Pulmonary Manifestations of Primary Immunodeficiency

Diseases

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Acknowledgment

We would like to express our gratitude to the technical editor of this book, Dr. Sara
Hanaei.
Nima Rezaei
Seyed Alireza Mahdaviani

vii
Contents

  1 General Considerations ����������������������������������������������������������������������������   1

Mikko Seppänen and Nima Rezaei
  2 Pulmonary Manifestations of Combined T- and B-Cell
Immunodeficiencies ���������������������������������������������������������������������������������� 37
Andrew R. Gennery
  3 Pulmonary Manifestations of Predominantly
Antibody Deficiencies�������������������������������������������������������������������������������� 77
Amene Saghazadeh and Nima Rezaei
  4 Pulmonary Manifestations of Congenital Defects of Phagocytes���������� 121
Seyed Amir Mohajerani, Marzieh Tavakol,
and Seyed Alireza Mahdaviani
  5 Pulmonary Manifestations of Genetic Disorders of Immune
Regulation�������������������������������������������������������������������������������������������������� 145
Sebastian F. N. Bode, Ulrich Baumann, and Carsten Speckmann
  6 Pulmonary Manifestations of Defects in Innate Immunity�������������������� 169
Persio Roxo-Junior, Isabela Mina,
and Catherine Sonaly Ferreira Martins
  7 Pulmonary Manifestations of Autoinflammatory Disorders����������������� 193
Ahmadreza Jamshidi, Saeed Aslani, and Mahdi Mahmoudi
  8 Pulmonary Manifestations of Complement Deficiencies������������������������ 213
Anete Sevciovic Grumach and Kathleen E. Sullivan
  9 Pulmonary Manifestations of Other Well-­Defined
Immunodeficiencies ���������������������������������������������������������������������������������� 237
Man Amanat, Mona Salehi, and Nima Rezaei
10 Treatment of Pulmonary Manifestations of Primary
Immunodeficiency Diseases���������������������������������������������������������������������� 257
Nahal Mansouri and Davood Mansouri
ix
Chapter 1
General Considerations

Mikko Seppänen and Nima Rezaei

1.1 Lungs Are an Immunologic Battlefield

Focus on the most obvious function of our lungs, gas exchange, has greatly shaped
the practice of respiratory medicine. However, blood contributes approximately
40–50% of the weight of human lungs [1]. Our lungs harbor a wide range of hema-
topoietic progenitors, with the capacity to repopulate the bone marrow after irradia-
tion. The lung is also an especial primary site for platelet biogenesis from
megakaryocytes, responsible for the origin of 50% of our platelets [2]. For blood to
oxygenate, circulating blood cells and their products traverse through the respira-
tory zone of lungs. Daily, over 10,000 L of ambient air in our lungs constantly and
effectively exposes our immune system to the outside environment through an alve-
olar surface that exceeds 100–150 m2 in a human adult, which consists the largest
epithelial surface in the body [3]. Consequently, our respiratory tract is equipped

M. Seppänen (*)
Rare Disease Center, New Children’s Hospital, University of Helsinki and Helsinki
University Hospital, Helsinki, Finland
Adult Primary Immunodeficiency Clinic, Inflammation Center, University of Helsinki and
Helsinki University Hospital, Helsinki, Finland
e-mail: [email protected]
N. Rezaei
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of
Medical Sciences, Tehran, Iran
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal
Scientific Education and Research Network (USERN), Tehran, Iran
Department of Immunology, School of Medicine, Tehran University of Medical Sciences,
Tehran, Iran
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 1

S. A. Mahdaviani, N. Rezaei (eds.), Pulmonary Manifestations of Primary
Immunodeficiency Diseases, https://doi.org/10.1007/978-3-030-00880-2_1
2 M. Seppänen and N. Rezaei

with a highly specialized localized immune system with an effective mucociliary

clearance machinery and specialized type II alveolar cells which produce innate
immunity surfactant proteins and cytokines. Type II cells in turn trigger resident
immune cells like alveolar macrophages and dendritic cells as well as the highly
complex adaptive immunity [4]. Any breaches in immunity, barrier, and clearance
functions of the local or systemic immunity predispose our lungs to impaired, pro-
longed, and/or hyperactivated immune reactions [5]. Thus, it is no wonder that
many genetic and acquired immune-mediated diseases affect the human respiratory
system.

1.1.1 Introduction to Primary Immunodeficiency Diseases

Many primary immunodeficiency diseases (PIDs) firstly present with lung and
upper airway manifestations and symptoms, giving the well-versed practicing pul-
monologist a unique opportunity to suspect these often highly debilitating and
potentially fatal diseases, with no delay or undue ensuing mortality. PIDs are inher-
ited, mostly monogenic and systemic disorders of immunity. Systemic PIDs are
essentially diseases of hematopoietic immune cells with genetically impaired or
dysregulated function. An increasing number of PIDs are due to impaired immunity
caused by genetic dysregulation of immune pathways by organ-specific tissues like
the skin [6]. Tissue-specific pulmonary PIDs (e.g., surfactant protein deficiencies,
cystic fibrosis, primary ciliary dyskinesia syndromes) could be envisaged but are
presently not classified as such and are thus outside the scope of this book, except
when differential diagnostic issues are discussed.
If suspecting PID, irrespective of a patient’s age, one should always exclude
human immunodeficiency virus (HIV) infection and obtain careful information on
received immunosuppressive treatments. If the onset of matching symptoms or
findings precedes any immunomodulatory therapy, especially if the ensuing depth
of given immunosuppression exceeds that normally seen, one should consider
whether a patient’s immunodeficiency is truly secondary or indeed primary. In a
rapidly growing number of PIDs and patients, the onset seems delayed well into
adult life [7].
Currently, there are more than 350 known PIDs. In variable combinations, these
diseases predispose individuals to infections, inflammatory complications, and
malignancies, often hematologic or virally induced cancers. Dysregulated acquired
immunity leads to autoimmunity and severe early-onset atopy, while dysregulated
innate immunity may lead to autoinflammation and impaired barrier function.
Similar to blood disorders, systemic PIDs often give rise to various hematologic
findings like cytopenias; deficient, disorganized, or hypoplastic lymphatic system;
lymphoproliferation; myelodysplasia; or bone marrow failure. Biopsies may fur-
ther reveal aberrant immune reactions like granulomas or hemophagocytosis
(Fig. 1.1).
1 General Considerations 3

Frequently recurring or chronic infections

Susceptibility to malignancies
• Very-early onset (<3-4 mo of age)
• Mostly hematologic malignancies
• Opportunistic or common pathogen
• Invasiveness
• Extension to adjacent or distant sites
• Need of prolonged therapy
• Recurrence after therapy Chronic or fluctuating lymphoproliferation
• Respiratory, gastrointestinal, bacteremic or lymphatic agenesis
• Lead to bronchiectasis • Lymphadenopathy
• Splenomegaly
• Lymphatic hyper- or hypoplasia
• Disturbed lymph node architecture
Cytopenias • Dysregulated immune responses
• 1-3 lineage cytopenias (e.g. granulomas, hemophagocytosis)
• Low absolute counts
– Lymphocyte differential
– May also display low immunoglobulins
• Before any immunomodulatory Organ-specific or systemic autoimmunity
medication • May be atypical
• Impaired production or increased – Poor response to therapy
turnover – Lack of autoantibodies
• e.g. thyroid, lung, liver, gut, skin, joint,
muscle, systemic (e.g. SLE, Sjögren)
Severe very early-onset atopy
• +/- hyperextensibility of connective
tissue
Autoinflammation
• Periodic fever or lupoid features
• Hemophagocytic lymphohistiocytosis
Failure to thrive • Inflammation of skin, joints, bowel,
• Early-onset chronic diarrhea muscle
• Severe generalized eczema • Lipodytrophy, Behcet-like features

Syndromic features Nonurticarial angioedema

• 22q11.2 deletion (DiGeorge) most • Mostly hereditary angioedema
common • Skin, airways and bowel

Fig. 1.1 Common features in primary immunodeficiency diseases. Usually ≥2 features present
(except in hereditary angioedema). If SCID is suspected in an infant, PID doctor should be con-
sulted urgently

1.1.2 Classification of Primary Immunodeficiency Diseases

Although there are no universally accepted classification systems for PIDs, the most
commonly accepted one, endorsed by the International Union of Immunological
Societies (IUIS), divides PIDs into eight different categories and further subcatego-
ries. IUIS classification is based on the affected cell types (e.g., B-cells, T-cells, and
phagocytes), arms of immunity (e.g., antibodies, complement system, intrinsic and
innate immunity), affected signaling pathways (e.g., type I interferons, IL-12-IFN-γ
axis), or predominant clinical manifestations (e.g., immune dysregulation diseases,
autoinflammatory diseases) [6, 8]. However, due to the complex nature of our
immunity, a known genetic disease often has features from multiple disease groups.
Helping clinical assessment, the defined PID categories commonly display pulmo-
nary complications typical for either just one or a few categories (Tables 1.1, 1.2,
and 1.3). IUIS maintains and updates regularly the list of known PIDs as well as
4 M. Seppänen and N. Rezaei

Table 1.1 Sentinel respiratory infections and their complications that most likely should result in
screening for immunodeficiency
Infection Setting Note
Upper respiratory Recurrent upper In most PIDs with infection susceptibility
tract respiratory tract
Deep tissue For example, mastoiditis after otitis media or
infection tonsillar abscess in infant: MyD88/IRAK4,
phagocyte, and antibody deficiencies
Severe viral Interstitial SCIDs, range of other CIDs (e.g., WAS, deficiencies
infections pneumonitis of DOCK2, MALT1, CARD11, BCL10, TCRα,
IL-21R, IKBKB, NIK, WIP)
Innate and intrinsic immunity defects predisposing to
severe viral infections (e.g., STAT1 AR-LOF,
deficiencies of STAT2, IRF7, IFNAR2, CD16, MDA)
Pyogenic Failure to thrive Susceptibility to a wide array of gram-positive and
pneumonia gram-negative microorganisms (also to viruses,
fungi, parasites), interstitial pneumonitis: SCID and
T-cell deficiencies
Recurrent Exclude a wide range of PIDs. Evaluate latest if >2–3
pneumonias during lifetime, earlier if warning signs:
In various loci, leads to bronchiectasis or bronchial
dilatation. In-between-episodes bronchial wall
thickening, signs of cryptogenic organizing
pneumonia, lymphoid interstitial pneumonitis,
follicular bronchiolitis or granulomas atypical for
sarcoidosis (i.e., low immunoglobulins/primary
lymphopenia)
Concurrent non-respiratory invasive infections,
recurrent bacterial rhinosinusitis, very early-onset
recurrent otitis media, adult-onset recurrent otitis
media, slow systemic inflammatory response, or no
demonstrable serum IgE
Complicated Pneumatocele formation: STAT3 deficiency
Empyema or abscess: CGD, other phagocyte defects,
STAT3 deficiency
Bronchiectasis or interstitial pneumonitis: wide range
of PIDs
Early-onset (<3–4 Phagocyte deficiencies, MyD88/IRAK4 deficiency,
mo) SCID, T-cell deficiencies, congenital asplenia (RPSA,
NKX2–5), FADD deficiency (functional
hyposplenism)
Pyogenic sepsis Recurrent Antibody deficiencies, phagocyte deficiencies,
+/− pneumonia/ complement deficiencies, SCID and various rather
meningitis profound CIDs, MyD88/IRAK4 deficiency, CD40/
CD40L deficiency, congenital asplenia (RPSA,
NKX2–5), NEMO/IKBKG, GATA2 deficiency
(+/-PAP), FADD deficiency
Early-onset (<3–4 Like in pyogenic pneumonias above
mo)
(continued)
1 General Considerations 5

Table 1.1 (continued)

Infection Setting Note
Pneumocystis Pneumonia SCIDs
jirovecii CID (e.g., DN STAT3; VODI; deficiencies of CD40,
CD40L CARD 11, MALT1, BCL10, TCRα, MHC II,
CD40/CD40L, IKBKB, IL-21R, NIK, MTHFD1,
STAT5b; idiopathic CD4 deficiency)
Syndromic CID (e.g., WAS, NEMO/IKBKG, IKBA,
VODI, immune-osseous dysplasias, bone marrow
failures like dyskeratosis congenita, Schaller sd)
Reported rarely in XLA and CVID, also remember
thymoma with hypogammaglobulinemia and
anti-IFN-γ-autoantibodies
Aspergillus spp., Invasive Phagocyte defects: especially CGD (also mulch
other filamentous pneumonitis, Nocardia, Paecilomyces, Trichosporon,
fungi S. aureus, rare opportunistic bacteria, Burkholderia
cepacia, Serratia marcescens), occasionally in SCN,
LAD 1, Pearson sd
Occasionally in SCID and CID; infections by other
opportunistic and pyogenic pathogens predominate
CID/T-cell def., e.g., STAT3-DN, STAT1-GOF
GATA2 deficiencya, WAS, 22q11.2 del,
APLAID/PLCG2
Also in idiopathic CD4 lymphopenia, thymoma with
hypogammaglobulinemia (Good sd)
Dimorphic fungia Invasive As part of MSMD: IL12Rβ1 and IFNγR1
deficiencies
CID (e.g., CARD9, STAT1-GOF, DOCK8, CD40LG,
GATA2 deficiency), idiopathic CD4 lymphopenia
Nontuberculous Mendelian Affecting IL-12-IFN-γ -signaling (e.g., IL12RB1,
mycobacteria Susceptibility to IL12, IFNGR1, IFNGR2, AD STAT1-LOF): recurrent
(NTM) Mycobacterial nontuberculous mycobacteriosis +/− salmonellosis,
Diseases (MSMD) BCG-itis, osteomyelitis, Klebsiella spp., intracellular
bacteria and viruses, invasive dimorphic fungi,
leishmaniasis
Dendritic cell deficiencies and GATA2 and AR/AD
IRF8 def; AD STAT1-GOF, JAK1-LOF, deficiencies
of Tyk2, ISG15, RORc
Other: SCID, 22q11.2 del (especially BCGosis),
CGD (especially BCGosis in CYBB), DN-STAT3,
CD40L /CD40 def, anti-IFN-γ-autoantibodies
Always look also for sentinel nonpulmonary infections that alert to the possibility of PID in lung
patient: cutaneous herpes simplex, chronic EBV viremia, EBV-associated lymphoproliferation,
+/− hemophagocytic lymphohistiocytosis, chronic CMV, severe cutaneous papilloma virus or
molluscum contagiosum, invasive or chronic mucocutaneous candidiasis, chronic Cryptosporidium,
invasive Neisseria
a
Histoplasmosis, coccidioidomycosis, paracoccidioidomycosis
 6

Table 1.2 Typical infections in various impaired arms of immunity

Specific (adaptive) immunity Innate immunity
Arm of
immunity B-cells T-cell or combined Phagocytic cells Complement Spleena
Infectious Upper respiratory Systemic viral Lymphadenitis Bacteremic infections Septic and meningeal by encapsulated
complications Lung Gastrointestinal Skin (encapsulated bacteria) pathogens, overwhelming postsplenectomy
Gastrointestinal Pyogenic bacterial Gingivitis, aphtous Meningococcal and other infection (OPSI)
Skin, joint, Liver abscesses pyogenic meningitides
meningeal Lung abscesses Disseminated
Urinary tract Gastrointestinal Neisseria gonorrhoeae
Urinary tract
Causative agents Pyogenic Viruses Bacterial (often Pyogenic bacteria S. pneumoniae
bacteria EBV,CMV, catalase+) Neisseriae N. meningitidis
Pneumococcus HPV,HSV, VZV S. aureus S. pneumoniae H. influenzae
Haemophilus Adenovirus, measles Klebsiella H. influenzae E. coli
influenzae Molluscum Burkholderia S. aureus
Staphylococcus contagiosum. cepacia Proteus Group B streptococci
aureus Pyogenic bacteria Nocardia P. aeruginosa
Enterococcus Pseudomonas Serratia C. canimorsus
Salmonella Haemophilus marcescens
Campylobacter Pneumococcus Fungal:
Mycoplasma sp. Campylobacter Aspergillus sp.
Parasites Mycobacteria Other filamentous
Giardia lamblia Listeria fungi
Viruses Fungal: Bacteria:
Enteroviruses Candida, Salmonella
VZV, HSV Aspergillus
Pneumocystis
jirovecii
Parasites:
Cryptosporidium
a
Also asplenia and functional hyposplenism may be genetic or acquired
M. Seppänen and N. Rezaei
1 General Considerations 7

Table 1.3 Examples of noninfectious pulmonary complications in various primary

immunodeficiency categories
Described noninfectious
pulmonary complications
PID category Examples besides bronchiectasis
1. Affect cellular and Severe combined ILD (exclude adenovirus,
humoral immunity immunodeficiencies (SCID) CMV, RSV, P. jirovecii)
(combined (T-B+ or T-B-)
immunodeficiencies, CID) Somewhat less severe CID ILD, LIP (STAT5B)
2. Combined Wiskott-Aldrich sd (WAS) Pulmonary NHL
immunodeficiencies with Ataxia-telangiectasia (AT) ILD, PF, aspiration
associated or syndromic Nijmegen breakage sd (NBS) Pulmonary NHL
features
22q11.2 sd (DiGeorge sd, Structural defects, aspiration,
velocardiofacial sd) tracheobronchomalacia
Cartilage-hair hypoplasia (CHH) PF, pulmonary NHL
AD-HIES (DN-STAT3) Pulmonary NHL
Dyskeratosis congenita: PF
AD-DKCs, AR-DKCs, XL-DKC
Anhidrotic ectodermodysplasia ILD
with immunodeficiency
Hepatic veno-occlusive disease ILD
with immunodeficiency (VODI)
CD40L and MST1 deficiencies Pulmonary NHL
Somech syndrome PF
3. Predominantly antibody Agammaglobulinemias (B- or ILD
deficiencies severely reduced)
Hypogammaglobulinemias ILD, GLILD, OP, LIP, PF,
(usually B+) NSIP
4. Diseases of immune Familial hemophagocytic ILD and pulmonary NHL
dysregulation lymphohistiocytosis (FHL) (SH2D1A)
FHL with hypopigmentation: PF
Hermansky-Pudlak type 2 (HPS2)
Regulatory T-cell defects ILD, OP (LRBA), DIP,
(autoimmunity): IPEX, STAT3 GLILD (CTLA4)
GOF, LRBA def, CTLA-4 def
Autoimmunity +/− ILD, NSIP
lymphoproliferation: APECED,
ITCH def
Autoimmune lymphoproliferative Pulmonary NHL
sds (ALPS)
Susceptibility to EBV-associated ILD (CD27 def)
lymphoproliferation
5. Congenital phagocyte Chronic granulomatous diseases “Mulch pneumonitis”
disorders (CGDs): XL-CGD, AR-CGDs (hypersensitivity)
Other nonlymphoid defects GATA2 def PAP, ILD, OP, GLILD
Pulmonary alveolar proteinosis sds PAP, PF
(PAP)
(continued)
8 M. Seppänen and N. Rezaei

Table 1.3 (continued)

Described noninfectious
pulmonary complications
PID category Examples besides bronchiectasis
6. Defects of innate and Predisposition to severe viral ILD
intrinsic immunity infections: AR STAT1 LOF
Chronic mucocutaneous ILD and vascular aneurysms
candidiasis (STAT1 GOF)
7. Autoinflammatory Type I interferonopathies: STING ILD, NSIP
disorders vasculopathy
Inflammasomopathies ILD, NSIP (DIRA/IL1RN,
APLAID/PLCG2)
Non-inflammasome-related ILD, alveolar hemorrhage
(Copa defect)
ADA2 deficiency ILD, pulmonary vasculitis
8. Complement deficiencies Deficiencies of circulating and ILD (SLE), pulmonary
membrane-associated factors embolism
DIP desquamative interstitial pneumonia, GLILD granulomatous-lymphocytic interstitial lung dis-
ease, ILD interstitial lung disease (not specified), LIP lymphocytic interstitial pneumonia,
NSIP nonspecific interstitial pneumonia, OP organizing pneumonia, PF pulmonary fibrosis.
Bronchiectasis seen in all groups at least occasionally, though rare in autoinflammatory disorders
without antibody deficiency and severe congenital neutropenias, not listed separately

helpful flowcharts to ease their identification based on clinical and immunologic

phenotype [8].

1.1.3 Epidemiology of Primary Immunodeficiency Diseases

Many erroneously believe that PIDs would be extremely rare, present exclusively in
children, and incurable. The first two notions are true for the most severe PIDs, e.g.,
severe combined immunodeficiencies (SCIDs), early diagnosis of SCID and hema-
topoietic stem cell transplantation before 3.5 months of age lead to long-term sur-
vival in over 94% of SCID [9]. Currently, many countries screen newborns for
SCIDs and note a rising prevalence in concurrently found milder PID cases. Even
before SCID screening, the overall incidence rate of PIDs in national or regional
registries exceeded 1 in 10,000 person years, while PID prevalence was close to
2:10,000 [10, 11].
Available worldwide data come from physician-confirmed regional registry data
and large patient surveys covering up to 140,000 patients [12–16]. Due to pro-
nounced geographic variability in their incidence, it is important to know the local
epidemiology of autosomal recessive PIDs [13, 17]. While in highly consanguine-
ous areas and genetic isolates, the combined prevalence of all PIDs may exceed
3:10,000; the prevalence of common variable immunodeficiency (CVID) exceeds
0.7:10,000 [13, 18]. Due to the relative commonness of X-linked PIDs, approxi-
1 General Considerations 9

mately 58% of PID patients are males [16]. Proportions of different PIDs thus con-
siderably differ according to the geographical area. Higher proportions of various
categories other than primarily antibody deficiencies are usually seen in consan-
guineous populations. In general, approximately 50% (ranging 20–75%) of PID
patients have had predominantly antibody deficiencies, 14% (ranging 5–30%) other
well-defined immunodeficiency syndromes, 8% (ranging 1–15%) autoinflamma-
tory disorders, 8% (ranging 5–60%) combined immune deficiencies, 6% (ranging
4–35%) phagocytic disorders, 6% (ranging 2–15%) complement deficiencies, 4%
(ranging 1–13%) disorders of immune dysregulation, and 1% (ranging 0–3%)
innate immunity defects, while 1–5% have remained unclassified [12–16].

1.1.4  rimary Immunodeficiency Diseases Need

P
to Be Diagnosed Early

Numerous studies have indicated that early diagnosis of PID reduces mortality and
morbidity [9, 19]. As reported by various surveys, up to 60–75% of people affected
with PID have survived to adulthood with improved diagnosis and therapy [12, 14,
16, 20], especially in CVID and some milder combined immunodeficiencies resem-
bling that, which may present at any age [7, 18, 21]. In a European study on 2212
CVID patients, disease onset in two-thirds of the patients took place after 10 years
of age [21]. In the majority, CVID was diagnosed in adulthood, and surprisingly in
approximately 20% of patients, the diagnosis has been made at 50 years of age or
later. In antibody deficiencies, a timely diagnosis and substitution therapy with IgG
seem to improve the patient’s prognosis in average by over 30 years [22].
Fascinatingly, even the innate immunity may be trained during an individual’s life
in order to provide a better protection [23]. Consequently, susceptibility to infec-
tions and complications due to dysregulated immunity from almost all genetic
defects seems to be aggravated and accumulated with aging, emphasizing the need
for timely diagnosis of PID. This may further save the patient from severe iatrogenic
complications like disseminated infections caused by live attenuated vaccines and
excessive immunosuppressive medication.

1.1.5 How to Recognize Primary Immunodeficiency Diseases

Early clinical recognition of a potential PID patient is largely based on “general

impression, shape, and size” or “jizz” (Fig. 1.1) [24]. Most PID patients present
with no immediately obvious clinical findings of an underlying disease. Typical
“sentinel” (e.g., warning sign) airway infections are listed in Table 1.1, and extra-
pulmonary infections are listed as footnotes. It is noteworthy that such sentinel
infections either present themselves in highly exposed surface niches of the body
10 M. Seppänen and N. Rezaei

(lungs, skin, gut) or involve cunning pathogens which due to effective immune eva-
sion establish chronic carrier state even in individuals with “normal” immunity.
The nature of associated infections often reveals which so-called arms of immunity
may be affected and thus how the patient should be screened for PID (Tables 1.1
and 1.2).
Examples of typical noninfectious pulmonary complications are listed in
Table 1.3 and involve immune dysregulation. This, due to chronic ensuing inflam-
mation, may further impair normal barrier function, like in bronchiectasis. When
carefully analyzed, most PID patients commonly have general sentinel immune dys-
regulatory features in variable combinations. These general sentinel features in
PIDs are depicted in Fig. 1.1. The presence of two or more of such features suggests
a potential underlying PID. Furthermore, one can list numerous rare sentinel clini-
cal findings that suggest more specifically some rare monogenic defects. Denoting
these would more efficiently help in targeted testing. If found and necessary, it is
recommended to consult further standard PID textbooks, local pediatric PID spe-
cialist, and clinical geneticist (Table 1.4). Moreover, if a monogenic disease is
found, genetic counseling is needed [13, 25]. Due to its relative commonness, all
pulmonologists should be able to discern CVID – almost invariably affecting the
respiratory system – and screen for it (Fig. 1.2) [26].
Collectively, the most common complication in PIDs is susceptibility to recur-
rent, chronic, or opportunistic infections, most commonly in upper or lower air-
ways. If the offending pathogen is opportunistic, e.g., of nature normally seen only
in immunocompromised individuals, and the patient has no known secondary
immunodeficiency, suspicion of PID may be straightforward. In SCID infants who
almost totally lack T+/-B lymphocytes, often multiple opportunistic infections are
found at presentation. Frequently, however, a single episode of respiratory infection
like pneumonia and even inflammatory complications like those resembling sar-
coidosis does not differ from those seen in individuals without immune compromise
(Tables 1.1 and 1.3) [27, 28]. Therefore, keys to finding PIDs include remembering
their existence and realizing their chronic, often systemic, and complex nature, all
necessitating a carefully conducted review of lifelong patient and careful family
history and findings from all organ systems (Fig. 1.1).
In childhood, atopy and PIDs may be present superficially rather similarly and
display recurrent viral infections. Particularly in respiratory and skin infections,
there is considerable overlap between recurrent infections in antibody deficient
patients and in those with Th2-dominant immune response (Table 1.1) [29, 30].
Actually, if other members of a large family are perfectly healthy, this argues against
common polygenic traits like chronic asthma or severe atopy that predispose to
recurrent rhinosinusitis, skin infections, and – to an extent – to recurrent pneumo-
nias. Early-onset severe atopy and life-threatening opportunistic infections are seen
in Omenn syndrome (OS). OS is caused by various hypomorphic or “leaky” SCIDs,
most often RAG1 and RAG2 deficiencies. In OS, expansion of oligoclonal T-cells
and defective AIRE expression in thymus lead to autoreactivity, lymphadenopathy,
hepatosplenomegaly, alopecia, exudative erythroderma, hypereosinophilia, and
increased serum levels of IgE despite the absence of B-cells. The term leaky SCID
1 General Considerations 11

Table 1.4 Examples of sentinel early-onset clinical findings not directly related to immune
dysfunction, which point toward rare monogenic primary immunodeficiency diseases
Hematologic Lack of or dysmorphic lymphatic tissue (e.g., thymus, tonsils, lymphnodes,
lymphangiectasia, primary lymphedema), congenital thrombopenia,
thrombasthenia, small platelets, bleeding diathesis, bone marrow hypo-/dysplasia
or failure, hepatomegaly, splenomegaly, asplenia
Nervous Microcephaly, macrocephaly, progressive neurologic deficits, psychomotor/
system mental retardation, ataxia, porencephalic cysts, cerebral infarction, optic atrophy,
retinal dystrophy and abnormalities, cataracts, strabismus, ptosis, coloboma,
cranial nerve dysfunction, autism, sensorineural hearing loss, cerebellar
hypoplasia, agenesis of corpus callosum, cerebral calcifications, cerebral palsy,
focal cortical heterotopy, hydrocephalus, cerebral cysts, cerebral atrophy
Skin and Severe erythrodermia or eczema, congenital ichthyosis, ectodermal dysplasia,
appendages hypo-/anhidrosis, absent or disfigured teeth, enamel defects, delayed or
incomplete eruption of teeth, microdontia, absent hair, hypotrichosis/fine and
course or sparse hair, trichorrhexis (bamboo hair), congenital alopecia, premature
graying of the hair, partial albinism/oculocutaneous hypopigmentation, skin
hypo-/hyperpigmentation, poikiloderma, incontinentia pigmenti, telangiectasia,
poor wound healing, ulcerative/vesicular skin lesions, nail dystrophy,
photosensitivity, multiple pigmented nevi, lipodystrophy, reduced facial fat,
palmar hyperkeratosis
Skeletal Scapular spurring, anterior rib cupping, flared costochondral junctions, cartilage
hypoplasia, joint hypermobility, osteopenia, high palate, kyphomelic dysplasia,
metaphyseal dysplasia, spondylo- or multiple epiphyseal dysplasia,
spondyloenchondrodysplasia, short limb dwarfism, scoliosis, craniosynostosis,
osteopetrosis, vertebral anomalies, butterfly vertebrae, cervical spine instability,
myopathy, hypotonia
Kidneys Kidney and ureter anomalies (e.g., single/horseshoe kidney, duplication of the
renal pelvis and ureter), nephrotic syndrome, abnormalities, kidney cysts, renal
mesangial sclerosis, hypouricemia, reduced urinary uric acid excretion, kidney
amyloidosis
Endocrine Hypogonadism, ovarian dysgenesis, bifid uterus, testicular atrophy, genital
hypoplasia, impaired fertility, growth hormone deficiency/insensitivity,
hyperprolactinemia, neonatal diabetes, hypocalcemia, hypoparathyroidism,
hypopituitarism, SIADH, adrenal gland cortical sclerosis
Various Intrauterine or postnatal growth failure, short stature, atresia of the choanae,
dysmorphic features (e.g., heart/conotruncal defects), cardiomyopathy, various
facial anomalies like eyelid changes, broad and depressed nasal tip or bridge,
low-set ears, velopharyngeal insufficiency, tracheoesophageal fistulae, asplenia,
early-onset arteriosclerotic changes, hepatic veno-occlusive disease, esophageal
dysmotility, Hirschprung disease, exocrine pancreatic insufficiency, vascular/
cerebral aneurysms
If sentinel clinical findings are found in a patient suspected to have PID, consulting standard gen-
eral textbooks on PIDs, pediatric PID specialist, and clinical geneticist are strongly advisable

refers to incomplete mutation(s) in a typical SCID gene leading to small numbers of

functional circulating B- and T-cells missing in classical SCIDs. In leaky SCID, the
patient may also have a later age of onset of clinical symptoms [31]. Among typical
associated autoimmune manifestations, hematologic cytopenias, hepatitis, vitiligo,
and villous atrophy have been reported most commonly [32]. Severe early-onset
12 M. Seppänen and N. Rezaei

Immune-mediated diseases
• Organ-specific and systemic
Frequently recurring infections autoimmunity
• Common pathogens • Interstitial lung diseases (GLILD, LIP, OP)
– Pneumococci, staphylococci, – May resemble sarcoidosis (see text)
haemophilus influenzae, moraxella • Hematologic, chronic or recurrent
• Recurrence after therapy (idiopathic thrombopenia, AIHA,
• Need of prolonged therapy Evans sd)
• Invasiveness • Gastrointestinal (e.g. aphthous stomatitis,
• Respiratory, gastrointestinal, bacteremic, atrophic gastritis, villous atrophy,
meninges, joint, skin enteropathy, inflammatory bowel
• Lead to bronchiectasis diseases)
• Occasional opportunistic pathogens • Liver (granulomatous and autoimmune
(e.g. mycoplasma arthritis, enteroviruses, hepatitis, nodular regenerative
cryptosporidiosis, norovirus, CMV colitis) hyperplasia)
• Bile ducts
• Thyroid, joint (JIA, SPA),
• Skin (psoriasis, vitiligo, alopecia)
• Systemic (SLE, Sjögren sd)

Susceptibility to malignancies
• Mostly hematologic malignancies
– B-cell nHL
• Gastric carcinoma (often H. pylori +)

Nonurticarial angioedema (rare)

Chronic or fluctuating lymphoproliferation

• Lymphadenopathy
• Splenomegaly
• Lymphatic hyperplasia
Autoinflammation – Lungs, gut
• Especially in monogenic diseases • Disturbed lymph node architecture
mimicking CVID (e.g. NFKB1, PIK3CD, • Dysregulated immune responses
PLCG2, CECR1) (e.g. missing plasma cells, granulomas)
• Sicca sd

Fig. 1.2 Common features in common variable immunodeficiency (CVID). Usually ≥2 features
present. Similar infections seen in other antibody deficiencies. GLILD granulomatous-­lymphocytic
interstitial lung disease, LIP lymphocytic interstitial pneumonia, OP organizing pneumonia, AIHA
autoimmune hemolytic anemia, JIA juvenile idiopathic arthritis, SPA spondylarthropathy, SLE
systemic lupus erythrematosus

allergy and atopy (or features resembling these) are among prominent presenting
features in a variety of PIDs and are often accompanied by eosinophilia and/or
increased concentrations of IgE in blood. These include hyper-IgE syndromes
(HIES) like dominant negative (DN) STAT3 mutations, Comel-Netherton syndrome,
and PGM3 deficiency, as well as WAS and DOCK8, RLTPR, ARPC1B, and ERBIN
deficiencies [6]. Also, rare monogenic disorders causing severe allergy as well as
impaired keratinocyte-specific immunity or barrier function like SAM (severe der-
matitis, multiple allergies, and metabolic wasting; DSP, DSG1) and Loeys-Dietz
syndromes (TGFR1/2, SMAD3) may cause differential diagnostic challenges [33].
Each of these diseases has typical associated features and/or predisposes to severe
opportunistic infections.
An increasing number of known PIDs display no or negligible infection suscep-
tibility, while various inflammatory, also pulmonary, complications predominate
1 General Considerations 13

(Fig. 1.1, Table 1.3). Inflammatory pulmonary complications are reported in most
PID categories, bronchiectasis in all of these. However, invasive sampling required
for an exact diagnosis and targeted therapy in many of these complications might
have been avoided, thus precluding exact diagnosis. Aiding in suspicion, recurrent
or chronic infectious and inflammatory complications are frequently found at
­further sites like the gastrointestinal tract, blood, skin, and various organs but need
to be looked for.
Especially in diseases causing immune dysregulation, there is great phenotypic,
genotypic, and intrafamilial variability in penetrance, nature, and severity of compli-
cations. Also in PIDs with T-cell deficiency, even the observed opportunistic patho-
gens within a family may differ. Familial polygenic and monogenic traits may thus
be difficult to tell apart, unless the index case presents clearly aberrant leukocyte
subset counts or function in the used screening tests. Positive family history increases
the probability that a patient has PID over tenfolds of a normal person. Family his-
tory should be obtained systematically, and any premature deaths in the family
should alert the attending physician [34]. Family history may seem negligible due to
factors like de novo mutations, incomplete penetrance, or X-linked inheritance,
which may not always be apparent if family history has been obtained only for the
immediate family. Factors like skewed X inactivation, uniparental disomy, or genetic
anticipation may further complicate the assessment of family history [35]. In genetic
anticipation, after the appearance of the mutation, each generation displays a more
severe phenotype. In PIDs, this is seen in dyskeratosis congenita (DKC).

1.2  ulmonary and Airway Manifestations in Primary

P
Immunodeficiency Diseases

1.2.1 Upper Airway Infections

Recurrent upper respiratory tract infections (URTIs) like otitis media and rhinosi-
nusitis are common in the general population and in, for example, atopic individu-
als. It is normal for a small child to have 6–8 episodes, with predisposing factors like
atopy and frequent exposure to smokers or to circulating viral pathogens in day care,
even 10–15 yearly URTIs [36]. In normal adults, 2–4 and with predisposing factors
up to 5–8 yearly URTIs are common. Smoking impairs, for example, airway muco-
ciliary clearance and antigen presentation by MHC molecules. Due to additional
commonly seen factors impairing sinus drainage through narrow or closed osteome-
atal complexes, even doctor-diagnosed chronic recurrent rhinosinusitis (CRRS) is
seen in 1–2.4% of population, in most without any evident PID [37]. Thus, even
chronic and recurrent noninvasive URTIs may poorly screen for PIDs. Moreover, the
acronym SPUR (severe, persistent, unusual, or recurrent) has been suggested as an
indication to check for primary and secondary antibody deficiency [38]. Early-onset
nasal polyposis may point to PID; it has been described in cartilage-­hair hypoplasia,
hypogammaglobulinemia, TAP1/TAP2, and CD3γ deficiency [39]. However, highly