partners and HBCs
As a result of the efforts of the newly launched Stop TB endorsed the Washington Commitment to Stop TB, com­
Initia­tive (23), several events with far reaching implications mitting themselves to the 2005 targets and to specific actions
on global TB control followed in rapid succession. A mini­ as outlined in the global plan to stop TB (26). From early 2015,
sterial conference on TB and sustainable health involving the Stop TB Partnership has moved to United Nations Office
several global partners and ministers of health, finance and for Project Services [UNOPS] with same functions as before.
 Building Partnerships for Tuberculosis Control 691

Table 50.5: Possible implementation roles of different partners

Public sector departments
 Education: training teachers and educating children about TB; including TB in school health campaigns; including TB awareness education
in non-formal education and adult literacy programmes
 Social welfare: possibly offering food subsidies and social assistance to families of TB patients
 Labour: promoting treatment and prevention at the workplace; ensuring that work environments are not places in which TB is easily
transmitted
 Defence and police: promoting treatment and prevention within these forces; coordination and collaboration between their health facilities,
where available, and those of the NTPs
 Women’s welfare: raising awareness through organised women’s groups and ensuring supportive environments for women to seek and
complete treatment more readily
 Youth and sports: promoting TB awareness among young people
 Media/communications: raising public awareness and helping shape public attitudes and opinions about people with TB, making the
communities aware of how they may participate in control, and informing people about public policies and facilities that are in place to
treat TB
NGOs
 Providing community-based care
 Training health care workers and volunteers to provide DOTS
 Generating awareness and educating the community on prevention and treatment
 Involving the community in implementing DOTS
 Conducting operational research
 Playing a major role in advocacy and in mobilizing community support
Private sector
 Notification of diagnosed TB patients and providing DOTS services in partnership
 Referring patients to the public sector from private dispensaries, clinics and hospitals when treatment is not feasible
 Undertaking research and development of drugs and simpler diagnostics
 Maintaining a healthy work environment to prevent the spread of TB
Academic bodies, professional associations
 Influencing health policy and practices at political and decision making levels
 Educating all health professionals on national guidelines for the diagnosis and treatment of TB
 Assisting in setting codes of ethics and maintaining standards, especially in research for TB control
International/regional organisations and associations
 Mobilizing resources and providing technical assistance to national programmes
 Promoting innovative approaches, including intercountry collaboration for TB control
 Co-ordinating national laws, standards and regulations on cross-border movement
Media
 Disseminating evidence-based information
 Educating the public and specific interest groups on TB
 Influencing attitudes and behaviour with regard to TB
 Advocating and communicating with policy makers to influence decisions relating to TB control
Opinion leaders [political, religious, traditional, etc.]
 Influencing attitudes and behaviour of and towards people with TB
 Influencing policy decisions relating to TB control
Communities
 Supporting TB patients and their families by fostering positive attitudes and non-discriminatory practices
 Involvement in planning, problem-solving, monitoring and reviewing TB programme initiatives
 Critical feedback on availability of services
Patients and their families
 Ownership of their health through active involvement to ensure that any affected member of their own family is treated properly until cured
TB = tuberculosis; NTPs = National Tuberculosis Programmes; NGOs = non-governmental organisations

Also in 2001, the G-8 at their 26th summit in Okinawa (27), newly established UN SDG. Goal 3 specifically pertains to
committed to reducing TB deaths and prevalence by half by health: Ensure healthy lives and promote well-being for all
2010. In January 2002, the GFATM was set up as a financial at all ages. Target 3.3 states: By 2030, end the epidemics
instrument to resource activities aimed at control of these of AIDS, TB, malaria and neglected tropical diseases and
three diseases (28). TB control was now firmly established combat hepatitis, water-borne diseases and other comm­
on the global health agenda. TB control also features in the unicable diseases (29).
692 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Partners in the South-East Asia Region corporate sectors and prison health services, as well as
private providers in TB management. In some countries, the
It had long been recognised in the Region that public
percentage of patients seeking services through the private
health systems alone could not deliver health care to all.
health sector is very high. Currently, all member countries
Health systems in the Region are already overstretched and
have clear policies and strategies to involve other sectors,
countries in the Region did not have sufficient sustainable
and their contribution to TB case notification stands at more
resources to meet the basic health needs of their populations.
than 25%.
Many are also undergoing a difficult process of health sector
A recent initiative have been the formal inclusion of
reform in order to address these challenges.
the principles and practices of TB control in pre-service
Therefore, partnership building has been a priority for
training and the establishment of referral mechanisms
countries in the SEAR. Specifically for pooling resources
through providing lists of treatment centres [DOT centres]
and strengthen the on-going care and control activities,
to teaching institutes. More than 1,000 private laboratories
Programmes have collaborated with international agencies,
are now included in national diagnostic networks and
as illustrated in Table 50.6. Joint efforts of national pro­
undergo quality assurance mechanisms. Indonesia has
grammes, funding agencies, technical agencies, non-govern­
intensified training of private and public hospital and labora­
mental organisations [NGOs] and grass roots organisations
tory staff. The country has also introduced co-ordination
have led to considerable success in the SEAR in combatting
meetings between community health facilities and hospitals
TB. There are several examples available from the region
to improve transfer mechanisms between lung clinics
that have been exemplified globally.
and puskesmas. In Myanmar, TB services are provided
throughout the network of Sun Quality Clinics and the
Success Stories From the Region NTP plans further expansion of public-private mix services
One deliberate and important strategy within SEAR to through the Myanmar Medical Association.
increase case detection and treatment success rates has Universities and medical schools in the region are
been the inclusion of public health care providers operating contributing to evidence-based policies and strategies
outside the Ministry of Health, such as the railways, military, through technical advisory groups at national level.

Table 50.6: List of major donors and partners supporting TB control in South-East Asia Region
Australian Agency for International Development [AusAID]
Bangladesh Rural Advancement Committee [earlier used as an acronym. Now only the “BRAC” is used]
Centers for Disease Control and Prevention [CDC], Atlanta, USA
Clinton Health Access Initiative [CHAI]
Canadian International Development Agency [CIDA]
Challenge TB [CTB, one of the flagship projects of United States Agency for International Development]
Danish International Development Agency [DANIDA]
Damien Foundation Belgium [DFB]
UK Department for International Development [DFID]
Global TB Drug Facility/Stop TB partnership [GDF]
Global Fund to fight AIDS, TB and Malaria [GFATM, also called GF]
Japan Foundation for AIDS Prevention [JFAP]
Japan International Co-operation Agency [JICA]
Royal Netherlands Tuberculosis Association [KNCV]
Norwegian Association of Heart and Lung Patients [LHL]
Management Sciences for Health [MSH]
Norwegian Agency for International Development [NORAD]
Research Institute for Tuberculosis [Japan] [RIT]
South Asian Association for Regional Co-operation [SAARC]
International Union Against TB and Lung Disease
United Nations Development Programme [UNDP]
United Nations High Commission for Refugees [UNCHR]
United States Agency for International Development [USAID]
World Bank [WB]
World Health Organization [WHO]
TB = tuberculosis; AIDS = acquired immunodeficiency syndrome
 Building Partnerships for Tuberculosis Control 693

More than 1,000 medical colleges, 25,000 private practitioners, refer for proper management of the side effects during TB
1,800 large public and private hospitals, 250 corporate treatment (31).
institutions, 2,500 NGOs, nearly 100 faith-based organisations
TB control in the Chittagong export processing zone
and over 900 prisons are now working with NTPs.
Chittagong is the largest industrial city in Bangladesh, and
The International Standards of TB Care [ISTC] (30)
therefore, attracts a large number of people seeking work.
have been endorsed by professional bodies and medical
There are over 600 garment factories in the city in the
associations in Bangladesh, DPR Korea, India, Indonesia,
addition to industries in the Chittagong Export Processing
Maldives, Myanmar, Nepal and Thailand. Intersectoral
Zone [CEPZ]. Within the CEPZ, operated by Bangladesh
collaboration and public-private partnerships for delivery
Export Processing Zone authority [BEPZA], there are
of services have been further scaled up in eight member 117 industries, employing 83,589 workers, mostly young
countries [Bangladesh, India, Indonesia, Myanmar, Nepal, women. These garment factories alone employ 1.8 million
Sri Lanka, Thailand and Timor-Leste]. workers, 80% of whom are females, between the ages of
Partnership with international and national NGOs have 15-35 years. Recognising that health facilities at individual
enabled TB service delivery outreach in remote areas and factory premises were inadequate, the Bangladesh garment
among marginalised populations in several countries of the manufacturers and exporters established two health centres
Region. Several thousand of community-based initiatives with one doctor and one nurse at each. There are 43 DOT
are also being incorporated into routine service delivery treatment centres, seven of which function also as diagnostic
by national programmes. However, successful approaches centres. These centres were established through collaboration
should be systematically documented in order to replicate between the NTP, the city corporation, local NGOs and the
winning models in similar settings in the countries of the National Anti-TB Association of Bangladesh [NATAB]. TB
region. cases identified at the health centres are referred to nearest
Business alliances in the region such as the Thai Business NTP centre.
Coalition and the Business Alliance in India are emerging as The Youngone Group in Bangladesh, which produces
players from the non-health private sector introducing TB and exports sportswear including garments, shoes, nylon
services into their workplaces. fabrics, quilting and luggage, operates within the CEPZ.
It employs 24,000 employees of which 80% are females in
Some Country Specific Examples the age group between 18-30 years, coming from many
of Successful Partnerships different districts in Bangladesh. TB was found to be
common among these factory workers. The medical staff
Bangladesh–Community-based DOTS also recognised that most workers concealed their illness for
Implementation through Non-Governmental fear of losing their jobs. Those with TB in the CEPZ either
Organisations had to attend the CEPZ hospital, or the nearest NTP centre
Bangladesh is an outstanding example of implementing TB as a result, most workers suffering from TB preferred to
control in partnership with NGOs. consult private practitioners. This resulted in most being
Community-based DOTS implemented through village treated incompletely. Recognising that these workers were
among the most vulnerable to TB on account of close regular
doctors and the network of shasthya shebikas [community
contact with affected workers, the management of Youngone
health volunteers] is the most common mechanism for super­
Industries decided to establish DOTS at Youngone Industry
vising drug intake.
in the CEPZ. So far the Youngone Industries have registered
The Bangladesh Rural Advancement Committee [BRAC]
186 cases of TB among its workers, of whom a third were
approach for TB diagnosis and treatment focusses on com­
smear positive cases.
munity level education and engagement. The BRAC conducts
As a result of this initiative, the company enjoys the
orientation with different stakeholders of the community to
economic benefit accruing from increased work efficiency
engage them in efforts to identify patients, ensure treatment
and better morale among its workers, national and inter­
adherence, and reduce stigma. The stakeholders include: national recogni­tion, and a better corporate image. There is
cured TB patients, local opinion and religious leaders, girls’ growing interest at the CEPZ hospital in establishing DOTS
guides and scouts, other NGO workers, village doctors, centre under NTP, due to the initiative by the Youngone
pharmacists and private practitioners. Group. Youngone is also interested in establishing a wider
The BRAC has created and trained a cadre of community partnership to address TB-HIV co-infection (32).
health volunteers known as shasthya Shebikas to serve as
front-line health care providers. Shasthya Shebikas educate India–Public-Private Mix through Non-Governmental
and empower people in the community about TB control
Organisation Interface
during household visits and health forums and also
provide referral services. They disseminate TB messages, Resource Group for Education and Advocacy for Community
identify suspects, refer them for sputum examination to Health [REACH] is an organisation formed in 1998 to raise
Upazila Health Complex [Government sub-district health awareness on issues which are critical to community health.
complex] or BRAC laboratory services, ensure daily intake REACH is a registered society being managed by an execu­
of medicine for identified TB patients through DOT and tive committee, with the main office based in Chennai,
694 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Tamil Nadu, India. One of the major issues addressed by increase comm­unity participation in interventions like case
REACH is TB control. For the past 10 years REACH has detection and accompanying TB confirmed patients for treat­
been involved in creating awareness on TB in slums, schools ment through DOTS. Aisyiyah also is engaged in increasing
and the community and specially caters to the lower socio- the role of non-governmental clinics to adopt counselling
economic strata of society. and treatment of TB patients through DOTS.
Private practitioners and private hospitals in Chennai, Activities of Aisyiyah include advocacy to local govern­
Tamil Nadu were actively sensitised by REACH for ment, DOTS training for TB Cadres, developing DOTS
participation in the Revised National TB Control Program curricula in Medical school, TB control in workplace and
[RNTCP]. Advocacy and training of Private Physicians was social mobilisation in the community. Aisyiyah managed to
carried out. The PPM project was set up as an informal non- increase case detection rate in the working area with close
profit collaboration initiated by REACH and Corporation of co-ordination to primary health care.
Chennai. The objectives of the PPM model were to increase To foster acceleration of hospital involvement in DOTS,
access for patients to RNTCP services by involving private 750 out of 1,645 hospitals has been trained in DOTS strategy
healthcare providers and devise innovative methods to with funding from Global Fund Round 1, Round 5 and
overcome barriers to successful PPM. REACH facilitated USAID. With funding from TBCAP/USAID through KNCV,
treatment of the private patients by providing assistance to several provinces were supported by Technical Officers
the PPM centres and the private practitioners. Since 1998- who specifically deal with DOTS expansion in hospital.
2010 the project has treated 5,264 patients with successful Coordination at central level with the Directorate General of
treatment outcomes. Advocacy, Communication and Social Medical Service has significantly intensified. Two guidelines
Mobilisation [ACSM] activities are presently being carried have been developed, namely the Managerial Guideline for
out in the 12 districts of Tamil Nadu as part of the GFATM TB service provision with DOTS strategy in hospital and
supported Axshya TB Project. Guideline for TB diagnosis and treatment in hospital. In
As part of the initiative to increase awareness about TB
addition, the Directorate General of Medical Service has
among journalists and journalist students and to increase
conducted assessment to several DOTS hospitals. Efforts to
media reporting on TB, the website www.media4tb.org was
integrate implementation of DOTS strategy into the current
launched which gives a whole range of information about
hospital accreditation system are underway (35).
TB, facts on TB, frequently raised questions on TB, some
of the international agencies working towards TB control, National movement for partnership Gerdunas [Gerakan
different stakeholders in the partnership, communication Terpadu National or National Integrated Movement] is a
materials developed by REACH (33). cross sector movement formed in 1999 at central and local
government levels in order to promote acceleration of TB
Corporate sector-public sector undertaking collaborates
to “Stop TB” Hindustan Copper Ltd, established in 1924 control measures through an integrated approach, involving
as Indian Copper Corp Ltd., is one of the oldest copper hospitals, private sectors, academia, NGOs, funding agencies,
mines in India. It runs its own hospital for employees and and other stakeholders. Following high level meetings held
ex-employees. The hospital has 80 beds, a fully functional during 2002, Gerdunas provincial chapters were established
lab, an operation theatre and an X-ray unit. As per the last in nearly all provinces. The function of partnership can be
available data, 14 doctors including four specialists, 21 nurses grouped into three categories: [i] planning and stewardship;
and 62 paramedical staff were working there. The company [ii] financing, resource allocation and use; and [iii] service
is also involved in community outreach programmes as provision (36).
part of its Corporate Social Responsibility and conducts
regular health camps in the surrounding villages every Nepal–Youth Organisation Involved in Human
month. The hospital is in a remote area and caters to a Immunodeficiency Virus Control
large rural population. Keeping this in mind a Designated
Bidhyarthi Jagarn Manch [BIJAM, Student Awareness Forum]
Microscopy Centre [DMC] and a DOT centre was started in
is a non-profitable and non-governmental organisation
the hospital in October, 2007. Two doctors, 4 pharmacists
focusing mainly on youth development, harm reduction, HIV,
and 3 laboratory technicians have been trained in RNTCP
at the District Tuberculosis Centre, Jamshedpur. The whole AIDS and sexually transmitted infections [STI] prevention
programme is running under the able leadership of the Chief and control and recently in TB diagnosis and treatment.
Medical Superintendent, whose enthusiastic response and BIJAM has worked for the last 17 years to reduce HIV and
initiative has made this programme possible in HCL. He AIDS related prejudice, behaviour change communication
was responsible for encouraging his staff to take active part interventions, access to clean needles and syringes, condom
in getting trained and following RNTCP norms (34). distribution, STI treatment, HIV counselling and treatment.
Recently, BIJAM has been implementing active case
Indonesia–Faith-based Organisation with finding for TB diagnosis among vulnerable groups in hard
to reach populations by screening for TB symptoms, sputum
Gender Sensitivities
collection of suspected cases, and referral of positive cases
Aisyiyah Aisyiyah formed in 1917 and is the first women’s to government treatment centres.
muslim organisation in Indonesia. Since, 2000 this organisa­ The TB interventions are part of the Stop TB Partnership
tion is involved in TB Programme. Aisyiyah efforts are to TB Reach funding with Family Health International [FHI]
 Building Partnerships for Tuberculosis Control 695

Nepal managing the grant. BIJAM is one of the many FHI 7. World Health Organization. What is DOTS—a Guide to
partners implementing the grant. Bijam works for the promo­ understanding the WHO-recommended TB control strategy
tion of community initiative by strengthening existing health known as DOTS. WHO/CDS/TB/99.270. Geneva: World Health
Organization; 1999.
and education system. Focusing to increase knowledge and
8. World Bank. World Development Report 1993. Investing in
under­standing by promoting education on health related health. New York: Oxford University Press; 1993.
issues (37). 9. World Health Organization. The Stop TB Strategy: Building
on and enhancing DOTS to meet the TB-related Millennium
Sri Lanka—Foundation as a Partner for Development Goals. WHO/HTM/TB/2006.368. Geneva: World
Tuberculosis Control Health Organization; 2006.
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Sevalanka Foundation Sevalanka, a registered non-profit, at URL: http://www.who.int/tb/strategy/en/. Accessed on
works with two “daughter organisations” to provide an December 18, 2017.
11. World Health Organization, Regional Office for South-East Asia.
integrated and complementary package of services. Seva
Bending the curve-ending TB: annual report 2017. Available at URL:
Finance is a registered microfinance institution that provides http://apps.who.int/iris/bitstream/handle/10665/254762/
financial services to community organisations and rural 978929022584-eng.pdf?sequence=1&isAllowed=y. Accessed on
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Sevalanka is currently active in 22 of Sri Lanka’s 25 dis­ TB Care and Control 2011-2015, SEA-TB-334. New Delhi: World
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provides specialised support services, most implementation 13. World Health Organization, Regional Office for South-East Asia.
decisions are taken at the district level by staff from that Health sector response to HIV in the South-East Asia Region
region. 2013. New Delhi: World Health Organization, Regional Office for
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tion to respond more quickly and appropriately to local 14. World Health Organization, Regional Office for South-East Asia.
Ending TB in South East Asia-Regional Strategic Plan 2016-2020.
needs. Specific activities vary from district-to-district and
New Delhi: World Health Organization, Regional Office for
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for facilitating a community-centred development process 15. Wells WA, Ge CF, Patel N, Oh T, Gardiner E, Kimerling ME.
through social mobilisation, institutional capacity building of Size and usage patterns of private TB drug markets in the high
civil society organisations, network formation, and livelihood burden countries. PLOS One 2011;6:e18964.
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Assembly. WHA62/2009/REC/1. Geneva: World Health
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Organization; 2009.
considered cross-cutting issues and are incorporated into 17. World Health Organization, Regional Office for South-East Asia.
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These success stories have led to reaffirmation of the for South-East Asia; 2012.
belief that considerable success in TB care and control can 18. World Health Organization, Stop TB Partnership. A pocket guide
be achieved by NTPs working in coordination and synergy to building partnerships: WHO/HTM/STB/2003.25. Geneva:
World Health Organization; 2003.
with partners. The available strengths need to be adequately 19. World Health Organization, Stop TB Partnership. Engaging
tapped to fill in the gaps of the national programmes. The stakeholders for retooling TB control. Geneva: World Health
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check what interventions are replicable, adapt them to local 20. World Health Organization, Regional Office for South-East Asia.
needs and scale up, to reach out all those afflicted by TB. Leadership and strategic management for TB control managers.
Module 8. Building Partnerships. SEA-TB-274. New Delhi: World
Health Organization, Regional Office for South-East Asia.
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December 22, 2016. Accessed on December 2, 2018.
 Integrating Community-based Tuberculosis
51
Activities into the Work of Non-governmental and
other Civil Society Organisations
[The ENGAGE-TB Approach]
Haileyesus Getahun, Thomas Joseph

INTRODUCTION governments could greatly enhance development out-

comes (3) that will in turn benefit TB prevention, treatment
In 2017, an estimated 10 million people around the world
and care activities.
became ill with tuberculosis [TB], and 1.3 million died from
The implementation and scaling up of community-
it (1). About 13% of TB occurs among people living with
based TB activities remains weak, despite the clear need,
human immunodeficiency virus [HIV], and TB causes almost
the documented cost-effectiveness of community-based
a quarter of acquired immunodeficiency syndrome [AIDS]
TB activities (4) and the tremendous efforts that have been
deaths. One-third of people estimated to have TB are either
expended in recent years. Effective and mutual engagement
not reached for diagnosis and treatment by the current health
of NGOs and other CSOs and the national TB programmes
systems or are not being reported. Even in patients who are
[NTPs] or their equivalents is essential to scale up community
identified, TB is often diagnosed and treated late. In order
based TB activities.
to reach the unreached and to find TB patients early in the
The core principles for effective engagement and to
course of their illness, a wider range of stakeholders already
improve collaboration and foster effective partnership
involved in community-based activities needs to be engaged.
between NGOs and other CSOs and the NTPs or their
These include the non-governmental organisations [NGOs]
equivalents include mutual understanding and respect
and other civil society organisations [CSOs] that are active
recognising differences and similarities in background,
in community-based development, particularly in primary
functions and working culture; consideration and respect
health care, HIV infection and maternal and child health, but
for local contexts and values while establishing collaborative
have not yet included TB in their priorities and activities (2).
mechanisms and scaling-up integrated community-based
NGOs and other CSOs are non-profit organisations that
TB activities; and support to a single national system for
operate independently from the state and from the private
monitoring implementation of activities by all actors with
for-profit sector. They include a broad spectrum of entities
standardised indicators (5). Respect for these principles
such as international, national and local NGOs, community-
will help to remove barriers and bottlenecks affecting
based organisations [CBOs], faith-based organisations
implementation of integrated community-based TB activities.
[FBOs], patient-based organisations and professional asso­
ciations. NGOs and other CSOs engage in activities that
range from community mobilisation, service delivery, and
COMMUNITY-BASED TUBERCULOSIS ACTIVITIES
technical assistance to research and advocacy (2). Community-based TB activities cover a wide range of
The strengths of NGOs and other CSOs active in health activities contributing to prevention, diagnosis, improved
care and other development interventions at the com­ treatment adherence and care that positively influence
munity level include their reach and spread and their the outcomes of drug-sensitive, drug-resistant and HIV-
ability to engage marginalised or remote groups. These associated TB. While diagnostic tests for TB continue
organisations have a comparative advantage because of their to be performed in clinical settings, for lack of simpler
understanding of the local context. Greater collaboration diagnostic methods, community-based TB activities are
between NGOs and other CSOs and local and national conducted outside the premises of formal health facilities
698 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 51.1: Examples of community-based TB activities

Theme Possible activities
Prevention Awareness-raising, IEC, BCC, infection control, training providers
Detection Screening, contact tracing, sputum collection, sputum transport, training providers
Referral Linking with clinics, transport support and facilitation, accompaniment, referral forms, training providers
Treatment adherence support Home-based DOT support, adherence counselling, stigma reduction, pill counting, training providers, home-
based care and support
Social and livelihood support Cash transfers, insurance schemes, nutrition support and supplementation, voluntary savings and loans,
inclusive markets, training providers, income generation
Advocacy Ensure availability of supplies, equipment and services, training providers, governance and policy issues,
working with community leaders
Stigma reduction Community theatre/drama groups, testimonials, patient/peer support groups, community champions,
sensitising and training facility and CHWs and leaders
TB = tuberculosis; IEC = information, education, communication; BCC = behaviour change communication; DOT = directly observed therapy;
CHWs = community health workers
Source: reference 6

[e.g., hospitals, health centres and clinics] in community- comprehensive socioeconomic and community problem.
based structures [e.g., schools, places of worship, congregate It proposes six areas to facilitate the engagement of NGOs
settings] and homesteads. and other CSOs in community-based TB activities. These are
Community health workers [CHWs] and community a situation analysis; an enabling legal and policy environ­
volunteers [CVs] carry out community-based TB activities, ment; guidelines and tools; assessing the relevant TB tasks
depending on national and local contexts. CHWs are people needed to be undertaken and included in action plans;
with some formal education who are given training to monitoring and evaluation to enable learning and continuous
contribute to community-based health services, including TB improvement; and enhancing the capacity of organisations to
prevention and patient care and support. CVs are community scale up their work sustainably. The ENGAGE-TB approach
members who have been systematically sensitised about TB emphasises the value of collaboration and partnership
prevention and care, either through a short, specific training between NGOs and other CSOs and the NTPs or equivalents.
scheme or through repeated, regular contact sessions with It also requires close alignment of systems, especially in
professional health workers. TB monitoring and reporting, to ensure that national data
Community-based TB activities could and should be adequately capture the contributions of community-based TB
integrated into other community-based activities support­
activities. Each component of ENGAGE-TB is independent,
ing primary health care services, including those for HIV
and all six components are not always required to implement
infection, maternal and child health and non-communicable
community-based TB activities [Figure 51.1].
diseases to improve synergy and impact. Community-based
TB activities utilise community structures and mechanisms
through which community members, CBOs and groups
Situation Analysis
interact, coordinate and deliver their responses to the A situation analysis helps to identify the specific needs
challenges and needs affecting their communities (6). Some and tasks for integrated community-based TB activities. It
examples of community-based TB activities are shown in involves information-gathering to analyse and understand
Table 51.1 (7). the existing situation. It is useful to involve and engage
NGOs and other CSOs could integrate TB into their multiple stakeholders, including the NTP, NGOs and other
community-based work in many ways, without trained CSOs, and community members, including patients and
medical staff. It is particularly important for them to do so their families. An NGO or CSO should take the lead for
when they are working with high-risk populations, [such as the situational analysis of its own operational area. The
people living with HIV and the very poor], people living in situation analysis should identify and prioritise problems
congested environments [urban slums and prisons], people and needs in TB prevention and care, especially those of
who use drugs, sex workers and migrant workers. Examples vulnerable groups such as prisoners, migrants, sex workers
of how NGOs and other CSOs could integrate TB into their
and injecting drug users who might face stigma and have
ongoing activities are shown in Table 51.2.
difficulty in using the services of the formal health system.
Information on the available TB diagnostic and treatment
THE ENGAGE-TB APPROACH facilities helps in understanding how the system will work
The ENGAGE-TB approach seeks to shift the global per­ in terms of activities, such as, referral, sputum collection,
spective of TB from only a medical illness to a more diagnosis, treatment and follow-up.
 Integrating Community-based Tuberculosis Activities into the Work of Non-governmental and other… 699

Table 51.2: Examples of how NGOs and other CSOs could integrate TB into their ongoing activities
HIV programmes and projects
TB/HIV awareness raising and stigma reduction
TB detection through screening, contact tracing and sputum collection and transport
TB referral by linking patients with clinics and assisting with transport
Treatment adherence support including home-based TB and HIV care
Social and livelihood support through nutrition supplementation, income generation and vocational training
Maternal and child health programmes and projects
TB prevention through awareness raising, stigma reduction, infection control and improved vaccine coverage, including BCG for infants
TB detection through screening at all ANC clinics, contact tracing and referrals to TB clinics
Treatment adherence support through home-based DOT by CHWs and CVs
TB advocacy on availability of supplies and drugs at facilities and on increasing access to services for women with young children who find
it difficult to travel
Education programmes and projects
 TB prevention by teaching about TB, especially the signs and symptoms of TB and cough hygiene, through simple curricula in school at all
levels
TB detection by training teachers to screen for TB
Teachers and literacy class facilitators can refer those with signs and symptoms
Treatment adherence can be improved with teachers supporting children to take medication
Stigma can be reduced by discussing TB in class and increasing knowledge and awareness of the disease
Livelihood development programmes and projects
 Assist in prevention by including TB education during regular visits to families and also use supervisors of such programmes to raise
awareness
Increase detection by providing training to leaders and participants on signs and symptoms to enable community-based screening
Link village development committees and staff to health facilities to enable referrals of all those with presumptive TB
Improve treatment outcomes through DOT support at home by staff and volunteers
Provide extra support to TB patients in livelihood programmes, such as, special nutrition or additional stipends during their treatment period
NGO = non-governmental organisations; CSOs = civil society organisations; TB = tuberculosis; HIV = human immunodeficiency virus; BCG =
bacille Calmette-Guérin; ANC = antenatal care; DOT = directly observed therapy; CHW = community health worker; CV = community volunteer

requirements between different government departments

could be key areas for government to support the operations
of NGO and other CSOs. Reducing the complexity of
transactions and increasing the speed of facilitation are
other factors that improve the operating environment for
NGOs and other CSOs. NTPs or their equivalents have
the responsibility of creating enabling national or local
legal, policy and administrative environments to support
the effective engagement of NGOs and other CSOs in TB
activities. NGOs and other CSOs should also stimulate and
support the development of an enabling legal and policy
environment through constructive dialogue and engagement
with the NTPs or relevant legislative structures, with the
participation of the segments of society they represent. This
can be best done on a sustained, continuing basis if NGOs
and other CSOs form an umbrella NGO co-ordinating
body [NCB] to represent their best interests and to allow
systematic sharing and dissemination of lessons learnt by
Figure 51.1: The ENGAGE-TB approach
individual organisations. NTPs should support the formation
of such NGO coalitions and make time to meet with them in
order to understand their needs, constraints and the lessons
Enabling Environment learnt.
A mutually enabling legal and policy environment will
increase the engagement of NGOs and other CSOs in TB Guidelines and Tools
activities, particularly those who are newly engaged in TB The NTPs or their equivalents should work with NGOs
prevention and care. A facilitated registration process of and other CSOs in the NCB to prepare national operational
NGOs and other CSOs in accordance with local norms and guidelines and standard tools based on internationally
needs and ensuring greater integration of processes and recommended, evidence-based policies and guidelines.
700 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

They should be adaptable to the mission, mandate, resources Evaluation should be an ongoing process and include
and activities of the NGOs and other CSOs. If necessary, evaluation of both the activities [process evaluation] and
NTPs or their equivalents should facilitate clearances achievement of the objectives [impact evaluation] of the
and approvals of these instruments. Existing tools and action plan. Qualitative methods and periodic surveys could
instruments should be used when feasible and adapted to be used to provide an understanding of how well NGOs and
the needs of NGOs and other CSOs. other CSOs are supported and how they have engaged in
community-based TB activities. One of the main challenges
Task Identification of monitoring the implementation of community-based TB
activities has been the lack of standardised indicators. The
TB is linked to HIV infection and also to social determinants suggested core indicators to measure the implementation of
of health and non-communicable diseases such as poverty, community-based activities that need to be included in the
crowding, malnutrition, drug and alcohol use and diabetes TB monitoring system of all stakeholders and linked with
mellitus. Therefore, the opportunities, capacities and the national monitoring and evaluation system of the NTP
comparative advantages of the NGOs and other CSOs or its equivalent are shown in Tables 51.3 and 51.4.
working in such areas should be considered in determining Periodic evaluation provides a qualitative view of the
how best to address TB. Consideration must also be given progress of community-based TB activities [Table 51.5].
to the availability of resources and expertise and ensuring In particular, it helps to assess the contributions of NGOs
synergy. Community-based TB activities could range from and other CSOs to new case notifications and to treatment
prevention, detection, referral and treatment adherence outcomes. It also indicates whether NGO contributions
support to social and livelihood support, advocacy and are increasing or decreasing and reflects the quality of the
stigma reduction. To increase synergy and effectiveness, relations between NTPs and NGOs on the basis of variables
all the parties involved [NGOs and other CSOs, NTPs or such as the frequency of meetings, the quality of such
equivalents] must determine which tasks are to be carried meetings, the cooperation of people involved, the factors
out by each organisation. in success and the overall interest and drive of the NTP in
The NTPs or their equivalents should include the imple­ involving NGOs and other CSOs in TB activities.
mentation and scaling up of community-based TB activities
through the engagement of NGOs and other CSOs in their
Capacity-building
medium- and long-term national TB strategic plans and
budgets as well as in annual national and subnational Capacity-building is necessary for strengthening and sus­
operational plans. taining the engagement of NTPs, NGOs and other CSOs
in implementing and scaling-up community-based TB
Monitoring and Evaluation activities. It requires joint actions by the NTPs or their
equivalents and NGOs and other CSOs and will be of mutual
Regular monitoring and evaluation will help in asses­ benefit. Increasing financial resources is crucial for scaling-up
sing the quality, effectiveness, coverage and delivery of community-based TB activities and the effective engagement
community-based TB activities and the engagement of of NGOs and other CSOs. Innovative resource mobilisation
NGOs and other CSOs. It promotes a learning culture and from internal [e.g. national governments, private donors,
serves as a foundation to ensure continuous improvement philanthropists] and external sources [e.g., the Global
of programme implementation. NTPs or their equivalents Fund to Fight AIDS, TB and Malaria, bilateral donors and
should ensure that there is a single national monitoring charitable foundations] should be undertaken by NGOs and
and evaluation system that recognises the contribution and other CSOs and the NTPs.
engagement of NGOs and other CSOs. In some countries, NTPs may have little prior experience
Quarterly reviews of progress would help to uncover of engaging with NGOs and other CSOs. Their capacities
issues in implementation and enable mid-stream correction should also be built to cultivate and maintain effective
to plans and budgets and to overall strategy. The NTP relationships with the nongovernmental sector. Health sector
should help to smooth any operational difficulties that governmental staff might require training in community
NGOs and other CSOs may face and cannot independently mobilisation, including communication styles and methods.
resolve. Quarterly meetings to discuss the review findings Health systems should be strengthened further to meet
could be held at subnational or local levels so that there increased demand for services from affected communities.
is cross-fertilisation of learning between NGOs and other Capacity-building interventions should also support
CSOs and with the NTP. Annual meetings at the national sharing and transfer of knowledge, skills and resources
level should be organised by the NCB and a broad spectrum between international CSOs and national CSOs, with
of implementing NGOs and other CSOs invited to share both groups gaining from the process. Regular forums for
their findings and report progress. The resulting national sharing knowledge, experience and good practices should
report issued by the NTP should be shared widely with all be established. Mutual learning and support can increase
stakeholders within government, NGOs and other CSOs, confidence and capability to scale-up activities.
patients and community members, donors and the general The WHO’s End TB Strategy clearly recognises the
public. value and importance of engaging with NGOs and other
 Integrating Community-based Tuberculosis Activities into the Work of Non-governmental and other… 701

Table 51.3: Indicators for monitoring implementation. Indicator 1: referrals and new notifications
Definition Number of new TB patients [all forms] diagnosed and notified with TB who were referred by CHWs and CVs expressed as a
percentage of all new TB patients notified in the BMU during a specified period
Numerator Number of new TB patients [all forms] referred by CHWs or CVs to a health facility for diagnosis and notified in the BMU[s] in
a specified period
Denominator Number of new TB patients [all forms] notified in the BMU[s] in the same period
Purpose To measure the level of engagement of CHWs and CVs in increasing new notifications of TB. It can also indicate the
effectiveness of the referral system in ensuring the flow of persons with presumptive TB from community-based structures to
the BMU
Method Community health worker refers to a person with some formal education who is trained to contribute to community-based
health services including TB prevention and patient care and support. Community volunteer refers to a community member
who has been systematically sensitised about TB prevention and care, either through a short and specific training scheme
or through repeated contact with professional health workers. Both can be supported by NGOs, other CSOs and/or the
government. It is important to use the definitions in this guidance in order to standardise the documentation, monitoring and
evaluation of community-based activities. This will prevent confusion about what constitutes ‘community engagement’ in TB
prevention and care. Entries on TB treatment cards, the presumptive TB register [also known as ‘TB suspects’ register] kept
at facilities, the BMU TB register and the laboratory register should be modified to include ‘Referral by community health
workers and community volunteers’, to allow standardised recording of the community contribution to referral. The quarterly
report on TB registration in the BMU should also be adjusted to record this contribution. These forms and registers should be
adapted locally and used by CHWs and CVs to ensure that data are reported to the NTP’s monitoring and evaluation system.
Indirect sources of data include historical data analysis of overall TB notifications and comparisons of geographical areas
with and without community-based activities, time trends in TB notifications and comparisons of referrals in areas with and
without community-based activities
Periodicity Quarterly and annually
Strengths and This indicator will depend on the completeness and reliability of community-initiated referral data at clinic level, especially
limitations ensuring that referred persons with presumptive TB when confirmed with TB are tagged as having been referred by CHWs
and CVs, supported either by an NGO, other CSO or the NTP
Responsibility All stakeholders [NGOs, other CSOs or the NTP or its equivalent] implementing community-based TB activities will ensure
accurate data collection at community and facility levels. NTP and their equivalents will aggregate data at district, subnational
and national level, depending on the local context, to ensure that the information is included in the national TB monitoring
system
Measurement Presumptive TB patients should be recorded on the ‘persons with presumptive TB’ register [also known as ‘TB suspects’
tools register], which should specify who referred them. If confirmed with TB, they should then be recorded in the TB register
as having been referred by CHWs or CVs supported by either the NTP structure or NGOs and other CSOs. Data should
be aggregated quarterly for the quarterly report on TB registration and for the yearly report on programme management in
districts or BMUs
TB = tuberculosis; CHWs = community health workers; CVs = community volunteers; BMU = basic management unit; NGO = non-governmental
organisations; CSO = civil society organisations; NTP = National Tuberculosis Programme

Table 51.4: Indicators for monitoring implementation. Indicator 2: treatment success

Definition New TB patients [all forms] successfully treated [cured plus completed treatment] who received support for treatment
adherence from CHWs or CVs among all new TB patients [all forms] provided with treatment adherence support by
CHWs or CVs [number and percentage]
Numerator Number of new TB patients [all forms] successfully treated and provided with treatment adherence support by CHWs or
CVs in the BMU[s] in a specified period
Denominator Total number of new TB patients [all forms] given treatment adherence support by CHWs or CVs in the same period
Purpose To measure the scope and quality of implementation of community-based TB activities particularly relating to treatment
outcome of patients. It can also indicate the acceptability of CHWs or CVs to patients with TB as treatment adherence
support providers
Method Community health worker refers to a person with some formal education who is trained to contribute to community-
based health services including TB prevention and patient care and support. Community volunteer refers to a
community member who has been systematically sensitised about TB prevention and care, either through a short
and specific training scheme, or through repeated contact with professional health workers. Both can be supported by
NGOs, other CSOs and/or the government. It is important to use the definitions in this guidance in order to standardise
the documentation, monitoring and evaluation of community-based activities. This will prevent confusion about what
constitutes ‘community engagement’ in TB prevention and care
Treatment adherence includes all efforts and services provided by CHWs and CVs to TB patients receiving treatment to
help them complete their treatment successfully. These can include treatment observation, adherence counselling, pill
counting and other activities to monitor both the quantity and timing of the medication taken by a patient
Contd...
 702 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Contd...
Periodicity Quarterly and annually
Strengths and Monitors how well treatment adherence is supported by the community-based activities of NGOs, other CSOs or the
limitations government
Responsibility All NGOs, other CSOs and the NTP or its equivalent implementing community-based TB activities will ensure that data
are collected at the community and facility levels. NTP and their equivalents will ensure that data are aggregated at
district, subnational and national levels, depending on the local context, to ensure that the information is included in the
national TB monitoring system
Measurement tools TB register
TB = tuberculosis; CHWs = community health workers; CVs = community volunteers; NGO = non-governmental organisation; CSO = civil
society organisation; NTP = National Tuberculosis Programme

Table 51.5: Periodic evaluation

Indicators Existence of a NCB
 Trends in membership
Frequency of meetings
Spread to subnational levels
Coordination between levels
Mechanisms for transferring knowledge, skills and resources
Quality of interaction with the NTP at various levels
 Frequency of meetings
Quality of follow-up on agreed actions
Availability of TB diagnostic services and drugs
The relative contributions of NGOs and other CSOs and of the government to new case notifications and treatment success,
with trends in these variables over time
Challenges and hurdles faced by different actors in government and civil society as well as successes and new opportunities
Method Qualitative techniques should be used, including focus group discussions and key informant interviews. Appreciative inquiry
techniques will help improve the quality of the feedback. NTP managers and district and clinic staff should be interviewed
both singly and in groups. Similarly, representatives of NGOs and CBOs at national, district and local levels should be
interviewed singly and jointly. The main issues emerging from the interviews should be identified, shared and discussed
at a meeting between the staff of the NTP at various levels and representatives of NGOs and CSOs at various levels. The
emphasis should be on sharing and learning in order to understand and improve the programme, rather than on fault finding
or ‘finger pointing’
Periodicity Every 3-5 years
Strengths and Provides a periodic assessment of the contributions of NGOs and other CSOs as well as the quality of the relations with the
limitations NTPs. The value of such studies depends on the professionalism and ability of the evaluators and the biases they may bring
to the process
Responsibility All NGOs, other CSOs and the NTP or its equivalent implementing community-based TB activities must be willing to
participate and share their views. The primary responsibility for organising such evaluations is with the NTP. They could
coincide with the national TB reviews generally held every 5 years in each country
NCB = non-governmental oranisation co-ordinating body; NTP = National Tuberculosis Programme; TB = tuberculosis; CSO = civil society
organisations; NGO = non-governmental oranisation

civil society organisations in order to achieve the goal of out and engage such organisations and encourage them to
ending the global TB epidemic. One of the four principles integrate community-based TB activities into their work.
of the WHO strategy is “strong coalition with CSOs and As NGOs and other CSOs start integrating TB services
communities.” The engagement of communities and CSOs into their work with communities, more and more of
is also one of the key components of the implementation those previously unreached will be reached and will gain
strategy (8). It is clear that many marginalised and vulnerable access to diagnosis, treatment and care. Community and
groups are unable to access the formal health system and civil society engagement must be seen as a necessary and
seek diagnosis, treatment and care. For these segments vital component of NTP strategies to secure the vision of a
of society, it will be necessary to go outside the health world free of TB with zero deaths, disease and suffering due
facilities to reach them in their own homesteads, within to TB.
their own community settings. NGOs and other CSOs are
able to do so effectively and already reach them with other REFERENCES
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The remaining challenge is for NTPs to more actively seek TB/2018.20. Geneva: World Health Organization; 2018.
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2. Getahun H, Raviglione M. Transforming the global tuberculosis other CSOs – operational guidance. Geneva: World Health
response through effective engagement of civil society organiza­ Organization; 2012.
tions: the role of the World Health Organization. Bull World 6. The Global Fund to Fight AIDS, Tuberculosis and Malaria.
Health Organ 2011;89:616-8. Community systems strengthening framework. Geneva; 2010.
3. Jareg P, Kaseje DC. Growth of civil society in developing 7. World Health Organization. ENGAGE-TB: integrating
countries: implications for health. Lancet 1998;351:819-22 community-based TB activities into the work of NGOs and
4. Sinanovic E, Floyd K, Dudley L, Azevedo V, Grant R, Maher D. other CSOs – implementation manual. Geneva: World Health
Cost and cost-effectiveness of community-based care for Organization; 2013.
tuberculosis in Cape Town, South Africa. Int J Tuberc Lung Dis 8. World Health Organization. Global strategy and targets for
2003;7:S56-62. tuberculosis prevention, care and control after 2015. World Health
5. World Health Organization. ENGAGE-TB: integrating Assembly resolution 67. Geneva: World Health Organization;
community-based TB activities into the work of NGOs and 2014.
 52
WHO’s New End TB Strategy
Mukund Uplekar, Diana Weil

INTRODUCTION A total of 139,114 people were started on treatment for drug-

resistant TB, only 29.9% of the estimated incidence; treatment
A Persisting Challenge success remains low, at 55% globally. Making large inroads
According to the 2018 Global TB Report of the World into these gaps requires progress in a particular subset of
Health Organization [WHO] (1), tuberculosis [TB] remains high TB burden countries. Ten countries accounted for 80%
a persistent development challenge. TB is one of the leading of the total gap between TB incidence and reported cases;
causes of death worldwide and the leading cause from a the top three were India [26%], Indonesia [11%] and Nigeria
single infectious agent. In 2017, there were an estimated [9%]. Ten countries accounted for 75% of the incidence-
1.3 million TB deaths among HIV-negative people and an treatment enrolment gap for MDR-TB/RR-TB; India and
additional 300,000 deaths among HIV-positive people. An China accounted for 39% of the global gap. Most of the
estimated 10 million people fell ill with TB in 2017: 90% were gaps related to HIV-associated TB were in the WHO African
adults, 58% were male, 9% were people living with human Region. TB preventive treatment is expanding, especially
immunodeficiency virus [HIV] [74% in Africa] and two- in the two priority risk groups of people living with HIV
thirds were in eight countries: India, China, Indonesia, the and children under 5. However, most people eligible for TB
Philippines, Pakistan, Nigeria, Bangladesh and South Africa. preventive treatment are not accessing it (1).
Drug-resistant TB [DR-TB] is a continuing threat. In 2017, Financing for TB care and prevention has been increasing
there were 558,000 new cases with resistance to rifampicin for more than 10 years, but funding gaps still exist [US$
[RR-TB], the most effective first-line drug, of which 82% 2.3 billion in 2017]. Total health spending also falls short of
had multidrug-resistant TB [MDR-TB]. Almost half [47%] of the resources needed to achieve universal health coverage.
these cases were in India, China and the Russian Federation. Closing these gaps requires more resources from both
Globally, the TB mortality rate is falling at about 3% per year. domestic sources [especially in middle-income countries] and
TB incidence is falling at about 2% per year and 16% of TB international donors [especially in low-income countries].
cases die from the disease. Most deaths from TB could be Broader influences on the TB epidemic include levels of
prevented with early diagnosis and appropriate treatment. poverty, HIV infection, undernutrition and smoking. Most
Millions of people are diagnosed and successfully treated high TB burden countries have major challenges ahead to reach
for TB each year, averting millions of deaths [53 million SDG targets related to these and other determinants (1).
2000-2016], but there are still large gaps in detection and The pipelines for new diagnostics, drugs, treatment
treatment (1). regimens and vaccines are slowly progressing. Increased
In 2017, 6.4 million new cases of TB were reported, investment in research and development is needed for
equivalent to 64% of the estimated incidence of 10 million; there to be any chance of achieving the technological
the latest treatment outcome data show a global treatment breakthroughs needed by 2025. The WHO Global Ministerial
success rate of 82%, in 2016 (1). There were 464,633 reported Conference on ending TB in the SDG era in November 2017
cases of HIV-positive TB [46% of the estimated incidence], and the first UN General Assembly high-level meeting on
of whom 84% were on antiretroviral therapy [ART]. TB in 2018 have provided historic opportunities to galvanize
 WHO’s New End TB Strategy 705

Table 52.1: The End TB Strategy at a glance

Vision A world free of TB
– zero deaths, disease and suffering due to TB
Goal End the global TB epidemic
Milestones for 2025 75% reduction in TB deaths [compared with 2015]
50% reduction in TB incidence rate
[less than 55 TB cases per 100,000 population]
No affected families facing catastrophic costs due to TB
Targets for 2035 95% reduction in TB deaths [compared with 2015]
90% reduction in TB incidence rate
[less than 10 TB cases per 100,000 population]
No affected families facing catastrophic costs due to TB
Principles
1. Government stewardship and accountability, with monitoring and evaluation
2. Strong coalition with civil society organisations and communities
3. Protection and promotion of human rights, ethics and equity
4. Adaptation of the strategy and targets at country level, with global collaboration
Pillars and components
1. Integrated, patient-centred care and prevention
A. Early diagnosis of TB including universal drug-susceptibility testing; and systematic screening of contacts and high-risk groups
B. Treatment of all people with TB including drug-resistant TB; and patient support
C. Collaborative TB/HIV activities; and management of co-morbidities
D. Preventive treatment of persons at high-risk; and vaccination against TB
2. Bold policies and supportive systems
A. Political commitment with adequate resources for TB care and prevention
B. Engagement of communities, civil society organisations, and public and private care providers
C. Universal health coverage policy, and regulatory frameworks for case notification, vital registration, quality and rational use of
medicines, and infection control
D. Social protection, poverty alleviation and actions on other determinants of TB
3. Intensified research and innovation
A. Discovery, development and rapid uptake of new tools, interventions and strategies
B. Research to optimise implementation and impact, and promote innovations
TB = tuberculosis; HIV = human immunodeficiency virus

the political commitment needed to step up the battle against and 2030. Table 52.2 presents key global indicators, miles­
TB and put the world and individual countries on the path tones and targets for the new strategy (5).
to ending the TB epidemic (2,3). Achievements with existing tools complemented by
On 19 May 2014, the 67th World Health Assembly Universal Health Coverage [UHC] and social protection
adopted the “Global strategy and targets for TB prevention, may not be sufficient to obtain the rate of decline required
care and control after 2015” labelled subsequently as the to achieve the 2035 targets. In particular, a new vaccine that
“End TB Strategy” (4). Table 52.1 presents the “End TB is effective pre- and post-exposure and better diagnostics
Strategy” at a glance and the strategy is elaborated below. as well as safer and easier treatment for TB and LTBI will
be needed. For such new tools to be available by 2025,
WHO’S END TB STRATEGY greatly enhanced and immediate investments in research
and development will be required. Figure 52.1 shows the
Vision, Goal, Milestones and Targets projected acceleration of the decline in global TB incidence
The vision for the End TB Strategy is “a world free of TB”, rates with optimisation of current tools combined with
also expressed as “zero deaths, disease and suffering due progress towards UHC and social protection from 2015, and
to TB”. The goal is to end the global TB epidemic by 2035. the additional impact of new tools by 2025.
Ending the TB epidemic implies bringing the levels of TB in
the whole world down to those already attained by many rich The Cross-cutting Principles of the Strategy
countries: less than 10 new TB cases per 100,000 population Government Stewardship and Accountability with
per year and TB deaths reduced by 95%. An additional target
Monitoring and Evaluation
is that by 2020, no TB-affected person or family should face
catastrophic costs due to TB care. Milestones that need to The success of the End TB Strategy will depend on effective
be reached before 2035 are also proposed for 2020, 2025, enhancement of the stewardship role of governments in
 706 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 52.2: Key indicators, milestones and targets for the post-2015 Global TB Strategy
Milestones Targets
Indicators with baseline values for 2015 2020 2025 2030 2035
Percentage reduction in deaths due to TB 35% 75% 90% 95%
[projected 2015 baseline: 1.3 million deaths]
Percentage and absolute reduction in TB 20% 50%  80% 90%
incidence rate [<85/100,000] [<55/100,000] [<20/100,000] [<10/100,000]
[projected 2015 baseline 110/100,000]
Percentage of affected families facing Zero Zero Zero Zero
catastrophic costs due to TB
[projected 2015 baseline: not yet available]
TB = tuberculosis

Figure 52.1: Projected acceleration in the decline of global TB incidence rates to target levels
TB = tuberculosis

engaging all stakeholders. To ensure accountability, regular Protection and Promotion of Human Rights,
monitoring and evaluation needs to be expanded to set and Ethics and Equity
pursue ambitious national targets and indicators. Table 52.3
presents an illustrative list of key global indicators that The End TB Strategy explicitly addresses human rights,
should be considered and adapted for national use. ethics and equity (6). This strategy is built on a rights-based
approach that ensures protection of human rights and
promotion of rights-enhancing policies and interventions.
Strong Coalition with Civil Society and
These include engagement of affected persons and com­
Communities
munities in facilitating implementation of all pillars and
The affected communities must also be an integral part of components of the draft strategy with special attention to key
the solution. Community representatives and civil society affected populations. TB care and prevention demand clarity
must be enabled to engage actively in expressing needs, on ethical values and sometimes pose ethical dilemmas
programme planning and design, service delivery, patient which need to be addressed in design and implementation of
support and monitoring and evaluation, and advocacy. services. The strategy promotes equity through identification
A national coalition can also help drive greater action on of the risks, needs and demands of those affected, to enable
the determinants of the TB epidemic. equal opportunities to prevent disease transmission, equal
 WHO’s New End TB Strategy 707

Table 52.3: Illustrative list of key indicators for the draft post-2015 Global TB Strategy
Component Illustrative indicators
Pillar one: Integrated, patient-centred care and prevention
A. Early diagnosis Percentage of people with suspected TB tested using WHO recommended rapid diagnostics
Percentage of all TB patients for whom results of drug susceptibility testing were available
Percentage of eligible index cases of TB for which contact investigations were undertaken
B. Treatment TB treatment success rate
Percentage of patients with drug-resistant TB enrolled on second-line treatment
C. TB/HIV and co-morbidities Percentage of TB patients screened for HIV
Percentage of HIV-positive TB patients on antiretroviral therapy
D. Preventive treatment Percentage of eligible people living with HIV and children aged under-five who are contacts of TB patients
being treated for latent TB infection
Pillar two: Bold policies and supportive systems
A. Government commitment Percentage of annual budget defined in TB national strategic plans that is funded
B. Engagement of communities Percentage of diagnosed TB cases that were notified
and providers
C. Universal health coverage Percentage of population without catastrophic health expenditures
and regulatory frameworks Percentage of countries with a certified TB surveillance system
D. Social protection, social Percentage of affected families facing catastrophic costs due to TB
determinants Percentage of population without undernutrition
Pillar three: Intensified research and innovation
A. Discovery Percentage of desirable number of candidates in the pipelines of new diagnostics, drugs and vaccines for
TB
B. Implementation Percentage of countries introducing and scaling-up new diagnostics, drugs or vaccines
TB = tuberculosis; HIV = human immunodeficiency virus; WHO = World Health Organization

access to diagnosis and treatment services, and equal access quality, integrated, patient-centred TB care and prevention
to means to prevent associated social and economic impacts. across the health system.
Component 1A: Early diagnosis of TB including universal
Adaptation of the Strategy at Country Level, drug susceptibility testing, and systematic screening of
with Global Collaboration contacts and high-risk groups Ensuring universal access
The End TB Strategy must be adapted to diverse country to early and accurate diagnosis of TB and drug-resistance
settings and epidemics and requires a comprehensive will require strengthening and expansion of a network
national strategic plan. Prioritisation of interventions should of diagnostic facilities enabling easy access to new rapid
be undertaken based on local needs and capacities. This molecular tests and systematic screening in selected high-
includes mapping of people at a greater risk, understanding risk groups. Further, additional screening tools such as a
of socioeconomic contexts of vulnerable populations, chest radiograph may facilitate referral for diagnosis of
and understanding the health system context including bacteriologically negative TB, extra-pulmonary TB [EPTB]
underserved areas. Ending the global epidemic requires and TB in children.
recognising its global reach and enabling close collaboration The burden of undetected TB is large in many settings,
among countries, including to address cross-border spread especially in high-risk groups. Mapping of high-risk groups
and the special needs of migrants. and carefully planned systematic screening for active
disease among them may improve early case detection (7).
Pillars and Components Contacts of people with TB, especially children aged five
years or less, people living with HIV [PLHIV], and workers
Pillar One: Integrated, Patient-centred Care exposed to silica dust should always be screened for active
and Prevention TB (8). Other risk-groups should be considered for screening
based on assessment of epidemiology, resources, system
Pillar one comprises patient-centred interventions required
capacity and feasibility of approaches.
for TB care and prevention. The national TB programme,
or equivalent, needs to engage and coordinate closely with Component 1B: Treatment of all people with TB including
other public health programmes, social support programmes, drug-resistant TB, and patient support New policies
public and private health care providers, non-governmental incorporating molecular diagnostics will help to strengthen
and civil society organisations, communities and patient management of smear-negative pulmonary TB and EPTB as
associations in order to help ensure provision of high- well as TB among children (9). Globally, about 4% of new
708 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

TB patients and about 20% of patients receiving retreatment TB and HIV care should be further integrated with services
have MDR-TB. Providing universal access to services for for maternal and child health and prevention of mother-to-
DR-TB will require a rapid scale up of diagnosis and treat­ child transmission of HIV in high-burden settings (13).
ment services. New models of delivering patient-centred Several non-communicable diseases and other health
treatment will need to be devised. Ambulatory, community- conditions including diabetes mellitus, undernutrition,
based services should be given preference over hospitalisa­ silicosis, as well as smoking, harmful alcohol and drug use,
tion, which should be limited to severe cases (10). and a range of immune-compromising disorders and treat­
The proportion of DR-TB patients successfully completing ments are risk factors for TB. Presence of co-morbidities may
treatment remains far too low on average due to a range of complicate TB management and result in poor treatment out­
factors. New safer, affordable and more effective medicines comes. Conversely, TB may worsen or complicate manage­
allowing treatment regimens that are shorter in duration ment of other diseases. Therefore, as a part of basic and
and easier to administer are key to improving treatment coordinated clinical management, people diagnosed with
out­c omes. Strengthened pharmacovigilance capacity is TB should be routinely assessed for relevant comorbidities,
needed. Interventions to improve quality of life for patients based on local epidemiology (14).
while enabling adherence to treatment include management
Component 1D: Preventive treatment of persons at high-
of adverse drug reactions and events, access to comprehen­
risk; and vaccination against TB LTBI is diagnosed by
sive palliative and end-of-life care, measures to alleviate
a tuberculin skin test [TST] or interferon-γ release assay
stigmatisation and discrimination, and social support and
[IGRA]. However, these tests cannot predict which persons
protection. Strong infection control practices need to be in
will develop active TB disease. Isoniazid preventive therapy
place in all health services providing TB care (11).
is recommended for the treatment of LTBI among PLHIV,
TB is an important cause of morbidity and mortality
close contacts of patients with TB and miners exposed to
among children. In countries with a high prevalence of
silica dust. Management of LTBI in people with a high-risk
TB, women of child-bearing age also carry a heavy burden
of developing active TB is an essential component of TB
of the disease. Maternal TB associated with HIV is a risk
elimination, particularly in low TB-incidence countries (15).
factor for transmission of TB to the infant and is associated
The bacille Calmette-Guerin [BCG] vaccination prevents
with premature delivery, low birth-weight of neonates,
disseminated disease including TB, meningitis and miliary
and higher maternal and infant mortality. NTPs need to
TB, which are associated with high mortality in infants and
address systematically the challenges of caring for children
young children. However, its preventive efficacy against
with TB, and child contacts of adult TB patients. These may
pulmonary TB, which varies among populations, is only
include, for instance, developing and using child-friendly
about 50%. BCG vaccination soon after birth should continue
formulation of medicines, and family-centred approaches
to be given to all infants except for those persons with HIV
to improve adherence. Proper management of TB among
living in high TB prevalence settings.
children requires development of affordable and sensitive
diagnostic tests that are not based on sputum specimens. TB
Pillar Two: Bold Policies and Supportive Systems
care should be integrated within community based maternal
and child health services (12). The second pillar encompasses strategic actions that will
Patient-centred care and support, sensitive and responsive enable care delivery as well as wider action to prevent
to patients’ educational, emotional and material needs, TB through addressing social determinants. These include
is fundamental to the End TB Strategy. Treatment and actions by and beyond NTPs, from across ministries and
support must also extend beyond cure to address any departments. This will require a well-resourced, organised
sequelae associated with TB. Examples of patient-centred and coordinated health system response backed up by
support include providing treatment partners trained by supportive health policies. In parallel, swift progress is
health services and acceptable to the patient, access to social essential to achieve UHC and social protection while also
protection, use of eHealth technology, and patient peer strengthening regulatory systems. NTPs, their partners and
groups to enable exchange information and experience. those overseeing the programmes need to engage actively
in the setting of broader social and economic development
Component 1C: Collaborative TB/HIV activities; and
agenda that reduce poverty and vulnerability to disease.
manage­ment of co-morbidities HIV-associated TB accounts
Eliciting actions from across diverse ministries will require
for about one quarter of all TB deaths and a quarter of all
commitment and stewardship from the highest levels of
deaths due to acquired immunodeficiency syndrome [AIDS].
government.
The vast majority of these cases and deaths are in the African
and South-East Asia regions. All TB patients living with HIV Component 2A: Political commitment with adequate
should receive ART. Integrated TB and HIV service delivery resources for TB care and prevention Scaling up and
has been shown to increase the likelihood that a TB patient sustaining interventions for TB care and prevention will
will receive ART, shorten the time to treatment initiation, require high-level political commitment along with adequate
and reduce mortality by almost 40%. Reducing delays in financial and human resources for central coordination
diagnosis, using new diagnostic tools and instituting prompt and capacity across the system. This must lead to, as a first
treatment can improve health outcomes among PLHIV. step, development of a national strategic plan embedded in
 WHO’s New End TB Strategy 709

a national health sector plan. A national TB strategic plan burden of TB do not have essential vital registration systems
should be ambitious and comprehensive. Coordinated efforts and the quality of information about the number of deaths
are required to mobilise additional resources to fund truly due to TB is often inadequate. Efforts underway to broadly
ambitious national strategic plans with a progressive increase strengthen vital registration systems in low-income countries
in domestic funding. need to be supported (20).
Poor quality TB medicines put patients at great risk.
Component 2B: Engagement of communities, civil society
Irrational prescription of treatment regimens leads to poor
organisations, and all public and private care providers
treatment outcomes and may cause drug resistance. Use of
Informed communities can help identify people with
inappropriate diagnostics, such as, serological tests leads to
suspected TB, refer them for diagnosis, provide support
inaccurate diagnosis. Regulation and adequate resources for
during treatment and help to alleviate stigmatisation and
enforcement are required for the registration, importation
discrimination. Civil society organisations may have the key
and manufacturing of medical products. Appropriate
competencies required to reach out to vulnerable groups,
regulation is also required to ensure effective infection control
mobilise communities, channel information, and help create
demand for care. NTPs should engage with civil society in health care services and other settings where the risk of
organisations and communities in policy development disease transmission is high (21). Calls for coherent national
and planning, in service delivery, as well as in programme prevention of antimicrobial resistance can further bolster
monitoring and evaluation (16). support for such measures.
In many countries, TB care is delivered by diverse public, Component 2D: Social protection, poverty alleviation and
voluntary, private and corporate care providers. The private actions on other determinants of TB A large proportion
providers include pharmacists, formal and informal practi­ of households affected by TB face a catastrophic economic
tioners, non-governmental and faith-based organisations burden related to the direct and indirect costs of illness and
as well as private and corporate hospitals. Several public health care. Its negative consequences often extend to the
sector providers outside the purview of NTPs also provide family of the persons ill with TB. Even when TB diagnosis
TB care. These include large public hospitals, social security and treatment is offered free of charge, social protection
organisations, prison health services and military health measures are needed to alleviate the burden of income loss
services. Leaving a large proportion of care providers out of and non-medical costs of seeking and staying in care.
an organised response to TB has contributed to stagnating case Social protection should cover the needs associated
notification, inappropriate TB management, and irrational with TB through mechanisms such as: [i] schemes for
use of TB medicines leading to the spread of DR-TB. NTPs compensating the financial burden associated with illness
must scale up country-specific public–private mix appro­ such as sickness insurance, disability pension, social
aches already working well in many countries. To this effect, welfare payments, other cash transfers, vouchers or
close collaboration with health professionals’ associations food packages; [ii] legislation to protect people with TB
will be essential (17). The International Standards for TB from discrimination such as expulsion from workplaces,
Care, other tools and guidelines developed by WHO as educational or health institutions, transport systems or
well as modern information and communication technology housing; and [iii] instruments to protect and promote human
platforms can help increase effective involvement (18). rights, including addressing stigma and discrimination,
Component 2C: Universal health coverage policy, and with special attention to gender, ethnicity, and protection
regulatory frameworks for case notification, vital registra­ of vulnerable groups. These instruments should include
tion, quality and rational use of medicines, and infection capacity-building for affected communities to be able to
control UHC is defined as “the situation where all people express their needs and protect their rights, and to call to
are able to use the quality health services that they need and account those who impinge on human rights, as well as those
do not suffer financial hardship paying for them”. UHC is who are responsible for protecting those rights.
achieved through adequate, fair and sustainable prepayment Actions on the determinants of ill health through
financing of health care with full geographical coverage, approaches that ensure “health-in-all-policies” will
combined with effective service quality assurance and immensely benefit TB care and prevention. Such actions
monitoring and evaluation. For TB specifically, this implies include, for example: [i] pursuing overarching poverty
expanding: [i] the array of quality health services provided in reduction strategies and expanding social protection;
line with this strategy; [ii] financing for all direct and indirect [ii] improving living and working conditions and reducing
health care costs associated with diagnosis, treatment and food insecurity; [iii] addressing the health issues of migrants
prevention; and [iii] access for all populations, especially and strengthening cross-border collaboration; [iv] involving
vulnerable groups (19). diverse stakeholders, including TB affected communities,
National policy on UHC and essential regulatory frame­ in mapping the likely local social determinants of TB; and
works are powerful levers for TB response. A comprehensive [v] preventing direct risk factors for TB, including smoking
and effectively enforced infectious disease legislation, that and harmful use of alcohol and drugs, and promoting healthy
includes compulsory notification of TB cases by all health diets, as well as proper clinical care for co-morbidities such
care providers, is essential. Most countries with a high as diabetes mellitus.
710 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Pillar Three: Intensified Research and Innovation a wide range of stakeholders, including communities most
Ending the TB epidemic will require substantial investments affected by TB, in order to consider, adopt and prepare for
in the development of novel diagnostic, treatment and adaptation of the strategy. The scope of existing TB advisory
prevention tools, and for ensuring their accessibility and panels will need to be expanded to include a wider range of
optimal uptake in countries alongside better and wider capacities from civil society and from the fields of finance
use of existing technologies. This will be possible only and development policy, human rights, social protection,
through increased investments and effective engagement regulation, health technology assessment, the social sciences,
of the broader National Health Research Institutions, TB and communications. National vision statements extending
Programmes, civil society, funders and policy makers. An to 2030 or 2035 should be devised and medium-term plans
International Roadmap for TB Research has outlined priority for the next five to ten years should be drafted. Proper
areas for future scientific investment across the research mapping should provide important information such as
continuum (21). population groups most affected by the disease and most
at risk of developing it; age and sex characteristics and
Component 3A: Discovery, development and rapid uptake trends; prevalence of different forms of TB and dominant
of new tools, interventions and strategies Since 2007, comorbidities, important urban–rural variations; distribution
several new tests and diagnostic approaches have been and types of care providers; health financing, access and
endorsed by WHO. However, an accurate and rapid point- social protection schemes and their current and their
of-care test that is usable in field conditions is still missing. potential implications for TB care and prevention. Where
This requires greater investments in biomarker research, data is lacking, expert and stakeholder consultations and
and overcoming difficulties in transforming sophisticated assessments to estimate burdens and system capacities will
laboratory technologies into robust, accurate and affordable be needed. WHO is currently in the process of developing
point-of-care platforms. guidance for countries to help implement the End TB
The pipeline of new drugs has expanded substantially Strategy.
over the last decade. There are nearly a dozen new or repur­
posed TB drugs under clinical investigation. As mentioned MEASURING PROGRESS AND IMPACT
above, two new TB drugs have been introduced for the
treatment of MDR-TB (22). Novel regimens, including new Target setting and monitoring of progress across the com­
or repurposed medicines and adjuvant and supportive ponents of the strategy are essential. Monitoring should
therapies, are being investigated. be done routinely using standardised methods based on
Globally, more than 2000 million people are estimated data with documented quality (20). Table 52.3 provides
to be infected with Mycobacterium tuberculosis [Mtb], but examples of the indicators that can be considered. Given
only 5% to 15% of those infected will develop active disease the overarching targets of the End TB Strategy, particular
during their lifetime. Ending the TB epidemic will require attention to measurement of trends in mortality and
eliminating this pool of infection. Research is needed to incidence is required. WHO provides a number of tools to
develop new diagnostic tests to identify people with LTBI assist in improving routine TB reporting, conducting TB
who are likely to develop TB disease. Further, treatment prevalence surveys and utilising vital registration data,
strategies that could be safely used to prevent development assessing under-reporting of cases and estimating inci­
of TB in latently infected persons will also need to be dence. Global financing and technical partners are keen to
identified. Moreover, research will be required to investigate help improve TB monitoring, evaluation and impact
the impact and safety of targeted and mass preventive measure­ment (24-27). Such data will be critical to measure
strategies (21). progress and drive commitment to move faster and with
Currently, there are 12 vaccine candidates in clinical increased impact.
trials (23). A post-exposure vaccine that prevents the
disease in latently infected individuals will be essential to ACKNOWLEDGEMENT
eliminating TB in the foreseeable future. This chapter is an abridged updated version of the WHO
Component 3B: Research to optimise implementation and document on “Global strategy and targets for tuberculosis
impact; and promote innovations Research can identify prevention, care and control after 2015” prepared by the
bottlenecks and help devise better policies and strengthen Global TB Programme.
health systems and service delivery. Research is also critical
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 53
The Revised National Tuberculosis
Control Programme
Jagdish Prasad, Sunil D Khaparde, KS Sachdeva

INTRODUCTION In 1946, the Bhore Committee estimated that about

2.5 million patients required treatment in the country while
Tuberculosis [TB] remains a serious public health problem
only 6000 beds were available (8). Work with Bacillus
in India, accounting for nearly one-fourth of the global
Calmette-Guérin [BCG] started in India as a pilot project
burden (1). India has more people with active TB than any
in two centres in 1948 and in 1951 mass BCG vaccination
other country in the world. Each year, in India an estimated
campaigns were introduced.
2.74 million people develops TB disease and approximately
In the 1950s and 1960s, research at the Tuberculosis
410,000 people die from TB (1).
Research Centre [TRC] in Chennai demonstrated that
Most TB patients are in the economically productive age
domiciliary treatment was as effective as and less costly than
group. A study of mortality in India has estimated that TB is
in-patient treatment for TB (9). Additionally, use of directly
among the top 4 causes of death between the ages of 30 and 69,
observed treatment [DOT], in which patients are observed
with an impact similar to cancer (2). The socio-economic
taking their medications, was shown to be essential (10). These
impact of TB in India is devastating and India continues
seminal findings led to a radical change in thinking regarding
to incur huge costs due to TB amounting to nearly US$
TB care worldwide (11). Indian researchers also pioneered
350 billion between 2006 and 2015 (3). Studies indicate that
the efficacy of intermittent treatment where medications
around 10% of children have to leave school as a result of
were successfully given 2-3 times a week (12). Improved
their parents’ TB (4).
case-finding using microscopy among patients attending
Ironically, TB persists as a major health problem in spite
health services was also demonstrated in India (13,14).
of the fact that many of the basic scientific precepts of the
In 1962, these and other path-breaking sociological and
World Health Organization [WHO] recommended DOTS
epidemiological studies led to the establishment of the
programme were discovered in India.
National Tuberculosis Control Programme [NTP] in 1962.
The NTP was implemented nationwide in a phased manner
HISTORY OF TUBERCULOSIS CONTROL IN INDIA through the establishment of District TB Centres, urban chest
TB control in India has a long and illustrious past (5-7). In clinics and in-patient beds. Short-course chemotherapy [SCC]
the early 1900s, TB was recognised as a serious problem and was introduced in 1985. Despite this intervention, ensuring
the first open air sanitarium for treatment and isolation of TB drug supply and adherence continued to be a problem and
patients was founded in 1906 in Tiluania, near Ajmer. The programme goals to control TB were not achieved.
main line of treatment relied on good food, open air and dry In 1992, a comprehensive joint review of the TB
climate. Without effective treatment, progress in TB control programme in India by members of several organizations
was minimal and despite an active sanatorium movement, including the Government of India, WHO and Swedish
millions of TB patients remained largely untreated. By 1920, International Development Agency found that less than
public opinion gained a momentum for effective measures half the patients with TB received an accurate diagnosis
for control of TB. India became a member of the International and that less than half of those were effectively treated (15).
Union against Tuberculosis [IUAT] in 1929 and the anti-TB Importantly, the NTP had not made significant epidemio­
movement grew with support from the government. logical impact on the prevalence of TB. Further, the human
 The Revised National Tuberculosis Control Programme 713

immunodeficiency virus [HIV]-acquired immunodeficiency by 2025, five years ahead of the Global Timelines. Goal of
syndrome [AIDS] epidemic and the spread of multi-drug NSP is to achieve a rapid decline in burden of TB, morbidity
resistance tuberculosis [MDR-TB] were threatening to and mortality while working towards ending TB in India by
worsen the situation. In order to overcome these limitations, 2025. In the 12th plan period, RNTCP achieved the annual
in 1993 the Government of India [GOI] decided to reenergise decline in new incident TB cases of around 1%-2%. Over the
the NTP, with assistance from international agencies. The period of the NSP 2017-25, RNTCP aims to accelerate the
Revised National TB Control Programme [RNTCP] thus decline by 10%-12% annually to achieve the goal by 2025.
formulated, adopted the internationally recommended DOTS
strategy, as the most systematic and cost-effective approach STRUCTURE OF REVISED NATIONAL
for TB control in India. TUBERCULOSIS CONTROL PROGRAMME
The RNTCP began in October 1993 as a pilot project.
Large-scale implementation of the RNTCP began in 1997 The structure of RNTCP comprises of five levels: National
[Figure 53.1]. The systems were further strengthened and level, State level, District level, Sub-district level and
the programme was scaled up for national coverage in Peripheral health institution level [Figure 53.3].
2006. The RNTCP encompasses the five principles of the
DOTS strategy. These five principles are: [i] political and National Level
administrative commitment; [ii] good quality diagnosis by At the central level, the RNTCP is managed by the Central
sputum smear microscopy; [iii] uninterrupted supply of TB Division [CTD] of the under the Ministry of Health and
good quality drugs; [iv] directly observed treatment; and Family Welfare [MoHFW]. The respective Joint Secretary
[v] systematic monitoring and accountability. The key of the MoHFW looks after the financial and administrative
objectives of the RNTCP were to achieve and maintain at aspects of the programme A national programme manager—
least 85% cure rate among the new smear-positive cases Deputy Director General-TB [DDG-TB], is in-charge of
initiated on treatment, and thereafter a case detection rate RNTCP. The CTD is assisted by 6 national level institutes,
of at least 70% of such cases. The RNTCP was built on the namely the NTI in Bengaluru, the NIRT in Chennai, the
infrastructure and systems built through the NTP. National Institute of TB and Respiratory Diseases [NITRD]
The programme has made rapid strides ever since its in New Delhi, National Japanese Leprosy Mission for Asia
implementation and has consistently been achieving global [JALMA] Institute of Leprosy and other Mycobacterial
benchmarks of case detection and treatment success rates Diseases in Agra, Bhopal Memorial Hospital and Research
since 2007 [Figure 53.2]. Since inception of RNTCP in 1997 Centre [BMHRC], Bhopal and Regional Medical Research
and up to December 2017, more than 20 million patients were Centre [RMRC], Bhubaneshwar.
initiated on treatment and about 3.5 million additional lives
have been saved.
State Level
RNTCP has achieved Millennium Development Goals
for TB and has prepared the National Strategic Plan [NSP] At the State level, the State Tuberculosis Officer [STO] is
[2017-25] to achieve Sustainable Development Goals for TB responsible for the planning, training, supervising and

Figure 53.1: Revised National Tuberculosis Control Programme geographical coverage: India
 714 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 53.2: Trend in new smear-positive case detection and treatment outcome: India
S+ve = smear-positive; CDR = case-detection rate

Figure 53.3: Organisational structure of Revised National Tuberculosis Control Programme

TB = tuberculosis; DGHS = Directorate General of Health Services; MoHFW = Ministry of Health and Family Welfare; NTI = National Tuberculosis
Institute, Bengaluru; NIRT = National Institute for Research in Tuberculosis, Chennai; NITRD = National Institute of TB Respiratory Diseases,
New Delhi; JALMA = National Japanese Leprosy Mission for Asia Institute of Leprosy and other Mycobacterial Diseases, Agra; TWG = Technical
Working Group; HIV = human immunodeficiency virus; STO = State TB Officer; MO = Medical Officer; DEO = Data Entry Operator; IEC =
Information, Education and Communication; DTO = District TB Officer; lakh = 100,000; MOTC = Medical Officer TB Control; STS = Senior
Treatment Supervisor; STLS = Senior Tuberculosis Laboratory Supervisor; LT = Laboratory Technician.

monitoring of the programme in their respective states as per State Government, whilst implementing the technical policies
the guidelines of the State Health Society and CTD. The STO, and guidelines issued by the CTD. The State TB Cells [STC]
based at the State TB Cell, is answerable to their respective have been provided with equipment, infrastructure and
 The Revised National Tuberculosis Control Programme 715

RNTCP contractual staff to carry out its functions. In most health services. In this regard, they are supervised by the
of the larger states, a State TB Training and Demonstration TU contractual paramedical staff [STS and STLS].
Centre [STDC] support’s the State TB Cell. The STDC has
3 units: a training unit, supervision and monitoring unit CASE FINDING AND DIAGNOSTICS
and an Intermediate Reference Laboratory [IRL]. There is
State Drug Store [SDS] for the effective management of Once a patient is diagnosed and appropriately treated
anti-TB drug logistics. One SDS per 50 million populations they rapidly become non-infectious. Thus, prompt case
is established in all larger states. finding and treatment is the principal means of controlling
transmission and reducing TB incidence.
Direct sputum smear microscopy by Ziehl-Neelsen/
District Level
fluorescence staining are the primary case detection tool
The District Tuberculosis Centre [DTC] is the nodal point in RNTCP for patients with infectious TB and is also
for all TB control activities in the district. In RNTCP, the for monitoring their response to treatment. From 2018,
primary role of the DTC has shifted from clinical to mana­ under Programmatic Management of Drug-resistant TB
gerial functions. The District TB Officer [DTO] at the DTC [PMDT] (16), “universal DST” and molecular testing
has the overall responsibility of management of RNTCP at {cartridge-based nucleic acid amplification test [CBNAAT]},
the district level as per the programme guidelines and the is being offered to all patients as per the new diagnostic
guidance of the District Health Society. The DTO is also algorithm under the programme [Figures 42.5A and 42.5B].
responsible for involvement of other sectors in RNTCP Chest radiograph is obtained simultaneously to avoid any
and is assisted by a Medical Officer, District Programme delay in diagnosis of TB patients with smear-negative results.
Coordinator, District PPM Coordinator, District DR-TB/ Chest radiograph is obtained simultaneously to avoid
HIV-TB supervisor, and other Office Operation staff. any delay in diagnosis of TB patients with smear-negative
results. Extra-pulmonary TB is also diagnosed based on other
Sub-District Level [Tuberculosis Unit Level] tests like cytology, histopathology, CBNAAT, radio-imaging,
and other supportive tests.
The creation of a sub-district level Tuberculosis Unit [TU] is Enormous efforts and achievements were highlighted
a major organizational change in RNTCP. The TU consists of in case finding under the 11th Five-Year Plan [2006-2011].
a designated Medical Officer-Tuberculosis Control [MO-TC] In the 12th plan period, India’s Revised National TB
who does RNTCP work in addition to other responsibilities. Control Programme notified about 70 lakh [lakh = 100,000]
There are two full-time RNTCP contractual supervisory staff TB patients [Figure 53.4]. The programme is exploring
exclusively for TB work—a Senior TB Treatment Supervisor significant new opportunities for improvement of case
[STS] and a Senior TB Laboratory Supervisor [STLS]. These finding at an early stage and achieve “Universal Access”.
TUs cover a population of approximately 150,000-250,000 Over the period of the NSP 2017-25, RNTCP aims to notify
population [largely aligned with NHM Blocks]. The MO- 260 lakh [lakh = 100,000] TB patients in 8 years including
TC at the TU has the overall responsibility of management public and private sector.
of RNTCP at the sub-district level, assisted by the STS and
STLS. Strategies to Augment Case Finding
There is one RNTCP Designated Microscopy Centre
[DMC] for every 100,000 population under a TU [50,000 The following strategies have been adopted by RNTCP
in tribal, desert, remote and hilly regions]. DMCs are also in 12th Five-Year Plan to increase notification under the
established in Medical Colleges, Corporate hospitals, ESI programme.
and Railway health facilities, NGOs, private hospitals, etc., Screening clinically vulnerable and socially vulnerable
depending upon the requirement. risk groups who are known to suffer disproportionately from
TB: The clinically vulnerable population includes PLHA,
Peripheral Health Institutions household contacts of TB cases, malnourished children,
diabetics, tobacco users, and those living in houses with
For the purpose of RNTCP, a peripheral health institution indoor air pollution. Socially vulnerable groups include
[PHI] is a health facility which is manned by at least a backward and tribal, migrants and urban slum dwellers,
medical officer. At this level, there are dispensaries, peri­ prisoners, occupational high risk groups, etc. These groups
pheral health clinics, community health centres, referral have been prioritized for systematic active TB case finding
hospitals, major hospitals, specialty clinics or hospitals and linking with diagnostic facilities.
[including other health facilities], TB hospitals, and Medical Ensuring use of rapid diagnostic technologies: CBNAAT
Colleges within the respective district. All health facilities provides a diagnosis of TB and rifampicin resistance within
in the private and non-governmental organisation [NGO] 2 hours. At present, CBNAAT laboratories are functional,
sectors participating in RNTCP are also considered as PHIs covering all districts of the country.
by the programme. Some of these PHIs also function as RNTCP has successfully field tested implementation
DMCs. Peripheral health institutions undertake TB case- of TrueNat—an indigenous rapid molecular diagnostic
finding and treatment activities as a part of the general technique which gives results in less than an hour, battery
 716 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 53.4: Rate of TB suspects examined per 100,000 population and smear-positive cases diagnosed, corrected for population covered under
Revised National Tuberculosis Control Programme
TB = tuberculosis

operated, and with minimal infrastructure requirement.

Established systems for programme-based evaluation of new
TB diagnostics, and support the establishment of minimum
performance standards for licensure of TB diagnostic tests.
Systems developed and deployed for notifying patients at
TB diagnosis from all sources.

Laboratory Network
The RNTCP laboratory network is composed of a three-tier
system with National Level Reference Laboratories [NRLs],
state level IRLs, and peripheral level laboratories as DMCs
[Figure 53.5]. At the top of laboratory network hierarchy
are six designated NRLs at national level under National Figure 53.5: Revised National Tuberculosis Control Programme
institutes. hierarchical lab network
National reference laboratories assist the programme on TB = tuberculosis; TU = Tuberculosis Unit; DMC = designated
technical issues, to develop laboratory guidelines, standard microscopy centre; EQA = external quality assurance; DTO = District
TB Officer; STLS = Senior TB Laboratory Supervisor; LT = laboratory
operating procedures [SOPs], conduct trainings to state level technician
IRL, conduct annual on-site evaluation/supervisory visits to
laboratories for microscopy, culture and drug-susceptibility
testing [C and DST], and for providing support for overall feedback for the same. Intermediate reference laboratory
laboratory quality improvement. National reference labo­ also monitors the quality assurance of DST by solid, liquid,
ratories are quality assured through the supra-reference line probe assay [LPA] and CBNAAT. There are 28 IRLs,
laboratory [SRL] coordinating laboratory at Antwerp, at the State level, at least one per major state, and one
Belgium. All NRLs are also participating in evaluation of additional IRL for larger states having more than 100 million
newer diagnostic technologies and research activities. population.
There is at least one IRL per major state. Each IRL A network of 1135 CBNAAT laboratories have been
conducts on-site evaluation visits to districts for panel testing established across the country, covering every district for
of STLS at each DTC at least once a year to ensures the access to rapid molecular diagnostic test for diagnosis of TB
proficiency of staff performing smear microscopy activities and DR-TB at decentralised level.
by providing training to LTs and STLS. Intermediate The most peripheral laboratory under the RNTCP
reference laboratory also provides technical support to C network is the DMC. Revised national tuberculosis control
and DST laboratories in medical college, private and NGO, programme has provided a binocular microscope for each
other laboratories under RNTCP. The IRL also visit CBNAAT DMC. The 200 high workload DMCs at Medical Colleges
sites across the state, monitor performance and provide have also been provided with LED-FM. Designated
 The Revised National Tuberculosis Control Programme 717

microscopy centre are manned by a trained LT of the state [RBR]. The Programme has provided a STLS, at each TU
health system. Smear Microscopy services are available for carrying out EQA activities-on-site evaluation visits to
through a network of more than 14,000 DMCs which are DMCs and random blinded rechecking of routine DMC
spread across the health systems and quality assured slides at the DTC level. STLS prepare staining solution
through a system of External Quality Assurance Programme for smear microscopy, check the quality through internal
[EQAP] in line with the international guidelines. Thousands quality control [QC] slides and extends on-site training with
of trained LTs perform sputum smear microscopy at the trouble shooting for quality improvement. The schematic
DMCs within general public health system. representation of the EQA reporting process is shown in
Figure 53.6.
Quality Assurance for Smear Microscopy
in the Country Extrapulmonary Tuberculosis
In order to provide high quality smear microscopy services RNTCP in the recent past has prioritized the diagnosis and
within the programme for avoiding false results in TB management of EPTB with use of CBNAAT as the first test
case diagnosis and to achieve uniform results across the of choice and has also developed SOPs for the IRLs and C
country, EQA programme has been established through and DSTs laboratories for processing EPTB specimens using
national laboratory network for sputum smear microscopy. other technologies [smear/culture and DST]. Table 53.1
The quality assurance [QA] activities include the: on-site describes various technologies used for diagnosis of different
evaluation; panel testing; and random blinded rechecking types of TB.

Figure 53.6: External quality assurance reporting process

CTD = Central TB Division; EQA = external quality assurance; NRL = National Reference Laboratory; OSE = on-site evaluation; RBRC = random
blinded rechecking; IRL = Intermediate Reference Laboratory; DTC = District Tuberculosis Centre; TU = Tuberculosis Unit; DMC = Designated
Microscopy Centre

Table 53.1: Technologies used for diagnosis of different types of TB

Type of TB Technologies Used by RNTCP
Pulmonary TB [HIV-Neg/presumed drug-sensitive] Smear Microscopy [ZN/LED-FM]
Pulmonary TB [PLHA and paediatric age] CBNAAT [+smear/CxR]
At risk of DR-TB [as per RNTCP] CBNAAT / LPA / MGIT
Confirmed MDR-TB [for FL/SLD] Automated MGIT System
Follow-up for DR-TB management Automated MGIT System and or LJ medium
EPTB CBNAAT, Automated MGIT System, other modalities [smear, FNAC, Biopsy,
USG, CT Scan, MRI, etc.]
TB = tuberculosis; HIV = human immunodeficiency virus; ZN = Ziehl-Neelsen; LED-FM = Light-emitting diode fluorescence microscopy;
PLHA = people living with HIV/ AIDS; CBNAAT = cartridge-based nucleic acid amplification test; LPA = line probe assay; DR-TB = drug
resistant tuberculosis; RNTCP = Revised National Tuberculosis Control Programme; MGIT = mycobacteria growth indicating tube; MDR-TB =
multidrug-resistant tuberculosis; FL = first-line; SLD = second-line drug susceptibility; LJ = Lowenstein-Jensen; FNAC = fine needle aspiration
cytology; USG = ultrasonography; CT = computed tomography; MRI = magnetic resonance imaging; EPTB = extrapulmonary tuberculosis
718 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Drug-resistant Tuberculosis Table 53.2A: Type of patients and regimens

Patients at risk of DR-TB as defined by the programme prescribed under Revised National Tuberculosis
[MDR-TB], are diagnosed using WHO endorsed rapid Control Programme
diagnostics [WRD] like CBNAAT/LPA. Response to Regimen
treatment for MDR is done by follow-up culture on liquid
Treatment Intensive phase Continuation
Culture [MGIT] system [critical follow-ups requiring clinical groups Types of patient [IP] phase [CP]
response] and Lowenstein-Jensen [LJ] medium for [for
New Sputum smear-positive 2HRZE 4HRE
crucial follow-ups], with identification of mycobacterial
Sputum smear-negative
species is performed by commercial immunochromatic test. Extrapulmonary Others
From 2018 onwards, the programme has introduced
policy of “universal DST” i.e. testing of all TB patients for Previously Smear-positive relapse 2HRZES/ 5HRE
treated* Smear-positive failure 1HRZE
at least rifampicin Sensitivity. With revision in diagnostic Smear-positive
algorithm of PMDT, all rifampicin resistant TB patients treatment after default
are tested for second-line drug susceptibility testing Others
[Figures 42.5A and 42.5B]. All rifampicin sensitive TB * With implementation of “universal DST” this treatment category
patients supposed to be tested for isoniazid resistance. has been discontinued from December 2018
Culture and anti-TB DST services are provided by all IP = intensive phase; CP = continuation phase
States IRL as well as certified culture and DST laboratories
and are currently available at 74 places. Culture and DST
services are also available outside the RNTCP, in the NGO
and Private sectors through provision of RNTCP certification. Table 53.2B: Drug dosage for adult TB
As on March 2018, 40 laboratory certified for SLD and it will Weight Injection
be further expanded. category [kg] Number of tablets [FDCs] streptomycin [g]*
Intensive phase Continuation phase
Quality Assurance HRZE HRE
EQA for C and DST is ensured by a process of pre- [75/150/400/275] [75/150/275]
assessment, on-site evaluation visit to the facility and the 25-39 2 2 0.5
actual certification procedure. The process of certification 40-54 3 3 0.75
was adopted from the standard international guidelines, and
has been in place from 2005. This inter-laboratory culture 55-69 4 4 1
exchange and testing process involves both NRL panel ≥70 5 5 1
cultures testing at IRL, and re-testing of select IRL cultures * Injection streptomycin to be added in IP phase for 2 months in the
by the NRL. All certified laboratories regularly participate in retreatment regimen of drug sensitive patients. In patients above
the Proficiency Testing programmes/rounds conducted by 50 years of age, maximum dose of streptomycin should be 0.75 g
NRLs. The certified laboratory submits quarterly laboratory Adults weighing less than 25 kg will be given loose drugs as per
body weight
performance indicators to CTD and NRLs. The data from the
TB = tuberculosis; FDCs = fixed-dose combinations
performance indicators are analysed by CTD and NRLs and
technical guidance provided for corrective actions.

TREATMENT SERVICES Table 53.2C: Drug dosage for paediatric TB

A standardised four drug [HRZE] daily regimen is used to Weight Injection
treat all new TB cases under RNTCP. Earlier, “previously category Number of tablets streptomycin
[kg] [dispersible FDCs] [mg]
treated” TB patients were treated using a standardised
5 drug [HRZES] regimen for 8-9 months [Table 53.2A]. Intensive phase Continuation
Presently, the regimen for “previously treated patients” phase
has been discontinued. Policy of Universal DST has been HRZ [50/75/150] E [100] HRE [50/75/100]
implemented. Under it, all diagnosed TB patients are offered 4-7 1 1 1 100
DST at least for rifampicin. The non-responders and failures
8-11 2 2 2 150
of first-line treatment are also offered DST. The regimens
currently used for drug sensitive TB patients in RNTCP 12-15 3 3 3 200
are daily regimens with fixed dose combination [FDC] 16-24 4 4 4 300
medications. Patients are given drugs according to body 25-29 3 + 1A* 3 3 + 1A* 400
weight [Tables 53.2B and 53.2C].
30-39 2 + 2A* 2 2 + 2A* 500
Directly observed treatment is the one of the patient
support systems that creates a human bond between the *A = Adult FDC [HRZE = 75/150/400/275; HRE = 75/150/275]
provider and the patient and motivate the patient to adhere TB = tuberculosis; FDC = fixed-dose combinations
 The Revised National Tuberculosis Control Programme 719

to and complete the treatment. Basic premises in identifying Strategies for controlling DR-TB include: [i] sustained
the treatment supporter [DOT providers] is that treatment high-quality DOTS implementation, daily regimen in high
supporter should be accessible and acceptable to the risk groups and patient friendly treatment to improve
patient and accountable to the health system. The treatment treatment adherence; [ii] implementing airborne infection
supporter [DOT provider] can be a medical or para-medical control [AIC] measures; cut down diagnostic delays
personnel or a community volunteer or someone from the with rapid diagnostics, offer universal DST and prompt
NGOs and private sector facility involved in the programme. appropriate decentralized treatment; [iii] strengthening
With community treatment supporters, community-based procurement, supply chain management of SLD: strengthen
care is ensured. Direct observation of treatment ensures that the procurement, supply and availability of second-line
the patient consumes every dose of the treatment before a anti-TB drugs in India; [iv] nutritional assessment and
trained health worker and provides additional opportunity supplementation: linkages with Public distribution systems,
to support treatment. Panchayati Raj Institutions, Corporate social responsibility,
However, the principle of direct observation is to be etc; and [v] improving adherence through counselling
applied logically and judiciously. Other modalities of treat­ support: one DR-TB counselor per DR-TB centre and district
ment adherence are deployed to enhance adherence to each for both institutional and home-based counselling.
treatment. Intelligent deployment of information communi­ The Guidelines for PMDT in India are available since 2006
cation technologies [ICT] is an example of such modalities. and are regularly updated based on evolving evidence-based
A patient who is unable to undergo supervised treatment policy decisions and implementation experiences to enhance
should not be denied treatment. Frequent on-job travel­ operational efficiency and ease. These guidelines were last
lers, truck drivers, sailors, etc. may require identification of updated in 2017 (16). The key features are as follows.
proper treatment supporter. To promote treatment adherence
among these patients, ICT modalities like frequent calls, SMS Diagnosis of M/XDR-TB
reminders, interactive voice response system [IVRS], Pill Box, Decentralised diagnosis with WRD with specimen transport
Pill in Hand method, etc. may be deployed. to laboratory in cold chain. Rapid Molecular DST [CBNAAT
or LPA] is the first choice of DST. The subsequent choice
Standards for Tuberculosis Care in India of diagnostic technology depends on locally available
laboratory capacity through an RNTCP Certified laboratory
The standards for TB care in India [STCI] (17) were released [Table 53.3]. RNTCP has been implementing “universal
on World TB Day 2014. This is India’s step towards the DST”. All TB patients are tested with rapid molecular
bold policy for Universal access to quality TB care. On one DST [CBNAAT or LPA]. All failures of first-line regimen,
side, these standards propagate best practices in TB control any patient with smear positive follow-up results, are also
in the private sector at the same time these also challenge offered DST.
the current policies and strategies of RNTCP to upgrade
to meet these standards and provide highest quality TB Treatment of M/XDR-TB
care under the programme. These standards highlight
improved high sensitivity diagnostic approaches and tools, Under PMDT, since 2018, treatment is based on DR/DST
daily treatment regimen with FDC, universal DST with DST results. Initial hospitalisation is done at DR-TB Centre
guided treatment regimen to tackle the menace of DR-TB, followed by ambulatory care. Standardised treatment
more patient friendly treatment support systems including algorithm for DR-TB (16) is shown in Figure 42.6.
family DOT and ICT enabled support systems, psychosocial
support systems, etc. public health responsibilities of Status and Progress in Scaling-up of
providers and standards for social inclusion. To implement Programmatic Management of Drug-resistant
these standards across India, RNTCP has developed the draft Tuberculosis Services in India
revised technical and operational guidelines for all forms of The year-wise scale up of PMDT service delivery components
TB in public sector as well as e-tools cum training tool kits is detailed in the Figure 53.7.
for promoting STCI in the private sector.
Table 53.3: Diagnosis of multidrug/extensively drug-
PROGRAMMATIC MANAGEMENT OF resistant tuberculosis
DRUG-RESISTANT TB Drug susceptibility testing technology Choice
World Health Organization Global TB Report 2018, India Molecular DST [e.g., CBNAAT or LPA DST ] First
accounted for 24% of global MDR-TB cases (1). The RNTCP Liquid culture isolation and LPA DST Second
is implementing the component for DR-TB services, Solid culture isolation and LPA DST Third
programmatic management of Drug resistant TB [PMDT],
Liquid culture isolation and liquid DST Fourth
[erstwhile DOTS Plus] since year 2007. After a modest
gradual scale up till 2010, PMDT services were systematically Solid culture isolation and DST Fifth
accelerated since 2011 to achieve complete geographical DST = drug susceptibility testing; CBNAAT = cartridge-based
coverage in March 2013. nucleic acid amplification test; LPA = line probe assay
 720 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 53.7: DR-TB case finding and treatment initiation effort, 2007-2017
TB = tuberculosis; DR-TB = drug-resistant TB; MDR TB = multidrug-resistant TB; RR TB = rifampicin-resistant TB; XDR TB = extensively drug-
resistant TB; CBNAAT = cartridge-based nucleic acid amplification test

TUBERCULOSIS-HUMAN IMMUNODEFICIENCY nationwide by both, National AIDS Control Programme

VIRUS COLLABORATIVE ACTIVITIES [NACP] and RNTCP.
TB is the most common opportunistic infection in HIV-
Progress so Far
infected individuals and HIV-infection is an important risk
factor for acquiring TB infection and its progression to active The HIV testing of TB patients is now routinely offered
TB disease (18). About 87,000 HIV-associated TB patients are through provider-initiated testing and counselling [PITC]
emerging annually in India and accounts for 8% of the global implemented in all states. In 2017, 75% TB patients knew
burden of HIV-associated TB. The mortality in this group is their HIV status and 36,315 were diagnosed as HIV positive
very high with nearly 12,000 people dying every year. [Figure 53.8]. All HIV-TB patients were provided CPT and
The interventions to reduce the burden of TB among 87% co-infected patients were put on ART. India has adopted
People Living with HIV/AIDS [PLHA] include the early all the recommendations suggested by the WHO for TB/
provision of ART for people living with HIV in line with HIV collaborative activities. Rapid Diagnostics are used for
WHO guidelines and the three I’s for HIV/TB – Intensified early diagnosis of TB among PLHIV, measures for effective
TB case finding followed by high quality ATT, Isoniazid implementation of AIC guidelines in HIV care settings are
preventive therapy [IPT] and Infection control for TB, all of taken and IPT has been implemented across all ART centres
which are being implemented under the programme. in the country.
The National Framework for Joint TB-HIV Collaborative With technical support from WHO, RNTCP-NACP joined
activities was developed in 2007 and has been updated hands for the implementation of ‘Innovative, Intensified TB
based on experiential learning and scientific evidence in case finding and appropriate treatment at selected 30 high
2009 and 2013. The mechanism for collaboration includes burden ART centres in India’ aimed at reducing the burden
coordinated service delivery at field level, and oversight of TB among PLHA which was launched on 24th March
and advisory groups at National, State and District level. 2015. The project features single window for service delivery
To enable effective coordination, joint trainings, standard of TB and HIV services from ART centres, diagnosis of
recording and reporting, joint monitoring and evaluation TB by CBNAAT and treatment of TB patients with daily
and operational research are strategically implemented. regimen among others. Based on the success of the project,
Currently, the TB/HIV package is being implemented the initiative has been scaled up across all States in 2016.
 The Revised National Tuberculosis Control Programme 721

Figure 53.8: Trends in Number [%] of registered TB patients with known HIV status, 2008-2017
TB = tuberculosis; HIV = human immunodeficiency virus; q = quarter

The reader is referred to the chapter “Tuberculosis and human cessation advice and DM screening protocol in RNTCP;
immunodeficiency virus infection” [Chapter 35] for details on and TB screening in NPCDCS and NTCP programme. The
this topic. Framework for TB-Diabetes Collaborative activities and
TB-Tobacco collaborative activities has been launched on
TUBERCULOSIS AND NON-COMMUNICABLE World TB Day and World No Tobacco Day respectively.
COMORBIDITIES [TOBACCO, DIABETE Bi-directional screening for TB-DM and TB-Tobacco is being
implemented in all districts wherein NPCDCS and NTCP are
MELLITUS]
functional.
The increasing co-occurrence of TB with tobacco consumption
and Diabetes Mellitus [DM] is well evident. Smoking is CHILDHOOD TUBERCULOSIS
three times more prevalent in TB patients and is strongly As per the Global TB Report 2018 (1), children [under 15 years
associated with increased rates of TB infection. Similarly, of age], accounted for more than one-fifth of the global TB
the prevalence of DM is as high as 13% and the prevalence burden among children. There are certain key programme
even goes higher in MDR-TB cases. Patients with TB may features for paediatric TB. The RNTCP in association
have lung damage that is aggravated by continued tobacco with Indian Academy of Paediatrics [IAP] has revised
use. Diabetes Mellitus is supposed to depress immunity the paediatric TB guideline in 2012. It laid down specific
and conversely TB is supposed to impair glucose tolerance algorithm diagnosis of TB among children. The treatment
resulting in concurrence. strategy comprises two key components. First, as in adults,
Feasibility of including tobacco cessation activities children with TB are treated with standard SCC, given under
with RNTCP, a TB Tobacco pilot project was conducted in direct observation and the disease status is monitored during
Gujarat by GOI in 2010. The pilot projects done by the TB- the course of treatment. Second, patient wise boxes designed
DM collaborative group has demonstrated at 8 tertiary care according to weight bands for complete course of anti-TB
centres that missed opportunities can be addressed through drugs (19). In order to simplify the management of paediatric
developing routine screening system in RNTCP with no TB, RNTCP has recently introduced a simplified diagnostic
additional cost to programme. algorithm for paediatric TB offering upfront CBNAAT for
Based on the above learning CTD, National Programme TB diagnosis [Figure 42.5B] and introduced child-friendly
for Prevention and Control of Cardiovascular Diseases, dispersible FDC formulation for treatment [Table 53.2C] (16).
Cancers, Diabetes and Stroke [NPCDCS] and National Considering difficulties in diagnosis of paediatric
Tobacco Control Programme [NTCP] took a decision to TB under field condition, the notification rates can be
develop a collaborative framework to integrate tobacco further strengthened. Contact screening is one of the ways
722 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

for intensified case finding activity which RNTCP has In addition partners like UNION, World Vision, FIND,
implemented since its inception. Under RNTCP all children also support the programme. These partners and national
less than 6 years of age, contacts of the family member institutes work in close liaison with RNTCP and play a
suffering with active TB are expected to be screened for TB key role in setting national priorities, training, carrying
and provided INH chemoprophylaxis once active TB has out operational research [OR] and also in assisting the
been ruled out. programme in its monitoring and evaluation activities.
The National Technical Working Group on Paediatric TB Medical colleges have been effectively organised at a
is in place to examine the policy and practices and provides large scale through task force mechanisms at state, zonal
suggestions to CTD for improving situation of childhood TB. and national levels, with RNTCP supporting with additional
To accelerate access to quality TB diagnosis for paediatric human resources, logistics for microscopy, funds to conduct
population, RNTCP had initiated a project in 10 major cities sensitisations, trainings and research in RNTCP priority
in India: RNTCP United States Agency for International areas. RNTCP has partnered with more than 350 Medical
Development [USAID] Foundation for Innovative New Colleges in India and they have contributed in a major way
Diagnostics [FIND] Paediatric TB Xpert Project. Key hospitals in finding more TB cases, especially smear-negative and
and private clinics catering to paediatric populations were EPTB cases (22).
identified and referral network was established for sample
collection and transport to facilitate early diagnosis using ADVOCACY COMMUNICATION AND SOCIAL
CBNAAT. RNTCP has incorporated the processes and MOBILISATION
learning’s of the project in programme guidelines.
Advocacy communication and social mobilisation [ACSM]
is an inbuilt component of RNTCP and is recognised as an
PUBLIC-PRIVATE MIX DOTS IN REVISED
important element of all activities of TB control essential to
NATIONAL TUBERCULOSIS CONTROL
achieve the goal of universal access. Advocacy communication
PROGRAMME and social mobilisation activities are expected to strengthen
In India, the private sector is the first point of care in many the efforts towards TB control in India by mobilising political
episodes of ill health (20,21). While most TB cases are administrative commitment resulting in availability of better
ultimately treated by the RNTCP, most patients by then resources for TB, early case detection and early complete
have already approached the private sector for TB diagnosis treatment, combating stigma and discrimination, motivating
and treatment. Hence, engaging the private sector [both for and empowering community and generating awareness and
profit and not for profit entities] effectively is an important demand in community.
intervention for RNTCP to achieve the overall goal of National Advisory Committee was constituted in 2013
universal access and early detection. for a period of two years to advise and guide the CTD by
Efforts, though isolated, have been made by RNTCP since infusion of newer ideas and experience. It includes experts
the earlier days of its inception to widen access to quality TB from field of Health communication, research, National and
care. After experiences of implementing models of private state teaching institutes, etc.
sector collaboration, CTD published guidelines for the Under RNTCP, ACSM planning and implementation
participation of the NGOs [in 2001] and private practitioners has been decentralised, and helps percolate relevant
[in 2002]. These guidelines provided opportunity to many messages in a language, that’s best understood by the local
NGOs and private practitioners to formally collaborate population through the best possible medium [e.g. miking at
with RNTCP. Based on experience of implementation, the bazaar haats or local festivals]. States develop information,
schemes are revised in 2008 (20) and in 2014 to increase its education and communication [IEC] materials based on their
uptake. Currently, 24 partnership options for involvement needs and keeping in mind the local cultural context, and
of NGOs, corporates, private practitioners and research have budgets allocated for this purpose. Additionally, IEC
institutions are incorporated under the National Guidelines materials are also developed at the national level and shared
for Partnership (21). with States for use-‘as is’ or post-modification to suit local
Indian Medical Association has been engaged with requirements. Several of these materials including TV spots,
the programme through Global Fund to Fight AIDS, radio jingles and posters are available in nearly 13 regional
Tuberculosis and Malaria [GFATM] supported project in languages. Advocacy communication and social mobilization
16 states and UTs. The objective of this project has been to module is incorporated in all health workers training on
improve the quality care for the TB patients availing services basic DOTS. To update the technical and operational aspects
from the private sector. Similarly, civil society organisation, of the programme a revised training module has been
CBCI-CARD [Catholic Bishops Conference of India-Coalition prepared for the private practitioners.
for AIDS & Related Diseases] is working under GFATM
project of RNTCP, to improve access to the diagnostic and TUBERCULOSIS–PATIENT SUPPORT
treatment services provided by the RNTCP within the
SYSTEMS IN INDIA
Catholic Church Healthcare Facilities [CHFs] and thereby
to improve the quality of care for patients suffering from In addition to better diagnostic tool and treatment regimens,
TB in India. other patient supportive initiatives including better nutrition,
 The Revised National Tuberculosis Control Programme 723

Table 53.4: Enhanced enables and incentives under Revised National Tuberculosis Control Programme
Item Existing norm Proposed by MoHFW and approved by MSG
Revision of incentives to Community DOT `250/- for completed course of treatment `1000/- for the completed course of
provider providing treatment support to Category I treatment
TB patients
Revision of incentives to Community DOT `250/- for completed course of treatment `1500/- for the completed course of
provider providing treatment support to Category treatment
II TB patients
Revision of incentives to Community DOT `2500/- for completed course of `5000/- for completed course of treatment.
provider providing treatment support to DR-TB treatment [`1000/- at the end of IP and [`2000/- at the end of IP and `3000/- at the
patients `1500/- at the end of CP] end of CP]
Incentives to patient in tribal and difficult areas `250/patient and one attendant `750/patient and one attendant
Incentive to volunteers for sputum sample `200/month/volunteer. If less than one `25 per sample transported to the DMC
transport in tribal and difficult areas visit per week then `100/ month
Travel cost to MDR-TB patient/suspect to DR-TB Actual travel cost using any public Up to `1000/visit/patient restricted to actuals
centre [outside district] transport by a public transport
Travel cost to MDR-TB patient/suspect to DR-TB Actual travel cost using any public Up to `400/visit/patient restricted to actuals
centre [within district] transport by a public transport
Transportation cost for co-infected TB-HIV patient Nil Up to `500/patient for only the first visit
travel restricted to actuals by a public transport
Incentive related to Injection prick Nil `25/injection prick
MoHFW = Ministry of Health and Family Welfare; MSG = mission-steering group; DOT = directly observed treatment; TB = tuberculosis;
DR-TB = drug-resistant tuberculosis; IP = intensive phase; CP = continuation phase; MDR-TB = multidrug-resistant tuberculosis;
HIV = human immunodeficiency virus

counselling and financial support are equally essential. As a result of state and district programme initiatives,
World Health Organization ‘End TB strategy’ has this impor­ large number of innovative patient support activities has
tant target of ‘no affected family face catastrophic costs due been implemented in the country to extend nutritional
to TB’. support to patient and families, financial support, vocational
Revised National Tuberculosis Control Programme support, counselling support. The support activities are
provides free diagnosis and treatment to all TB patients implemented through departments such as social welfare
who access care from the programme. Pre-treatment department, public distribution system, NGOs, CSR funding,
investigations, ancillary drugs for managing side effects are etc. Significant role of local self-governments can be seen in
ensured free of cost. Enhanced enables and incentives under many of these initiatives, where financing for these are done
programme are listed in Table 53.4. through their own local fund.
However the free diagnosis and treatment is only
accessible to those patients seeking care under RNTCP. Large HUMAN RESOURCES MANAGEMENT
number of patients seeking care in private sector has to bear
substantial cost for TB care. Revised National Tuberculosis The goal of RNTCP’s HRD strategy is to optimally utilize
Control Programme under the guidelines for partnership has available health system staff to deliver quality TB services,
initiated number of schemes in which services are procured and to strengthen the supervisory and managerial capacity
from private sector for reducing cost to the patients in the of programme staff overseeing these services. TB care and
private sector. Innovative private sector engagement pilots control services are becoming more complex and demanding,
are on in which diagnosis and treatment for TB patients in with multiple new tasks for MDR-TB management and TB-
the private sector is also given free. HIV care. An adequately staffed, trained, and motivated
Though large part of cost of treatment is born by the health workforce is required to achieve the ambitious TB
programme, patients still have to bear expenditures such control objective of Universal Access.
as cost for travel to the facilities, loss of wages due to In the 12th Five year plan of RNTCP a cadres/series of
sickness, etc. Apart from financial hardship, nutritional and new positions have been approved under program at all
counselling supports to TB patients are other elements the level to strengthen programme management, laboratory
national programme was not supporting directly. In order services and PPM services.
to address these challenges, CTD had sent recommendation Training institutes [national and state] play pivotal
to state programmes to facilitate TB patients to have access role in capacity building of all concerned. National
to various social support programmes and systems already Training institutes like NTI, Bangalore; NITRD, New Delhi
existing, and to actively support innovative models. and NIRT, Chennai are capacity building arms of CTD,
724 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

MoHFW-GoI. The efficient state level institutes can also come TUBERCULOSIS NOTIFICATION AND
up as regional level training hubs, e.g. State TB Training & SURVEILLANCE
Demonstration Centres of many states.
The Government of India declared TB as a notifiable disease
MONITORING AND SUPERVISION through a Government Order dated 7th May 2012. All public
and private health providers are now required to notify TB
Proper supervision, modular training, and regular cross- cases diagnosed and/or treated by them to the District nodal
checking of work plays a key role in maintaining quality officers. This is an initiative which is intended not only to
services. Regular reviews of the programme at the state and improve epidemiological surveillance but also to extend the
district level are a key component of the process. In addition range of services available to patients regardless of whether
to the routine supervision and monitoring by the programme they are registered under the public sector or treated in the
staff, each state conducts internal evaluation of two districts private sector. These services are listed in the STCI. The
in a quarter. Central evaluations are conducted by the RNTCP has developed a guide for notification that enables
team from the CTD to evaluate one or two districts each cases to be notified through email, mobile application or
month. The CIE team consists of representatives from CTD, paper-based records.
National AIDS Control Organization [NACO], WHO, STO’s With efforts for sensitisation of programme officials and
from other state and also from civil society partners, etc. staff and then subsequently to private sector, the number
These activities help program managers in understanding of private health facilities registered in Nikshay for TB
determinants of good as well as poor performance for notification further increased in 2018.
replication of good practices in other states/districts and
take appropriate measures for improvement. PROCUREMENT AND SUPPLY CHAIN
The programme is also reviewed in terms of State co- MANAGEMENT
ordination committee meetings for TB HIV and review of
Programmatic Management of DR-TB, both at the state Procurement
and regional level. National Task Force meeting regarding
Ensuring a reliable and un-interrupted supply of good quality
the involvement and contribution of Medical colleges at
anti-TB drugs and other commodities is the main objective of
the state, zonal and national level are also conducted to
the supply chain management. The Procurement & Supply
review their participation and also for taking suggestions
Chain Management Unit in CTD carries out procurement
for improvement of the programme. With respect to DR-TB,
planning and monitoring, policy formulations, coordination
Coordination committee meeting of the NRL along with the
with procurement agents, reporting and coordination with
annual Meeting of the National Diagnosis and Treatment
the donors, implementation of procurement risk mitigation
Committee for RNTCP was held to formulate the future
plans, handling day-to-day supply related issues and
course of action.
monitoring of the contracts (23).
One of the greatest strengths of the RNTCP is the
First-line and second-line Anti-TB drugs are procured
recording and reporting system. Based on the patient treat­
under RNTCP and the logistics function ensures its seamless
ment card, the laboratory registers and the TB notification
availability of all these essential items at the different levels
register, this simple but robust system ensures accountability
of the programme to be further provided to the patients.
for each and every patient initiated on treatment.
In addition to drugs RNTCP also procures various
However, the data available at district, state or national
diagnostics and equipment’s under RNTCP like LED-FM,
level was in aggregated form, with a lead time of >4 months,
CBNAAT kits. For diagnosis of TB patients, appropriate
excluding private sector and neither could help much for
arrangements shall be made to ensure that X-ray facilities
TB burden estimation or individual case management or
in the states from the RNTCP budget. States have been
monitoring. To address this CTD in collaboration with
permitted for local procurement of purified protein
National Informatics Centre [NIC] undertook the initiative to
derivative vials, as per their requirement, following RNTCP
develop a Case Based Web online [cloud] application named
specifications/guidelines.
NIKSHAY. The objectives of NIKSHAY implementation are
Quality Assurance of anti-TB drugs has been accorded
to facilitate tracking and monitoring of individual TB patient,
special importance by RNTCP and measures are taken to
automated reporting, online referral/transfer mechanism,
ensure both pre- and post-dispatch inspection of all the anti-
eliminate lead time in reporting, aid focused supervision,
TB drugs.
and for real-time programme management.
The notification of all TB patients in the notification
register in NIKSHAY ensures monitoring and follow-up
Drug Logistics Management
of each patient individually and real time. Reports on case The first-line anti-TB drugs procured are stored at the
finding, sputum conversion and treatment outcome then six Government Medical Store Depots [GMSDs] situated
can be obtained from them for analysis of the performance in Chennai, Guwahati, Hyderabad, Karnal, Kolkata and
indicators of the respective areas [TB unit, District, State or Mumbai which are the direct consignees. The second-line
National]. anti-TB drugs [MDR and XDR] are received directly by the
 The Revised National Tuberculosis Control Programme 725

States as loose drugs and the States [i.e. State Drug Store] Table 53.5: The consistent increase in allocation in
is the direct consignee. The States then repack these into health sector in last three Five Year Plans
monthly patient wise boxes which are then distributed to
Five Year Plans 10th [2002-07] 11th [2007-12] 12th [2012-17]
the districts.
Drugs are released by CTD from the GMSDs every Allocation 37,153 1,40,135 3,00,018
[` in crore]
quarter to the States considering closing stocks at the end
of quarter, consumption of drugs during the quarter, with a Crore = 10,000,000
reserve stock of 7 months using Nikshay aushadhi. The SDS
subsequently releases drugs to their respective districts for
one quarter’s consumption, with a reserve stock of 4 months. Table 53.6: Allocation and expenditure under
From the districts, the drugs are released to each TB unit Tuberculosis Control Programme in India
every quarter to maintain a reserve stock of two months, and Expenditure
from the TU drugs are released to the PHIs with one month Five Year Plans Plan period Allocation ` in crore
stock for consumption and one month’s stock as reserve after Tenth 2002-07 743.17 757.15
receipt at the TUs of the monthly report from the PHIs. In Eleventh 2007-12 1447.00 1595.13
addition, drugs are also released any time during the month Twelfth 2012-17 4500.15 2161.14.
or quarter, from all levels in the instance of an increase in
Crore = 10,000,000
consumption or extra requirement of drugs due to other
reasons, after submission of an “Additional Drug Request”
[ADR]. to provide technical support and assistance in monitoring
Trainings on drug logistics is a regular feature in RNTCP the programme. As per analysis of the Joint TB Programme
to ensure that the capacity of the concerned staff in this Review of 2003, RNTCP is highly economical, costing on
important area are built adequately from time to time. SOP an average less than two rupees [5 US cents] per capita per
and manuals have been developed for Drug Management year (24). Policy direction, supervision, surveillance, drugs
at State and District Drug Stores under RNTCP, along with and microscopes are provided by the Central Government.
a Training Manual.
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FINANCE 1. World Health Organization. Global Tuberculosis Report 2018.
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5. Mahadev B, Kumar P. History of tuberculosis control in India.
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level state staff receives training from the Centre. They are Book Depot; 1972.p. 4-15.
also provided guidelines and modular training materials to 7. Tuberculosis Association of India. India’s fight against tuber­
train staff in the field. culosis; New Delhi: Tuberculosis Association of India; 1956.p.7.
The Government of India in line with the objective of 8. Bhore J. Report of the Health Survey and Development
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steadily increasing the allocations in health sector as well as 9. Tuberculosis Chemotherapy Centre. A concurrent comparison
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funding from a World Bank credit and a Global Fund Grant. 10. Fox W. Self-administration of medicaments. A review of
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from other donors including the USAID, Bill and Melinda Tuberc 1961;31:307-31.
Gates Foundation [BMGF], EXPAND TB, Centre for Disease 11. Tuberculosis Research Centre, Madras. Ten year report. New
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consultants deployed at the national, state and district levels Madras Bull World Health Organ 1964;31:247-71.
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13. Banerji D, Anderson S. A sociological study of awareness of 19. The behaviour and interaction of TB patients and private for-
symptoms among persons with pulmonary tuberculosis. Bull profit health care providers in India: a review. WHO/TB/97.223.
World Health Organ 1963;29:665-83. Geneva: World Health Organization; 1997.
14. Baily GV, Savic D, Gothi GD, Naidu VB, Nair SS. Potential yield 20. Central TB Division. Revised schemes for NGOs and private
of pulmonary tuberculosis cases by direct microscopy of sputum providers. Available at URL: http://www.tbcindia.org/pdfs/
in a district in South India. Bull World Health Organ 1967;37: New%20Schemes%20NGO-PP%20140808.pdf. Accessed on
875-92. October 12, 2008.
15. Khatri GR, Frieden TR. Controlling Tuberculosis in India. N Engl 21. Central Tuberculosis Division, Ministry of Health and Family
J Med 2002;347:1420-5. Welfare, Govt. of India. Partnerships. Technical and Operational
16. Revised National Tuberculosis Control Programme, Directorate Guidelines for TB Control in India. Available at URL: https://
General of Health Services, Ministry of Health and Family tbcindia.gov.in/showfile.php?lid=3211. Accessed on December
Welfare, Government of India. Guidelines on programmatic 29, 2018.
management of drug-resistant tuberculosis in India 2017. New 22. Sharma SK, Mohan A, Chauhan LS, Narain JP, Kumar P, Behera
Delhi: World Health Organization, Country Office for India; D, et al. Contribution of medical colleges to tuberculosis control
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for TB Care in India. New Delhi: World Health Organization, J Med Res 2013;137:283-94.
Country Office for India; 2014. 23. Salhotra VS. Drug procurement and management. J Indian Med
18. Guidelines for use of Pediatric Patient Wise boxes under the Assoc 2003;101:175-6.
Revised National Tuberculosis Control Programme. Available at 24. World Health Organization. Joint tuberculosis programme
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pdf. Accessed on October 11, 2008. Organization Regional Office for South-East Asia; 2003.
 54
Tuberculosis Vaccine Development:
A Current Perspective
AK Tyagi, B Dey, R Jain

INTRODUCTION established in Chennai, Tamil Nadu, in 1948 to aid the BCG

immunisation programme in the country and to supply
Tuberculosis [TB] is one of the most fatal infectious diseases,
BCG to some neighboring countries. Though Pasteur strain
which continues to be a major global health problem (1-3).
remains the international reference strain of BCG (6),
However, in spite of all the available drugs, difficulty in
owing to the variations in production and preservation
maintaining compliance to long treatment regimens along
methodologies in different countries, BCG strains with
with complications in the diagnosis of drug-resistant
genotypic and phenotypic differences have emerged. Varia­
pattern, there is a general perception that in the absence of
tions in these strains have been observed with respect to
an effective vaccine, the real control of TB on a worldwide
tuberculin conversion rate, frequency of adverse reactions
basis is unlikely. A vaccine represents one of the most
and even vaccine efficacy ranging from 0% to 80% (7-10).
efficacious and potent defenses against infectious diseases,
Nevertheless, more than 3 billion children all over the world
however, a perfect vaccine against TB that would be most
effective in the control of this disease has eluded us all the have been vaccinated with BCG. Despite the global use of
time. Unfortunately, Bacille Calmette-Guérin [BCG], the BCG, scepticism about its safety and efficacy has persisted
currently used TB vaccine that was developed more than 90 till date. Other than the most frequent and mild side effects
years ago, has generated little protection and a great deal of BCG vaccina­t ion like local indurations and regional
of controversy. suppurative adenitis (11), the only serious complication
observed is disseminated BCG disease seen in some children
with human immunodeficiency virus [HIV] infection (12).
HISTORY OF THE BACILLE CALMETTE-GUÉRIN
However, the variable efficacy of BCG in different human
VACCINE: THE SCIENTIFIC FABLE AND THE populations has remained the most controversial issue.
LESSONS LEARNED Meta-analyses of several BCG efficacy trials in humans
BCG is the only available and widely used vaccine against have resulted in some important observations concerning
TB. It was developed by Calmette and Guérin between the suscep­tibility to infection and elicitation of immune
1908 and 1921 by serial passaging of Mycobacterium bovis responses (13-16). Different human populations respond
for 13 years (4). Based on the encouraging results in infants differently to immunisation as well as Mycobacterium
during the next four years, BCG was distributed around the tuberculosis [Mtb] infection. Various host factors, variability
world and its use as a preventive vaccine against TB was in the BCG strains, and differences in the virulence of Mtb
encouraged. By 1948, more than 10 million immunisations strains represent some of the multifactorial reasons for the
were carried out and in the first international BCG congress apparent variability in the protective efficacy of BCG.
held in the same year in Paris, it was concluded that BCG The role of host factors is well exemplified by the fact
vaccination was effective in preventing TB. In 1974, BCG that only 10% of the exposed individuals actually develop
vaccination was included in the expanded immunisation the disease and rest 90% are efficiently able to control the
programme of the World Health Organization [WHO] to infection, which may remain latent for many years (17).
strengthen the fight against TB in children in developing Several animal as well as human studies have provided
countries (5). In India, the BCG vaccine laboratory was strong evidence of genetic influence on immunity to
728 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Mtb infection (18). For example, several investigations bacilli, which requires special enriched media for its growth
have demonstrated association of polymorphism in genes in vitro. The TB bacillus has characteristic thick, hydrophobic
encoding interferon-γ [IFN-γ] receptor, human leucocyte and waxy cell wall rich in mycolic acids (27,28). This unique
antigen-D related [HLA-DR], natural resistance-associated cell wall structure imparts natural resistance to a number of
macrophage protein [NRAMP], dendritic cell-specific antibiotics that disrupt cell wall biosynthesis. In addition,
intercellular adhesion molecule-3-grabbing non-integrin tubercle bacilli can survive long exposure to acids, alkali,
[DC-SIGN], nucleotide-binding oligomerisation domain- detergents, oxidative agents and lysis by complement (29).
containing protein 2 [NOD2], vitamin D receptor, etc. with The exceptionally slow growth of Mtb and its unique ability
pulmonary TB (19). In addition, the contribution of other to enter a quiescent state on exposure to stress conditions
factors like age, nutritional status, co-existence of other encountered in vitro or in vivo offers survival advantage to
diseases, immune status, etc. may play an important role in the pathogen even in the presence of anti-bacterial agents,
determining the risk of developing TB. While HIV infection which act only on actively dividing bacteria (30). In addition,
is well known to weaken the immune system, infections, its ability to subvert the host immune responses and
such as schistosomiasis and hookworm infections have also manipulate the host machinery for its own survival makes
been found to downregulate the T-cell responses, thereby it one of the most successful human pathogens (31,32).
resulting in a reduced protection by BCG against TB (20-22).
Apart from the host genetic factors and differences in IMMUNOPATHOLOGY OF TUBERCULOSIS
BCG strains, which result in enormous variability, there is
emerging evidence that various Mtb strains may vary in their Immune mechanisms involved in TB primarily comprise a
genetic composition as well as phenotype, and thus, may complex series of interactions between the bacilli and various
substantially affect the evaluation of vaccine candidates. The cells of the immune system resulting either in the elimination
Beijing strain of Mtb, for example, which is one of the most of the bacilli completely, or containment of infection for a
prevalent strains in Asian countries, has been implicated in prolonged period or immediate progression to active disease
TB outbreaks in BCG-vaccinated populations and has been with clinical illness (33-58). Thus, a complete understanding
found to be frequently associated with drug resistance (23). of this disease with varying outcomes requires extensive
This strain has also been found to be much more virulent research. Several excellent studies have addressed the role
in mice than the laboratory strain Mtb H37Rv, which is of different components of the immune system and their
conventionally used in the guinea pig and mouse models involvement in the containment of tubercle bacilli during
of Mtb infection. Thus, evaluation of new vaccines against infection. However, the knowledge about the specificity of
the challenge of Beijing strain requires serious consideration. immune responses required for the clearance of bacilli still
Castañon-Arreola and colleagues (24) have reported that a remains fragmented. The reader is referred to the chapter
recombinant BCG strain over-expressing the 38kDa antigen “Immunology of tuberculosis” [Chapter 5] for more details.
of Mtb was able to provide better protection against a
Beijing strain of Mtb than BCG. The enhanced protective Tuberculosis–Human Immunodeficiency Virus
efficacy of recombinant BCG was not apparent when Mtb Co-infection and its Impact on Tuberculosis
H37Rv was employed as the challenge organism. The
Vaccine Development
mechanism of influence of various strains of Mtb on the final
outcome of the TB pathogenesis is not yet fully understood. A significant proportion of HIV/acquired immunodeficiency
However, rapid characterisation of various strains of Mtb syndrome [AIDS]-related deaths are caused by TB, which
by robust deoxyribonucleic acid [DNA] and ribonucleic is the single largest killer of HIV/AIDS patients (1,59).
acid [RNA] sequencing technologies are improving our Individuals living with HIV are 20-30 times more likely
understanding regarding the strain variation and its effect to develop active TB than people without HIV. In most of
on TB pathogenesis. the cases, HIV-infected patients develop active TB due to
The inadequate and variable protective efficacy imparted endogenous reactivation of latent infection and not due
by BCG suggests that a new vaccine may require to be to exogenous infection. In addition, pregnant women and
tested in several populations as it may exhibit optimum children are at a high risk of death when co-infected with
effectiveness only in certain populations based on age, HIV and TB.
genetic and environmental background, immune status, During HIV infection, a progressive decline in CD4+
nutritional status and lifestyle. Thus, a single TB vaccine T-cell count, especially Th1 subtype with a shift towards
may not meet the global expectations. Th2, results in failure to control most of the invading
opportunistic organisms. Mtb, being the robust of all, is
UNIQUE FEATURES OF THE PATHOGEN often the earliest to break the host defense (60). Besides
The TB bacillus, one of the most virulent and pathogenic the potentiating effect of HIV on the progression of TB,
species of its kind, belongs to the genus Mycobacterium, which generation of cytokines like tumour necrosis factor-alpha
contains at least 100 different species; a majority of these are [TNF-α] during control of TB infection may act as a potent
saprophytic, water and/or soil-borne organisms (25,26). enhancer of HIV replication resulting in an increased viral
Mtb is described as a slow-growing, strictly aerobic, acid-fast burden (61). Furthermore, the immune response generated
 Tuberculosis Vaccine Development: A Current Perspective 729

during active TB has been shown to prime peripheral blood and non-human primate, have vastly contributed to the
cells and enhances their susceptibility to HIV infection (62). understanding of TB. Each animal model has its strengths
Another important aspect is ‘BCG–HIV’ inter-dependence and weaknesses with varying degrees of extrapolation of
and their counter responses. While BCG vaccination in their research findings to humans. Nevertheless, all these
HIV-infected children may cause severe disseminated animal models resemble important facets of human TB in
mycobacteriosis (63), it also accelerates the course of HIV one way or the other. First, animals can be easily infected
infection (64). HIV infection has also been reported to reduce by pulmonary route, which precisely epitomises the way
the efficacy of BCG against extra-pulmonary TB (65,66). Due humans acquire infection. Secondly, various stages of disease
to these reasons, the WHO has recommended to discontinue progression in TB, like granuloma formation, liquefaction,
BCG vaccination in HIV-infected children (67). Taking into cavity formation and hematogenous spread, can be easily
studied in some of the animal models, especially in guinea
account the dangerous liaison between HIV–TB and the
pigs, rabbits and non-human primates [NHP]. Thirdly,
adverse events associated with BCG vaccine in the face of
distinctive signs of TB, like fever, weight loss, radiological
HIV infection, development of subunit and non-replicating
abnormalities and respiratory distress can also be observed
viral vector-based vaccines has been proposed as a suitable in these animal models. If left untreated, infected animals
option for HIV-infected individuals. eventually die of pulmonary insufficiency, a fate typical of
human TB patients. Hence, various animal models have been
Importance of Animal Models in successfully used for screening new TB vaccines as well as
TB Vaccine Development chemotherapeutic agents. Figure 54.1 depicts the protocol
used for the screening of TB vaccine candidates. For short-
Contribution of different animal models to TB research has term evaluation, two major parameters are conventionally
a long-standing history that can be traced back to the time assessed for vaccine efficacy studies in the animal models:
of Robert Koch. TB being an extremely complex disease [i] bacillary load in lungs and spleen and [ii] pathology. In
with diverse clinical outcomes, requires adequate animal long-term studies [i] survival of animals, and [ii] clinical
models that can mimic the disease process in humans. symptoms, such as, weight loss, radiological abnormalities,
The animal models, such as, mouse, guinea pig, rabbit and blood parameters, are measured.

Figure 54.1: Variables involved in the screening of vaccine candidates

ID = intradermal; SC = subcutaneous; IM = intramuscular; IV = intravenous; IFN-g = interferon-gamma; IL-2 = interleukin-2; IL-12 = interleukin-12;
IL-4 = interleukin-4; IL-10 = interleukin-10; TGF-β = transforming growth factor-beta
730 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Mouse Model of Tuberculosis the center (77,78). Further, the event of cavity development,
which is one of the hallmark events in clinical TB, does not
Amongst various animal models of TB, mouse model is the
form in mouse TB (79). Thus, despite its definite advantages
most popular and has provided huge wealth of information in the study of immunological aspects of TB, mouse model
regarding the basic mechanisms of immune responses. The has only been recommended for the first order screening
evidence for involvement of lymphocytes in mediating of vaccine candidates, which needs further validation
immunity to TB was successfully shown by the ability of from other animal models such as guinea pig, rabbit and
whole blood and spleen homogenates [from an infected NHP.
mice] to transfer delayed-type hypersensitivity [DTH] to a
naive mice (68). It was also observed that CD4+ cells, when
Guinea Pig Model of Tuberculosis
adoptively transferred, conferred immunity to TB and a
population of CD4+ memory cells also remains in the system Guinea pig is currently one of the most useful models of
after clearance of the infection by chemotherapy (69,70). human TB for evaluation of new vaccines. The primary
Further, seminal work in mouse model firmly established reason for this preference stems from the ability of guinea
the importance of Th1 pathway in the expression of pigs to initially develop a strong immunity leading to the
protective immunity (71,72). The mouse data have also formation of well-organised granulomas as seen in humans.
shown a potential role for CD8+ (73), CD4-/CD8- (74) These granulomas then undergo extensive caseation and
and g/d T-cells (75) in generating immune response to TB tissue necrosis eventually killing the animal. Moreover,
vaccines. In fact, there are several instances, where findings guinea pigs are sensitive to skin testing and can be used to
originally obtained in the mouse model have later been determine vaccination-induced DTH reaction. Further, in
verified in humans. For example, knockout mice deficient contrast to mouse model, guinea pigs, like human beings,
in IFN-g and interleukin –12[IL-12] genes were found to have a group of CD1+ molecules that are responsible for the
be highly susceptible to Mtb infection akin to patients with presentation of mycobacterial glycolipids to a specialised
hereditary deficiency in IFN-g and IL-12 signalling (76). Mice T-cell population. These CD1+ molecules have been shown
with deficient TNF-a signalling exhibited similarity with to present mycolic acids, lipoarabinomannan and other
rheumatoid arthritis patients who developed reactivation components of the mycobacterial cell wall to human T cells
TB on treatment with anti-TNF-a monoclonal antibodies. in vitro.
The most evident similarity is observed with dramatically The guinea pig model has also been employed to study
increased incidence of primary and secondary TB in the effect of malnutrition on TB, which is known to induce
knockout mice devoid of CD4+ cells, thus mimicking HIV a state of immunodeficiency. McMurray and colleagues
infection (76). have documented a series of immunological abnormalities
The usefulness of the mouse model has grown tremen­ associated with protein deficiency in guinea pigs, which,
dously over the last two decades due to the availability of when viewed in a clinical context, mimic the situation, where
a vast array of reagents like monoclonal antibodies to T-cell malnutrition in humans results in an increased suscepti­
surface markers, cytokines and chemokines. Moreover, bility to TB (80). Malnutrition is known to impair several
advancement in the field of transgenic expression, gene aspects of mycobacterial antigen-specific peripheral T-cell
knock-out, gene knock-in technologies, along with the function, including lympho-proliferation, interleukin-2 [IL-2]
availability of a large variety of mouse mutants with defined production, expression of the CD2 marker and the ability to
immune deficiencies have immensely helped the scientific mount a DTH response (81-83). These immunological altera­
investigators in dissecting the precise nature of immune tions, which seem to be associated with the loss of vaccine-
response to Mtb infection. The mouse genome sequence has induced and naturally acquired resistance to pulmonary TB
further helped in designing genome-based experiments to in guinea pigs, can serve as suitable surrogate markers for
pinpoint the importance of key genes involved in innate and protection.
adaptive immunity against TB and understanding the role Most of the vaccine candidates are first screened in mouse
of downstream signaling pathways. model of TB and only promising candidates are taken up
Although, mouse model provides a huge advantage for screening in guinea pigs. But this strategy of prioritising
in terms of cost effectiveness, it fails to completely mimic any vaccine candidate should be analysed very carefully as
the entire spectrum of human TB. The mouse is innately there are chances of losing those candidates, which, though
resistant to TB and generates a strong cellular immune may not be efficacious in mice, but may have tremen­
response against Mtb infection and controls bacterial dous potential in guinea pigs. For several years, paucity
growth and disease progression. However, mouse does of immunological reagents for guinea pigs, has precluded
not develop a strong DTH response in contrast to what is its use as a first-order screening model. However, recent
observed in humans. In addition, the cellular organisation advancements in microarray (84) and RNA sequencing
in the granuloma in mice is characterised by aggregation of technology (85) as well as availability of immunological
lymphocytes towards the centre, which is in striking contrast reagents, is now allowing simultaneous assessment of
to humans and guinea pigs wherein lymphocytes form a immune responses and vaccine efficacy in this extremely
peripheral ring with arrangements of macrophages towards valuable animal model.
 Tuberculosis Vaccine Development: A Current Perspective 731

Non-human Primate Model of Tuberculosis helped the process of identification of vaccine candidate by
interspecies comparison of the genome sequences (97,98).
On comparative assessment of all the existing animal models
Moreover, it has also helped to understand the source of
of TB, NHP like rhesus monkey, cynomolgus monkeys, etc.
antigenic variation among different strains of Mtb. Appli­
were found to mimic several aspects of human TB (86).
cation of microarray and RNA-sequencing technologies have
Apart from the susceptibility to natural infection with a range
revealed a repertoire of new-stage specific antigens of Mtb,
of mycobacterial species, NHPs are very similar to humans
which are expressed in different phases of infection (99,100).
in terms of granuloma architecture and various stages
Unlike the conventional targeted gene knockout methodo­
of disease progression (87,88). In addition, NHP [rhesus
logy, application of techniques like transposon muta­
monkey] and humans share the presence of similar functional
genesis and signature-tagged mutagenesis have made it
major histocompatibility complex [MHC] molecules,
possible to screen a large number of mutants simultaneously
which bind specifically to mycobacterial peptides (89,90).
for their growth and virulence in experimental animal
Further, both humans and NHP have CD1 molecules in
models (101,102). Two other areas namely subunit and DNA
common, those are required for presenting several non-
vaccines have also been significantly benefited from the
peptide mycobacterial products to the T cells (91,92). Besides,
genome sequencing of Mtb. For example, several secreted
in NHP, the course of infection can be easily followed up
or surface-exposed proteins, which are widely used as
by chest radiograph, weight loss, as well as by performing
vaccine candidates, were discovered based on the presence
a variety of immunological assays, which provide a detailed
of specific sequences or motifs. This in silico analysis to
insight into the disease progression. It has also been further
identify new vaccine candidates, which is termed as ‘reverse
developed to study HIV and TB co-infection, which has helped
vaccinology’, has tremendously boosted the entire vaccine
in understanding the disease pathogenesis and treatment
development program (103,104). It has also provided access
of HIV-related TB (93). Langermans and colleagues (94)
to the entire repertoire of Mtb antigens. With the application
using the macaque model showed that protection against a
of advanced immuno-informatic tools, several antigenic
high dose of Mtb infection could be achieved in cynomolgus
secretory proteins and their potent T-cell epitopes have been
monkeys with BCG vaccination, although no such protection
identified for the development of novel protein, peptide or
was observed in case of rhesus monkeys. Though rhesus
epitope-based vaccines.
and cynomolgus monkeys are closely related species, they,
differ markedly in their susceptibility to Mtb infection and
STRATEGIES FOR THE DEVELOPMENT OF
BCG-induced protection; these two species, thus-represent
the two extremes of the degree of protection induced by TB VACCINES
BCG in humans. Since most of the vaccines need to be Despite the lack of a perfect understanding about protective
compared to BCG, cynomolgus can be very useful for the immunity against TB, there are several reasons to believe
evaluation of subunit and DNA vaccines, whereas live that a better TB vaccine is biologically possible. Less than
attenuated vaccines [like recombinant BCG] may show a 10% of individuals infected with Mtb develop the disease
clear improvement over BCG in rhesus monkeys (94,95). which strongly supports the notion that most people are
Though the studies in macaque model have tremendously immunocompetent and well equipped to keep the pathogen
helped gaining an insight into the immune responses and in check. However, reactivation of persistent tubercle bacilli
pathogenesis associated with human TB, several critical in asymptomatic individuals suggests that natural infection
disadvantages have reserved this model only for the final with Mtb does not provide complete sterility, leaving behind
stage of vaccine evaluation. The disadvantages, such as, some bacilli in dormant state. Thus, to outperform natural
high cost, requirement of extensive biohazard containment Mtb infection, a vaccine should induce a more potent
facility, difficulty in handling, difficulty in maintaining immune response than the pathogen. Figure 54.2 depicts
disease-free colonies of these primates, which are extremely various stages of the disease progression, where specific
susceptible to mycobacterial infections, have resulted in the intervention strategies like drugs and vaccines can be used.
testing of only a few candidate vaccines in primates till date. Various vaccination strategies that have emerged in the last
two decades are listed in Table 54.1.
IDENTIFICATION OF VACCINE TARGETS
IN THE POST-GENOMIC ERA Recombinant Bacille Calmette-Guérin
The complete genome sequencing of Mtb in 1998 has not It is well acclaimed that BCG protects children against
only brought a paradigm shift in the cellular and biochemical childhood TB. Hence, instead of replacing BCG with
dissection of the pathogen but has also tremendously another vaccine, it is now logical to improve the current
accelerated the vaccine development program (96). Modern vaccine by expressing in BCG the immuno-dominant Mtb
bio-informatic methods have provided means for in silico antigens involved in pathogenesis, persistence and immuno-
genome wide characterisation of immuno-dominant antigens modulation. Alternatively, BCG or a recombinant BCG
allowing rapid discovery and development of new vaccines. [rBCG] can be employed in a prime boost strategy. Thus,
Further, sequencing of the genomes of 18 Mycobacterium without hampering the childhood immunisation programme,
species has opened up several new vistas and has significantly an rBCG vaccine would help in improving the protective
 732 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Figure 54.2: Different stages of Mycobacterium tuberculosis infection and intervention strategies. The figure illustrates the heterogeneity in terms
of the outcome of infection in different individuals and various stages of the disease progression, where specific intervention strategies like drugs
and vaccines can be used
TB = tuberculosis; HIV = human immunodeficiency virus; MDR-TB = multidrug-resistant tuberculosis

efficacy against adult pulmonary TB. Along with its potent of a protein into the extra-cellular milieu (105-111). Apart
immuno-adjuvant property, high degree of safety for human from the restoration of the lost genes like early secretory
use and the availability of expression systems that provide antigenic target-6 [ESAT-6] and MPB-64, which are absent
enhanced and stable expression of genes in mycobacteria, from BCG, several other antigens like major secretory
BCG became a very attractive vehicle for the development 30-32 kDa protein, 16 kDa HspX, etc. have been expressed
of new rBCG vaccines. In addition, several strategies have in BCG and evaluated for their protective efficacy in mice
been devised to enhance the expression and/or secretion and guinea pig models of TB (112-114). It is an excellent
 Tuberculosis Vaccine Development: A Current Perspective 733

Table 54.1: Various vaccination strategies that have highly immuno-dominant antigens (124). This has provided
emerged in the last two decades rationale for the development of live vaccines using an Mtb
background rather than M. bovis BCG background. Such
Recombinant BCG
strains can be developed by either producing auxotrophic
Live attenuated mutants and auxotrophs of Mycobacterium
mutants of Mtb with limited replication capacity in immuno-
tuberculosis
compromised subjects or by disrupting virulence genes
NTM vaccines
necessary for host–pathogen interaction (125).
Subunit vaccines A number of auxotrophic Mtb mutant strains developed
DNA vaccines by random transposon-mutagenesis, signature-tagged
Epitope-based vaccines mutagenesis, illegitimate recombination and allelic exchange-
Prime-boost immunisation strategies homologous recombination have been assessed for their
BCG = bacille Calmette-Guérin; NTM = nontuberculous
protective efficacy in experimental animal models (125-130).
mycobacteria; DNA = deoxyribonucleic acid For example, a leucine auxotroph of Mtb that was severely
attenuated in severe combined immunodeficiency syndrome
[SCID] mice was completely cleared from mouse organs
approach and has resulted in the development of several within a few weeks of immunisation. However, at least
promising new TB vaccine candidates (112-114). However, two doses were required to elicit significant protection in
care must be exercised in the selection of genes as over- immunocompetent C57BL/6 mice. Due to its remarkable
expression of the genes involved in pathogenesis may result safety in immunocompromised mice, it is a potential candi­
in a BCG strain with enhanced virulence. For example, re- date vaccine for use in immunodefficient individuals (130).
introduction of complete region of difference-1 [RD1] locus, The tryptophan and proline auxotrophs of Mtb have also
although resulted in a better protection in immunocompetent been found to be highly attenuated and confer protection
mice, it was found cause virulence in immuno­compromised equivalent to proline or better tryptophan than BCG against
mice (115,116). Also, over-expression of antigens like 19 kDa Mtb infection in DBA/2 mice (129). A panCD mutant of Mtb
lipoprotein or superoxide dismutase [soda] in RBCG has [genes required for de novo biosynthesis of pantothenate] was
resulted in an overall change in the immunomodulatory nature observed to be highly attenuated in immuno-compromised
of BCG, resulting in loss of protective immune responses SCID and IFN-g deficient mice. The panCD mutant was
induced by BCG alone (117,118). found to be much safer than BCG and elicited long-term
An efficient anti-TB immunity relies upon a Th1 immune memory response, which persisted for several months after
response, which has led to the development of rBCG vaccines immunisation (131). A double auxotroph of Mtb [leucine
expressing human Th1 cytokines like IFN-γ, interferon- and pantothenate] also provided long-term protection
alpha [IFN-α], IL-2 and IL-12 (119-122). Although, all these against Mtb infection in guinea pig model and was found
recombinant strains exhibited improved Th1 response, their to be safe in non-human primate model (127,132). Further,
protective efficacy is not satisfactory. BCG is known to lysine lysA and secA2 double mutant of Mtb was found to
induce a detectable cytotoxic T-lymphocyte [CTL] response, be highly efficacious and safe in mouse model compared to
however, its inability to access class I antigen-processing BCG vaccination (133).
pathway has necessitated procedures to augment CD8+ T-cell A second approach relies on attenuation of Mtb genes
response. An rBCG strain expressing listeriolysin of Listeria required for virulence. Till date, several virulence genes
monocytogenes, which forms pores in the phagolysosomal have been identified, disrupted and the resulting mutants
membrane, has been reported to escape to the cytoplasm assessed for their growth in vitro and in vivo (134-139).
thereby promoting antigen processing by class I pathway These knock-out strains were found to have differences in
resulting in a greater cytotoxic T cell response and a better their virulence and growth characteristics. For example, Mtb
protection against Mtb infection (123). This vaccine is now mutants deficient in dormancy-associated genes replicate in
undergoing phase II clinical trial for its protective efficacy mice lungs in an unconstrained manner early after infection,
against TB.
but cease to grow at later stages due to their impaired
dormancy gene program (134).
Live Attenuated Mutants and Auxotrophs of Due to highly pathogenic nature of Mtb, development
Mycobacterium tuberculosis of mutant strains for vaccine development requires careful
The development of Mtb mutants as vaccine candidates consideration. An ideal Mtb mutant should have at least two
primarily relies upon the assumption that the vaccine or more unlinked genes deleted to reduce the probability
strain should be antigenically as identical as possible to the of reversion. However, such mutants should be able to
disease-causing organism. By comparative genomics, it has survive inside the host for sufficient time to generate an
been revealed that in comparison to Mtb 16 defined regions efficient immune response. Altogether, mutations should
[RD1-RD16] are deleted from the currently used BCG strains. result in a fine balance between attenuation and immuno­
These regions encode 129 open reading frames [ORFs], genicity as over-attenuated bacilli may be devoid of key
including several regulatory genes as well as some of the antigens necessary for protective immunity. In addition,
734 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

these mutants need to be tested rigorously in immuno- The apparent inability of the subunit vaccines to mount a
suppressed animal models to ensure complete safety. strong T-cell response has accelerated the process of adjuvant
discovery required to induce a potent Th1 response by these
Atypical Mycobacterial Vaccines subunit vaccines. New adjuvants like dimethyl dioctadecyl
ammonium bromide [DDA], monophosphoryl lipid A
Atypical and saprophytic species of mycobacteria that [MPL-A] and AS02A, which are potent modulators of T-cell
are closely related to Mtb have been evaluated for their responses, have been shown to enhance the immunogenicity
vaccine efficacy in various animal models and human trials. and protective efficacy of several subunit vaccines when
The close phylogenetic relationship of these organisms compared with the traditional adjuvants (158-160). For
with Mtb renders them antigenically similar to the patho­ instance, early secreted antigenic target 6 [ESAT 6] as a
gen. Apart from having an adjuvant-like property, these stand-alone purified protein failed to stimulate the adaptive
atypical mycobacteria are non-pathogenic even in immuno­ arm of immune response, but stimulated protective immune
compromised individuals. In a human trial, M. microti, when responses equivalent to BCG, when injected along with
used in a prophylactic mode, conferred 77% protection, a mixture of DDA and MPL-A (161). The fusion protein
comparable to BCG against TB in infants (140,141). Several 72f, when used along with an adjuvant AS01, exhibited
studies have also been carried out with killed/live or very promising results in several animal models and is
recombinant M. vaccae in both prophylactic and immuno- currently in phase II clinical trials (153). In addition, fusion
therapeutic mode resulting in protective efficacy comparable of antigen 85B and ESAT-6 proteins in two different adjuvant
to BCG (142-144). In a separate study, M. habana exhibited formulations [IC31 and CAF01] are currently in phase I
improved protection over BCG in a mouse model (145,146). clinical trials (153).
In another approach, killed Mycobacterium indicus pranii
[previously known as M. w] caused reduction in the bacillary Deoxyribonucleic Acid Vaccines
load in mice and prevented formation of granulomatous
lesions in guinea pigs (147-151). A long-term human trial The observation that immunisation with naked DNA could
covering a very large population in north India revealed direct the immune system towards stronger and persistent
protective efficacy of M. indicus pranii against leprosy. The cellular and humoral immune responses attracted many
follow-up studies on the same population showed that investigators towards this area (162,163). Intramuscular
M. indicus pranii also reduced the incidence of TB in this injection of a mammalian expression vector encoding a
population by 61.5% (152,153). However, the unpublished desired gene, results in the expression of corresponding
data on M. indicus pranii in phase III clinical trials shows protein, which subsequently induces a potent cellular
that the vaccine failed to show any protection against TB. immune response against the encoded antigen. This
is especially advantageous in the context of TB as the
Subunit Vaccines protective immunity against Mtb is primarily dependent
on the cellular fraction of the immune system (76). DNA
Subunit vaccines represent one of the most popular appro­ vaccine allows continuous expression of a particular antigen,
aches for vaccine development. Subunit vaccines against Mtb thereby exposing the immune system to the antigen for a
mainly comprise secretory [culture filtrate proteins] and non- prolonged time. The usefulness of DNA vaccines has led to
secretory proteins, lipids and carbohydrate antigens derived the development of a variety of methods for their delivery
from Mtb cell wall, which have been used in adjuvanted or to a desired site in the host. Direct injection, electroporation
non-adjuvanted formulations. In addition, several subunit or gene–gun based delivery into muscles, delivery to the
vaccines have been developed by using non-mycobacterial respiratory mucosa using liposome encapsulated DNA
vectors, such as attenuated pox and adenoviruses. vaccines, etc., are in common use for delivery of DNA
Mtb alters its antigenic repertoire when it shifts from vaccines (164-168). Expression of antigens by DNA vaccines
an active state to a dormant non-replicating state (154). and their subsequent processing and presentation along with
Thus, it can be advocated that for a prophylactic vaccine, the MHC class I molecules mimic the antigen-processing
the candidate antigens should comprise proteins that are pathway followed by an intracellular pathogen. Several DNA
rapidly secreted during early infection. On the other hand, vaccines have been developed in the last decade and have
the proteins associated with dormancy-induced genes would been evaluated for their efficacy against TB in various animal
serve better for a post-exposure vaccine. Indeed, a vaccine models. DNA vaccination with genes encoding the members
that includes antigens from both the classes is most likely to of Ag 85 complex of Mtb and 65 kDa heat shock protein of
protect individuals from various populations with different M. leprae conferred protection equal to BCG (169,170). A
age groups and exposure levels. The widespread use of BCG significant protection [equivalent to BCG] was also observed
in neonates and its apparent effectiveness against paediatric in case of ESAT-6, MPT-64 [a 24-kDa protein secreted by
TB has made it difficult to replace BCG with a new vaccine. Mtb] (171), phosphate-binding protein [PstS] (172) and a
Thus recently, the focus of TB vaccine research has shifted proline-proline-glutamic acid [PPE] protein (173) when used
towards using these subunit vaccine candidates as a boosting as DNA vaccines in mouse model of experimental TB. The
agent in populations that have already been immunised with advancements in the field of recombinant DNA technology
BCG (155-157). have facilitated simultaneous expression of more than one
 Tuberculosis Vaccine Development: A Current Perspective 735

gene using a mammalian expression vector. DNA vaccines the immune system once primed with an antigen elicits
based on fusion of antigen Ag85B with either ESAT-6 or a heightened response to the secondary exposure of the
MPT-64 gene conferred protection better or equivalent to antigen, has been utilised to develop effective prime-boost
BCG (174). DNA vaccines expressing latency-associated vaccination strategies against TB. Repeated administration
antigen HspX has demonstrated remarkable protection with the same vaccine [called homologous boosting] has
as a booster vaccine following BCG or rBCG vaccination proved to be relatively inefficient at boosting cellular
in animal models (113,157). Moreover, expression of co- immunity, instead it generates a very strong humoral
stimulatory molecules, such as, different cytokines and response. This has been especially observed in case of BCG
chemokines and inclusion of CpG motifs in the DNA vaccine which, when administered, repeatedly offered little benefit
backbone has helped in enhancing the immunogenicity of in humans as well as in various animal models (186).
DNA vaccines. Despite several promising results in animal Besides, these studies also demonstrated that the myco­
models, issues related to antibiotic markers in the plasmid bacterial sensitisation dramatically lowers the effectiveness
DNA backbone, concerns regarding integration of these of BCG (187-190). In order to circumvent this problem,
plasmids in host genome and development of anti-DNA ‘heterologous boosting’ came into being, which involves
antibodies leading to autoimmune diseases have prevented sequential administration of vaccines with appropriate
their entry into the human clinical trials till date. However, intervals using different antigen-delivery system such that
several regulatory measures have been introduced globally the immune system is primed to the antigen using one vector
to improve the safety and usefulness of DNA vaccines in and is then boosted with the same antigen delivered through
humans (175-177). a different vector. The key strength of this strategy lies in
the synergistic effect of vaccines on immunity, instead of the
Epitope-based Vaccines additive effect generally observed in the case of homologous
boosting (191-193). This synergistic enhancement of
Epitope-based vaccines, the latest entry in the field of vaccine
immunity to the target antigen is reflected by an increased
development, have quickly emerged as one of the promising
number of antigen-specific T cells and selective enrichment
advancements in the field of vaccine discovery. Recently,
of high avidity T cells. Moreover, it also induces an elevated
strategies for exclusive delivery of immuno-dominant T-cell
level of both CD4+ and CD8+ T-cell response. The tremen­
epitopes of a single or multiple proteins have emerged.
dous power of prime-boost was highlighted in a murine
One of the potential advantages of this epitope-based
model, wherein intranasal vaccination of mice with BCG,
approach includes higher safety as it helps in getting rid of
followed by a booster of a recombinant modified vaccinia
the unwanted, toxic or immunosuppressive regions from a
virus Ankara expressing antigen 85A [MVA85A], resulted
protein. This also provides the opportunity to appropriately
in a nearly 300-fold reduction in bacillary load in the lungs
engineer the epitopes to elicit a desired immune response.
following aerosol infection with Mtb (194). This would
Several immuno-dominant epitopes have been identified
mimic the situation where a gradually declining immunity
by employing either the bioinformatics or by screening
of BCG can be enhanced by boosting with a candidate
the T-cells derived from TB patients at various stages of
antigen specifically recognised by memory immunity. Under
disease progression by in vitro assays employing different
the European Union, TB vaccine screening program, 26
overlapping peptides of a protein (178-180). Moreover,
comparative genomics have also helped in the identification different strategies involving various antigens and delivery
of conserved epitopes across various pathogenic organisms, approaches were simultaneously evaluated in guinea pig
which can be incorporated along with the Mtb epitopes to model. Amongst all the strategies, the MVA85A-based prime
generate a multipurpose vaccine (181). This approach can boost vaccination described above was the only successful
prove to be extremely beneficial, if the specificity of T-cells strategy that significantly prolonged the survival of guinea
isolated from exposed but asymptomatic individuals is pigs in comparison to BCG vaccination (195). This vaccine
characterised against a vast array of peptides isolated from became the first new generation TB vaccine to enter the
Mtb proteome. These peptides can be further assessed for human trials. Although, the vaccine was found to be safe
their immunogenicity in the form of multivalent epitope- and immunogenic in phase I and phase II human trials,
based vaccine. Till date, several epitope-based vaccines have however, the vaccine failed to show any protection against
been developed and evaluated in animal models (182-185). TB in phase III trial (196-199). Apart from the viral vectors,
Some of these vaccines have shown encouraging results; which have been highly recommended as boosting agents,
however, none of the vaccines have moved to clinical trials. subunit vaccines including both recombinant proteins and
With the availability of an effective delivery system, a multi- DNA vaccines, are now being used to boost the immunity
epitope-based vaccine may emerge as one of the potential imparted by BCG. In a study, it was observed that with
means of immunisation. age, mice vaccinated with BCG gradually lose their capacity
to resist an aerosol infection with Mtb. However, if these
mice are boosted with the Ag85A protein [with MPLA as
Prime-boost Immunisation Strategies
an adjuvant] in midlife, it restored back the resistance in
The concept of ‘boosting’ the immune responses traces elderly mice to levels equivalent to young ones; with reduced
its history back to the time of Louis Pasteur. The fact that pathological damage and bacillary load on lung (200).
736 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Besides the use of BCG as the priming agent, several efforts which may have unfavorable consequences. For instance, use
to develop other heterologous prime-boost immunisation of anti-TNF-a antibodies although reduced the pathology
strategies have also been tested, wherein, subunit or DNA and inflammation associated with rheumatoid arthritis,
vaccines have been employed as priming agents (201-204). it resulted in increased incidence of reactivation of latent
Success of heterologous prime-boost immunisation strategies infections in these patients (212,213). However, when anti-
has generated optimism for the development of effective TNF-a antibodies were used as an adjunct to chemotherapy,
anti-tubercular vaccines in future. it substantially improved the body weight, radiological
scores and sputum culture conversion in patients with TB-
IMMUNOTHERAPEUTIC APPROACH TO HIV co-infection (214). Due to these dual effects, use of anti-
COMBAT TUBERCULOSIS TNF-a antibodies for the treatment of TB patients is still in
the pre-clinical stage.
Current strategies for TB control are based on the reduction With growing evidence for the role of various cytokines
of transmission by treatment of active cases and prevention like IFN-g, IL-2, interleukin-4 [IL-4], IL-12, interleukin-18 [IL-
of disease by prophylactic vaccination. The available 18] etc., in TB pathogenesis and protection, several immuno-
chemotherapy comprises a very lengthy treatment schedule therapeutic strategies have been developed. For example,
[6-9 months] with a combination of four drugs, namely, an aerosol delivery of IFN-γ was found to produce clini­
isoniazid, pyrazinamide, rifampicin and ethambutol. This cally encouraging response in treating multidrug-resistant
therapy, although successful against drug sensitive TB, TB [MDR-TB], although the effect was transient (215,216).
often fails due to non-compliance with the lengthy treatment In another study, treatment with granulocyte-macrophage
regimens. Non-compliance with anti-TB treatment often colony-stimulating factor [GM-CSF] along with IFN-γ
leads to relapse and emergence of drug resistance. Thus, in success­fully treated patients with refractory central nervous
order to reduce the incidence of relapse and emergence of system MDR-TB (217,218). Further, a cocktail of six recombi­
drug resistance cases, it is imperative to develop effective nant proteins [six antigens: 85B, 38Kda, ESAT6, CFP21,
means to reduce the duration of TB therapy. However, Mtb8.4, and 16Kda] along with IFN-γ and Ribi adjuvant,
till the difficult goal of shorter chemotherapy is achieved, monophosphoryl lipid A-trehalose dicorynomycolate
parallel research is underway to develop effective immuno­ [MPLA-TD] conferred a significant protection against Mtb
therapeutic agents that can serve as an adjunct to standard infection in mouse model (218). Besides, IL-2 immunotherapy
chemotherapy (205-207). It may not only reduce the prolonged in MDR-TB patients resulted in a significant immune
chemotherapy period but may also eliminate dormant activation and reduced bacillary burden (219). However,
bacilli and consequently prevent reactivation. Additionally, in a separate study, no significant reduction in the clinical
a reduction in the conversion of re-infection into active symptoms was observed when IL-2 was used as an immuno­
disease may be another possible spin-off. therapeutic agent in adults suffering from drug-susceptible
DNA vaccine immunotherapy along with chemotherapy TB (220).
has shown considerable promise in the treatment of TB Another important class of immunotherapeutic agents
are modulators of host cell signalling pathways, however,
disease in pre-clinical animal models. In a study, a combi­
most of them are involved in regulating various cytokine
nation of two DNA vaccines [Ag85A and PstS-3] in mice
pathways. One of the recent examples is the use of phospho­
along with chemotherapy was found to prevent exogenous
diesterase inhibitor, which increases the cyclic adenosine
re-infection as well as endogenous reactivation (208).
monophosphate [c-AMP] production by macrophages
Supplementing the chemotherapy with DNA vaccine
leading to reduced levels of TNF-a and TB-associated
encoding the Mycobacterium leprae hsp60 also resulted in
pathology. Phosphodiesterase inhibitors when used along
a significantly reduced course of treatment (209). In an with TB chemotherapy demonstrated enhanced bacterial
alternative approach, the use of Mycobacterium vaccae as clearance compared to treatment with the chemotherapy
an immunotherapeutic agent successfully enhanced the alone (221,222).
Th1 response, however, the expected improvement in the Poor nutrition has long been associated with the increased
treatment of HIV- infected adults with pulmonary TB was risk of TB (223,224). Several studies have addressed the role
not observed (210,211). of vitamin D supplements and its immunotherapeutic effects
Immunotherapy can also be used to downregulate a in TB patients. Particularly, vitamin D supplement was found
highly exaggerated immune response in the patients with to be beneficial as an adjunct to chemotherapy in patients
severe disease. The aggravated pathological damage in active with severe vitamin D deficiency. The proposed mechanism
pulmonary TB, which stems from a localised and a systemic behind the effect of vitamin D is the action of bioactive
production of high levels of Th1 cytokines such as IFN-g or 1,25-dihydroxy vitamin D 3 in potentiating autophagy,
TNF-a, can be reduced by targeted suppression of these phagolysosomal fusion and release of antibacterial peptide
cytokines by using neutralising antibodies. Besides, the use cathelicidin (225,226). Although adjunctive immunotherapy
of systemic immuno-suppressing agents like corticosteroids, is reasonably effective, it still poses serious problems such
etc. can also produce similar effects. However, in the use as, high cost, occasional adverse effects and induction of
of these immuno-modulatory agents, extreme care should tolerance during long-term application of immune adjunctive
be taken to avoid over-suppression of the immune system, agents. Identification of newer immuno-therapeutic agents,
 Tuberculosis Vaccine Development: A Current Perspective 737

their delivery mode and dosage may possibly help in In some industrialised and developed countries, animal
shortening the prolonged chemotherapy period and an TB control and eradication programme, together with milk
effective management of the disease in future. pasteurisation have drastically lowered the incidence of TB
caused by Mycobacterium bovis in both animal and human
Impact of Zoonosis on TB Vaccine Development population (240), however, a developing country like India,
which has the largest livestock population in the world, has
Zoonotic diseases in humans include all the diseases that are no effective control and eradication programme for bovine
acquired from or transmitted to any other vertebrate animal.
TB. Apart from developing vaccines against both human
Among the various zoonotic diseases, TB represents one of
and bovine form of TB, control of zoonotic TB in India and
the most common diseases transmitted to humans. Although,
other developing countries needs co-ordination between the
Mtb is the causative agent of human TB, a significant
human and bovine TB vaccine development programmes
proportion of human infections is caused by Mycobacterium
along with strict regulatory measures. As the degree of cattle
bovis—the aetiological agent of bovine TB. The pulmonary
movement in a country also enhances the incidence of TB
TB caused by Mtb and Mycobacterium bovis are clinically
and other zoonotic diseases, strict surveillance of animal
indistinguishable with similar radiographic and pathological
migration may further help in bringing down the incidence
features (227,228). In many African and Asian countries,
rate (241). In addition, specific and effective surveillance
where cattle are an integral part of social life, close physical
strategies for different species of Mycobacterium will aid in
contact between humans and infected animals leads to
detection of TB cases of diverse origin, which would help
significant proportion of human TB of bovine origin. Several
in developing effective prevention and treatment strategies
incidences of human TB caused by Mycobacterium bovis were
for TB.
reported from Africa (229,230), Latin America (231,232) and
some of the Asian countries (227,233). In Latin America, 2%
of the total pulmonary cases and 8% of extra-pulmonary TB Tuberculosis Vaccines in Clinical Trials:
cases were reported to be caused by Mycobacterium bovis (227). Key Issues
Analysis of the cerebrospinal fluid from patients suffering Last decade has clearly witnessed a resurgence in the field of
from TB meningitis in India revealed that in comparison to TB vaccine research; more than 200 new vaccine candidates
Mtb (2.8%), 17% of the samples were found to be positive have already been evaluated for their efficacy in various
for Mycobacterium bovis (234). In addition, 8.7% and 35.7% animal models and several promising candidates are now in
of the samples collected from human sources and cattle, various phases of human clinical trials (153). These vaccine
respectively were classified as mixed infections with Mtb candidates have shown encouraging results in various pre-
and Mycobacterium bovis (235). The incidences of TB due clinical animal models, including the non-human primate
to Mycobacterium bovis infection have also been reported in model. However, success in various animal models does
HIV-seropositive TB patients. For example, in France, 1.6% not always guarantee effectiveness of a vaccine in human
of TB cases in HIV-positive patients were found to be caused trials. The best examples are MVA85A, one of the most
by Mycobacterium bovis infection (236). On the other hand, promising candidate vaccines. Recent report of MVA85A
cases of Mtb infection in cattle have also been reported from phase IIb trial in infants in South Africa, showed no evidence
India as well as some of the European countries, though the of protection against Mtb infection, although, it did meet
incidence rate was not very high (235,237). the primary objective of the trial, i.e. safety (199). TB being
As the performance of BCG in preventing bovine TB a chronic disease with diverse clinical and pathological
is doubtful, devising an effective vaccination strategy outcomes in different individuals, it may be unwise to expect
against bovine TB would be a viable option in controlling a single vaccine to work efficiently in all these different
Mycobacterium bovis-based human infections in addition to situations. Hence, lack of protection in one population does
reducing the burden of bovine TB. Several recombinant BCG not negate the possibility of beneficial effects of MVA85A in
strains, subunit vaccines and DNA vaccines expressing Mtb other populations. This also justifies testing of new vaccine
antigens, have also been assessed for their efficacy in bovine candidates in multiple target populations encompassing
model against M. bovis infection. Prime-boost vaccination different age groups, immune and nutritional status as well
strategies by using DNA vaccines encoding Hsp65, Hsp70 as geographical and genetic background. Another important
and Apa as priming agent followed by a booster of BCG have question that emerged from this study is regarding the
provided substantial evidence that this regimen can provide existing immunological correlates of protection. Although,
better protection in calves than either of the vaccines when in animal models, induction of antigen-specific Th1 and
used alone (202). In another strategy, Martin and colleagues Th17 responses were found to be associated with protection
reported substantial protection in cattle immunised with conferred by MVA85A, a similar immune response in
BCG followed by a booster of MVA85A and attenuated humans did not lead to protection (199). These observations
fowl pox strain FP9 [FP85A], expressing antigen 85A (238). raised an alarm regarding the insufficiency of the existing
Furthermore, a combination of DNA vaccines encoding immunological correlates of protection and, thus, demand
Ag85B, MPT64 and MPT83 when tested for their efficacy identification and development of new parameters that can
using DDA as an adjuvant, was found to be highly effective be employed both in animal models and humans. Recently,
in controlling bovine TB (239). primary analysis of the ongoing randomised, double-blind,
738 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

placebo-controlled, phase IIb trial (242) of the M72/AS01E diseases in the area; [iii] identification of specific inclusion
TB vaccine in Kenya, South Africa, and Zambia, revealed and exclusion criteria of subjects for enrolment of volunteers
that M72/AS01E provided 54.0% protection for Mtb-infected in the clinical trial based on the type of vaccine and its target
adults against active pulmonary TB disease. Nonetheless, the population; [iv] development of novel, cost-effective and
ongoing clinical trials have generated tremendous hope in easy-to-perform robust diagnostic assays and harmonisation
the TB research community as well as in general population. of the assay procedures and data analysis are critical for
These trials have not only addressed the safety issues comparison among various vaccine candidates tested in
pertaining to different types of vaccines, but also provided different trials; [v] along with adherence to the global
the opportunity to perform detailed immunological assays ethical and regulatory norms, local factors at the trial sites
on multiple samples obtained from different populations. such as, cultural perceptions, economic condition, language,
The detailed characterisation of immune responses will education, technological advancements must be given
prove to be instrumental in selecting the most reliable set of due consideration; and [vi] finally, a continuous financial
immunological parameters for future studies. support and participation from governmental as well as
Table 54.2 shows the current status of the pipeline non-governmental organisations is the key to the success of
for new TB vaccines (153). Presently, eight vaccines are any clinical trial.
in phase II or phase III trials. An efficient management One of the greatest challenges of the 21st century medi-
of regulatory and operational issues is one of the major cal research is developing an improved TB vaccine, which
challenges while conduc­ting a successful clinical trial for provides complete protection against TB. Although several
TB vaccines. This requires [i] a focused and co-ordinated key questions related to TB still need to be answered, a
effort of multi-disciplinary expertise or networks, such as great deal of hope has emerged due to rapid increase in
mycobacteriologists, epidemiologists, clinical trial specialists, our understanding of cellular immunity, knowledge of
vaccine biologists, immunologists, clinicians, statisticians, entire genome of several Mycobacterium species and advent
social workers, etc.; [ii] selection of an appropriate trial of new and improved approaches for studying global gene
site based on detailed epidemiological knowledge of TB, regulatory patterns. Besides, development in the area of
HIV and incidences of other infectious and non-infectious proteomics and metabolomics is facilitating the identifica-
tion and characterisation of new virulent determinants and
immunodominant antigens, which is allowing the develop-
Table 54.2: The development pipeline for new TB ment of novel intervention strategies. In addition to a strict
vaccines, 2018 regional surveillance and international cooperation, if all the
Phase I necessary resources are committed for the development of
Boosting vaccines TB vaccines, we might be able to go a long way in our fight
   Ad5 Ag85A [McMaster, CanSino] against this enormous global health problem.
   IDR93 + GLA-SE [IDRI, Aeras]
   DAR-901 [Darmouth University, Aeras] ACKNOWLEDGEMENTS
   ChAdOx1.85A [Oxford, Birmingham]
   Crucell Ad35 – MV85A prime-boost [UOXF, Aeras, Crucell] A part of the work included in this chapter was supported
Priming vaccines by financial grants received from the Department of
   MTBVAC [Biofabri, TBVI, Zaragosa] Biotechnology, Government of India. The help rendered by
Phase IIa Rajiv Chawla in the preparation of the manuscript is also
Boosting vaccines acknowledged.
   Crucell Ad35 / Aeras402 [Crucell, Aeras]
   H I + IC31 [SSI, TBVI, Intercell, EDCTP]
   H56: IC31 [SSI, Intercell, Aeras] REFERENCES
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 55
Ethical and Legal Issues in Tuberculosis Control
John Porter

INTRODUCTION The field of ethics, because it is to do with questions

about ‘how we ought to live’ (3), provides a framework
Scientific thought succumbed because it violated the first law
which is included in the other disciplines which address
of culture, which says that the more man controls anything,
health care issues and is also a useful tool for creating a
the more uncontrollable both become
framework with which to untangle the dilemmas that occur
Tyler SA (1)
around the treatment and ‘control’ of people with TB. The
In the early years of the twenty-first century, increasing morality of the individual is intimately connected with the
links are being made between communities, countries and ethics of the medical and public health fraternity and both
continents. There are more opportunities for us to witness of these entities also link with the legal profession and the
life in other places and to view and review our own law [Figure 55.1]. The law and the legal system provide a
structures and perceptions of the way we live and to learn framework within a society to ‘assist and protect people’ (4);
from people of different cultures and religions. This new protecting the rights of individuals but at the same time
‘internationalism’ brings with it increasing ‘complexity’ and protecting the rights of institutions and organisations like
an added importance for each of us to review our own beliefs professional medical bodies. The basic function of the law
and perceptions in order to allow increasing co-operation is to establish legal rights, and the basic purpose of the legal
and understanding.
In the field of public health there are discussions aimed
at widening the scope of health care beyond the treatment of
diseases like tuberculosis [TB], to a broader concept of ‘the
creation of health’; that health is an entity that communities
and societies have the opportunity of developing (2). This
broader perception, uses biomedical health care concepts
and systems, but adds to them by including other disciplines
like anthropology, environmental sciences, ethics and
human rights. It is anticipated that the result of this fusion,
created through inter-disciplinary work, will be a change in
biomedicine’s perception of health and health care. Now,
those of us working in TB control have an opportunity
to view our control measures from different perspectives.
Perhaps it is time to take note of the quotation at the
beginning of the chapter and to consider whether the current,
control methods for TB are violating the first law of culture,
and therefore, making TB more uncontrollable. Is this why
we have an increasing international problem with multi-
drug-resistant TB [MDR-TB] and extensively drug-resistant
TB [XDR-TB]? Figure 55.1: Ethics and the law
 Ethical and Legal Issues in Tuberculosis Control 747

system is to define and enforce these rights (5). Ethics is in order to combat the increasing problem of multidrug
not separate from the law, it is an integral part of the legal resistance. The strategy includes: government commitment
system and how laws are made and enforced. to a national programme; case detection through ‘passive’
This chapter looks at TB control from the perspectives case finding [sputum smear microscopy for pulmonary TB
of ethics and law. It begins with an introduction to the suspects]; short course chemotherapy for all smear positive
two disciplines and then applies them to the current inter­ pulmonary TB cases [under direct observation for at least
national strategy for TB control. The ‘ethical’ issues of TB the initial phase of treatment]; regular, uninterrupted supply
are addressed through highlighting the potential problems of all essential anti-TB drugs; and a monitoring system for
for a TB patient who is seeking care through the health programme supervision and evaluation (10,11).
care system [relationship with the health care worker, inter­ The international strategy for controlling TB, has been
action with the health care system, etc.]. The legal issues developed from a science base and has been created from
concentrate on groups of people at high-risk for TB [e.g., many disciplines including medicine, epidemiology and
alcoholics, prisoners, etc.,] to try to untangle the legal the basic science. Now, however, with several new TB
problems. Examples from India, the United States and the drug and vaccine candidates, who are in various stages
United Kingdom are used to provide the context for the of trials and testing, the health care fraternity has to look
discussion. at the basic human behavioural issues in TB control. The
issues of how individual patients interact with health care
BACKGROUND systems, and in particular, how they interact with health care
workers (12,13). For a person to complete their six months
Public Health and Tuberculosis
of anti-TB treatment, they need to be supported and cared
The control of infectious diseases is an important part of for and this requires strong health systems. This is a basic
public health policy. In most countries, TB control is the function of health care provision but one which has been
responsibility of public health departments. Public health increasingly neglected with the rise of the rapid technological
is ‘the science and art of preventing disease, prolonging approaches to treating disease. Are the current TB control
life and promoting health through the organised efforts methods consistent with the broad public health agenda of
of society’ (6). A more succinct definition comes from the preventing disease and promoting health? Is there sufficient
Institute of Medicine in the United States, which says that emphasis on the care of TB patients in order to promote/
public health is ‘what we, as a society, do to assure the create health? All of these questions become increasingly
conditions for people to be healthy’ (7). Both definitions difficult and complex with the increase in prevalence of HIV
imply an imperative to balance the needs of the individual in communities and its link with TB (14).
with the needs of the population in the control of infectious
diseases. Inherent in this, as in all balances, is a tension, Infectious Disease Control and Tuberculosis
and this tension often engenders debate and even conflict
between decision makers. The framework of ethics can assist Methods for the control of infectious diseases have been
in developing a course of action to resolve these conflicts developed principally through the study of epidemiology.
by providing clarification of the questions and a system for The perspectives of biomedical scientists have dominated
weighing alternatives through ethical debate (8). thinking in this area, and the control methods currently used
During the past 150 years, scientific structure and reflect this focus. Epidemiologists look at the interaction
discourse have framed the development of technological between the agent, host and environment, and the main
medicine which has produced sophisticated treatments strategies for control are to attack the source [e.g., the treat­
and medications to treat illnesses, like TB. From the ment or isolation of cases/carriers]; to interrupt transmission
time that Koch discovered the tubercle bacillus in 1882, [e.g., environmental and personal hygiene, vector control];
there has been an understanding that TB is caused by or to protect the susceptible population [e.g., immunisation,
Mycobacterium tuberculosis [Mtb] and that destroying chemoprophylaxis] [Table 55.1] (15).
the bacillus with drugs would provide an appropriate The categories, attacking the source and protecting
treatment. With the development of streptomycin and the the susceptible population, both relate to the treatment of
subsequent development of other anti-TB drugs, short-course patients. Attacking the source refers to the treatment of
chemotherapy was developed; a solution for controlling a case of disease: the patient is treated [a benefit to him/
TB worldwide had been found (9). However, by the early her] and the population is protected from being infected by
1990s, there were signs of increasing TB cases in all countries him [a benefit to the population]. A person with infectious
associated with the movement of people from high to low pulmonary TB needs to be treated not only for his/her
TB prevalence countries, the increasing spectre of human benefit but also for the benefit of the public health, to
immunodeficiency virus [HIV] infection and acquired prevent further transmission of Mtb to others. Protecting
immunodeficiency syndrome [AIDS], and decreasing funds the susceptible population requires the use of medication
to support public health infrastructures to control TB (9). to prevent the development of a disease [treatment of latent
In the early 1990s, the World Health Organization [WHO] TB infection].
developed the DOTS strategy to try to improve the uptake The four principle methods for controlling TB are stated
of TB control measures around the world, particularly to be: the improvement of socioeconomic conditions, case
748 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 55.1: Main strategies for control of infectious ethical guidelines laid down by governments and profes­
disease sional bodies; and/or [iii] the application of ethical principles
in daily life (19). The ethical process is not a once-and-for-
Protect susceptible
all, nor a once-in-a while pursuit. On the contrary it forms
Attack source Interrupt transmission people
part of our day to day interactions and is an integral part
Treatment of Environmental hygiene Immunisation of our public health interventions (19). In the study of
cases and
carriers
ethics, philosophers develop theories about the interaction
between moral values and the ways in which societies
Isolation of cases Personal hygiene Chemoprophylaxis
operate. Morals–the values and norms that frame societies’
Surveillance of Vector control Personal protection ideas about ‘right’ and ‘wrong’–are inherently cultural
suspects
constructions. All cultures and societies have moral codes,
Control of animal Disinfection and Better nutrition but because these are culturally and historically contingent,
reservoir sterilisation they shift and change over time. The work of moral
Notification of Restrict population – philosophers both reflects and to some extent informs this
cases movements process.
Adapted from reference 12 With the increasing co-operation and collaboration
between countries in public health research, this cultural and
historical contingency is important to understand. People’s
finding and treatment, chemoprophylaxis and bacille perceptions and understanding of TB, ethics and the law,
Calmette-Guérin [BCG] vaccination (16). Although the are framed by the cultural values and historical background
improvement of socioeconomic conditions undoubtedly of the society in which they live. The moral construct used
has a major impact on TB (17) in public health terms, TB in some societies is seen as ‘absolute’; for example, certain
control focuses on finding infectious cases [sputum positive] religious texts dictate the ‘way the community ought to
and treating them so that they are no longer infectious to live’, whereas in others, moral values are seen as ‘relative’
others. This is the method for disrupting transmission; it and more flexible, being seen to be different according to
concentrates on the individual with the aim of treating the context of the situation in which the ethical dilemma
the person and protecting the community from further arises. Each community needs to be understood in terms of
infection and disease. As has already been mentioned, the its history and cultural values.
current international TB control strategy is DOTS. Part of
the strategy is direct observation of treatment [DOT] which Ethics in the West
has been established to prevent the development of drug In the western industrialised world, there has been a shift
resistant strains of TB. The ‘direct observation’ component in moral thinking from absolute to relative values: from
of the strategy introduces ethical issues around the right to a deonotological model of ethics to a utilitarian model. The
‘control’ individuals with TB, in order to protect the majority utilitarian theories suggest that answers to moral questions
[community]. on right and wrong depend solely on the nature of the
But is case finding and treatment sufficient? Although it consequences of those actions or proposed actions, whereas
makes scientific and logical sense to concentrate on infectious deontology relates to moral rules not related to consequences,
TB cases, are there no other social, environmental and from the Greek word deon meaning duty (20). Although to
economic issues that need to be considered? What about some extent framed within the Judaic Christian religious
structural interventions for example? traditions, the ethical theories and models developed in the
Structural factors within the field of HIV infection have west attempt to be ahistorical, abstract and formal.
been broadly defined as physical, social, cultural, organi­ It has been argued that the ‘utilitarian’ structure has
sational, community, economic, legal or policy aspects of emerged with the growth of technology in the North (21).
the environment that impede or facilitate persons’ efforts If one accepts Bell’s definition of technology as ‘the effort
to avoid infection (18). With the increasing complexity of to transform nature for utilitarian purposes’ (21,22), one
health care, the requests for a broad perception of health, may then step back for a moment and look at the profound
and with the increasing inter-disciplinary nature of public social and moral dilemmas inherent in this phenomenon.
health work, there is an opportunity to re-evaluate the When applied to health one consequence of the ‘utilitarian’
current control measures. Are these control measures for TB approach is the generation of interventions which are geared
appropriate? Are they sensitive to the needs of people with towards maximising majority over individual benefit (19).
TB? Can they be improved to ensure the rights and dignity
of all patients? Ethics in the East
It is difficult to locate the Eastern tradition in the historical,
ETHICS
abstract and formal theories of ethics that have been
When one speaks of ethics, one might be speaking from developed in the West. Ethics in the East is framed by the
one or a combination of three mutually interconnected religions of Islam, Hinduism and Buddhism as well as many
perspectives: [i] the study of ethics; [ii] the adherence to others.
 Ethical and Legal Issues in Tuberculosis Control 749

In the Brahmanical-Hindu and Jaina traditions for with our professional ethics and with the legal system of the
example, it is recognised that ethics is the ‘soul’ of the wider society (29).
complex spiritual and moral aspirations of the people, co- The four principles which currently dominate international
mingled with social and political structures forged over bio-ethical debate are: respect for autonomy, beneficence,
a vast period of time. This accounts for the cultures profuse non-maleficence and justice (30). These principles-plus
literature in wisdom, legends, epics, liturgical texts, legal attention to their scope [i.e., how and to whom they apply]
and political treatises. There are a variety of ethical systems provide the basis for a rigorous consideration and resolution
within the Hindu tradition, but the tradition itself contains of ethical dilemmas. Although they do not provide “rules”,
within it a diverse collection of social, cultural, religious these principles can help public health workers make
and philosophical systems (23). The highest good is decisions when moral issues arise. In effect they make
identified with the total harmony of the cosmic or natural a common set of moral commitments, a common moral
order, characterised as rita: this is the creative purpose language, and a common set of moral issues (20) more visible
that circumscribes human behaviour. The social and moral and more accessible. These principles are considered to be
order is, thus, seen as a correlate of the natural order. This prima facie: they are binding unless they conflict with other
is the ordered course of things, the truth of being or reality moral principles. They are outlined briefly below.
[sat], and hence, the ‘Law’ (24). The convergence of the
cosmic and the moral orders is universally commended in Autonomy
the all-embracing category of dharma, which becomes more
or less the Indian analogue for ethics (23). What counts as Autonomy, “self-rule”, although perceived differently in
‘ethics’ then although in appearance naturalistic, is largely different cultures, is an attribute of all moral agents. Auto­
normative; the justification usually is that this is the ‘divined’ nomy gives one the ability to make decisions on the basis of
ordering of things, and hence, there is a tendency also to deliberation. Autonomy is also reciprocal: we have a moral
view the moral law as absolute. obligation to respect the autonomy of others as long as it is
compatible with equal respect for the autonomy of all those
Ethics Principles and Tasks potentially affected. According to the Western philosopher
Kant, respect for autonomy means ‘treating others as ends in
In the development of international guidelines for the control
themselves and never merely as means’ to some [externally
of infectious diseases like TB the western philosophical
defined] end (20). The person with TB is an autonomous
model tends to dominate the process. There is, however,
individual, a decision maker, and the decisions that they
continuing research to try to develop an appropriate set
make about their treatment should be respected not only
of international ethical principles (25). In 1994 at the 38th
by the health care worker with whom they are interacting
Council for International Organisations of Medical Sciences
but also by the health care system that is providing the
[CIOMS] Conference in Ixtapa a declaration was issued
treatment. The quality of the relationship between the patient
describing the emergence of bioethics as a global and
and the health care provider is a key to the provision of
multi-layered enterprise and ‘the need to continue to work
towards an ethics of health which calls on us to consider appropriate TB treatment.
the interconnections among all of our choices and actions
that affect the health status of people anywhere’ [CIOMS, Beneficence and Non-maleficence
Declaration of Ixtapa] (26,27). There is always a need to balance the effort to help and the
There have been suggestions as to how ethics can be used risk of causing harm. The traditional Hippocratic moral
in practice to assist with ethical dilemmas in medicine and obligation of medicine is to provide beneficence with non-
public health. De Beaufort and Dupuis (28) have suggested maleficence: net medical benefit to patients with minimal
that the ethical process might be used to [i] clarify concepts, harm. Once again, the relationship between the health care
[ii] analyse and structure arguments, [iii] weigh alternatives; provider and the patient determines whether there is a net
and [iv] provide advice on an “appropriate” course of action. benefit to the TB patient. It is also important to remember,
Another way of looking at ethical argument is that it can however, that the health care provider will be more able
assist us to identify the obstacles that prevent us from acting to provide support and be beneficent to the person with
“morally”. Once these obstacles have been identified, it is TB if they are appropriately supported in their job by the
easier to find ways of overcoming them. organisation/system that employ them. So, although the
As human beings we are moral agents: we interact daily relationship between health care worker and the patient
with our family, friends, colleagues and acquaintances and is important, the relationship of the health care worker
these interactions are framed by the values and norms that with their employer is also part of the process of ensuring
prevail in our society. By going to our jobs, taking care of beneficent/non-maleficent care.
our families and talking to our neighbours, we are acting
as engaged participants in our moral community. As health
Justice
care workers, we are moral agents too. In this we do not stop
engaging with our moral community, but we expand the Justice refers to the moral obligation to act on the basis of fair
boundaries of that community: at this level we also interact adjudication between competing claims. Equality is at the
750 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

heart of justice, but as Aristotle argued, justice is more than exercised over any member of a civilised community,
mere equality—people can be treated unjustly even if they against his will, is to prevent harm to others. His own good,
are treated equally (31). Equity entails treating no portion either physical or moral, is not a sufficient warrant (37).
of the population in a disproportionate manner. Inequity, This principle provides the ethical and legal foundation for
then, is a descriptive term used to denote existing differences establishing public health programmes designed to require
between groups or individuals in the distribution of or access those with communicable diseases to behave in ways that
to resources. However, inequity also denotes the reasons are likely to reduce the risk of transmission.
behind and responsibilities for underlying conditions of
inequality. As such, it is inherently a statement of justice (32). THE LAW
People with TB need to be treated fairly and justly. If a
community wishes to prevent the spread of TB, patients need What is it and what does it Do?
to have access to a health care structure that provides them The values that are contained within a community help to
with treatment and care. This access needs to be available define the legal statutes that are created. Ethics and the law
to all TB patients equally. are intimately connected [Figure 55.1]. The legal system in
every country is unique, although it may use certain struc­
The Application of Ethics in Public Health tures or processes, like ‘common law’, as a foundation (5).
Little has been written in regard to moral issues in public It is useful to have a working definition of the law to
health (33) or the application of ethics to public health assist with the legal issues that pertain to TB control. Wing,
decision making. In 1980, Shindell (34) suggested that from the United States, states that the law is ‘the sum or set
a public health intervention should: [i] relate to well- or conglomerate of all the laws in all of the jurisdictions: the
understood disease aetiology; [ii] be feasible; and [iii] entail constitutions, the statutes and the regulations that interpret
only an appropriate trade-off of the rights of the individual them, the traditional principles known as common law, and
against the benefits that accrue to the population. It is the judicial opinions that apply and interpret all these legal
the third point that leads to moral debate and a tension rules and principles’. Wing argues that the law is also the
between public health and civil liberties. In infectious legal profession and the legal process–legislatures and their
disease control, interventions usually relate to diseases with politics and finally ‘the law is what it is interpreted to be’ (5).
a well-understood aetiology. The feasibility of a particular The basic function of the law is to establish legal rights,
intervention will depend on the details of the disease and the basic purpose of the legal system is to define and
outbreak [location, numbers, demographic character of enforce those rights. Legal rights are the relationships
people involved, etc.,] and the possibility of using standard that establish privileges and responsibilities among those
control measures to intervene. In TB control, the aetiology of governed by the legal system. Finally, some rights are
the disease is fairly well understood, the intervention [case protected, not by statute or regulation, but by an under­
finding and treatment] is feasible and there is an accepted standing and application of the prevailing ethics in an
[taken for granted] trade-off between the rights of the area. In general, ethics are regulated through whatever
individual and the benefits of the population. sanctions are imposed against censured behaviour by peers
Public health interventions tend to embody an imbalance or colleagues. These statements underlie the essential link
of power and capacity between the implementers and the between ethics and the law, but ‘it is normally accepted that
recipients: public health professionals decide when and ethics is something more than the law’ (38).
where to intervene, and normally what the intervention
will consist of. It is presumed that whatever ‘harm’ the Legislation for Infectious Disease Control in the
intervention may impose on individuals is outweighed by United States and United Kingdom
the ‘good’ it will bring to the population as a whole. This
form of practice does not exemplify respect for the autonomy Surveillance of infectious diseases began in the United States
of the people at the receiving end of the intervention (35,36). in 1874 in Massachusetts, when the State Board of Health
Hall has argued that although individuals surrender some instituted the first state wide voluntary plan for weekly
degree of personal freedom in exchange for membership of reporting of the prevalence of diseases by physicians. By
a society, ‘individual autonomy remains to some degree’. He the turn of the century, the forerunners of the Public Health
states that this residual autonomy is not addressed within Service had been established, and laws in all states required
public health and suggests that the utilitarian support for that certain communicable diseases be reported to local
the practice of public health must be subordinated to the authorities (39). During the period 1940 to 1970, states added
deontological rights of the individual (35). many diseases to their mandatory lists. Even in states that
Within liberal democracies it is generally accepted that did not enact legislation to require additional reporting,
the state may intervene when the exercise of one person’s surveillance and reporting efforts were broadened during
freedom may result in harm to another (8). This is known this period through state regulation or directives from the
as the ‘harm principle.’ The nineteenth century philosopher state health commissioners (40).
John Stuart Mill defined this principle in the following In the United Kingdom, the Infectious Disease Notification
way: ‘The only purpose for which power can be rightfully Act of 1988 amended the Infectious Disease [Notification]
 Ethical and Legal Issues in Tuberculosis Control 751

Extension Act of 1899 which required compulsory nation- necessary for the health programmes recommended by the
wide notification of certain infectious diseases [but not Bhore Committee. However, in keeping with the government
TB]. In England and Wales, this list was re-enacted with policy of doing as little legislation in the field of health as
modifications on a number of occasions and the current possible, such a consolidated act was never adopted (38).
‘notifiable diseases’ are contained in section 10 of the Public
Health [Control of Disease] Act of 1984. Notification of TB TUBERCULOSIS CONTROL—ETHICAL ISSUES
is contained in Schedule 1 of the 1988 Regulations.
The law for infectious diseases has two parts: surveillance The following section looks at the ethical issues and
and control, with control being further subdivided into dilemmas within the treatment and control of a person
control of the environment [in its widest sense to include with TB. It focuses on the interaction between the patient
premises and articles] and control of people. The control of and the health care provider, the interaction of the patient
actions by people is contained in both the 1984 Act and the with the health care system, and on the separate stages of
1988 Regulations, and the powers are wide ranging, from TB treatment from the problems of access to the systems
exclusion to incarceration. Section 10 of the 1984 Act allows established for monitoring and follow-up. Many of the
the proper officer of any district to request any person to ethical questions that arise in the control of TB are to do
discontinue work ‘with a view to preventing the spread’ of with relationship, particularly the relationship between the
TB and if they fail to do so, this may be an offence under patient and the health care provider whether that person
section 19 of the 1984 Act. Under the powers contained is a nurse, physician, community worker or manager, but
in section 32[1][a]a person can be requested to leave his also the broader interaction of the patient with the overall
or her residence and under section 32[1] [b] compulsory health structure.
removal can be effected, under a court order, to alternative In public health decision making, there is always the
accommodation when any infectious disease occurs in a issue of balancing the rights of the individual versus the
house. In addition, provisions are included in the 1984 Act to rights of the population. Each of us is inextricably linked
allow compulsory removal to and incarceration in a hospital to the community in which we live and what happens to
if the person is considered a serious risk (41). us affects the wider community. Our individual morality
Legislation for the control of diseases like TB can have is interlinked with the ethics of the public health system
a range of ‘control’ measures, from ‘an order to complete [in this case the TB control programme] and with the laws
treatment’, to ‘an order for detention while infectious’ (42). of the state [Figure 55.2].
In New York City in 1993, the health code was revised to In the case of TB control, the biomedical model has
permit ‘compulsory actions to protect the public health’ in established that a person with sputum positive TB is
relation to TB (42). The types of regulatory action included: infectious to others and is therefore capable of transmitting
order for examination for sus­pected TB as outpatient or the infection with the risk of the development of TB disease.
in detention; order to complete treatment; order for DOT; However, it is important to remember that the determinants
written warning of possible detention; order for detention of risk for TB are personal, societal and programmatic
while infectious; order for detention while non-infectious; [Figure 55.3]. The main ethical issue therefore in TB control
discharge from detention before cure [for non-infectious is the perspective on this balance between the individual and
patient] (43).

Legislation in India
In India, health regulation is a responsibility of each state.
The central government has some authority but the laws are
created through the state legislature; each state can make and
enforce its own laws. Central government can also develop
health legislation but has to depend solely on each state to
enforce it.
Just before independence in 1948, the Bhore Committee (44)
produced recommendations on health laws including state­
ments on the control of infectious diseases. While showing
great concern for the measures required to prevent and
combat the spread of diseases between provinces, it made
recommendations for giving the central government some
legal powers in line with those existing in the United States
at the time. Public Health Acts were recommended for the
central as well as state governments to bring together existing
legal provisions relating to health, to modify sections of the
laws which required change in the interest of promoting Figure 55.2: Ethics of TB control programme, law and morality
efficient administration and to incorporate new provisions TB = tuberculosis
 752 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

severity of the illness, its impacts on their family members

and their ability to obtain access to treatment, against the
other conflicting priorities and demands of daily life. Patients
with acute TB tend to comply with treatment because of the
desire to get well and to be free from troubling symptoms of
fever, cough and night sweats. Compliance after the initial
phase of treatment, when the patient feels well, is more
difficult to ensure—the balance of benefits and priorities
has shifted from an immediate benefit to the patient, to a
more abstract [from the patient’s perspective] benefit to the
community. From the patient’s point of view the “costs”
Figure 55.3: Determinants of risk of tuberculosis
of staying on treatment once symptoms have disappeared
may well outweigh the benefits, which must be difficult
to assess. Thus, while the “failure” of patients to comply
the community in which she/he lives; the balance between with maintenance therapy may appear to be irrational from
accepting the autonomy of the individual versus the process the physicians’ or health care workers’ perspective, it is
of justice and equity. The official process of justice in a intelligible when seen from the patient’s point of view (48).
society is provided through the legal system which through Ethically, compliance relates to the interaction between
the law courts provides a structure for people to be heard the autonomy of the TB patient and the beneficence of the
and also develops the laws to govern and protect the society. health care worker. Although health care workers may
The law is there to assist and protect people (4). It can be be trying to ‘do good’ and to avoid harm to the patient,
argued that in the case of TB, the rights of the individual however, they have difficulty acting as independent moral
are justifiably sacrificed for the overall good of the popula­ agents because they are participants in a health structure, and
tion (45). As stated above, however, ethics demands a are therefore, bound to uphold the ethics of that structure
balance: while infected people have a right to be treated with [Figure 55.2]. As members of professional organisations and
dignity, worth, value and respect, they have a duty not to players in TB programmes, they are expected to conduct
spread the infection to others (46). themselves in a particular manner, to follow the regulations
of the programme, and to encourage patients to take and
Relationship of a Tuberculosis Patient with the complete their treatment until cured. Cure is the goal, the
Health Care Provider outcome measure, which health care worker are obliged to
bring about. But, there is a danger inherent in this process. At
A patient with TB wants both to understand what is
some stage the health care worker’s compliance to the system
wrong with them and to receive treatment. A person with
may lead to coercion of patients: the end [cure] may come
a persistent cough will seek advice from members of their
to justify any means taken to reach it, even if those means
community who they know to have knowledge of health
transgress against respect for the autonomy of patients. If
and disease. In some places this person will be the local
patients are treated autonomously, then it must be accepted
traditional healer, in others it will be a physician practising
that they may choose not to follow the ‘orders’ of the system.
in the private or government health system. The relationship
The relationship between the health care worker and the
that is developed with this person and with the health care
patient, the trust and respect between them and the success
system to which they belong will dictate how the person
of their communication, are vital for ensuring an ethical
is treated and whether they are treated with dignity and
approach to TB treatment (12,13).
respect.
Improved adherence to TB therapy will depend on an
The whole ‘context’ of where a person comes from, their
improved understanding of the social epidemiology of
socioeconomic conditions and level of education is essential
TB. Wherever it occurs TB is a disease of poverty. There is
for the health care worker to understand. Without an attempt
strong evidence that the poorest compliance occurs in the
to understand the patient’s perspective, health care providers
poorest communities (49). It is, therefore, essential that the
will be unable to provide an appropriate service. How far
social and economic factors involved in non- compliance
does the person have to travel to come to the health facility?
are understood and appreciated. Compliance will only be
Can they afford to come? What is their job and how is it
improved if these factors are taken into account. As Farmer
being affected by their illness? How can the health care
has noted, “those least likely to comply are those least able to
worker provide a relationship of trust?
comply” with treatment (50). In the United States and other
industrialised nations TB is concentrated among the elderly
Compliance and Adherence
and people from minority ethnic groups, many of whom are
Compliance can be defined as the extent to which a person’s poor and/or have compromised access [social, physical and
health related behaviour coincides with medical advice (47). economic] to care (14,51). The main TB burden, however,
When seeking care patients carry out their own “cost/ occurs in the developing world where TB cases occur across
benefit analyses”, balancing out their understandings of the a wide spectrum of society (52,53).
 Ethical and Legal Issues in Tuberculosis Control 753

Direct Observation of Treatment beneficence/non-maleficence of the health care worker and

should lead to net benefit with minimal harm. If the health
As has already been mentioned in the background to this
worker attempts to force the patient into a type of treatment
chapter, DOT is part of the international DOTS strategy
which they do not understand or agree with, then the
for TB control (10). But, DOT has potential difficult ethical
relationship becomes coercive.
questions relating to coercion and control, an imbalance
A person goes to a medical practitioner because he is
between the autonomy of the individual patient and the
sick and wants to get well. The practitioner has access to
control exerted by the health care worker in the system. It
technology and knowledge that the patient needs. It is an
can be argued that ‘if a person’s health related behaviour
inherently unequal relationship. Yet this relationship is
does not coincide with medical advice, then it is appropriate
also the key relationship in health care. In TB control, the
to ensure that it does’ (19).
discipline of ethics helps to frame this relationship in order
The ethical, legal and constitutional principles that
to ensure that this inequality is not abused. Indeed codes
justify efforts to control TB in the United States are broad
of conduct are an important part of ethics in medicine. The
enough to justify efforts to ensure that all patients with TB
stronger this relationship the more appropriate the care
are treated until cured. Legal commentators have endorsed
provided. This relationship is destroyed if power is abused.
the goal of treatment to cure (44,54,55). There has been
Those opposing direct observation may feel that it
controversy, however, over the nature of the public health
threatens this very important relationship. It is not that
interventions that might be employed to achieve this goal
DOT is wrong. In fact, the DOT is a rational approach to the
and the extent to which the legal and ethical principles that
delivery of TB drugs. The problem comes, however, with the
guide medical and public health practice should constrain
abuse of power that is potentially inherent in a relationship
those interventions (8).
between a powerful medical worker and a sick vulnerable
In the United States, DOT has proven effective in increas­
patient (19).
ing rates of treatment completion (56,57) and in decreasing
the prevalence of drug resistance and relapse in communities
in which it is used (58). It was initially recommended for
Interaction/Relationship of a Tuberculosis
persons with poor records of treatment adherence and for Patient with the Health Care Structure
those whose demographic or psychological profile suggested [Official and Unofficial]
a high risk of failure. Now, however, DOT has emerged as a In every country there is a health care structure whether
standard of care (57). This change has come about because official or unofficial. In some, it is organised and controlled
of the rise of drug resistance in the United States. by the government [regulated system], and in others it is a
In the United States, it has been argued that because system established through traditional systems of medicine
DOT is standardised [is the same for all patients], the initial and health care [unregulated system]. Increasingly, the
treatment decisions should not violate the principle of justice, health care systems in many countries are being administered
and should thus, preclude acts of discrimination (59). The through a mixture of public and private providers.
fact that all patients start their post-hospitalised treatment
under a common programme of supervision should help The Health Care Structure
to reduce the stigma of being under treatment and create
For a health care system to work and to provide appropriate
an effective public health plan for the control of TB. Yet
care for people, it must be consistent with the underlying
is it reasonable to assume that such a programme will be
health beliefs and social norms of the community (64). If
equally appropriate in all settings, no matter how socially
the government does not provide appropriate health care
or economically diverse? Does DOT respect the autonomy of
individuals everywhere in the same way? Indeed universal for communities, they will establish their own systems. The
DOT has been challenged as an unethical intrusion on rise of the private sector in countries in Asia is an example.
autonomy, as ‘gratuitously annoying’ (60), as a violation The ethical issues that relate to health care structures are
of the Constitutional requirement that the least restrictive to do with the rights of individuals to have a system of
measure be used, and as contrary to the requirements of the health care provided for them by government. In western
Americans with Disabilities Act [That decisions involving industrialised countries, governments are considered to have
restrictions on those with disabilities be based on an a duty to provide systems of health care for the population
individualised assessment (61). DOT has also been criticised and individuals consider that it is their right to be provided
on the basis that it is resource and manpower intensive, with a service.
and so may be wasteful of scarce resources (59,62).
It has been argued that the discourse of direct observation
Access
is one of domination and control of the health care worker While it is important for health care to be consonant with
over the patient (63). In ethical terms, it can be argued that patient belief systems, it must also be accessible to them
the approach fails to respect the autonomy of the person in physical/geographic and economic terms (50,65). Not
with TB. The ‘care relationship’ between patients and all people have equal access to health care structures and
providers should, in ethical terms, be characterised by a it is usually the most vulnerable groups [e.g., displaced
balance between the autonomy of the TB patients and the populations, the poor, the unemployed, etc.,] that find it
754 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

most difficult to use the health care services (66). In terms of anti-TB drugs. This requires a system to have been
of ethics, it is important to look at the relative autonomy of developed to ensure that there is a regular drug supply.
people with TB within their community, the balance between For this to be achieved, questions need to be asked about
beneficence and non-maleficence, the net gain for being the type of health care system established in a country. It
enrolled in TB treatment [the DOTS strategy for example], asks governments to be committed to dealing with TB and
and finally whether they are treated justly. to ensuring an appropriate management and distribution
system for TB drugs. It is not simply the uninterrupted
Social and Cultural Burden supply of drugs that is important, however, it is also the
access to those drugs by the people who need them.
How people use the health care system [treatment seeking]
relates to cultural as well as social and economic factors.
Monitoring
While the burden of has been well-defined from the
epidemiological perspective, there have been surprisingly Monitoring and evaluation of the TB system is obviously
few attempts to define the social and economic burden of essential and can either promote equity and efficiency or
TB (52). Similarly, there are only a limited number of studies seriously detract from it (10,11). It is important, for example,
on the actual costs or economic consequences of TB borne that health care workers are able to perform the tasks and
by families, communities, and economies in the developing achieve the targets they are being evaluated on: the criteria
world (67). Nevertheless it is apparent that not all people for evaluation need to be realistic and appropriate for
are equally able to access health care structures (50). This particular contexts and given the real constraints faced on
is a question of equity. Ethical processes are critical in the ground. Recent operations research in India, for example,
promoting equity. ‘Equity-promoting action in the health indicate that targets set at the national and international
sector must put the needs and interests of the poorest and level may be placing stresses on health workers that do not
most vulnerable at their heart, as the relatively worse health promote the care of patients (12,13,69).
outcomes of this group in comparison with other groups Ethical questions that need to be asked in relation to
are most often a function of circumstances beyond their monitoring and evaluation include: Is the system just and
control’ (68). equitable? Does the system respect both the TB patients
and the health care workers that care for them? Does the
Stigma system encourage health care workers to identify problems
or does it penalise them for ‘not doing it right?’ Problems
Another issue which needs to be highlighted when consi­
need to be identified and dealt with positively. This is
dering a patient’s interaction with the health care structure
the art of making difficult problems soluble, a process
as well as the ethics of the ‘passive case-finding’ approach
which Medawar called the ‘art of the soluble’ (70). After
[The health care system waits ‘passively’ for patients to
all it is through tackling problems that we find a process
present with TB rather than ‘actively’ looking for patients]
of engagement and integration between people with TB,
advocated in TB control strategies, is stigma. TB carries a
their communities, districts, states, government and the
social stigma. It is also a disease which affects the most
international community (71).
marginalised, most poor and most vulnerable groups in
The international DOTS strategy makes sense scientifi­
communities, the very groups who tend to have the least
cally, but if the emphasis is only on targets rather than the
autonomy. Although it is clear that the effects of stigma on
process developed to achieve these targets, then health care
passive case-finding needs to be better understood, there
workers and patients may be used as ‘means’ to achieving
is evidence which indicates that it will have an effect on
a particular ‘end’: they may be abused. A system needs to
delaying treatment-seeking and that it may substantially
be established in which both patients and providers are
constrain the ability of young people and women in parti­
respected. The health service is, after all, there to provide a
cular to seek and obtain care (67). Passive case finding is the
service for patients. A danger of having inappropriate targets
method of waiting for people with TB to present to health
for the health care worker is that they will focus on attaining
facilities rather than actively going out to find cases.
these targets rather than on caring for the patient. This may
Passive case-finding may well be sound in public health
lead to coercion by the health worker of the patient, or to
terms, and even in macro-economic terms, but the ethical
the exclusion of the patient from the system. Targets need
implications need to be taken into consideration as well.
to be adapted to the local community situation and made
Considered and well-informed debate should enable the
appropriate to them.
development of solutions which meet the needs of the system
As noted above, ethics requires people to treat each
as well as the needs of the patients and the communities in
other as ends in themselves and not merely as the means
which they live.
to achieving a particular outcome ‘end’ (72). Concentrating
on the moral and social aspects of a monitoring system
Treatment and Drugs
will help to ensure that this is achieved, that people are
Once the patient has accessed the system and been diagnosed respected and TB patients are not abused in the process.
with TB, she/he needs to be provided with a regular supply ‘The provision of social services has a strong person element:
 Ethical and Legal Issues in Tuberculosis Control 755

the quality of service depends heavily on the attitudes of injection drugs, 183 [60%] had used ‘crack’ cocaine, 191 [63%]
the people undertaking it, and it is hard to monitor. Service had a history of alcohol abuse and 145 [48%] had a history
provisioning, furthermore, often involves a position of power of incarceration (42).
over users. Hence, the importance of professional ethics (73).
High-risk Groups
TUBERCULOSIS CONTROL—LEGAL ISSUES
In ethics there is a dictum which states ‘ought implies can’ (8).
The next section focuses on some legal issues contained It can be argued, therefore, that a person cannot be held
within the current TB control strategy. The examples used ethically accountable for failing to adhere to moral or legal
are from a western legal perspective. standards [e.g., TB treatment], if he or she cannot do so, or
In the industrialised world the legal cases that are if he or she faces insuperable obstacles to adherence. This
reported in the literature tend to relate to the loss of civil statement highlights the plight of the most vulnerable groups
liberties. For example, in order to protect ‘the majority’, the in our communities (52). Ethically it is important to consider
legal system is used to ‘control’ people with TB who fail to the duties of the community to support these groups of
follow public health recommendations and regulations to vulnerable people to ensure that they are appropriately
prevent the spread of Mycobacterium tuberculosis [Mtb] (8). treated for TB, but perhaps more importantly, to find ways
These people are a minority of cases but affect certain of preventing them from acquiring TB.
groups who are themselves ‘minorities’; for example, the This ethical principle of ‘ought implies can’ compels
homeless, ethnic minorities, drug users and alcoholics (19). us to recognise that the elimination of impediments that
It can be argued that these people are the ‘outliers’ of impinge on the capacity of an individual to cooperate
a community, people who live on the fringes of society in his or her own care for TB is essential and we need
and who are not seen as part of the majority, i.e. they are to look for appropriate structural interventions (18). For
different from ‘the norm’. If ‘equality’ is the only aspect of example, homeless persons cannot reasonably be expected
justice that is important, then it could be argued that this to comply with their treatment unless they are provided
situation is appropriate. However, the question of equity with a secure residence, and in many cases with other social
is also important. In the section on ‘ethics, principles and supports (8). This is echoed in social science research which
tasks’ it has already been stated that inequity denotes the indicates that those with strong community and/or familial
reasons behind and responsibilities for underlying conditions support are more likely to adhere to a full course of TB
of inequality, and it is therefore inherently a statement therapy (64,67,74,75). The New York City Tuberculosis
of justice (32). Ethical processes are critical in promoting Working Group has argued that ‘the government that fails
equity (29,68). to provide adequate social supports for the most vulnerable
loses the legal, as well as the moral, authority to threaten
Legal Processes Affect the Minority of with a deprivation of liberty those whose behaviour poses
Tuberculosis Patients a health risk’ (61).
Thus, the laws we develop in our communities and
A study conducted in New York City and published in societies are a reflection of how we see the world, of the
1999 indicates that between 1992 and 1997, legal action was values we use to frame our legal system and in the case of
required only for a minority of patients with TB (42). In 1993, TB control, how we perceive and deal with these vulnerable
because of the increasing rates of TB and cases of multi-drug groups of TB patients. Is it not easier to develop a law
resistance, the New York City Department of Health updated which confines high-risk groups to ensure that they do not
its Health Code to permit compulsory action to protect the spread the disease to the larger population than to address
public health. From this date, the commissioner of health the difficult; some may say impossible, social questions
could issue orders compelling a person to be examined for of homelessness? Is there not also the moral responsibility of
suspected TB, to complete treatment, to receive treatment the society to try to find ways of supporting these groups of
under direct observation, or to be detained for treatment (43). people to prevent them from acquiring TB without resorting
The types of regulatory action ranged from ‘an order for to coercion and control? Indeed is we are to believe Tyler’s
examination for suspected TB’ to ‘an order for detention statement at the beginning of the chapter, our efforts to
while infectious’. control TB patients in this way may be making the TB
The study by Gasner evaluated legal actions in TB situation worse.
control and showed that regulatory orders were issued for
less than 4% of the 8000 TB patients treated between 1993
Prisons
and 1995 (42). The paper strikingly highlights the social and
demographic characteristics of those who were detained Incarceration is the final legal action that can be taken to
[‘the outliers’]; of the 304 patients who required regulatory ensure that a person with TB takes their medication. However,
action, 211 [69%] were black, 68 [22%] were Hispanic, 21 [7%] prison itself is an important site for the transmission of TB as
were white and 4 [1%] were Asian. HIV infection was demonstrated by recent outbreaks of MDR-TB in prisons in
documented in 147 cases [48%]. One hundred and fifty-two the United States, Spain and Russia (76,77). These outbreaks
[50%] had a history of homelessness, 128 [42%] had used have called for ‘inter- national efforts to ensure effective
756 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

global initiatives to control TB in these setting; strategies operating in an ‘ethical vacuum’. It is important to ensure
to screen, diagnose, and treat frequently neglected popula­ that the autonomy and freedom of individuals is not being
tions residing in jails and prison throughout the developing inappropriately jeopardised by the government, the legal
world’ (78). system or the public health profession. It is important to
Prisoners have been confined to prison through the legal protect the population from infectious disease epidemics,
system in a particular country, but it is the responsibility but it is equally important to ensure that the rights of the
of the government system which manages the prisons to infected individual are not being violated, and that these
ensure that prisoners are treated and cared for appropriately individuals are supported by their communities and by
[duties]. In the case of TB, this means both ‘establishing the their legal systems. If we agree that ‘the human condition is
conditions in which people can be healthy’ in prisons [i.e., inherently a condition of vulnerability but that some are more
no overcrowding, poor nutrition, etc.] as well as providing vulnerable than others, then the most vulnerable groups in
appropriate treatment of TB cases when they arise. In many our populations need to be protected and supported. It can
countries, the primary reason for the higher prevalence of even be argued in TB control strategies that if the socially
Mtb infection and increased incidence of TB disease within vulnerable are targeted and their issues are addressed, then
prisons is the disproportionate number of inmates who are the problems of the remainder [the majority] of TB patient
otherwise at high-risk for acquiring infection and developing will also be covered (81).
active disease (78). With increasing globalisation, it continues to be important
The discussion of ethical and philosophical matters in to remember that individuals as well as communities need
health care is not new. Over 2000 years ago the writings to be respected and treated with the dignity they deserve.
of Hippocrates debated the duties of doctors towards TB control methods developed for one country may not be
their patients and the community. However, the last three appropriate for another. If the ethical principles discussed
decades of the 20th century and the start of the 21st have in this chapter were to become part of the public health
seen a dramatic transformation in medical ethics. What has process, notions of autonomy, empowerment and justice
been limited in the past to codes of professional conduct would feature in public health decision-making at all levels.
became in the 1960s the new academic discipline called International, national and local decision-makers would
biomedical ethics or bioethics (27). By the 1980s bioethics be compelled to engage in a debate which problematised
had included the societal debate encompassing discussions
the taken-for-granted assumptions behind the principle of
about priority setting and health care reform. Now, in the
non-harming. Public health paternalism could no longer
1990s, a new phase is evolving which transcends health care
prevent control programmes from achieving the success they
matters, encompassing the full range of health determinants.
promise, and individuals and communities might come to
This phase has moved towards the ‘bioethics of population
enjoy the freedom to obtain care, and cure, for TB without
health’ with a focus on the broader ethical issues in public
having to compromise their autonomy (19).
health such as social justice, equity, sustainable health,
sustainable living, globalisation and environmentalism (79).
As was stated in the introduction, the 1990s and early 2000 ETHICAL ISSUES IN TUBERCULOSIS CARE AND
is witnessing increasing ‘internationalism’ and ‘complexity’ CONTROL: RECENT DEVELOPMENTS
and the increasing need to address cross cultural ethical Recently, greater range of concerns associated with ethical
issues as well as the theoretical and practical convergence issues in TB care, control and research are increasingly
of public health and human rights (80). This is highlighted being recognised, especially in the context of X/MDR-TB
in the spectre of the HIV pandemic and the research being and HIV-TB co-infection. In order to help governments and
conducted in this area, which is driving an international their national TB programmes and other stake-holders, the
agenda that is forcing individuals and governments to WHO had issued guidance to facilitate implementation of
address broad ethical concerns about research and control.
efforts at TB prevention, care control and research in an
At the 38th CIOMS [Council for International Organisa­
ethical manner (82-85). Further integration of these ethical
tions of Medical Sciences] Conference in 1994, a Declaration
principles in TB control programmes is expected in the
was issued describing the emergence of bioethics as a global
ensuing years.
and multi-layered enterprise. The following statement from
that conference sums up the contemporary importance of
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 56
Airborne Tuberculosis Transmission and
Infection Control Strategies
Kamini Walia, Jai P Narain

INTRODUCTION AIRBORNE TUBERCULOSIS TRANSMISSION

Tuberculosis [TB] is transmitted through inhalation of DYNAMICS
droplet nuclei or residue from evaporated droplets con­ Mycobacterium tuberculosis complex [Mtb] which principally
taining TB bacilli. These bacilli can survive outside the body causes TB in humans is carried in airborne particles, called
and remain suspended in the air for long periods of time. droplet nuclei, of 1-5 µ in diameter, generated by persons
Unsuspected TB cases contribute to TB transmission as these with active pulmonary or laryngeal TB disease, when they
patients are not being treated and may go unsuspected for cough, or sneeze. Droplet nuclei remain airborne lasting for
weeks and visit number of health facilities or even may several hours. Those who inhale these droplets can become
remain indoor patients also before being diagnosed as TB infected. The infectiousness of a person with TB disease is
and put on treatment. The risk of contracting infection directly related to the number of tubercle bacilli that he or
becomes higher in the closed settings, such as, home, health she expels into the air (6). Fennelly et al (7) documented that
care settings, prisons, etc., where a TB patient may cough
cough aerosol emanating directly from TB patients contained
and sneeze putting others at risk of exposure. The health
3-4 colony forming units [CFU] to a maximum of 633 CFU
care workers are also at high-risk as they are continuously
containing viable, growing, and infectious organisms.
exposed to patients with infectious TB, and therefore, require
TB transmission occurs when a healthy person inhales
protection from the disease at their work environment.
droplet nuclei containing Mtb. The probability that a person
Recently, the international health community has set an
ambitious goal to eliminate TB by 2050 and to cut the annual who is exposed to Mtb will become infected depends
incidence of new cases to less than 1 per million population. primarily on immune status of the exposed individual,
These targets cannot be achieved without comprehensively environmental factors that affect the concentration of Mtb
addressing all aspects of disease transmission, rapid and the proximity, frequency and duration of exposure
diag­nosis and appropriate management (1,2). Of all the to a person with infectious TB disease (6). The closer the
measures which are likely to bring down the TB cases, proximity and the longer the duration of exposure, the
infection control strategies have been most neglected yet higher the risk is for being infected. The risk is often also
most important as highlighted by various studies in India associated with infectious load, although infectiousness
and globally (3). Given that the annual risk of TB infection gets reduced after initiation of an effective therapy.
in high prevalence countries remains high, reducing person- Persons at higher risk for exposure to and infection with
to-person transmission of TB should be a top priority (4). Mtb are shown in Table 56.1. It is well recognised that TB
Recognising this, India’s Revised National TB Control outbreaks are facilitated in crowded living conditions with
Programme [RNTCP] issued infection control guidelines in prolonged close exposure to an infectious person among
April 2010 (5). close contacts.
760 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table 56.1: Persons at a higher risk for exposure to In India, airborne transmission of TB at health care facili­
and infection with Mtb ties is an important issue for a variety of reasons. Prevalence
of TB is higher among patients attending the health care
Persons in crowded living conditions with prolonged close exposure
to an infectious case of TB among close contacts
facilities than in general population, therefore the likelihood
of airborne transmission is higher in health facilities. Many of
Residents and employees of congregate settings that are at high risk
[e.g., correctional facilities, long-term care facilities, and homeless these patients remain infectious for a longer period of time
shelters] due to delays in diagnosis and treatment. There is general
Health care workers who serve patients who are at high-risk lack of awareness regarding infection control principles and
practice among health care workers. The patients lack cough
Health care workers with unprotected exposure to a patient with TB
disease before the identification and correct airborne precautions of etiquette and patient education is sub-optimal. Many health
the patient facilities do not have policies and programmes relating to
Certain populations who are medically underserved and who have infection control, nor are there adequate infrastructure or a
low income, as defined locally system in place.
Populations at high-risk who are defined locally as having an Nosocomial transmission poses major threat for the
increased incidence of TB disease health care workforce, which could adversely affect health­
Infants, children and adolescents exposed to adults in high-risk care services over time (35). Studies in hospitals and health
categories care facilities have documented that poor ventilation
Mtb = Mycobacterium tuberculosis; TB = tuberculosis design or construction contributes to the transmission of
infection, particularly among clinical personnel in patient
rooms with fewer than two air changes per hour (36). In
FACTORS ENHANCING TUBERCULOSIS a study of skin test conversion from Lima, Peru a 25.5%
TRANSMISSION AT VARIOUS SETTINGS conversion risk among medical students doing their clinical
training in a hospital with a room volume of 16.2 m3/bed,
The patterns of communicable disease are influenced by
compared to 12.7% for students training in a hospital with
the existence of pockets of high transmission (8). Outbreaks
41.4 m3/bed (37) thus indicating efficacy of good ventilation
are often initiated among persons exposed to poor living
system (38,39).
conditions, characterised by poor ventilation, crowding,
migration, and limited health care access (9-11). Many TB
outbreaks have been documented in resource-poor hospitals
Communities and Household Settings
in which dozens of patients share poorly ventilated rooms In communities, factors such as urban dwelling, crowding,
and waiting halls, and in crowded prison cells or mining poor housing with lack of ventilation, limited access to health
barracks (12-17). Hence hospital wards, nursing homes for services and, at individual level, smoking and alcohol use,
elderly, prisons and mines are also referred to as institutional human immunodeficiency virus [HIV] infection, exposure to
amplifiers for TB transmission (18,19). In the past several indoor air pollution, diabetes mellitus, and under-nutrition
years, the World Health Organization [WHO] and other have been linked to enhanced susceptibility and thus
major public health bodies have recognised social factors increased trans­mission (40-42).
critical to influencing TB transmission risks and the risks of Overcrowding has been identified as a risk factor for TB
recurrent or resistant disease (20). transmission (43,44). In communities where persons with TB
disease live, crowded housing with limited air movement
Health Care/Hospital Settings leads to an increased risk in terms of exposure to Mtb (37,43).
In hospital settings, TB transmission has been associated Lienhardt (38) has summarised a number of studies showing
with variety of factors like cough-generating procedures (21), that crowding is a risk factor for infection and for increased
and other medical examination and treatment such as broncho­ risk of disease after infection. Beggs et al (44) noted that
scopy (22), endotracheal intubation and suctioning (23), occupancy density, room volume and air change rate are
open abscess irrigation (24), and autopsy (25). All these all directly correlated with the number of new TB infections
situa­tions and procedures create infectious droplets and among persons who share airspace (44). Inadequate air
environmental factors like poor ventilation and air circula­ change rates, negative airflow and recirculation of air have
tion enhance the risk of TB transmission by increasing the been identified as an occupational hazard in hospitals with
exposure to the source of infectious droplet nuclei thus respect to TB transmission (36).
increasing the TB transmission. Transmission of TB can have TB transmission in families in which there are two or
serious con­sequences, particularly with multidrug-resis­ more new cases [apart from the index case] of TB, within a
tant TB [MDR-TB]. Several outbreaks in the United States specified time period, are identified as microepidemics (45).
demonstrated the role that hospitals can play as focal points In communities where the prevalence of TB is high, micro­
of MDR-TB transmission (26-29), a phenomenon also seen epidemics may go unnoticed simply because the pattern is
in Europe, South America, South Africa, and Russia (30-32). not apparent. It was found that new TB cases more frequently
These outbreaks have been associated with high death rates as [41%] came from families that had been characterised as
hospitalised patients are often immunocompromised (33,34). having microepidemics than from families in which only a
 Airborne Tuberculosis Transmission and Infection Control Strategies 761

single new case had occurred [21%], and that it was a small Administrative Controls
number of families that generated the most new TB cases in
The rationale for implementing administrative control
the study of contacts.
measures is to minimise potential opportunities of exposure
of susceptible individuals to infectious TB patients.
Congregate Settings
Administrative controls are important since environmental
The congregate settings are those where a group of people controls and personal respiratory protection will not work
share an environment or facilities. These range from prisons in the absence of solid administrative control measures.
and military barracks, to homeless shelters, refugee camps, Administrative measures include [i] identifying rapidly
and nursing homes. Of these, prison settings are considered persons with respiratory symptoms; [ii] separating or
high risk-group for TB. Infection and disease rates have been isolating them into appropriate environment; [iii] using
documented to be as high as 5 up to more than 80 times simple surgical masks on patients with infectious TB,
higher compared to national averages (45-47). The fact that especially if they are not segregated; [iv] fast-tracking them
prison inmates mostly come from marginalised populations through the health care facility to reduce exposure time
with poor socioeconomic living conditions, suffer from to others; [v] diagnosing and treating those likely to have
malnutrition, co-morbidities and live in poorly ventilated TB, with minimal delay; [vi] minimising hospitalisation of
prison cells explains the markedly high TB incidence and TB patients; and [vii] educate admitted patients for cough
prevalence in prison populations. hygiene and have adequate sputum disposal provision.
TB in prison has been found to strongly influence TB and At facility level, administrative interventions play a major
TB control in general populations by Stuckler et al (48) who role in reducing the risk of TB transmission and are essential
established a clear relationship between rises in incarceration for the implementation of other controls [i.e. environmental
rates and increased TB incidence and MDR-TB prevalence controls and personal protective equipment]. In the United
rates in Eastern European and Central Asian countries. States, administrative measures [early detection, isolation,
Prisons thus play the role of a pocket of high transmission and treatment of patients with TB] have been the most
of TB with, similarly like, mines and communal hospital effective components of TB infection control programmes (28).
wards among others. In India, of all the recommended interventions, imple­
menting administrative controls is likely to be the most
OVERALL STRATEGIES FOR REDUCING feasible and effective strategy (54).
AIRBORNE TRANSMISSION Administrative measures are often said to be the least
expen­sive and most effective interventions such as rapid
In order to prevent airborne transmission of TB, the World diagnosis and community-based treatment, are both
Health Organization [WHO], Centers for Disease Control administrative policy decisions. They are likely to be highly
and Prevention [CDC] and other agencies recommend effective and cost-effective in terms of both treatment
implementation of basic TB infection control programmes in outcomes and transmission prevention. Conventional
all health care settings (49,50). Implementing interventions administrative strategies includes early detection of patients
to prevent TB transmission requires action from the national with infectious TB, isolating or at least segregating those
policy to the institution level, and all levels in between (50). with infectious pulmonary TB from other patients, and
The WHO recommends developing an infection control rapidly initiating anti-TB treatment, supported by measures
plan, educating healthcare workers and patients, improving to improve adherence [e.g., DOTS]. Depending on existing
sputum collection practices, performing triage and evaluation conditions, building renovations or new construction may
of suspected TB patients in outpatient settings, and reducing be essential for effective airborne infection control (54).
exposure in the laboratory (35). Early diagnosis, triaging
infected persons, and rapidly and effectively treating persons
Implementing Environmental Controls
with TB are crucial for an effective TB infection control in
healthcare settings (51-53). Current TB transmission control Implementing many of the recommended environmental
guidelines assume a prominent role for hospitals and clinics or engineering measures is not feasible in most health care
who manage MDR-TB and extensively drug resistant TB facilities in resource-limited settings because of the high
[XDR-TB] owing to substantial delays in the identification of costs of such interventions [e.g., negative-pressure isolation
TB patients and the diagnosis of drug-resistant cases because rooms]. Studies indicate that ventilation has an important
of the diagnostic limitations. role in reducing the risk of airborne transmission of TB (36).
The standard approach to TB transmission control in These include mechanical as well as natural ventilation,
health care settings includes: [i] administrative measures; such as, simply keeping windows open. A “Finding TB
[ii] environ­mental or engineering measures, and [iii] personal cases Actively, Separating safely, and Treating effectively”
respiratory protection (50). [FAST] approach is recommended (55). In fact, separation or
This approach is detailed in both the WHO TB infection segregation of smear-positive TB patients in private or semi-
control policy and the existing facility-level document, (35,50) private rooms or wards with simple mechanical exhaust
as well as the CDC guidelines, although the latter are written ventilation [e.g., window fans] could be feasible in some
primarily for low-prevalence, resource-rich settings. settings, particularly in the private sector and well-funded
762 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

public hospitals. These measures have been shown to be apply to room air cleaners using filters with or without
useful in terminating an outbreak of nosocomial TB (26). germicidal lamps. The efficacy of UV germicidal lights is
This intervention is particularly necessary at centres that being evaluated in other low-income countries, and results of
manage patients with MDR-TB; at such centres, patients such studies are needed to determine their value in reducing
with infectious TB must not be admitted to the same wards nosocomial transmission.
as patients with HIV infection.
There is a growing need for architects and engineers Use of Personal Protection Measures
trained in airborne infection control owing to growing
awareness on the role of design in limiting transmission The first two levels of the infection control hierarchy,
of infections. The design process includes: [i] an in-depth administrative and environmental controls, minimise the
study of work practices; [ii] patient volume and flow; exposure to Mtb might occur but do not eliminate, the risk.
[iii] an understanding of high-risk and lower risk areas; and The third level of the hierarchy is the use of respiratory
[iv] an appreciation of local climate and resource limitations. protective equipment in situations that pose a high-risk for
Comprehensive, evidence-based guidelines on natural exposure. Respirators encompass a range of devices that
ventilation to control airborne infections in health care vary in complexity from flexible masks covering only the
settings have recently been issued by the WHO (56). A number nose and mouth, to units that cover the user’s head, such
of minimal hourly average ventilation rates is suggested, as, loose-fitting or hooded powered air purifying respirators
taking into account fluctuations in conditions and the indoor [PAPRs] and to those that have independent air supplies
gas exchange rates are monitored using carbon dioxide as [e.g., airline respirators] (60).
tracer gas when windows are open compared to when they The overall effectiveness of respiratory protection is
are closed in some settings (57). Facilities in warm climates affected by [i] the level of respiratory protection selected
can take advantage of outdoor waiting areas, covered open [e.g., the assigned protection factor]; [ii] the fit characteristics
walkways and open windows most of the time of the year. of the respirator model; [iii] the care in donning the respi­
While facility planners try to take full advantage of natural rator; and [iv] the adequacy of the fit-testing program.
ventilation, it may not be sufficient owing to different Although data on the effectiveness of respiratory protection
direction of airflow under various climatic conditions and from various hazardous airborne materials have been
at different times of day. The effect of opening and closing collected, the precise level of effectiveness in protecting
interior doors is also considered. When these rates and health care workers from Mtb transmission in health care
airflow direction cannot be reliably achieved by natural settings has not been determined.
ventilation alone, mechanical ventilation or mixed mode The most widely used respirators are certified in the
systems are recommended. United States as N95 [Figure 56.1] and in Europe as FFP2.
Germicidal air-disinfection is also an attractive alter­ The disposable models consist of a filtering face piece in
various configurations [cup, duckbill] and sizes, generally
native as a low-cost complementary system to natural
two elastic bands to achieve a tight face seal, and a malleable
ventilation, for example at night or during cold seasons when
nose clip to prevent leaks around the nose. The US CDC
windows may be closed (58), especially in cold climates not
provides guidance on all aspects of an effective respirator
suitable for natural ventilation or high-volume mechanical
programme (61).
ventilation systems (59). Germicidal irradiation is used in
Besides high cost, many barriers have been identified that
three different ways: [i] direct, unshielded room disinfection;
prevent the effective use of respirators in resource-limited
[ii] disinfection in ventilation duct or room air cleaners; and
[iii] upper room air disinfection.
The application of ultraviolet germicidal irradiation
[UVGI] for TB transmission control is not very effective as
[i] there is no evidence that Mtb, once settled on surfaces,
can be resuspended as particles small enough to reach the
alveoli of the lung where infection must begin; [ii] UV is
not an ideal surface decontaminant, missing any shadowed
surfaces; and [iii]air disinfection is most useful for protecting
room occupants when the infectious source is present (45).
UVGI in a properly designed room air cleaner will effectively
disinfect the air going through it, but the overall effect in a
room is limited to the number of germ-free equivalent room
air changes added per hour, or ‘clean air delivery rate’ (46).
Small air cleaning units, sold as a quick and easy solution
for TB transmission control, with very low clean air delivery
rates are often mounted to the walls of corridors or placed
in patient rooms. These units give a false sense of security
and no meaningful risk reduction. The same limitations Figure 56.1: N95 respirator
 Airborne Tuberculosis Transmission and Infection Control Strategies 763

settings as respirators are uncomfortable and cannot be worn Table 56.3: Recommendations for TB ward
continuously. For respirator to function optimally respirator
TB wards should be located away from the other wards, with
models and sizes should be available since no single model adequate facilities for hand washing and good maintenance and
or size fits everyone. All of this entails cost and training. cleaning
There is a concern around the cost [ranging from US$1-$2]
TB wards should have adequate ventilation [natural and/or assisted]
each in low-resource settings. The masks tend to become to ensure >12 ACH at all times
flaccid fairly quickly, depending on quality and how often
In TB wards there should be adequate space [at least 6 feet]
the respirator is doffed and donned. between 2 adjacent beds
Better non-disposable respirator designs that have a more
Cough hygiene should be promoted through signage and practice
clinical appearance and allow better verbal communication ensured through patients and staff training, ongoing reinforcement
are needed for medical use in resource-limited settings (39). by staff
Adequate sputum disposal, with individual container with lid,
SPECIFIC STRATEGIES FOR REDUCING containing 5% phenol, for collection of sputum should be provided
AIRBORNE TRANSMISSION OF TUBERCULOSIS All staff should be trained on standard precautions, airborne
AT HEALTH CARE FACILITIES infection control precautions, and the proper use of personal
respiratory protection. A selection of different sizes of re-usable N95
TB infection control requires action at national and sub­ particulate respirators should be made available for optional use by
national level to provide policy and managerial direction, staff
and at health facility level to implement TB infection Sputum pots in the inpatient wards should be disinfected with 5%
control measures. The recommended set of activities for phenol for one hour, and then emptied into the routine drain
national and subnational TB infection control is neces­ TB = tuberculosis; ACH = air changes per hour
sary to facilitate implementation of TB infection control in
health care facilities, congregate settings and households
[Tables 56.2 and 56.3].
These activities should be integrated within existing Table 56.4: Specific strategies for reducing airborne
national and sub-national management structures for general transmission of TB at health care facilities
infection prevention and control.
Developing an infection control plan and allocation of specific
Based upon international recommendations [WHO, budget and time line for the activity
CDC, etc.] following specific measures may be undertaken
Identifying and strengthening local coordinating bodies for
[Table 56.4]. For reducing transmission in the health care
TB infection control, and developing a facility plan [including
settings, the TB infection-control programme should be based human resources, and policies and procedures to ensure proper
on a three-level hierarchy of control measures that have implementation of the controls listed below] for implementation
been described earlier, namely, administrative, engineering/ Rethinking the use of available spaces and considering renovation
environmental and personal protective equipment. of existing facilities or construction of new ones to optimise
implementation of controls
Reducing Transmission in the Conduct on-site surveillance of TB disease among health workers
Laboratory Facilities and assess the facility
Address ACSM for health workers, patients and visitors
TB bacteriology laboratory activities that may generate
aerosols include preparing specimens for centrifugation Organising training of health care workers
Monitor and evaluate the set of TB infection control measures

Table 56.2: Set of activities for national and Participate in research efforts
sub-national TB infection control TB = tuberculosis; ACSM = advocacy, communication and social
mobilisation
Identify and strengthen a coordinating body for TB infection control,
and develop a comprehensive budgeted plan that includes human
resource requirements for implementation of TB infection control at
all levels
Conduct surveillance of TB disease among health workers, and and mycobacterial culture, centrifugation of specimens,
conduct assessment at all levels of the health system and in inoculating cultures from specimen sediment, handling
congregate settings unopened primary- isolation plates or tubes, staining smear
Ensure that health facility design, construction, renovation and use of material from culture, manipulating cultures [suspension
are appropriate preparation, vortex, and transferring] of Mtb complex on
Address TB infection control advocacy, communication and social solid medium, transferring large volumes of cultures or
mobilisation [ACSM], including engagement of civil society suspensions of bacilli, disposing of cultures of Mtb complex,
Monitor and evaluate the set of TB infection control measures inactivation of specimens for isolation of deoxyribonucleic
acid [DNA] and other macromolecules on Mtb complex
Enable and conduct operational research
species and during shipping of cultures or specimens of
TB = tuberculosis
Mtb complex.
764 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

While general principles of instituting administrative, In laboratories where only smear microscopy is per­
enginee­ring and personal protective activities [outlined formed, personal respiratory protection [e.g., respirators] is
above], given the greater mycobacterial burden in environ­ not needed. Laboratories working with liquid suspensions
ment of laboratories, some of the additional important of Mtb should be equipped with a BSC class I. Personal
actions need to be taken. These include the following. respiratory protection is not recommended if the BSC
Written TB infection control measures {standard opera­ is functioning appropriately and all work with liquid
ting procedures, [SOP]} for laboratory are available, and suspensions is carried out in the cabinet.
laboratory technologists [LTs] are trained/oriented in
laboratory standard operating procedures in ensuring Designated Microscopy Centres
airborne precautions through periodic trainings. Shipping
of cultures to reference laboratory needs to follow bio-safe- Direct sputum microscopy is a relatively low-risk activity
triple packaged containers. Laboratory is either placed at as long as safe work practices are implemented properly.
the blind-end of building and/physically isolated from The following work practices are recommended to ensure
the common laboratory/hospital environments. Access to that microscopy laboratory technicians are not exposed to
the culture and drug susceptibility testing [DST] rooms aerosols from sputum specimens.
is through an anteroom. The entry to lab is restricted to Sputum collection Sputum must be collected in a well
trained laboratory personnel. The containment room where ventilated area with direct sunlight. It should not be collected
culture and DST is carried out is sealable in case of spill and in laboratories, toilets, waiting rooms, reception rooms,
aerosolisation for decontamination. Biological safety cabinets or any other enclosed space. If indoor sputum collection
[BSCs] class II, with 100% exhaust [i.e. ducted outside] are is required due to space constraints, it should be done in
provided and used. BSCs ducted to outside, while switched sputum collection booth.
“on”, would maintain an inward air flow into the culture and Smear preparation Smears should be prepared in a well
DST facilities. Bio-safe centrifuges with aerosol-seal buckets ventilated environment, near an open flame.
is provided and used. Handwash sink is provided in the
culture and DST room with effective disinfectant. Autoclave Work bench Work Benches should be cleaned daily with
[steam sterilisation facility] is provided within the laboratory 70% alcohol.
facility. Following protection measures to be followed in the Sputum container/applicator sticks/slides Sputum con­
laboratory by staff [Table 56.5]. tainers, applicator sticks and slides should be disinfected
with 5% Phenol overnight before discarding. They may be
discarded in deep burial pits or may be tagged for appro­
priate disposal via the hospital biomedical waste manage­
Table 56.5: Protection measures to be followed in the ment system.
laboratory by staff
For sputum collection and smear microscopy Acid-fast Bacilli Smear Preparation
Proper cough hygiene needs to be explained to the patients
Many laboratories which process infectious sputum in
Collection should be in an open area, or in a properly designed and resource-limited countries perform only direct smear
maintained indoor sputum collection booth
microscopy. Performing direct smear microscopy has not
Laboratory technician would maintain at least one arm length been documented to result in the transmission of Mtb
distance and upwind when a patient is collecting a sputum sample
[assuming centrifugation is not being used]. Direct smear
Wear lab coats while performing the laboratory work microscopy can be safely performed on the open bench.
For culture and DST activities Neither environmental controls nor personal respiratory
All personnel working in culture laboratory need to wear separate protection are necessary during the preparation of smears.
clothing, not the common laboratory coat In laboratories performing only smear preparation
Separate closed-toe foot-wear to be used at all times. Chappals or without the use of a centrifuge, perhaps the greatest threat to
sandals are not appropriate the personnel is contact with coughing patients. Administra­
All personnel are to wear an N95 particulate respirator while tive controls should be used to limit this exposure.
performing
DST, or manipulating cultures for any reason Preparation of Liquid Suspensions of
Decontaminate lab coat before laundering or disposal Mycobacterium tuberculosis
Personal protective equipment should be worn in the following Laboratories which process liquid preparations of suspended
order: [i] disposable gloves; [ii] coats/suits/overalls; and Mtb [e.g., centrifugation, cultures, and DST] should be
[iii] respirator/mask
considered at higher risk for nosocomial Mtb transmission.
Personal protective equipment should be removed in the following Safety can be improved by enhancing ventilation in areas
order before leaving the laboratory: [i] respirator/mask; [ii] coats/
where culture and susceptibility testing of Mtb isolates is
suits/overalls; and [iii] disposable gloves
performed; reducing the number of laboratories handling
DST = drug-susceptibility testing concentrated specimens containing Mtb; and only allowing
 Airborne Tuberculosis Transmission and Infection Control Strategies 765

laboratories with appropriate biosafety cabinets [BSC I and TB disease among individuals in congregate settings
or BSC II] and experienced staff to work with liquid exceeds the incidence among the general population
suspensions of Mtb. particularly among inmates of prisons. Therefore, the
policy makers responsible for congregate settings should
Reducing Transmission in Households be made part of the coordinating system for planning
and Communities and implementing interventions to control TB infection.
In particular, the medical service of the ministry of justice
To reduce exposure in households, patients and their and correctional facilities should be fully engaged and
families should be educated on the importance of infection encouraged to implement TB infection control. Congregate
control practices to be observed at home. Houses should be settings should be part of the country surveillance activities,
adequately ventilated, particularly rooms where people with and should be included in facility assessment for TB infection
infectious TB spend considerable time [natural ventilation control. Any advocacy and information, education and
may be sufficient to provide adequate ventilation]. Anyone communication material should include a specific focus on
who coughs should be educated on cough etiquette and congregate settings, as should monitoring and evaluation of
respiratory hygiene, and should follow such practices at TB infection control measures.
all times while smear positive, TB patients should spend as
much time as possible outdoors; sleep alone in a separate, Facility-level Managerial Activities should Also
adequately ventilated room, if possible; and spend as little
Apply with Some Adaptation to Congregate
time as possible in congregate settings or in public transport.
Patients with MDR-TB usually sputum convert later
Settings
than those with drug-susceptible TB and remain infectious To decrease TB transmission in congregate settings, cough
for much longer, thus prolonging the risk of transmission etiquette and respiratory hygiene, and early identification,
in the household. Additional infection control measures followed by separation and proper treatment of infectious
should, therefore, be implemented for the management of cases should be implemented. All staff should be given
MDR-TB patients at home. Awareness of infection control appropriate information and encouraged to undergo TB
in the community should be promoted. In households with diagnostic investigation if they have signs and symptoms
culture-positive MDR-TB patients, the following guidance suggestive of TB. People suspected of having TB should be
should be observed, in addition to the measures given above. diagnosed as quickly as possible and managed.
While culture positive, MDR-TB patients who cough should In congregate settings with a high prevalence of HIV
always practice cough etiquette [including use of masks] and [in particular in correctional services], patients living with
respiratory hygiene when in contact with people. Ideally, HIV and other forms of immunosuppression should be
health service providers should wear particulate respirators separated from those with suspected or confirmed infectious
when attending patients in enclosed spaces. Further, family TB. All staff and persons residing in the setting should
members living with HIV, or family members with strong be encouraged to undergo HIV testing and counselling.
clinical evidence of HIV infection, should ideally not provide If diagnosed with HIV, they should be offered a package
care for patients with culture-positive MDR-TB. If there is of prevention and care that includes regular screening
no alternative, HIV-positive family members should wear for active TB. In congregate settings with patients having,
respirators, if available. or suspected of having, drug-resistant TB, such patients
Children below five years of age should spend as little should be separated from other patients [including other
time as possible in the same living spaces as culture-positive TB patients], and referral for proper treatment should be
MDR-TB patients. Such children should be followed up established. Buildings in congregate settings should comply
regularly with TB screening and, if positive, DST and with national norms and regulations for ventilation in public
treatment. While culture positive, XDR-TB patients should buildings, and specific norms and regulations for prisons,
be isolated at all times, and any person in contact with a
where these exist.
culture positive XDR-TB patient should wear a particulate
India has the highest number of patients with MDR-TB
respirator. If at all possible, HIV-positive family members,
globally. Given the threat of drug-resistant TB, in addition
or family members with a strong clinical evidence of HIV
to unprecedented massive scale-up of complex, effective
infection, should not share a household with culture positive
treatment programmes, simultaneous seismic shift in efforts
XDR-TB patients. If possible, potential renovation of the
to control transmission in congregate settings as well as in
patient’s home should be considered, to improve ventilation
communities is the need of the hour. The apparent solutions
[e.g. building of a separate bedroom, or installation of a
to improve the current situation includes the introduction
window or wind catcher, or both].
of improved diagnostic methods, rapid detection of
drug resistance, newer drugs and regimes, and strengthen
Reducing Transmission in Congregate Settings
the infection control practices to reduce the spread of
Like any other health care facility, the set of TB infection infection as well as curtail the re-infection by instituting
control measures should be implemented in congregate measures to reduce transmission in hospital and community
settings especially prisons, as the incidence of TB infection settings (62,63).
766 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The most affordable measures which can be easily of death in patients co-infected with tuberculosis and HIV in a
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that can be utilised to break the cycle of transmission in 15. Godfrey-Faussett P, Sonnenberg P, Shearer SC, Bruce MC, Mee C,
Morris L, et al. Tuberculosis control and molecular epidemio­logy
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be made to segregate potentially infectious patients from 17. Keshavjee S, Gelmanova IY, Farmer PE, Mishustin SP, Strelis AK,
Andreev YG, et al. Treatment of extensively drug-resistant
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 57
Standards for TB Care in India

Reproduced with kind permission (in part) from World Health Organization, Country Office for India. Full document can be accessed
from URL://http://www.searo.who.int/india/mediacentre/events/2014/stci_book.pdf accessed on October 10, 2015
 Standards for TB Care in India 769

© World Health Organization 2014

All reasonable precautions have been taken by the World Health Organization to verify the information contained in
this publication. However, the published material is being distributed without warranty of any kind, either expressed
or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the
World Health Organization be liable for damages arising from its use.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
This publication contains the collective views of a national and international group of experts and does not necessarily
represent the decisions or the policies of the World Health Organization.
This publication can be reprinted for wider dissemination of standards for TB care under due acknowledgment
to Central TB Division, Ministry of Health & Family Welfare, Government of India and World Health Organization,
Country Office for India.
 770 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Table of contents

Acknowledgements...............................................................................................................................................................................771
Development process............................................................................................................................................................................772
Introduction............................................................................................................................................................................................772
STCI summary........................................................................................................................................................................................773
Standard 1 Testing and screening for Pulmonary TB.....................................................................................................................779
Standard 2 Diagnostic technology......................................................................................................................................................780
Standard 3 Testing for extra-pulmonary TB.....................................................................................................................................781
Standard 4 Diagnosis of HIV co-infection in TB patients and diagnosis of Drug Resistant TB (DR-TB)..............................782
Standard 5 Probable TB........................................................................................................................................................................783
Standard 6 Paediatric TB......................................................................................................................................................................783
Standard 7 Treatment with first-line regimen..................................................................................................................................784
Standard 8 Monitoring treatment response......................................................................................................................................786
Standard 9 Drug Resistant TB management.....................................................................................................................................787
Standard 10 Addressing TB with HIV infection and other comorbid conditions......................................................................789
Standard 11 Treatment adherence......................................................................................................................................................790
Standard 12 Public health responsibility...........................................................................................................................................791
Standard 13 Notification of TB cases..................................................................................................................................................792
Standard 14 Maintain records for all TB patients............................................................................................................................792
Standard 15 Contact investigation......................................................................................................................................................792
Standard 16 Isoniazid Prophylactic therapy.....................................................................................................................................793
Standard 17 Airborne infection control.............................................................................................................................................793
Standard 18 Quality assurance systems.............................................................................................................................................794
Standard 19 Panchayati Raj Institutions............................................................................................................................................794
Standard 20 Health education.............................................................................................................................................................794
Standard 21 Death audit among TB patients....................................................................................................................................795
Introduction to Standards for Social Inclusion for TB....................................................................................................................795
Standard 22 Information on TB prevention and care seeking.......................................................................................................795
Standard 23 Free and quality services...............................................................................................................................................795
Standard 24 Respect, confidentiality and sensitivity.......................................................................................................................796
Standard 25 Care and support through social welfare programmes...........................................................................................796
Standard 26 Addressing counseling and other needs.....................................................................................................................796
 Standards for TB Care in India 771

Acknowledgements

Development of the Standards for TB Care in India (STCI) is the culmination of a series of discussions involving
various stakeholders and review of literature. Central TB Division, Ministry of Health & Family Welfare, Government
of India and WHO Country Office for India took the lead in the process. The national TB institutions in India namely
National Institute of TB and Respiratory Diseases (NITRD) New Delhi, National Institute for Research in Tuberculosis
(NIRT) Chennai and National TB Institute (NTI) Bangalore contributed significantly in the development process.
USAID has provided funding support to this initiative through WHO Country Office for India.
We acknowledge the contribution of all participants of the workshop and also those experts who reviewed the
report and made comments for its betterment. Programme managers of Revised National Tuberculosis Control
Programme (RNTCP) at central, state and district level have contributed substantially to finalize this document. Special
appreciation is due for the medical consultants of WHO-RNTCP technical assistance network for their contribution
in literature search and in providing necessary technical and operational support for the development of STCI.
WCO-India communications team has provided crucial support in editing this document and we thank them for this.
The writing group comprised of (alphabetically) Dr A Sreenivas, Dr K Rade, Dr KS Sachdeva, Dr M Ghedia,
Dr M Parmar, Dr R Ramachandran and Dr Shepherd J.
The draft guidelines have been reviewed and valuable comments have been provided by a group of experts
comprising of: (alphabetically) Dr A Mohan, Dr A Joshi, Dr B John, Dr C Rodrigues, Dr GR Sethi, Dr N Kulshrestha,
Dr N Wilson, Dr O George, Dr P Dewan, Dr RN Solanki, Dr R Sarin, Dr RV Ashokan, Dr S Gutta, Dr S Sahu,
Dr S Swaminathan, Dr S Vijayan and Dr V Singh. These contributions are gratefully acknowledged.
772 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Development process

The first edition of the Standards for TB Care in India was conceived by a wider community of clinicians, public
health specialists, community workers and patient advocates both within and outside of the Government of India as a
necessary step in requiring and monitoring a widely accepted standard of TB care for the people of India. International
guidelines and standards for TB care which existed such as International Standards for TB Care 2006 and 2009 editions,
American Thoracic Society Standards, European Standards 2011, WHO Guideline for Treatment of TB 2010 and WHO
Guidelines for PMDT 2011 were used as a foundation for developing India’s standards. However with its unique challenges,
approximately one third of the world’s TB burden, and long history of dealing with a TB problem that appears to be
resilient to the best efforts, it was felt that India should have its own standards that could be used as a benchmark by all
providers managing TB patients within India. It is hoped that a set of standards recognized as appropriate for the specific
challenges of India will spur observance to these standards by all care providers of India when managing a TB patient.
The standards developed and described here are the result of a long process that culminated in a three day national
workshop organized by Central TB Division at New Delhi in December 2012 with technical assistance from WHO
Country Office for India. The objective of the workshop was to develop the Standards for Tuberculosis Care in India
that will be applicable to providers in public, private and other settings across India. About 120 experts from national
and international level including various public health administrators, programme managers, representatives from
various professional associations (Indian Medical Association, Association of Physicians of India, College of Physicians
Association of India, Indian Association of Paediatricians, Federation of Obstetricians and gynecologists congress of India,
Family Physician Association of India etc.), academicians and specialists from public and private sectors (pulmonologists,
physicians, surgeons, paediatricians, gynaecologists, orthopaedic surgeons, microbiologists, public health specialist
etc.), donors, technical and implementation partners, pharmaceutical companies, pharmacists association, consultants,
management experts, social science experts and civil society representatives participated at the workshop and actively
worked to develop the evidence based Standards for Tuberculosis Care in India.
The methodology consisted of panel discussions and group work and the approach was to find appropriate answers
to the following questions:
• What should be the standard tools and strategies for early and complete detection?
• What should be the standards of treatment in terms of drugs and regimens for best patient outcome?
• What should be the public health standards including regulations, strategies and systems for public health impact?
• What should be standards for patient support systems, both in public and private sectors and for community engagement
for social inclusion?
As part of the development process, noted experts in the field of TB in India modified the international standards,
following detailed review of Indiaspecific and India-relevant evidence. As an output of the workshop, 26 standards
developed and the India-relevant evidence debated, and listed for each of the standards in this document. This includes
a new set of standards for social inclusion that goes beyond the areas covered in the International Standards for TB Care
(ISTC) 2009. After the statement of each standard a brief summary of the international and national evidence are described
along with the references to the literature. The standards thus evolved, are intended to be used to enhance quality and
mutually acceptable engagement with the private and other sectors in India to enhance TB care. This is thus, an important
tool for achieving the goal of universal access to quality TB care.

Introduction

India, the world’s second most populous country, accounts for a quarter of the world’s annual incidence of TB.
Every year around two million people develop TB in India and 300,000 die of TB. Over 15 million patients have been
treated and three million additional lives have been saved by the Revised National TB Control Programme (RNTCP) over
the last decade. Cure rates have consistently been above 85% and the TB Millennium Development Goals are reachable.
However, despite a comprehensive national TB control program guiding states for implementation of TB diagnosis and
treatment there is still a long way to go. The decline in TB incidence has been slow, mortality remains unacceptably high
and the emergence of drug-resistant TB has become a major public health concern.
 Standards for TB Care in India 773

There are many challenges for TB control in India. Prompt, accurate diagnosis and effective treatment of TB are not
only essential for good patient care, but they are also the key elements in the public health response to tuberculosis
and the cornerstone of any initiative for tuberculosis control. The private sector holds a factual predominance of health
care service delivery in India. There is very little information about the TB patient from the private sector available to
the programme and little is known about their quality of treatment, including treatment outcomes. Engaging the private
sector effectively is the single most important intervention required for India to achieve the overall goal of universal access
to quality TB care.
The vision of India’s national TB control programme is that the people suffering from TB receive the highest standards
of care and support from healthcare providers of their choice. It is spelt out in the National Strategic Plan (2012-17) to
extend the umbrella of quality TB care and control to include those provided by the private sector (1). The need for
quality and standards for TB care is made particularly acute where a largely unregulated and unmonitored private sector
accounts for almost half of the TB care delivered in India with gross challenges as far as quality of diagnosis and treatment
is concerned. Thus, it was felt essential to develop and disseminate the standards of TB care that is particularly relevant
in Indian context, acceptable to the medical fraternity in both the public and private sector in India.
Also, the availability of new diagnostic tools and strategies for early TB diagnosis, emerging evidences on
existing regimens and newer regimens, and the need for better patient support strategies including addressing social
inclusiveness necessitated the development of Standards for TB Care in India.
To paraphrase the ISTC, the standards in this document differ from existing guidelines in that the standards present
what should be done whereas guidelines describe how the action is to be accomplished. There are comprehensive
national guidelines from the Central TB Division, GoI [www.tbcindia.nic.in] that are regularly reviewed and updated.
These standards represent the first what is expected from the Indian healthcare system. It is expected that the standards
discussed in this document are clear and usable and will be accessible to all TB providers as an easy reference.

Reference:
1. Rosenblatt MB. Pulmonary tuberculosis: evolution of modern therapy. Bull NY Acad Med 1973;49:163-96.

STCI summary

Standard 1: Testing and screening for Pulmonary TB

1.1 Testing:
• Any person with symptoms and signs suggestive of TB including cough >2 weeks, fever >2 weeks, significant
weight loss, haemoptysis etc. and any abnormality in chest radiograph must be evaluated for TB.
• Children with persistent fever and/or cough >2 weeks, loss of weight/no weight gain, and/or contact with
pulmonary TB cases must be evaluated for TB.
1.2 Screening:
• People living with HIV (PLHIV), malnourished, diabetics, cancer patients, patients on immuno­suppressant
or maintenance steroid therapy, should be regularly screened for signs and symptoms suggestive of TB.
• Enhanced case finding should be undertaken in high risk populations such as health care workers, prisoners,
slum dwellers, and certain occupational groups such as miners.

Standard 2: Diagnostic technology

2.1 Microbiological confirmation on sputum:
• All patients (adults, adolescents, and children who are capable of producing sputum) with presumptive
pulmonary TB should undergo quality-assured sputum test for rapid diagnosis of TB (with at least two samples,
including one early morning sample for sputum smeer for AFB) for microbiological confirmation.
2.2 Chest X-ray as screening tool:
• Where available, chest X-ray should be used as a screening tool to increase the sensitivity of the diagnostic
algorithm.
774 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

2.3 Serological tests:

• Serological tests are banned and not recommended for diagnosing tuberculosis.
2.4 Tuberculin Skin Test (TST) & Interferon Gamma Release Assay (IGRA)
• TST and IGRA are not recommended for the diagnosis of active tuberculosis. Standardised TST may be used as
a complimentary test in children.
2.5 CB-NAAT (cartridge-based nucleic-acid amplification test) is the preferred first diagnostic test in children and
PLHIV.
2.6 Validation of newer diagnostic tests:
• Effective mechanism should be developed to validate newer diagnostic tests.

Standard 3: Testing for extra-pulmonary TB

• For all patients (adults, adolescents and children) with presumptive extra-pulmonary TB, appropriate specimens
from the presumed sites of involvement must be obtained for microscopy/culture and drug sensitivity testing
(DST)/CB-NAAT/molecular test/histo-pathological examination.

Standard 4: Diagnosis of HIV co-infection in TB patients and Drug Resistant TB (DR-TB)

4.1 Diagnosis of HIV in TB patients:
• All diagnosed TB patients should be offered HIV counselling and testing.
4.2 Diagnosis of multi-drug resistant TB (MDR-TB):
• Prompt and appropriate evaluation should be undertaken for patients with presumptive MDR-TB or Rifampicin
(R) resistance in TB patients who have failed treatment with first line drugs, paediatric non-responders,
TB patients who are contacts of MDR-TB (or R resistance), TB patients who are found positive on any follow-up
sputum smear examination during treatment with first line drugs, diagnosed TB patients with prior history of
anti-TB treatment, TB patients with HIV co-infection and all presumptive TB cases among PLHIV. All such
patients must be tested for drug resistance with available technology, a rapid molecular DST (as the first choice)
or liquid/solid culture-DST (at least for R and if possible for Isoniazid (H); Ofloxacin (O) and Kanamycin (K),
if R-resistant/MDR).
• Wherever available DST should be offered to all diagnosed tuberculosis patients prior to start of treatment.
4.3 Diagnosis of Extensively Drug Resistant TB (XDR-TB):
• On detection of Rifampicin resistance alone or along with isoniazid resistance, patient must be offered sputum
test for second line DST using RNTCP approved phenotypic or genotypic methods, wherever available.

Standard 5: Probable TB
• Presumptive TB patients without microbiological confirmation (smear microscopy, culture and molecular diagnosis),
but with strong clinical and other evidence (e.g. X-ray, Fine Needle Aspiration Cytology (FNAC, histopathology) may
be diagnosed as “Probable TB” and should be treated.
• For patients with presumptive TB found to be negative on rapid molecular test, an attempt should be made to obtain
culture on an appropriate specimen.

Standard 6: Paediatric TB
6.1 Diagnosis of paediatric TB patients:
• In all children with presumptive intra-thoracic TB, microbiological confirmation should be sought through
examination of respiratory specimens (e.g. sputum by expectoration, gastric aspirate, gastric lavage, induced
sputum, broncho-alveolar lavage or other appropriate specimens) with quality assured diagnostic test, preferably
CB-NAAT, smear microscopy or culture.
6.2 Diagnosis of probable paediatric TB patients:
• In the event of negative or unavailable microbiological results, a diagnosis of probable TB in children should
be based on the presence of abnormalities consistent with TB on radiography, a history of exposure to
pulmonary tuberculosis case, evidence of TB infection (positive TST) and clinical findings suggestive of TB.
 Standards for TB Care in India 775

6.3 Diagnosis of extra-pulmonary paediatric TB patients:

• For children with presumptive extra-pulmonary TB, appropriate specimens from the presumed sites of
involvement should be obtained for rapid molecular test, microscopy, culture and DST, and histo-pathological
examination.

Standard 7: Treatment with first-line regimen

7.1 Treatment of New TB patients:
• All new patients should receive an internationally accepted first-line treatment regimen for new patients.
The initial phase should consist of two months of Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), and
Ethambutol (E). The continuation phase should consist of three drugs (Isoniazid, Rifampicin and Ethambutol)
given for at least four months.
7.2 Extension of continuation phase:
• The duration of continuation phase may be extended by three to six months in special situations like bone &
joint TB, spinal TB with neurological involvement and neuro-tuberculosis.
7.3 Drug dosages:
• The patients should be given dosages of the drugs depending upon body weight in weight bands.
7.4 Bio-availability of drugs:
• The bio-availability of the drug should be ensured for every batch, especially if fixed dose combinations (FDCs)
are used, by procuring and prescribing from a quality-assured source.
7.5 Dosage frequency:
• All patients should be given daily regimen under direct observation. However, the country programme may
consider daily or intermittent regimen for treatment of TB depending on the available resources and operational
considerations as both are effective provided all doses are directly observed.
• All paediatric and HIV infected TB patients should be given daily regimen under direct observation.
7.6 Drug formulations:
• Fixed dose combinations (FDCs) of four drugs (Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol), and three
drugs (Isoniazid, Rifampicin and Ethambutol) and two drugs (Isoniazid and Rifampicin) are recommended.
7.7 Previously treated TB patients:
• After MDR-TB (or R resistance) is ruled out by a quality assured test, TB patients returning after lost to follow up
or relapse from their first treatment course or new TB patients failing with first treatment course may receive
the retreatment regimen containing first-line drugs: 2HREZS/1HREZ/5HRE.

Standard 8: Monitoring treatment response

8.1 Follow-up sputum microscopy:
• Response to therapy in patients with pulmonary tuberculosis, new as well as retreatment cases, should be
monitored by follow-up sputum microscopy (one specimen) at the time of completion of the intensive phase of
treatment and at the end of treatment.
8.2 Extension of intensive phase:
• The extension of the intensive phase is not recommended.
8.3 Offer DST in follow-up sputum positive cases:
• If the sputum smear is positive in follow-up at any time during treatment, a rapid molecular DST (as the first
choice) or culture-DST (at least for R and if possible for Isoniazid (H); Ofloxacin (O) and Kanamycin (K),
if R-resistant/MDR) should be performed as laboratory facilities become available.
8.4 Response to treatment in extra-pulmonary TB:
• In patients with extra-pulmonary tuberculosis, the treatment response is best assessed clinically. The help of
radiological and other relevant investigations may also be taken.
8.5 Response to treatment in children:
• In children, who are unable to produce sputum the response to treatment may be assessed clinically. The help of
radiological and other relevant investigations may also be taken.
776 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

8.6 Long-term follow-up:

• After completion of treatment the patients should be followed up with clinical and/or sputum examination at
the end of six months and 12 months.

Standard 9: Drug Resistant TB management

9.1 Treatment of M/XDR-TB (or R resistant TB):
• Patients with tuberculosis caused by drug-resistant organisms (especially M/XDR or only R resistance or with
O or K resistance), microbiologically confirmed by quality assured test, should be treated with specialized
regimens containing quality assured second-line anti-tuberculosis drugs.
9.2 Model of care for drug resistant TB:
• Patients with MDR-TB should be treated using mainly ambulatory care rather than models of care based
principally on hospitalization. If required, a short period of initial hospitalisation is recommended.
9.3 Regimen for MDR/R-Resistant TB cases:
• The regimen chosen for MDR-TB may be standardized and/or based on microbiologically confirmed drug
susceptibility patterns. At least four drugs (second line) to which the organisms are susceptible, or presumed
susceptible, should be used. Most importantly the regimen should include at least a later-generation Fluoro­
quinolone (such as high dose Levofloxacin) and a parenteral agent (such as Kanamycin or Amikacin), and
may include Pyrazinamide, Ethambutol, Ethionamide (or Prothionamide), and either Cycloserine or PAS
(P-aminosalicylic acid) if Cycloserine cannot be used.
9.4 Regimen for MDR patients with Ofloxacin and/or Kanamycin resistance detected early:
• Treatment regimen may be suitably modified in case of Ofloxacin and/or Kanamycin resistance at the initiation
of MDR-TB treatment or during early intensive phase, preferably not later than four to six weeks.
9.5 Surgery in MDR/XDR TB patients:
• All patients of MDR/XDR-TB should be evaluated for surgery at the initiation of treatment and/or during
follow up.
9.6 Treatment Duration in MDR TB patients:
• Till newer effective drugs are available with proven efficacy with shorter duration of MDR-TB treatment;
total treatment should be given for at least 24 months in patients newly diagnosed with MDR-TB (i.e. not
previously treated for MDR-TB) with recommended intensive phase of treatment being six to nine months.
The total duration may be modified according to the patient’s response to therapy.
9.7 Specialist consultation in M/XDR TB patients:
• Consultation with a specialist experienced in treatment of patients with MDR/XDR tuberculosis should be
obtained, whenever possible.
9.8 Ensuring adherence in M/XDR TB patients:
• Patient support systems, including direct observation of treatment, are required to ensure adherence. It should
be ensured that the patient consumes all the doses of the drugs.
9.9 Single sample follow-up culture in M/XDR TB patients:
• The use of sputum culture (1 sample) is recommended for monitoring of patients with MDR-TB during
treatment.
9.10 Second line DST during treatment of MDR TB:
• During the course of MDR TB treatment, if the sputum culture is found to be positive at 6 months or later, the
most recent culture isolate should be subjected to DST for second-line drugs (at least O and K) to decide on further
course of action. DST to other drugs namely Moxifloxacin, Amikacin and Capreomycin may also be done if
laboratory facilities are available to guide treatment.
9.11 Regimen for MDR patients with Ofloxacin and/or Kanamycin resistance detected later:
• The patients with MDR-TB found to be resistant to at least Ofloxacin and/or Kanamycin during the later stage
of MDR TB treatment must be treated with a suitable regimen for XDR TB using second line drugs including
Group 5 drugs such as Amoxicillin Clavulanate, Clarithromycin, Clofazimine, Linezolid, Thioacetazone,
Imipenem to which the organisms are known or presumed to be susceptible.
 Standards for TB Care in India 777

9.12 New drugs:

• New drugs need to be considered for inclusion in regimens whenever scientific evidence for their efficacy
and safety becomes available as per the national policy for newer antimicrobials. Appropriate regulatory
mechanisms for distribution control needs to be ensured.

Standard 10: Addressing TB with HIV infection and other comorbid conditions
10.1 Treatment of HIV infected TB patients:
• TB patients living with HIV should receive the same duration of TB treatment with daily regimen as HIV
negative TB patients.
10.2 Anti-retroviral & Co-trimoxazole prophylactic therapy in HIV infected TB patients:
• Antiretroviral therapy must be offered to all patients with HIV and TB as well as drug-resistant TB requiring
second-line anti-tuberculosis drugs, irrespective of CD4 cell-count, as early as possible (within the first eight
weeks) following initiation of anti-tuberculosis treatment. Appropriate arrangements for access to antiretroviral
drugs should be made for patients. However, initiation of treatment for tuberculosis should not be delayed.
Patients with TB and HIV infection should also receive Co-trimoxazole as prophylaxis for other infections.
10.3 Isoniazid preventive therapy in HIV patients without active TB:
• People living with HIV should be screened for TB using four symptom complex (current cough or, fever or
weight loss or night sweats) at HIV care settings and those with any of these symptoms should be evaluated for
ruling out active TB. All asymptomatic patients in whom active TB is ruled out, Isoniazid Preventive Therapy (IPT)
should be offered for six months or longer.

Standard 11: Treatment adherence

11.1 Patient centered approach for adherence:
• Both to assess and foster adherence, a patient-centered approach to administration of drug treatment, based on
the patient’s needs and mutual respect between the patient and the provider, should be developed for all patients.
11.2 Measures for treatment adherence:
• Supervision and support should be individualized and should draw on the full range of recommended inter­
ventions and available support services, including patient counselling and education. A central element of
the patient centred strategy is the use of measures to assess and promote adherence to the treatment regimen
and to address poor adherence when it occurs. These measures should be tailored to the individual patient’s
circumstances based on details of the patient’s clinical and social history and be mutually acceptable to the patient
and the provider.
11.3 Trained treatment supporter for treatment adherence:
• Such measures may include identification and training of a treatment supporter (for tuberculosis and, if
appropriate, for HIV, Diabetes Mellitus etc.) who is acceptable, accessible and accountable to the patient and
to the health system.
11.4 Use of Information Communication Technology (ICT) to promote treatment literacy and adherence:
• Optimal use of ICT should be done to promote treatment literacy and adherence.

Standard 12: Public health responsibility

• Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility to prevent
on-going transmission of the infection and the development of drug resistance.
• To fulfil this responsibility the practitioner must not only prescribe an appropriate regimen, but when necessary,
also utilize local public health services/community health services, and other agencies including NGOs to assess
the adherence of the patient and to address poor adherence when it occurs.

Standard 13: Notification of TB cases

• All health establishments must report all TB cases and their treatment outcomes to public health authorities
(District Nodal Officer for Notification).
• Proper feedback need to be ensured to all healthcare providers who refer cases to public health system on the
outcome of the patients which they had referred.
778 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Standard 14: Maintain records for all TB patients

• A written record of all medications given, bacteriologic response, adverse reactions and clinical outcome should be
maintained for all patients.

Standard 15: Contact investigation

• All providers of care for patients with tuberculosis should ensure all household contacts and other persons who are
in close contact with TB patients are screened for TB
• In case of pediatric TB patients, reverse contact tracing for search of any active TB case in the household of the child
must be undertaken.

Standard 16: Isoniazid Prophylactic therapy

• Children <6 years of age who are close contacts of a TB patient, after excluding active TB, should be treated with
isoniazid for a minimum period of 6 months and should be closely monitored for TB symptoms.

Standard 17: Airborne infection control

• Airborne infection control should be an integral part of all health care facility infection control strategy.

Standard 18: Quality assurance (QA) systems

18a QA for diagnostic tests:
• All health care providers should ensure that all diagnostic tests used for diagnosis of TB are quality assured.
18b QA for anti-TB drugs:
• Quality assurance system should ensure that all anti-TB drugs used in the country are subjected to stringent
quality assurance mechanisms at all levels.

Standard 19: Panchayati Raj Institutions

• Panchayati Raj Institutions and elected representatives have an important role to share the public health responsibility
for TB control with the healthcare providers, patients and the community.

Standard 20: Health education

• Every TB symptomatic should be properly counselled by the healthcare provider.
• TB patients and their family members should get proper counselling and health education at every contact with
healthcare system

Standard 21: Death audit among TB patients

• Death among TB patients should be audited by a competent authority.

Standard 22: Information on TB prevention and care seeking

• All individuals especially women, children, elderly, differently abled, other vulnerable groups and those at increased
risk should receive information related to TB prevention and care seeking.

Standard 23: Free and quality services

• All patients, especially those in vulnerable population groups, accessing a provider where TB services are
available should be offered free or affordable quality assured diagnostic and treatment services which should be
provided at locations and times so as to minimize workday or school disruptions and maximize access.

Standard 24: Respect, confidentiality and sensitivity

• All people seeking or receiving care for TB should be received with dignity and managed with promptness,
confidentiality and gender sensitivity. Ensure that infection control procedures do not stigmatise TB patients.
 Standards for TB Care in India 779

Standard 25: Care and support through social welfare programmes

• Patient support system should endeavour to derive synergies between various social welfare support systems to
mitigate out of pocket expenses such as transport and wage loss incurred by people affected by TB for the purpose
of diagnosis and treatment.

Standard 26: Addressing counselling and other needs

• Persons affected by TB should be counselled at every opportunity, to address information gaps and to enable
informed decision making. Counselling should address issues such as treatment adherence, adverse drug reactions,
prognosis and physical, financial, psycho-social and nutritional needs.

Standard 1
Testing and screening for Pulmonary TB

1.1 Testing:
• Any person with symptoms and signs suggestive of TB including cough >2 weeks, fever >2 weeks, significant
weight loss, haemoptysis etc. and any abnormality in chest radiograph must be evaluated for TB.
• Children with persistent fever and/or cough >2 weeks, loss of weight/no weight gain, and/or h/o contact
with pulmonary TB cases must be evaluated for TB.
1.2 Screening:
• People living with HIV (PLHIV), malnourished, diabetics, cancer patients, patients on immunosuppressant
or maintenance steroid therapy, should be regularly screened for signs and symptoms suggestive of TB.
• Enhanced case finding should be undertaken in high risk populations such as healthcare workers, prisoners,
slum dwellers, and certain occupational groups such as miners.
The most common symptom of pulmonary TB is prolonged cough that lasts longer than the cough with most other acute
lung infections. However cough is a common symptom and most coughing patients do not have TB (1). Many countries
have attempted to distinguish likely TB cases from other lung infections by specifying a chronic cough lasting two
to three weeks (2,3). The evidence from India suggests that cough lasting > 2 weeks is a more sensitive indicator for
TB than >3 weeks cough and is thus recommended here (4,5,7,8). A high level of clinical suspicion for TB is necessary
as many TB patients will not have a cough, particularly if they are infected with HIV or are otherwise immuno­
suppressed. Children can present a diagnostic challenge and a high level of suspicion for TB must accompany the
approach to any child with prolonged illness not otherwise explained, especially if there is a history of contact with a
pulmonary TB case (5).
Enhanced case finding means maintaining a high index of suspicion for TB in all encounters, with proactive
exclusion of TB using the appropriate combination of clinical queries, radiographic or microbiologic testing. For PLHIV,
the WHO has developed a four-symptom screen that has proven highly sensitive for active TB (3,6). Recent evidence from
surveys in southern India has pointed to the significant comorbidities of TB and type 2 diabetes (10,11) and consequently
diabetics are included in the high risk categories for regular screening (12). Any other immunosuppressed patients are
also at considerably heightened risk and should be enquired about symptoms of TB at every healthcare encounter. In
addition, slum dwellers are a large and recognized portion of Indian urban society where the transmission of infection is
high. A recent estimate of the ARTI in Delhi was 2.3-3% (9), indicating that screening for active TB may be cost-effective
and sensible. Occupational groups such as miners have been reported to have high risk of tuberculosis and they could
be specially targeted for active case finding. An additional group with high risk for TB is certain indigenous populations
in the tribal areas of India.

References:
1. International Standards for TB Care, Second Edition (2009) Tuberculosis Coalition for Technical Assistance, The Hague, 2009.
2. Treatment of Tuberculosis: guidelines 4th Ed. (2009) World Health Organization, Geneva
3. Systematic Screening for Active Tuberculosis: Principles and Recommendations (2013) World Health Organization, Geneva
4. Revised Guidelines for Diagnosis of Pulmonary TB (2009) Revised National TB Control Programme, Delhi
780 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

5. National Guidelines on Diagnosis and Treatment of Paediatric Tuberculosis (2012) Revised National TB Control Programme,
Delhi
6. Cain, KP et al; An Algorithm for TB Screening and Diagnosis in People with HIV (2010) New England Journal of Medicine 362,
707
7. Santha T et al, Comparison of cough of 2 weeks and 3 weeks to improve detection of smear-positive tuberculosis cases among
out-patients in India, IJTLD, 2005, 9(1), 61-68
8. Thomas A et al., Increased yield of smear positive pulmonary TB case by screening patients with >2weeks cough compared to
>3 weeks cough and adequacy of 2 sputum smear examinations for diagnosis, IJTLD 2008, 55: 77-83
9. Sarin R, Behera D et al, Annual Risk of Tuberculosis Infection (ARTI) in the slum population covered under RNTCP by LRS
Institute, National OR Committee for RNTCP, meeting, 2012. (under publication)
10. Viswanathan V. et al, Prevalence of Diabetes and Pre-Diabetes and Associated Risk Factors among Tuberculosis Patients in India,
PLOS ONE. 2012 7(7); e41367
11. Balakrishnan S. et al, High Diabetes Prevalence among Tuberculosis Cases in Kerala, India, PLOS ONE, 2012. 10 (7); e46502
12. Baker et al. The impact of diabetes on tuberculosis treatment outcomes–A systematic review: BMC Medicine 2011. 9 (81);1741-7015

Standard 2
Diagnostic technology

2.1 Microbiological confirmation on sputum:

• All patients (adults, adolescents, and children who are capable of producing sputum) with presumptive
pulmonary TB should undergo a quality-assured sputum test for rapid microbiological diagnosis of TB
2.2 Chest X-ray as screening tool:
• Where available, chest X-ray should be used as a screening tool to increase the sensitivity of the diagnostic
algorithm
2.3 Serological tests:
• Serological tests are banned and not recommended for diagnosing tuberculosis.
2.4 Tuberculin Skin Test (TST) & Interferon Gamma Release Assay (IGRA):
• TST and IGRA are not recommended for the diagnosis of active tuberculosis. Standardized TST may be used as
a complimentary test in children.
2.5 Cartridge-Based Nucleic-acid Amplification Test (CB NAAT) is the preferred first diagnostic test in children and
PLHIV
2.6 Validation of newer diagnostic tests:
• Effective mechanism should be developed to validate newer diagnostic tests. One of the first responsibilities of
the TB programme is to endeavour to make a bacteriological diagnosis of TB if at all possible. Currently, only
sputum tests are sufficient and recommended under the programme for the microbiologic testing of TB (1). The
Government of India recently issued government orders banning the manufacture, importation, distribution
and use of serological tests for diagnosing TB (2). In addition Tuberculin Skin Test (TST) and Interferon-Gamma
Release Assays (IGRA) are not recommended for diagnosis of TB, although in certain cases TST may be useful
as an additional test for the diagnosis of children (3). Chest radiograph is an unquestionably sensitive test for
the detection of pulmonary disease in adults and children, and is recommended as a screening tool for TB.
Due to the non-specific nature of radiographic testing for TB, any abnormal chest radiograph should prompt
further bacteriologic and clinical assessment for TB (4).
As sputum tests are the key to TB diagnosis, attention to collection of a good sputum sample is paramount; a number
of studies have looked at this, including studies in India. A consensus is that two samples are almost as good as three
samples and a morning sample is better than a spot sample for detection of mycobacteria (5,6,7).
Acceptable methods for bacteriologic testing of sputum include sputum smear microscopy (both conventional and
fluorescent), culture (on solid or liquid media), commercial line probe assay (LPA), or CB NAAT. The most commonly-
used method for bacteriologic diagnosis of TB for the last 70 years, sputum smear microscopy, has had enormous
value in TB diagnosis, but has limited sensitivity, particularly in children where microscopy is less than 50% sensitive.
Sputum culture remains a highly sensitive, specific, and under-utilized method for TB diagnosis, but requires weeks
 Standards for TB Care in India 781

to yield results and hence alone does not help clinicians for early diagnosis. Nucleic acid amplification testing (NAAT)
offers enormous potential for accurate rapid diagnosis, but only commercial kits have been validated and are trustworthy
for replicable results (8).
While both “in-house” manual NAAT is widely available, their lack of reproducibility and quality assurance concerns
means that such in-house assays cannot be recommended (9). Commercial semi-automated NAAT have been developed
in India, these are yet to be validated, hence are not recommended. With the advent of CB-NAAT the sensitivity and
specificity of rapid TB diagnosis from sputum has increased to approximately levels seen in solid-media sputum culture,
particularly valuable for the assessment of children.
A list of RNTCP approved diagnostics tests are given in the guidelines for TB notification accessible at www.tbcindia.
nic.in.

References
1. Technical and Operational Guidelines for Tuberculosis. 2005. www.tbcindia.nic.in/pdf
2. TB India 2013. Pg 53. www.tbcindia.nic.in/annual reports/pdf
3. New Paediatric TB guidelines. www.tbcindia.nic.in/documents/pdf
4. Koppaka R, Bock N. How reliable is chest radiography? In: Frieden TR, ed. Toman’s tuberculosis. Case detection, treatment and
monitoring, 2nd Edition. Geneva: World Health Organization, 2004:51-60.
5. Van Deun A, Salim AH, Cooreman E, et al. Optimal tuberculosis case detection by direct sputum smear microscopy: how
much better is more? Int J Tuberc Lung Dis 2002; 6(3): 222–30.
6. Sarin R, Mukerjee S, Singla N, Sharma PP. Diagnosis of tuberculosis under RNTCP: examination of two or three sputum
specimens. Indian J Tuberc 2001(48):13–16.
7. TB diagnostics and laboratory strengthening–WHO policy. www.stoptb/wg/gli/resources
8. WHO policy statement: automated real-time nucleic acid amplification technology for rapid and simultaneous detection of
tuberculosis and rifampicin resistance: Xpert MTB/RIF assay. WHO/HTM/TB/2011.4
9. Pai M. The accuracy and reliability of nucleic acid amplification tests in the diagnosis of tuberculosis. Natl Med J India 2004;17(5):
233–6.

Standard 3
Testing for extra-pulmonary TB

3.1 Testing for extra-pulmonary TB

• For all patients (adults, adolescents and children) with presumptive extra-pulmonary TB, appropriate specimens
from the presumed sites of involvement must be obtained for microscopy/culture/CB-NAAT/molecular
test/histopathology examination and drug sensitivity testing (DST).
Even as pulmonary TB presents significant diagnostic challenges, extra-pulmonary TB diagnosis can be more challenging.
Signs and symptoms are not specific and yield of mycobacteria are generally low from most tissue and fluid sources (1,2,3).
Extra-pulmonary TB is comparatively common in PLHIV (approximately 30% of cases) and in these hosts the non-specificity
of symptoms and low yield of mycobacteria present an even greater challenge. The basic principle of seeking bacterio­
logic diagnosis at every opportunity where TB is suspected applies to extra pulmonary TB as well. The use of unvalidated
non-commercial ‘in-house’ NAAT on tissue specimens is not recommended; histopathology examination, smear micro­
scopy, culture and validated commercial NAAT are the only acceptable options. Recently the use of CB-NAAT for
specimens other than sputum was explored in many studies; although the test is not as sensitive on most of these samples
compared with its sensitivity on sputum nevertheless it performs well and in all cases better than smear microscopy (4,5).

References:
1. Wares F et al.; Extrapulmonary Tuberculosis: Management and Control (2011) Revised National TB Control Program, Delhi
2. International Standards for TB Care, Second Edition (2009) Tuberculosis Coalition for Technical Assistance, The Hague, 2009
3. National Guidelines on Diagnosis and Treatment of Paediatric Tuberculosis (2012) Revised National TB Control Programme,
Delhi. www.tbcindia.nic.in
4. Rapid Molecular Detection of Extra pulmonary Tuberculosis by the Automated GeneXpert MTB/RIF System. Journal Clin Micro.
2011; 4:1202–1205
5. Gerardo A-U, Azcona JM, Midde M, Naik P.K, Reddy S and Reddy Ret al. Hindawi Publishing Corporation Tuberculosis
Research and Treatment, Volume 2012, Article ID 932862
782 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Standard 4
Diagnosis of HIV co-infection in TB patients and
diagnosis of Drug Resistant TB (DR-TB)

4.1 Diagnosis of HIV in TB patients:

• All diagnosed TB patients should be offered HIV counselling and testing.
4.2 Diagnosis of Multi-Drug Resistant TB (MDR-TB):
• Prompt and appropriate evaluation should be undertaken for patients with presumptive MDR-TB or Rifampicin
(R) resistance in TB patients who have failed treatment with first line drugs, paediatric non-responders,
TB patients who are contacts of MDR-TB (or R resistance), TB patients who are found positive on any follow-
up sputum smear examination during treatment with first line drugs, diagnosed TB patients with prior history
of anti-TB treatment, TB patients with HIV co-infection and all presumptive TB cases among PLHIV. All such
patients must be tested for drug resistance with available technology, a rapid molecular DST (as the first choice) or
liquid/solid culture-DST (at least for R and H; and at least for Ofloxacin (O) and Kanamycin (K), if MDR).
Wherever available DST should be considered and offered to all diagnosed tuberculosis patients prior to star of
treatment.
4.3 Diagnosis of Extensively Drug Resistant TB (XDR-TB):
• On detection of Rifampicin and isoniazid resistance, patient must be offered sputum test for second line DST
using quality assured phenotypic or genotypic methods, wherever available.
TB is a very clear clinical sign of possible HIV infection, and all TB patients deserve to have HIV ruled out through
voluntary counselling and testing. India is considered a low HIV endemic area with high rates of TB, and the countrywide
average HIV prevalence in TB patients is around 5%. In any given case of TB, at any age, HIV infection is possible. Early
detection of HIV offers the opportunity for potentially life-saving additional interventions. Thus it is recommended
that all patients with active TB be tested for HIV (1). If HIV infection is detected then, TB treatment and anti-retroviral
therapy is as described in Standard 10.
Drug resistant TB is a growing problem worldwide including in India. Current surveillance data estimates a
prevalence of MDR-TB of 2-3% in new, untreated TB patients and more than 15% in previously treated TB cases (2). The
Programmatic Management of Drug Resistant TB (PMDT) has recently been expanded in order to treat DR-TB in the
RNTCP and extend standards and monitoring of DR-TB treatment to the private sector. The laboratory support for this
programme is in development and a growing network of accredited, quality-assured drug sensitivity testing labs will
support the goal of universal DST for all TB patients. In order to provide timely information to the clinical team treating
the patient and reduce primary transmission of DR-TB, rapid testing for rifampicin resistance is recommended (3).
The emergence of extensively-drug resistant TB (XDR-TB) underlines the importance of developing a laboratory
infrastructure to support DST for second-line drugs. The most important tests are for resistance to the Fluoroquinolones
(Ofloxacin) and the injectable agent (Kanamycin), which forms the backbone of MDR-TB treatment and resistance to
these drugs defines XDR-TB (4). It is recommended that, as facilities allow, all MDR-TB isolates are further tested for
Ofloxacin and Kanamycin resistance.

References:
1. WHO policy on collaborative TB/HIV activities guidelines for national programmes and other stakeholders. Updated version
of a document originally published in 2004 as Interim policy on collaborative TB/HIV activities (WHO/HTM/TB/2004.330;
WHO/HTM/HIV/2004.1) WHO/HTM/TB/2012.1 and 012.1 WHO/HIV/2012
2. Ramachandran R, Nalini S, Chandrasekar V, Dave PV, Sanghvi AS, Wares F, Paramasivan CN, Narayanan PR, Sahu S, Parmar M,
Chadha S, Dewan P, Chauhan LS. Surveillance of drug-resistant tuberculosis in the state of Gujarat, India. Int J Tuberc Lung Dis.
2009. 13(9):1154-60
3. Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update. WHO/HTM/TB/2011.6
4. Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, van Soolingen D, Jensen P, Bayona J. Multidrug-resistant and extensively
drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet. 2010. 375(9728):1830-43
 Standards for TB Care in India 783

Standard 5
Probable TB

5.1 Probable TB
• Patients with symptoms suggestive of TB without microbiological confirmation (sputum smear microscopy,
culture and molecular diagnosis), but with strong clinical and other evidence (e.g. X-ray, Fine Needle Aspiration
Cytology (FNAC), histopathology) may be diagnosed as “Probable TB” (1).
Despite the advent of new tests for TB diagnosis with greater sensitivity than smear microscopy of appropriate sputum
samples, about 20-30% of TB patients will not have microbiologic confirmation. This figure may be much higher in children
and patients with extra-pulmonary TB or PLHIV. Although it is recommended that any sample from a suspected TB patient
that is initially negative by a rapid diagnostic test be cultured for TB growth and confirmed diagnosis, there will be a
group of patients that have TB but without microbiologic confirmation. These are included in the Government of India
TB case notification as “patients diagnosed clinically as a case of TB, without microbiologic confirmation, and initiated on
anti-TB drugs” (2).

References:
1. WHO Case Definitions 2011 Update. http://www.stoptb.org/wg/gli/assets/documents
2. TB Notification, GO No. Z-28015/2/2012-TB, dated 7th May 2012, Ministry of Health, Government of India

Standard 6
Paediatric TB

6.1 Diagnosis of paediatric TB patients:

• In all children with presumptive intra-thoracic TB, microbiological confirmation should be sought through
examination of respiratory specimens (e.g. sputum by expectoration, gastric aspirate, gastric lavage, induced
sputum, broncho-alveolar lavage or other appropriate specimens) with a quality assured diagnostic test,
preferably CB-NAAT, smear microscopy or culture.
6.2 Diagnosis of probable paediatric TB patients:
• In the event of negative or unavailable microbiological results, a diagnosis of probable TB in children should be
based on the presence of abnormalities consistent with TB on radiography, a history of exposure to pulmonary
TB case, evidence of TB infection (positive TST) and clinical findings suggestive of TB.
6.3 Diagnosis of extra-pulmonary paediatric TB patients:
• For children with presumptive extra-pulmonary TB, appropriate specimens from the presumed sites of
involvement should be obtained for rapid molecular test, microscopy, culture and DST, and histo-pathological
examination.
Diagnosis of TB in children is particularly challenging as in small children it can be difficult to collect samples and the
paucibacillary nature of TB in children reduces the sensitivity of testing. Regardless, there should be every effort to
obtain bacteriologic diagnosis. Standardised TST may be used as a complimentary test in children, in combination with
microbiological investigations, history of contact, radiology, and symptoms. The guidelines of the Indian Academy of
Paediatrics (IAP) and paediatric TB guidelines of the RNTCP recommend obtaining specimens for mycobacteriology,
the use of standardised TST with a cut-off of 10mm induration in non-immunosuppressed children, and specialist
consultation. Serodiagnostic tests and IGRA have no role in paediatric TB diagnosis.

References:
1. Emily C. Pearce, A Systematic Review of Clinical Diagnostic Systems Used in the Diagnosis of Tuberculosis in Children, Hindawi
Publishing Corporation AIDS Research and Treatment Volume 2012, Article ID 401896, 11 pages doi: 10.1155/2012/401896)
2. National Guidelines on diagnosis and treatment of Paediatric Tuberculosis, In consultation with Indian Academy Paediatrics
during January- February 2012
3. New Paediatric TB guidelines. www.tbcindia.nic.in/documents/pdf
784 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Standard 7
Treatment with first-line regimen

7.1 Treatment of New TB patients:

• All new patients should receive an internationally accepted first-line treatment regimen for new patients.
The initial phase should consist of two months of Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), and
Ethambutol (E). The continuation phase should consist of three drugs (Isoniazid, Rifampicin and Ethambutol)
given for at least four months.
7.2 Extension of continuation phase:
• The duration of continuation phase may be extended by three to six months in special situations like Bone &
Joint TB, Spinal TB with neurological involvement and neuro-tuberculosis.
7.3 Drug dosages:
• The patients should be given dosages of the drugs depending upon body weight in weight bands.
7.4 Bio-availability of drugs:
• The bioavailability of the drug should be ensured for every batch, especially if fixed dose combinations (FDCs)
are used, by procuring and prescribing from a quality-assured source.
7.5 Dosage frequency:
• All patients should be given daily regimen under direct observation. However, the country programme may
consider daily or intermittent regimen for treatment of TB depending on the available resources and operational
considerations as both are effective provided all doses are directly observed.
• All paediatric TB patients and HIV associated TB patients should be given daily regimen under direct observation.
7.6 Drug formulations:
• Fixed dose combinations (FDCs) of four drugs (Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol), three
drugs (Isoniazid, Rifampicin and Ethambutol) and two drugs (Isoniazid and Rifampicin) are recommended.
7.7 Previously treated TB patients:
• After MDR-TB (or R resistance) is ruled out by a Quality Assured test, TB patients returning after lost to follow up,
relapsing from their first treatment course or new TB patients failing with first treatment course may receive
the retreatment regimen containing first-line drugs: 2HREZS/1HREZ/5HRE.
Treatment of drug-susceptible pulmonary TB with RHZE for two months followed by four months of RH or RHE has
been highly effective in clinical trials (1). More than 95% of patients are cured using this regimen (1,2,3). The results are
so impressive and repeatable that the lower rates of cure in national TB programs highlight the operational challenges
of delivering a daily regimen over an extended period of time (4,5). The concept of daily, directly observed therapy,
incorporating a full six months of R has been adopted by the majority of countries worldwide as a major part of Stop TB
Strategy (5). India implemented the Revised National TB Control Program (RNTCP) in 1996 as a national government
run system that used a thrice weekly regimen administered by DOT (6). Cure rates in India have been comparable with
countries using daily dosing, TB mortality has dropped significantly, and the prevalence of TB has declined slightly over
the last two decades (6). Nevertheless, high relapse rate of 11-13% has been reported in patients treated by DOT in the
RNTCP in India from several different locations over the last several years (21,23,24). In places where the background
of H resistance is high and/or HIV co-infection is common and in patients with cavitary disease the daily regimen is
preferred because the intermittent dosing schedules result in higher rates of treatment failure and relapse (7,8,9). In India,
H resistance is 11% in untreated TB patients and 37% in previously treated cases and the prevalence of HIV co-infection
is 5% (6). In countries where H resistance is prevalent a full six months course of Rifampicin is recommended with a third
drug, Ethambutol, added to the four months continuation phase (2,3,18,19). Recent data indicates that this is also safe in
paediatric patients (20). The extension of the continuation phase for extra-pulmonary TB to 9 or 12 months is based on
expert opinion rather than evidence.
The recommendation for “category 2” treatment for previously treated cases with the addition of streptomycin to the
intensive phase is currently under review and it is safe to say that a drug sensitivity test, if available, is a better guide
to retreating TB than a “category 2” regimen (13,14,15,16,17,18,19,21,22,23). The addition of a single drug to a failing
regimen violates one of the tenets of TB therapy so close follow up of patients on a retreatment regimen is especially
important (14).
 Standards for TB Care in India 785

Fixed dose combinations (FDCs) are desirable as they simplify drug procurement and logistics, the delivery of DOT
and may increase adherence (10). It is important that the provider prescribe only quality-assured pills of fixed drug combi­
nations in RNTCP and WHO recommended dosing (2,3,10). Individual drug dosing should be reserved for patients with
toxicities or contraindications to one or more components of the FDC (10). The RNTCP guidelines outline dosing based
on weight bands. Suggested weight bands for adults are: 30-39 kg, 40-54 kg, 55-70 kg and >70 kg. Recommended weight
bands for paediatric patients are: 6-8 kg, 9-12 kg, 13-16 kg, 17-20 kg, 21-24 kg and 25-30 kg.
The expert group acknowledged that the intermittent regimen used under the programme over the past decade
is equally effective under direct observation as compared to the daily regimen, and choosing daily regimen does not
undermine the successes of the programme (11,12). However, based on the above evidences and in the interest of having
uniformity of care across all healthcare sectors to achieve the future vision of the programme for universal access to
quality TB care and prevention of further drug resistance to TB; the choice for daily regimen was required. It was
recommended that the programme to undertake an operational research to assess the feasibility of implementing daily
therapy using FDCs under direct observation under programmatic settings.

References
1. Menzies D, Benedetti A, Paydar A, Martin I, Royce S, et al. (2009) - Effect of Duration and Intermittency of Rifampin on
Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis. PLoS Med 2009. 6(9): e1000146. doi:10.1371
2. World Health Organisation. Treatment of Tuberculosis Guidelines. 4th edition. Geneva: World Health Organisation; 2010.
3. International Standards for TB Care, Second Edition (2009) Tuberculosis Coalition for Technical Assistance, The Hague 2009.
4. World Health Organization, Global Tuberculosis Report 2012; Geneva 2012
5. World Health Organization, Stop TB Strategy, 2013; Geneva 2013
6. Revised National TB Control Programme, 2013; tbcindia.nic.in
7. Kwok Chiu Chang et al. Dosing Schedules of 6-Month Regimens and Relapse for Pulmonary TB. Amer Journal of Respir Crit
Care Medicine. 2006; 174: 1153-1158.
8. Chang KC et al. Treatment of tuberculosis and optimal dosing schedules – Downloaded from thorax.bmj.com on June 29, 2011 –
Published by group.bmj.com
9. Chang K Cetal. – A Nested Case-Control Study on Treatment – related Risk Factors for Early Relapse of Tuberculosis. Amer
Journal of Respir Crit Care Medicine. 2004; 170: 1124-1130.
10. MonederoI. et al. Evidence for promoting fixed-dose combination drugs in tuberculosis treatment and control: a review. Int J
Tuberc Lung Dis. 2011;15(4):433–439.
11. Alvarez TA et al.Prevalence of drug-resistant Mycobacterium tuberculosis in patients under intermittent or daily treatment. J Bras
Pneumol. 2009;35(6):555-560.
12. Wells AW et al. Implications of the current tuberculosis treatment landscape for future regimen change. Int J Tuberc Lung Dis.
2011; 15(6):746–753.
13. Ramachandran R, S Nalini, V. Chandrasekar, P. V. Dave, A. S. Sanghvi, F. Wares, C. N. Paramasivan, P. R. Narayanan, Sahu S,
Parmar M, Chadha S, Dewan P, L. S. Chauhan.Surveillance of drug-resistant tuberculosis in the state of Gujarat, India - Int J Tuberc
Lung Dis. 13(9):1154–1160.
14. Bhargava A, Pai M, et al. - Mismanagement of tuberculosis in India: Causes, consequences, and the way forward - Hypothesis 2011,
9(1): e7.
15. Mahmoudi A, Iseman MD. Pitfalls in the Care of Patients with Tuberculosis. JAMA 1993 July 7, 1993; 270:65
16. Bhargava A, Jain Y. The Revised National Tuberculosis Control Programme in India: Time for Revision of Treatment regimens
and rapid up – scaling of DOTS–Plus initiative. National Medical Journal of India 2008;21(4):187–91
17. Espinal MA. Time to abandon the standard retreatment regimen with first–line drugs for failures of standard treatment. Int J
Tuberc Lung Dis 2003;7:607–8.
18. Patricio E et al. – Treatment of Isoniazid-Resistant Tuberculosis in Southeastern Texas – Chest 2001; 119; 1730-1736
19. Menzies D et al. Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance
to Isoniazid: A Systematic Review and Meta-analysis – PLoS Med 6(9): e1000150.doi: 10.1371.
20. Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendations
2006; 10;1318-1330.
21. GS Azhar – DOTS for TB relapse in India: A Systematic Review. Lung India. 2012. 29(2).
22. Poncea M, et al. (2009) - Additional evidence to support the phasing-out of treatment category II regimen for pulmonary
tuberculosis in Peru - Transactions of the Royal Society of Tropical Medicine and Hygiene 106 (2012) 508– 510
23. Thomas A et al. Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS programme in a DOTS
programme in South India. International Journal of Tuberculosis and Lung Diseases 2005;9(5):556-561
24. Dave P, Rade K, Modi B, Solanki R, Patel P, Shah A, Vadera B. Assessment of Long-term Outcome among New Smear
Positive Pulmonary TB Patients Treated with Intermittent Regimen under RNTCP – A Retrospective Cohort Study. Natl J
Community Med 2013; 4(2):189-194.
786 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Standard 8
Monitoring treatment response

8.1 Follow-up sputum microscopy:

• Response to therapy in patients with pulmonary tuberculosis, new as well as retreatment cases, should be
monitored by follow-up sputum microscopy/culture (one specimen) at the time of completion of the intensive
phase of treatment and at the end of treatment.
8.2 Extension of intensive phase:
• The extension of the intensive phase is not recommended.
8.3 Offer DST in follow up sputum positive cases:
• If the sputum smear is positive in follow-up at any time during treatment, a rapid molecular DST (as the
first choice) or culture-DST (at least for R and if possible for Isoniazid (H); Ofloxacin (O) and Kanamycin (K),
if R-resistant/MDR) should be performed as laboratory facilities become available.
8.4 Response to treatment in extra-pulmonary TB:
• In patients with extra-pulmonary tuberculosis, the treatment response is best assessed clinically. The help of
radiological and other relevant investigations may also be taken.
8.5 Response to treatment in children:
• In children, who are unable to produce sputum, the response to treatment may be assessed clinically. The help
of radiological and other relevant investigations may also be taken.
8.6 Long- term follow up:
• After completion of treatment the patients should be followed up with clinical and/or sputum examination at
the end of six and 12 months.
International standards recommend that a sputum sample should be collected at the end of the intensive phase
(two months) and at the end of treatment (six months) to monitor the success of therapy (1,2). Recent evidence from
India shows that collecting more than one sample added little to the detection of failure of treatment and therefore
only one sample at two months is recommended for initial treatment monitoring (3,4,6). If the sample is positive for TB
then it is recommended that a DST be done to guide further selection of therapy, either by a molecular probe for drug
resistant loci or phenotypic DST in liquid culture. Consensus summarised by the WHO found little benefit for extending
the intensive phase to three months if the two months smear was positive (2). It is, however, necessary to re-address
adherence issues and/or other comorbid conditions that may have affected proper completion of the two months
intensive phase (1).
Follow up of extra-pulmonary and smear negative TB is challenging and best done by regular clinical review.
Chest X-ray has shown limited accuracy (5).

References:
1. International Standards of TB Care (2009)
2. WHO Guidelines of Treatment of TB (2010) Geneva
3. Kundu D, MV Kumar A, Satyanarayana S, Dewan PK, Achuthan Nair S, et al. (2012) Can Follow-Up Examination of
Tuberculosis Patients Be Simplified? A Study in Chhattisgarh, India. PLoS ONE 7(12): e51038. doi:10.1371/journal.pone.0051038
4. Toshniwal M, MV Kumar A, Satyanarayana S, Dewan PK, Achuthan Nair S, et al. (2012) – IUATLD – Abstract Book – UNION
World Conference for Lung Health, November 2012 – Kuala Lumpur, Malaysia
5. Horne et al., Lancet Infectious Diseases 2010 Gandhi MP, Kumar AMV, Toshniwal MN, Reddy RHR, Oeltmann JE, et al. (2012)
Sputum Smear Microscopy at Two Months into Continuation- Phase: Should It Be Done in All Patients with Sputum Smear-
Positive Tuberculosis? PLoS ONE 7(6): e39296. doi: 10.1371/journal.pone.0039296
 Standards for TB Care in India 787

Standard 9
Drug Resistant TB management

9.1 Treatment of M/XDR-TB(or R resistant TB):

• Patients with TB caused by drug-resistant organisms (especially M/XDR or only R resistance or with O or
K resistance), microbiologically confirmed by an accredited laboratory, should be treated with specialized
regimens containing quality assured second-line anti-tuberculosis drugs.
9.2 Model of care for drug resistant TB:
• Patients with DR-TB should be treated using mainly ambulatory care rather than models of care based principally
on hospitalization. If required, a short period of initial hospitalisation is recommended.
9.3 Regimen for MDR-TB (or R resistant cases):
• The regimen chosen for MDR-TB may be standardized and/or based on microbiologically confirmed drug
susceptibility patterns. At least four drugs (second line) to which the organisms are known or presumed to be
susceptible, should be used. Most importantly the regimen should include at least Pyrazinamide, Ethambutol,
a later-generation Fluoroquinolone (such as high dose Levofloxacin) and a parenteral agent (such as Kanamycin
or Amikacin), Ethionamide (or Prothionamide), and either Cycloserine or PAS (P-aminosalicylic acid), if
Cycloserine cannot be used.
9.4 Regimen for MDR-TB patients with O and/or K resistance detected early:
• Treatment regimen may be suitably modified in case of Ofloxacin and/or Kanamycin resistance at the initiation
of MDR-TB treatment or during early intensive phase, preferably not later than four to six weeks.
9.5 Surgery in M/XDR-TB patients:
• All patients of M/XDR-TB should be evaluated for surgery at the initiation of treatment and/or during follow up.
9.6 Treatment duration in MDR-TB patients:
• Till newer effective drugs are available with proven efficacy with shorter duration of MDR-TB treatment; total
treatment should be given for at least 24 months in patients newly diagnosed with MDR-TB (i.e. not previously
treated for MDR-TB) with recommended intensive phase of treatment being six to nine months. The total
duration may be modified according to the patient’s response to therapy.
9.7 Specialist consultation in M/XDR-TB patients:
• Consultation with a specialist experienced in treatment of patients with M/XDR-TB should be obtained,
whenever possible.
9.8 Ensuring adherence in M/XDR-TB patients:
• Patient support systems, including direct observation of treatment, are required to ensure adherence. It should
be ensured that the patient consumes all the doses of the drugs.
9.9 Single sample follow up culture in M/XDR-TB patients:
• The use of sputum culture (1 sample) is recommended for monitoring of patients with M/XDR-TB during
treatment.
9.10 Second line DST during treatment of MDR-TB:
• During the course of MDR-TB treatment, if the sputum culture is found to be positive at 6 months or later,
the most recent culture isolate should be subjected to DST with second-line drugs (at least Ofloxacin and
Kanamycin) to decide on further course of action. DST to other additional drugs may also be done if laboratory
facilities are available to guide treatment.
9.11 Regimen for MDR-TB patients with Ofloxacin and/or Kanamycin resistance detected later:
• The patients with MDR-TB found to be resistant to at least Ofloxacin and/or Kanamycin during the later stage
of MDR-TB treatment must be treated with a suitable regimen for XDR-TB using second line drugs including
Group 5 drugs such as Amoxicillin-Clavulanate, Clarithromycin, Clofazimine, Linezolid, Thioacetazone,
Imipenem to which the organisms are known or presumed to be susceptible.
9.12 New drugs:
• The new drugs e.g. Bedaquiline, Delaminid may be considered whenever scientific evidence for their efficacy
and safety becomes available as per the national policy for newer antimicrobials. Appropriate regulatory
mechanisms for distribution control needs to be ensured.
788 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The treatment of drug resistant TB is much more complex and challenging than the treatment of drug susceptible TB and
requires drugs with greater toxicities for longer periods of time with relatively less encouraging outcomes. Unfortunately
the evidence for drug regimen recommendations for drug-resistant TB are based on observational studies and expert
opinion and no large scale randomized controlled clinical trial data has been generated across the globe. Newer agents
and newer regimens are becoming available and it is hoped the level of evidence for treatment choices increases in the
next few years.
The new drugs e.g. Bedaquiline, however, may be considered whenever scientific evidence for their efficacy
and safety is available as per the national policy for newer antimicrobials. Appropriate regulatory mechanisms for
distribution control need to be ensured. This is of utmost importance to safeguard the new drugs from the risk of unregulated
irrational use and emergence of resistance to these precious drugs.
Laboratory based microbiological confirmation of drug resistance is an important pre-requisite for deciding
on an appropriate treatment regimen under consultation with a specialist experienced in management of M/XDR
TB, wherever possible. Patients with tuberculosis caused by drug-resistant organisms (especially M/XDR or only
Rifampicin resistance or with Ofloxacin or Kanamycin resistance), microbiologically confirmed by an accredited
laboratory, should be treated with specialized regimens containing quality assured second-line anti-tuberculosis drugs. For
all practical purposes, Rifampicin resistance should be considered as a surrogate of MDR-TB and treated with the same
regimen for MDR-TB. While all efforts should be made for microbiological confirmation, in exceptional circumstances
(e.g. paediatric and extra-pulmonary cases) the MDR treatment may be considered in absence of the microbiological
confirmation. Clear guiding principles need to be laid down by the national programme to define the eligibility of
patients under such exceptional circumstances for treatment with second line anti-TB drugs in absence of microbiological
confirmation.
The basic principles of drug-resistant TB treatment include using at least four second line drugs that the organism
has demonstrated susceptibility to through DST or that guided by the current epidemiology of drug-resistance in the
relevant population. In the treatment of patients with MDR-TB, four second-line anti-TB drugs likely to be effective
(including a parenteral agent), as well as Pyrazinamide and Ethambutol should be included in the intensive phase (1,2),
the duration of that should be at least for six to nine months. Consider extending treatment at least 18 months beyond
the last evidence of mycobacteria in a culture from the patient. Thus, the total duration of treatment should be at least
24 months up to a maximum of 27 months in patients newly diagnosed with MDR-TB (i.e. not previously treated for
MDR-TB). The total duration of treatment may be modified according to the patient’s response to therapy.
In the treatment of patients with MDR-TB, regimens should thus include at least Pyrazinamide, a Fluoroquinolone, a
parenteral agent, Ethionamide (or Prothionamide), and either Cycloserine or PAS (P-aminosalicylic acid) if Cycloserine
cannot be used (1,2). Treatment regimen may be suitably modified in case of Ofloxacin and/or Kanamycin resistance
detected early at the initiation of MDR-TB treatment or during early intensive phase, preferably not later than four to
six weeks. However, for patients on MDR-TB regimen that are found to be resistant to at least Ofloxacin and/or
Kanamycin during the later stage of MDR-TB treatment; they must be treated with a suitable regimen for XDR-TB using
second line drugs including Group 5 drugs to which the organisms are known or presumed to be susceptible.
Ambulatory care is the preferred choice for management of DR-TB patients rather than models of care based
principally on hospitalization as there are convincing evidences that improving access to treatment for DR-TB through
decentralization of care to centers near the patient’s residence reduced the risk of default (2,3). However, if required,
a short period of initial hospitalisation is recommended (2). Patient support systems, including direct observation of
treatment, are required to ensure adherence. It should be ensured that the patient consumes all the doses of the drugs as
missed doses for more than a week increases the odds of further augmentation of drug resistance and adversely affects
treatment outcomes. Monitoring of treatment should be done by collecting a single monthly sample of sputum for culture
from month three to month seven and then quarterly until the end of therapy. It has been observed in an operational
research conducted under the RNTCP that there is no meaningful advantage in using two specimens and a single
specimen policy could be safely implemented with negligible clinical effect on MDR-TB patients and favourable resource
implications for RNTCP (4). Prompt identification of early failures of MDR-TB regimen and timely actions for initiating
second line DST in culture isolates of such patients is alluded to in Standard 4. However, if the sputum culture is found
to be positive at six months or later and the patient has no clinical or radiological deterioration, a repeat DST may be done
to confirm sensitivity status.
 Standards for TB Care in India 789

Last but not the least, it must be emphasized that treatment of drug resistant TB can be complicated by drug toxicities,
drug to drug interactions and emerging DST patterns and enlisting the help of an expert in DR-TB should be sought
sooner rather than later through more than 100 established DR TB centers across the country.

References:
1. Guidelines for the programmatic management of drug-resistant tuberculosis (2011 update), World Health Organization, WHO/
HTM/TB/2011.6. www.who.int/publications
2. Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India, Revised National Tuberculosis Control
Programme, Central TB Division, Directorate General of Health Services,Ministry of Health & Family Welfare, Nirman Bhavan,
New Delhi, www.tbcindia.nic.in/documents
3. M. T. Gler,* L. J. Podewils,† N. Munez,* M. Galipot,* M. I. D. Quelapio,* T.E. Tupasi* et al. (2012) - Impact of patient and
program factors on default during treatment of multidrug-resistant tuberculosis-INT J TUBERC LUNG DIS 16(7):955–960 © 2012
The Union http://dx.doi.org/10.5588/ijtld.11.0502-7 May 2012
4. Nagaraja SB, Kumar AMV, Sachdeva KS, Ramachandran R, Satyanarayana S, Parmar M et al. (2012) Is One Sputum Specimen
as Good as Two during Follow-Up Cultures for Monitoring Multi Drug Resistant Tuberculosis Patients in India? PLoS ONE
7(9): e45554. doi:10.1371/journal.pone.0045554

Standard 10
Addressing TB with HIV infection and other comorbid conditions

10.1 Treatment of HIV infected TB patients:

• TB patients living with HIV infection should receive the same duration of TB treatment with daily regimen as
HIV-negative TB patients.
10.2 Anti-retroviral therapy and co-trimoxazole prophylactic therapy in HIV infected TB patients:
• Anti-retroviral therapy must be offered to all patients with HIV and TB as well as drug-resistant TB who require
second-line anti-TB drugs, irrespective of CD4 cell-count, as early as possible (within the first eight weeks)
following initiation of anti-TB treatment. Appropriate arrangements for access to anti-retroviral drugs should
be made for patients. However, initiation of treatment for TB should not be delayed. Patients with TB and HIV
infection should also receive Co-trimoxazole as prophylaxis for other infections.
10.3 Isoniazid preventive therapy in HIV patients without active TB:
• People living with HIV (PLHIV) should be screened for TB using four symptom complexes (current cough
or fever or weight loss or night sweats) at HIV care settings and those with any of these symptoms should
be evaluated for ruling out active TB. All asymptomatic patients in whom active TB is ruled out, Isoniazid
Preventive Therapy (IPT) should be offered to them for six months or longer.
PLHIV are more susceptible to TB infection, more likely to develop active TB disease after infection and more likely to
suffer from severe TB and disseminated, extra-pulmonary TB. In general, the treatment for TB in PLHIV is the same as
treatment for patients without HIV and treatment outcomes are successful although the mortality rate of PLHIV is higher,
more so with DR-TB comorbidity than the HIV uninfected (1).With growing evidences it is globally recommended,
that HIV infected TB patients should be treated with daily regimen (2,3,4,5). Intermittent regimen has been proven to lead
to higher risk for relapse and development of acquired Rifampicin resistance if intermittent dosing of Rifampicin was
started during the intensive phase of treatment in HIV-infected patients treated with Rifampicin-based regimens (2,3,4,5).
Anti-retroviral therapy must be offered to all patients with HIV and TB as well as drug-resistant TB who require
second-line anti-TB drugs, irrespective of CD4 cell-count, as early as possible (within the first eight weeks) following
initiation of anti-TB treatment (2,3,5). A number of recent studies have investigated the optimal timing of TB and HIV
treatment to reduce mortality and it seems clear that as soon as possible after initiating treatment for active TB in a PLHIV
they should be started on antiretroviral therapy (2,5). ART reduces the risk of TB relapse and acquired drug resistance
to rifampicin in HIV infected TB patients (2,3,5). Further, in settings with high Fluoroquinolone resistance and extensive
prior second-line treatment, encouraging results are being achieved in an ambulatory MDR-TB programme in a slum
setting in India. Rapid scale up of both Antiretroviral Therapy (ART) and second-line treatment for MDR-TB are needed
to ensure survival of co-infected patients and mitigate this growing epidemic (6). Considerations such as the ability to
790 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

tolerate a large pill burden, drug interactions and toxicities all have to be balanced with the life-saving treatment of
both TB and HIV simultaneously.
Appropriate arrangements for access to anti-retroviral drugs should be made for patients. However, initiation of
treatment for TB should not be delayed. Patients with TB and HIV infection should also receive co-trimoxazole as
prophylaxis for other infections (3). In PLHIV that do not appear acutely ill and do not have one or more of the WHO
recommended four symptom screens for active TB are very unlikely to be suffering from active TB and may safely be
given Isoniazid Preventative Therapy (IPT) for at least six months as part of a comprehensive package of HIV care (7).
IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART,
those who have previously been treated for TB and pregnant women (7). Recent studies have demonstrated the profound
protective effect of IPT although those that derive the most benefit are TST positive. In addition, evidence from India,
along with other countries, points to a prolonged course of IPT being more protective than the standard six month course.

References:
1. S. Tripathy, A. Anand, V. Inamdar et. al - Clinical response of newly diagnosed HIV seropositive &seronegative pulmonary
tuberculosis patients with the RNTCP Short Course regimen in Pune, India - Indian J Med Res 133, May 2011, pp 521-528
2. Faiz Ahmad Khan, Jessica Minion, Abdullah Al-Motairi, Andrea Benedetti, Anthony D. Harries, and Dick Menzies - An Updated
Systematic Review and Meta-analysis on the Treatment of Active Tuberculosis in Patients With HIV Infection - 1154 CID 2012:55
(15 October) HIV/AIDS
3. WHO Guidelines for Treatment of Tuberculosis –2010 update
4. Jiehui Li et.al. Relapse and Acquired Rifampicin Resistance in HIV-Infected Patients with Tuberculosis Treated with Rifampicin–
or Rifabutin-Based Regimens in New York City, 1997-2000 – Clinical Infectious Diseases 2005;41:83-91
5. PayamNahid et.al. – Treatment outcomes of patients with HIV and Tuberculosis - American Journal of Respiratory Critical
Care Medicine – Vol 175 pp 1199-1206, 2007
6. Isaakidis P, Cox HS, Varghese B, Montaldo C, Da Silva E, et al. (2011) Ambulatory Multi-Drug Resistant Tuberculosis Treatment
Outcomes in a Cohort of HIV-Infected Patients in a Slum Setting in Mumbai, India. PLoS ONE 6(12): e28066. doi:10.1371/journal.
pone.0028066
7. DelphineSculier and HaileyesusGetahun.Scaling up TB screening and Isoniazid preventive therapy among children and
adults living with HIV: new WHO guidelines. Africa Health, November 2011, page 18-23

Standard 11
Treatment adherence

11.1 Patient-centered approach for adherence:

• To assess and foster adherence, a patient-centered approach to administration of drug treatment, based on the
patient’s needs and mutual respect between the patient and the provider, should be developed for all patients.
11.2 Measures for treatment adherence:
• Supervision and support should be individualized and should draw on the full range of recommended inter­
ventions and available support services, including patient counselling and education. A central element of the
patient centered strategy is the use of measures to assess and promote adherence to the treatment regimen
and to address poor adherence when it occurs. These measures should be tailored to the individual patient’s
circumstances based on details of the patient’s clinical and social history and be mutually acceptable to the
patient and the provider.
11.3 Trained treatment supporter for treatment adherence:
• Such measures may include identification and training of a treatment supporter (for tuberculosis and, if appro­
priate, for HIV, Diabetes Mellitus etc.) who is acceptable, accessible and accountable to the patient and to
the health system.
11.4 Use of ICT to promote treatment literacy and adherence:
• Optimal use of ICT should be done to promote treatment literacy and adherence.
Treatment adherence is a critical determinant of treatment outcomes, prognosis and further emergence of DR-TB in
patients experiencing irregular and incomplete treatment. The DOTS Strategy has been the backbone of most country’s
 Standards for TB Care in India 791

TB programmes for the last decade. In certain places, strict healthcare worker DOTS has been cost-effective and
sustainable and resulted in control of limited TB epidemics. However, accumulating evidence has pointed to the effective­
ness of a wide variety of approaches including community and family-centered DOTS, which is more achievable for
most developing healthcare systems and produce comparable outcomes to healthcare worker supervised DOTS (1).
However, treatment adherence goes beyond the realm of DOTS to a larger concept of treatment support system
developed with mutual trust and respect between the patient, family, providers, treatment supporters and the health
system at large to promptly identify and address all possible factors that could lead to treatment interruptions. This
includes not only medical factors such as promptly addressing co-morbidities, adverse drug reactions and emergencies
but also spans out to addressing various social, vocational, nutritional, economic, psychological stress experienced by the
patient throughout the course of treatment. Periodic regular and effective supervision by the public health supervisors
at various levels and close monitoring of the progress made by the patient on treatment by the treating provider are
critical components to ensure high standards of care. Capacity building and engaging with local community based
organizations, self-help groups and patient support groups could prove to be effective interventions to promote treatment
adherence (2,3).
India is enabled with highly functional ICT systems and a population that is technology-literate. Through the use of
SMS reminders and call center linkages between patients, providers and pharmacists, it is hoped that adherence to
treatment will reach the necessary levels to reduce the prevalence of TB throughout India.

References:
1. International Standards of TB Care
2. Volmink J, Garner P - Directly observed therapy for treating tuberculosis (Review) - The Cochrane Library - 2009, Issue 1,
http://www.thecochranelibrary.com
3. Munro SA, Lewin SA, Smith H, Engel ME, Fretheim A, et al. (2007) Patient adherence to Tuberculosis treatment: A systematic
review of qualitative research. PLoS Med 4(7): e238. doi:10.1371/journal.pmed.

Standard 12
Public health responsibility

12.1 Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility to prevent
on-going transmission of the infection and the development of drug resistance.
12.2 To fulfil this responsibility, the practitioner must not only prescribe an appropriate regimen, but when
necessary, also utilize local public health services/community health services, and other agencies including
NGOs to assess the adherence of the patient and to address poor adherence when it occurs (1).
India continues to have high TB incidence and the mortality due to TB is still unacceptably high. The challenges of TB
control in India are magnified by the existence of parallel systems for TB diagnosis and treatment – the public and private.
Each system takes care of approximately half the TB cases (2) and methods and standards vary greatly depending on
whether public or private care is accessed and furthermore what type of private care is sought, from super-speciality
tertiary institutions to non-qualified providers (3). In part publishing, these standards of care attempts to standardise
care so that certain responsibilities of the provider, whether public or private, are clear. In addition Standard 13, the
notification of TB cases from both public and private providers, is expected to improve surveillance and quality of the
care delivered and a subsequent reduction in the burden of TB in India.

References:
1. International Standards of TB Care
2. Satyanarayana S, Nair SA, Chadha SS, Shivashankar R, Sharma G, et al. (2011) From Where Are Tuberculosis Patients Accessing
Treatment in India?
Results from a Cross-Sectional Community Based Survey of 30 Districts. PLoS ONE 6(9): e24160. doi:10.1371/journal.pone.0024160
3. AnuragBhargava et al., Mismanagement of Tuberculosis in India: Causes, Consequences, and the Wayforward. Hypothesis
2011, 9(1): e7.
792 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Standard 13
Notification of TB cases

13.1 All health establishments must report all TB cases and their treatment outcomes to public health authorities (District
Nodal Officer for Notification).
13.2 Proper feedback need to be ensured to all healthcare providers who refer cases to public health system on the outcome
of the patients which they had referred.
TB is a notifiable disease in India as per the government order dated 7 May, 2012 and requires that all healthcare providers
who have diagnosed a case of TB through microbiological testing or clinically diagnosed and/or started treatment for TB
must report to the District Nodal Officer for Notification (1). Notification is a basic public health activity common to diseases
of public health importance. With notification, public health authorities can identify TB patients and offer necessary public
health care, supervise and support for the quality of treatment, and monitor disease trends. Ensuring notification of all TB
cases is the most important step for a comprehensive TB surveillance system, which is required for effective TB control in
the country. Cases are defined as anyone who has a microbiological (smear or culture) or approved molecular test proven
disease or anyone who has a clinical syndrome consistent with active TB and is started on TB treatment. The requirement
for reporting applies equally to government-run facilities and to private facilities. In both settings, it is the primary TB care
provider or laboratory diagnostician’s responsibility to ensure that the required notification is completed (2). RNTCP has
an electronic TB notification system (NIKSHAY) wherein all providers can register and notify cases -http://nikshay.gov.in

References:
1. Notification of TB in India http://www.tbcindia.nic.in/pdfs/TB%20Notification%20Govt%20%20Or der%20dated%2007%
2005%202012.pdf
2. Guidance tool for TB notification http://tbcindia.nic.in/pdfs/Guidance%20tool%20for%20TB%20notificati on%20in%20India%
20-%20FINAL.pdf

Standard 14
Maintain records for all TB patients

14.1 A written record of all medications given, bacteriologic response, adverse reactions and clinical outcome should be
maintained for all patients.
Patient-level recording of details of diagnosis, treatment and outcome are the foundations of any effective public health
surveillance system. Use of appropriate technology such as Nikshay should improve the quality and accessibility to a
primary provider initiated record that is linked at every level from a primary clinic to the State Department of Health.
In turn, it is the duty of the programme to monitor outcomes, both at primary level and aggregated into larger units,
on a regular basis and reports the information that allow timely actions to improve services as needed.
The Government of India through a gazette notification has made all anti-TB drugs under schedule H1. These drugs
should not be dispensed without a valid prescription from a qualified practitioner. A copy of the prescription should
be maintained and details of the patient to be recorded by the chemist and should be made available for verification by
the responsible public health authorities.

Standard 15
Contact investigation

15.1 All care providers to patients with TB should ensure all household contacts and other persons who are in close contact
with TB patients are screened for TB as per defined Diagnostic Standards.
15.2 In case of paediatric TB patients, reverse contact tracing for search of any active TB case in the household of
the child must be undertaken.
 Standards for TB Care in India 793

The highest priority contacts for active screening are:

• Persons with symptoms suggestive of tuberculosis
• Children aged <six years
• Contacts with known or suspected immune-compromised patient, particularly HIV infection
• Contacts with Diabetes Mellitus
• Contacts with other higher risks including pregnancy, smokers and alcoholics etc.
• Contacts of patients with DR-TB. In case of contact with a DR-TB index case, close clinical monitoring should be
provided, as there is no evidence that treatment of latent infection with available drugs is presently effective
A contact investigation should focus on those in close contact with the index case, most importantly family members
and other members of the household who may have prolonged exposure. Among this group of contacts past studies
have found 4.5% to have TB (1,2). A recent study in India found 8.7% of household contacts were diagnosed with TB (3).
Particular attention should be paid to contacts with the highest susceptibility to TB infection and subsequent active disease,
namely small children and immunosuppressed people.

References:
1. Recommendations for investigating contacts of persons with infectious tuberculosis in low and middle income countries.
www.who.int/tb/publications/2012/en/index.html
2. Fox GJ, Barry SE, Britton WJ, Marks GB. Contact investigation of tuberculosis, a systematic review and meta-analysis. European
Respiratory Journal, 2012
3. Evaluation of TB case finding through systematic contact investigation, Chhattisgarh, India – Presented at the 43rd UNION
World Lung Conference, Nov 2012, Kuala Lumpur, Malaysia

Standard 16
Isoniazid Prophylactic therapy

16.1 Children <6 years of age who are close contacts of a TB patient, after excluding active TB, should be treated with
isoniazid for a minimum period of six months and should be closely monitored for TB symptoms.
Because children are more susceptible to TB infection, more likely to develop active TB disease soon after infection, and
more likely to develop severe forms of disseminated TB, it is widely recommended (The Union, WHO) that close contacts
of index cases under the age of 6 who do not have active TB should receive IPT. Close contacts of index cases with
proven or suspected DR-TB should be monitored closely for signs and symptoms of active TB as isoniazid may not be
prophylactic in these cases.

Standard 17
Airborne infection control

• Airborne infection control should be an integral part of all health care facility infection control strategy.
Each healthcare facility caring for patients who have, or are suspected of having, TB should develop and implement an
appropriate airborne infection control plan as per the national guidelines. Administrative, environmental and personal
protective measures should be implemented in all health care facilities as per national airborne infection control guidelines.
Protection of health care workers from airborne infection should be ensured through adequate preventive measures
including training, personal protection measures in high risk situations and periodic screening at least once a year.
TB is an airborne bacillus spread through inhalation of droplets. Therefore, in addition to general infection control
procedures recommended for all health care facilities such as regular hand-washing, attention must be paid to limiting
risk from airborne transmission. Airborne infection control measures are generally grouped into three main categories;
environmental, administrative and managerial. Environmental controls require safe infrastructure and involve designing
buildings and systems that promote safe air exchange e.g. HVAC systems, air flow management and UV light sterilization
of areas. These tend to be expensive and installation is disruptive. Managerial controls refer to management plans that
794 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

promote and enable safe practices in every facility and as such every healthcare facility, whether public or private,
should have clear plans for an airborne infection control strategy that are implemented and monitored for completeness.
Administrative controls are the most cost-effective and should be within the reach of every facility. They include screening
and timely diagnosis of TB in all clients of the facility, respectful and non-stigmatizing removal of people with active
TB from the general circulation of clients for rapid assessment and care, and use of personal protective equipment by
active TB patients and staff to protect both staff and other patients. Such guidelines for Indian facilities are available at
www.tbcindia.nic.in

Standard 18
Quality assurance systems

18.1 Quality assurance for diagnostic tests:

• All healthcare providers should ensure that all diagnostic tests used for diagnosis of TB are quality assured.
18.2 Quality assurance for anti-TB drugs:
• Quality assurance system should ensure that all anti-TB drugs used in the country are subjected to stringent
quality assurance mechanisms at all levels (from manufacturer to patients). Providers should ensure that all
anti-TB drugs prescribed come from a Quality assured source.
India has banned the use of commercial serology tests for diagnosis of TB. However, any diagnostic test used for diagnosing
TB should have a quality assurance system in place. India’s national TB programme (RNTCP) have established a good
external quality assurance system for TB diagnostics, and is available to both public and private laboratories.
The same principle applies to the use of drugs; the drugs should be from a quality assured source and should be under
a standard Quality Assurance process.

Standard 19
Panchayati Raj Institutions

19.1 Panchayati Raj Institutions (PRIs) and elected representatives have an important role to share the public health
responsibility for TB control with the healthcare providers, patients and the community.
Health being an important responsibility of the PRIs in India, there are many opportunities for greater involvement of
the PRIs for TB control. Because the diagnosis and treatment of TB is complicated and takes long, and mistreatment of
TB and emergence of drug-resistant TB affects everybody in the community, the Panchayat should be involved in all
aspects of TB control. PRIs can facilitate good communication between facilities, public or private, that diagnose and
treat TB and the communities, which they serve thus greatly helping in mobilizing community support for TB control.
PRIs can help TB patient to link to other social welfare schemes, can help in nutritional and rehabilitation support etc.

Standard 20
Health education

20.1 Every TB symptomatic should be properly counselled by the healthcare providers

20.2 TB patients and their family members should get proper counselling and health education at every contact with
healthcare system
Proper health education to the patient and family is very important for TB care. There should be systems for education
and counselling as an integral part of TB treatment. Every visit of the patient to the healthcare provider and visit of the
health worker to the patient’s home should be utilised for health education.
 Standards for TB Care in India 795

Standard 21
Death audit among TB patients

21.1 Every death among TB patients should be audited by a competent authority.

Investigation into the cause of death is an important standard which needs to be followed to study the conditions that
led to the death in order to initiate actions to prevent development of such conditions to other TB patients. Every TB
death should be notified to the concerned authority. Competent authority at the district level should do the death audit
of every TB death and provide a report to the programme to take necessary steps for preventing avoidable deaths.

Introduction to Standards for

Social Inclusion for TB

The principles for introducing Standards for Social Inclusion in TB Care are:
• To ensure all individuals presenting to the healthcare facility are treated with dignity, irrespective of their health
and socio-economic status.
• To ensure universal delivery of quality assured TB diagnostic and treatment services across public and private
sector.
• To ensure visibility and accessibility of the TB service programme to all, irrespective of socio-economic status.
• To find and treat women, children and the elderly within hard to reach populations (Marginalized communities in
rural and urban populations).
• To eliminate out of pocket expenditure including those incurred on covering travel costs and bridging the nutrition
gap.
• To address loss of income when work day is lost due to TB.
• To ensure no one is left without a plan of action to address their presenting complaint if it is not because of TB.
The Patients Charter (accompanying the ISTC) is the key operational guideline in engaging with patients in all TB care
settings.

Standard 22
Information on TB prevention and care seeking

22.1 All individuals especially women, children, elderly, differently abled, other vulnerable groups and those at
increased risk should receive information related to TB prevention and care seeking.

Standard 23
Free and quality services

23.1 All patients, especially those in vulnerable population groups, should be offered free or affordable quality
assured diagnostic and treatment services, which should be provided at locations and times so as to minimize
workday or school disruptions and maximize access.
796 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Standard 24
Respect, confidentiality and sensitivity

24.1 All people seeking or receiving care for TB should be received with dignity and managed with promptness,
confidentiality and gender sensitivity. Public health responsibilities including notification, contact tracing, chemo­
prophylaxis, fast tracking, outcome monitoring etc. should be sensitive to respect and confidentiality of patients.

Standard 25
Care and support through social welfare programmes

25.1 Healthcare providers should endeavour to derive synergies between various social welfare support systems such
as RSBY, nutritional support programmes, national rural employment guarantee scheme etc. to mitigate out of
pocket expenses such as transport and wage loss incurred by people affected by TB.

Standard 26
Addressing counseling and other needs

26.1 Persons affected by TB and their family members should be counselled at every opportunity, to address infor­
mation gaps and to enable informed decision-making. Counseling should also address issues such as healthcare,
physical, financial, psycho-social and nutritional needs.
 58
International Standards for
Tuberculosis Care

Reproduced (in part) with kind permission of Dr PC Hopewell. Full document can be accessed from URL://https://www.who.int/
tb/publications/ISTC_3rdEd.pdf accessed on August 3, 2019
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 59
Index-TB Guidelines
[Guidelines on Extra-pulmonary
Tuberculosis for India]

Reproduced with kind permission (in part) from World Health Organization, Country Office for India. Full document can be accessed from
URL: https://apps.who.int/iris/bitstream/handle/10665/278953/IND-tb-guidelines-eng.pdf?sequence=5&isAllowed=y accessed on
August 3, 2019
Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 887
888 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Convenors
Department of Medicine, All India Institute of Medical Sciences, New Delhi
WHO Collaborating Centre (WHO-CC) for Training and Research in Tuberculosis
Centre of Excellence for Extra-Pulmonary Tuberculosis, Ministry of Health and Family Welfare, Government of India

Partners
Global Health Advocates, India
Cochrane Infectious Diseases Group
Cochrane South Asia
World Health Organization Country Office for India

© World Health Organization 2016

All rights reserved. The World Health Organization Country Office for India welcomes requests for permission to
reproduce or translate its publications, in part or in full. The designations employed and the presentation of the material
in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its
frontiers or boundaries.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors
and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information contained in
this publication. However, the published material is being distributed without warranty of any kind, either expressed
or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the
World Health Organization be liable for damages arising from its use. The views expressed by authors, editors or expert
groups do not necessarily represent the decisions or the stated policy of the World Health Organization.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 889

Abbreviations
ADA adenosine deaminase, or adenosine aminohydrolase
AFB acid-fast bacilli
AIIMS All India Institute of Medical Sciences
ART antiretroviral therapy
ATT anti-tuberculosis therapy
CNS central nervous system
CoE Centre of Excellence
CSF cerebrospinal fluid
CT computed tomography
CXR chest X-ray
DGHS Directorate General of Health Services
ECG electrocardiogram
ENT ear, nose and throat
EPTB extra-pulmonary tuberculosis
ESR erythrocyte sedimentation rate
FGTB female genital TB
FNAC fine-needle aspiration cytology
GHA Global Health Advocates
GI gastrointestinal
GRADE Grading of Recommendations Assessment, Development and Evaluation
HIV human immunodeficiency virus
ICP intra cranial pressure
IGRA interferon-gamma release assay
INDEX-TB Indian extra-pulmonary tuberculosis
IRIS immune reconstitution inflammatory syndrome
LDH lactate dehydrogenase
LNTB lymph node tuberculosis
MRI magnetic resonance imaging
Mtb Mycobacterium tuberculosis (referring to the organism causing tuberculosis disease)
PCR polymerase chain reaction
PET-CT positron emission tomography–computed tomography
PGIMER Post Graduate Institute of Medical Education and Research
RNTCP Revised National Tuberculosis Control Programme
TAC Technical Advisory Committee
TB tuberculosis (referring to the disease caused by Mycobacterium tuberculosis)
TBM tuberculous meningitis
TST tuberculin skin testing (also referred to as Mantoux test)
VCT voluntary counselling and testing
WHO World Health Organization
WHO-CC World Health Organization Collaborating Centre
890 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Treatment nomenclature
The first-line anti-tuberculosis drugs are referred to by single-letter abbreviations, as follows:
R – rifampicin
H – isoniazid
Z – pyrazinamide
E – ethambutol
S – streptomycin
Regimens are described using shorthand, with numbers to denote the number of months the treatment should be
given for. So, 2RHZE/4RHE refers to 2 months’ treatment with rifampicin, isoniazid, pyrazinamide and ethambutol,
followed by 4 months’ treatment with rifampicin, isoniazid and ethambutol.
Clinicians should refer to the current RNTCP guidelines for dosing of ATT drugs in adults and children. At the time of
publication, daily dosing regimens are being introduced in five states with a view to all TB patients nationwide receiving
daily ATT.

Executive summary
The main objective of these guidelines is to provide guidance on up-to-date, uniform, evidence-informed practices for
suspecting, diagnosing and managing various forms of extra-pulmonary tuberculosis (EPTB) at all levels of healthcare
delivery. They can then contribute to the National Programme to improve detection, care and outcomes in EPTB; to help
the programme with initiation of treatment, adherence and completion whilst minimizing drug toxicity and overtreatment;
and contribute to practices that minimize the development of drug resistance.
The Core Committee, commissioned by the Central TB Division (CTD) and Directorate of Health Services of
the Ministry of Health and Family Welfare, Government of India, with the assistance of 10 Technical Advisory
Subcommittees representing the different organ systems affected by EPTB, in partnership with the Methodology
Support Team, initiated a process of evidence-informed guidelines development in December 2014 drawing on best
international practices. This group produced three outputs:
a. Agreed principles relevant to EPTB care, and complementary to the existing 2014 country standards;
b. Agreed recommendations developed using current international evidenceinformed methods on priority areas for EPTB,
in Xpert MTB/RIF, use of steroids and length of treatment; and
c. Clinical practice points for each organ system, based on accumulated knowledge in the country and in the working
groups.

Principles
In line with the International Standards of TB Care (TB CARE I, 2014), the Guidelines Group as a whole agreed on a
set of principles about what every EPTB patient in India needs as a basic standard of care. These principles are a
complementary set to the Standards for TB Care in India 2014 (Sreenivas, 2014).

Principle 1 Patients first

The provider should adopt a patient-centred approach to managing EPTB, to promote well-being and
adherence to treatment and to relieve suffering. Patients have the right to be fully informed about
their care at every stage, to be able to make decisions about their treatment and to be treated with
dignity and respect.
Principle 2 Promoting early diagnosis
Providers should be informed of the clinical features and risk factors for various forms of EPTB and
carry out prompt clinical evaluation and appropriate early diagnostic investigation.
Principle 3 Access to a tissue-based diagnosis
Where facilities exist, all patients suspected of having EPTB should have appropriate samples taken
for microbiological and histological testing, unless diagnostic sampling is deemed to risk undue harm.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 891

Principle 4 Addressing drug resistance

All patients with a diagnosis of EPTB should be risk-assessed for drug resistance prior to starting
treatment, and drug susceptibility testing should be available for all patients at risk of drug-resistant
tuberculosis.
Principle 5 Avoiding unnecessary invasive and costly tests
Providers should consider the impact of diagnostic tests on patient management before referring
patients for costly or invasive tests, or repeating these tests.
Principle 6 Access to HIV testing
As EPTB is particularly associated with HIV, integrated counselling and testing should be made
available to all patients suspected of having EPTB.
Principle 7 Identifying patients with concurrent active pulmonary TB
All patients suspected of having EPTB should have clinical assessment for pulmonary TB in line with
RNTCP guidance for investigating suspected pulmonary TB.
Principle 8 Ensuring effective treatment
All patients should receive an appropriate treatment regimen.
Principle 9 Promoting adherence
Providers should monitor adherence to treatment and address factors leading to interruption or
discontinuation of treatment. Services should promote retention of patients in care.
Principle 10 Record keeping and public health promotion
A reliable, well-maintained record of all diagnostic tests, treatments given, treatment monitoring,
outcomes and adverse events should be kept for each patient, and data should be collected at the
national programme level for the purposes of health-care system planning and development.

Recommendations
The Core Committee and Technical Advisory Subcommittees initially considered the first draft of the clinical guides
prepared by each of the organ system subcommittees. This raised many potential points of equipoise that could be subject
to formal evidence-informed guideline development using the Grading of Recommendations Assessment Development
and Evaluation (GRADE) process. From this process, the Core Committee and Methodology Support Team identified
priority topics cutting across several organ systems in EPTB for development of guidelines. These were areas where
systematic review of the evidence was feasible given the available study data and time and resource constraints,
where there were current important dilemmas in what to recommend and where decisions could improve patient care,
patient outcomes, or had important resource implications. For example, agreeing on length of treatment has substantive
effects on drugs cost and resource use. The committee viewed this guideline process as an essential step in embedding
evidence-based processes in the guidelines development and part of a long-term vision for the country. While the topics
appeared clinical, all the decisions had potentially profound public health expenditure and management implications.
In addition, the guidelines could have an impact towards improving public health outcomes.
The questions addressed were:
1. Should Xpert MTB/RIF be recommended for use in the diagnosis of: a) lymph node TB; b) TB meningitis; c) pleural
TB?
2. Should corticosteroids be recommended for use in the treatment of: a) TB pericarditis; b) TB meningitis; c) pleural TB?
3. How long should ATT be given in the treatment of: a) lymph node TB; b) abdominal TB; c) TB meningitis?
Evidence summaries were then produced by members of the Technical Advisory Subcommittees and the
Methodology Support Team, and presented to the Guidelines Panel. The Guidelines Panel considered the evidence in
accordance with GRADE criteria and decided on recommendations by consensus.
The guidelines process has adhered to the GRADE criteria (GRADE Working Group, 2008) to produce a set of
recommendations that are explicitly linked to the evidence they are based on, with consideration given to the various
healthcare settings across India. The use of GRADE is in line with the WHO Handbook for Guideline Development
(WHO, 2014).
892 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The GRADE criteria require that:

• quality of evidence, as well as the effect estimate, is clearly defined;
• risk of bias of the relevant studies, directness of evidence, consistency of results, precision and other sources of bias
in the available evidence are considered and reported for each important outcome;
• evidence summaries are used as the basis for judgements about the quality of the evidence and the strength of
recommendations;
• the balance of desirable and undesirable consequences, quality of evidence, values and preferences should be
considered and reported when deciding on the strength of a recommendation;
• the strength of recommendations is clearly reported and defined.

Recommendations: Diagnosis of EPTB using the Xpert MTB/RIF test

Lymph node TB
Xpert MTB/RIF should be used as an additional test to conventional smear microscopy, culture and cytology in fine-
needle aspiration cytology (FNAC) specimens.
Strong recommendation, low quality evidence for sensitivity estimate, high quality evidence for specificity estimate.
TB meningitis
Xpert MTB/RIF may be used as an adjunctive test for tuberculous meningitis (TBM). A negative Xpert MTB/RIF result
on a cerebrospinal fluid (CSF) specimen does not rule out TBM. The decision to give anti-tuberculosis treatment (ATT)
should be based on clinical features and CSF profile.
Conditional recommendation, low quality evidence for sensitivity estimate, high quality evidence for specificity estimate.
Pleural TB
Xpert MTB/RIF should not be routinely used to diagnose pleural TB.
Strong recommendation, low quality evidence for sensitivity estimate, high quality evidence for specificity estimate.
Recommendations: Adjunctive steroids in the treatment of EPTB
TB meningitis
Steroids are recommended for TB meningitis in HIV-negative people. Duration of steroid treatment should be for at
least 4 weeks with tapering as appropriate.
Strong recommendation, high quality evidence.
Steroids may be used for TB meningitis in HIV-positive people, where other life-threatening opportunistic infections
are absent.
Conditional recommendation, very low quality evidence.
TB pericarditis
Steroids are recommended for HIV-negative patients with TB pericarditis with pericardial effusion.
Conditional, low quality evidence.
Steroids are recommended for HIV-positive patients with TB pericarditis with pericardial effusion.
Conditional, low quality evidence.
Pleural TB
Steroids are not routinely recommended in pleural TB.
Conditional, low quality evidence.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 893

Recommendations: length of treatment for EPTB

Lymph node TB
Six months ATT standard first-line regimen is recommended for peripheral lymph node TB.
Strong recommendation, low quality evidence.
Abdominal TB
Six months ATT standard first-line regimen is recommended for abdominal TB.
Strong recommendation, very low quality evidence.
TB meningitis
TB meningitis should be treated with standard first-line ATT for at least 9 months.
Conditional recommendation, very low quality evidence.

Clinical practice points

EPTB takes many forms, and evidence regarding best practice for many aspects of case finding, diagnosis and treatment
is lacking. In order to reflect the needs of health-care providers and develop a platform for future guidelines and
research, the Technical Advisory Subcommittees produced clinical practice points on each aspect of EPTB care. These are
summarized in Part 2. These are based on the expert opinion of senior clinicians in medicine and surgery from across
India, and provide a basis for further refinement in evidence-informed guideline development in future. This section
of the guidelines seeks to address all aspects of diagnosis and treatment of EPTB, and should be used as a reference.
 Part 1
Guidelines

1 Introduction

1.1 EPTB and Revised National Tuberculosis Control Programme

The Revised National Tuberculosis Control Programme (RNTCP) has developed comprehensive guidelines for diagnosis
and treatment of pulmonary TB. However, management of extra-pulmonary TB (EPTB) under the programme continues
to be a challenge.
The burden of EPTB is high, ranging from 15–20% of all TB cases in HIV-negative patients, while in HIV-positive
people it accounts for 40–50% of new TB cases (Sharma S.K., 2004).
The programme has identified the need to expand support for diagnosis and treatment of EPTB and has outlined
the following issues:
• lack of evidence-based guidelines on diagnosis and treatment of various types of EPTB;
• absence of adequate infrastructure and resources up to the peripheral level of health facilities to identify, diagnose and
treat EPTB;
• lack of skilled and trained staff for appropriate sample collection, transportation and diagnosis;
• uncertainty among clinicians about the optimum duration of treatment and treatment end-points;
• lack of data on EPTB, as most of the cases are being treated outside the public sector.
In response, the Department of Medicine at the All India Institute of Medical Sciences (AIIMS), New Delhi, which is
the WHO Collaborating Centre (WHO-CC) for Training and Research in Tuberculosis and also the Centre of Excellence
(CoE) for Extra-Pulmonary Tuberculosis in collaboration with Central TB Division and Directorate General of Health
Services (DGHS) of the Ministry of Health and Family Welfare (MoHFW), Government of India (GoI), with support from
Global Health Advocates India (GHA India) has taken an initiative to develop Indian extra-pulmonary TB (INDEX-TB)
guidelines.

1.2 National planning for universal access in EPTB

The public health emphasis on infectious pulmonary TB is central to the health of the Indian people. Nevertheless,
EPTB remains extremely common and is probably underrecognized and treated. These guidelines aim to help improve
awareness, diagnosis and proper treatment of EPTB, thus promoting universal access to appropriate, effective care.

1.3 Objectives
The main objective of these guidelines is to provide guidance on up-to-date, uniform, evidence-based practices for
suspecting, diagnosing and managing various forms of EPTB at all levels of delivery.
A subsidiary objective is to help direct further research by identifying knowledge gaps.
These guidelines will contribute to the programme to improve detection, care and outcomes in EBTP; to provide
guidance on initiation of treatment, adherence and completion whilst minimizing drug toxicity and overtreatment; and
contribute to practices that minimize the development of drug resistance.

1.4 Scope
The main purpose of the guidelines is to inform national treatment protocols. The major part of the document is
concerned with primary and secondary level health care, i.e. at district hospitals and places that have sufficient expertise,
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 895

clinical capacity and resources to care for EPTB patients. The aim is to standardize practice across the country. The guidelines
address diagnosis and treatment in all forms of EPTB, providing recommendations based on systematic reviews of the
evidence where possible. The guidelines are intended to be synergistic with existing RNTCP policy.
The guidelines focus on important current areas of debate in EPTB policy and practice. This helps identify priorities
and guide resource use and helps policy makers, clinical managers and clinicians implement best practice in these
critical areas in the first instance as part of continuous quality improvement in the detection and treatment of EPTB.

1.5 Target audience

The main document is for public and private sector clinicians in primary, secondary and tertiary care, and associated
field-level health workers. Suggested points of referral are included to guide general practitioners and field health
workers. The guidelines are also intended to inform health-care providers, TB programme managers and policy makers
about best practice based on a review of the current evidence.

1.6 Updating the guidelines

The Core Committee and GoI recognized that this guideline represented the start of a process of developing evidence-
informed EPTB guidelines in India that would be further developed over time. There was a commitment to updating
aspects of these guidelines in the next 3 to 6 years, at which time these topics would be revisited and additional priority
topics considered.
 2 Methods used to reach
recommendations

Representatives from the RNTCP and the Central TB Division of the Ministry of Health and Family Welfare, GoI,
worked with representatives from the Department of Medicine at AIIMS New Delhi and other technical advisors to
establish a Core Committee for the development of the guidelines (see Annex 1) and a Technical Advisory Committee
(TAC), with subcommittees of specialists in each of the organ systems. The Core Committee recruited a Methodology
Support Team to provide guidance in the development of the guidelines.
The Core Committee prepared a document that outlined the methods, teams, management of the process and how
conflicts of interest would be handled. This was termed the Scoping Document and was approved by representatives
from the Central TB Division. The Scoping Document set out the purpose and objectives of the guidelines. This was
circulated to members of the TAC along with a suggested framework for identifying key questions for each form of
EPTB around diagnosis, treatment and follow-up. During February and March 2015, each TAC subcommittee performed
a scoping exercise to identify key questions, and began literature reviews. Each subcommittee carried out a consultation
across institutions with experts in every relevant medical specialty to identify topics of interest and key questions
relating to the diagnosis and management of all forms of EPTB. Each TAC then prepared a comprehensive state-of-the-art
summary of knowledge and opinion about each organ system. This was done using traditional narrative approaches to
reviewing. The Methodology Support Team provided advice on taking a systematic approach wherever possible, with
training courses organised by Cochrane South Asia.
During the meeting of the guidelines group in March 2015, TAC subcommittees presented their findings for discussion
with the Core Committee and Methodology Support Team. This meeting concluded with plans to refine the questions
addressed by each subcommittee and outline cross-cutting themes requiring more detailed evidence review. These questions
were identified as key policy and clinical questions facing the providers at this point in time.
These questions were around:
• use of tuberculin skin testing
• the role of the Xpert MTB/RIF test in diagnosing EPTB
• the role of other polymerase chain reaction (PCR)-based tests in diagnosing EPTB
• empirical treatment of EPTB in the absence of a laboratory diagnosis, including therapeutic trials and the use of
corticosteroids in EPTB
• the duration of anti-tuberculosis treatment (ATT) in EPTB
• the definition of treatment failure in terms of clinical parameters prompting extended treatment, revised diagnosis, or
consideration of drug resistance.
The Core Committee and Methodology Support Team selected themes to take forward to systematic evidence review.
These were selected on the basis of: a) clinical importance as expressed by the TAC subcommittees; b) current availability
of evidence; and c) feasibility of assembling up-to-date evidence within the time frame required.

2.1 Evidence review

The Methodology Support Team, along with members from TAC subcommittees, prepared the evidence summaries for
review by the guidelines panel between March and July 2015. As part of this process, existing systematic reviews were
updated; and where no review was available, new systematic reviews were developed and carried out. Given the time,
three topic areas were prioritised:
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 897

1. The use of Xpert MTB/RIF in diagnosing EPTB

2. The use of corticosteroids in EPTB
3. The duration of treatment in EPTB
We intended to summarize the available evidence for all forms of EPTB within each of these topic areas, but due to time
and resource constraints, we limited our systematic reviews to areas where there is substantive evidence available or there
is urgent priority for evidence-based clinical policy. Hence, the questions covered in the evidence review were as follows:
1. Should Xpert MTB/RIF be recommended for use in the diagnosis of:
• lymph node TB
• TB meningitis
• pleural TB?
2. Should corticosteroids be recommended for use in the treatment of:
• TB pericarditis;
• TB meningitis;
• pleural TB?
3. How long should ATT be given in the treatment of:
• lymph node TB;
• abdominal TB;
• TB meningitis?
The Core Committee recognised the need to revisit many of the topic areas identified in the scoping process for systematic
evidence review to inform the next iteration of these guidelines.
Details of the methods used in the preparation of each review are summarised in Annex 2, which will be made available
in the supplementary materials on-line on CTD website as well as ICMR website. The general principles of systematic
review followed those set out in the Cochrane Handbook (Higgins, 2011) (Panel 1).

Panel 1. Steps in synthesising the evidence used for the main guidelines
1. Identify the question (or objective) of the review
2. Identify the outcomes that are most important – to patients, to clinicians, to policy makers
3. Write a protocol setting out the inclusion criteria for the review – what studies will help to answer the question?
4. Two researchers then carry out steps 5 and 6 independently, to limit bias in the review process.
5. Perform a structured search of the literature and screen the results using the inclusion criteria set out in the protocol.
Only include studies that can address the review question.
6. Perform data extraction from each study using a pre-defined tool – find the data in the included studies that answers
the question and describe each of the studies and their populations.
7. Perform a risk of bias assessment of each study using a pre-defined tool – how reliable are the data from each study?
8. Resolve any discrepancies between the two researchers’ data collection by discussion.
9. Perform data synthesis that is appropriate – this could include performing a meta-analysis across studies, or simply
describing the findings, depending on the level of heterogeneity between the studies and the types of studies included
in the review.
10. Summarize the findings in a table, and apply the GRADE criteria to assess the level of certainty and the applicability
of the effects estimates.

2.2 Making recommendations

The recommendations were made during a meeting of the INDEX-TB guidelines group in July 2015 at AIIMS, New Delhi.
The Methodology Support Team apprised the guidelines panel of the methods used in conducting the systematic reviews,
and advised on the interpretation of the evidence in the summaries. Each evidence summary was presented by the author,
and the guidelines group had time to consider the methods and results of the review before considering the GRADE
assessment of the main effects estimates, guided by the Methodology Support Team.

2.3 Quality of the evidence

GRADE assessments were appraised in detail, and revised where appropriate to reflect applicability to the Indian
context.
898 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

The quality of the evidence from systematic reviews was assessed for each outcome and rated on a four-point
scale, after consideration of the risk for bias (including publication bias) and the consistency, directness and precision
of the effect estimates. The terms used in the quality assessments refer to the confidence that the guideline development
group had in the estimate and not solely to the scientific quality of the investigations reviewed, as follows:

Quality of evidence Interpretation

High The group is very confident in the estimates of effect and considers that further research is very
unlikely to change this confidence.
Moderate The group has moderate confidence in the estimate of effect but considers that further research
is likely to have an important impact on their confidence and may change the estimate.
Low The group has low confidence in the estimate of effect and considers that further research is very
likely to have an important impact on their confidence and is likely to change the estimate.
Very low The group is very uncertain about the estimate of effect.

2.4 Strength of the recommendation

The group considered the trade-offs between benefits and harms, the implications for primary, secondary and tertiary
health-care contexts and values and preferences relevant to the question. A recommendation was then formulated by the
group based on consensus decision-making. Each recommendation was qualified as either “strong” or “conditional” based
on the level of certainty in the effects and the degree of concordance among the group.
Recommendations were formulated after considering the quality of the evidence, the balance of benefits and
harms and the feasibility of the intervention. Although cost is a critical factor in setting national treatment policies, cost
was not formally considered. Areas of disagreement were extensively discussed and consensus reached. Voting was not
required.

Factor considered Rationale

Balance of benefits and The more the expected benefits outweigh the expected risks, the more likely it is that a strong
harm recommendation will be made. When the balance of benefits and harm is likely to vary by
setting or is a fine balance, a conditional recommendation is more likely.
Values and preferences If the recommendation is likely to be widely accepted or highly valued, a strong recom­
mendation is more likely.
Feasibility If an intervention is achievable in the settings in which the greatest impact is expected,
a strong recommendation is more likely.

2.5 Strong and conditional recommendations

There was careful discussion about whether recommendations were strong, where very few people would argue against
the recommendation; or conditional, where most people would recommend, but it would not be everyone, or that the
intervention may be used in some circumstances and not others, or where some may choose a different management option.

For patients For clinicians For programme managers and

policy makers
Strong Most people would want the Most patients should receive the The recommendation can be
recommended test or treatment recommended test or treatment. adopted as standard policy and
and only a small proportion practice in most situations.
would not.
Conditional Most people would want the Clinicians need to be prepared There is need for substantial
recommended test or treatment, to help patients make a decision debate and involvement of
but many would not. that is consistent with their own stakeholders when considering
values, as this test or treatment adopting this policy and practice.
might not be right for everybody.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 899

2.6 Drafting the guidelines

Following the meeting of the guidelines group in July 2015, the guidelines were drafted under the supervision of the Core
Committee and Methodology Support Team.
The recommendations as drafted and agreed by the Guideline Panel are outlined with accompanying summaries of
the evidence and decision-making process.
Each TAC subcommittee drafted a report on current best practice in their specialist field, supported by review of the
literature. The Methodology Support Team extracted the Clinical Practice Points from the submitted TAC reports, in
dialogue with the TAC leads.
The guidelines, supporting evidence summaries and Clinical Practice Points were submitted for peer review by national
and international experts. The Core Committee appraised the results of the peer review process, made necessary changes,
if any, and submitted the completed document to the CTD for consideration.
The recommendations laid out in this guidelines document are the result of the process of systematic review and
critical appraisal described above, and were agreed upon by the entire guidelines panel. The Clinical Practice Points
include these recommendations, but also include other information relevant to clinicians and policy makers on each form
of EPTB. The Clinical Practice Points were formulated by the expert clinicians who formed each TAC subcommittee, and
reflect the consensus opinions of these experts, rather than the guidelines group as a whole.
In future iterations of these guidelines, it is hoped that time and resources will again be committed to producing
transparent, evidence-based recommendations to address more of the many questions that remain in tackling EPTB.

2.7 Panel members and organization

The INDEX-TB Guidelines Core Committee comprises major stakeholders from scientific bodies pertaining to EPTB,
and was responsible for recruiting the members of the other committees. The Core Committee prepared the Scoping
Document for the guidelines and oversaw the guidelines development process from start to finish.
The Technical Advisory Committee (TAC) is comprised of expert clinicians, public health officials, GoI officials and
WHO Regional Office for South-East Asia representatives. Members of the TAC were selected in order to maximize
diversity, relevant expertise and representation of both stakeholders and patient groups. TAC subcommittees of expert
clinicians generated the key questions to be addressed in the guidelines for each form of EPTB, prepared literature
reviews and participated in the appraisal of the evidence summaries and formulation of the main recommendations.
The Methodology Support Team is comprised of staff from the Cochrane South Asia centre at the Christian Medical
College in Vellore and from the Cochrane Infectious Diseases Group at the Liverpool School of Tropical Medicine, United
Kingdom. The Methodology Support Team was recruited to advise the Core Committee and TAC subcommittees on best
practice in terms of the selection of priority questions, production of evidence summaries and systematic reviews, use of
evidence summaries to generate recommendations and the drafting of the guidelines document.
The Coordinating Committee organised logistics and periodic meetings as deemed essential by the Central TB Division.
The Peer Review Committee is comprised of national and international experts chosen by the Core Committee and the
TACs to appraise the final guidelines document and supply corrections.

2.8 Declaration of interests

Declarations of interest were required from every member of the guidelines group. These were submitted to the CTD.
At the commencement of the final guidelines meeting in July 2015, all members of the guideline panel verbally stated
any financial or intellectual interests to the rest of the group. The participants and their declarations of interests are
published in Annex 1.

2.9 Funding
The preparation of the guidelines was funded exclusively by the National TB Programme through a grant from
Global Health Advocates. The WHO Country Office, India, funded the printing of the guidelines. A grant to the Liverpool
School of Tropical Medicine from the UK Government Department for International Development for evidenceinformed
policy development helped support the Methodology Support Team. No external source of funding from industry was
solicited or used.
 3 Principles

In line with the International Standards of TB Care (TB CARE I, 2014), the guidelines group as a whole agreed on a set
of principles about what every EPTB patient in India needs as a basic standard of care. These principles relate to a basic
standard of care that all providers should seek to achieve, a complementary set to the Standards for TB Care in India
(Central TB Division and WHO Country Office for India, 2014).

Principle 1 Patients first

The provider should adopt a patient-centred approach to managing EPTB, to promote well-being and
adherence to treatment and to relieve suffering. Patients have the right to be fully informed about their
care at every stage, to be able to make decisions about their treatment and to be treated with dignity
and respect.
Principle 2 Promoting early diagnosis
Providers should be informed of the clinical features and risk factors for various forms of EPTB and
carry out prompt clinical evaluation and appropriate early diagnostic investigation.
Principle 3 Access to a tissue-based diagnosis
Where facilities exist, all patients suspected of having EPTB should have appropriate samples taken
for microbiological and histological testing, unless diagnostic sampling is deemed to risk undue harm.
Principle 4 Addressing drug resistance
All patients with a diagnosis of EPTB should be risk-assessed for drug resistance prior to starting
treatment, and drug susceptibility testing should be available for all patients at risk of drug-resistant
tuberculosis.
Principle 5 Avoiding unnecessary invasive and costly tests
Providers should consider the impact of diagnostic tests on patient management before referring patients
for costly or invasive tests, or repeating these tests.
Principle 6 Access to HIV testing
As EPTB is particularly associated with HIV, integrated counselling and testing should be made available
to all patients suspected of having EPTB.
Principle 7 Identifying patients with concurrent active pulmonary TB
All patients suspected of having EPTB should have clinical assessment for pulmonary TB in line with
RNTCP guidance for investigating suspected pulmonary TB.
Principle 8 Ensuring effective treatment
All patients should receive an appropriate treatment regimen.
Principle 9 Promoting adherence
Providers should monitor adherence to treatment and address factors leading to interruption or
discontinuation of treatment. Services should promote retention of patients in care.
Principle 10 Record keeping and public health promotion
A reliable, well-maintained record of all diagnostic tests, treatments given, treatment monitoring,
outcomes and adverse events should be kept for each patient, and data should be collected at the national
programme level for the purposes of health-care system planning and development.
 4 Working definitions of
cases and outcomes

4.1 Purpose of defining a TB case

The RNTCP has developed clear definitions for pulmonary TB cases that allow clinicians to categorize patients in terms
of their diagnostic status and outcomes of treatment. This provides common terminology that practitioners treating TB
patients and policy makers can understand.
Many TB patients never have their diagnosis confirmed by a positive microbiological test due to the limitations of the
diagnostic tests currently available, or lack of access to a microbiological test. These patients are often treated based on the
clinician’s suspicion alone (empirical treatment). Defining EPTB cases by diagnostic status enables clinicians to be clear
about treatment decisions, and is essential to facilitate accurate national reporting within the RNTCP.
During the guidelines development process, it became clear that the panels were all using the terms used in pulmonary
TB for EPTB. However, because the disease is different for each organ system, individuals were using the terms loosely, and
the lack of clarity around treatment end-points and when to classify an EPTB patient as successfully treated or requiring
further treatment sometimes caused confusion during discussions.
Creating outcome definitions to guide treatment decisions in EPTB and aid reporting is challenging due to the uncertainty
around diagnostic test accuracy, the fact that diagnostic sampling often requires an invasive procedure and the lack of
surrogate markers for microbiological cure. However, the Core Committee appreciated that there was a need to agree on
a provisional set of definitions for outcomes to assist the panel with decisionmaking.
A comprehensive classification of EPTB case definitions and outcome definitions has not previously been attempted,
and the Core Committee was aware that given the nature of EPTB, these outcomes will not directly map on to pulmonary
TB outcomes. Nevertheless, these definitions are required for transparent and clear decision-making. Each TAC
subcommittee worked with the Methodology Support Team to formulate these definitions with reference to the
RNTCP’s definitions for pulmonary TB cases. The committee appreciated that this was a pragmatic approach to help
decision-making and used these outcomes in the development of guidelines.
The Core Committee proposed these working definitions be used to help transparent guidance in the clinical
guides. The Core Committee discussed that there needed to be refinements in national reporting for EPTB to capture
more detailed information about the epidemiology of the disease and patient outcomes. It is proposed to examine
the approach and utility of these working definitions with user guidelines users in 2017, and continue dialogue with
the RNTCP in relation to improved reporting for EPTB.
Standardized outcome definitions specific to each form of EPTB have not been established internationally. The
guidelines group recognized that this creates problems in the treatment of EPTB patients, particularly when a patient
still has on-going symptoms after several months of treatment. Recognizing when first-line treatment is failing is not
always straightforward, and uncertainty around what clinical, radiological, biochemical/haematological markers
suggest successful treatment probably leads to some patients receiving excessively long or repeated treatment courses,
or being switched to second-line drugs unnecessarily. Conversely, other patients who are likely to have drugresistant
EPTB may not be recognized as early as they could be, and may not receive the optimum treatment. The TAC
subcommittees have attempted to produce outcome definitions that they felt were appropriate through consensus in
their expert groups, and some of these are included in the Clinical Practice Points. The setting of standardized outcome
definitions for each form of EPTB requires an extensive evidence review and consultation process, and is beyond the
scope of this guidelines project. However, the guidelines group recognizes the importance of this task, and supports
efforts to achieve this internationally.
 902 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Working case definitions1

Presumptive case: A patient with symptoms and signs of EPTB who needs to be investigated.
Bacteriologically confirmed case: A patient who has a microbiological diagnosis of EPTB, based on positive microscopy,
culture or a validated PCR-based test.
Clinically diagnosed case: A patient with negative microbiological tests for TB (microscopy, culture and validated
PCR-based tests), but with strong clinical suspicion and other evidence of EPTB, such as compatible imaging findings,
histological findings, ancillary diagnostic tests or response to anti-TB treatment.*
A presumptive case started on ATT empirically, without microbiological testing, should also be considered a clinically
diagnosed case (empirically treated). A clinically diagnosed case subsequently found to be bacteriologically positive
(before or after starting treatment) should be reclassified as bacteriologically confirmed.
Non-EPTB case: A patient who has been investigated for EPTB and has been diagnosed with a different condition, with
no microbiological evidence of EPTB found.
Presumptive relapse: A patient who was declared successfully treated at the end of ATT and now presents again with
symptoms and signs of any form of TB.
Bacteriologically confirmed relapse: A patient with presumptive relapse who has microbiological evidence of persisting
Mycobacterium tuberculosis (Mtb) infection on subsequent diagnostic sampling.
Clinically diagnosed relapse: A patient with presumptive relapse who does not have microbiological evidence of
persisting Mtb infection on repeat diagnostic sampling, and has no evidence of another disease process.
A patient with presumptive relapse who is started on ATT empirically without repeat microbiological tests should
also be considered a clinically diagnosed relapse (empirically treated). A clinically diagnosed relapse subsequently found
to be bacteriologically positive (before or after starting treatment) should be reclassified as bacteriologically confirmed
relapse.
“Ancillary diagnostic tests” refer to organ system-specific tests such as pleural fluid adenosine deaminase activity
(ADA) in pleural TB, or CSF biochemistry and differential cell count in TB meningitis.

Working outcome definitions1

Successfully treated: A TB patient who has clinical and radiological evidence of resolution of active TB at the end of ATT.
It is recognized that some people have residual tissue damage that causes on-going symptoms or radiological change
(sequelae) despite resolution of TB infection.
Completed treatment: A TB patient who completed treatment without clinical evidence of failure but with no record to
show complete resolution by radiological or bacteriological evidence of persisting infection by the last month of treatment,
either because tests were not done or because results are unavailable.
Presumptive treatment failure: A patient who has no satisfactory clinical or imaging response to treatment after completing
3–6 months ATT.
At what point in the course of treatment clinicians should consider a patient to have presumptive treatment failure is
uncertain, and is likely to vary between forms of EPTB. For example, in TB meningitis it may not be acceptable to wait
longer than 3 months before taking action for presumptive treatment failure, whereas persisting with first-line treatment
for up to 6 months may be more acceptable in lymph node TB. Further research is necessary to help inform clinical
judgement on treatment endpoints.
Bacteriologically confirmed treatment failure: A patient with presumptive treatment failure who has microbiological
evidence of persisting Mtb infection on repeat diagnostic sampling.
Clinically diagnosed treatment failure: A presumptive treatment failure case who does not have microbiological
evidence of persisting Mtb infection on repeat diagnostic sampling and has no evidence of another disease process, but
has strong clinical suspicion of treatment failure and other evidence of active TB, such as imaging findings.

1 These
definitions from the Core Committee are provisional, working definitions to help people use these guidelines. Appraisal of their
usefulness is anticipated in 2017.
* Compatible histological findings include AFB-negative granuloma. If histological examination reveals AFB-positive histological
changes, this is consistent with bacteriological confirmation, and the case should be classified as bacteriologically confirmed.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 903

Sequelae of EPTB
Part of the difficulty in defining treatment end-points in EPTB relates to the development of sequelae as a result of the
inflammation and subsequent fibrosis produced in different tissues by Mtb infection. Patients with sequelae may have
complete microbiological cure following ATT, but continue to have symptoms. In many forms of EPTB, sequelae can mimic
the signs and symptoms of active TB infection, making the decision to stop treatment and declare the patient successfully
treated difficult. Examples of sequelae include:
• small volume fibrotic lymph nodes following lymph node TB
• neurological deficits following TB meningitis
• intestinal strictures leading to abdominal pain and vomiting following gastrointestinal (GI) TB
• deformity and back pain following spinal TB.
The clinician must balance the risks of possibly terminating treatment prematurely with the risks of continuing treatment
with drugs that have well characterised adverse effects. The INDEX-TB Guideline Group acknowledge that this is an area
where further research is needed to provide clinicians with better information and tools to guide their decision-making.
New diagnostic technologies may be helpful in future, but at present involvement of experienced specialists is suggested
in cases where uncertainty exists.

4.2 Paradoxical reactions and IRIS in EPTB

The phenomenon of paradoxical reaction in TB infection has long been observed in both HIV-positive and HIV-negative
TB patients. Multiple definitions of paradoxical reaction exist in the literature, but essentially this term refers to the
phenomenon of clinical (or radiological) deterioration of TB lesions, or the development of new lesions in a patient with
TB who has initially improved on ATT occurring in the early phase of treatment (during the first 3 months). Paradoxical
reactions manifest in a wide variety of ways, and can sometimes be life-threatening or lead to increased disability in
EPTB survivors. A review of case reports detailing paradoxical reactions in HIV-negative patients found 122 episodes
with 17 different clinical and radiological presentations (Cheng, 2002). In this review, the paradoxical reaction occurred
in a different organ system to the initial TB lesion in 25.4% of cases. Pathogenesis of paradoxical reaction is not yet fully
understood, and may occur due to a variety of mechanisms. The predominant theory is that it occurs as a result of an
excessive immune response to Mtb antigens in patients on effective ATT, involving dysregulation in innate and acquired
immune pathways (Garg, 2014).
Immune reconstitution inflammatory syndrome (IRIS) refers to a clinical syndrome observed in HIV-positive people
after starting antiretroviral therapy (ART) caused by an inflammatory response to an antigen, thought to be due to
the reconstitution of the immune response to that antigen. While extensive research has been done and is ongoing,
pathogenetic mechanisms and the best strategies to prevent and treat IRIS are not fully understood. IRIS involving TB
infection is common, and can manifest in two principal ways: paradoxical TBIRIS, where an inflammatory exacerbation
of TB symptoms occurs after commencing ATT in patients being treated for TB; and unmasking TB-IRIS, where active TB
presents in a patient who has commenced ART (Bell, 2015).
Both paradoxical reaction and IRIS pose significant challenges to physicians treating TB patients in India. Worsening
of clinical and radiological features of EPTB in both HIV-positive and HIV-negative patients raises several questions:
• Does the patient have treatment failure due to drug-resistant TB?
• Does the patient have drug-sensitive TB that is not responding to ATT for some reason, such as malabsorption or
inadequate adherence to treatment?
• Does the patient have another ongoing disease process?
• Does the patient have a drug fever?
• Should the regimen be changed?
• Should the patient be admitted for inpatient care?
• Are adjunctive treatments required to manage the inflammation?
The INDEX-TB guidelines group acknowledge that these are important questions in EPTB, and that detailed evidence
review and further research is needed to support recommendations around these issues. Guidance on the initiation of
ART in HIV–TB co-infected patients exists elsewhere (see Section 19 Special groups).
 5 Recommendations for the use
of Xpert MTB/RIF in EPTB diagnosis

What is Xpert MTB/RIF?

Xpert MTB/RIF is a commercially available diagnostic test for Mycobacterium tuberculosis complex, which uses
polymerase chain reaction (PCR) to test specimens for genetic material specific to Mtb, and simultaneously detects a gene
which confers resistance to rifampicin, rpoB (Blakemore, 2010). It is manufactured by Cepheid, Sunnyvale, California,
USA. Unlike other commercial PCR based tests, it is a fully automated test using the GeneXpert® platform. The
specimen is loaded into a cartridge and all the steps in the assay are then fully automated and contained within the unit.
One of the reagents is powerfully tuberculocidal, making the used test cartridges safe to handle outside of a specialist
laboratory environment. This allows the test to be brought closer to the clinical setting.
Xpert MTB/RIF was originally designed to test sputum samples from patients with active pulmonary TB, and has
been shown to have high accuracy for diagnosing TB in these patients (Steingart, 2014).

What makes the use of Xpert MTB/RIF in EPTB different?

Since its introduction to research settings in 2010, several investigators have tested the accuracy of this test in non-
respiratory samples for the diagnosis of various forms of EPTB. There are several a priori reasons why the Xpert MTB/RIF
may perform differently with non-sputum samples: Xpert MTB/RIF has a specimen treatment step which is designed to
liquefy sputum but this may not be an optimum pre-test processing for nonsputum samples; although the test has a limit
of detection of 131 colony forming units per mL, it has been shown to perform less well in paucibacillary disease; as
many forms of EPTB require invasive sampling methods, the size and quality of the specimens may affect the sensitivity
of the test. In 2016, a new version of Xpert MTB/RIF, Xpert MTB/RIF Ultra, will be introduced with a lower limit of
detection. We anticipate that roll-out and accumulation of efficacy data will take time, and so we have summarized the
available evidence for the current version of the test.

Why is this a priority question for these guidelines?

MoHFW has engaged with international partners to roll out Xpert MTB/RIF for the diagnosis of pulmonary TB as part
of the RNTCP. Members of the INDEX-TB TAC subcommittees recognized the need for evidence-informed guidance
on the use of Xpert MTB/RIF for the diagnosis of EPTB in India, because as this test becomes more widely available,
clinicians will need to know when to use and how to interpret this test in different forms of EPTB. The advantages of
having a rapid test for EPTB must be weighed against the accuracy of the test and the possible harms from misdiagnosis
when considering the use of this test.
The evidence considered by the guideline group in making these recommendations was based on a systematic review
carried out by Denkinger et al. In this review, diagnostic test accuracy studies using Xpert MTB/RIF and culture for the
diagnosis of M. tuberculosis infection in three forms of EPTB were summarized, with pooled estimates of sensitivity and
specificity (Denkinger, 2014). As there was little data on sensitivity and specificity of Xpert MTB/RIF for the diagnosis of
rifampicin resistance, this was not addressed in this review, and hence has not been addressed within these recommendations.
To ensure the guideline group was able to make recommendations based on the most up-to-date information, a summary
of studies published since this review was undertaken in 2013 was also presented to the guidelines group (See Annex 2,
online supplementary materials).
WHO has endorsed standard operating procedures for the use of Xpert MTB/RIF for non-respiratory specimens
(https://www. ghdonline.org/uploads/GeneXpert_SOP_Xpert_processing_EPTB_specimens_DRAFT. pdf).
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 905

5.1 Lymph node TB

Recommendation Xpert MTB/RIF should be used as an additional test to conventional smear microscopy, culture and
cytology in FNAC specimens.
Strength of Strong
recommendation
Evidence Pooled sensitivity against culture 83.1% (95% CI 71.4–90.7%) (13 studies, 955 specimens with
362 culture positive, low quality evidence)
Pooled specificity against culture 93.6% (05% CI 87.9–96.8%) (13 studies, 955 specimens with
362 culture positive, high quality evidence)
In a population of 1000 patients with presumptive lymph node tuberculosis (LNTB) where 200 truly
have the disease, if treatment was determined only by Xpert MTB/RIF:
• 166 (142 to 182) would be correctly treated for TB (low quality evidence)
• 34 (58 to 18) with TB would be missed (low quality evidence)
• 48 (96 to 24) without TB would be treated (high quality evidence)
Panel’s view on Quicker diagnosis
advantages of May lead to fewer patients being treated with ATT when they do not have LNTB (no direct
using the test evidence available)
Reduced stigma from reduction in overtreatment
May identify rifampicin resistance (evidence not formally reviewed)
Panel’s view on Patients with false negative Xpert results may have ATT withheld or stopped inappropriately
disadvantages of False negatives may go on to develop disseminated disease
using the test
False positives exposed to ATT unnecessarily
May falsely diagnose rifampicin resistance – harm to patient from side effects of second line drugs,
and high cost
Cost implications of managing missed cases (repeat diagnostic sampling, repeat hospital/clinic visits)
Stigma for patients given a false positive diagnosis
Litigation for misdiagnosis
Explanatory notes
The guidelines group considered the evidence for the diagnostic accuracy of Xpert MTB/RIF in lymph node specimens
obtained by fine needle aspiration and biopsy. In making the recommendation, the group considered the context of a
district level health-care centre, acknowledging that the current basis for diagnosis of lymph node TB under the RNTCP
is cytological examination and smear microscopy for acid-fast bacilli of fine needle aspirate from an affected lymph
node (FNAC). The group considered whether there was sufficient evidence to recommend that Xpert MTB/RIF replace
FNAC as the principal diagnostic test, and concluded that this would be inappropriate given the fact that one in five
patients are missed by Xpert MTB/RIF. The group agreed that Xpert MTB/RIF can be useful in confirming a diagnosis
in patients suspected of LNTB when considered alongside the results of FNAC, noting that a negative Xpert MTB/RIF
test does not rule out LNTB.
Diagnostic investigations should be carried out in the context of quality of care that can assure patient safety, in line with
the Guideline’s Principles 3 and 4. Xpert MTB/RIF is of use where clinicians have appropriate expertise in carrying out
diagnostic sampling from lymph nodes safely and accurately, and where there is access to Xpert MTB/RIF testing in a
laboratory with adequate quality assurance.

5.2 TB meningitis

Recommendation Xpert may be used as an adjunctive test for tuberculous meningitis (TBM). A negative Xpert result
does not rule out TBM. Decision to give ATT should be based on clinical features and CSF profile.
Strength of Conditional
recommendation
906 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Evidence Pooled sensitivity against culture 80.5% (95% CI 59.0–92.2%) (13 studies, 839 specimens with
159 culture positive, low quality evidence)
Pooled specificity against culture 97.8% (05% CI 95.2–99.0%) (13 studies, 839 specimens with
159 culture positive, high quality evidence)
In a population of 1000 patients with presumptive TB meningitis where 100 truly have the disease,
if treatment was determined only by Xpert MTB/RIF result:
• 81 (59 to 92) would be correctly treated for TB (low quality evidence)
• 19 (41 to 8) with TB would be missed (low quality evidence)
• 18 (45 to 9) without TB would be treated (high quality evidence)
Panel’s view on If Xpert MTB/RIF is positive it is highly likely to be TBM – this could increase access to a reliable
advantages of diagnosis
using the test Quick result
Already widely available
Panel’s view on High number of false negatives – significant concern that this could lead to missed or delayed
disadvantages of diagnosis, although direct evidence of the impact of Xpert MTB/RIF test results on patient outcomes
using the test in TBM is lacking
Delayed diagnosis leads to worse outcomes (death)
Additional costs
Explanatory notes
The group noted that the stakes are high in the diagnosis of TBM due to the high mortality associated with this disease,
particularly when the diagnosis is delayed. Although the sensitivity of smear microscopy of CSF specimens is extremely
low and Xpert MTB/RIF has a higher sensitivity than this test, the fact that one in five patients with TBM are missed
by Xpert MTB/RIF raised concerns that patients could be harmed by delayed treatment if clinicians relied on a negative
result. The guidelines panel concluded that as Xpert MTB/RIF is not sufficiently sensitive for TB meningitis, the decision
to give or withhold ATT should not be based on a negative Xpert result alone. A positive Xpert MTB/RIF result
may be reassuring due to the high specificity of the test, but it should only be used as an adjunct to other diagnostic
methods.
A concentration step in the processing of CSF before using Xpert MTB/RIF appears to increase the sensitivity of the
test. In a subgroup analysis, a concentration step involving centrifugation and resuspension of the sample appeared
to enhance the sensitivity of Xpert (84.2% (95% CI 78.3–90.1%) versus 51.3% (95% CI 35.5–67.1%) for unconcentrated
samples; specificity 98.0% (95% CI 96.7–99.2%) versus 94.6% (95% CI 90.9–98.2%) for unconcentrated samples
(Denkinger, 2014).

5.3 Pleural TB

Recommendation Xpert MTB/RIF should not be used to diagnose pleural TB

Strength of Strong
recommendation
Evidence Pooled sensitivity against culture 46.4% (95% CI 26.3–67.8%) (14 studies, 841 specimens with
92 culture positive, low quality evidence)
Pooled specificity against culture 99.1% (95% CI 95.2–99.8%) (14 studies, 841 specimens with
92 culture positive, high quality evidence)
In a population of 1000 patients with presumptive pleural TB where 200 truly have the disease,
if treatment was determined only by Xpert MTB/RIF results:
• 92 (52 to 136) would be correctly treated for TB (low quality evidence)
• 108 (148 to 64) with TB would be missed (low quality evidence)
• 8 (40 to 0) without TB would be treated (high quality evidence)
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 907

Panel’s view on • If Xpert is positive it is highly likely to be pleural TB – this could increase access to a reliable
advantages of diagnosis, although direct evidence of the impact of Xpert MTB/RIF test results on patient
using the test outcomes in pleural TB is lacking
• May help in avoiding invasive procedures like pleural biopsy (closed and thoracoscopic)
• Quick result
• Already widely available
Panel’s view on • High number of false negatives – significant concern that this could lead to missed or delayed
disadvantages of diagnosis, although direct evidence of the impact of Xpert MTB/RIF test results on patient
using the test outcomes in pleural TB is lacking
• Delayed diagnosis leads to worse outcomes (pleural thickening, impaired lung function, active
pulmonary TB)
• Additional costs
Explanatory notes
Although the pooled estimate of specificity was high, the sensitivity of Xpert MTB/RIF in pleural fluid specimens was
very low, with more than half of all pleural TB patients being missed by this test. The guidelines panel felt that although
a positive Xpert result might help if the diagnosis was unclear, there were concerns regarding possible harm to patients
associated with reliance on this test, whether the result is positive or negative. Anecdotally, some group members
described patients they had treated who had positive Xpert results and were started on ATT, but also had malignancy,
diagnosis of which was delayed as the positive Xpert test had led to a diagnosis of pleural TB
 6 Recommendations for use of
corticosteroids in EPTB

6.1 In treating tuberculous meningitis in HIV-negative people

Tuberculous meningitis (TBM) is a lifethreatening condition affecting adults and children, which can leave survivors
with a range of neurological disabilities. The causes of death and disability in TBM are multifactorial. The main
pathological mechanisms are persistent or progressive raised intracranial pressure with or without hydrocephalus,
arachnoiditis and involvement of optic nerves or optic chiasma leading to visual deficit, cranial neuropathies and
vasculitis of the cerebral blood vessels, leading to stroke.
Steroids are thought to reduce inflammation, improve blood flow and reduce cerebral oedema and intracranial pressure.
However, the risks associated with steroids include immunosuppression, which is a major concern in the context of an
infectious disease, GI bleeding, hyperglycaemia and hypertension, among others. Several randomized controlled trials have
been conducted on the effect of corticosteroids in managing TBM. The conclusions from these trials, seen individually,
appear inconsistent. One trial (Thwaites G.E., 2004) showed that dexamethasone increases survival rate, but it also raised
two questions; do patients who survive because of dexamethasone therapy tend to be left with severe disability, and are
there differential effects among subgroups of patients with different degrees of disease severity?
The guideline group reviewed evidence from the updated Cochrane review “Corticosteroids for managing
tuberculous meningitis” (Prasad, 2016).
Recommendation Steroids are recommended for TBM in HIV-negative people. Duration of steroid treatment should
be for at least 4 weeks, with tapering as appropriate.
Strength of Strong
recommendation
Evidence Corticosteroids reduce death from TBM from 41 per 100 people to 31 (27 to 36) per 100 people
(nine studies, 1318 participants, high quality evidence). These studies were conducted in a variety
of settings, and only one included HIV-positive people (n = 98).
Disabling neurological deficit is not common in survivors, and steroids may have little or no effect
on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1295 participants, low quality evidence).
Panel’s view on Reduced mortality from TBM
advantages of
using steroids
Panel’s view on Adverse effects of steroids such as GI bleeding, bacterial infection, high blood pressure, high blood
disadvantages of sugar
using steroids Increased numbers of survivors with severe disability, although the evidence from the review does
not support this
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 909

Explanatory notes
The panel considered the evidence in the systematic review relevant and applicable to the Indian context, noting that
three of the eight studies included were carried out in India, while three others were carried out in South-East Asia.
The group noted that the effects may be greater for patients with British Medical Research Council (MRC) Stage I and II,
which indicate mild and moderate severity in TBM, but the recommendation should stand for all TBM patients (MRC,
1948). MRC staging is explained in the Clinical Practice Points, Section 2 - CNS TB.
Duration of corticosteroids was discussed. The group agreed that there is no clear evidence for any one regimen of
steroids and debated what the best option would be. The expert group agreed that steroids should be given for at least
4 weeks and then tapered. Some patients may need longer treatment with steroids, of up to 6–8 weeks, and decision to
extend the course of steroids should be made based on disease severity and complications of TBM.

6.2 In treating tuberculous meningitis in HIV-positive people

The guideline group considered the evidence separately for HIV-negative and HIV-positive people because HIV
co-infection is associated with particular complications of TBM disease, and particular adverse events associated with
steroid use.
Recommendation Steroids may be used for TB meningitis in HIV-positive people, where other life-threatening
opportunistic infections are absent.
Strength of Conditional
recommendation
Evidence Corticosteroids reduce death from TB meningitis from 41 per 100 people to 31 (27 to 36) per 100
people (nine studies, 1318 participants, high quality evidence).
Eight out of the nine studies either excluded HIV-positive people or did not report HIV status. One
study included 98 HIV-positive people out of 545 participants (Thwaites G.E., 2004). A subgroup
analysis showed that corticosteroids had no effect on mortality in this group (RR 0.90, 95% CI 0.67
to 1.20), although this result should be interpreted with caution as the authors did not stratify the
randomization by HIV status, and the number of HIV-positive participants was small.
The very small numbers of events reported in this single study for the outcome disabling neurological
deficit mean that we do not know what the effect of corticosteroids is in HIV-positive people for
this outcome.
Panel’s view on Reduced mortality from TBM
advantages of
using steroids
Panel’s view on • Adverse effects of steroids such as GI bleeding, bacterial infection, high blood pressure, high
disadvantages of blood sugar
using steroids • Increased numbers of survivors with severe disability
• Increased morbidity and mortality from opportunistic infections and HIV-associated cancers
• Increased adverse drug reactions and interactions with ARVs
Explanatory notes The group was concerned about the lack of evidence for the use of steroids in people with HIV and
TBM. The group noted that there are circumstances where steroids are clearly indicated, for example
in cases of raised intracranial pressure/mass effect from a tuberculoma.
Steroids are associated with increased risk of serious, lifethreatening opportunistic infections in
patients with advanced HIV disease. The criteria to be taken into account are stage of TBM disease,
evidence of raised intracranial pressure or mass effect, CD4 cell count and presence or absence
of other opportunistic infections. Giving long courses of steroids in patients with HIV may be
undesirable, especially in patients with advanced HIV disease. Specialist advice in managing such
cases is warranted.
Important opportunistic infections to rule out include cryptococcal meningitis and cerebral
toxoplasmosis. There is evidence that steroids are associated with increased adverse events and
disability in patients with HIV-associated cryptococcal meningitis (Beardsley J, 2016).
910 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

6.3 In treating TB pericarditis in HIV-negative people

TB pericarditis is a potentially life-threatening form of EPTB, which can also lead to disability in survivors. TB pericarditis
is generally characterized by pericardial effusion, which can be immediately life-threatening. Some patients go on to
develop constrictive pericardial disease which causes cardiac disability and may be life-threatening, despite the resolution
of TB infection. Corticosteroids have long been used to relieve the inflammation that causes the pericardial effusion,
although their effect on reducing mortality and rates of long-term constrictive pericardial disease have been controversial.
Corticosteroids are associated with certain risks, including immunosuppression, which is a major concern in the context of
an infectious disease like TB and in HIV coinfection, as well as gastrointestinal bleeding, hyperglycaemia and hypertension,
among others.
The guideline group reviewed evidence summarised from the draft updated Cochrane review “Corticosteroids and
other interventions for treating tuberculous pericarditis” (Wiysonge, 2016).
Recommendation Steroids are recommended for HIV-negative patients with TB pericarditis with pericardial effusion.
Strength of Conditional
recommendation
Evidence The review included six studies, all from sub-Saharan Africa.
The majority of the participants in these trials were HIV-positive; these estimates are based on
disaggregated data for HIV-negative participants where possible.
Corticosteroids may have no effect on all-cause mortality (RR 0.85, 95% CI 0.64 to 1.11, 810
participants, three studies, low quality evidence), but probably reduce death from pericarditis
(RR 0.55, 95% CI 0.31 to 0.98, 810 participants, three studies, moderate quality evidence).
Corticosteroids may have no effect on progression to constrictive pericarditis (RR 0.62, 95% CI 0.35
to 1.1, 431 participants, 1 study, low quality evidence).
The guideline group further downgraded the quality of the evidence by 1 for indirectness as all
the studies took place in sub-Saharan Africa, and because the HIV status of some participants was
uncertain.
Most of the data comes from one large trial in mainly HIV-positive patients. Steroids were associated
with more people developing cancer, mainly HIV-related cancers. The authors note this some of
these patients also received immunotherapy with M. indicus pranii. The review team is currently
clarifying whether there is an interaction between M. indicus pranii and corticosteroids in relation
to cancer with the trial authors.
Panel’s view on • Increased survival, although the results of the systematic review do not support this
advantages of • Reduced incidence of constrictive pericarditis
using steroids • Reduced need for pericardectomy, although the review did not find clear evidence of this
• Reduction of ATT-associated adverse effects, although the results of the systematic review do
not support this
Panel’s view on • Adverse effects of steroids such as GI bleeding, bacterial infection, high blood pressure,
disadvantages of high blood sugar
using steroids • Increased numbers of survivors with severe disability due to constrictive pericarditis
Explanatory notes
The group noted that the effects estimates in the review suggest that steroids have little or no effect on all-cause
mortality, but probably do reduce mortality from TB pericarditis. The largest study (which had one-third HIV-negative
participants) showed a reduction in the number of participants with constrictive pericarditis at the end of treatment
in the analysis of all patients. The GRADE tables are based on data disaggregated into people that are HIV-positive
and HIV-negative. Both these analyses give point estimates that show reduced risk of constrictive pericarditis with
corticosteroids, although disaggregation means that in the smaller group of participants who were HIV-negative the result
is not statistically significant. The group felt that it was likely that the result for HIV-negative participants did not reach
statistical significance due to the meta-analysis being underpowered, rather than because corticosteroids had no effect
on progression to constrictive pericarditis. The group felt that risk of constrictive pericarditis and associated morbidity
was the most important outcome for consideration in making this recommendation. The recommendation therefore
only relates to steroid use in patients who present with pericardial effusion caused by TB pericarditis; the group did not
recommend steroids for patients presenting with constrictive TB pericarditis.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 911

6.4 In treating TB pericarditis in HIV-positive people

The group considered the evidence for HIV-positive people with TB pericarditis separately, principally because there is a
concern about corticosteroids leading to increased risk of HIV associated adverse events.
Recommendation Steroids are recommended for HIV-positive patients with TB pericarditis with pericardial effusion.
Strength of Conditional
recommendation
Evidence The review included four studies, all from sub-Saharan Africa.
The majority of the participants in these trials were HIV-positive; these estimates are based on
disaggregated data for HIV-positive participants where possible.
Corticosteroids may have no effect on all-cause mortality (RR 1.14, 95% CI 0.88 to 1.49, 997
participants, two studies, low quality evidence), or on death from pericarditis (RR 1.33, 95% CI 0.68
to 2.62, 939 participants, 1 study, low quality evidence).
Corticosteroids probably reduce progression to constrictive pericarditis (RR 0.51, 95% CI 0.28 to 0.94,
997 participants, two studies, moderate quality evidence).
Corticosteroids may have no effect on HIV-associated opportunistic infections over 2 years’ follow-up
(RR 1.12, 95% CI 0.82 to 1.53, 939 participants, 1 study, low quality evidence). There may increase the
risk of HIV-associated cancer over two years follow-up, but this was from one trial and participants
also received M. indicus pranii which may have confounded the result.
Panel’s view on • Increased survival, although the results of the systematic review do not support this
advantages of • Reduced incidence of constrictive pericarditis
using steroids • Reduced need for pericardectomy, although the review did not find clear evidence of this
• Reduction of ATT-associated adverse effects, although the review did not find clear evidence of
this
Panel’s view on • Adverse effects of steroids such as GI bleeding, bacterial infection, high blood pressure, high
disadvantages of blood sugar
using steroids • Increased adverse events associated with HIV such as opportunistic infections and cancer
• Increased numbers of survivors with severe disability
Explanatory notes
As for HIV-negative people, the group considered the outcome of greatest clinical significance to be the risk of constrictive
pericardial disease following TB pericarditis. Again, the group recognized that there was a lack of evidence of effect on
mortality. The evidence for steroids increasing the risk of HIV-associated cancers was also considered. The group felt that
this may be of less concern in India as the epidemiology of HIV-associated diseases is different compared with Africa,
notably, the prevalence of Kaposi’s sarcoma is low. The group concluded that the priority was to reduce rates of constrictive
pericardial disease, as this is associated with long-term morbidity and the need for invasive surgery (pericardectomy) for
patients, and high cost and resource use for the health-care system. Therefore they made a conditional recommendation
to use steroids in HIV-positive people with TB pericarditis with pericardial effusion. Steroids may be even more risky in
patients with advanced HIV disease with low CD4 cell counts, and may increase the risk of opportunistic infections and
HIV associated cancers. This risk needs to be balanced with the risk of constrictive pericarditis in HIV-positive people
with TB pericarditis.

6.5 In treating pleural TB (irrespective of HIV status)

Pleural TB is one of the most common forms of EPTB. Characterized by pleural effusion, it usually resolves without
treatment of any kind, but untreated patients may experience longer duration of the acute symptoms and risk recurrence
of active TB at a later point in time (Light, 2010). Pleural TB can be complicated by massive effusion leading to respiratory
compromise in the short term; pleural thickening, fibrosis and pleural adhesions causing impaired respiratory function
in the medium to long term.
It is though that pleural TB is caused by a delayed-type (type IV) hypersensitivity reaction following mycobacterial
infection of the pleura (Rossi, 1987). This explains the tendency towards resolution of the effusion and associated
symptoms with or without treatment of the TB infection. There appears to be a spectrum of disease in pleural TB in terms
of the extent of the underlying lung infection, which could be important in terms of patient outcomes and the potential
912 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

for corticosteroids to be effective. The extent of underlying lung infection seems to be an important determinant of
outcome (Shu, 2011).
The guideline panel considered evidence based on a rapid update of an existing Cochrane review “Corticosteroids
for tuberculous pleurisy” (Engel, 2007). This review was conducted because there was uncertainty about the efficacy of
corticosteroids in reducing the short-term and long-term effects on the acute symptoms of pleural TB and the long-term
sequelae. Steroids are associated with several adverse effects, especially in people with HIV, and administering them in
the absence of evidence of efficacy may be exposing patients to unnecessary risk.
Recommendation Steroids are not routinely recommended in pleural TB.
Strength of Conditional
recommendation
Evidence The review included four studies, all from sub-Saharan Africa.
The majority of the participants in these trials were HIV-positive.
Corticosteroids may reduce pleural effusions at 4 weeks (RR 0.76, 95% CI 0.62 to 0.94, 394 participants,
three studies, low quality evidence), but we don’t know whether corticosteroids have an effect on
resolution of pleural effusion at 8 weeks (RR 0.72, 95% CI 0.46 to 1.12, 399 participants, four studies,
very low quality evidence).
Evidence Corticosteroids may reduce pleural thickening at the end of follow up (RR 0.69, 95% CI 0.51 to 0.94,
309 participants, four studies, low quality evidence).
Corticosteroids may increase the risk of adverse events (RR 2.80, 95% CI 1.12 to 6.98, 586 participants,
six studies, low quality evidence).
This review found insufficient data to estimate the effect of corticosteroids on respiratory function.
The reviewers deemed it inappropriate in this case to attempt to generate separate estimates for
HIV-positive and HIV-negative people due to a lack of disaggregated data.
Panel’s view on • Faster recovery
advantages of • Reduced chest X-ray changes at the end of treatment
using steroids • Return to baseline lung function
• Reduced long-term pulmonary disability
Panel’s view on • Adverse effects of steroids such as GI bleeding, bacterial infection, high blood pressure,
disadvantages of high blood sugar
using steroids • Risk of adverse events, such as HIV-related cancer due to further immunosuppression in
HIV-positive people
Explanatory notes
Pleural TB is not associated with high mortality; therefore the group felt that the most important outcome to consider
was respiratory function. The review found insufficient data addressing this outcome, and the panel felt that the
outcomes reported in the review were not appropriate proxy measures for this outcome. The panel noted that chest X-ray
appearance at the end of treatment may be important to some patients for social or financial reasons, but otherwise
pleural thickening causing chest X-ray changes was not a clinically relevant outcome. Given the lack of evidence of
effect on respiratory function, and the risks associated with steroid use, the group made a conditional recommendation
against the use of steroids for pleural TB.
 7 Recommendations for duration
of treatment in EPTB

There are variations in existing guidelines and in clinical practice around the world about the optimum duration of ATT in
the various forms of EPTB. While the 6-month regimen using the first-line drugs rifampicin, isoniazid, pyrazinamide and
ethambutol has long been in use for pulmonary TB, there has been considerable uncertainty about duration of treatment
for some forms of EPTB. The guidelines group considered the evidence for the optimum length of treatment for three
forms of EPTB – lymph node TB, abdominal TB and TB meningitis.

7.1 In peripheral lymph node TB

Lymph node tuberculosis (LNTB) can present with involvement of peripheral, mediastinal and/or abdominal lymph
nodes. As well as enlarged lymph nodes perceivable clinically or visualized on chest X-ray, abdominal ultrasound scan or
computed tomography (CT) scan, clinical features sometimes include weight loss, fever and night sweats. The problem of
persistently enlarged lymph nodes at the end of treatment has vexed clinicians and some practitioners extend treatment
duration in such patients, fearing relapse of active TB disease in this group.
Recommendation Six months ATT standard first-line regimen (2RHZE/4RHE) is recommended for peripheral lymph
node TB.
Strength of Strong
recommendation
Evidence The review included two randomised controlled trials, one from multiple secondary care hospitals
in the United Kingdom and another from a single tertiary care hospital in Hong Kong, China.
Participants were adults and adolescents with newly diagnosed peripheral and mediastinal LNTB,
and HIV status was not reported in either study.
Evidence There may be no difference between 6-month and 9-month ATT regimens in terms of relapse
rates (RR 0.89, 95% CI 0.37 to 2.16, 253 participants, two studies, low quality evidence). There
is probably no difference between 6-month and 9-month ATT regimens in terms of successful
treatment at the end of follow up (21–55 months) (RR 1.11, 95% CI 0.97 to 1.26, 312 participants,
two studies, moderate quality evidence).
A review of five prospective cohort studies (706 participants) where patients with residual
lymphadenopathy at the end of ATT were followed up demonstrated that relapse in this
subgroup of patients was uncommon – 6 cases of relapse were reported across all studies.
Committee’s view • Cure rates and relapse rates are similar in the data collected for 6 months and 9 months
on advantages of (low quality evidence)
6-month treatment • Patients more likely to complete shorter regimens
• Less exposure to adverse effects of ATT
Committee’s view Theoretically, risk of relapse is higher with shorter regimens, but existing evidence is unclear
on disadvantages
of 6-month
treatment
914 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Explanatory notes
The guidelines group considered evidence from randomized controlled trials comparing 6 months’ with 9 months’ ATT
in terms of outcomes such as relapse after completion of ATT, treatment completion and default. The group noted that
the rates of relapse in the 6-month and 9-month groups were similarly very low, although there were concerns that the
pooled data was still not sufficiently powered to detect a difference in this uncommon event.
The group noted that all the evidence pertained to peripheral LNTB, and that other factors needed to be taken into
consideration for patients with mediastinal or abdominal LNTB, or disseminated TB. No recommendation was made
regarding treatment duration in these patients.
A subgroup of patients, dubbed partial responders, have persisting small volume lymphadenopathy (<1 cm) at the end
of treatment. The group agreed that the available evidence suggests that few partial responders appear to relapse, and
that these patients generally do not require extension of ATT and can be managed by observation only. Further evidence
is required to make firm recommendations for this particular group.
While this recommendation applied to adults and children with LNTB, the group noted that the evidence only relates
to adults and adolescents, and so providers treating children should bear in mind that this recommendation is based
on indirect evidence for children.

7.2 In abdominal TB
Abdominal TB can present with isolated involvement of any of the following sites: peritoneal, intestinal, upper GI
(oesophageal, gastroduodenal), hepatobiliary, pancreatic and perianal. The clinical features as well as diagnostic modalities
depend on the site of involvement. Internationally, most guidelines recommend treating all types of abdominal TB with
the same regimen as for pulmonary TB – a 2-month intensive phase with four drugs (isoniazid, rifampicin, pyrazinamide
and ethambutol) followed by a 4-month continuation phase with isoniazid and rifampicin. However, the evidence base
for this practice is extrapolated from studies of pulmonary TB cases, and direct evidence for the optimum duration of
treatment in abdominal TB has been lacking.
Shorter duration of treatment may increase compliance, leading to reduced numbers of relapses as well as the
emergence of drug-resistance strains. Furthermore, shorter regimens decrease the risk of anti-TB drug toxicity. Whether
a 6-month regimen achieves successful treatment rates as good as with a 9-month regimen without significantly
increasing the number of relapses is the key concern for accepting a shorter ATT regimen. The present review aims to
evaluate the effects of treatment with the 6-month regimen compared to the 9-month regimen for abdominal TB.

Recommendation Six months ATT standard first-line regimen is recommended for abdominal TB.
Strength of Strong
recommendation
Evidence The review included three randomised controlled trials, two from India and one from South Korea,
with 328 participants. One trial included both GI TB and peritoneal TB patients, and the other two
included GI TB patients only. None of the studies included children, or HIV-positive people.
We do not know whether there is a difference in relapse rates in patients treated for 6 months and
those treated for 9 months (RD 0.01, 95% CI -0.01 to 0.04, 328 participants, three studies, very low
quality evidence).
Committee’s view • Patients more likely to complete shorter regimens
on advantages • Less exposure to adverse effects of ATT
of 6-month
treatment
Committee’s view • Theoretically, risk of relapse is higher with shorter regimens, but existing evidence does not
on disadvantages support this
of 6-month
treatment
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 915

Explanatory notes
The guidelines group reviewed the evidence and felt that for new patients with abdominal TB and with low risk
of drug resistance, 6 months ATT followed by a period of observation was appropriate. The group recognized the
paucity of data to answer this question, but noted particularly that there were very few relapses in both arms across
all studies. The group noted that the available evidence came from patients with GI and peritoneal TB, and were
concerned that other forms of abdominal TB, while comparatively rare, may require different management. The group
agreed that some patients may require extension of ATT and the need for this should be assessed by the treating
clinician, with particular regard to the patient’s total ATT dosing.
The gastroenterologists in the group pointed out that some patients have lasting sequelae which may cause symptoms
mimicking relapse of abdominal TB or failed treatment. It is important to differentiate these patients, who have
peritoneal adhesions or luminal strictures from patients with active TB disease. Giving continued ATT in these patients
is not required and could be harmful.

7.3 Duration of treatment in TB meningitis

Tuberculous meningitis (TBM) constitutes a medical emergency, and it is essential to start ATT as soon as it is suspected,
in order to reduce rapidly progressing, life-threatening outcomes. In contrast to pulmonary TB, there is a lack of
standardized international recommendations for treating TBM. This is partly due to the limited existing evidence
regarding the optimal choice and dose of anti-TB drugs, as well as the most appropriate duration of treatment for this
form of extrapulmonary TB.
Two main arguments have led to the perception that longer treatment (than for pulmonary TB) is needed for
TBM to bring about microbiological cure and prevent relapse. The first one is that the blood-brain barrier hinders the
penetration of anti-TB drugs to reach adequate drug concentration in the infected site. The second one concerns relapse
rates. When assessing pulmonary TB regimens, relapse rates of 5% are generally considered acceptable (Donald, 2010).
However, relapse of TBM is fearsome as it is a life-threatening condition and can lead to severe neurodisability. Thus,
whether any risk of relapse is tolerable for TBM is to be considered when establishing TBM regimens. However, longer
anti-TB treatments reduce compliance and increase drug toxicity and costs (Van Loenhout-Rooyackers, 2001).
The standard first-line regimen for drug sensitive TBM, according to WHO guidelines, is a 2-month intensive phase
with isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin followed by a 10-month continuation phase
with isoniazid and rifampicin – 2 HRZE or S/10 HR (WHO, 2014). Several different regimens are used in current practice,
with variations regarding doses, selection of the fourth drug and duration of treatment from 6 to more than 24 months.
There are variations in practice regarding the number of drugs used in both the intensive and continuation phases. As
an example, the South African regimen consists of a 6-month intensive course with four drugs (isoniazid, rifampicin,
pyrazinamide and ethambutol) with no continuation phase. A study reviewing the duration of treatment for TBM by
comparing case series of both adults and children showed similar completion and relapse rates for 6-month treatment
regimens including at least isoniazid, rifampicin and pyrazinamide and longer treatment (van Loenhout-Rooyackers
et al., 2001).
Given the potentially devastating outcomes of relapse on the one hand, and the disadvantages of long therapy on
the other hand, we performed a systematic review of the literature in an attempt to establish the most appropriate
duration of treatment for TBM.

Recommendation TB meningitis should be treated with standard first-line ATT for at least 9 months.
Strength of Conditional
recommendation
Evidence The review included six observational (cohort) studies, with two reporting a comparison between
short (6 to 9 month regimens) and long (12 months or more) regimens. The studies were from a
variety of settings: Turkey, Ecuador, Papua New Guinea, South Africa and two from Thailand. None
reported the HIV status of the participants, who were a mix of adults and children.
As the data were from a highly heterogeneous set of observational studies, a meta-analysis was not
performed. The data were presented to the group in a table demonstrating the absolute numbers of
relapsed cases, defaulters, all-cause deaths and deaths after 6 months’ treatment across all studies.
The evidence was graded as very low quality.
916 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Committee’s view • Patients are more likely to complete shorter regimens

on advantages of • Less exposure to adverse effects of ATT
shorter treatment • Low numbers of relapses
• Good cure rates
Committee’s view • Longer ATT regimens are associated with poor compliance
on disadvantages • Longer regimens expose patients to increased risk of adverse effects of ATT
of shorter • Concern that shorter regimens may increase the risk of relapse, leading to death or disability
treatment
Explanatory notes The group recognized that there is very low quality evidence for the use of 6 to 9 months versus
12 months or longer ATT in TB meningitis. There is considerable variation in existing guidelines,
with the WHO currently recommending 12 months and the RNTCP recommending 9 months for
adults and 12 months for children. There is also considerable variation in current clinical practice,
with some clinicians present reporting that they are happy to treat for 9 months while others are
treating for 12 or 18 months as a minimum. The neurologists in the group were particularly concerned
about this question, highlighting that this is an area of clinical equipoise. The paediatricians present
were also concerned, as TBM disproportionately affects children and is an important cause of
childhood mortality and disability.
The key factors dictating mortality in TB meningitis may be early treatment and the use of
corticosteroids, and the role of treatment duration remains unclear. Extension of ATT may sometimes
be indicated, and this should be assessed by the treating clinician on a case-by-case basis.
There was disagreement about the optimum duration of treatment, with some group members
arguing that 12 months should be the minimum duration recommended; however, the final
recommendation was the consensus view of the group.
All group members recognized that there is a need for high-quality, large scale randomized trials
to answer this question.
 8 Research priorities

Relative to pulmonary TB, there is much less research into EPTB. There are several reasons for this, most notably that
PTB is transmissible and accounts for four-fifths of all TB disease. However, EPTB remains an important public health
problem in India and around the world, and is likely to remain so in the future, especially given the association with
HIV co-infection and other forms of immunosuppression.
Several research gaps have been identified during the INDEX-TB guidelines process. Here, we summarize:
a. Some aspects of research priorities related to the specific areas of EBTP addressed by formal GRADE assessment and
recommendations in these guidelines;
b. Topics raised during the scoping stage that have not been subject to formal evidence review in this iteration of the
guidelines, but may be a priority in subsequent editions.
We also reflect on the type of evidence that would help to answer these questions.

8.1 Key questions from Index-TB 2015 recommendations

The duration of ATT in EPTB
Research into the optimum duration of treatment for all forms of EPTB is lacking. Randomized trials comparing 6-month
and 9-month regimens have been carried out for lymph node TB and abdominal TB, but no randomized comparative
studies have been conducted directly comparing regimens of different durations containing rifampicin, isoniazid and
pyrazinamide (RHZ) for most forms of EPTB. In settings such as India where there are variations in practice, it might be
possible to answer these questions using well-conducted prospective cohort studies rather than randomized controlled
trials. Lifethreatening forms of EPTB, particularly TB meningitis, require particular attention. As the most important
concern when determining the length of ATT is the risk of relapse of TB infection, future cohort studies need to recruit
large numbers and have follow-up periods lasting several years to determine relapse rates.

Treatment end-points
A crucial area for further research, closely related to duration of treatment, is establishing clear treatment end-points in
EPTB. Each TAC subcommittee identified a group of patients in every form of EPTB who have an equivocal response to
treatment, and the clinicians in each group described the uncertainty on how to proceed with these patients—whether
to continue ATT for longer or to observe. Newer diagnostic modalities such as PCR-based tests and positron emission
tomography–computed tomography (PET-CT) are potentially useful in such cases, but further research is needed to
establish their role.
Again, long-term follow-up data from cohort studies would help to address some of these questions. With the widespread
use of mobile phones and increasing numbers of Indians having access to the Internet, new ways of keeping track of
participants in large cohort studies need to be investigated.

The role of the Xpert MTB/RIF test in diagnosing EPTB

As Xpert MTB/RIF is rolled out across high TB burden countries, further diagnostic test accuracy studies in EPTB are
required to better inform the use of this test. The data used to inform the recommendations made in this guideline are
based on diagnostic test accuracy studies from a variety of settings using a variety of diagnostic samples and sample
processing techniques.
918 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Changes to the test, and the introduction of diagnostic sample processing standard operating procedures endorsed by
WHO (WHO, 2014), mean that the accuracy of Xpert MTB/RIF is likely to improve. However, this may not be true for all
specimen types and all settings. Future studies are needed to:
• provide estimates of sensitivity and specificity in moderate and high TB burden settings for the latest version of
Xpert MTB/RIF;
• provide estimates of sensitivity and specificity in HIV-positive and HIV-negative people with EPTB;
• provide estimates of sensitivity and specificity in forms of EPTB where study data are currently lacking—bone and
joint TB, TB pericarditis, urogenital TB, abdominal TB, ENT TB and ocular TB.
There is also an emerging research agenda on how use of Xpert MTB/RIF may improve patient outcomes. Operational
and evaluation studies related to its deployment and use in general health services are needed.

The use of corticosteroids in EPTB

In people with TB pericarditis
The updated Cochrane review which informed the recommendation for steroids in TB pericarditis attempted to
disaggregate all data by HIV status, because HIV-positive people may be more at risk of adverse events due to pre-existing
immunosuppression. The guideline group agreed that rather than reduced mortality during the acute illness with pericardial
effusion, the principal goal of giving steroids was to reduce progression to constrictive pericardial disease. Further studies
powered to detect an effect of steroids on risk of developing constrictive pericardial disease due to TB pericarditis, with
HIV-positive and negative participants, would be useful to inform future recommendations. The largest trial in the
systematic review supporting the recommendations included another intervention. M. indicus pranii, an immunotherapy
used in the treatment of leprosy, was tested alongside prednisolone in a 2x2 factorial design. In this trial, the number of
people developing cancer was higher in the group receiving both prednisolone and M. indicus pranii. These findings are
still being discussed with the authors of the review and the investigator of the trial as it seems uncertain whether this
effect is attributable to prednisolone, M. indicus pranii, or a synergy between the two.

In people with pleural TB

The studies included in the Cochrane review informing the recommendation against the routine use of steroids in people
with pleural TB looked at a variety of short-term outcomes (such as resolution of pleural effusion) as well as some proxy
outcomes for lasting lung damage (pleural thickening, pleural adhesions). Future studies investigating the effects of steroids
on long-term lung function and disability, as well as adverse events related to steroids and to HIV, are needed to inform
future recommendations.

In people with TB meningitis

The Cochrane review update that informed the recommendation in this guideline concluded that there was high
quality evidence of reduced mortality in HIV-negative TBM patients who received corticosteroids, and that there was
low quality evidence of no effect on disability among survivors. Given this clear benefit in terms of reduced mortality,
further placebo-controlled studies of corticosteroid use in TBM would not be ethical. However, further research would be
beneficial to address the following:
• Effects of corticosteroids in HIV-positive people with TBM, with long-term follow up of survivors to identify
HIV-related adverse events;
• Optimum choice of corticosteroid and dosing regimen. As some corticosteroid related adverse effects are dose-
dependent, it would be helpful to know the optimum regimen for effectiveness and reduced adverse events.

8.2 Key questions identified during INDEX-TB scoping

Several topics were identified during the scoping phase for this guideline that we did not have the time to address with
formal evidence review. These include the following:
• Empirical treatment of EPTB
• Tuberculin skin testing in EPTB
• PCR-based diagnostics for EPTB
• Radiological imaging for diagnosis in EPTB (including USS, CT, MR and PET)
• Interventions to improve diagnosis in children with suspected EPTB
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 919

• Duration of treatment in EPTB (TBM, abdominal TB and LNTB in progress)

• Diagnostic algorithms in EPTB – impact on patient-important outcomes
• Diagnosis of EPTB in people living with HIV, including EPTB immune reconstitution
• Diagnosis and management of drugresistant EPTB
• Interventions to improve adherence to treatment in EPTB
• Diagnosis and management of paradoxical reactions in EPTB
• Treatment end-points in EPTB
• Radiological imaging for assessing treatment success in EPTB
• Markers of treatment failure in EPTB
• Surgical management in EPBT (particularly in bone and joint, pericardial and urogenital TB)
• Treatment of EBPT in people with chronic kidney and liver disease
• Operational interventions to improve pharmacovigilance and promote safe prescribing in EPTB.
The TAC subcommittees also identified research topics that were specific to particular forms of EPTB.
Several of these topics could be addressed through collaborative efforts between the RNTCP, the medical colleges
and specialist centres and international partners such as the Union and the WHO. The RNTCP is well placed to initiate
collaborative projects across India to further this research agenda in a coordinated fashion. The guideline group recognized
that enhanced operational data collection through the RNTCP could provide evidence to assist with some of these
questions, and establishing large-scale cohort studies in collaboration with providers across India could prove fruitful,
but would require significant systems strengthening and planning to be successful. One important factor in addressing
the burden of EPTB in India is establishing reliable baseline data collection for all forms of EPTB, so that priorities can be
set in accordance with accurate prevalence data.

Working case and outcome definitions in EPTB

Throughout the guidelines process, all members of the guidelines group noted the difficulties arising from a lack of
standardized case definitions and outcome definitions in EPTB (see Section 4). This is a challenging task, given the
difficulties with diagnosis and determining treatment end-points in each form of EPTB; however, inconsistencies in
definitions compound the problems in carrying out research and interpreting research findings, reporting cases to the
national programme and treating patients. In Section 4 of this document, generic case and outcome definitions for EPTB
were laid out in order to standardize the language in the guidelines.
Further evidence review and consultation work is required internationally to establish definitions that clinicians,
researchers, policy makers and patients can recognize and use.
An evaluation of the experiences of the working definitions with clinicians is anticipated in 2017.
 Part 1 References

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Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med. 374:542–54.
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Garg RK, Malhotra HS, Kumar N (2014). Paradoxical reaction in HIV-negative tuberculous meningitis. J Neurol Sci. 340 (1–2):26–36.
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site of inflammation in the early phase of the infection. American Review of Respiratory Disease. 136(3):575–9.
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Shu CC, Wang JT, Wang JY, Lee L, Yu C (2011). In-hospital outcome of patients with cultureconfirmed tuberculous pleurisy: clinical
impact of pulmonary involvement . BMC Infectious Diseases. 11:46.
Sreenivas A, Rade K, Sachdeva KS, Ghedia M, Parmar M, Ramachandran R, et al. (2014). Standards for TB Care in India. New Delhi:
World Health Organization Country Office for India.
Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N (2014). Xpert® MTB/RIF assay for pulmonary tuberculosis
and rifampicin resistance in adults. Cochrane Database Systematic Rev. (1):CD009593. doi: 10.1002/14651858.CD009593.pub3.
TB CARE I (2014). International Standards for Tuberculosis Care, third edition. The Hague: TB CARE I.
The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) (2015). 2015
ESC Guidelines for the diagnosis and management of pericardial diseases. European Heart Journal. 36:2921–64.
Thwaites GE, Nguyen Duc Bang ND, Nguyen Huy Dung NH, Hoang Thi Quy HT, Do Thi Tuong Oanh DTT, Nguyen Thi Cam Thoa
NTC, et al. (2004). Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 351(17):1741–51.
Van Loenhout-Rooyackers JH, Keyser A, Laheij RJ, Verbeek AL, van der Meer JW (2001). Tuberculous meningitis: is a 6-month treatment
regimen sufficient? Int J Tuberc Lung Dis. 5(11):1028–35.
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Reviews , publication pending
 Part 2
Clinical practice points

9 Ocular TB

Ocular infection with M. tuberculosis is uncommon, but the difficulty of diagnosing it means that prevalence estimates
may not be reliable. Incidence of TB as a cause among patients presenting with uveitis has been reported at 10.1% in
north India (Singh, 2004), but much lower in south India at 0.6% (Biswas, 1996-1997). This discrepancy may be due to
several factors, including access to ophthalmology services, evolution of diagnostic criteria, description of new diagnostic
entities and improvement in diagnostic tools.
Ocular TB can cause moderate to severe visual impairment in up to 40% of affected eyes (Basu, 2014). Delay in
diagnosis and treatment can result in chronic inflammation and loss of vision. Improving access to a diagnosis is
therefore a high priority.

9.1 Patients who should be referred for assessment by an ophthalmologist

Patients with symptoms consistent with anterior, intermediate, posterior or pan-uveitis, including the following:
• Red eye
• Blurred vision
• Photophobia
• Irregular pupil
• Eye pain
• Floaters
• Flashing lights (photopsia).

9.2 Patients who should be investigated for ocular TB

Presumptive A patient with one of the following clinical presentations:

ocular TB • Granulomatous anterior uveitis
• Non-granulomatous anterior uveitis, not associated with any other known clinical entity, e.g. HLA-B27
• Intermediate uveitis, with/without healed/active focal lesions
• Posterior uveitis, including subretinal abscess, choroidal/disc granuloma, multifocal choroiditis,
retinal periphlebitis and multifocal serpiginous choroiditis
• Panuveitis
• Rarely, scleritis (anterior and posterior), interstitial and disciform keratitis
Note: Extraocular TB disease is often absent in ocular TB patients, and patients do not usually have
systemic symptoms of fever and weight loss.

9.3 Diagnosis

Test Patients Comments

X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest
X-ray. CT of the chest may also be useful as this test is more sensitive for evidence
of current or previous pulmonary TB infection. Evaluation by a TB specialist or
general physician as well as the ophthalmology team is advised.
922 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Test Patients Comments

HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
Ocular imaging All Depending on the presentation, imaging is required to assess extent or complications
of disease, and to monitor response to treatment. Fundus photography, fluorescein
angiography, optical coherence tomography, or multimodal imaging may be required.
Tuberculin skin All Although usually not recommended in active TB disease, tuberculin skin testing (TST)
testing (Mantoux test) may be useful in establishing supporting evidence of TB infection. While a positive
result may support the diagnosis of TB, a negative test cannot rule out TB. Clinical
evaluation by a TB specialist or general physician as well as the ophthalmology
team is advised.
PCR testing of vitreous Selected Various PCR-based tests exist for TB, but evidence of diagnostic test accuracy for the
or aqueous specimens diagnosis of ocular TB is highly variable. Whilst the accuracy of these tests seems
to vary significantly, they are often the only specific test that may identify ocular
TB. Further evidence is needed to determine which tests are the most accurate, and
when they are best used.
Vitreous/aqueous humour sampling must only be carried out by a trained
practitioner.
Biopsy Highly Biopsy of the structures of the eye is highly invasive and carries the risk of
selected exacerbating visual loss. However, in rare cases such as scleral or iris granuloma, it
may be the only way to make a diagnosis and ensure effective treatment. Specimens
should be sent for histopathology with staining for acid-fast bacilli (AFB) and culture.

9.4 Diagnostic categories

Possible ocular TB: Patients with the following (1, 2 and 3 together or 1 and 4) are diagnosed as having possible ocular TB:
1. At least one clinical sign suggestive of ocular TB (see Presumptive ocular TB), and other aetiology excluded
2. X-ray/CT chest not consistent with TB infection and no clinical evidence of extraocular TB
3. At least one of the following:
• Documented exposure to TB
• Immunological evidence of TB infection
4. Molecular evidence of Mtb infection.
Clinically diagnosed ocular TB: Patients with all the following (1, 2 and 3 together) are diagnosed as having probable
ocular TB:
1. At least one clinical sign suggestive of ocular TB (see presumptive ocular TB), and other aetiologies excluded
2. Evidence of chest X-ray consistent with TB infection or clinical evidence of extraocular TB or microbiological confirmation
from sputum or extraocular sites
3. Documented exposure to TB and/or immunological evidence of TB infection.
Bacteriologically confirmed ocular TB: A patient with at least one clinical sign of ocular TB, along with microbiological
(smear/culture) or histopathological confirmation of Mtb from ocular fluids/tissues.

9.5 Treatment
Treatment of ocular TB
All patients with possible ocular TB, clinically diagnosed ocular TB or bacteriologically confirmed ocular TB need treatment
with ATT with or without other adjuvant therapy.

Aims
1. Protect visual function
2. Control ocular inflammation
3. Prevent recurrence of inflammation.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 923

First line treatment Drugs RHZE/4RHE

for adults and Corticosteroids (local or systemic) and other immunosuppressants are often used
children with as adjunctive treatments. There is insufficient evidence currently to make specific
ocular TB recommendations regarding their use.
Duration Total treatment duration: 6 to 9 months
Referral All patients with presumptive ocular TB must be referred to an ophthalmologist
for assessment and treatment.
Follow up Regular review during and after treatment. Suggested methods for monitoring
treatment:
• Clinical evaluation (slit-lamp biomicroscopy and indirect ophthalmoscopy)
• Fundus photography
• Fundus autofluorescence
• Optical coherence tomography
Response to Treatment outcomes in ocular TB need to be defined differently, as microbiological
treatment confirmation of TB is rarely possible in ocular tissues. Thus, treatment success or
failure is primarily guided by the level of inflammation seen inside the eye.
• Remission: Inactive disease for at least 3 months after discontinuing all
therapy based on the Standardization of Uveitis Nomenclature recommenda­
tions (Jabs, 2005).
• Treatment failure: No decrease in inflammation, or less than a two-step decrease
in level of inflammation after 3 months of ATT (inflammatory scores of fundus
lesions such as retinal perivasculitis or multifocal serpiginous choroiditis are
not yet defined and are left to the judgment of treating physicians).
• Relapse: An increase in the level of inflammation after complete remission
(at least two-step increase).
Approach 1. Rule out non-TB aetiology: detailed ocular and systemic evaluation, ancillary
to treatment tests
failure 2. Rule out paradoxical reaction: usually occurs within 2 months of starting ATT;
responds to continuation or escalation of corticosteroid therapy
3. Rule out drug resistance: once previous two points have been ruled out, check
contact with MDR TB patient; if facilities exist, consider ocular fluid sampling for
molecular diagnosis of drug resistance
Surgery The main indications for surgery in ocular TB are as follows:
• Complications of retinal vasculitis—retinal neovascularization, vitreous
haemorrhage, tractional or combined retinal detachment, epiretinal membrane
• Diagnostic vitrectomy when conventional methods fail to establish diagnosis
• Non-resolving vitreous inflammation
• Visually significant vitreous floaters after completion of medical therapy
• Management of complications of uveitis such as cataract and glaucoma
 10 Central nervous system TB

10.1 Background
TB can cause meningitis (TBM), cerebral and spinal tuberculoma, myelitis and arachnoiditis. These are all severe forms
of TB associated with high incidence of death or disability.
Exact prevalence of CNS TB in India is not known, but it accounts for an estimated 1% of all cases of TB, which equates
to around 17 000 cases in India in 2014 (WHO, 2015). Case fatality rates for the most common form of CNS TB, i.e. TB
meningitis, are high. All forms of CNS TB can leave survivors with long-term disabilities.

10.2 Patients who should be investigated for TBM

TBM is a medical emergency. Early diagnosis and prompt treatment with ATT saves lives.
TBM classically presents as subacute or chronic meningitis with symptoms developing over days or weeks. Evidence
suggests that patients presenting with less than 5 days of symptoms are more likely to have bacterial or viral meningitis
than TBM (Thwaites, 2009). However, it should be noted that TBM can present acutely with a short duration of illness,
and this acute presentation is not uncommon.

Presumptive TBM Any patient with clinical features of meningitis in the form of fever, headache, neck rigidity and
vomiting, with or without altered sensorium and associated focal neurological deficits for a period
of 5 days or more

Common symptoms Less frequent symptoms Uncommon symptoms

Headache Confusion Photophobia
Fever Cranial nerve palsy Paraparesis
Vomiting Hemiparesis Seizures
Neck stiffness Coma
Weight loss

10.3 Diagnosis
The most important aspect of TBM diagnosis is to suspect TBM and act quickly to refer the patient to a centre where they
will receive:
• rapid access to CSF examination
• rapid access to neuroimaging
• prompt treatment with ATT and supportive care.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 925

Diagnostic workup

Test Patients Comments

Lumbar puncture for All (unless absolutely CSF findings typical of TBM: lymphocytic (more rarely neutrophilic)
CSF contraindicated) pleocytosis with low serum:CSF glucose ratio and high protein.
Additional tests on CSF are summarized in the table below.
HIV testing All HIV infection predisposes people to CNS infections, including TBM.
All patients should be offered integrated counselling and testing.
Chest X-ray All Chest X-ray may assist the diagnosis with evidence of current or previous
pulmonary TB infection.
CT brain with All High priority for comatose or deteriorating patients helps to diagnose
contrast hydrocephalus, which may require neurosurgical intervention.
MRI brain with Selected Magnetic resonance imaging (MRI) provides more detailed information
contrast than CT. May be of assistance where diagnosis is uncertain, in complex
cases, and in HIV-positive patients.

CSF sampling and testing

Lumbar puncture should be performed in every patient (unless there are contraindications to the procedure) and
CSF should be analysed with the following tests given in the table below. Other tests may also be indicated in some
circumstances.
At least 6 mL of CSF should be collected for adults, 2–3 mL for children.

Results available Tests

Hours to days • Cell count and differentiation
• Protein
• CSF:serum glucose ratio (serum samples need to be taken alongside the CSF)
• Gram stain for bacterial meningitis (e.g. N. meningitidis, S. pneumonia)
• AFB stain for TB
• India ink and cryptococcal antigen testing for cryptococcal meningitis
• Xpert MTB/RIF can be used as an adjunctive test in the diagnosis of TBM, but a negative
test does not rule out a diagnosis of TBM. If it is safe to obtain, 1 mL of CSF is optimal for
this test (Nhu, 2014).
• Other PCR-based tests for Mtb are available, but diagnostic accuracy is highly variable.
• PCR-based tests for viral pathogens, as appropriate
Days • Bacterial culture, speciation and drug susceptibility testing
• Cytological examination for malignant cells
Days to weeks • Fungal culture, speciation and drug susceptibility testing
• Mycobacterial culture, speciation and drug susceptibility testing

Recommendation
Xpert may be used as an adjunctive test for TBM. A negative Xpert result does not rule out TBM. The decision to give
ATT should be based on clinical features and CSF profile.
(Conditional recommendation, high quality evidence for specificity estimate, low quality evidence for sensitivity estimate).

Other tests
Interferon-gamma release assays such as ELISPOT and Quantiferon Gold are designed for the diagnosis of latent TB,
and are not indicated in the diagnosis of TBM. Currently, the use of these tests is restricted in India.
Adenosine deaminase (ADA) is not useful in the diagnosis of TBM.
926 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

MRC staging
The British Medical Research Council (MRC) staging is a widely recognized system for classifying disease severity in
TBM (MRC, 1948).
Stage I Mild cases, for those without altered consciousness or focal neurological signs
Stage II Moderate cases, for those with altered consciousness who are not comatose and those with moderate neurological
signs, e.g. single cranial nerve palsies, paraparesis, and hemiparesis
Stage III Severe cases, for comatose patients and those with multiple cranial nerve palsies, hemiplegia or paraplegia,
or both.

10.4 Treatment
Aims
• Microbiological cure
• Prevention of complications, morbidity and mortality
• Management of treatment complications

First line treatment Drugs Intensive phase: 2 months RHZE

for adults and The was the recommendation made by the INDEX-TB Guidelines Panel at the
children with TB INDEX-TB meeting in 2015, based on the evidence summarized in Annex 2 in the
meningitis online supplementary materials, as follows:
Continuation phase: at least 7 months RHE
The Technical Advisory Sub-committee for CNS TB, who drafted these clinical
practice points, expressed a preference for an alternative approach to the
continuation phase that differs from the INDEX TB recommendation in two ways:
a) recommend the use of pyrazinamide instead of ethambutol; and b) treatment to
be continued in all patients for a total of at least 12 months.
The current RNTCP guidance is to use ethambutol in the continuation phase because
of the risk of isoniazid mono-resistance. The variations in expert opinion reflect
the uncertainty regarding the optimum choice of regimen, and further research is
required.
If vision is impaired or cannot be assessed, use streptomycin instead of ethambutol
in the intensive phase. Use of streptomycin in pregnant women, and patients with
kidney impairment or hearing loss should be avoided.
Duration Recommendation:
TB meningitis should be treated with standard first-line ATT for at least 9 months
(conditional recommendation, very low quality evidence)
Note: see Drugs section above.
Referral ATT should be started as early as possible in all cases of TBM.
Presumptive TBM patients should be referred to a secondary/tertiary care centre
immediately.
If referral and transfer is likely to take more than 24 h, or if the patient is critically
ill, treatment with ATT may be started prior to transfer. Where possible, CSF
sampling prior to initiation of treatment is preferred, as ATT reduces the accuracy
of the diagnostic tests for TB, but this should not unduly delay initiation of ATT.
Follow up Patients should be assessed for clinical response at the end of the treatment period
and at intervals for 2 years. Sustained resolution of clinical features including
headache and fever should guide stopping of ATT. Residual neurological deficits
may be permanent and should not be used to assess for active TB infection.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 927

Drug-resistant cases Drug-resistant TBM should be suspected in patients with poor response to standard
ATT and history of exposure to MDR-TB.
Steroids HIV-negative Recommendation:
patients Steroids are recommended for TB meningitis in HIV-negative people. Duration of
steroid treatment should be for at least 4 weeks, with tapering as appropriate (strong
recommendation, high quality evidence)
HIV-positive Recommendation:
patients Steroids may be used for TB meningitis in HIV-positive people, where other life-
threatening opportunistic infections are absent (conditional recommendation, low
quality evidence)
Important opportunistic infections to consider include cryptococcal meningitis and
cerebral toxoplasmosis. There is evidence that steroids are associated with increased
adverse events and disability in patients with HIV-associated cryptococcal meningitis
(Beardsley J, 2016).
Suggested In hospital: intravenous dexamethasone 0.4 mg/kg/24 h in 3–4 divided doses may be
regimen preferred with a slow switch to oral therapy and taper. Currently, there is insufficient
evidence to recommend one formulation/regimen of steroids over any other.
Surgery Patients who develop hydrocephalus with raised intracranial pressure may require
CSF diversion by ventriculo-peritoneal shunt insertion. Such patients should be
managed in settings with neurosurgical services.

10.5 Complications

Complication Clinical features Management

Hydrocephalus Symptoms and signs of raised Ventriculo-peritoneal shunt insertion is indicated for patients
intracranial pressure (ICP) such at all stages of severity with hydrocephalus or raised ICP not
as worsening headache, vomiting, responding to ATT and steroids. Early shunt insertion may be
ocular palsies, decreasing con­ beneficial.
scious level, papilloedema Treatment with diuretics such as mannitol should be limited to
Urgent neuroimaging is needed emergency management, aimed at decreasing ICP until shunt
to assess cause of raised ICP if insertion can be performed.
patient is deteriorating External ventricular drainage is not usually recommended,
unless surgery is contraindicated or urgent CSF diversion is
indicated to buy time before a shunt can be inserted.
Stroke Focal neurological deficit consis­ Most effective treatment strategy is uncertain and evidence is
tent with a stroke syndrome. lacking.
Stroke in TBM may not be clini­ Acute stroke or evidence of on-going vasculopathy may warrant
cally apparent and may be diag­ continuation of steroids, usually intravenously.
nosed on neuroimaging. There is some evidence that aspirin may prevent stroke in TBM
Stroke is a significant contributor in adults. Further trials in adults and children are on-going.
to disability following TBM.
Optico-chiasmatic Visual loss, which may arise Most effective treatment strategy uncertain
arachnoiditis during treatment with ATT, or on Steroid therapy is the first-line treatment, using intravenous
the withdrawal of corticosteroids dexamethasone.
Characteristic CT and MRI Pulsed methylprednisolone or oral thalidomide has been used
findings in some case series for patients not responding to steroids.
Microsurgical intervention and intrathecal hyaluronidase are
controversial and not currently recommended.
928 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Complication Clinical features Management

Seizures Generalized seizures secondary to Acute management with anti-epileptic drugs as per local
encephalopathy protocol for seizure
Tuberculoma or infarction may The use of anti-epileptic drugs alongside ATT must be carefully
cause secondary generalized managed due to the potential for drug interactions and increased
seizure risk of liver dysfunction with multiple hepatotoxic agents.
Prophylactic anti-epileptic drugs are not required in TBM
patients who have not had seizures during their clinical course.
Continued treatment with anti-epileptic drugs may be necessary
in patients with recurrent seizure and decisions about duration
and withdrawal should be individualized to the patient by the
treating specialist.

10.6 CNS tuberculoma

Tuberculoma of the central nervous system (CNS) is less common than TBM and has lower morbidity and mortality,
but remains an important cause of intracranial space-occupying lesions. Tuberculoma can arise anywhere in the brain
or spinal cord, and may present as a mass lesion causing focal neurological deficits depending on anatomical location
and/or seizure, or may be found in concurrence with TBM.

Presumptive CNS Any patient presenting with seizures, headache, fever or focal neurological deficits with
tuberculoma neuroimaging features consistent with a mass lesion of inflammatory nature.

Patients with presumptive CNS tuberculoma should be referred for investigation and treatment by a specialist.
Neuroimaging, particularly multimodal MRI, with interpretation by a specialist is indicated to characterize the lesion(s).

Diagnosis
Diagnosis is based on the following:
• Patient history – previous TB disease and contact with a pulmonary TB patient make tuberculoma more likely.
• Clinical findings – active TB elsewhere in the body makes tuberculoma more likely. Chest X-ray should be performed.
Other imaging such as CT chest should be considered to look for TB, identify other lesions amenable to biopsy, and look
for features suggestive of other pathology such as malignancy.
• HIV status – HIV testing is important as HIV-positive people are at increased risk, not only of tuberculoma, but also
other diagnoses such as coccidiomycosis and toxoplasmosis. Other causes of immunosuppression are also important.
• MRI/CT scan findings consistent with tuberculoma
• CSF findings – CSF can be normal, or show features similar to TBM. The sensitivity of culture for Mtb is low, and
PCR-based tests require further investigation in tuberculoma.
Stereotactic or open biopsy is rarely performed as this is a highly invasive procedure, but it may be indicated in patients
where the diagnosis remains very uncertain after non-invasive tests, or there is no response to ATT.
The differential diagnosis for tuberculoma includes, but is not limited to:
• neurocysticercosis
• pyogenic abscess
• metastatic lesions from a primary malignancy elsewhere in the body, e.g. lung cancer
• glioma
• demyelinating lesion.

Treatment
The aims of treatment are:
• Resolution of neurological and constitutional symptoms
• Resolution of the lesion on neuroimaging.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 929

There is a lack of evidence as to the optimum duration of treatment in CNS tuberculoma. The expert group suggested
that ATT should be given for 9 to 12 months initially, with repeat neuroimaging at 3 months and 9–12 months to monitor
response to treatment. Treatment should then be tailored to the clinical and radiological response of the patient.
Paradoxical reaction with increase in the size and number of lesions can occur, usually in the first 3 months of treatment,
and requires treatment with steroids as well as continued ATT.
Treatment failure should be suspected when lesions either increase in size or fail to reduce in size after 3 to 6 months
ATT despite appropriate dosing and good adherence. The treating clinician needs to weigh the benefits and risks of biopsy
against those of commencing second-line treatment empirically for suspected MDR-TB, or persisting with first-line treatment
for suspected paradoxical reaction. If a biopsy is performed due to strong consideration of an alternative diagnosis, the
specimens should be sent for: a) histopathology with staining for AFB; b) Mtb culture and drug susceptibility testing; c)
other microbiological tests as indicated by the case history.
 11 Ear, nose and throat TB

Head and neck TB constitutes 10–15% of all EPTB cases, with the majority of these cases being cervical lymph node TB,
and <1% extra-nodal head and neck TB cases. Malignancy is the most important differential diagnosis in ear, nose and
throat (ENT) TB and diagnostic approaches must take this into account.

11.1 Presentation
Laryngeal TB

Presents with hoarse voice and pain on swallowing, mimicking non-specific laryngitis or laryngeal carcinoma. Can be
infectious, unlike other forms of EPTB.

Ear TB
Usually presents with chronic suppurative otitis media – painless discharging ear not responding to antibiotics, with
hearing loss disproportionate to the clinical appearance. Can be complicated by facial paralysis, promontorial fistulae and
inner ear involvement, which may also occur in TB meningitis.

Oral TB
Multiple presentations as TB can affect any part of the mouth. Lesions are usually ulcerative and painless, sometimes with
a necrotic base and discharge.

Oropharyngeal TB
TB of the tonsils presents with asymmetrical enlargement with ulceration, mimicking carcinoma. TB of the cervical spine
can extend to cause retropharyngeal abscess presenting with pain on swallowing, and complicated by airway compromise
which requires emergency intervention.

Sinonasal TB
Very rare, usually presents with nasal obstruction, bleeding and runny nose and lymphadenopathy

Salivary gland TB
Very rare; usually associated with immunosuppression. Presents with swelling

Thyroid gland TB
Very rare; multiple presentations from isolated nodules to thyrotoxicosis.

11.2 Diagnosis
Test Patients Comments
X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest X-ray.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 931

Test Patients Comments

Incisional or punch All Incisional or punch biopsy from the affected site, carried out by a trained specialist
biopsy from the practitioner is the preferred method of diagnostic sampling for ENT lesions, and
affected site should be sent for:
• histopathology
• staining for acid-fast bacilli (fluorochrome or ZN staining)
• culture for Mtb
Fine needle aspiration Selected FNAC may also be used, particularly where there is lymph node involvement or an
cytology (FNAC) abscess, with aspirate sent for:
• microscopy for AFB
• Xpert MTB/RIF
• cytology
• culture for Mtb
CT or MR imaging of Selected May be required to further characterize the disease, look for involvement of
the head and neck bone/deep structures, and aid in diagnosis. This should be requested and interpreted
by a specialist.

11.3 Treatment

First line treatment Drugs 2RHZE/4–7RHE

for adults and Steroids have no role in the treatment of ENT TB, and should be avoided as they
children with ENT may do harm.
TB
Duration Total treatment duration: 6 to 9 months
All cases involving bone, including all TB otitis media cases, should receive 9 months
treatment.
Referral All patients with ENT TB, except those who have accessible cervical lymph nodes
which are amenable to FNAC, will need referral to ENT specialists for diagnosis.
Follow up Monthly follow-up for patients with sinonasal and ear/temporal bone TB is suggested
during treatment to assess response and monitor adherence, and after treatment to
assess resolution and detect recurrence.
Surgery May be indicated in some circumstances to treat complications or for reconstruction
of the ear or nose.
Where facial nerve palsy complicates tuberculous otitis media, surgical decompression
should be considered if there is no improvement after 3 to 4 weeks of ATT (good
practice statement).
Surgical drainage of retropharyngeal abscess complicating TB of the cervical spine
may be considered, but requires specialist judgement.
Surgery should be avoided in TB of the salivary glands or thyroid; medical treatment
is usually sufficient.
There is little evidence to guide recommendations about the duration of treatment in ENT TB, and so this outline is based
on the consensus of the ENT expert group.

11.4 Sequelae
Sequelae are related to tissue destruction. Serious complications result from resorption of facial bone. Airway compromise
resulting from ankylosis is a lifethreatening complication, which requires emergency surgical treatment.
TB of the ear can lead to permanent hearing loss, facial nerve palsy and balance problems (vestibulopathy). It can be
complicated by infection of the underlying bone and meningitis from spread into the central nervous system.
Sinonasal TB can lead to deformity of the nose, and can be complicated by involvement of the eye socket.
 12 Lymph node TB

Lymph node TB (LNTB, also called TB lymphadenitis) refers to Mtb infection of the lymph nodes, and may occur as the
sole manifestation of TB infection, or alongside pulmonary or miliary TB. LNTB is the most common form of EPTB in
India, accounting for around 35% of EPTB cases (Sharma S.K., 2004). Total estimated incidence of LNTB was 30.8 per
100 000 population in India in 2013 (RNTCP, 2014).
Care should be taken to identify patients who need to be investigated for LNTB, as there are multiple differential
diagnoses for chronic lymphadenopathy.
TB of the deep lymph nodes in the chest (mediastinal TB) may present with cough or shortness of breath. Abdominal
LNTB patients may have abdominal pain or distension.

12.1 Patients who should be investigated for LNTB

Presumptive Patients with enlarged lymph nodes (over 1 cm across) in the neck, armpit or groin. Patients may
peripheral LNTB also present with symptoms of fever, weight loss, night sweats and cough
Presumptive Patients with cough, fever, shortness of breath, weight loss or night sweats who have hilar widening
mediastinal LNTB on chest X-ray and/or mediastinal lymphadenopathy on chest CT in the absence of evidence of
active pulmonary TB
Presumptive Patients with dull or colicky abdominal pain, abdominal distension, weight loss, night sweats or
abdominal LNTB fever, and evidence of abdominal lymphadenopathy on abdominal ultrasound scan, CT or MR

12.2 Diagnosis
Test Patients Comments
X-ray of chest All All patients presenting with symptoms consistent with LNTB, to seek for active or
previous pulmonary TB
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
Ultrasound or CT Selected Indicated when diagnosis is not clear, and in HIV-positive people
scans of chest and Finding abdominal lymphadenopathy should prompt biopsy to rule out lymphoma
abdomen as a differential diagnosis.
Fine needle aspiration All Send specimen for: a) Xpert MTB/RIF test; b) microscopy and culture for
cytology (FNAC) Mtb with drug susceptibility testing; c) Cytology
Excision biopsy Selected IF FNAC has been inconclusive, or where malignancy is suspected.
Send specimen for: a) Xpert MTB/RIF test; b) microscopy and culture for Mtb with
drug susceptibility testing; c) histopathology
Specimens should be taken from the affected lymph nodes prior to commencing ATT.
A non-dependent aspiration with Z-technique for manipulating overlying skin by an appropriately trained operator is
suggested for superficial lymph nodes. Deep lymph nodes require radiologically-guided sampling. In abdominal LNTB,
ultrasound/CT-guided percutaneous FNAC or biopsy is required. In mediastinal LNTB, endobronchial ultrasoundguided
FNAC is preferred where facilities exist.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 933

Recommendation:
Xpert MTB/RIF may be used as additional test to cytology for LNTB (strong recommendation, high quality evidence
for specificity, low quality evidence for sensitivity).

Diagnostic definitions

Bacteriologically A patient with symptoms and signs of LNTB and has at least one of the following:
Confirmed LNTB case • positive microscopy for AFB on examination of lymph node fluid or tissue
• positive culture of Mtb from lymph node fluid or tissue
• positive validated PCR-based test (such as Xpert MTB/RIF)
Clinically diagnosed A presumptive LNTB patient who undergoes diagnostic testing and has all of:
LNTB case • negative microscopy, negative culture and negative PCR-based tests
• no other diagnosis made to explain signs and symptoms
• strongly suggestive evidence on other tests, such as radiological findings, histopatho­
logical findings, clinical course

12.3 Treatment

First line treatment Drugs 2RHZE/4RHE

for adults and Duration Recommendation
children with
Six months ATT standard first-line regimen is recommended for peripheral lymph
LNTB
node TB (strong recommendation, low quality evidence).
Referral Generally, LNTB patients can be managed at primary care level. Referral to secondary
care for specialist diagnostic sampling may be required.
Follow up Assess response to treatment at 4 months. Consider possible treatment failure in
patients who have worsened or deteriorated after initial improvement – this requires
diagnostic investigation and possibly a change of treatment. Deterioration in the first
3 months may be due to paradoxical reaction – this does not require repeat diagnostic
tests or change of treatment.
Some patients with LNTB have residual lymphadenopathy at the end of treatment.
This is not usually due to continued active TB infection where the largest node is
less than 1 cm in size. Some patients have residual nodes more than 1 cm in size,
and these patients are classified as partial responders. There is uncertainty about
whether continued ATT in these patients is beneficial. The expert group suggested
these patients should receive an additional 3 months of RHE, followed by a biopsy
sent for histology and TB culture in patients who fail to respond to that. While
some evidence suggests that these patients may not require further ATT, the data is
insufficient at this stage.
For mediastinal TB, progress on ATT can be monitored with chest X-ray, but CT scan
may be indicated if lymph nodes do not reduce in size after 4 months. In patients
who fail to improve on ATT, the alternative diagnoses of lung cancer, lymphoma,
sarcoidosis and fungal infection should be considered. Current expert opinion on
when to stop ATT in patients with persistently enlarged mediastinal lymph nodes
is to stop when there is documentation of absence of interval change in CT/MRI of
mediastinal lymph nodes for more than 4 months, with resolution of all other signs
and symptoms.
 13 Pleural TB

The second most common form of EPTB, pleural TB is a common cause of pleural effusion in India. Pleural TB usually
presents with pleural effusion caused by the immune system’s response to the presence of mycobacterial antigens in the
pleural space, generating inflammation and causing fluid to accumulate. The effusion will usually resolve spontaneously
even without ATT, but patients who are not treated are at risk of recurrent active TB infection.

13.1 Patients who should be investigated for Pleural TB

Presumptive pleural A patient with cough, chest pain or shortness of breath, with or without fever and weight loss,
TB with evidence of a pleural effusion on examination or CXR

13.2 Diagnosis
Test Patients Comments
X-ray of chest All To confirm presence of a pleural effusion and look for underlying pulmonary disease.
Progress may be monitored using CXR.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
CT scans of chest and Selected Useful when diagnosis is not clear, particularly if malignancy is suspected; or in in
abdomen HIV-positive patients who are at higher risk of disseminated TB
More sensitive than CXR for identifying underlying pulmonary disease
Ultrasound of chest Selected Alternative to CXR to identify pleural effusion, and is more sensitive in picking up
pleural effusion than CXR
Pleural aspiration/ All Most patients do not require complete therapeutic drainage of their pleural effusion,
thoracocentesis unless it is causing respiratory compromise; in which case, specialist monitoring is
required during and following drainage. All patients should have a diagnostic sample
of pleural fluid taken.
Pleural aspiration/ All Send specimen for: a) glucose, protein, ADA and lactate dehydrogenase (LDH) levels
thoracocentesis (send concurrent blood sample for serum protein and LDH); b) differential cell count;
c) microscopy and culture for Mtb; and d) cytology
Pleural TB usually causes an exudative effusion, defined on the basis of Light’s criteria
(pleural fluid/serum protein >0.5; pleural fluid/serum LDH >0.6; pleural fluid LDH
> two-thirds the upper limit of serum LDH) (Light R.W., 1972)
Test for adenosine deaminase activity (ADA) level performed on pleural fluid can
help support a diagnosis of pleural TB (Greco, 2003) (Liang, 2008). It should be noted
that other causes of pleural effusion such as empyema, rheumatoid serositis and
lymphoma can occasionally also lead to elevated ADA (Porcel, 2010).
> 70 U/L – highly likely to be pleural TB
40–70 U/L – indeterminate level, other risk factors need to be considered
<40 U/L – low likelihood of pleural TB, investigate for other causes
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 935

Test Patients Comments

Because the most common differential diagnosis in children is partially treated
parapneumonic effusion, ADA may yield a higher proportion of false positives in
this group. Further investigation is required as to the utility of ADA in the diagnosis
of pleural TB in children.
Sputum samples Selected Send sputum for Xpert MTB/RIF, microscopy and culture as per pulmonary TB
guidelines whenever concurrent pulmonary and pleural TB is suspected.
Pleural biopsy (closed Selected Much higher yield than pleural fluid when subjected to microscopy and culture for
or thorascopic) Mtb; also, histopathological examination can be performed
Thoracoscopically-obtained specimens have a higher diagnostic yield than closed
pleural biopsy.
Indicated where diagnosis is uncertain despite other tests, or where pleural
malignancy is a significant differential diagnosis.

Recommendation:
Xpert MTB/RIF should not be used to diagnose pleural TB (strong recommendation, high quality evidence for specificity,
low quality evidence for sensitivity).

13.3 Treatment

First line treatment Drugs 2RHZE/4RHE

for adults and Recommendation: Corticosteroids are not routinely recommended in pleural TB
children with (conditional recommendation, low quality evidence).
pleural TB
Duration Total duration of treatment: 6 months
Referral Uncomplicated cases do not require referral to specialist centres.
Follow up Most patients who respond to treatment will have improvement in their general
condition by 2 weeks, and significant improvement in pleural effusion by 6–8 weeks.
A follow up CXR at 8 weeks after starting ATT is useful to assess progress. Increasing
size of effusion despite treatment may be due to paradoxical reaction, or an alternative
diagnosis requiring further investigation.
 14 TB of the heart

TB infection of the heart most commonly manifests as TB pericarditis. TB myocarditis is a recognized form of EPTB, but
is very rare. In this summary, the main practice points for the diagnosis and management of TB pericarditis are covered.
While it has a low prevalence overall, TB pericarditis accounts for 60–80% of cases of acute pericarditis in high TB
burden countries, and 75% of cases of constrictive pericarditis (Fowler, 1991). TB pericarditis has a high mortality
if untreated in the acute phase of illness, and survivors can develop constrictive pericardial disease as the acute
inflammation resolves, which can cause disability and death later on. ATT greatly reduces both death in the acute phase
of illness and the development of constrictive pericardial disease.

14.1 Patients who should be investigated for TB pericarditis

Presumptive TB A patient with chest pain, shortness of breath, with or without fever and weight loss or
pericarditis haemodynamic abnormalities, who has evidence of pericardial effusion or constriction on chest
X-ray (CXR) electrocardiogram (ECG) or echocardiogram

14.2 Diagnosis
Test Patients Comments
X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest X-ray.
Features suggestive of pericardial disease include hilar widening, and a globular
or “water bottle” heart shadow, although the cardiac shadow may appear normal.
Evidence of pulmonary TB or pleural effusions may be noted.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
ECG All May reveal evidence of pericardial effusion (low voltage trace, T wave flattering or
inversion). Patients are at risk of atrial arrhythmia.
Echocardiogram All Reveals or confirms pericardial effusion and/or constriction, and can detect signs of
(transthoracic) impending tamponade which requires urgent intervention.
CT of the chest Selected Useful for demonstrating pericardial thickening or calcification, or associated lung/
mediastinal abnormalities.
Not routinely required.
Cardiac MRI Highly Only required in patients where a diagnosis of restrictive cardiomyopathy is being
selected considered as a significant differential diagnosis.

Cardiac tamponade

Cardiac tamponade occurs when fluid accumulating in the pericardial sac impedes ventricular filling, causing cardio­
vascular compromise, which can progress to cardiac arrest. Pericardiocentesis is urgently required to relieve the
pressure in the pericardial sac and allow normal ventricular filling.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 937

Pericardiocentesis

The European Society of Cardiology guidelines give recommendations about pericardiocentesis (The Task Force for the
Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC), 2015). If the patient
does not have signs of cardiac tamponade, pericardiocentesis can be considered for diagnostic purposes, but should only
be carried out by trained personnel using ultrasound guidance.

Microbiological tests

Microscopy and culture of pericardial fluid for Mtb have very low sensitivity, meaning that few cases have a microbio­
logically confirmed diagnosis. In patients with concurrent pulmonary disease, smear and culture of serial sputum
samples may yield a diagnosis.
Very few studies have assessed the diagnostic accuracy of Xpert MTB/RIF in pericardial fluid, and so the INDEX-TB
guidelines panel did not make a recommendation regarding the use of Xpert MTB/RIF on pericardial specimens.
If pericardial fluid is obtained, it should be sent for culture for Mtb, despite low sensitivity of this test. A differential
cell count and raised ADA level may support the diagnosis.

14.3 Treatment

First line treatment Drugs 2RHZE/4RHE

for adults and Recommendation: Corticosteroids are recommended for all patients with TB
children with TB pericarditis who have pericardial effusion (conditional recommendation, low quality
pericarditis evidence for HIV-positive people, very low quality evidence for HIV-negative people).
Duration Total treatment duration: 6 months
Referral Patients who develop cardiovascular compromise require urgent management in a
specialist setting.
Patients who develop constrictive pericardial disease as a late complication may
benefit from assessment by a cardiologist.
Follow up Assess response to treatment at 4 months. Consider possible treatment failure in
patients who have worsened or deteriorated after initial improvement – this requires
diagnostic investigation and possibly a change of treatment. Deterioration in the first
3 months may be due to paradoxical reaction; this does not require repeat diagnostic
tests or change of treatment.
Surgery Pericardiocentesis is indicated as an urgent intervention in cardiac tamponade
resulting from pericardial effusion.
Pericardectomy is sometimes indicated in patients who develop constrictive peri­
cardial disease as a late complication. Some of these patients will improve without
surgery, but others may require pericardectomy too for progressive cardiac failure.
 15 Abdominal TB

Abdominal TB refers to TB infection of any organ in the abdominal cavity, including the gut and peritoneum. Abdominal
TB cases make up about 3% of all EPTB cases in India (Sharma S.K., 2004).
Abdominal TB causes a variety of presentations relating to the site of disease within the abdomen, stage of disease
and complications. When treated with appropriate ATT, mortality is low, but some patients experience ongoing compli­
cations which can affect their long-term health, such as strictures in the bowel and adhesions. The most commonly
affected sites in the abdomen are the GI tract distal to the duodenum (the ileum, jejunum and colon) and the peritoneum.
The other organs are more rarely affected.

15.1 Patients who should be investigated for abdominal TB

Site Typical presentation
Peritoneal Abdominal distension, abdominal pain, fever
Intestinal Recurrent intestinal colic, partial or complete intestinal obstruction, chronic diarrhoea, unexplained
weight loss, palpable mass in lower abdomen, lower GI bleeding
Oesophageal* Dysphagia, odynophagia, hematemesis, constitutional symptoms
Gastroduodenal* Gastric outlet obstruction, upper GI bleeding
Hepatobiliary* Fever of unknown origin, hepatomegaly with or without space occupying lesions, abnormal LFTs
(especially elevated alkaline phosphatase), abnormal imaging (abscess, space occupying lesions),
jaundice
Pancreatic* Abdominal pain, and/or obstructive jaundice, and/or dilated pancreatic and/or bile ducts with
evidence of (peri)-pancreatic mass or cyst with or without constitutional symptoms
Perianal Complex perianal fistulae, persistent discharge from the fistula, fistulae
which recur after multiple surgical excisions
* Sites where other differential diagnoses like malignancy are more common than TB infection

Presumptive A patient with abdominal pain, distension, fever, unexplained weight loss, chronic diarrhoea or
abdominal TB an abdominal mass.

15.2 Diagnosis
All patients with presumptive abdominal TB

Test Patients Comments

X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest X-ray.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 939

Patients with presumptive peritoneal TB

Ascitic fluid sampling All Simple percutaneous sampling of ascitic fluid can aid in the diagnosis of peritoneal
TB. Specimens should be sent for: a) cytology; b) albumin and protein; c) adenosine
deaminase (ADA); d) microscopy for AFB; e) culture for Mtb and other organisms
A serum albumin:ascitic fluid albumin ratio (SAAG) of <1.1 with a high protein
(>2.5 g/mL) is suggestive of an exudative process, in keeping with abdominal TB
(although several other conditions also cause this).
ADA >39 IU/mL in ascitic fluid is suggestive of abdominal TB (Riquelme A, 2006).
Sensitivity of smear microscopy and culture for Mtb on ascitic fluid samples is low;
however, culture is required to confirm the diagnosis and test for drug susceptibility.
PCR-based methods for identifying Mtb in ascitic fluid samples are highly variable
in terms of diagnostic accuracy, and so no recommendation on the use of these tests
has been made.
Ultrasound of All Many abnormal features may be noted, including intra-abdominal fluid (free or
abdomen loculated), inter-loop ascites, mesenteric lymphadenopathy, bowel wall thickening,
enlarged lymph nodes with central necrosis and peripheral enhancement and
peritoneal and omental thickening.
US-guided FNAC Selected Microscopy and culture of FNAC/biopsy specimens of affected structures is more
or core biopsy of sensitive than ascitic fluid testing alone.
mesenteric or retro­ Requires a trained practitioner. Specimens should be sent for:
peritoneal lymph a) histology; b) microscopy for AFB; c) culture for Mtb and other organisms.
nodes, omentum or
peritoneum
CT or MR scan of Selected Many abnormal features may be noted, but as with ultrasound, none are diagnostic
abdomen for peritoneal TB. These tests may be useful when other differential diagnoses
are being considered. Not routinely suggested. Radiation exposure should be
considered when deciding to perform a CT.
Laparoscopy Selected Visual appearance on laparoscopy can be highly suggestive of peritoneal TB. Typical
appearances include:
• Thickened peritoneum with tubercles: multiple, yellowish white, uniform sized
(about 4–5 mm) tubercles diffusely distributed on the parietal peritoneum.
The peritoneum is thickened, hyperaemic and lacks its usual shiny lustre. The
omentum, liver and spleen can also be studded with tubercles.
• Thickened peritoneum without tubercles.
• Fibro-adhesive peritonitis with markedly thickened peritoneum and multiple
thick adhesions fixing the viscera.
Targeted diagnostic sampling at laparoscopy may improve the yield from biopsy
specimens sent for microscopy and culture for Mtb and histopathology.
Laparoscopy is not routinely recommended due to the high cost and invasive nature
of the procedure, and is usually reserved for cases where the diagnosis remains
unclear after other tests.
940 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Patients with presumptive peritoneal TB

Ileocolonoscopy All Unless contraindicated, all patients suspected of TB affecting the lower GI tract should be
offered endoscopic examination with appropriate biopsy sampling.
Examination of the ileum by retrograde ileoscopy is important, as this is the commonest
site of involvement in GI TB.
Appearances vary considerably, and differentiating GI TB from other bowel diseases such
as Crohn’s disease is often challenging.
Biopsy specimens should be sent for: a) histology and staining for AFBs; b) culture for Mtb
PCR-based methods for identifying Mtb in biopsy specimens from the GI tract are highly
variable in terms of diagnostic accuracy, and so no recommendation on the use of these
tests has been made.
CT/MR Selected Assessment of the small intestine may require specialist imaging to identify and characterise
enterography/ lesions. Selecting the appropriate test depends on what pathology is suspected, and should
enteroclysis be at the discretion of a specialist clinician and/or radiologist.
Common findings include short segment strictures and ileocecal wall thickening with
enlarged necrotic lymph nodes.
Upper GI Selected If symptoms suggest involvement of the upper GI tract, endoscopy with biopsy is indicated.
endoscopy
Barium studies Selected Barium studies of the upper GI tract and small bowel may be indicated where endoscopy
is not available or not possible, or where small bowel stricture is suspected.

Diagnosis of other forms of abdominal TB

The principal differential diagnosis in biliary and pancreatic TB patients is usually malignancy, and some patients are
diagnosed post-operatively after surgery to resect a suspected tumour. Specialist imaging and image-guided diagnostic
sampling techniques are required in cases of suspected biliary and pancreatic TB, and patients should be referred to centres
providing these services.
Perianal TB is relatively uncommon, and the differential diagnosis includes a variety of conditions such as Crohn’s
disease, foreign body reactions, malignancy and sexually transmitted diseases. Careful assessment by specialists is advised.

15.3 Treatment
First line Drugs 2RHZE/4RHE
treatment Recommendation: 6 months ATT standard first-line regimen is recommended for abdominal TB.
for adults Strong recommendation, very low quality evidence
and
Duration Total treatment duration: 6 months, extended at the discretion of the treating clinician
children
with Referral Patients with presumptive GI, hepatobiliary, pancreatic or perianal TB will require referral to
abdominal a gastroenterologist for clinical assessment and diagnosis.
TB Patients with presumptive peritoneal TB where the diagnosis is uncertain also require referral.
Follow Assess response to treatment at 3 months and 6 months. Consider possible treatment failure in
up patients who have worsened or deteriorated after initial improvement – this requires diagnostic
investigation and possibly a change of treatment. Deterioration in the first 3 months may be due
to paradoxical reaction – this does not require repeat diagnostic tests or change of treatment.
Surgery Complications of GI TB include strictures that can cause acute and recurrent partial obstruction,
and perforation in some cases.
Strictures can be managed with endoscopic dilatation, but some cases require resection of the
stricture or hemicolectomy.
Oesophageal and gastroduodenal TB patients rarely require surgery; ATT alone is usually
adequate. Duodenal strictures may be treated with balloon dilatation. Bypass surgery may be
required if this is not successful.
Hepatobiliary or pancreatic TB patients who develop biliary obstruction may require endoscopic
or percutaneous biliary stenting. Liver abscess which fails to respond to treatment, or ruptured
abscesses may require surgical intervention.
Perianal TB cases with complex fistula may require surgical intervention.
 16 Urogenital TB

Urogenital TB refers to TB of the female and male genital tract and the urinary tract. It is usually an insidious disease,
and can lead to a variety of presentations depending on the affected site and stage of disease. Serious adverse outcomes
include infertility in both women and men, chronic pelvic pain, dysmenorrhoea, bladder dysfunction, renal failure and
death. Some (particularly female) patients may experience no symptoms at all other than infertility, meaning that a high
index of suspicion and careful clinical evaluation are needed to make the diagnosis.
Urogenital TB makes up approximately 4% of all EPTB cases annually in India. This may be an underestimate of the
true number of cases, as the difficulty of diagnosing the condition and lack of clear case definitions may be hampering
reporting of cases.
In this summary of the key practice points, forms of urogenital TB are divided into three broad categories:
• Urinary TB – referring to TB of the kidney, ureters and/or bladder
• Female genital TB – referring to TB of the uterus, fallopian tubes and/or ovaries
• Male genital TB – referring to TB of the epididymis and/or testes

16.1 Urinary TB
Patients who should be investigated for urinary TB

Presumptive A patient with lower urinary tract symptoms (frequency, urgency and nocturia) associated with dysuria
urinary TB and/or haematuria for at least 2 weeks, which has not responded to a 3–7 day course of antibiotics. Some
patients have systemic symptoms of fever, weight loss and night sweats.
Note: The use of fluoroquinolones in the treatment of UTI can reduce the sensitivity of subsequent tests
for Mtb in the urinary tract, and should therefore be avoided, unless an organism is identified in urine
cultures and antibiotic susceptibility test results support fluoroquinolone use.

Diagnosis

Test Patients Comments

X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest X-ray
to look for evidence of previous or active pulmonary TB.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
Renal function tests All An important complication of urinary TB is renal impairment. All patients should
have blood tests and calculation of estimated glomerular filtration rate (eGFR) to
detect this.
Renal impairment should prompt rapid assessment of the urinary tract using
ultrasound to look for outflow tract obstruction as a cause. This requires urgent
intervention with urinary catheterisation; or in the instance of hydronephrosis,
percutaneous nephrostomy or double J stent insertion to decompress the affected
kidney.
942 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Test Patients Comments

Urine microscopy All To identify sterile pyuria, which may suggest urinary TB
and culture for To diagnose active infection with other bacteria. The patient should be reassessed
non-mycobacterial after appropriate antibiotic treatment for symptom resolution. Superadded bacterial
organisms infection can occur with urinary TB.
Early morning urine All Three to five early morning urine samples collected for staining and microscopy
sampling for AFBs and culture for Mtb. While the sensitivity of these tests is low, culture
remains the most reliable way to confirm a diagnosis of urinary TB and allows drug
susceptibility testing to be carried out.
Ultrasound of the All This scan may be normal in early disease. It can help identify structural abnormalities
kidneys, ureters and such as hydronephrosis which can either suggest a diagnosis or guide further tests.
bladder (US KUB) It is non-invasive and well-tolerated.
Intravenous Selected This test also helps identify lesions in the urinary tract and has the advantage of
urography (using being widely available and cheap; however, it has low sensitivity for early lesions.
plain X-ray) Risks include contrast nephropathy (patients with renal impairment are at particular
risk), and contrast reaction (asthmatic patients and patients with cardiac failure may
be at higher risk).
Contrast-enhanced CT Selected This test is more sensitive than IV urography using plain X-rays for identifying and
urography characterising TB lesions in the urinary tract.
Risks include contrast nephropathy and contrast reaction. The relatively high dose
of ionizing radiation involved must be taken into account when considering this
test, particularly for children and women of childbearing age. It is contraindicated
in pregnant women.
MR urography Selected This test is also gives structural information about the urinary tract, and is sensitive
without contrast for identifying and characterising TB lesions.
It is more expensive and less accessible than plain X-ray and CT urography, but has
the advantage of not requiring intravenous contrast and not necessitating a dose of
radiation.
Pregnant women, children and patients with preexisting renal function may benefit
from this test.
FNAC Selected Where accessible mass lesions or fluid collections are identified on imaging,
radiologically guided aspiration with specimens subjected to staining and microscopy
for AFBs, culture and cytology may confirm the diagnosis of TB.
Urethrocystoscopy Selected Indicated when
with/without bladder • other less invasive tests are inconclusive
biopsy • bladder malignancy is also suspected
Although this is an invasive test, risk to the patient is low when carried out by an
experienced practitioner. Has the advantage of allowing visualisation of lesions and
targeted biopsy
Biopsy Most Biopsy of lesions in the urinary tract is required when
• other less invasive tests are inconclusive
• malignancy is also suspected
Specimens should be subject to: a) staining and microscopy for AFBs; b) culture and
drug susceptibility testing; c) histopathology

Treatment
Aims of treatment are:
• to achieve TB cure
• to prevent the long term sequelae
• to restore normal anatomy if it has been distorted.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 943

First line Drugs 2RHZE/4RHE

treatment for Duration Six months
adults and Referral Requires assessment by a urology team to perform specialist diagnostic tests and treat
children with structural urinary tract complications.
urinary TB
Urgent referral is required for patients presenting with renal failure secondary to bilateral
hydronephrosis.
Follow up Assess response to treatment at 8 weeks – resolution of systemic symptoms, improvement
in urinary symptoms, check renal function.
Repeat imaging may be indicated, especially if partial or impending ureteric stricture was
identified at diagnosis. Obstruction can occur as a late complication as the healing of the
lesion results in fibrotic stricture.
If early morning urine culture is positive at diagnosis, this may be repeated at 8 weeks,
and at the end of ATT.
Surgery Urgent surgical intervention is required when ureteric obstruction prevents drainage of
urine from the kidney, to prevent renal damage.
Reconstructive procedures are required when there are ureteric strictures or small capacity
bladder complicates urinary TB. Nephrectomy is rarely indicated, except where chronic
pain, hypertension, nephrocutaneous fistula or stone formation complicates a poorly- or
non-functioning kidney.

16.2 Female genital TB

Presentation is varied and a high index of clinical suspicion is required to make the diagnosis. Most cases of female
genital TB (FGTB) are found in premenopausal women, theoretically because an atrophic endometrium provides a poor
milieu for mycobacterial growth. Around 11% of patients present with no symptoms other than infertility, and these
patients require a diagnostic workup to look for all common causes of infertility. In patients with pelvic symptoms or
vaginal bleeding post menopause, malignancy is an important differential diagnosis to consider.

Patients who should be investigated for female genital TB

Presumptive A premenopausal woman presenting with infertility, menstrual problems, unexplained abdominal pain
FGTB or pelvic mass. Rarely, patients have systemic symptoms of fever, weight loss and night sweats. Ectopic
pregnancy and cervical/vulval lesions are rare presenting features.
A postmenopausal woman presenting with vaginal bleeding

Diagnosis

Test Patients Comments

X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest
X-ray to look for evidence of previous or active pulmonary TB.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counseling and testing.
Pregnancy test All of To rule out pregnancy as possible cause of symptoms, and to ensure further
childbearing testing is safe and appropriate
age
Pelvic ultrasound All Part of the initial assessment of most patients presenting with gynaecological
symptoms
Hysterosalpingogram Selected May be done as part of the investigation of infertility, but many women with
FGTB will have a normal HSG
CT pelvis or MRI Selected To further characterize lesions and plan surgical intervention in selected patients.
pelvis Disadvantage of CT is exposure to ionising radiation, which is particularly a
concern in women of childbearing age
944 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Test Patients Comments

FDG-PET CT Selected Although not widely available, PET scans may give more information about the
presence and activity of tubercular tubo-ovarian mass lesions. Further evidence
about the diagnostic accuracy of PET CT for detecting and monitoring the
progression of FGTB is needed.
Endometrial aspirate Selected Where facilities exist, endometrial aspirate can be obtained and sent for: a) staining
and microscopy for AFB; b) culture and drug susceptibility testing. Sensitivity is
low, and negative results cannot rule out FGTB.
Laparoscopy Selected Laparoscopy with biopsy of lesions is required when
• other less invasive tests are inconclusive
• malignancy is also suspected
• as part of infertility investigations when less invasive tests are inconclusive
Laparoscopy offers the dual advantage of pelvic organ visualization and
specimen collection from otherwise inaccessible sites. Specimens should be
subject to: a) staining and microscopy for AFBs; b) culture and drug susceptibility
testing; and c) histopathology.

Making a diagnosis
The group concluded that the diagnosis of FGTB should be made based on any one of:
• laparoscopic appearance typical for FGTB
• any gynaecological specimen positive for AFBs on microscopy or positive for Mtb on culture
• any gynaecological specimen with findings consistent with FGTB on histopathological examination.

Treatment
Aims of treatment:
• To achieve TB cure
• To prevent the long term sequelae
• To restore normal anatomy if has been distorted

First-line treatment Drugs 2RHZE/4RHE

for adults and Duration Six months
children with Referral Requires assessment by a gynaecologist to make the diagnosis and treat complications.
urinary TB Empirical ATT in women presenting with infertility alone should only be started
following assessment by a specialist.
Follow up Assess response to treatment at completion of 6 months’ ATT
Surgery Surgery is not part of primary treatment in FGTB; however, it is sometimes needed
for large, residual tubo-ovarian abscesses. Surgery in FGTB is associated with higher
complication rates as there are a lot of adhesions as well as the possibility of infection
recurrence.
Tubal anatomy can sometimes be restored surgically in infertile women following
a course of ATT. However, infertility may be an irreversible long-term consequence
of FGTB. Giving repeated courses of ATT to women who remain infertile following
completed ATT for FGTB is not necessary.

16.3 Male genital TB

Patients who should be investigated for male genital TB (MGTB)

Presumptive A patient with scrotal pain or swelling for 2 weeks or more not responding to a 7–14 day course of
MGTB antibiotics, or with discharging sinuses in the scrotum. Rarely, patients have systemic symptoms of fever,
weight loss and night sweats.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 945

Diagnosis

Test Patients Comments

X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest
X-ray to look for evidence of previous or active pulmonary TB.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated
counselling and testing.
Renal function tests All All patients with suspected MGTB must be evaluated for co-existent urinary TB
Urine microscopy (see above).
and culture for
nonmycobacterial
organisms
Early morning urine
sampling
Ultrasound of the
kidneys, ureters and
bladder (US KUB)
Ultrasound scan of All To evaluate swelling/mass lesions and guide FNAC
the scrotum
FNAC epididymal All Specimens should be subject to:
mass a. staining and microscopy for AFB;
b. culture and drug susceptibility testing; and
c. cytology
There is a risk of damaging the epididymis and causing infertility.
Biopsy Selected If FNAC does not confirm the diagnosis or malignancy is suspected, biopsy of
the lesion is indicated.
Specimens should be subject to:
a. staining and microscopy for AFBs;
b. culture and drug susceptibility testing;
c. histopathology

Treatment

First-line treatment Drugs 2RHZE/4RHE

for adults and Duration Six months
children with Referral All cases need evaluation by an urologist to make the diagnosis.
MGTB
Follow up Assess at 8 weeks to assess for response to treatment. Repeat FNAC/biopsy may
be required for mass lesions which continue to grow despite treatment (specialist
assessment required).
Surgery Surgery is not usually required, and is not a routine part of treatment. Epididymectomy
may be required if there is a caseating abscess which persists despite completing a
course of ATT.
Sequelae Infertility is a possible long-term complication of MGTB. Infertility following com­
pleted treatment for MGTB should not be interpreted as indicative of treatment failure
or recurrence of infection.

PCR-based tests in urogenital TB

Confirming the diagnosis in urogenital TB is very difficult. Often, invasive procedures must be done to obtain specimens.
Conventional diagnostic methods (microscopy and culture) have low sensitivity.
946 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

PCR-based tests (either commercially available or in-house assays) are increasingly used to diagnose FGTB. A literature
review prepared for this guideline found that estimates of sensitivity and specificity varied widely across reports in the
literature, and the Technical Advisory Subcommittee for FGTB raised concerns about their experience of high rates of
false positives when these tests are applied to peritoneal/gynaecological specimens. There were no data at the time
of publication looking at the use of Xpert MTB/RIF for the diagnosis of FGTB. The guideline group decided that a
recommendation was not possible at this time regarding the use of PCR-based tests in FGTB, and noted that high quality
diagnostic test accuracy studies are needed to address this question.
Similarly, further evidence is needed on the diagnostic test accuracy of Xpert MTB/RIF and other PCR-based tests on
urine, FNA aspirates and biopsy specimens for the diagnosis of urinary TB or MGTB. Again, the expert group acknowledged
that while these tests are in current use, the guideline group could not make a recommendation about their use at the
present time.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 947

17 Spinal TB and other forms

of bone and joint TB

TB infection of the bones and joints causes chronic pain, deformity and disability, and TB of the cervical spine can be life
threatening. Bone and joint TB makes up around 10% of all EPTB cases, with spinal TB being the most common form
(Sharma S.K., 2004). Around 1–2% of all TB cases worldwide are spinal TB cases (Watts, 1996). Both adults and children
can be affected.
Since it is the most common and most disabling form, spinal TB is covered in detail here, with key practice points at
the end about TB affecting other parts of the skeletal system.

17.1 TB of the spine

Presumptive A patient with localized back pain for more than 6 weeks with tenderness on examination of the spinous
spinal TB processes, fever and weight loss, with or without signs of spinal cord compression. Patients with advanced
disease may have severe pain, spinal deformity, paraspinal muscle wasting and neurological deficit.
In addition in children, failure to thrive, night cries, inability to walk/cautious gait, and use of hands to
support the head or trunk are important signs.

Diagnosis

Test Patients Comments

X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest X-ray.
HIV test All EPTB is associated with HIV infection. All patients should be offered VCT.
X-ray of spine Limited Spinal lesions take 3 to 6 months to appear on plain X-ray, so this test is of limited use
use in the early stages of the disease. However, X-rays are useful to evaluate treatment
response on follow up.
MRI spine All All patients with suspected TB spine require an MRI to assess the extent of disease and
the degree of bony destruction, and confirm spinal cord involvement in patients with
neurological signs. MRI is useful in making a diagnosis in the early stages of disease
while some MRI appearances are highly suggestive of a diagnosis of spinal TB (Jain, 2012).
CT spine Selected Some patients may require CT of the spine in addition to MRI, although CT cannot be
used to detect early spinal cord involvement.
Biopsy of the All The INDEX-TB guidelines TAC subcommittee for bone and joint TB assert that in
lesion TB endemic areas, it is reasonable to start ATT in patients with strong clinical and
radiological/MRI evidence of TB of the spine and monitor their progress. Where possible,
all patients should have a biopsy of the lesion to provide a specimen for culture to confirm
the diagnosis and perform drug susceptibility testing, and to rule out other diagnoses.
Percutaneous CT-guided biopsy is preferred, but some patients may require open biopsy.
The risks and benefits of obtaining a biopsy must be considered.
Specimens should be sent for: a) Microscopy and culture for pyogenic bacteria;
b) Microscopy and culture for Mtb; and c) histopathology/cytology.
There is currently insufficient evidence surrounding the use of PCR-based tests such
as Xpert MTB/RIF in the diagnosis of TB of the bones and joints.
948 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Treatment

There is uncertainty surrounding the optimum duration of treatment for TB of the bones and joints. Some older trials
suggested that 6 months treatment may be sufficient, but more advanced diagnostic imaging has led to uncertainty
whether these patients are cured for spinal TB at the end of that time. The TAC subcommittee performed a brief review
of the literature to inform their decision regarding duration of treatment in bone and joint TB; a systematic review was
not performed. The group found that there is a lack of consensus about what constitutes healed status in the literature.
The expert group agreed that all cases of bone and joint TB should be treated with extended courses of ATT with a
2-month intensive phase consisting of four drugs (isoniazid, rifampicin, pyrazinamide and ethambutol), followed by a
continuation phase lasting 10–16 months, depending on the site of disease and the patient’s clinical course.

Drugs 2RHZE/10RHE
All patients require close monitoring for development or progression of neurological deficit
in the first 4 weeks of treatment.
Some patients require surgical intervention.
Duration Total treatment duration: 12 months (extendable to 18 months on a case-bycase basis)
Referral Optimum management of spinal TB requires the involvement of multiple specialists including
a spinal orthopaedic surgeon, microbiologist/infectious diseases specialist and spinal
radiologist, as well as physiotherapists and orthotists. All presumptive spinal TB cases should
be referred and managed in specialist centres.
Follow up Patients without neurological deficit should be advised to return to the clinic immediately if
new symptoms develop, and all ambulant patients should be assessed weekly for neurological
signs.
Patients with neurological deficit require staging and grading of their deficit. These patients
should be assessed weekly with neural charting to detect neural recovery or deterioration.
Repeat X-rays of the spine are suggested every 3 months following initiation of treatment to
assess for radiological healing.
Repeat MRI scans are suggested at 6, 9, 12 and 18 months following initiation of treatment
to assess healing.
At the end of treatment, all patients require follow up every 6 months for at least 2 years, and
should be told to return to the clinic promptly if they develop new symptoms in the interim.
Surgery While some require early surgical intervention, most patients can be managed with ATT
alone in the initial phase of treatment.
Surgery may be required for two principal purposes in spinal TB-to establish diagnosis, or
to treat spinal deformity, instability and neurological deficit.
Where available, percutaneous biopsy under CT guidance reduces the need for open biopsy,
but this may still be required in some cases, particularly where imaging results are atypical
for spinal TB and the diagnosis is uncertain.
Patients with large, fluctuant cold abscesses may require therapeutic aspiration to relieve
symptoms and promote healing.
Indications for surgery in TB spine with neurological deficit:
• Neural complications developing or getting worse or remaining stationary during the
course of non-operative treatment (3–4 weeks)
• Paraplegia of rapid onset
• Spinal tumour syndrome
• Neural arch disease
• Severe paraplegia – flaccid paraplegia, paraplegia in flexion, complete sensory loss and
complete loss of motor power for more than 6 months
• Painful paraplegia in elderly patients.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 949

Indications for surgery in spinal TB without neurological deficit:

• When diagnosis is uncertain and open biopsy is indicated
• Mechanical instability – panvertebral disease, where bony involvement of both the
vertebral body and posterior complex is seen on imaging, or disease affects facet joints
bilaterally
• Suspected drug resistance – where patients show inadequate clinical improvement or
deterioration on ATT
• Spinal deformity – severe kyphotic deformity at presentation, or in children at high risk of
progression of kyphosis with growth after healing of disease.
Surgery • Indications for instrumented stabilization:
• Panvertebral disease
• Long segment disease where a > 4–5 cm long graft is required to bridge the gap after
surgical decompression in dorsal spine
• In lumbar and cervical spine
• When kyphosis correction surgery is contemplated
• Lesion in a junctional area.
Sequelae Early onset paraplegia:
Some patients have paraplegia secondary to acute inflammation in and around the cord in
early disease. This generally carries a good prognosis with prompt treatment with ATT. MRI
and intraoperative findings suggestive of extradural fluid compressing the cord, cord oedema
or myelitis generally correlate with neural recovery.
Late onset paraplegia:
This is defined as the reappearance of neural deficit after a disease-free period of at least 2
years in patients who completed ATT and achieved healed status with a residual kyphotic
deformity. This can occur as a result of progression of deformity in healed patients, or as a
result of relapse of active TB infection. These two scenarios necessitate different treatment
and carry different prognoses. Expert management is required.
Deformity:
Bony destruction and subsequent healing leads to deformity, which will depend on the
site and extent of infection. Some deformity requires surgical correction to prevent further
progression or restore function. There is debate over the optimum timing of surgery to correct
deformity, but the group agreed that surgery should preferably take place during treatment
with ATT for active TB infection.

17.2 TB of the appendicular skeleton

TB of the bones and joints can affect people of any age, but some forms are seen more frequently in children.
Risk factors include previous TB infection, immunosuppression caused by conditions such as HIV, diabetes mellitus
and chronic liver or kidney failure, among others; or by immunosuppressive drugs such as long-term corticosteroids.
Key principles of diagnosing TB of the bones and joints are:
• Suspect TB as a possible cause in people with signs of joint infection with an insidious onset
• Refer to an orthopaedic team who can assess the joint and perform a biopsy for culture (for M. tuberculosis as well as
other organisms) and histopathology
• All patients should have specimens taken for microscopy and culture where possible
Invasive diagnostic procedures are not always practicable, and in such circumstances the treating clinician must use his
judgement as to whether treatment with ATT should be started without a microbiological/histopathological diagnosis,
or whether a period of observation is appropriate. The INDEX-TB guidelines TAC subcommittee for bone and joint TB
assert that in TB-endemic areas, it is reasonable to start ATT in patients with strong clinical and radiological evidence of
TB of the bones and joints and monitor their progress. Where the diagnosis is uncertain, tissue specimens are required
before giving ATT.
950 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Where possible and safe for the patient, getting specimens for microscopy, culture and histopathology prior to starting
ATT is beneficial because:
• positive culture confirms the diagnosis
• drug susceptibility testing can be carried out to guide ATT
• false negative culture results are more likely if specimens are taken after ATT has been started
• alternative diagnoses can be picked up.
When taking specimens for microbiological testing and histopathology, the following principles are important:
• Early in the course of TB joint infection, aspiration of fluid from the joint will not usually yield a diagnosis, and so tissue
biopsy of the affected structures is preferred. This may be done under radiological guidance, using arthroscopy, or
via open surgical biopsy. Arthroscopy with biopsy offers the advantage of visualization of the lesion with excision of
affected tissue for diagnostic testing, and simultaneous therapeutic intervention if required.
• Fluid or pus from joint aspirates, and pus from collections/cold abscesses should also be sent for microscopy and
culture.
• Enlarged lymph nodes regional to the infected site may also be considered for biopsy/FNAC.
• Sinus tract curettage/edge biopsy may also be sent for culture and histopathology, but microbiological results should
be interpreted with caution as contamination/colonization/secondary infection with skin commensals or coliforms is
common.
• As a general principle, specimens for culture should be collected whenever a therapeutic invasive procedure is
carried out, e.g. when a joint is debrided following unsuccessful non-operative management.
• Specimens should be sent for
– microscopy and culture for non-mycobacterial pathogens (pyogenic bacteria, Brucella, fungal species)
– microscopy and culture for TB
– histopathology.
This table lists the presenting features of TB of the joints, with basic information about diagnosis and treatment. This section
is based on the expert opinion of the INDEX-TB TAC subcommittee for bone and joint TB.

Hand and wrist Identify:

Hand and wrist More common in children under 5 years, but can affect any age group
Patients present with a variety of features depending on the site of infection. The hand
or wrist gradually becomes painful and/or swollen with joint effusions and synovial
thickening, causing boggy swelling with restricted range of motion. Systemic symptoms
such as fever, weight loss, anorexia and regional lymphadenopathy may be present. In
advanced disease, wasting of the muscles of the hand and forearm, deformity, enlargement
of digits/metacarpals (sausage finger/spina ventosa), discharging sinuses, cold abscess and
compound palmar ganglia may be present. Rarely, patients have carpal tunnel syndrome,
or nail involvement.
Diagnose:
Early X-ray changes are subtle and easily missed, but later in the disease sequential X-ray
changes are seen which can be used to classify the disease (Martini M, 1986). USS, CT and
MRI features are non-specific but these modalities may be used to assess extent of disease
or identify biopsy sites or drainable collections.
Treat:
2RHZE/10–16RHE with rest to the joint provided by immobilisation in plaster/brace for
4 to 6 weeks followed by gradual mobilisation as tolerated (specialist management by upper
limb orthopaedic surgeon required). Surgery is rarely needed, but may be indicated for nerve
compression, impending bone collapse, joint debridement, drainage of large abscesses and
correction of deformity in healed disease.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 951

Elbow Identify:
Can affect any age group
Patients present with a variety of features depending on the site of infection. The elbow
gradually becomes painful and/or swollen with joint effusions and synovial thickening,
causing boggy swelling with restricted range of motion. Systemic symptoms such as fever,
weight loss, anorexia and regional lymphadenopathy may be present. Rarely, ulnar nerve
or posterior interosseous nerve palsies may be the presenting feature. In advanced disease,
wasting of the arm and forearm muscles, deformity on flexion/extension, pathological
dislocation, discharging sinuses and cold abscesses may develop.
Diagnose:
See Hand and wrist TB
Treat:
See Hand and wrist TB
Shoulder Identify:
Can affect all ages, but is more common in adults than children. Relatively rare, it usually
presents in the advanced stage with disabling symptoms that may mimic more common
pathologies such as neuropathic shoulder, rheumatoid arthritis, and adhesive capsulitis. A
high index of suspicion and careful clinical evaluation are required to make the diagnosis.
Patients present with pain in the shoulder and restricted range of motion (particularly
limited external rotation and abduction), with muscle wasting (particularly deltoid and
supraspinatus). Systemic symptoms such as fever, weight loss, anorexia and lymphadenopathy
are uncommon, as is swelling of the joint. In advanced disease, there may be marked
destruction of the humeral head and glenoid with muscle atrophy, or deformity (particularly,
fibrous ankylosis with humeral head pulled up against the glenoid and the arm fixed in
adduction and internal rotation). Discharging sinuses around shoulder, arm and scapula
and cold abscess are uncommon. “Caries sicca” is the most common form – which is a dry
arthropathy (rather than exudative).
Diagnose:
See Hand and wrist TB.
In early disease, arthroscopic biopsy offers the advantage of direct visualization of joint,
allowing excision of tubercular synovium, granulation tissue, rice bodies and pannus
over cartilage. However, in advanced disease where arthroscopy is not feasible, an open
debridement and biopsy is indicated.
Treat:
2RHZE/10-16RHE with rest in sling or brace and gentle mobilization as tolerated. Prolonged
immobilisation with spica is no longer widely advocated. Surgery is rarely needed, but may
be indicated for drainage of large abscess, excision of persistent sinuses, joint debridement
to remove loose bodies and pannus, arthrodesis to relieve a painful fibrous ankylosis,
or joint replacement in healed disease with severe joint destruction. Resection arthroplasty
has not been shown to improve outcomes, and should be avoided in favour of nonoperative
treatment even in cases with severe bony destruction at diagnosis.
Hip Identify:
Can affect any age, but most common in children and young adults
There are three stages in the course of the disease:
1. Synovitis. Characterized by gradual onset of hip pain and limping (antalgic gait) with
fullness around the hip caused by joint effusion, restricted range of movement and
deformity (the affected limb is flexed, abducted and externally rotated with apparent
lengthening of the extremity).
952 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

2. Early arthritis. Characterized by progression of bony destruction leading to deformity

with the limb flexed, adducted and internally rotated with apparent limb shortening.
There is pain with every hip movement, with muscle spasm and atrophy.
3. Advanced arthritis. Characterized by very painful joint movements and grossly restricted
range of movement with shortening of the limb. Pathological dislocation or subluxation
may occur due to bony destruction at the acetabulum/femoral head. The attitude of the
limb and deformity does not always correlate with the stage of arthritis.
Hip Diagnose:
1. Synovitis stage. X-ray changes and US appearance, with aspiration of the joint effusion
for microscopy, AFB smear and culture may provide sufficient information in high TB
burden areas to start treatment. MRI scan can give more information about the extent of
the disease. Biopsy should be carried out if there is uncertainty about diagnosis.
2. Early arthritis. Radiographic changes with biopsy
3. Advanced arthritis. Radiographic changes with biopsy
Treat:
1. Synovitis. 2RHZE/10–16RHE with appropriate analgesia and rest to the joint in above-
knee skin traction or skeletal traction for around 4 weeks. Active assisted exercises to
mobilize thereafter. Surgery is rarely required.
2. Early arthritis. 2RHZE/10–16RHE with appropriate analgesia and rest to the joint in
above-knee skin traction or skeletal traction until spasm is relieved, and non-weight
bearing exercises as tolerated.
S ynovectomy
  and joint debridement are sometimes indicated if the response to
nonoperative treatment is inadequate at 6 to 8 weeks. Drainage of large joint effusions
or abscesses may be required. Send specimens for culture.
3.  dvanced arthritis. 2RHZE/10-16RHE with appropriate analgesia and rest to the joint
A
in traction. Arthrolysis with joint debridement is usually indicated, followed by a period
of skeletal traction, with early supervised mobilization of the hip as tolerated.
4. Advanced arthritis with subluxation/dislocation. 2RHZE/10–16RHE with appropriate
analgesia and rest to the joint in traction. Gross bony destruction at this stage requires
surgical management with excision arthroplasty, arthrodesis or total hip replacement.
Knee Identify:
Can affect any age group
Patients present with a painful, swollen, tender knee which may be warm to touch, with
limping and reduced range of motion. Systemic symptoms of fever, weight loss and anorexia
may be present, with regional lymphadenopathy on examination. In advanced disease, the
joint may feel boggy due to synovial thickening, with joint effusion and wasting of the thigh
muscles. Discharging sinuses or cold abscess may be seen. Deformity ranging from a mild
flexion deformity to severe triple deformity consisting of flexion, posterior subluxation,
external rotation and valgus may be present.
Diagnose:
X-ray changes are non-specific in early disease, with progressive changes in late disease, which
can be used to classify the stage of disease. MRI changes can be highly suggestive of TB of
the knee. Diagnosis is confirmed with microscopy, culture and histopathological examination
of US-guided/arthroscopic/open surgical biopsy of the synovium.
Treat:
1. Synovitis stage. 2RHZE/10–16RHE with rest to the joint in traction to prevent flexion
deformity with gentle mobilization for 6 weeks, and then reassess. Arthroscopic or open
joint debridement may be necessary in some cases if there is little improvement with
nonoperative treatment.
 Index-TB Guidelines [Guidelines on Extra-pulmonary Tuberculosis for India] 953

2. Early arthritis stage. 2RHZE/10–16RHE with rest to the joint in double traction to prevent
triple deformity. Joint debridement is usually necessary, with corrective plaster/bracing
following surgery if joint is unstable.
3. Advanced arthritis stage. In children, 2RHZE/10– 16RHE with rest to the joint in double
traction, followed by corrective plaster, with arthrodesis deferred until growth is complete.
In adults, with painful arthritic knee or fibrous ankylosis, arthrodesis by compression is
often necessary.
4. Healed tubercular knee with deformity. Corrective osteotomy or total knee replacement
may be necessary to restore normal alignment and improve function.
Ankle Identify:
More common in children and young adults, but can affect any age group
Patients present with a slow-onset painful, swollen ankle with pain on weight bearing
causing a limp, and a history of weight loss, anorexia and fever. On examination, the joint
may be warm, red and tender, boggy to palpate due to synovial thickening, with regional
lymphadenopathy and restricted range of motion. In advanced disease, calf muscle wasting,
effusion, deformity and discharging sinuses may be seen.
Differential diagnoses: non-mycobacterial septic joint, neoplastic lesion, e.g. chondroblastoma
in children.
Diagnose:
X-ray features are non-specific, and are subtle in early disease. MRI and CT scan may
demonstrate changes, but these are not specific to TB.
Treat:
2RHZE/10–16RHE with rest to the joint in a functional position (in plaster/ankle-foot
orthoses) for 4–6 weeks followed by gentle non weight-bearing mobilization as tolerated.
Surgery is rarely required, but is indicated for impending bone collapse, large abscess, or
correction of deformity in healed patients.
Foot Identify:
More common in children and young adults, but can affect any age group
Patients present with slow-onset pain, swelling of the foot and a limp. Specific features depend
on which bones are involved, e.g. TB of the calcaneus causing heel-up limp and tenderness
over heel. Systemic features such as fever, weight loss and lymphadenopathy are uncommon.
In advanced disease, there may be effusion, synovial thickening, deformity (caused by collapse
of tarsal bone), discharging sinuses or a cold abscess.
Diagnose:
As for Ankle TB
Treat:
As for Ankle TB

Outcomes
Healed status
For patients with a diagnosis of confirmed/probable bone TB, healed status is determined by:
• completion of ATT and no relapse of disease at 2 years’ follow up
• resolution of fever, night sweats, weight loss (if initially present)
• resolution of sinuses/ulcers (if initially present)
• radiological signs of bone healing, including remineralisation of affected bone, sharpening of joint/vertebral margins.
On MRI, resolution of marrow oedema, fatty replacement in marrow and no contrast enhancement
954 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Presumptive treatment failure

For patients with a diagnosis of bacteriologically confirmed or clinically diagnosed bone TB, treatment failure should be
suspected when they have any of the following after completing at least 5 months’ ATT:
• Persisting or worsening local and systemic symptoms and signs
• No improvement, or deterioration of the lesion on repeat imaging
• Appearance of new lesion(s)
• Non-healing ulcer/sinus
• New abscesses/lymphadenopathy
• Wound dehiscence post-operatively.
Possible causes of deterioration on treatment or failure to improve on treatment:
• Poor adherence to ATT – inadequately treated skeletal TB
• Drug resistance
• Paradoxical reaction
• Immune reconstitution syndrome associated with HIV
• Alternative diagnosis – patient does not have TB or has two diagnoses.
Suggested investigations in patients with presumptive treatment failure:
• Complete blood count and inflammatory markers such as ESR, liver enzymes, urea and electrolytes, fasting blood
glucose/HbA1c and HIV test
• Repeat imaging and repeat diagnostic sampling, for example CT-guided biopsy of the lesion
• Send tissue for: a) staining for AFB and culture for Mtb with drug susceptibility testing; b) Gram’s stain and bacterial
and fungal culture; c) histopathology. PCR-based diagnostic tests are of variable sensitivity in bone TB, and there is
uncertainty about specificity in previously treated TB patients.
The expert group suggests that patients with bacteriologically confirmed or clinically diagnosed treatment failure be treated
with second-line drugs. For patients with bacteriologically confirmed treatment failure, treatment should be guided by
drug susceptibility testing. For clinically diagnosed treatment failure, the specialist team should carefully monitor empirical
treatment with second-line drugs.

Paradoxical reaction
A patient with confirmed or probable skeletal TB on ATT who initially improves and then subsequently has worsening
constitutional symptoms or signs of TB in the absence of another diagnosis or drug resistance. Features include increased
size of lesion, appearance of new lesions, recurrent fever and night sweats, or development of another form of TB.
In drug-resistant cases, the patient will usually fail to improve from the start of ATT, or deteriorate from the start of
ATT. There will be no improvement until an effective second-line ATT regimen is started.
In paradoxical reaction, there is usually an initial improvement, followed by deterioration. The patient will usually
begin to improve again without changes to the ATT regimen; ATT should not be stopped or altered. NSAIDs and other
supportive treatment are usually sufficient.
 18 Cutaneous TB

Cutaneous TB is caused by M. tuberculosis, M. bovis, and, rarely, Bacille Calmette-Guerin (BCG). TB of the skin is
uncommon, accounting for around 1.5% of EPTB cases. Cutaneous TB often coexists with other forms of TB, especially
pulmonary TB and lymph node TB.
Scrofuloderma and lupus vulgaris are the most common manifestations of cutaneous TB, and are particularly
prevalent in children. The manifestations of cutaneous TB are summarized in the table below (Tappeiner, 2008).
Although it is not life threatening, cutaneous TB can cause profound distress to the patient due discomfort and
disfigurement if not adequately treated. As some manifestations mimic other skin diseases, it can be difficult to diagnose,
and patients may have received unnecessary or inappropriate treatment from several practitioners before the correct
diagnosis is made. Evaluation by an experienced dermatologist is crucial if the diagnosis is not clear.

Clinical disease Aetiology Host immune status

Lupus vulgaris Haematogenous spread Can affect immunocompetent or
Scrofuloderma immunocompromised people
Acute miliary TB Haematogenous spread Usually seen in immunocompromised
Orificial TB people
Metastatic tuberculous abscess
(tuberculous gumma)
Primary Inoculation TB Inoculation of the skin with Mtb, e.g. by No previous TB infection,
needle stick injury, or at site of trauma immunocompetent
Tuberculosis verrucosa cutis Inoculation of the skin with Mtb, e.g. by Previous TB infection,
needle stick injury, or at site of trauma immunocompetent
Normal primary complex-like reaction BCG innoculation No previous TB infection
Post-vaccination lupus vulgaris
Perforating regional adenitis
Lichen scrofulosorum True tuberculids – thought to represent Not clear; likely some immunity due
Papulonecrotic tuberculid hypersensitivity reactions, rather than to previous exposure
local TB infection of the skin
Nodular vasculitis (erythema Facultative tuberculids – Mtb may Not clear; likely some immunity due
induratum of Bazin) be one of several aetiological agents to previous exposure
Erythema nodosum causing this pathology

18.1 Patients who should be investigated for cutaneous TB

Presumptive Patients with the following clinical presentations:

cutaneous TB • Ulcers or discharging sinuses over the sites of lymph nodes, bones and joints
• Persistent, asymptomatic raised reddish/reddish brown skin lesion of more than 6 months’
duration, which may show scarring at one end
• Persistent warty skin lesion of more than 6 months’ duration
956 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

18.2 Diagnosis

Test Patients Comments

X-ray of chest All All patients presenting with symptoms consistent with TB should have a chest X-ray to
look for previous or active pulmonary TB.
HIV test All EPTB is associated with HIV infection. All patients should be offered integrated counselling
and testing.
Further Selected All patients require clinical assessment for TB affecting other organ systems such as the
radiological chest, abdomen, lymph nodes, bones and joints and CNS. Radiological evaluation should
tests be focused according to the history and examination findings.
Skin biopsy All Skin biopsy is required to determine the aetiology of the lesion.
Histopathological examination by an experienced specialist remains the most reliable way
of making the diagnosis.
Staining and microscopy for AFB has very low sensitivity.
Culture has low sensitivity; but if positive, confirms the diagnosis of cutaneous TB and
facilitates drug susceptibility testing
PCR-based tests are in use with variable diagnostic accuracy, but a lack of evidence from
high quality studies means they cannot be recommended for routine use currently.
Mantoux test Selected The Mantoux test is not usually part of the diagnosis of active TB infection. However,
(tuberculin the Cutaneous TB Group agreed that in selected cases where diagnosis was equivocal,
skin testing) it might be used as an ancillary test. However, only a strongly positive result (with
a diameter of 22 mm or more at reading) supports a diagnosis of cutaneous TB
(Ramam, 2011). A negative or weakly positive result does not rule out TB. Sensitivity and
specificity estimates for this test vary widely across case series, and the result must be
interpreted in the context of the other clinical findings.

18.3 Treatment
All patients with the following results should be treated for cutaneous TB:
• Patients with histology diagnostic of cutaneous TB
• Patients with positive culture of Mtb or microscopy for AFBs from skin biopsy
• Patients with equivocal histology findings and negative microscopy and culture, but strongly positive Mantoux test

First line Drugs 2RHZE/4RHE

treatment for Duration 6 months
adults and Referral Referral to a dermatologist for diagnosis and management is encouraged. Physicians in
children with primary or secondary care can used teledermatology services to guide referral decisions.
TB pericarditis
Complex cases where the diagnosis is uncertain or the response to ATT is inadequate may
require referral to a specialist centre.
Follow up Assess response to treatment at 4–6 weeks. Most patients will show significant improvement
by this time. Failure to improve or deterioration may be due to misdiagnosis or drug
resistance. Specialist referral is advised for such patients.
Subsequent follow up of patients responding to treatment can continue at 8 weekly intervals
until treatment is completed.
Sequelae Scarring caused by the initial infection and then healing of the skin can cause disfigurement.
There is an increased risk of squamous cell carcinoma in patients with long-standing
untreated disease.
 19 Special groups

Pregnant and breast-feeding women may be treated with RHZE with pyridoxine 10 mg daily, as for other patients. There is
no need to cease breast feeding. Some drugs used in secondary regimens such as streptomycin, prothionamide, ethionamide
and the quinolones are contraindicated due to teratogenicity.
Women who need contraception should be counselled on the use of oral contraceptives while receiving rifampicin. Women
should be offered an oral contraceptive pill containing a higher dose of oestrogen (50 μg) after consultation with a clinician,
or a non-hormonal method of contraception while taking rifampicin and for 1 month after the end of treatment.
Patients with kidney impairment may need dose titration of some ATT drugs, and may not tolerate certain drugs at all.
Specialist guidance is recommended. There are specialist guidelines for patients with chronic kidney disease elsewhere,
such as the British Thoracic Society Guidelines for the Prevention and Management of TB infection in Adult Patients with
Chronic Kidney Disease (British Thoracic Society Standards of Care Committee and Joint TB Committee, 2010).
Patients with previous liver disease such as history of acute hepatitis or current alcoholic or non-alcoholic fatty liver
disease do not require changes to standard first-line treatment. Patients with acute hepatitis and a non-life-threatening
form of EPTB should have treatment with ATT deferred until liver function tests normalize. If EPTB is life threatening,
e.g. TB meningitis, specialist advice to select an ATT regimen, which contains the least hepatotoxic drugs, is required.
There is uncertainty around the safety of the standard first-line regimen in patients with liver cirrhosis. People with more
advanced liver cirrhosis (Child’s B and C liver disease) may be at increased risk of drug-induced hepatoxicity (Sharma,
2015).
The WHO guidelines recommend that the number of hepatotoxic drugs used in this setting should depend on the severity
of liver disease (WHO, 2010). The following possible regimens are suggested, after consultation with expert clinicians. The
choice of regimen depends on the balance of risks and harms relating to effective treatment of TB and prevention of liver
injury.
Regimens containing two hepatotoxic drugs (rather than the three in the standard regimen):
• Nine months of isoniazid and rifampicin, plus ethambutol (until or unless isoniazid susceptibility is documented)
• Two months of isoniazid, rifampicin, streptomycin and ethambutol, followed by 6 months of isoniazid and rifampicin
• Six to nine months of rifampicin, pyrazinamide and ethambutol
Regimens containing one hepatotoxic drug:
• Two months of isoniazid, ethambutol and streptomycin, followed by 10 months of isoniazid and ethambutol.
Regimens containing no hepatotoxic drugs:
• Eighteen to twenty-four months of streptomycin, ethambutol and a fluoroquinolone

People with HIV

TB and HIV disease are linked, and identifying people who have both conditions is important to improve outcomes. All
EPTB patients should be offered an HIV test as part of their diagnostic process. People with HIV require specialist advice
and support pertaining to their diagnosis and treatment options.
958 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

HIV-positive people are more likely to have disseminated TB infection at presentation. More detailed diagnostic tests
to look for other opportunistic infections and to assess the extent of disease may be useful.
There is increasing evidence that newer diagnostic tests for TB, including Xpert MTB/RIF, have different diagnostic
test accuracy in people with advanced HIV and low CD4 counts. These guidelines have not addressed this issue in detail,
but information about this can be found elsewhere in the literature.
HIV-positive people are at higher risk of paradoxical reactions, or immune reconstitution inflammatory syndrome (IRIS),
and these reactions may be lifethreatening. The decision to commence ART must also be considered in patients who are
not already receiving it. Guidance on initiation of ART can be found elsewhere at: BHIVA guidelines 2011 (Pozniak, 2011);
Rapid Advice on ART for HIV infection in adolescents and adults (WHO, 2009); Guideline on when to start ART and on
pre-exposure prophylaxis for HIV (WHO, 2015).
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 Index
Page numbers followed by f refer to figure and t refer to table.

A Acute respiratory distress syndrome 125, 126, American Thoracic Society 638
323, 432-436, 437f, 439 Amikacin 386, 560, 562, 618, 623
Abacavir 474, 475 diagnosis of 432, 432t, 438 Amino acid 74, 81
Abdomen epidemiology 435 Amino salicylic acid 458
doughy feel of 357 management 440 Aminoglycosides 384, 610, 627
ultrasonography of 215 pathogenesis 432 Amniotic fluid 31
Abdominal distension 209, 215 predisposing factors 435 Amyloidosis 163, 428
Abdominal lymph nodes, tuberculosis of 208 prognosis 440 secondary 419, 496
Abdominal pain 215, 394, 638 tuberculosis and 432-441 Anaemia 148, 209, 395, 442, 443, 448, 630
acute 456 Addison’s disease 77, 455 drug-induced 443
Abdominal tuberculosis 40, 129, 208-221, 496, Addisonian crisis 456 in tuberculosis, aetiological factors for 443t
498f, 505 Additive toxicities 475t Anal canal 214
classification of 208t Adenocarcinoma 496 Aneurysmal phenomenon 271
complications 41 Adenosine Angiopoietin-2 433
diagnostic criteria for 213 deaminase 109, 179, 180, 186, 215, 513 Angiotensin converting enzyme 185
differential diagnosis 41 monophosphate, cyclic 736 Ankle and foot, tuberculosis of 282
role of surgery 496 triphosphate 597 clinical features 282
treatment 217 Adhesiolysis 499 management 283
Abdominal vague 357 Adrenal glands, tuberculosis of 135 pathology 282
Abdominal wall, discharging sinus in 554f Adrenocorticotrophic hormone 456 radiographic features 282
Abortion 326, 365 Adverse drug reaction 472, 513, 626t Ankle joint 298f
Abscess 142 Advocacy communication and social contrast-enhanced MRI of 298f
Bartholin 357 mobilisation 722 Ankylosed wrist 289f
Brodie’s 292 Aerosol infection 95 Ankylosing spondylitis 77
collar-stud 314 AFB See Acid-fast bacilli Anorectal tuberculosis 131
complete resolution of 363f Ageing and immunosenescence 509 Anorexia 280, 394, 510f
drainage 522 AIDS See Acquired immunodeficiency syndrome Ansamycins 561
fungal 247, 247t Air Anthracofibrosis 151, 165
intra-abdominal 210 cleaners, in-room 525 Anti-aspergillus IgG antibodies 152
metastatic 392 crescent’ sign 126f Antibiotics, inhaled 582
para-articular cold 294 filtration and disinfection 525 Antidiabetic drugs 460
paravertebral 139f, 175, 271f, 271 Airborne Antidiuretic hormone 512
perinephric 496 infections, control 762 Antigen detection 235
prevertebral 139f, 326, 328f transmission Anti-hypertensive drug prescription 385
psoas 139, 401f of tuberculosis, reducing 763, 763t Antimicrobial resistance, surveillance of 610
pus from cold 403 strategies for reducing 761, 763 Antimycobacterial antibodies 235
pyogenic 132, 247, 247t tuberculosis transmission 759, 760 Antimycobacterial effector functions,
retropharyngeal 327 and infection control strategies 759-767 free radical-based 61
scrotal 370 Air-bronchogram 437f Anti-retroviral drugs 19, 405, 476
subcutaneous 309 Air-fluid levels 122 classification of 472t
type of 247 Airway side effects of 475t
Acetabulum and granulation tissues, complications 126 Anti-retroviral therapy 468, 472, 474
destruction of 276f in autopsy 160 goals of 472t
Acid-fast bacilli 27, 29, 109, 112, 156, 162, 177f, involvement 114, 123 highly active 473
186, 303, 308f, 488, 490, 524, 551, 586, malacia 167 Anti-retroviral treatment 632
627 obstruction, major 500, 501 provision of 15
smear preparation 764 stenosis 165 Anti-tuberculosis
Acidic environment 216 stents 168 immunity 731
Acquired immunodeficiency syndrome 10, 25, trauma 168 medicines 15
30, 92, 113, 175, 208, 222, 226, 227, Alanine amino transferase 638 pathogenesis of 637
227t, 231, 313, 326, 335, 368, 448, 468, Albumin 599 Anti-tuberculosis drug 5, 214, 276, 342, 440, 458,
473, 533, 545, 609, 681, 685, 690, 692, Alcohol 639 621, 624, 626t, 747
697, 712, 713 Alimentary tract 32 absorption of 385
clinical trials group 473 All India Organisation of Chemists and classification of 623t
related deaths 468 Druggists 681 effects of 295
Acromioclavicular joint, tuberculosis of 290 Allergic bronchopulmonary aspergillosis 123, 152 for adults, doses of first-line 625t
Actinomyces 240 Alveolar epithelial cell 433 grading of activities of 623t
Actinomycetales 52 Alveolar macrophages 61f induced hepatotoxicity
Actinomycetes 240 Ambulatory gastric lavage 486 management of 627
Actinomycosis 131, 152, 165, 357 Amenorrhoea 148 risk of 514
 962 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

induced liver injury, mechanism of 637 Autonephrectomy 369 haemoglobin 531

newer 629 Autopsy studies, earlier 161 in stools 214
regimens 406t Axillary lymphadenitis 412 Blood pressure
resistance 660 Axillary lymphadenopathy, right 558f control 385
surveillance 609-620 Axillary nodes 129 loss of control of 238
second-line 350, 385, 724 Azathioprine 387 B-lymphocytes, role of 65
Anti-tuberculosis therapy 535 Azithromycin 560, 562, 623 BMI See Body mass index
incidence of hepatotoxicity with 638 Azotemia 370, 376 BMU See Basic management unit
Anti-tuberculosis treatment 167, 189, 214, 218, Body mass index 185, 543
236, 247, 253, 272, 276f, 322, 323, 328f, Body temperature 238
329, 329f, 364, 414, 442, 448t, 483, 496,
B Boggy oedema 286
627, 644, 648, 761 Bacille Calmette-Guérin 10, 33, 111, 304, 309, Bone 33, 456
acetabulum following 278f 488, 524, 529, 533, 699, 733 biopsy 445f
and contraception 351 immunotherapy 296 erosion 118
benefits, assessment of 639 induced protection 731 tuberculosis of 305f
hepatotoxicity with 637-643 infection 448 Bone infection 471
induced ocular toxicity 342 recombinant 731 focus of 139
initiation of 165, 436 vaccination 309t, 386, 492, 521, 522, 526, 712, Bone marrow 380, 445
principles of 383 729, 748 changes in tuberculosis 445, 445t
regimens, standard 624 side effects of 727 examination 446
standard 290 vaccine, history of 727 granulomas 445
Aortic valve, continuous Doppler study of 259f Bacteraemia 471 necrosis 445
Aortic wall involvement 265f catheter-related 550 suppression 475
Aortoarteritis, non-specific 265f Bacteria 28, 406 trephine biopsy of 416f
Aphasia, acute onset 234f Bacterial endocarditis 240 Bony ankylosis 278
Aphthous ulcers 214 Bacterial fitness 81 Boosting vaccines 738
Aplasia 445 Bacterial infections 151, 420 Borrelia burgdorferi 240
Aplastic anaemia 443, 448 severe 471 Bowel wall abnormalities, detection of 130
Appendiceal tuberculosis 131 Bacterial meningitis 230 Brain 33, 136, 380
Appetite, loss of 214 partially-treated 233, 240 lesion, enhancing 243
Apple-jelly nodules 302, 303, 331 Bacterial pneumonia 152, 177 Breast
Aquaporin 434 acute 484 cancer 123
Arabinogalactan 53 Bacteriocins 55 carcinoma 124f, 412, 412f
Architectural distortion 124 BAL See Bronchoalveolar lavage diseases 411
ARDS See Acute respiratory distress syndrome Balloon bronchoplasty 167 feeding 351
Argon plasma coagulation 167 Barium lump 412f
Arogyavaram Medical Centre 5 meal 497f tuberculosis of 411
ART See Antiretroviral treatment studies 210 bilateral 412f
Arterial blood gas 399 Bartholin gland clinical presentation 411
Arterial carbon dioxide tension, low 438 swelling 357 development of 411t
Arthritis 550 tuberculosis of 356 diagnosis 413
reactive 295 Bartholin swelling 357 differential diagnosis 414
stage of Basal ganglia 45f epidemiology 411
advanced 275 Basal meninges, enhancements of 233 open biopsy 414
early 275 Basal meningitis 238 pathogenesis 411
Arthrocentesis 298 Basal serum cortisol 456 surgical treatment 414
Arthrodesis 289 Basic management unit 701 treatment 414
ARV drugs See Anti-retroviral drugs B-cell 26 Breath
Ascites 209, 357, 394 BCG See Bacille Calmette-Guérin shortness of 551
amount of 131 Bedaquiline 589, 591, 597, 629, 660 test 151
Ascitic fluid analysis 215 Behcet’s disease 77, 240, 296 Britain’s arthrodesis 278
Asherman’s syndrome 135, 365 Behçet’s syndrome 165 Bronchial arteritis 126
Aspergilloma 125, 126, 152, 419-421, 652 Beta polypeptide 95 Bronchial artery
cases of 651 Biatrial enlargement 259f angiogram 128f
clinical features 421 Bidhyarthi Jagarn Manch 694 embolisation 420
diagnosis 421 Bile ductsm, tuberculosis of 225 pseudoaneurysm 125
treatment 422 Bile granulomas 223 Bronchial asthma 151, 152
Aspergillus 123, 126, 240, 422, 423, 579 Biliary cirrhosis, primary 222, 223, 226, 228 Bronchial carcinoid 406
fumigatus 420 Biliary tract, tuberculosis of 224 Bronchial lesions 37, 39
lesions 651 Bilirubin, total 640 Bronchial obstruction 484
species 422 Biopsies Bronchial stenosis 150, 650
specific immunoglobulin G 421 endometrial 358 evaluation of 165
Aspiration cytology 225 multiple 331 Bronchial wall thickening 125
Assmann infiltrates 37 Bladder Bronchiectasis 123f, 126, 151-153
Asthma 151 carcinoma 135 sicca 126
subacute mimicking 161 plain X-ray of 369f Bronchiolitis obliterans 125
Auditory meatus, internal 331f Blastomycosis 406 Bronchoalveolar carcinoma 406
Aural tuberculosis 330f Bleeding 420 Bronchoalveolar lavage 109, 177f, 204, 400, 524
Autoimmune manifestations 209 Bronchogenic carcinoma 151, 152
diseases 511 Blood Bronchography 165
haemolytic anaemia 448 cells 98 Broncholith 420
thrombocytopenia 448 groups, ABO and Rh 74 Broncholithiasis 125, 205
 Index 963

Bronchopleural fistula 125, 127f, 188, 428, 648 CBNAAT See Cartridge-based nucleic acid Cholestatic jaundice 395
treatment of 649t amplification test Cholesterol mediates 66
Bronchopneumonia 39 Cefoxitin 560 Chondritis 125
Bronchopneumonic tuberculosis, extensive Celiac disease 77 Chondrosarcoma 273
bilateral 123f Cell Chordoma 140, 273
Bronchoscopic cryotherapy 168 clara 433 Chorioretinitis 138
Bronchoscopic modalities 167 club 433 Choroid plexitis 231
debulking 167 lung cancer 425 Choroidal granulomas 339
mechanical dilatation 167 wall lipid bound 54 Choroidal tubercles 338, 392, 394
thermal debulking using lasers 168 Cell mediated multiple 338f
Bronchoscopic secretions 401 autoimmune 444 Choroidal tuberculoma 339f
Bronchoscopy 151, 163 immunity 33, 78, 97, 179 Choroidal tuberculosis 338
Bronchostenosis 123, 125 impaired 47 Chromosomes 95
Bronchovascular distribution 123f Central genes 74 Chronic diseases, symptoms of 2
Bronchus intermedius 120 Central granular necrosis 27f CHWs See Community health workers
Brucella 240 Central necrosis 133f Chylothorax 189, 314
abortus 227 Central necrotic crust 307f Chylous ascites 314
canis 227 Central nervous system 136, 230, 475, 512, 736 Chyluria 314
melitensis 227 disease 485 Ciprofloxacin 561, 623
suis 227 Central tuberculosis division 669, 713, 717 Civil Society Organisations 697, 699, 701
Brucellosis 227, 240, 357, 406 Centrilobular nodules 162 Clarithromycin 560, 562, 623
Buccal mucosa, tuberculosis of 328f Cerebellum 245f Clofazimine 561, 564, 591, 596, 623, 627
Bulbar conjunctiva 336 Cerebral artery Club sandwich sign 131
Bullectomy 651 middle 232 Coagulation abnormalities 445
Bullous lung disease, bilateral 424f territory 45 Coal worker pneumoconiosis 205
Cerebral oedema 232 Coccidioides immitis 227, 240
Cerebral parenchymal Coccidioidomycosis 406
C disease 136 Cold abscess 268, 269, 273
tuberculosis 136 formation of 268
Cachexia 148
Cerebrospinal fluid 109, 110, 137, 231, 248, in chest wall 651
Calcaneum, plain radiograph of 284f
403, 552
Calcified nodules 244f Colon
parameters 247
Calcium, resorption of 30 ascending 214
study 234
Calorie stores 531 descending 214
Cervical
Calve’s disease 271, 273 Combat tuberculosis, immunotherapeutic
cancer 357
Calyceal calcification, bilateral 372f approach to 736
disease, severe paralysis from 274
Cancellous bone grafts 281 Communicable disease 760
lymph nodes 32, 129, 313, 327
Cancer antigen, elevation of 215 Communication and community
tuberculosis of 326
Candida 240 awareness disease 689
lymphadenitis 35, 314, 323f
Candidate genes 93, 96 Communication technologies 21
nodes 499
studies 97 Communities and household settings 760
spine 327
Capillary walls 435 Community acquired pneumonia 459
radiograph 328f
Capreomycin 350, 386, 598, 618, 623 Cervico-dorsal spine 243f Community health
Carbamazepine 222 Cervix 359 education and advocacy for 693
Carbohydrate antigens 734 tuberculosis of 356 worker 698, 699, 701
Carcinomatous meningitis 233 CFTR See Cystic fibrosis Community volunteers 701
Cardiac catheterisation 260 transmembrane receptor Community-based
Cardiac tamponade 257f, 258f, 261 Charaka samhita 2 directly observed treatment short course 693
development of 254 Cheese-like necrosis 28 implementation, Bangladesh 693
Cardiac tuberculosis 263 Chemical exposure 240 organisations 697
Cardiopulmonary Chemokine 64, 82, 87, 433 tuberculosis
exercise testing 399 Chest activities 697, 698, 698t, 700
status 650 computed tomography of 162f integrating 697-703
Cardiovascular diseases 153, 510 discomfort 216, 435 Complete blood count 545
Cardiovascular infections 550 radiograph 113, 115f, 117f-123f, 125f-127f, Complex genes, major histocompatibility 75, 76
Cartridge-based nucleic acid amplification test 9, 139f, 146f, 149f, 150f, 157, 157f, 177f, Complex infectious diseases,
186, 215, 236, 272, 322, 363, 466, 469, 201f, 202f, 256f, 262f, 270f, 396f, 397f, genetic dissection of 93
552, 591, 618, 720 405f, 424f-427f, 437f, 439f, 459f Computed tomography 113, 114, 124, 126, 135,
Caseating granuloma 209, 223, 445 radiology, role of 106 138, 141, 142, 246, 320, 553
with liquid centre 245 ultrasonography of 119f Condyloma acuminata 357
with solid centre 245 Chest pain 148, 161, 216, 394 Condyloma lata 357
Caseating hepatic granulomas 491 atypical 428 Congenic strains 95
Caseating tubercuolma 244f Chest signs 357, 394 Congenital diseases 151
Caseation necrosis 253 abnormal 485 Congenital disorders 123
Cauda equina paralysis, severe 274 Chest wall Congestive heart failure 395, 512
Cauliflower sign 131 abscess, anterior 502f Conglomerate ring enhancing lesions 242f
Cavernous sinus thrombosis 557f complications 125, 128 Conglomerate tuberculomas 244f
Cavitary lesions, bilateral 397f Child with pulmonary tuberculosis 501f Conjunctiva 32, 336
Cavitary pulmonary tuberculosis 436 Childhood tuberculosis 721 Conjunctival granulomas, types of 336
Cavity gain 147 Chlamydiae 28 Conjunctival infection 336
Cavity wall 420 Chlorpromazine 222 Conjunctival tuberculosis 336
CBC See Complete blood count Chlorpropamide 222 Connective tissue disorders 123, 240
 964 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Constipation 209, 214 Cystogram 376f global surveillance of 613

Constitutional symptoms 513 Cystoscopy 374 patterns, individual 618t
Constrictive pericarditis 125, 259f Cytokines 64, 82 testing 11
chronic 255, 257f, 258f, 259f role of 62 Drug-resistant tuberculosis 17, 19, 57, 81, 333,
Contiguous disease 336 Cytomegalovirus 123, 227 488, 579-608, 613, 614, 718, 723, 746,
Contrast-enhanced computed tomography Cytotoxic drugs 394 765
115-117, 127, 132-136, 150, 244, 265, active case finding for 600
271, 497 adverse effects 596
D causes of 579
Coomb’s test 448
Cord, anterior compression of 272f Darrach’s procedure 289 clinical epidemiology 579
Corneal tuberculosis 337 de Novo biosynthesis 733 clinical presentation 590
Cornual occlusion, bilateral 360f Deep vein thrombosis 395, 442, 445 diagnosis of 584, 686
Cor-pulmonale Deoxyribonucleic acid 52, 107, 521, 560, 622, 728, diagnostic algorithm 590f
chronic 419, 427 733, 763 during pregnancy, treatment of 349
diagnosis of chronic 427 vaccine 734 extensively 10, 581, 610, 617, 618, 647
Corpus callosum 45f immunotherapy 736 global prevalence of 610
Corticosteroid 92, 166, 405, 440, 491 Designated microscopy centre 671, 764 infection control 601
role of 237 Diabetes 509, 532 management of 595t, 597, 616, 715, 719
short-courses of 491 insipidus 239, 453 meningitis 238
treatment 228 Diabetes mellitus 77, 151, 459f, 509, 530, 668, 721 pathogenesis 582
role of adjuvant 261 and tuberculosis 459, 530 prevention 600
Cough 2, 394, 402f, 551 epidemiology 459 prognosis 599
chronic 209 management 460 programmatic management of 616, 686, 719
etiquette 525 pathogenesis 460 services, management of 719
suppressants 203 Diarrhoea 187, 394 surgery for 597
Cranial nerve palsies 238 chronic 214 transmission dynamics of 581
Cranial tuberculosis meningitis, Didanosine 475 treatment 596, 704
complication of 136 principles of 590
Directly observed therapy short-course 654
C-reactive protein 420, 443 regimens for 597
component of 660
Crohn’s disease 27, 40, 40t, 77, 116, 131, 131t, Drug-sensitive tuberculosis 630t
evolution of 654
Drug-susceptibility
165, 213, 214, 214t, 228, 357, 542, 546 expansion 656
microscopic observation 585
in humans 542 frameworks 654
testing 11, 107, 110, 560, 579, 586, 617,
Cryptic miliary tuberculosis 511 in global tuberculosis control, role of 654-667
716, 764
Cryptococcal meningitis 233 programmes 656
DST See Drug susceptibility testing
Cryptococcosis 227, 406 role of 654
DTC See District Tuberculosis Centre
Cryptococcus neoformans 240 strategy, original 663
Duodenum, tuberculosis of 129
Cryptosporidium 52 Discharing sinuses, multiple 415f
Dynein 87
Crystalline silica, phagocytosis of 204 Disease manifestations and mortality 532
Dysphagia 402f, 510f
Crystalline silicon dioxide 200 Disseminated disease 33, 217, 224, 545t, 550
Dyspnoea 161, 187, 394, 428
CSF See Cerebrospinal fluid Disseminated intravascular coagulation 394, 442,
Dysuria, symptoms of 370
CSOs See Civil Society Organisations 445, 448
CTD See Central TB division Disseminated tuberculosis
Culture filtrate proteins 182, 734 laboratory abnormalities in 395t E
Culture-based tests 584 signs in 394t
Eale’s disease 335, 340
Culture-negative sputum 533 symptoms in 394t
Eale’s vasculitis 340
Cushing’s syndrome 308f District Drug Stores 725
Ear 327
Cutaneous lesions 308 District Tuberculosis Centre 715, 717
tuberculosis of 330
Cutaneous reactions, management of 627 District Tuberculosis Officer 715
clinical manifestations 330
Cutaneous tissue 380 DMC See Designated microscopy centre pathogenesis 330
Cutaneous tuberculosis 57, 302-312 DNA See Deoxyribonucleic acid Eastern mediterranean region 20
clinical features 302 DNTM See Disseminated nontuberculous Ectopic gestation 357
clinical varieties of 303t mycobacterial Ectopic pregnancy 365
epidemiology 302 Dormancy gene program 733 Eczematous reaction 309
laboratory diagnosis 308 Dorsolumbar spine 271f Education programmes and projects 699
treatment 310 DOTS See Directly observed treatment, Efavirenz 472, 474, 475, 598
CVs See Community volunteers short-course Egg shell calcification 202f
Cyanosis 394 Doughy swelling 279 Ejaculatory ducts 377
Cyclopentyl-substituted rifamycin 631 Doxycycline 560 Elbow joint 286
Cyclophosphamide 135 DR-TB See Drug-resistant tuberculosis plain radiograph of 288f
Cycloserine 385, 386, 448, 610, 623, 624, 627 Drug 227 tuberculosis of 286
Cyclosporine 380 logistics management 724 clinical features 286
Cyclosporine-based protocols 380 metabolism 584, 637 management 286
Cystectomy 376f request, additional 725 pathology 286
Cystic angiomatosis 140 second-line 350 radiographic features 286
Cystic fibrosis 564 supply and management system, effective 662 Electrolyte derangement 598
transmembrane susceptibility testing 108, 719 Electronic tuberculosis surveillance system 663f
conductance regulator 434 toxicities, monitoring for 566t ELISA See Enzyme-linked immune sorbent assay
receptor 543 Drug-drug interaction 514, 566t, 598t, 599 Ellis curve 109f
Cystic lesions 142 Drug-resistance Embryo transfer 365
Cystic lung lesions, multiple 125 development of 632 Emphysema 148
Cystitis 495 develops 582 compensatory 427f
 Index 965

Empyema 118, 126, 471 Erythema Fever 161, 187, 209, 214, 216, 234f, 242f, 248f, 280,
acute 419 induratum 296, 303, 307, 307f 357, 394, 447f
chronic 120f, 419, 428 nodosum 296, 296f, 307, 307f, 309 low grade 210, 243f, 402f, 415f
necessitans 118, 125 Erythematous macules 392 with miliary pattern on chest radiograph,
Encephalitis 231 Erythrocyte sedimentation, elevated 224 causes of 406t
Encephalopathy 242f Escherichia coli 371 Fever of unknown origin 414, 415f, 510
End tuberculosis strategy 663, 700, 705t, 723 Etanercept 394 diagnosis 414
cross-cutting principles of strategy 705 Ethambutol 236, 342, 349, 385, 386, 491, 561, 562, epidemiology 414
pillars and components 707 564, 590, 601, 618, 622-627 treatment 415
Endobronchial related ocular toxicity 342 Fibrin ring granulomas 223
disease 160 Ethics and law 746f Fibrocaseous
granulomas 161 Ethics in public health, application of 750 cavity, large 284
infection, mechanisms of 160 Ethionamide 386, 596, 618, 623, 624, 627 tuberculosis 37
inflammatory tissue 163 Eustachian tube 32 Fibrosarcoma 273
Endobronchial tuberculosis 39, 151, 160-174, 424 Ewing’s sarcoma 123 Fibrosing mediastinitis 125, 128f
actively caseating 164 Ewing’s tumour 273 Fibrothorax 125, 419, 428
chemotherapy of 167 Extracorporeal membrane oxygenation 440 Fibrotic bands 125, 126
chest radiograph 162 Extra-intestinal manifestations 214 Fibrotic parenchyma 132
children 165 Extraocular muscles 337 Fibrous ankylosis 278
classification of 163, 164f Extra-pulmonary cryptococcosis 471 Filariasis 357
clinical course 161 Extra-pulmonary tuberculosis 110, 113, 129, 203, Fine needle aspiration 717
208, 224, 231, 294, 335, 453, 474, 511, cytology 124, 134, 320, 414, 490
computed tomography 162
512, 715, 717
diagnosis and treatment of 161 First-line anti-tuberculosis drugs 475t
diagnosis of 107
differential diagnosis 165 in children 491t
roentgenographic manifestations of 113-145
elderly 165 mechanism of action of 622t
Extrathoracic disease 485
epidemiology 160 Fissure, elevated minor 127f
Extrathoracic skeletal muscle 647
fibrostenotic 164 Fistula 370
Extrathoracic tuberculosis 485
granular 163 Fitness cost 584
Eye 33, 327
laboratory and radiological investigations 162 Flank pain 370
Eyelid
macroscopic appearance 161 Fleischner sign 130
lesion 336
management of 169 tuberculosis 336 Fluid restriction 239
non-specific bronchitic 163 Fluid-attenuated inversion recovery 246
oedematous hyperaemic 163 Fluorodeoxyglucose 114, 124, 141, 263
pathophysiology 160 F Fluoroquinolone 560, 601, 610, 617, 623
pregnancy 166 FNAC See Fine needle aspiration cytology
Faber’s test 289
sign of 161 Focal bacterial nephritis, acute 135
Facial nerve palsy 329f
sputum examination 162 Focal neurological deficits 238
Fallopian tube 33, 44, 135, 355, 358, 359f,
treatment 167 Folate deficiency 443
360f, 370
tumourous 164 tuberculosis 355 Follistatin-like domains 2 87
ulcerative 164 Family health international 690, 694 Foot
Endobronchial ultrasound 169 Fatal bronchopneumonia, acute 36 plain radiograph of 284f
Endocrine disturbances 238 Fatal infectious disease 668 small bones of 292f
Endometriosis 357 Fatigue 187, 394 Foreign body 28
Endometrium 358 FDG See Fluorodeoxyglucose aspiration 161
stroma of 355f Female genital tuberculosis 44, 135, 354-367 granulomas 26
Endoplasmic reticulum 76 adhesions 362 Four-drug regimen 625
Endoscopic techniques, newer 212 caseosalpinx 361 Functional residual capacity 399
Endothelial cells 444 chronic stage 362 Fungal ball 419, 422f
Endotracheal intubation 162 computed tomography 362 existence of 420
Environmental controls, implementing 761 diagnosis of 358, 358t Fungal disease 179
Enzyme 215 diagnostic algorithm 364 Fungal infection 138, 140, 152, 331, 406
Enzyme-linked diagnostic modalities for 358t Fusarium 420
immunosorbent assay 106, 108, 111, 181, 235 differential diagnosis of 357, 357t Fusiform bird nest paravertebral abscess 139f
immunospot assay 181 hydrosalpinx 361
Eosinophil 28 hysteroscopy 362 G
Eosinophilia 152, 448 laparoscopy 360
Eosinophilic granuloma 140 magnetic resonance imaging 363 Gaenslen’s test 289
Ependymitis 216 nodular salpingitis 360 Gallbladder 225
Epididymis 33, 44 patchy salpingitis 361 tuberculosis of 225
Epididymitis 44 physical signs 357 Galloping consumption 1, 14
Epithelial cyst 309 positron emission tomography 363 Gamma interferon 65
Epithelioid cell 29, 39, 223, 226, 231, 437f, 454 serological tests 363 Gas exchange abnormalities 399
clusters of 355f signs in 357t Gastric aspirate 107, 108, 110
Epithelioid cell granulomas 36, 44, 223, 320, 398f subacute stage 360 smear 112
confluent 43f surgical intervention in 365t Gastric contents 123
necrotising 38f, 42f treatment 364 Gastric lavage 110, 403
histomorphology of 27f ultrasonography 362 Gastroduodenal tuberculosis 216
perivascular 46f Female reproductive endocrine system, Gastrointestinal bleeding 216
Epituberculosis 36, 147 tuberculosis of 461 lower 210
Epstein-Barr virus infection 78 Femur, proximal 278 Gastrointestinal intolerance 475
 966 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

Gastrointestinal tract 30, 32 Golf club appearance 359 Hand hygiene 525
lesions 28 Gomori’s stains 152 HCWs See Health care workers
tuberculosis 129 Gram’s stain, negative 235 Head and neck 32
Gastrointestinal tuberculosis 208, 497f Gram-positive tuberculosis 327t, 332, 332t
Gatifloxacin 623, 629 bacteria 53 extranodal 138
Gene filaments 152 Headache 234f, 242f, 248f, 394
amplification methods 559 Granulation tissue 292 Health care
knock-in technology 730 formation of 164 structure 753
knock-out technology 730 Granulocyte 67, 434 workers 520, 524, 525
probes 559 cell 379 Health education department 690
seven autosomal 95 functions 379 Health services, directorate general of 714
Generalised tuberculosis 33 macrophage colony stimulating factor 543 Hearing defects 238
Genetic studies 98 Granuloma 26, 28, 214, 222, 223, 226, 445 Heart failure 427, 428
in human populations 95 aetiology of 27 Heart-lung complex 31f
in mice 93 confluent 29 Hemangioma 138
GeneXpert See Xpert MTB/RIF drug related 228 Hemichorea 238
Genital organs 354 formation 64, 94 Hemochromatosis disease 74
Genital tuberculosis 356t, 370, 374 histology of 26 HEPA See High-efficiency particulate air
advanced 365 inguinale 357 Hepatic adaptation, clinical significance of 638
at laparoscopy, incidence of 361t types of 28, 40, 223 Hepatic failure, drug induced 224
minimal 364 Granulomatoid reaction 223 Hepatic granulomas 222, 223t, 226, 227
Genital ulcers 240 Granulomatous causes of 222t, 227t
Genitourinary diseases 28 development of 226
and skeletal tuberculosis 512 inflammatory disease 331 morphological types of 223t
system 132, 380 liver disease 226 prevalence of 226
tract 33, 495 lymphadenitis 414 Hepatic granulomatous disease 228
Genitourinary tuberculosis 41, 132, 368-378, 495, myositis 240 Hepatic injury 638
496, 504 pleuritis 178 Hepatic lesions 226
clinical features of 495t reaction 309 Hepatic tuberculosis
clinical presentation of 370, 370t, 495 Granulomatous hepatitis 222-229 lesions 225
diagnosis 372 aetiology 222 primary 224
causes of 228 Hepatic vein, pulse Doppler study of 259f
epidemiology 368
clinical presentation 223 Hepatitis 222
imaging studies 372
diagnosis of 225, 228 B 474, 475, 639
microbiological methods 371
differential diagnosis 224 infection 226
molecular methods 372
laboratory abnormalities 224 virus 473, 474
pathogenesis 368
pathology 222 virus infection, chronic 226
role of surgery 496
prognosis 228 C 639
surgery for 377
treatment 228 infection 226
surgical interventions in 374t
Granulomatous infection 28t virus 474
surgical management of children with 496f
causes of 26 chronic 226
treatment 374
Granulomatous inflammation 415f Hepatobiliary tuberculosis 217, 224-226
urine examination 371 clinical syndromes of 224t
Genome sequencing 582, 589 in tuberculosis 27
Graves’ disease 77 Hepatocyte
Genome-wide ballooning degeneration of 225f
association scans 98 Growth factor-β, transforming 63
Guinea pig 54, 729, 730 growth factor 434
association studies 73, 87, 93 Hepatomegaly 394
linkage studies 98 model 529
of tuberculosis 730 Hepatotoxic
Genotype and compensatory mutations 584 agents 640
Geriatric population 160 Gyriform hypointensity 245f
drugs 640
Germicidal air-disinfection 762 Gyriform tuberculoma 245f
risk mitigation 640
Ghon’s complex 30, 116, 147 Hepatotoxicity 475, 638
Ghon’s focus 116, 147 H clinical manifestations of 638
Giant cell 26, 29, 34, 231 development of 237
multinucleated 226 Haematemesis, massive 395 drug-induced 631
types of 26 Haematogenous dissemination 117, 161 potential risk factors for 639t
Gingivitis 471 Haematologic cancers 511 risk factors for 639
Girdlestone arthroplasty 278 Haematological changes, drug-induced 448 risk for 639
Glands, endometrial 355f Haematopoeitic system 566 severe 638
Glandular destruction 458 Haematopoietic bone marrow 509 Herpes simplex infection, chronic 471
Glans penis mimicking malignancy, Haematuria 370 Heterologous boosting 735
tuberculosis of 371f symptoms of 370 Hibb’s arthrodesis 278
Global health emergency 19 Haemodialysis 380 High-efficiency particulate air 524
Global tuberculosis Haemoglobinopathy 140 High resolution computed
incidence rates 706f Haemolytic anaemia 443 tomography 118, 121, 127
strategy 706t, 707t Haemophagocytic lymphohistiocytosis 395, 446 Hip involvement, type of 277f
Glutathione 638 Haemophagocytosis 445 Hip joint 278f
S-transferase gene 638 Haemoptysis 209, 394, 419, 551, 650 plain radiograph of 274f-278f
Gluteal abscess, post-injection 556f massive 148 tuberculosis of 274
Gluteal region 416f Haemorrhage, massive 218 atrophic type 276
Glycosylated haemoglobin 156 Haemorrhagic eruptions, non-specific 309 clinical features 275
GM-CSF See Granulocyte macrophage colony Haemospermia 370 dislocating type 276
stimulating factor Hamstrings spasm 279f management 276
 Index 967

normal type 276 Hydropneumothorax 125 Immuno-dominant T-cell 735

pathology 278 Hydroureteronephrosis 373f Immunoglobulin 108, 182
perthes’ type 276 Hypercalcaemia 395 G 106
radiographic features 280 Hyperinflation, contralateral 125f M tests 106
radiological types of 277f Hyperplasia 41 production, reduced 529
Histoplasma capsulatum 227, 240 Hyperplastic inflammatory polyps 164 Immunoinflammatory disorders 406
Histoplasmosis 227, 240 Hyperprolactinaemia 453 Immunologic disorders 123
HIV See Human immunodeficiency virus Hypersensitivity 56 Immunological relatedness, measurements of 522
Hodgkin’s disease 222, 228 disease 564 Immunological tests 235
Hodgkin’s lymphoma 227 Hyperthyroidism 151 role of 106
Homogeneous Hypoalbuminemia 513, 599, 639 Immuno-modulatory agents 736
enhancement 132 Hypoglycorrhachia 240 Immunosuppressive
lesions 149 Hypointense masses 363f agents 339
Host’s immune system 114 Hyponatraemia 232, 239, 440, 455, 512 therapy 526
Human genome containing 98 causes of 239 Immunotherapeutic agents 736
Human immunodeficiency virus 10, 25, 30, 57, Hypoplasia 445 Immunotherapeutic vaccines 738
77, 110, 113, 166, 294, 308, 323f, 326, Hypoplastic anaemia 443 In vitro
456, 468, 483, 591, 598, 632, 660, 677, Hypoproteinaemia 382 fertilisation 81, 365
685, 690, 699, 704, 713, 747, 760, 765 Hypotension, severe 456 proliferation 64
activities 476t Hypothalamic disorder 238 INDEX-TB guidelines 183, 186, 187, 213, 236-238,
cohorts of 639 Hypothalamo-pituitary 454t 261, 273, 299, 310, 322, 332, 341, 342,
co-infection 187, 514, 728 Hypovolaemic shock 456 364, 374, 405, 486, 490, 628, 672, 674,
control, youth organisation involved in 694 Hypoxaemia, severe 438 886-960
disease Hypoxaemic ventilatory failure 205 Indian Medical Association 680
clinical staging of 471t Hysterosalpingogram 360f Indinavir 472, 475
progression 77 Infant born to mother with tuberculosis,
encephalopathy 471
I management of 491
impact of 685 Infection
infected patients 151 Iatrogenic rheumatism 294 control 582
infection 5, 92, 128, 148, 166, 226, 232, 238, Ibuprofen 240 hierarchy 762
253, 315, 423, 448, 466, 522, 540, 596, ICA See Immunochromatographic assay measures 612, 765
609, 639, 644, 685, 685t, 704, 727, 748 Icterus 394 strategies 759
during 728 Idiopathic granulomatous hepatitis 228 efforts to avoid 748
epidemic of 208 Idiopathic hepatic granulomas 228 intercurrent 147
impact of 332 IFNGR See Interferon-gamma receptor part of primary 161
stages of 149 IGRAs See Interferon-gamma release assays
subpleural focus of 177
tuberculosis in early 469t Ileal replacement 374
Infectious cases, treatment of 765
people living with 468, 514, 540, 685 of ureter 376f
Infectious disease 25, 73, 529, 611
positive tuberculosis 472t Ileitis, chronic 213f
chronic 146
prevalence 685t Ileocaecal
control
programmes and projects 699 area 214
and tuberculosis 747
seropositive 129 involvement in tuberculosis 131t
globally 16 legislation for 750
region 130
management of 238 strategies for control of 748t
tuberculosis 130, 497f
status 238 Infectious tuberculosis 761
Ileum 214
testing of tuberculosis 477, 720 Infertility 357
Iliac lymph nodes, external 306f
tuberculosis 468 Iliac lymphadenopathy, external 415f Inflammation, non-suppurative 296
co-infection 531 Iliofemoral arthrodesis 278 Inflammatory cells 176
during pregnancy, treatment of 350 Ilium, tuberculosis of 290 Inflammatory cytokine 82
pathogenesis 468 Ill-defined parenchymal lesion 487f Inflammatory granulomas 504f
treatment of 470 Imipenem 560 Inflammatory process, chronic 209
wasting in 531 Immune Inflammatory rheumatological disorders 295
Human leucocyte antigen 77, 97 activation 469 Inflammatory syndrome 597
Human mononuclear macrophages 435 based tuberculosis tests 108f Infliximab 394
Human nontuberculous mycobacterial complexes, circulating 235 Information technology 658
pathogens, emerging 551t events, adaptive 60 Infundibular stenosis 132
Human racial groups 73 reconstitution inflammatory syndrome 166, Inguinal nodes 129
Human resources management 723 323, 394, 438, 474, 492, 597 Inhalational prevention strategies 525
Human rights regulation 74 Insulin-like growth factor 434
ethics and equity, protection and response 88 Intense inflammatory reaction 175
promotion of 706 genes 74 Intercarpal joints 289f
groups 689 status and comorbidities 522 Interferon 544
Human T cells system 87, 734 regulatory factor 95
in vitro 730 functioning of 93 Interferon-alpha 459
lymphotropic virus 78 thrombocytopenia 444 Interferon-gamma 63, 96, 215
Human tuberculosis, pathogenesis of 67f Immunity 56 receptor 544
Hy’s law 638 acquired 25 release assay 106, 109-111, 149, 181, 234, 318,
Hybrid stents 168 adaptive 63 341, 372, 395, 521, 524, 532
Hydatid disease 273 innate 59 Interferon-induced protein 95
Hydrocarbons 123 protective 59 Interferon-stimulated gene 544
Hydrocephalus 231, 232, 237, 238, 239 Immunochromatic test, commercial 718 Interleukin 62, 63, 96, 544
Hydronephrosis 135 Immunochromatographic assay 552 Intermittent treatment, basis of 624
 968 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

International and National Technical Isoniazid 236, 240, 342, 349, 384, 386, 448, 491, Latent tuberculosis infection 106, 108, 110, 111,
Agencies 689 535, 564, 583, 590, 596, 613, 618, 631, 640
International Standards for Tuberculosis 621-627, 630, 632 diagnosis of 110
Care 673, 797-885 cavities 425 dosages of drugs for 632t
International Tuberculosis Control Strategy 748 induced peripheral neuropathy, risk of 237 in elderly 514
International Union against Tuberculosis 712 metabolites of 384 newer regimens for 631
Internuclear ophthalmoplegia 238 preventive shorter regimens for treatment of 632
Interpeduncular cistern 233f therapy 466, 632 testing and management 110f
Interstitial keratitis 336 treatment 111 treatment 351, 386, 526, 631, 639
Interventional pulmonary techniques 167 resistant tuberculosis, risk for 632 options for 632t
Intestinal colic 209 therapy, preventive 526 regimens for 632t
Intestinal diameter, normal 209 LED-FM See Light emitting diode-fluorescent
microscopy
Intestinal lesions 209, 212 J Left knee joint, flexion deformity of 279f
Intestinal lumen 212
Intestinal luminal diameter decreases 209 Janus kinase 544 Left ventricular
Johne’s bacillus 57 end-diastolic pressures 260
Intestinal obstruction 496
Johne’s disease 542 pressure tracing 264
complete 210
Joint systolic pressure 260
partial 210, 214
infection 471 Legionella 29
Intestinal perforation 210
tenderness 286 micdadei 52
Intestinal tract 226
Jugular venous pressure 254, 428 Legionellosis 406
Intestinal tuberculosis 40, 40t, 208-210, 339f, 499f
Juvenile idiopathic arthritis 295 Leprosy 9f, 93, 227, 331, 357
clinical features 209 Leptospira icterohaemorrhagiae 240
complications of 210t Lesion 39
differential diagnosis 214 K lobar and segmental 36
endoscopy 212 multiple ring 246f
imaging 210 Kanamycin 350, 386, 590, 618, 623
post-primary 147
features of 130t Kaplan-Meier analysis 380
primary 35, 147, 336
laboratory investigations 210 Kaposi’s sarcoma 166, 471
Leucocyte changes 444
pathogenesis 208 Kartagener’s syndrome 123
Leucocytosis 395, 442
pathological and clinical correlation 209 Keloid 309
mild 444
pathology 209 Kenya’s drug-susceptible 663f Leucopenia 394, 442, 448
site of involvement 209 Keratitis 550 development of 379
Intestinal ulcer 496 Keratoconjunctivitis 33, 336 Leukaemoid reaction 394, 444, 511
Intestine 33, 210 Keratotic boot 305f Levofloxacin 386, 618, 623
decreases 209 Kidney 33, 384, 456 Lichen scrofulosorum 303, 306, 307f
small 212 disease 668 Light emitting diode 11, 107
Intra-arterial digital subtraction angiography 421f chronic 379, 384t, 387 fluorescent microscopy 586
Intracardiac masses 395 plain X-ray of 369f Line probe assay 10, 11, 29, 108, 341, 401, 470,
ureter and bladder 370 552, 559, 581, 586, 588-591, 616, 628,
Intracellular
Knee joint 281, 380 716, 717, 719
microorganism 65
plain radiograph of 280f, 281f Linezolid 560, 629
pathogen 95
radiograph of 297f Lipid patterns 557
Intracerebral tuberculoma 246t
tuberculosis of 278, 281f Lipogranulomas 223
types of 254t
clinical features 279 Listeria 240
Intracranial calcifications 238
management 280 monocytogenes 733
Intracranial tension 247
pathology 278 Live attenuated mutants 733
Intracranial tuberculomas 230, 241, 504
radiographic features 280 Liver 32, 222, 456
diagnosis 241 Koch’s lymph 4
epidemiology 241 disease 640, 668
Koch’s phenomenon 56 pre-existing chronic 639
management 241 Koenig’s syndrome 40
pathology 241 tuberculosis of 41
Krishna Yajurveda Samhita 2f Lobar distribution 134
Intramuscular injection 734 Kyphotic deformity, severe 269 Lobectomy 651
Intraocular tuberculosis 335
Lobular pneumonia 37
Intrathoracic tuberculosis 484
lymphadenitis 115 L Loculated encysted empyema 503f
Lowenstein-Jensen media 552
Intravenous Lacrimal gland 337 Lower abdominal pain, chronic 357
immunoglobulin 548 Lacrimal system, tuberculosis of 337 Lower lobe 155
pyelography 496 Lamivudine 474 consolidation 532
urogram 369f, 372f, 376f Langerhan’s cell histiocytosis 273 lesions 510
Intrinsic immune status 522 Langhans’ giant cells 39, 41, 253, 446, 446t Lower lung
Invasive aspergillosis 152 Laparoscopy 215 field bacterial pneumonia 156
Iodophendylate dye 240 role of 499 field tuberculosis 155-159
IPT See Isoniazid preventive therapy Larva migrans 240 prevalence of 156t
Iron 532 Laryngeal disease 332 terminology of 155
smelting 200 Laryngeal tuberculosis 329f zones 202
Irritative voiding symptoms 370 Laryngitis, chronic 332 LTBI See Latent tuberculosis infection
Ischaemic enteritis 41 Larynx 328 Lumbosacral spine 270f
Ischiopubic ramus, tuberculosis of 290 tuberculosis of 328 plain radiograph of 272f
Ischium, tuberculosis of 290 clinical features 329 Luminal imaging 210
Isoenzyme and protein electropherograms 557 epidemiology 328 Lump
Isointense masses 264f pathogenesis 328 abdominal 357
Isolation rooms, negative-pressure 761 pathology 328 appendicular 357
 Index 969

Lung 31 Lymphangitis carcinomatosa 406 Meningitis 231, 392, 471

abscess 152 Lymphatic spread 161 causes of chronic 240t
biopsies 38f Lymphocyte 454, 529 chronic 239, 240
cancer 205, 425 and plasma cells 231 aetiology 239
carcinoma 406 count 449 clinical evaluation 240
cavities 2 in pleural fluid 175 diagnostic evaluation 240
cough 1 transfer 529 management 240
destroyed 428 Lymphocytic infiltration 355f syndrome, acute 232
left 502f Lymphocytic meningitis, chronic benign 240 Menstrual pattern 357
destruction, extensive 125, 126 Lymphocytopenia 442 Mental dullness 510
disease 547 Lymphogranuloma venereum 131 Mesenteric tuberculosis 130
disseminated calcification of 419 Lymphoid tissues 64 Mesothelial cells 39, 176, 178
fever 1 Lymphoma 138, 273, 406 Metal stents 168
function 187 Lymphomatoid granulomatosis 406 Metastases 132, 138
primary 231 Lymphoproliferative diseases 240 Metastatic carcinoma 225, 406
type of 426 Lymphoproliferative disorders 406 MGIT See Mycobacteria growth indicator tube
injury, acute 432 Microbiological tests 212, 235
lower zones of 203 Microgranulomas 223
middle zones of 203 M
Micronutrient 534
physical examination of 2 M/XDR-TB See Multidrug and extensively deficiencies 531
surgery, resectional 647 drug-resistant tuberculosis Microscopic haematuria 371
tuberculosis, whole 39 MAC See Mycobacterium avium complex Mid-foot swelling 282f
Lupus vulgaris 1, 303, 303f, 304, 304f, 308, 336 MacConkey agar 557 Migrating acetabulum, development of 277
of ear lobe 304f Macrocytic anaemia 443 Miliary
of external ear 330 Macronodular splenic tuberculosis 134f disease 35, 328
Lyme disease 240 Macronutrient interventions 533 lesions 397
Lymph node 33, 110, 114, 117, 135, 142, 148, 402f Macrophage 454 nodules 531
biopsy 398f activation syndrome 446 pattern 396f
calcification of 149 inflammatory protein 176 tubercles 33, 138
caseous 36 Miliary tuberculosis 33, 39, 67, 114, 118f, 150,
T-cell interaction 62
cervical and axillary 305f
Magnetic resonance 135, 137, 138, 246 152, 224, 225, 337f, 338f, 391, 392, 394t,
characterisation of 115t
imaging 114, 135, 244, 246, 363f 395t, 396f, 400f, 404, 407f, 435, 455,
enlarged 484
of brain 234f, 243f, 245f, 400f 484, 511
enlargement 209, 216
of dorsolumbar spine 272f classical 395t
granulomas 40
spectroscopy 243f clinical presentation 392
intrathoracic 500f
Male genital complications 406
mesenteric 209
tract 44 cryptic 395t
multiple enlarged hypoechoic 133f
tuberculosis 135 diagnosis 401
paratracheal 115f
Male reproductive endocrine system, differential diagnosis 403
peri-pancreatic 217
tuberculosis of 461 epidemiology of 391, 391t
regional 35
Malignant disease 147 gross pathology of 393f
sampling, indications for 500t
subcarinal 116f Malnutrition 210, 640 laboratory abnormalities in 395t
tracheobronchial 30 Managerial activities, facility-level 765 laboratory findings 394
Lymph node tuberculosis 129, 313-325 Mantoux technique 111 manifests 511
abdominal 131 Massive pleural effusion, causes of 177 molecular methods 401
clinical presentation 314 Maternal and Child Health Programmes 699 of skin 303f
cytopathology 319 MDR-TB See Multidrug-resistant TB acute 303
diagnosis of 317, 319, 321 Measles virus 28 pathogenesis 392
differential diagnosis 317 Mechanical ventilation 161, 440 prognosis 407
epidemiology 313 systems 762 signs in 394t
histopathology 319 Mediastinal complications 125, 127 symptoms in 394t
imaging 318 Mediastinal lymph node 31, 33, 36 treatment 403
in HIV-negative patients 317t tuberculosis in children 651 Mimicking pyelonephritis, acute presentation 370
in HIV-positive patients 317t Mediastinal soft tissue 128f Ministry of Health and Family
microbiological methods 321 Mediastinal sonography 116 Welfare 669, 713, 723
paediatric 490f Mediastinal tuberculosis, treatment of 323 Mitral inflow 258f
pathogenesis 313 Medical Colleges in Tuberculosis Control, Mitral valve, pulse Doppler study of 258f, 259f
physical appearance of 317t role of 668-675 M-mode echocardiogram 258f
serodiagnostic methods 322 Medicines Regulatory Authority 690 Model Rural Health Research Unit 9
treatment 322 Megaloblastic anaemia 448 MODS See Microscopic observation drug-
Lymphadenitis 348, 499, 564 Megaloblastoid maturation 445 susceptibility
reactive 317 Melanoma 138 Molecular genetics 74
Lymphadenopathy 114, 357, 394, 546 Melioidosis 406 Molecular methods 236
abdominal 447f Mendelian susceptibility 93, 95 Molecular typing 55
hilar 125 Meningeal enhancement 233f, 234f Mollaret’s meningitis 240
intra-abdominal 397 abnormal 137f Money bag sign 260f
intrathoracic 157 Meningeal irritation, signs of 232 Monocyte chemoattractant protein-1 82
mediastinal 532 Meningeal tuberculosis 348 Monocytopenia 442
residual 327f Meningeal veins 231 Monocytosis 442
subcarinal 265f Meninges 33, 136 MO-TC See Medical Officer Tuberculosis Centre
tracheobronchial 147 enhancement of 248f Moxifloxacin 385, 590, 596, 618, 623, 629
 970 Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases

MRI See Magnetic resonance imaging boenickei 541 Mycobacterium fortuitum 297, 310, 387, 549, 560
MTB See Mycobacterium tuberculosis bohemicum 541 group 549
Mucosal biopsy 212 bolletti 541 third biovariant complex 541, 549
Mucosal inflammation 169 brisbanense 541 Mycobacterium kansasii 47, 52, 188, 203, 387,
Mucosal invasion, superficial 130 canariasense 541 540, 541, 546
Mucosal lesions, biopsy of 332 celatum 540, 541 disease 204
Multibacillary leprosy 81 chelonae 310, 387, 550, 559, 560 Mycobacterium leprae 29, 52, 540, 736
Multidisciplinary multimodality management 169 chelonei 297 protein of 734
Multidrug and extensively drug-resistant chimaera 546 Mycobacterium simiae 541, 547
tuberculosis 720 colombiense 546 complex 547
treatment of 710, 719 conceptionense 549 Mycobacterium terrae 548
Multidrug-resistant conspicuum 540, 541 complex 541, 548
organisms 167 diernhoferi 541 Mycobacterium tuberculosis 2, 15, 52, 73, 107,
pulmonary tuberculosis 150f elephantis 541 114, 123, 146, 146f, 149f, 158, 188, 208,
Multidrug-resistant tuberculosis 10, 15, 57, 108, europaeum 547, 548 226, 240, 268, 294, 302, 335, 348, 368,
florentinum 544-547 394, 411, 420, 468, 483, 534, 540, 545,
110, 128, 209, 230, 476, 583, 617, 631,
genavense 47, 540, 541, 547 585, 587t, 609, 615t, 621, 710, 747, 755,
647, 685, 704, 713, 717, 723, 760
gordonae 52, 541
diagnosis of 627, 719t 760
habana 541, 734
management of 350, 673, 679 antigenic structure 54
haemophilum 541, 548, 554
prevalence of 616f antigens of 733
heckeshornense 541
treatment of 599, 710 atypical clinical manifestations in 395t
heidelbergense 547
Multifocal fibrosis 202f auxotrophs of 733
houstonense 541
Muscle immunogenum 541 bacteria 582
atrophy 267 indicus pranii 261, 734 biochemical properties 54
mass 531 infection, prevalence of 756 complex 759, 763
spasm fixes 284 interjectum 541, 547 culture characters 53
Musculoskeletal diseases 296 intracellulare 188, 541, 546, 559 discoverer of 3f
Musculoskeletal manifestations 294 kumamotonense 548 genome 586
of tuberculosis 294-301 lentiflavum 547 infection 59, 93, 94, 95, 443, 484, 648, 727, 730
Musculoskeletal tuberculosis 46, 138, 294 lepraemurium 52 dose of 731
diagnosis of 297 longobardum 548 reverse genetic of 94
unusual manifestations of 296 macrophage interactions 59 stages of 732f
Mycetoma 420, 423 mageritense 549 isolates 615t
in tuberculosis cavity 126f malmoense 541, 550 morphology 52
Mycobacteria 28, 47, 52-58, 152, 320, 406, 435, marinum 52, 57, 309, 541, 548, 554 mutants, development of 733
540, 544 mucogenicum 541, 549 pathogenesis 55
atypical 540 neoaurum 541 physical and chemical agents 54
classification of 52, 52t neworleansense 541 preparation of liquid suspensions of 764
cultivation of 54 nonchromogenicum 541, 548 receptor 87
growth indicator tube 560, 717 palustre 541 transmission of 523
growth inhibitor 554 parascrofulaceum 541, 547 virulence in animals 54
methods of demonstration of 29t paratuberculosis 52, 57, 541, 559 Mycobacterium xenopi 297, 541, 547
producing skin ulcers 57 parmense 541 pulmonary disease 562, 565t
release of 524 peregrinum 549 severe 565
soluble antigen sharing in 54t phocaicum 541 Mycolic acids 53
survival of 53 porcinum 541, 549 Mycophenolate 380
Mycobacterial pseudoshottii 541 Mycoplasma pneumonia 406
antibodies 235 scrofulaceum 305, 541, 547, 559 Mycotic aneurysm of aorta 395
antigens 63, 235, 437, 730 senegalense 549 Myelofibrosis 446
cell wall 53 senuense 548 Myeloid hyperplasia 445
septicum 541, 549 Myeloma, multiple 140, 273
components 55t
shottsii 541 Myelopathy, progressive 243f
deoxyribonucleic acid 303f
smegmatis 52, 57, 541 Myelophthisic anaemia 443
disease 9, 9f, 81, 93, 95, 674
species 738 Myocarditis 395
growth inhibitor tube 586
stomatepiae 547 Myocobacterial lymphadenitis 313
isolation 358
szulgai 541, 548
lymphadenitis 313 Myoedema 148
thermoresistibile 541
pathogens, emerg