MEDICINE

CORONAVIRUS DISEASE-2019 (COVID-19)

Last Updated: OCTOBER 5, 2021
14th revision since January 2020

Table of Contents N. Co-infection with Varicella-Zoster Virus ................... 25

I. COVID-19 .......................................................................... 2 O. Gastrointestinal Manifestations of COVID-19 .......... 25
A. Betacoronaviruses ..................................................... 2 P. Liver Injury in COVID-19 .......................................... 25
B. SARS-CoV-2 ............................................................. 2 Q. Thrombocytopenia Mechanism of COVID-19 .......... 25
C. Epidemiology............................................................. 3 R. Renal Involvement in COVID-19 .............................. 25
D. Mode of Transmission ............................................... 4 S. COVID-19 in Semen and Urine................................ 26
E. Length of Viability on Surfaces .................................. 5 T. Risk of Reinfection ................................................... 26
F. Viral Dynamics ........................................................... 5 U. Post-Acute Sequelae of SARS-CoV-2 (PASC) ........ 26

II. COVID Variants ................................................................ 5 IX. Classification of Patients ............................................... 26

A. COVID-19 at a Biomolecular Level ............................ 5 X. Algorithms ...................................................................... 28
B. Older Variant Classifications...................................... 6 XI. Diagnostic Tests............................................................ 29
C. Spike D614G ............................................................. 7 XII. Ancillary Imaging .......................................................... 32
D. Occurrence of Variants .............................................. 7 XIII. Diagnostic Tests for Suspected, Probable or Confirmed
E. Nomenclature ............................................................ 7 COVID-19 cases ............................................................ 35
F. Main Mutations of Concern in SARS-CoV-2 .............. 8 XIV. Collection and Handling of Specimens........................ 35
G. CDC/WHO Criteria for classifying variants ................ 8 XV. Equipment needed in Units Managing COVID Patients 36
H. New Variants Based on Pango Lineage .................... 9 XVI. COVID-19 in Pediatric patients ................................... 36
I. Summary of Variants .................................................12 XVII. COVID-19 in Pregnant Patients ................................. 37
III. Pathogenesis..................................................................13 XVIII. Treatment ................................................................. 38
IV. Immunology of COVID-19 ..............................................13 A. Mainstay Supportive Treatment ............................... 38
V. Clinical Manifestations, Risk Factors and Complications of B. Investigational Pharmacologic Treatment ................ 39
COVID-19 .......................................................................14 C. Convalescent Plasma Therapy ................................ 44
A. Risk Factors For Acquiring the Disease ....................14 D. Role of Traditional Chinese Medicine (Lianhua Qingwen)
B. Risks Factors For Death ...........................................15 44
C. Incubation Period and Temporal Profiles ..................15 E. Pre-exposure or Post-exposure Prophylaxis ............ 45
D. SARS-CoV-2 Transmission According to Stage of F. Mechanism of Action of Drugs ................................. 45
Infection ........................................................................15 G. Management Algorithm ........................................... 45
E. Signs and Symptoms................................................15 H. Additional Supportive Therapy and Monitoring for Patients
F. Findings ....................................................................16 with Pneumonia ........................................................... 46
G. PUM vs PUI Old Classification .................................16 I. Management of Sepsis and Septic Shock ................. 47
H. Old VS New Classification ........................................16 J. Non-sedation in Critically-ill or Mechanically Intubated47
I. CDC Updated Guidance ............................................16 K. Management of Acute Respiratory Distress Syndrome47
J. Isolation VS Quarantine ............................................16 L. Management for Discharged Patients ...................... 48
VI. Contact Tracing..............................................................16 M. Ventilator Management ........................................... 48

VII. Pathology ......................................................................18 XIX. Management for Asymptomatic COVID-19 Positive.... 48

VIII. COVID-19 Complications .............................................19 XX. Prevention of Complications ........................................ 49
A. Most Common Complications ...................................19 XXI. Outcomes ................................................................... 49
B. Evaluation of Patients in Shock ................................19 XXII. Main Goal VS the Pandemic ...................................... 49
C. Evaluation of Dyspnea .............................................19 XXIII. Guidelines for Advance Directives ............................ 51
D. COVID-19 related Strokes ........................................19 XXIV. Recommendations for Repeat Testing ..................... 51
E. Presumptive Case of Encephalitis ............................19 XXV. Criteria for Discontinuation of Transmission-based ... 52
F. Other Neurologic Manifestations ...............................20 XXVI. Criteria for Discharge................................................ 52
G. Cytokine Storm Syndrome & Immunosuppression ...20 XXVII. Recommendations for Confirmed COVID-19
H. Musculoskeletal Manifestations ................................20 Healthcare Workers Returning to Work .......................... 52
I. Pulmonary Vascular Endothelialitis, Thrombosis, and XXVIII. DOH Guidelines for Triaging COVID-19 patients
Angiogenesis ................................................................21 including PUM/PUIs ....................................................... 52
J. Cardiac Manifestations and Complications................21 XXIX. COVID-19 Vaccines ................................................. 53
K. Kawasaki-like Disease..............................................22 A. Vaccine.................................................................... 53
L. Pediatric Inflammatory Multisystem Syndrome temporarily B. Phases of Clinical Trials .......................................... 53
associated with SARS-CoV-2 (PIMS-TS) ......................23 C. COVAX Initiative...................................................... 54
M. Dermatologic Manifestations of COVID-19 ...............24
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D. Emergency Use Listing.............................................54
E. Emergency Use Authorization in the Philippines.......54
F. COVID-19 Vaccines Tracker.....................................54
G. COVID-19 Vaccine Types ........................................55
H. General Guidelines for Vaccination ..........................57
I. Vaccines Against Variants .........................................57
J. Vaccines Currently in Approved for Use and in Phase 4
Clinical Trials ................................................................57
K. Other Vaccines in Development in Phase 3..............63
L. Other Vaccines in Development in Phase 2 ..............65
M. Other Vaccines in Development in Phase 1 .............66
N. Other Vaccines in Development ...............................66
O. Vaccine Rollout Recommendations..........................66
P. Special Considerations in COVID-19 Vaccines ........66
Q. What to Expect after receiving COVID-19 Vaccines .68
R. Reasons for Deferral of COVID-19 Vaccination ........68
S. Side Effects of COVID-19 Vaccination......................68
2. Compared to Other Betacoronaviruses
T. Antibodies in Human Breast Milk Post-vaccination ...71
Coronavirus SARS-CoV-1 MERS-CoV SARS-CoV-2
U. Vaccine in Pregnancy...............................................71
Primary Host Bats Bats Bats
V. COVID-19 Vaccines for Pediatric Age Group ..... Error! Intermediate
Bookmark not defined. Civets Camels Pangolins
Host
W. Timing of Co-Administration of Other Vaccines .......72 Infectivity Rate 1% 3% 4%
X. Even After Getting COVID-19 Vaccines, You Should Still: Case Fatality
11% 34% 2.047%
72 Rate

Y. Diagnosis and Management of Severe Allergic Reactions

B. SARS-CoV-2
after COVID-19 .............................................................72
• Dr. Li Wenliang “李文亮”= a Chinese doctor who
Z. Health Worker Communication For COVID-19 Vaccination courageously raised the alarm about COVID-19 in the early
73 days of the outbreak
AA. Interim Public Health Recommendations for Fully o Discovered the disease (November 17,2019)
Vaccinated People ........................................................73 o Died of the disease (Feb. 7,2020)
• Belongs to Betacoronavirus 2B lineage
BB. Recommendations for Isolation, Quarantine, and Testing
• WIV04 strain (GISAID accession no. EPI_ISL_402124)
74
• 82% homology to that of SARS-CoV Tor2 (GenBank
XXX. COVID-19 Third Dose VS Boosters............................76 accession no. AY274119)
• bat SARS-like coronavirus WIV1 (bat SL-CoV-WIV1,
GenBank accession no. KF367457.1)
I. COVID-19
• “Coronavirus Disease discovered in 2019” 1. Hosts
• Responsible for the global pandemic from December 2019 to • Natural Animal Reservoirs: Bats
date of writing • Considered Reservoir host: Snakes
• Declared to be a Global Pandemic by World Health • Intermediate hosts: Pangolins
Organization on March 11,2020 • Final hosts: Humans
• Caused by SARS-CoV-2 “Severe Acute Respiratory • Transmission Theory
Syndrome Coronavirus 2” o Virus resides in bats and has been transmitted into
o Due to 79% genetic similarities with SARS-CoV in 2002 pangolins;
• COVID-19 = disease; SARS-CoV-2 = agent o Recombination of bat coronaviruses and an origin-
• Previously known as “Novel Coronavirus (nCoV)” unknown coronavirus (theories suggesting pangolin or
• Informerly known as “Wuhan Coronavirus” snake coronavirus)
o Virus resides its pre-pandemic form for a long period of
A. Betacoronaviruses time
• “Corona” means crown (protein spikes resembles crown) o Genetically mutates into infecting humans
• Coronaviruses circulating in humans are typically benign
• Causes 25% cases of common cold illnesses
• Single-stranded; enveloped; positive sense RNA virus
• Zoonotic in Origin

1. Taxonomy
• Order: Nidovirales
• Family: Coronaviridae
• Genera: Betacoronavirus
• Other generas: Alphacoronavirus, Deltacoronavirus,
Gammacoronovirus

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2. Life Cycle of the Virus C. Epidemiology
• SARS-CoV2 involves binding of the viral S protein to ACE2 • Outbreak was believed to have originated from Wuhan City,
• Receptor-binding domain on the surface subunit S1 of the S Hubei Province from the People’s Republic of China
protein attaches to ACE2. • Believed Source of Outbreak: Wuhan Huanan Market
• After binding, the S protein is cleaved at the S1/2 and S2′ • Has since spread to 188 countries/regions all over the world
regions (in a process known as S protein priming) by the • Declared as a Global Pandemic in March 11,2020 by the
transmembrane serine protease TMPRSS2, World Health Organization
• Fusion of the viral membrane with the membrane of the host • As of November 27,2020
cell and direct entry of the virus into the cytoplasm.
• Respiratory tract epithelial cells express both ACE2 and 1. Prevalence
TMPRSS2 on their surface, • Total of cases worldwide diagnosed = 234,609,003
• Direct or ‘early’ entry pathway = predominant mode of in vivo • Total of deaths worldwide = 4,797,368
entry by SARS-CoV • Total worldwide recoveries = 210,858,488
• Endosomal entry pathway • Case Fatality rate = 2.047%
o ACE2–virus complex is translocated to endosomes and S As of Oct 4,2021
protein priming is performed by the endosomal cysteine • Recovery rate = 90.638%
proteases cathepsin B and cathepsin L As of Oct 4,2021
o can be blocked by either lysosomotrophic agents (such as
• Vaccine Doses administered worldwide = 6,188,903,420
hydroxychloroquine) or cathepsin inhibitors,
As of Oct 4,2021
• After the release of the viral genomic RNA into the cytoplasm,
• 47 years old = average age of infected
the first ORF is translated into polyproteins pp1a and pp1ab,
• Equally affects Male and Female
à cleaved by viral proteases into small non-structural proteins
such as RdRP.
2. Worldwide Distribution
• Genomic RNA and structural proteins are assembled into new
viral particles, leading to their release through exocytosis.

Global Cases Global Fatality

(Global cases as of Oct 4,2021)

(Global fatality as of Oct 4,2021)

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3. Cases 6. Carriers

(as of Oct 4,2021)

4. Case Fatality Rate

• Fatality Rate = 2.047%
o Average across different countries and timeframes
• Case Fatality Rate in China was initially at 16% during Jan 1- • Age 20-29 = considered primary carriers of COVID-19 and
10 and was immediately brought down to 0.8% on February 1 may not show any signs or symptoms (asymptomatic carriers)
due to better equipment, testing, and processes
DISEASE COVID-19 INFLUENZA D. Mode of Transmission
Case Fatality Rate 0.8% 0.1% • When a person sneezes, the virus may directly spread via tiny
droplets as it lands to another person’s mouth, nose, eyes
• COVID-19 is 8-35x more deadly than the flu • If a person sneezes, and the virus lands on surfaces, this could
• Case Fatality Rate according to age in years be transmitted via Fomites
Age in Years Case Fatality Rate in % o Droplets can survive for over a day (24 hours average)
0-9 --- • Can be transmitted via Droplet, Contact, Fomites and
10-19 0.2% Person to Person transmission
20-29 0.2% • Imported Case – when a person infected with COVID-19 goes
30-39 0.2% to a non-affected area
40-49 0.4% • Local Transmission – if a person with imported case of
50-59 1.3% COVID-19 comes into contact with household people and
spreads the disease
60-69 3.6%
• Community Transmission – when people starts to contract
70-79 8.0%
the disease without a clear source
>80 14.8%
• Confirmed human to dog transmission
• Case Fatality according to co-morbidities: o However, the dog did not show any symptoms; thus no
Co-morbid conditions Case Fatality Rate in % precautionary measures needed to be taken
Hypertension 6.0% • Fecal samples remained positive for SARS-CoV-2 RNA for a
Diabetes 7.3% mean of 11.2 days after becoming negative for respiratory
Cardiovascular disease 10.5% tract samples
Chronic Respiratory disease 6.3% • Virus is actively replicating in the patient's gastrointestinal tract
Cancers 5.6% and fecal–oral transmission could occur after viral clearance in
None 0.9% the respiratory tract
• Most elderlies have a lot of co-morbid conditions • Evidence is not yet sufficient to develop practical measures for
the group of patients with negative respiratory tract sample
• Number of new case/day has decreased due to
results but positive fecal samples
o Quarantining
o Aggressive testing • Further research into the viability and infectivity of SARS-CoV-
o Right equipment and staffing 2 in fecal is required
• >80% are asymptomatic, or have mild to moderate disease
• Case Fatality across the world

(as of Oct 4,2021)

5. R0
• R0 – defined by how quickly the virus spreads
o R0 = 1 (1 person can spread the disease to 1 person)
o R0 = 2 (1 person can spread the disease to 2 persons)
• Interpretation of R0
o If R0 < 1 the disease subsides
o If R0 = 0 the disease becomes steady
o If R0 > 1 the disease continues to spread
DISEASE COVID-19 INFLUENZA
R0 2.2-3.9 1.3
• Interpretation: COVID-19 spreads more easily than influenza

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• Viability of SARS-CoV-2 on surfaces

SURFACE SARS-CoV-2 SARS-CoV-1
Aerosol Up to 3 hours
Copper Up to 4 hours Up to 8 hours
Latex Gloves Up to 8 hours
Aluminum Up to 2-8 hours
Cardboard Up to 24 hours Up to 8 hours
Plastic Up to 72 hours Up to 72 hours
Stainless steel Up to 72 hours Up to 48 hours
Wood and Glass Up to 120 hours
Paper Up to 120 hours
Ceramic Up to 120 hours

F. Viral Dynamics
• The mean viral load of severe
cases was around 60 times
higher than that of mild cases =
higher viral loads might be
associated with severe clinical
outcomes
• Mild cases were found to have
an early viral clearance, with
90% of these patients
repeatedly testing negative on
RT-PCR by day 10 post-onset
• Patients with severe COVID-19
tend to have a high viral load
and a long virus-shedding
period
• Viral load of SARS-CoV-2
might be a useful marker for
assessing disease severity and
prognosis

II. COVID Variants

A. COVID-19 at a Biomolecular Level
E. Length of Viability on Surfaces 1. Biomolecular level
• Virus can remain viable and infectious in aerosols for hours • Like other betacoronavirus
and on surfaces up to days (depending on the inoculum shed) • Positive sense; single-stranded RNA
• Transmission were associated with nosocomial spread and • Inciting event: Exchange of genes between two
super-spreading events homologous chromosomes
• SARS-CoV-2 was more stable on plastic and stainless steel o Recombination of bat coronaviruses and an origin-
than on copper and cardboard unknown coronavirus (theories suggesting pangolin or
• Differences in the epidemiologic characteristics of these snake coronavirus)
viruses probably arise from other factors, including high viral o This recombination event led to the pathogenicity of
loads in the upper respiratory tract and the potential for COVID-19
persons infected with SARS-CoV-2 to shed and transmit the o Involved this Spike (S) protein à cell surface protein
virus while asymptomatic essential for determining which cells it can infect
• The virus could remain viable in the environment for days, o Viral entry into host cells by binding into ACE-II receptors
found in the lungs

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2. Genome of SARS-CoV-2
• Genome of SARS-CoV-2 has:
o Long ORF1ab polyprotein at 5’ end
o Followed by 4 major structural proteins including:
§ spike surface glycoproteins,
§ small envelope protein,
§ matrix protein, and
§ nucleocapsid protein
o has 3 deletions in the genomes of SARS-CoV-2 from
Japan, USA, aand Australia
§ 2 deletions (3 nucleotides and 24 nucleotides) in
ORF1ab polyprotein
§ 1 deletion (10 nucleotides) in the 3’ end of the
genome

Figure showing the genetic sequence of SARS-CoV-2

• Mutations in spike surface glycoprotein = might induce
conformational changes; lead to antigenicity
• Mutation in the spike protein could change the tropism of a
3. Difference VS Sars-CoV-1 virus including new host or increasing viral pathogenesis (like
HIV)
• 93 mutations VS SARS-CoV-1 • The mutations switch co-receptor use CCR5 to CXCR4 =
o 42 mis-sense mutation identified in all major non-structural increasing the viral pathogenesis
and structural protein, except the envelope proteins
o 29 missense mutation in the ORF1ab polyprotein
o 8 in the surface glycoprotein
o 1 in matrix protein
o 4 in nucleocapsid protein
o 3 mutations in spike surface glycoprotein receptor-binding
domain (D354, Y364, and F367)

4. Spike (S) surface glycoprotein B. Older Variant Classifications

1. Variant Strains according to older study
o plays essential role in binding to receptors on the host cell
and determines host tropism • Two different types of SARS-CoV-2 identified
o major target of neutralizing antibodies
o includes 2 subunits (S1 and S2) a. Type L strain
§ resulting from cleavage of the one precursor into two § accounting for 70% of the strains
parts § predominated during the early days of epidemic in China
§ S1 determines the virus host range and cellular § accounted for a lower proportion of strains outside of
tropism with the key functional domain - receptor Wuhan than in Wuhan
binding domain (RBD) § newer strain
§ S2 contains two tandem domains, heptad repeats 1 § transmits faster and replicates faster in humans
(HR1) and heptad repeats 2 (HR2), to mediate virus-
cell membrane fusion b. Type S strain
§ fusion process is similar to that of HIV-1 § Accounting for 30% of the strains
• When S1 binds to the receptor on the cell membrane, the § Older strain
fusion peptide at the N terminus of S2 inserts into the cell
membrane, then three HR1s attach to each other in parallel as
a trimer, followed by binding of three HR2s separately onto the
outside of the trimer to form a 6-helix bundle, thus bringing
virus and cell membranes close to each other to trigger fusion.

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2. Variant Strains according to the August 2020 Study
• As of May 7,2020 = 3 variant strains are present

a. Variant A
o Original human virus genome
o Present in Wuhan
o Surprisingly not the city’s predominant virus type
o Mutated versions of A were seen in Americans who lived
in Wuhan
o Large number of Mutated A found in patients from US and
Australia
o Most found in bats and pangolins
o Described as the root of the outbreak

b. Variant B
o Mutation derived from Variant A
o Has a slower mutation rate in East Asia than elsewhere
o Prevalent in patients across East Asia
o Variant didn’t travel much beyond the region without
further mutations D. Occurrence of Variants
o “Founder event” in Wuhan • variants seem to spread more easily and quickly than other
o “Resistance” against this type in East Asia variants
• increase in the number of cases will put more strain on health
c. Variant C care resources, lead to more hospitalizations, and potentially
o Mutation derived from Variant B more deaths
o Major European type • Mutations are changes in the genetic code of a virus that
o Found in early patients from France, Italy, Sweden, naturally occur over time when an animal or person is infected
England • Many mutations do not affect the virus’s ability to spread or
o Absent in Chinese mainland sample cause disease because they do not alter the major proteins
o Also seen in Singapore, Hong Kong, and South Korea involved in infection

C. Spike D614G
• Dubbed as the “new strain”
• More contagious than the original strain E. Nomenclature
• Based on a research of joint American and British team led by 1. Mutations
Los Alamos National Laboratory
• SARS-CoV-2 S-protein has a 10-20 fold higher affinity for • Amino acid mutation as first letter
ACEII than corresponding S-protein of SARS-CoV • Position as middle number
• D616G mutation = dramatically increasing in frequency • Change in amino acid as last letter
globally • Example:
• L8V mutation = local epidemic in Hongkong o E484K mutation
• Missense mutation o mutation of position 484, glutamic acid to glutamine
o D Glycine was replaced with D Aspartic Acid substitution
• Mutation L5F = occurs in many geographic regions in many
distinct clades 2. Variants of Pango lineage
• Mutation S943P = seems to have been transferred by Lineage Most Common Countries Description
recombination into diverse viral A United States of America Root of the pandemic lies
backbones that are co- 27.0%, within lineage A. Many
United_Arab_Emirates sequences originating from
circulating in Belgium
12.0%, China 9.0%, China and many global
• Associated with enhanced Germany 8.0%, Japan 5.0% exports; including to South
infectivity East Asia Japan South Korea
• Increases transmission rate Australia the USA and Europe
• Moderate effect on represented in this lineage
transmissibility (PHE) B United Kingdom 29.0%, Second major haplotype (and
United States of America first to be discovered)
• Nicknamed “DOUG” 20.0%, China 11.0%, Spain
• Correlates with the prevalence 3.0%, Iceland 3.0%
of loss of smell as a symptom of
COVID B.1 United States of America A large European lineage the
• Superior infectivity of G614 45.0%, United Kingdom origin of which roughly
results from decreased S1 9.0%, Turkey 7.0%, France corresponds to the Northern
4.0%, Germany 3.0% Italian outbreak early in 2020.
shedding and higher level of S
protein in the virion C.1 South_Africa 91.0%, Alias of B.1.1.1.1, South Africa
Zambia 4.0%, USA 3.0%,
Mozambique 1.0%, UK
1.0%

P.1 Brazil 32.0%, United States Alias of B.1.1.28.1, Brazilian

of America 29.0%, Canada lineage with a number of spike
18.0%, Chile 5.0%, Mexico mutations with likely functional
3.0% significance E484K, K417T,
and N501Y

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F. Main Mutations of Concern in SARS-CoV-2 G. CDC/WHO Criteria for classifying variants
1. N501Y Classification Variant of Variant of Variant of High
Interest Concern Consequence
o present in B.1.1.7, P.1, and B.1.351 variants;
Impact on Causes More severe More severe
o responsible for increased transmissibility Disease surges; disease;
o increases binding affinity
o nicknamed “NELLY” May be more More More
contagious Contagious hospitalizations
2. E484K Reduced Possible YES YES
Immunity
o present in the P.2, P.1, and B.1.351 variants
Impact on Reduces Reduces Reduces
o hinders antibody binding; Tests
o mutation of position 484, glutamic acid to glutamine Variants on 2 4 0
substitution CDC Watchlist
o confers stronger binding potential to ACE2
o nicknamed “Eeek” 1. Variant of Concern

3. K417T • Criteria:
o Increase in transmissibility or detrimental change in
o the P.1 variant COVID-19 epidemiology; OR
o responsible for immune escape o Increase in virulence or change in clinical disease
presentation; OR
4. K417N o Decrease in effectiveness of public health and social
o for the B.1.351 variants measures or available diagnostics, vaccines,
o responsible for immune escape therapeutics.
• Current Variants under the classification
5. Y453F WHO Pango Earliest Date of
o mutation found in the B.1.1.298 variant found in Danish Label Lineage documented Designation
minks Alpha B.1.1.7 UK Dec 18 2020
Sep 2020
6. L452R Beta B.1.351 South Africa Dec 18 2020
May 2020
o mutation found in California variant B.1.429 Gamma P.1 Brazil Jan 21,2021
o responsible for immune escape Nov 2020
o mutation of position 452, leucine to arginine substitution
Delta B.1.617.2 India VOI Apr 4,2-21
o stronger affinity to the spike protein for the ACE2 receptor
Oct 2020 VOC May 11,2021
o decreased recognition capability of the immune system
o could make COVID resistant T cells
2. Variant of Interest
7. P681R • Criteria:
o Found in B.1.617 o with genetic changes that are predicted or known to affect
o mutation of position 681, proline to arginine substitution virus characteristics such as transmissibility, disease
o may boost cell level infectivity of the variant by facilitating severity, immune escape, diagnostic or therapeutic
cleavage of the S precursor protein to the active S1/S2 escape; AND
configuration o Identified to cause significant community transmission or
multiple COVID-19 clusters, in multiple countries with
8. S477G/N increasing relative prevalence alongside increasing
number of cases over time, or other apparent
o Show highest flexibility region in RBD epidemiological impacts to suggest an emerging risk to
o Strengthens the binding of SARS-CoV-2 with the hACE2 global public health.
receptor • Current Variants under the classification
WHO Pango Earliest Date of
9. P681H Label Lineage documented Designation
o Preprint mutation Lambda C.37 Peru Dec 2020 June 14,2021
o Similarly found in B.1.1.7 and B.1.1.207 Mu B.1.621 Colombia August 30,2021
o Showing significant exponential increase in worldwide Jan 2021
frequency
3. Variant of Monitoring
10. E484Q
• A SARS-CoV-2 variant with genetic changes that are
o Refers to exchange of glutamic acid to glutamine suspected to affect virus characteristics with some indication
o Enhances ACE2 receptor binding ability that it may pose a future risk, but evidence of phenotypic or
o Reduces existing antibodies from attaching to this epidemiological impact is currently unclear, requiring
mutated spike protein (differently folded) enhanced monitoring and repeat assessment pending new
evidence.
• Former VOIs currently designated as VUMs:
o Kappa: B.1.617.1;
o Iota: B.1.526;
o Eta: B.1.525;
o Epsilon: B.1.427/B.1.429.
• Former VOIs no longer designated as VUMs:
o Zeta: P.2;
o Theta: P.3
• Current Variants under the classification

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Pango Earliest documented Date of H. New Variants Based on Pango Lineage
Lineage Designation 1. Lineage B.1.1.7
B.1.427 US VOI Mar 5,2021
• SARS-CoV-2 Variant B.1.1.7
B.1.429 Mar 2020 VUM Jul 6,2021
• United Kingdom Variant (UK)
R.1 Multiple countries Jan 2021 Apr 7,2021
• Also known as the Alpha Variant
B.1.466.2 Indonesia Nov 2020 Apr 28,2021
• Classified as a Variant of Concern by the World Health
B.1.1.318 Multiple countries Jan 2021 Jun 2,2021
Organization
B.1.1.519 Multiple countries Nov 2020 Jun 2,2021
• First emerged at around September 2020
C.36.3 Multiple countries Jan 2021 Jun 16,2021
• First reported in UK in December 2020
B.1.214.2 Multiple countries Nov 2020 Jun 30,2021
• More transmissible than certain SARS-CoV-2 lineages
B.1.1.523 Multiple countries May 2020 July 14,2021
• the predominant variant in the US in March 2021
B.1.619 Multiple countries May 2020 July 14,2021
• mutation in the spike protein that causes S-gene target failure
B.1.620 Multiple countries Nov 2020 July 14,2021 (SGTF) in the Thermo Fisher Scientific TaqPath COVID-19
C.1.2 South Africa May 2021 Sep 1,2021 reverse transcription–polymerase chain reaction (RT-PCR)
B.1.617.1 India, Oct 2020 VOI Apr 4,2021 assay
VUM Sep 30,2021 • overall RT-PCR result is positive but is negative for the S-gene
B.1.526 USA Nov 2020 VOI Mar 24,2021 target and positive for the other two assay targets
VUM Sep 20,2021 • SGTF has served as a proxy for identifying the B.1.1.7 variant
B.1.525 Multiple countries Dec 2020 VOI Mar 17,2021
• carries a mutation in the S protein (N501Y) that affects the
VUM Sep 20,2021 conformation of receptor-binding domain
• deletion at positions 69 and 70 (del69–70)
• N501Y affects the receptor binding affinity of the spike protein
and it is possible that this mutation alone or in combination with
the deletion at 69/70 in the N terminal domain (NTD) is
enhancing the transmissibility of the virus
• variants with the del69–70 produce a negative result for S-
gene target and a positive result for the other two targets
• Three of these mutations have potential biological effects that
have been described previously to varying extents:
o Mutation N501Y is one of six key contact residues within
the receptor-binding domain (RBD) and has been
FIGURE: Phylogenetic tree* showing genetic distance† between SARS-CoV-2–
positive specimens with the B.1.1.7 variant (n = 8) and exposure histories identified as increasing binding affinity to human ACE2.
related to travel, household contacts, and others in the community o The spike deletion 69-70del has also occurred a number
of times in association with other RBD changes.
o Mutation P681H is immediately adjacent to the furin
cleavage site, a known location of biological significance.
• B.1.1.7 is harder to neutralize than parental virus,
compromising neutralization by some members of a major
class of public antibodies through light chain contacts with
residue 501.
• N501Y enhances RBD: ACE2 binding affinity
• N501Y compromises neutralization by many antibodies with
public V-region IGHV3-53
• B.1.1.7 is unlikely to increase the risk of SARS-CoV-2
reinfection
• B.1.1.7 escapes a subset of RBD-specific antibodies
• B.1.1.7 remains sensitive to neutralization, albeit at moderately
reduced levels (∼sim;2-fold), by serum samples from
convalescent individuals and recipients of an mRNA vaccine
(mRNA-1273, Moderna) and a protein nanoparticle vaccine
(NVX-CoV2373, Novavax)
• 1.5 more transmissible in all age groups
• Increased mortality and hospitalization in >65y/o with co-
morbidities
• Unlikely to increase
the risk of re-
infection
• No evidence of more
severe cases in
children
• Vaccines are
effective against this
variant

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2. Lineage B.1.351
• SARS-CoV-2 Variant B.1.351
• South African Variant
• Also known as the Beta Variant
• Classified as a Variant of Concern by the World Health
Organization
• variant included a mutation (N501Y) associated with increased
transmissibility
• Originally detected in early October 2020
• The variant strain (PANGO [Phylogenetic Assignment of
Named Global Outbreak] lineage B.1.351††) was first detected
in the Eastern Cape Province of South Africa from specimens
collected in early August, spread within South Africa,
• displaced the majority of other SARS-CoV-2 lineages
circulating in that country
• associated with higher viral loads
• contains another spike protein mutation (E484K) that might
hinder antibody binding
• 4 amino acid differences when compared with Wuhan-Hu-1,
which included the D614 G mutation which has been observed
to correlate with increased case fatality rates 4. Lineage P.2 or B.1.1.248
• P4715 L mutation which has been observed to occur in almost
all strains with D614 G mutation, which might affect the speed • SARS-CoV-2 Variant B.1.1.248 (P.2)
of virus replication • Japanese Variant
• Phylogenomic analysis showed that the detected SARS-CoV- • Also known as the Zeta Variant
2 belonged to lineage B.1.1 sharing the most common recent • P1176F is exclusive to the Japanese variant
ancestor with SARS-CoV-2 strains recovered from South • with 3 spike missense mutations
Africa
• B.1.351 neutralization titer reduced 8- to 9-fold for Pfizer and 5. Lineage P.3
AstraZeneca vaccines • SARS-CoV-2 Variant P.3
• Reduced B.1.351 neutralization by mAbs and sera induced by • Philippine Variant
early SARS-CoV-2 isolates • Also known as the Theta Variant
• NTD deletion in B.1.351 abrogates neutralization by a potent • Mainly detected from the Central Visayas region of the
neutralizing human mAb Philippines
• E484K, K417N, and N501Y cause widespread escape from • Characterized by 13 lineage-defining mutations
mAbs • Co-occurrence of the E484K, N501Y and P681H mutations
• suggested that convalescent and vaccine sera have • Three additional radical amino acid replacements towards the
decreased cross-neutralization of B.1.351 lineage variants C-terminal end of the protein
• 3-amino acid deletion at positions 141 to 143
3. Lineage P.1 (LGV141_143del)
• SARS-CoV-2 Variant B.1.1.28 or B.1.195 • Third generation descendants of P.1
• Brazilian Variant • Discovered from analysis of 33 samples of University of the
• Also known as the Gamma Variant Philippines from samples collected in January to February
• Classified as a Variant of Concern by the World Health 2021
Organization • most widespread is at position 614 (D614G)
• first identified in travelers from Brazil in November 6,2020 • mutations E484K and N501Y are seen in the P.1 and
• Whole-genome sequencing revealed that the two infections B.1.1.248 and many other strain
were caused, respectively, by the two most prevalent SARS- • suggests this region of the spike carries neutralizing epitopes
CoV-2 Brazilian lineages B.1.1.33 (primo-infection) and and is vital for virus entry to host cell
B.1.1.28 (reinfection) • mutation to this placement may bolster resistance to
• the B.1.1.28 virus detected at reinfection corresponds to a new neutralization, making these variants all the more resistant to
emergent Brazilian viral lineage, initially detected in the Rio de antibodies
Janeiro state, containing the mutation E484K in the Spike • unique spike mutations, notably at placements 1092 (E1092K)
protein and 1101 (H1101Y
• recently identified B.1.1.28 subclade (renamed “P.1”) • Astrazeneca vaccine indicate neutralization efficacy of only
• with 12 spike missense mutations 10%
• new variant isolate (GISAID ID: EPI_ISL_792680 to 792683)
belongs to B.1.1.248 lineage and has 12 mutations in the spike
protein, including N501Y and E484K
• variant contains a set of additional mutations that may affect
its ability to be recognized by antibodies
• mutation E484K is located in the receptor-binding domain
(RBD) and has also been recently described in an independent
SARS-CoV-2 lineage rapidly spreading in South Africa
• a variant isolate with E484K belonging to B.1.1.248 was
reported on January 6, 2021 (5), but it is not identical to the
new variant isolate identified in Japan

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6. Lineage B.1.427 and B.1.429 12. Lineage B.1.525
• SARS-CoV-2 Variant B.1.427 and B.1.429 lineages • Also known as the Eta Variant or the Nigerian Variant
• California or West Coast Variant
• Also known as the Epsilon Variant 13. Lineage B.1.526
• Classified as a Variant of Concern by the World Health • SARS-CoV-2 Variant B.1.526
Organization • New York Variant
• • Potentially more transmissible and more virulent
• Emerged in late spring or early summer of 2020 • Concerns about vaccine efficacy and immune escape
• Two variants carry similar, though slightly different, genetic
mutations 14. Lineage B.617.2
• One mutation L425R, may be linked to increased infectivity
• More contagious, causes increase transmissibility and
• More transmissible than local variant
increase immune evasion
• contains four missense mutations in spike, one of which is a
• Also known as the Delta Variant
single L452R RBD mutation
• Classified as a Variant of Concern by the World Health
7. Lineage B.1.1.207 Organization
• Not enough evidence to tell if more severe disease
• SARS-CoV-2 Variant B.1.1.207 • R naught of 5-9
• Nigerian Variant • Monoclonal antibodies may not be as effective
• Also known as the Eta Variant • Can be neutralized by Bharat’s BBV152 Covaxin but with lower
• No evidence of increased transmissibility efficacy
• No evidence of increased disease severity • Resistant to Bamlanivimab
• has L452R, T478K and P681R in the spike protein which may
8. Lineage A.23.1 contribute to increased infectivity, pathogenicity and immune
• SARS-CoV-2 Variant A.23.1 evasion, resulting in re-infection or resistance to vaccine-
• Ugandan Variant elicited antibody and therapeutic antibodies
• Potential for immune escape being investigated • One of Delta-associated variants, B.1.427 and B.1.429 also
• Unknown effect on transmissibility and effect on disease known as Epsilon have L452R mutation, causing reduction in
severity antibody neutralization
• B.1.1.519 has common mutation sites with Delta at T478 and
9. Lineage COH.20G.501Y P681 residues, in common with Alpha variant
• SARS-CoV-2 Variant COH.20G/501Y • Associated with greater transmissibility and higher viral RNA
• Columbus or Ohio variant loads in both unvaccinated and fully vaccinated individuals
• No evidence of increased transmissibility • The Delta variant displaced the Alpha variant to constitute
• No evidence of increased disease severity 88.2% of the circulating lineages in the National Capital Region
by July, 2021.
10. Lineage B.1.1.298 • The Delta variant associated with increased breakthrough
infections in fully vaccinated individuals that were mostly
• SARS-CoV-2 Variant B.1.1.298 symptomatic when compared to the Alpha breakthrough
• Mink Cluster 5 infections
• SARS-CoV-2 transmission between humans and minks in • Delta variant is associated with increased infectious virus loads
Denmark with a variant when compared to the Alpha variant and decreased upper
• harbors a two-amino acid deletion and four missense respiratory antiviral IgG levels.
mutations including Y453F in RBD • Effectiveness after one dose of vaccine (BNT162b2 or
ChAdOx1 nCoV-19) was notably lower among persons with
11. Lineage B.1.617.1 the delta variant than among those with the alpha variant
• SARS-CoV-2 Variant B.1.617.1 / B.1.617.2 / B.617.3 • With the BNT162b2 vaccine, the effectiveness of two doses
• Indian Variant was 93.7% (95% CI, 91.6 to 95.3) among persons with the
• Kappa Variant alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those
• Discovered in October 2020 with the delta variant.
• Very few detections until January 2021 • With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two
• Dubbed as a Variant of Global concern on May 10,2021 doses was 74.5% (95% CI, 68.4 to 79.4) among persons with
• Referred to as “Double Mutation” the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among
• On April 2021, had spread to at least 20 countries in all those with the delta variant.
continents • Increased morbidity was observed in pregnancy with COVID-
• Has 15 defining mutations including: 19 during the recent surge associated with the Delta variant,
o D111D particularly in an underserved pregnant population where
o G142D vaccine acceptance is low
o P681R • significant 2.5-fold higher difference in VL levels between the
o E484Q Delta variant and the Beta variant
o L452R • A two-fold difference in the ORF1ab VL was also observed
• Considered as variant under investigation VUI-21APR-2021 between the Delta variant and the Alpha and Beta variants
• 2 new subvariants B.1.617.2 and B.1.617.3 not considered as • The receptor-binding β-loop-β motif adopts an altered but
variant under investigation VUI-21APR-02 and VUI-21APR-03, stable conformation causing separation in some of the
respectively antibody binding epitopes
• 32% of patients both hospitalised and outside hospitals were • While current vaccines are still shown to be protective against
aged below 30 in second wave this variant, it is also becoming clearer that it can escape the
immune system by making neutralizing Abs from prior
infections or elicited by vaccines less sensitive to binding with
the spike protein.

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18. Lineage B.1.621
• Also known as the Mu Variant/ Colombian Variant
• Listed as Variant of Interest by the WHO
• First detected in January 2021 in Colombia
• Has mutations in protein E484K, K417N (similar with B.1.351)
• Currently known to dominate cases in Florida
• Alters the spike protein via insertion at protein 146N along with
substitutions of amino acid in 195I, 144T, Y145S, R346K,
N501Y, P681H,, currently targeted by RT-PCR and may cause
interference with test results and falsely increasing number of
cases thought to be due to other variants
• Potential immune evasiveness and vaccine resistance

15. Lineage B.1.618

• Has been growing recently in West Bengal
• First detected in October 2020
• Has a mutation in E484K
I. Summary of Variants
Variant Transmissibility Virulence Immune Vaccine Impact on
16. Lineage C.37 Evasion Efficacy Tests
UK Increased Some evidence Little to no Little to no Decreased
• First detected in December 2020 in Peru B.1.1.7 of increased concern concern sensitivity of
• Also known as Lambda Variant South Increased No evidence Potential Possible Effect
only S gene
No Known
• May have increase resistance to COVID-19 vaccines African Impact
B.1.351
• Designated as Variant of Interest in June 14,2021 by WHO Brazilian Potentially No evidence Unknown Increased No Known
P.1 more propensity Impact
Philippine Potentially Requires more Currently being Currently being No Known
17. Lineage C.1.2 P.3 more investigation investigated investigated Impact
Japanese Potentially Requires more Currently being Currently being No Known
• First discovered in the South Africa in June 2021 B.1.1.248 more investigation investigated investigated Impact
• Causes concern as mutation from the wild type virus Californian Potentially Requires more Requires more Requires more No Known
B.1.429 more investigation investigation investigation Impact
• Mutant strain of the Lambda Variant C.1 Nigerian No evidence of No evidence Unknown Unknown No Known
• Furthest strain that has mutated from the pango lineage B.1.1.207
Ugandan
increase
Unknown Unknown Potential Currently being
Impact
No Known
• 41.8x mutation rate which could possibly impact vaccine A.23.1 investigated Impact
effectiveness and immune evasion Columbus No evidence of No evidence Unknown Unknown No Known
COH.20G increase Impact
• It has mutations of proteins N440K and Y449H New York Potentially Potentially Potential Potential No Known
B.1.526 more more virulent Impact
• Currently detected in England, Portugal, Mauritius, China, and Mink No evidence of No evidence Requires more Requires more No Known
New Zealand Variant increase investigation investigation Impact
B.1.1.298

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WHO Lineage Informally Transmissibility Immune Vaccine
Name Known As Evasiveness Effectiveness
B. Blood Vessels, Heart, Brain, Kidney
WILD
TYPE
WIV04
STRAIN
Wuhan Baseline - ü • binds to endothelial cells and causes damage to the blood
ALPHA B.1.1.7 UK +++ - ü vessel (endothelial shedding, and thrombosis) especially the
BETA B.1.351 South + ++++ ü microcirculation of the small blood vessels à leads to platelet
Africa
GAMMA P.1 Brazilian ++ ++ ü aggregation à increased blood clots è increased D-dimer
DELTA B.1.617.2 Indian ++++ ++ ü levels
KAPPA B.1.617.1 Indian ++++ ++ ü
EPSILON B.1.429 California ü
• also causes fine interstitial mononuclear inflammatory
+ ++
ETA B.1.525 Nigerian UI + ü infiltrates but no viral inclusions in the heart
IOTA B.1.526 New York UI + ü • could predispose patients into hypoxia-induced myocardial
THETA P.3 Philippines + + ü injury, cardiac microvascular damage, and systemic
ZETA P.2 Brazilian + + ü
MU B.1.621 Colombian ü inflammatory response syndrome
LAMBDA C.37 Peru ü • Fulminant myocarditis à may mimic STEMI

C. Expression of ACE-II Receptors in the Body

III. Pathogenesis
A. Lungs
• Causes Acute Respiratory Distress Syndrome
• S1 sub-unit of the receptor binding domain of spike has a
significant effect on SARS-CoV2-spike/ACEII interaction and
produced a reduction in the binding energy è Cause of rapid
viral spread in humans
• Coronavirus binds to ACE-II
receptor in the lungs à fluid
builds up within the lung alveoli
à causes severe inflammatory
reaction to the lungs à Severe
lung damage à ARDS
• Severe infection of the lung à
causes septic shock (Fever and
Hypotension)
• FEVER and SHOCK – are the
main cause of death for people
with the infection
• Initially diagnosed as “pneumonia of unknown etiology” • ACE2 receptor is expressed in the lungs, small intestine, testis,
o defined as an illness without a causative pathogen kidneys, heart, thyroid, adipose tissue, brain, blood vessels,
identified that fulfills the following criteria: and muscle
§ fever (≥38°C),
§ radiographic evidence of pneumonia,
§ low/normal white-cell count or low lymphocyte
count,
§ no symptomatic improvement after antimicrobial
treatment for 3 to 5 days following standard clinical
guidelines

IV. Immunology of COVID-19

• Innate Immune Sensing
o first line of antiviral defense and is essential for immunity
to viruses
• Virus-Host interaction pathways are initiated through
engagement of pattern-recognition receptors (PRRs) by viral
single-stranded RNA (ssRNA) and double-stranded RNA
(dsRNA) via cytosolic RIG-I like receptors (RLRs) and
extracellular and endosomal Toll-like receptors (TLRs)
• PRR activation à downstream signaling cascades trigger the
secretion of cytokines
o proinflammatory tumor necrosis factor alpha (TNF-α), and
interleukin-1 (IL-1), IL-6, and IL-18
• IFN is protective early in disease but later becomes pathologic

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 COVID-19
• Reduced numbers of NK cells in the peripheral blood of • Strict social distancing guidelines, the population remains
COVID-19 patients, which is associated with severity of the unexposed to the virus to develop herd immunity
disease • Shield immunity concept has the potential to enrich safer social
• NK cells express inhibitory and activating receptors that networks through substitution of interactions to control the
regulate their cytotoxicity. evolving dynamics of pandemic.
• Patients with mild symptoms, however, typically present with
normal or slightly higher T cell counts
• Cause of peripheral T cell loss in moderate to severe COVID-
19, though a phenomenon also observed in other viral
infections, remains elusive, and direct viral infection of T cells
• CD8 T cells seem to be more activated than CD4 T cells
• CD8 T cells in severe COVID-19 appear less cytotoxic and
effector-like with reduced CD107a degranulation and
granzyme B (GzmB) production
• Humoral immune response is critical for the clearance of
cytopathic viruses and is a major part of the memory response
that prevents reinfection
• Seroconversion occurs in most COVID-19 patients between 7
and 14 days after the onset of symptoms
• Antibody titers persist in the weeks following virus clearance
• The B cell response to a virus serves not only to protect from
the initial challenge, but also to offer extended immunity
against reinfection
• IgG specific to SARS-CoV-2 trimeric spike protein was
detectable in serum up to 60 days after symptom onset, but
IgG titers began decreasing by 8 weeks post symptom onset
• Immunity to SARS-CoV-2 may diminish following a primary
infection
• Blood group A to be associated with a higher risk for acquiring
COVID-19 when compared to non-A blood groups; blood
group O had the lowest risk for the infection
• Low eosinophil count has been suggested as a poor prognostic
marker in COVID-19 patients
• Decreased production of type I and III IFN is maintained during
the late stages of disease (14 days post infection),
accompanied by increased production of pro-inflammatory
cytokines such as IL-6, IL-8, and TNF
• chain breaks when a significant proportion of the population
has immunity against the viral or bacterial disease, through
what is known as herd immunity
V. Clinical Manifestations, Risk Factors and Complications
of COVID-19
A. Risk Factors For Acquiring the Disease
• Increased age (>60 years old)
• Obesity
o BMI 25-29.2kg/m2 has `12% need for invasive mechanical
ventilation
o BMi >45kg/m2 has 108% higher need for mechanical
ventilation
• Smokers
• Previous Medical conditions
o Diabetes Mellitus
o Hypertension
o Pulmonary Diseases (Asthma, Emphysema, COPD)
o Heart Disease
o Kidney Disease
o Weakened immune system
o Cancer
o Cerebrovascular Diseases
o Children with underlying conditions
o Chronic Kidney Disease
o Down Syndrome
o Pregnancy
o Sickle cell disease and Thalassemia
o Substance use disorders
o Use of corticosteroids and other immunosuppressive
medications
o Solid organ or blood stem cell transplantation
o HIV
o Neurologic conditions such as dementia

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ANG, D.K.
 COVID-19
• Possible risk factors but mixed evidence
o Asthma
o Immune deficiencies
o Liver disease

B. Risks Factors For Death

• Lack of Oxygen due to damage can cause increased risk for
heart attacks, kidney failure, strokes, clotting disorders
• Risk depends on access to care and general health
• Death is rare among young and healthy people
• More common in older adults
o 65-75 y/o (2-5% die)
o 75-85 y/o (4-10% die)
o > 85 y/o (>10% die)

C. Incubation Period and Temporal Profiles

E. Signs and Symptoms
• Days before the virus manifest
• 5-24 days (Average abundance of caution: 14 days) • 90% of cases presented with >1 sign or symptom
• Mean incubation period: 5.2 days • Most common complaint are Fever & Dry Cough
• Traces of virus can be found in stool samples 33 days after • Fever >108.4F or >38C 98-99%
1st symptom onset (suggesting oral-fecal transmission) • Dry Cough 76-82%
• 4 days median time between symptom onset to • Shortness of Breath/ Dyspnea 31-55%
hospitalization o = develops at around Day 8
• Older COVID-19 patients and those with severe disease had • Runny Nose 4%
higher viral load • Fatigue 70%
• Underlying chronic illness did not affect the viral load of SARS- • Myalgia 29-44%
CoV-2 • Sore throat 5-17.4%
• Amount of SARS-CoV-2 detected in COVID-19 patients were • Sputum production 27%
highest in the 1st week when symptoms appeared • Headache 6.5-8%
• Antibodies were detected 10 days after symptom onset and • Chills
viral load gradually decline as more antibodies were produce • Nausea/Vomiting 10%
• Virus still detectable even after 3 days • Hemoptysis
• Congestion (either Nasal or Conjunctival)
• Diarrhea 3-10%
• Ageusia 64-80%
• Anosmia 64-80%

Day Symptom Infection Grade

0 No Symptoms Exposure
Influenza-like illness
4 Loss of taste/smell Mild Infection
Pneumonia
Dyspnea; Hypoxia
9 Severe Infection
Severe pneumonia
Respiratory failure
12 Critical Illness
Shock; Multi-organ failure
D. SARS-CoV-2 Transmission According to Stage of
Infection
Stage of Infection Pre-symptomatic Symptomatic Post-Acute
Asymptomatic Symptomatic
RNA detectable in Yes Yes Yes
Respiratory Samples, Often
Blood, and Feces prolonged
Viable Virus Yes Yes No
Detectable in
Respiratory Samples
Transmission Can Yes Yes No
Occur
Mode of Transmission
Droplet Yes Yes No
Natural Aerosol Strongly Suspected Yes No
Aerosol-Generating Strongly Suspected Yes No
Procedure
Direct Contact Suspected Strongly No
Suspected
Indirect Contact Suspected Suspected No
Enteric Route Unknown Unknown No
Minimum Recommended Level of Precautions
Protection from Yes Yes Accordance
Droplet and Contact with updated
Transmission during standard
routine care precautions
Protection from Yes Yes (Face mask,
Airborne & Contact Face shields,
Transmission during
Goggles)
aerosol-generating
procedure

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 COVID-19
F. Findings • So you know patient was infectious 2 days before they became
• Previous travel to Wuhan or other infected countries with ill and at least 10 days after their onset
outbreak • Making the patient highly infectious from July 7-19
• + History of exposure to patients with COVID-19
• Fever 3. When to start contact tracing?
• Elevated Respiratory Rate • Always identify the infectious period
• Respiratory distress (Use of Accessory Muscles of • Most important date to identify are the contacts the patient had
Respiration) 2 days before the patient fell ill
• Widespread crackles on auscultation • So in this case, identify all contacts from July 7-10

G. PUM vs PUI Old Classification

Person Under Person Under
Investigation Monitoring
Travel History + +
Exposure + +
Signs and Symptoms + -

H. Old VS New Classification

Old New
Neither PUI nor PUM Non-COVID case
Possible case
PUM (With exposure/contact, 4. How long should the people have in contact with the
but no symptoms) patient stay in quarantine?
PUI -mild, severe, critical
has not been tested/for testing
Suspected case • 14 days following the LAST contact
PUI -mild, severe, critical with • Almost all infected will develop illness within 14 days
inconclusive, inadequate or Probable case • If patient develops symptoms, it should be considered a case
unavailable testing
COVID-19 + Confirmed case B. Factors that Increase Risk for Infection and Severe
Disease
I. CDC Updated Guidance 1. Populations at increased risk
• Prior Guidance: an infected person must à • Dense contact environment
o isolate for at least 10 days after onset of symptoms, and o Large crowds of people
o may be released from isolation if their symptoms have o Close contact interaction
improved AND o Within 6 feet for prolonged periods of time
o They have no fever, without the use of medicines for o Can lead to a superspreading event
at least 3 days • An unusually high reproductive number
• New Guidance: an infected person must à o Examples: Conferences, mass transit, religious services,
o Isolate for at least 10 days after onset of symptoms, and demonstrations, workplaces, bars, gyms, schools,
o May be released from isolation if their symptoms have sporting events, concerts
improved AND • Difficult to contact trace and identify exposures
o They have no fever, without the use of medicines for o Close contact may be unknown
at least 24 hours o Recall of close contacts may not be reliable
o Too many contacts
J. Isolation VS Quarantine o Difficult to determine who is at highest risk for infection
Isolation Quarantine o Examples: Concerts, Restaurants, Clubs, Bars, Homeless
Keeps sick people separate from healthy people Restricts movement shelter
Restricted to home or hotel and contact of healthy • Difficult to isolate or quarantine
people who have been o Unable to distance from others
Separate space in hospital to limit contact exposed
o Developmental disabilities
For duration of infectiousness:
o Not enough resources
• 2 days before onset For 14 days since the
o Social pressures
• <10 days after onset of illness, symptoms last contact with the
must be improving and no fever within the person who is infected o Unwilling to cooperate
past 3 days o Example: Intermediate Care facility (Home of individuals
with special needs, uncooperative residents)
VI. Contact Tracing • Higher risk of infection and severe disease or death
o May be more likely to get infected due to close contacts
• Is a public health intervention that is used every day to stop o More likely to have underlying conditions
disease transmission o May get exposed to the virus multiple times
A. Questions to be Asked
1. Infectivity
• Most infectious 2 days before the symptoms occur
• Infectious within 10 days after first symptom onset
• Infectious till 24 hours after symptom resolution

2. Case example
• Assume you call the case on July 10
• Patient tells you he became ill on July 9

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C. Basic Steps in Contact Tracing D. Ethical principles for Contact Tracing
1. Ethical Principles
a. Privacy
o Right of a person to be free from intrusion or publicity
concerning personal matters
o Everyone has the right to keep their personal life personal

b. Confidentiality
o Right of an individual to have personal, identifiable
medical information kept private and not released without
his/her/their consent
1. Step 1: Calling the case o Your medical information cannot be shared with anyone
o Identify organization else unless you agree -- but your COVID-19 test results
o Confirm identity and residence can be shared to protect public health
o Discuss the positive test
o Describe the importance of the call c. Autonomy
o Confirm that the call is confidential o Right of a person to make their own decisions, it is known
as right to “self” or as “agency”
2. Step 2: Inquire about infectious period
o Ask questions to determine the infectious period d. Justice
o Ask for symptoms o act to treat an individual justly or fairly regardless of race,
o Ask when did the symptoms develop ethnicity, creed, background, sexual orientation, gender,
or socioeconomic status
3. Step 3: Identify contacts
o Ask questions to list the case’s contacts e. Public Good
o Anything that benefits or provide for the well-being of the
4. Step 4: Instruct on how to isolate public
o Four components of isolation instructions
§ Explain isolation in simple terms 2. Three Legal Tests
§ Ask questions to check that they understand • Intervention must be respectful of individuals and their rights
completely and help them plan • Must be a benefit to society that is balanced with the limits on
§ Identify challengers that may stop them from individuals
following your isolation instructions • Must benefit all members of society
§ Offer resources to improve their chances of
following your isolation instructions 3. Respect for Privacy and Confidentiality During Contact
5. Step 5 Call contacts Tracing
o Inform about exposure • Assure cases and contacts that the information provided will
o Ask about symptoms be confidential and used ONLY for the public health
o Instruct on quarantine investigation and will not be shared with anyone else
o Answer their questions • Assure cases and contacts that the information will be kept
o Make a plan to follow-up private – contacts identified will be told that they have been
exposed, but they will not be told who the case is
6. Step 6: Implement regular check-ins with the case and
contacts 4. Rationale for using technology for contact tracing
o You may regularly check with cases and contacts to
• Public health staff time is often limited
determine when they can end their isolation or quarantine
• Timing of events is very important – we need to reach people
quickly
• Technology can improve efficiency and speed of some public
health functions
• Technology should meaningfully improve the process without
creating major difficulties

5. Example of Technology Used

• Phone to phone notification of contacts
• Centralized database of phone numbers and locations

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VII. Pathology 4. Histologic changes from case 1.
1. Cytoblock Preparation of Pleural Effusion Fluid (A) Proteinaceous exudates in alveolar spaces, with granules;
• Aggregates of dysmorphic mesothelial cells with enlarged (B) scattered large protein globules (arrows);
nuclei and multinucleated cells and enlarged nuclei (C) intra-alveolar fibrin with early organization, mononuclear
• These features suggest viral infection as confirmed by inflammatory cells, and multinucleated giant cells;
positivity of RT-PCR for SARS-CoV-2 on cytological specimen (D) hyperplastic pneumocytes, some with suspected viral
inclusions (arrow).

2. Cytoplasm of Type II Pneumocyte

• Post-mortem autolytic
phenomena prevent a precise
visualization of sub-cellular
compartments. 5. Histologic changes of coronavirus disease 2019
• Several spherical particles pneumonia in case 2.
outlined with electron-dense (A) Evident proteinaceous and fibrin exudate;
dots that could mimic (B) diffuse expansion of alveolar walls and septa owing to
coronavirus-like virions. fibroblastic proliferations and type II pneumocyte hyperplasia,
• Some of these particles are consistent with early diffuse alveolar damage pattern;
clathrin-coated intracytoplasmic (C) plugs of proliferating fibroblasts or “fibroblast balls” in the
vesicles (arrowheads) or cross- interstitium (arrow);
sections of the rough endoplasmic reticulum (D) abundant macrophages infiltrating airspaces and type II
• Evident microvesicular body/autophagosome (arrow) pneumocyte hyperplasia.

3. Microscopic examination from peripheral border to the 6. Pathogenesis of COVID-19 from A Cell Biology
center of the lesion shows:
o A: Alveolar wall edema, congestion congestion, infiltration
of lymphocytes, neutrophils and eosinophils and fibrin
material deposition,
o B: Alveolar spaces filled by fibrinoid material deposition
admixed with mixed inflammatory cells infiltration,
o C: Early alveolar destruction with infiltration of
inflammatory cells and fibrinoid material deposition,
o D: Complete destruction of alveolar spaces with necrosis.

• Human alveolar type II cells infected with SARS-CoV

• Viral particles are seen in double membrane vesicles in the
type II cells (left panel) and along the apical microvilli (right
panel)

7. Placental Pathology
• COVID-19 placentas show increased prevalence of decidual
arteriopathy and other features of MVM
• Maternal Vascular Malperfusion (MVM)
• Fetal Vasculr Malperfusion (FVM)
• No pathognomonic features are identified
• Increased rates of maternal vascular malperfusion features,
and intervillous thrombi, suggesting a common theme of
abnormal maternal circulation
• Presence of diffuse perivillous fibrin and an inflammation
infiltrate composed of macrophages as well as T lymphocytes
• A pattern of placental injury reflecting abnormalities in
oxygenation within the intervillous space associated with
adverse perinatal outcomes.

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1. Sudden Strokes in young adults
• First reported in adults in 30s and 40s who are not otherwise
terribly ill
• Increased clotting in the larger arteries causing severe strokes
• FAST mnemonic for suspected stroke
o F = Facial Drooping
o A = Arm weakness
o S = Speech difficulty
o T = time to call 911
• Large vessel occlusion
• Young patient didn’t have risk factors for stroke and mortality
has much higher than expected (close to 50%)
• 5 patients in New York adults ranging from late 20s-early 40s
o Mostly has no known co-morbidities
• A, Maternal arteriole with atherosis and fibrinoid necrosis
• Must receive the standard stroke care and should be evaluated
• B, Small focus of fetal villi with lymphocytic villitis
for potential thrombolysis with intravenous tissue plasminogen
• C, Intervillous thrombus showing lines of Zahn
activator (tPA) or tenecteplase (TNK) along with endovascular
• D, Fetal villi with chorangiosis and edema thrombectomy (ET) when large vessel occlusion is suspected
VIII. COVID-19 Complications 2. Ischemic Stroke in adult patients
A. Most Common Complications • Case presented in Wuhan with Acute Ischemic Stroke
Complication % Median o 79 y/o man presenting with right limb weakness & cough
ARDS 19.6 12 days o Caused hypoxemia and excessive secretion of
Arrhythmia 16.7 inflammatory cytokines
Shock 8.7 o Clopidogrel 75mg and Atorvastatin 20mg orally given
Acute Cardiac Injury 7.2 15 days to treat the patient
Sepsis 9.0 days o Recovered after 12 days and can walk normally and
communicate with near fluent language
Pulmonary Fibrosis Young people
• 6 patients reported in QueenSquare, UK with acute ischaemic
Acute Kidney Injury 15.0 days
stroke and markedly elevated D-dimers (>1000 ug/L)
ECMO 3-4% o Ages from 53-64
Invasive Ventilation 2-17% o Had co-morbidities such as Hypertension, Diabetes, Atrial
Discharged 28-47% Fibrillation
Death 6-11% o Received high-intensity LMWH
Clinical Course of COVID-19 Patients among survivors vs non-survivors
3. Sign, Symptoms and Physical Examination Findings Acute
Ischemic Stroke in Confirmed COVID-19 patients
• Reduced consciousness
• Progressive dysarthria with both numbness and weakness in
her left arm and leg
• Inability to speak
• Right-sided weakness
• Right-sided facial droop
• Inability to speak or comprehend
• Conjugated gaze preference toward the left side
• No blink to threat on the right side
• No movement in the right arm and leg

B. Evaluation of Patients in Shock E. Presumptive Case of Encephalitis

• Check for Bedside Shock Index if >1 • Clinicians from Henry Ford Health System in Detroit Michigan
o Compute by measuring Systolic BP and Heart Rate • Reported 1st “Presumptive Case of Acute Necrotizing
o Formula = Heart Rate/Systolic BP Hemorrhagic Encephalopathy”
• Check for GCS if alert • Presentation of the patient (same presentation as COVID-19)
• Check for Capillary refill time (Cold extremities) o Fever
o Normal <2 secs o Cough & Dyspnea
o Abnormal >4 secs o Muscle aches
• Check for Urine Output o Confusion/Disorientation/Lethargy
o Normal: 1mL/kg/hr • Diagnosed via: Neuroimaging
o CT Scan (Non-Contrast): Symmetric Hypoattenuation
C. Evaluation of Dyspnea within bilateral medial thalami with normal CT angiogram
and CT Venogram
• Early evaluation of silent hypoxia o MRI: Hemorrhagic rim enhancing lesion within bilateral
• O2 saturation must be >94% thalami
• Check for signs and symptoms • Treatment: Intravenous Immunoglobulin
o Altered consciousness / Unconsciousness
• Acute Necrotizing Encephalopathy (ANE)
o Use of accessory muscles/ retractions
o Rare complication of viral infections
o Cold extremities / Cyanosis
o Until now has not been known to have occurred sa a result
o Tripod positioning / Slow or rapid breathing
of COVID-19 infection
• Presence of Crackles and Rhonchi o Has been associated with intracranial “cytokine storm”
D. COVID-19 related Strokes
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• 6 patients reported (2 from China, 2 from Switzerland, 1 from
Japan, 1 from US)
o Presenting symptoms: Fever, Cough, Deteriorating level
of consciousness
o (+) Nuchal rigiditiy, Bruzinski, Kernigs
o Lumbar puncture: Lymphocytic pleocytosis typical of viral
meningoencephalitis
o Tx: IV Clobazam and Valproate

A, Unenhanced CT scan of head demonstrates symmetric low attenuation within the bilateral medial
thalami (arrows). B, Axial CT venogram demonstrates patency of the cerebral venous vasculature,
including the internal cerebral veins (arrows). C, Coronal reformation of CT angiogram demonstrates G. Cytokine Storm Syndrome & Immunosuppression
normal appearance of the basilar artery and proximal posterior cerebral arteries.
• Secondary Hemophagocytic lymphohistiocytosis (sHLH)
o Underrecognized hyperinflammatory syndrome
characterized by a fulminant and fatal
hypercytokinaemia with mutli-organ failure
o Most commonly triggered by viral diseases
o Occur in 3.7-4.3% of sepsis cases
o Symptoms include:
§ Unremitting fever
§ Cytopenia
§ Hyperferritinaemia
§ Pulmonary involvement
o Characterized by increase in the following:
§ IL-2, IL-7, Tumor necrosis factor
§ Granulocyte-Colony Stimulating Factor
§ Interferon-Y inducible protein 10
§ Monocyte chemoattractant protein 1
§ Macrophage inflammatory protein 1-A
F. Other Neurologic Manifestations • Central mediator for the lung injury and resulting ARDS found
1. Guillain-Barre Syndrome associated with COVID-19 in cases of severe or critical COVID-19 patients
• Clinical Manifestations: • Elevated IL-6 and Ferritin = suggests mortality may be due to
o Acute progressive symmetric ascending quadriparesis hyperinflammation
o Lower-limb weakness • Therapeutic options include:
o Paresthesia o Selective Cytokine Blockade (Anakinra & Tocilizumab)
o Facial diplegia o Intravenous Immunoglobulin
o Ataxia o JAK inhibitors
• AMSAN variant of GBS o Steroids
• Proposed Mechanism: COVID-19 stimulates inflammatory • Hscore = generates probability for the presence of secondary
cells and produces various inflammatory cytokines à creates HLH
immune-mediated process • Bone marrow hemophagocytosis = not mandatory for
• GBS – is an immune mediated disorder and molecular mimicry diagnosis
as a mechanism of autoimmune disorder plays important role • Defined as all criteria combined or either:
in creating it o HgB <9.2 mg/dL
• It is unclear if COVID-19 induces production of antibodies o WBC <5000 mm
against specific gangliosides o Platelets <110,000 mm or less

• 2/3 have prior COVID-19 infection before onset of symptoms H. Musculoskeletal Manifestations
• Therapy: 1. Rhabdomyolysis
o Intravenous Immunoglobulin 0.40g/kg/day • Presented with pain and weakness in lower limbs and
o Plasmapheresis tenderness on physical examination
• Urgent laboratories:
2. Bell’s Palsy o Increased myoglobin (>12,000 ug/L)
• Left facial droop preceded by 2 day history of pain in the o Increased Creatine kinase (11,842 U/L)
mastoid o Increased Lactate dehydrogenase (2347 U/L)
• No fever, cough, or respiratory symptoms o Increased Alanine aminotransferase (111 U/L)
• Tx: Ribavirin and Umifenovir o Increased Aspartate aminotransferase (213 U/L)
o Normal kidney function tests and electrolytes
3. Acute Myelitis o Urinalysis – light yellow color of the urine
• Presented with Bilateral weakness of lower limbs, urinary and o + occult blood test
bowel incontinence, rapidly progressing to flaccid lower o + urine protein
extremity paralysis and paresthesia and numbness below T10 • Tx: Hydration, Supportive therapy, Alkalinization, Plasma
• Tx: Gancyclovir, Lopinavir/Ritonavir, Moxifloxacin, transfusion, gamma globulin
Dexamethasone, IVIg, Mecobalamin

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2. Myalgia and Myositis
• Significantly higher creatine kinase
• Higher CRP and levels à manifestation of increased
inflammatory response and associated coagulopathy

I. Pulmonary Vascular Endothelialitis, Thrombosis, and

Angiogenesis
• Progressive Respiratory Failure
o Primary cause of death of COVID-19
o Histologic pattern of peripheral lung in autopsy:
§ Diffuse Alveolar Damage With Perivascular T-
Cell
§ presence of distinctive vascular features, severe
endothelial injury associated with the presence of
intracellular virus and disrupted cell membranes
o Histologic analysis of pulmonary vessels
§ Widespread thrombosis with microangiopathy
• Alveolar capillary microthrombi were 9x prevalent in COVID-
19 vs Influenza
• Presence of new vessel growth (by form of intussusceptive
angiogenesis) = 2.7x higher in lungs vs Influenza

4. Fulminant Myocarditis
• Manifestations of fever, cough, dyspnea,
• Past history of Hypertension
• MR scan shows
J. Cardiac Manifestations and Complications
o Subepicardial late gadolinium enhancement of the apex
1. Acute Myocardial Infarction and inferolateral wall – suggestive of myocarditis
• Evidence of cardiac injury was associated with 5-fold increase • Cytokine Storm = main pathophysiologic mechanism and is
in the need for invasive mechanical ventilation reasonable to consider heart damage
• 11-fold increase in mortality o Increased in the levels of IL-1, IFN-g, MCP-1, GCSF, MIP-
• Markers of myocardial injury were predictive of the risk of in- 1A (Macrophage Inflammatory Protein), TNF
hospital mortality in patients with severe COVID-19 o Direct myocardial injury from pro-inflammatory cytokines
• Case report described a patient with low-grade myocardial o Including endothelial cells
inflammation and myocardial localization of coronavirus • Acute plaque rupture – leading to acute coronary syndromes
particles (outside of cardiomyocytes), as measured by as part of systemic inflammation and catecholamine surge à
endomyocardial biopsy, suggesting that SARS-CoV-2 might increased plaque vulnerability à precipitates acute coronary
infect the myocardium directly syndrome
• Revealed the presence of mild inflammation and viral RNA in
the hearts of patients with COVID-19 5. Cardiac risk factors and established CVD
• A marked increase in macrophage infiltration with evidence of o Heightened vulnerability to develop COVID-19
myocardial damage was also detected, suggesting that SARS- o Tend to have more serious clinical outcomes
CoV can infect the heart directly o Based on (Wang et al) (Huang et al) (Zhou et al)
§ Hypertension
2. Heart Failure § Coronary Artery Disease
• Most commonly observed complications of COVID-19, with a § Cardiovascular disease
reported incidence of 24% in all patients and 49% in patients
who died 6. ECG & Cardiac Marker changes
• MRI might help to detect changes induced by COVID-19 in • ECG changes
patients with heart failure with preserved ejection fraction, o Signs of Left Ventricular Hypertrophy
cardiac o Diffusely inverted T waves in anterior leads
• Acute myocardial injury and ACS triggered by COVID-19 o Non-ST elevation MI
can also aggravate pre-existing heart disease or provoke o Concave ST-segment elevation
contractile dysfunction. In the advanced stages of COVID-19 o PR-segment depression
• Troponin I = may be increased over 10,000 ng/L
3. Arrhythmias and sudden Cardiac Arrest • CK-MB = > 100ng/L
• Patients with elevated levels of troponin T were more likely to • Pro-BNP increased
develop malignant arrhythmias, such as ventricular • Echocardiography
tachycardia and fibrillation, than those with normal levels of o Pericardial effusion (+)
troponin T o Myocardial thickening (may be seen as concentric
• Exact contribution of COVID-19 to cardiac arrhythmias hypertrophy)
remains uncertain given that arrhythmias • Transthoracic echocardiography – recommended for an
• Heart palpitations have been reported to be the main inpatient with heart failure, arrhythmia, ECG changes, or newly
presenting symptom of COVID-19 in patients without a fever diagnosed cardiomegaly
or cough

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7. Cardiac Biopsy K. Kawasaki-like Disease
• Not all patients with fulminant myocarditis in COVID-19 • Rare acute pediatric vasculitis with coronary artery aneurysms
patients would have (+) RNA in cardiac myocytes as main complication
• Presence of Interstitial Mononuclear Inflammatory cells = o Diagnosed mainly with persistent fever, exanthema,
COVID-19 + Fulminant myocarditis lymphadenopathy, conjunctival injections
• Incidence 30-fold increase than the normal Kawasaki
8. Management • Majority responds well to Intravenous Immunoglobulin
o Based on Case reports from Lombard, Italy • Pediatric patients would manifest as:
§ Aspirin o Shock
§ Fondaparinux o Multisystem inflammation
§ Hydrocortisone o Coronary artery aneurysm
o Based on Case report from Barcelona, Spain • Theory: might represent post-infectious inflammatory
§ Immunoglobulins 80mg/d for 4 days syndrome which might be immune-complex mediated since
§ Methylprednisolone 500mg/day at tapering doses there are no evidence of viral replication
for 14 days • Mostly mediated by the innate immunity
§ IFN B 0.25mg/48h • Some patient are temporarily diagnosed as “Pediatric
§ Ritonavir/Lopinavir 400mg/100mg/12h Inflammatory Multisystem Syndrome temporarily associated
9. Use of ACEI and ARBS with SARS-CoV-2”/ “PIMS-TS
• Multiple cardiac societies (AHA, ACC, ESC)
o Previously did not recommend the use of ACEI or ARBS 1. Kawasaki disease Shock Syndrome
o ACEI who express excess ACE receptors has been o Defined as presence of macrophage activation syndrome
postulated to increase risk of contracting COVID-19 (MAS), circulatory dysfunction
• Neither ACEI nor ARB use was associated with increased o Defined as systolic arterial hypotension (decrease by
likelihood of COVID-19 infection. >20%), appearance of signs of peripheral hypoperfusion
• Decreased odds of COVID-19 infection among adults o Kawasaki-like presentations were managed as Kawasaki-
≥85 years using ACEIs warrants further investigation. Disease using the American Heart Association (AHA)
• RAAS blockers alter the evolution of the disease, thereby guidelines
mainly affecting its severity
• Neither ACE inhibitors nor ARBs showed an independent
association with Covid-19 in patients with mild-to-moderate 2. Criteria for Diagnosis
disease or in those with severe disease o Criteria used for Classic Type:
• Covid-19 had much more frequent use of loop diuretics and § Fever > 5 days + >4 clinical criteria:
mineralocorticoid-receptor antagonists than controls, and • Bilateral bulbar non-exudative conjunctivitis
treatment with loop diuretics was associated with an increased • Changes of lips or oral cavity
risk of Covid-19 in the multivariable analysis • Non-suppurative laterocervical lymphadenopathy
• Polymorphic rash
10. QTC prolongation • Erythema of palms and soles
• Several COVID drugs would affect QTc prolongation • Firm induration of hands or feet or both
• Close monitoring of drug-drug interaction o Criteria used for Incomplete Type:
• Monitor ECG changes of QTc and electrolytes (Magnesium, § Fever >5days + 2/3 aforementioned criteria
Potassium) before and after starting medications o CRP, ESP = was taken as additional diagnostic criterion
in association with presence of anemia, thrombocytosis
11. Potential Side Effects of Medications currently used for after 7 days of fever
COVID-19
3. Treatment
• QTc prolongation and Risk for Torsade de pointes
o Combination of Azithromycin + Hydroxychloroquine o IV Immunoglobulin 2g/kg (accdg to Kobayashi score)
• Disorders of Cardiac conduction o Aspirin maintained until 48 hours after defervescence and
o Interferon and Hydroxychloroquine continued at an antiplatelet dose of 3-5mg/kg/day for 8
• Tocilizumab - Increases Cholesterol levels weeks
• Remdesivir - Hypotension and Bradycardia Kobayashi Score <5 Kobayashi Score >5
• Interferon – Myocyte toxicity Aspirin 50- Aspirin 30mg/kg/day for 5 days &
• Ribavirin (+ lopinavir/ritonavir) - reduces effect of warfarin 80mg/kg/day for 5 Methylprednisolone at 2mg/kg/day
• Methylprednisolone – hypertension, Fluid retention, Electrolyte days for 5 days taper for 2 weeks
derangements • Response to treatment = Normalization of vital signs, CRP,
blood tests, resolution of signs and symptoms
12. Prognosis
• 80% will get mild form of disease
• 15% critical cases and requires hospitalization
• 5% intensive care
• 2-5% mortality rate

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L. Pediatric Inflammatory Multisystem Syndrome 1. Criteria in Diagnosing MIS-C
temporarily associated with SARS-CoV-2 (PIMS-TS) • patient is 21 years of age or younger and has had a fever of
• European Center for Disease Prevention and Control 38°C for at least 24 hours
• Presenting signs and symptoms of Kawasaki Disease and • blood work shows indications of inflammation
Toxic Shock Syndrome • requires treatment at a hospital (often in the intensive care
• Multi-system Inflammatory Syndrome (MIS-C) led to unit)
serious and life-threatening illness in previously healthy • due to severe illness that includes dysfunction of two or more
children and adolescents organs, particularly the heart, blood vessels, GI organs, lungs,
• A serious, rare condition in children in which the body’s own kidneys, skin, eyes, or nervous system
immune system overreacts to a stimulus • absence of other diagnoses that explain inflammatory
• Results in inflammation of multiple organ systems → leads to symptoms
impaired organ function and organ failure • A positive test for current or past infection by SARS-CoV-2, or
• Diagnosed in <21 years of age in mostly Europe and the USA failing a positive test, evidence of exposure to someone with
• Median hospitalization stay is at 7 days the virus within four weeks of the onset of symptoms of MIS-C
• Most common system involvement: • Evidence of inflammation (including but not limited to 1 or more
o Gastrointestinal System 92% of the ff)
o Cardiovascular 80% o Elevated CRP
o Hematologic 76% o Elevated ESR
o Mucocutaneous 74% o Elevated fibrinogen
o Respiratory 70% o Elevated procalcitonin
o Elevated D-dimer
o Elevated ferritin
o Elevated LDH
o Elevated IL-6
o Elevated neutrophils
o Reduced lymphocytes
o Low albumin
• Other evaluations:
o ECG
o 2D echocardiography
o Cardiac enzyme or troponin
o B-type natriuretic peptide

2. Treatment
• There is no evidence that recovery from MIS-C differed after
primary treatment with IVIG alone, IVIG plus glucocorticoids,
• Characterized by: or glucocorticoids alone, although significant differences may
o Fever emerge as more data accrue
o Abdominal Pain or GI symptoms (50-60%) • The adjusted odds ratios for a reduction in disease severity
o Rash were similar in the two groups, as compared with IVIG alone
o Conjunctivitis (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids
o Irritablity alone).
o Cardiac Involvement • The time until a reduction in disease severity was similar in the
• 2 fatalities (1 in UK, 1 in France) three groups.
• All reported cases to were between age 0-14
• Most patients had elevations in > 4 biomarkers of inflammation
o Elevated CRP/ ESR
o Lymphocytopenia
o Neutrophilia
o Elevated Ferritin levels
o Hypoalbuminemia
o Elevated ALT
o Anemia and Thrombocytopenia
o Elevated D-dimer
o Increased INR / Fibrinogen
• Use of immunomodulating therapies was common
o IV Immune Globulin
o Glucocorticoids
o Interleukin-6
o 1RA Inhibitors
• Risk assessment:
o Overall risk in children in EU/EEA and UK = low
§ Based on probability of COVID-19 in children and
moderate impact of disease
o Overall risk of PIMS-TS in children in EU/EEA and UK =
low
§ Based on very low probability of PIMS-TS in children
and high impact of disease

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2. Urticaria
o Urticarial wheals reported in COVID-19 patients in Italy,
observed in confirmed as well as suspected cases in
France, Finland, and US
o Affects mostly trunk and in disperse cases of palmar area

3. Livedo reticularis
o Transient blanching or
mottling of skin from
ischemia of cutaneous blood
vessels

4. Vesicular
M. Dermatologic Manifestations of COVID-19 o Chickenpox-like vesicles
• Reported in 20% of patients in Northern Italian Hospital on erythematous base
• Manifestations of Rash in confirmed, suspected, and o Seen in Italy
asymptomatic cases o Appears early in the
• Case Fatality rate of 1.9% course of disease (15%)
• Majority of the lesions are localized in the trunk (66%), hands
and feet (19%) 5. Petechial
• Timing of skin lesion was from 3 days to 13 days o Noted in 19 confirmed patients in Italy
• Cutaneous manifestations are important in the diagnosis of o Petechial eruption from bleeding under the skin
various infectious diseases à toxic shock syndrome,
meningococcemia, rickettsial diseases, measles, scarlet fever
• COVID-19 has a tendency to produce asymptomatic cases for
up to 14 days after infection, cutaneous manifestations may
serve as an indicator of infection,
• Emerging Skin Manifestations:
o Vesicular Eruptions – early onset
o Pseudo-chilblain pattern – late onset
o Other manifestations occurs with other symptoms of
COVID-19 6. Acral Ischemia/Pseudo-chilbain
• Mechanisms of cutaneous disturbances are not yet well known
o Micro-thrombi resembling perniosis
o Often painful and itchy
1. Theories of Cutaneous Manifestations
o Seen in many health workers in US
• Postulate #1: o “Pseudo-chilblain pattern”
o Viral particles present in the cutaneous blood vessels à o Also known as “COVID Toes”
lead to lymphocytic vasculitis à similar to observed in o Frequently appears in the late stage of the disease (59%)
thrombophilic arteritis (induced by blood immune o Usually asymmetrical
complexes that activates cytokines) o Affects both hands and feet
§ Keratinocytes – may be a secondary target after o Occurs more often in warmer areas
Langerhans cells activation à induces a spectrum o Tends to be more severe and symptomatic
of different clinical manifestations o More likely to ulcerate
• Postulate #2: o Takes longer to resolve
o Virus does not target the keratinocyte à immune o Includes finger and toe cyanosis, skin bullae, dry
response to infection leads to Langerhans cells activation gangrene à skin ulceration and necrosis
o Results in a state of vasodilation and spongiosis o All of the patients presenting with this had
• Postulate #3: hypercoagulable state
o Livedo-reticularis-resembling manifestations can result § Elevated D-dimers
due to the accumulation of microthomboses originating in § Elevated fibrinogen degradation products
other organs à reduce blood flow to cutaneous § Prolonged PT
microvasculature system o Poor prognosis despite with treatment of low-molecular
• Postulate #4: weight heparin
o Low grade disseminated intravascular coagulation o 5 died with a median time from acro-ischemia onset of 12
o Hypoxia-related accumulation of deoxygenated blood in days
venous plexes
• Postulate #5:
o Pauci-inflammatory thrombogenic vasculopathy with
deposition of C5b and C4d
o Co-localization with COVID-19 spike glycoproteins
• It is still unclear whether they are a secondary consequence of
respiratory-related infection or a primary infection itself

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7. Morbilliform P. Liver Injury in COVID-19
o Diffuse maculopapular eruption • Increased ALT/AST are more frequent in severe COVID-19
o Seen in Italy, France, Finland cases
• SARS-CoV-2 enters the cell by binding into ACE-II, although
no strong evidence supports the presence of ACE-II in the
liver, articles have expressed that there are presence of SARS-
CoV-2 in the cholangiocytes
• Multiple respiratory viruses can disrupt liver functions via CD
8+ immune cell-mediated reactions
• Postulated Mechanisms: Drug-induced liver injury through
novel anti-coronavirus drugs
o Like in cases of hepatitis C and HIV
• Azithromycin-induced hepatotoxicity appears only 1-3 weeks
after azithromycin initiation
N. Co-infection with Varicella-Zoster Virus • Monocyte chemoattractant protein 1 (MCP-1)
o Increased serum levels in COVID-19 patients
• Reactiviation of latent VZV in cranial nerve or dorsal root o Chemokine known to exacerbate steatohepatitis
ganglia leads to Shingles
• Post-mortem histopathological analysis of a liver biopsy of
• Preparatory itching sensation à stinging sensation à COVID-19 patients: Microvesicular Liver Steatosis
vesicular pustulates
• Acute phase of pain may continue up to a month Q. Thrombocytopenia Mechanism of COVID-19
• Pain persists up to 90 days after rash resolution
1. Three mechanisms
• SARs-CoV-2 directly infects lymphocytes à dysfunctional
antiviral effect à decreased T cell and CD 8 levels à • Decrease platelet production
progression of the hyperinflammaory state à immune cell o Infects bone marrow à induces growth inhibition and
dysfunction à creates optimum habitat for VZV apoptosis à abnormal hematopoiesis à
• Presenting symptom: Vesicular rash thrombocytopenia
• Tx: Famcyclovir 500 mg every 8 hours for 7 days • Increase platelet destruction
• Some patients have concomitant pulmonary symptoms o Increase levels of autoantibodies and immune complexes
• Patients manifesting with HZ warrant healthcare workers to à molecular mimicry and binds to antigens of platelets à
rule out COVID-19 and apply maximum personal protective specific destruction of platelets in the immune system
equipment when handling such patients. • Increase platelet consumption
o Viral infection and inflammation result in lung damage à
a. Herpes-Zoster Ophthalmicus activation of platelets resulting in aggregation and
formation of microthrombi à increase platelet
o Rare variant of herpes zoster affecting the ophthalmic
consumption
nerve
o Serious ocular manifestations: Conjunctivitis and Ocular
Inflammation
o Meantime between onset of COVID-19 and HZO
diagnosis was 4.5 days
o Systemic Steroids = reduce the long-term incidence of
postherpetic neuralgia or ocular complications and can
decrease the host inflammatory responses in patients with
severe manifestations of COVID-19

O. Gastrointestinal Manifestations of COVID-19

• SARS-CoV RNA has been identified in stool specimens
• Viral receptor ACE2 was found highly expressive in the
gastrointestinal epithelial cells and liver cells
• SARS-CoV-2 can actively infect and replicate in the GI tract
• GI symptoms include:
o Lack of appetite R. Renal Involvement in COVID-19
o Diarrhea • Renal Manifestations:
o Vomiting o Proteinuria (65.8%)
o Abdominal pain o Hematuria (41.7%)
o Nausea • Proteinuria and Hematuria in COVID-19 is not different in
o Anorexia patients with other critical illness
• Fecal samples remained positive for 27.9 days – 33 days • Renal abnormalities occur in majority of patients with COVID-
• Found in stool samples of patients without gastrointestinal 19 pneumonia
symptoms
• Patients who had more diarrhea had more viral RNA in their 1. Acute Kidney Injury
stool • 50% patients with AKI recovered from AKI symptoms after 3
• COVID-19 was more severe in patients with gut symptoms weeks of infection onset
• 48.1% had detectable traces in stool when ill • Patients with renal involvement had higher mortality than
• 70.3% had viral RNA in stool even when tested negative in patients without renal involvement
lungs • Incidence of AKI is lower in COVID-19
• Presence of GI symptoms was not correlated with fecal • Transient Febrile/Illness-related proteinuria
sample viral RNA positivity and severity of disease was not o In early phase, proteinuria is associated with fever and
correlated with extended duration of fecal RNA positivity systemic inflammation
• Characteristic of GI symptoms are more insidious than
respiratory symptoms

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 COVID-19
• It still remains unclear if AKI is largely due to hemodynamic • Sequelae persistence since infection spanned 14 days to three
changes and cytokine release of if the virus leads to direct months.
cytotoxicity • Persistent pulmonary lesions secondary to SARS-COV-2
• AKI without requiring RRT should be managed with limited infection was one of the disease outcomes
contact. • initial chest CT pattern showing pure consolidation or mixed
• PE and ultrasound findings should be coordinated within consolidation/GGOs patterns has tendency to have persistent
teams to minimize contact when possible. pulmonary lesions by 4.98 times especially upon considering
• Indications for renal replacement therapy in COVID-19 the findings of Hani et al.
patients remain the same regardless of COVID-19 status • A unit increase in the CRP and ferritin levels increases the risk
o 1:1 nurse to patient ratio of progression to persistent pulmonary lesions development by
o Co-localization on a floor within adjacent rooms 1.2%, 0.3% respectively.
o Continuous RRT needed for critically ill patients with AKI • Decreasing lymphocytic count by one unit was associated with
a 75% increase in the odds of exhibiting post COVID-19
persistent pulmonary lesions
2. End-Stage Kidney Disease • BMI increase the risk of persistent pulmonary lesions by
• Vulnerable to patients with severe COVID-19 12.5%.
• Majority of patients are treated with some form of dialysis • 38.5% of moderate and severe COVID-19 patients tend to
• On Hemodialysis: have pulmonary residuals
o Suspected or Confirmed COVID-19 patients who are not • Independent predictors of pulmonary residuals as a sequela of
critically ill should be dialyzed in their own isolation rooms COVID-19 are:
rather than being transported o Male gender
o COVID-19 should be co-localized on a floor or ICU when o High BMI
possible o Initial chest CT of consolidation & mixed
consolidation/GGOs,
S. COVID-19 in Semen and Urine o Lymphocytopenia
o High serum CRP and ferritin levels.
• In a case report by D. Paoli et al
o Possible viral detection in different body fluids than
respiratory droplets
o Semen and urine samples for SARS CoV-2 of a COVID-
19 + male was NEGATIVE
o Must be interpreted cautiously
o Viral clearance kinetics may match the progressive clinical
recovery of the patient

T. Risk of Reinfection
• currently being analyzed in patients with a history of COVID-
19
• mainly led by the production of IFN
• lung inflammation lasted a few more days, so it is not ruled out
that the persistence of a long-term “protective” humoral
immune response may be associated with previous disease
severity.
• presence of a second SARS-CoV-2 positive PCR does not
necessarily mean viral activity and infectious capacity

U. Post-Acute Sequelae of SARS-CoV-2 (PASC)

IX. Classification of Patients
• There is currently no clearly delineated consensus definition
for the condition: terminology has included “long COVID,” A. New Patient Classification
“post-COVID syndrome” and “post-acute COVID-19 1. Suspect case
syndrome.” • Person who is presenting with any of the conditions below
• The most commonly reported symptoms include: o All SARI cases where NO other etiology fully explains the
o Fatigue Dyspnea Cough clinical manifestations
o Arthralgia Chest pain o ILI cases with any one of the following:
o Cognitive impairment; Depression § No other etiology that fully explains the clinical
o Myalgia Headache presentation AND history of travel to or residence in
o Fever Palpitations area that reported local transmission of COVID-19
• More serious complications appear to be less common but disease during the 14 days prior to symptom onset
have been reported. These complications include: OR
o Cardiovascular: myocardial inflammation, ventricular § With contact to a confirmed or probable case of
dysfunction COVID-19 disease during the 14 days prior to
o Respiratory: pulmonary function abnormalities symptom onset
o Renal: acute kidney injury o Individuals with fever or cough or shortness of breath or
o Dermatologic: rash, alopecia other respiratory signs or symptoms fulfilling any one of
o Neurological: olfactory and gustatory dysfunction, sleep the following conditions
dysregulation, altered cognition, memory impairment § Aged >60
o Psychiatric: depression, anxiety, changes in mood § With a comorbidity
• Radiological and spirometric changes were mild and observed § Assess as having a high-risk pregnancy
in less than 25% of patients. § Health worker
o Alterations in spirometry were noted in 25/269 (9.3%),
o Alterations in radiographs were noted in 51/277 (18.9%).

26
ANG, D.K.
 COVID-19
2. Probable case C. Classification of patients suspected or confirmed to
• Suspect case who fulfills anyone of the following: have COVID-19
o Inconclusive COVID-19 test • A = Patients with stable or no co-morbid disease and
o Suspect who underwent with COVID-19 test but not uncomplicated upper respiratory tract infection
conducted in a national or subnational reference • B = Patients with stable or unstable co-morbid diseases and
laboratory pneumonia
o Suspect case for whom testing could not be performed for • C = Patients with severe pneumonia, severe sepsis, or septic
any reason shock (manage as CAP-HR based 2016 Philippine CAP
Guidelines)
3. Confirmed case • D = Patients with Acute Respiratory Distress Syndrome
• any individual, irrespective of presence or absence of clinical
signs and symptoms, who was laboratory-confirmed for D. Classification of Adult patients suspected or confirmed
COVID-19 in a test conducted at the national reference to have COVID-19 infection
laboratory, a subnational reference laboratory, and/or officially Recommended
Group Signs and Symptoms Management
accredited laboratory testing facility Diagnostics
Adult (age <60 years) May opt to quarantine at
with no home for 14 days without
4. Contact comorbid illness, and COVID-19 testing with
mild non- home quarantine
• is a person who experienced any one of the following specific symptoms instructions or send to
exposures during the 2 days before and the 14 days after the A None needed
such as fever, community health facility.
onset of symptoms of a probable or confirmed case: cough, sore throat, Give symptomatic treatment
o Face-to-face contact with a probable or confirmed case nasal congestion, and supportive care as
headache, muscle needed.Most cases will not
within 1 meter and for more than 15 minutes; pain or malaise require antibiotic treatment.
o Direct physical contact with a probable or confirmed case; Adult (age >60 years) May opt to send home
Consider CXR,
o Direct care for a patient with probable or confirmed or young
CBC,
young patients with stable
adult with stable co- co-morbid diseases; Admit
COVID-19 disease without using proper PPE; OR morbid illness, and
ALT, AST,
to a COVID-19 designated
o Other situations as indicated by local risk assessments B pneumonia (e.g. RR
creatinine
room/unit, and manage as
CXR or CT
Note: For confirmed asymptomatic cases, the period of contact is <30/min, HR<125/ CAP-Low Risk based on
imaging,
measured as the 2 days before through the 14 days after the date on min,SpO2 >93% on
ECG
2020 Philippine CAP
which the sample was taken which led to confirmation. room air) Guidelines
Any adult with fever or
severe acute
B. Disease Severity Classification of Adult Patients respiratory infection, as
(Modified from WHO Interim Clinical Guidance) follows: Manage as CAP-Moderate
respiratory rate >30 Risk based on 2020
Recommended
Severity Signs and Symptoms Management breaths/minute Philippine CAP Guidelines
Diagnostics
severe respiratory
Home isolation for 14 distress, or SpO2
Fever, cough, fatigue, days with instructions
anorexia, myalgias <93% on room air
or send to community
Other non-specific Sepsis: life-threatening
quarantine facility. organ
symptoms such as sore
throat, nasal congestion, Admit if elderly or with dysfunction caused by
headache, diarrhea, unstable/uncontrolled a dysregulated host CBC
nausea and vomiting, SARS-CoV-2-RT- co-morbid conditions. response to suspected
Mild or proven infection, Comprehensive
Loss of smell (anosmia) PCR
or loss of taste (ageusia) Give symptomatic with organ dysfunction metabolic panel
preceding the onset of treatment and presenting as follows: Ferritin, LDH,
respiratory symptoms supportive care as altered mental status procalcitonin,
needed. difficult or fast CRP,
Manage as CAP-High Risk
NO signs of pneumonia C breathing; low oxygen INR/PT, D dimer,
based on 2020
or hypoxia Empiric antibiotics saturation; reduced lactate
NOT needed Philippine CAP Guidelines
urine output; fast heart CXR or CT
With signs of Non- SARS CoV-2 RT- rate, weak pulse, cold imaging
severe pneumonia PCR extremities or low Sputum GS/CS,
(e.g. fever, cough, Admit to a COVID-19 blood pressure blood cultures, as
Moderate dyspnea or difficulty of CXR or CT scan designated room/unit skin mottling, or appropriate
breathing), CBC, ALT, AST, laboratory evidence of ABG
RR 21-30/minute, Creatinine coagulopathy,
SpO2 >92% on roomair) ECG thrombocytopenia,
Severe Pneumonia or SARS CoV-2 RT- acidosis, high lactate
severe acute respiratory PCR; CBC or hyperbilirubinemia
infection, as follows: Comprehensive Septic Shock:
Fever, cough, dyspnea metabolic panel persisting hypotension
Ferritin, LDH, despite volume
Admit to a COVID-19 Manage as CAP-High Risk
RR >30 breaths/minute, Procalcitonin or resuscitation requiring
Severe designated ICU based on 2020 Philippine
CRP, INR/PT, D- vasopressors to
CAP Guidelines
Severe respiratory dimer, Lactate maintain MAP ≥ 65
distress CXR or CT scan mmHg and serum
Sputum GS/CS, lactate level >2 mmol/L
SpO2 <92% on room air Blood cultures, as Within 1 week of ABG, Ferritin,
appropriate; ABG known clinical LDH, CRP,
SARS CoV-2 RT- insult or new or INR/PT, D
Onset within 1 week of
PCR; CBC worsening respiratory dimer,Procalcitoni
known clinical insult Consider ARDS –
Comprehensive symptoms, progressing n,
(pneumonia) or new or management will depend
worsening respiratory
metabolic panel D infiltrates on CXR or Lactate; Repeat
on classification of ARDS.
ABG; Ferritin, Consider COVID-19 chest CT), with CXR or CT
symptoms, progressing See Section VIII.
LDH, CRP, ARDS Admit to a respiratory failure imaging
infiltrates on CXR or
Critical INR/PT, D- dimer, COVID-19 ICU not fully explained by ETA GS/CS,
chest CT, with
Procalcitonin, cardiac failure or fluid blood cultures, as
respiratory failure not
Lactate Repeat overload appropriate
fully explained by
CXR or CT scan
cardiac failure or fluid
ETA GS/CS,
overload (COVID-
Blood cultures, as
ARDS)
appropriate

27
ANG, D.K.
 COVID-19
E. Classification of Children patients suspected or X. Algorithms
confirmed to have COVID-19 infection A. Algorithm for Triage of Suspected and Probable COVID
Group Signs and Symptoms Management patient
• Admit to the designated
isolation room.
Non-specific symptoms such as
• Give symptomatic
fever, cough, sore throat, nasal
treatment and supportive
A congestion, headache, muscle
care as needed.
pain or malaise.
• Most cases will not
require antibiotic
treatment.
Child w/ non-severe pneumonia
has: • Admit to a designated
• cough or difficulty breathing isolation room
• fast breathing (in
B
breaths/min): • Manage as pediatric
- <2 months, ≥60 community-acquired
- 2–11 months, ≥50 pneumonia (pCAP)
- 1–5 years, ≥40 A/ B (Annex D)
• and no signs of severe
pneumonia
Child with cough or difficulty in
breathing, plus at least one of
the following:
• central cyanosis/ pO2
<90%
• severe respiratory distress
(e.g. grunting, very severe
chest indrawing) • Admit to a designated
• signs of pneumonia with a isolation room
general danger sign:
inability to breastfeed or • Manage as pediatric
drink, lethargy or community-acquired
unconsciousness, or pneumonia (pCAP) C
convulsions (Annex D)
B. Algorithm for Acute Stroke in COVID-19 patients
Other signs of pneumonia may
be present: chest indrawing, fast
breathing (in breaths/min):
• <2 months, ≥60
• 2–11 months, ≥50
• 1–5 years, ≥40

Sepsis: suspected or proven • Admit to the designated

C
infection and ≥2 SIRS criteria, of isolation room
which one must be abnormal • Manage as pediatric
temperature or white blood cell community-acquired
count pneumonia (pCAP) C
(Annex D)
Septic Shock: any hypotension
(SBP <5th centile or >2 SD
below normal for age) or 2-3 of
the following:
• altered mental state
• tachycardia or bradycardia • Admit to the designated
(HR <90 bpm or >160 bpm isolation room
in infants and HR <70 bpm
or >150 bpm in children) • Manage as pediatric
• prolonged capillary refill (>2 community-acquired
sec) or warm vasodilation pneumonia (pCAP) D
with bounding pulses (Annex D)
• tachypnea
• mottled skin or petechial or
purpuric rash
• increased lactate
• oliguria
• hyperthermia / hypothermia

New or worsening respiratory Management will depend

D symptoms within one week of on classification of ARDS
known clinical insult

28
ANG, D.K.
 COVID-19
XI. Diagnostic Tests 4. Results
A. Nucleic Acid Amplification Tests via Reverse • Viral RNA is measured by the cycle threshold (Ct) value which
Transcription Polymerase Chain Reaction (rT-PCR) becomes detectable as early as day 1 of symptoms and peaks
• Current GOLD STANDARD within the first week of symptom onset.
• Can detect SMALL amounts of viral RNA • Ct is the number of replication cycles required to produce a
• Detects the presence of viral nucleic acid fluorescent signal, with lower Ct values representing higher
viral RNA loads.
• Can detect levels of viral nucleic acid
• Ct value < 40 is clinically reported as PCR positive.
• Presence of viral nucleic acid may not always indicate
o Low Ct Value = indicates higher viral load
contagiousness
o High Ct Value = indicates a lower viral load
• Can remain positive for weeks to months after initial infection
• Currently not correlated with a person being or not
• Performed best when person is tested when viral load is
being infectious or risk level of severity
generally highest
• The positivity starts to decline by week 3 until it becomes
• Best performed in symptomatic people within a certain number
undetectable.
of days from symptom onset
• False negative results of RT-PCR assays may be due to
inadequate sample and inappropriate timing of sample
1. Other Methods of Detecting and identifying NAATs
collection in relation to symptom onset.
• Isothermal amplification including: Day False-Negative Result
o Nicking Endonuclease Amplification Reaction (NEAR) Day 1 100%
o Transcription Mediated Amplification (TMA) Day 4 68%
o Loop-mediated Isothermal Amplification (LAMP) Day of Symptom onset 38%
o Strand Displacement Amplification (SDA) Day 8 (or 3 days after 20%
o Helicase-Dependent Amplification (HDA) symptom onset)
o Clustered Regularly Interspaced Short Palindromic
Day 9 21%
Repeats (CRISPR)
Day 21 66%
2. Detection Process and Interpretation
• In the early onset of the disease, RT-PCR can miss the RNA
• Most tests target one or more of the envelope (env),
nucleocapsid (N), spike (S), RNA-dependent RNA polymerase
(RdRp), and ORF1 genes.
• Viral RNA is measured by the cycle threshold (Ct) value which
becomes detectable as early as day 1 of symptoms and peaks
within the first week of symptom onset.
• Bronchoalveolar lavage = highest sensitivity and specificity
• Ct – is the number of replication cycles required to produce a
fluorescent signal, with lower Ct values representing higher
viral RNA loads.
• Ct value < 40 is clinically reported as PCR positive.
• The positivity starts to decline by week 3 until it becomes
undetectable.
• The mean cycle threshold values of all specimen types were
more than 30 except for nasal swabs with a mean Ct value of 5. Recommendations for Testing
24.3 • All symptomatic individuals suspected of having COVID-19
• In the early days of the pandemic, 30-70% sensitive for acute patients should undergo SARS CoV-2 RT-PCR assay testing
infection to diagnose COVID-19 infection.
o (3-7 out of every 10 patients can yield negative result) • Nasopharyngeal specimens rather than oropharyngeal or
o Early disease = decrease viral load to be detected saliva specimens are preferred for swab-based SARS-CoV-2
o Incorrect usage of the kit testing.
• Current US data shows, RT-PCR is >95% sensitive • Specimens from sputum, endotracheal aspirates, and
bronchoalveolar lavage among hospitalized patients may also
3. Specimen Samples be sent directly to the microbiology laboratory for processing.
Specimen Samples • The qualitative reporting of results of SARS-COV-2 RT-PCR
as positive or negative is sufficient for DIAGNOSIS but may
Upper respiratory tract Lower respiratory tract
be supplemented by a CYCLE THRESHOLD report, a semi-
§ Nasopharyngeal § Sputum
quantitative value, correlated with timing of symptom onset to
swab § Endotracheal
guide infection control, public health and occupational health
§ Oropharyngeal aspirate
decisions
swab § Bronchoalveolar
lavage
6. Effect of mutations on sensitivity of the TaqPath COVID-19
Blood Feces
diagnostic tests
Sensitivity % Specificity % • 69-70del S gene mutation most often associated with, but not
(95% CI) (95% CI) limited to, B.1.1.7
Oral 56 99 • these assays are designed to detect multiple genetic targets,
Nasal 76 100 the overall test sensitivity should not be impacted by the
Nasopharyngeal 97 100 B.1.1.7 variant
Nasal VS NP 95 100 • TaqPath COVID-19 diagnostic tests use a multi-target (orf1ab,
Saliva 85 100 N gene, s gene) design to compensate for emerging SARS-
Mid-turbinate 100 100 CoV-2 variants and mutations
• None of the mutations in B.1.351, P.1, B.1.427, B.1.429 are
known to affect our TaqPath COVID-19 portfolio of tests

29
ANG, D.K.
 COVID-19
B. COVID-19 IgG and IgM Rapid Diagnostic Test (RDT) kits • Several factors affect the performance of the test including:
• FDA approved the use of antibody-based test kits for SARS- o Time from onset of illness,
COV2 testing on March 30,2020 o Concentration of virus in the specimen
• Sensitivity of 88.86% o Quality of the specimen collected from a person
• Specificity of 90.63% o How it is processed,
• High positive predictive value = high prevalence o Precise formulation of the reagents in the test kits
• Cross-reactivity with other coronaviruses and flu viruses are • False-positive results could occur if the antibodies on the test
yet to be determined strip also recognize antigens of viruses other than COVID-19
(e.g. cross-reaction).
• False negative results should be considered
• Potentially be used as triage/screening tests to rapidly identify
• Low sensitivity during the early phase of infection
patients who are very likely to have COVID-19, reducing or
• Insufficient evidence to use the kits as stand-alone kits for
eliminating the need for expensive molecular confirmatory
definitive diagnosis of COVID-19
testing.
• Methods:
• Sample: Salival sample or Human Nasopharyngeal Swab
o ELISA
o Chemiluminescence Assay • Method: Rapid Immunochromatographic Test
o Lateral Flow Immunoassay • Method: Lateral Flow Immunofluorescent Sandwich Assay
o Qualitative Detection of the Nucleocapsid Protein Antigen
• Cannot be used for mass-testing and clearance for work of
from SARS- CoV-2 in nasopharyngeal and nasal swab
asymptomatic people due to its low sensitivity and high false
specimens
negative results
o Directly or after the swabs have been added to either the
• Can only be used in people who had onset of symptoms for
universal transport media or viral transport media from
atleast Day 5-21 (IgM-IgG)
o individuals who are suspected of COVID-19.
• Interpretation:
• Average sensitivity was 56.2 - 71.4%
IgM IgG Interpretation
• Average specificity was 98.4-99.5%
+ - Confirm with RT-PCR
• Positive Predictive Value = 33.3%-87.0%
- - Does not rule our COVID-19
• Negative Predictive Value = 98.8%
If symptomatic = remain isolated à swab for
RT-PCR • Overall sensitivity is 73.3%
- + Presumptive past COVID-19 à do further • Median Cycle Threshold was 23.28
validation (Plaque Reduction Neutralization • Patients with less than seven days onset of symptoms showed
Test or Viral culture) a higher viral load and sensitivity of 86.5%
If symptomatic à do rT-PCR • Comparative evaluation of 2 SARS-CoV-2 Antigen tests:
If asymptomatic à no need to test using rT- STANDARDTMF SARS-CoV-2 Rapid
PCR COVID-19 Ag FIA Antigen tests (RAT)
Sensitivity 45.4% 50.3%
Specificity 97.8% 97.7%

• 103 fold less sensitive than viral culture

• 105 fold less sensitive than RT-PCR
• Detected between 11.1 % and 45.7 % of RT-PCR-positive
samples from COVID-19 patients.
• Diagnostic Testing on Symptomatic Persons within the first 5
to 12 days of symptom onset
• When used as screening, results should be considered
presumptive
• Pretest probability
o If High à positive test à no need for confirmatory
o If Low à positive test à isolate until confirmed by RT-PCR
o If Low à negative test à repeat on a recurring basis
• Results must be reported “PRESUMPTIVE NEGATIVE”

• WHO does not currently recommend the use of antigen-

• Use of IgG test detecting rapid diagnostic tests for patient care, although
o Adjunct test to clear quarantined patients who remain research into their performance and potential diagnostic
asymptomatic at 14 days post-discharge utility is highly encouraged
o Presence of this antibody typically indicates viral • Potentially be used as an alternative to RT-PCR assay for the
clearance diagnosis of COVID-19 among symptomatic patients during
o If IgG + è patient can be released from self-quarantine the first week of illness.
o If IgG - è repeat rT-PCR should be performed • Negative results from an antigen test should be confirmed with
an RT-PCR test prior to making treatment decisions to prevent
C. Rapid Test Based on Antigen Production undue transmission.
• Rapid antigen test detects the presence of viral proteins • The rapid antigen test alone is not recommended for an initial
(antigens) expressed by the COVID-19 virus in a sample from COVID-19 diagnosis because of its low sensitivity
the respiratory tract of a person. • PSMID recommend the use of rapid antigen test under all
• Target antigen present in sufficient concentrations in the these conditions in patients suspected of COVID-19 infection
sample, it will bind to specific antibodies fixed to a paper strip o Symptomatic AND
enclosed in a plastic casing o Early phase <7days from onset of symptoms AND
• Visually detectable signal within 30 minutes. o Specific brands that demonstrated sensitivity of >80% and
• The antigen(s) detected are expressed only when the virus is have very high specificity
actively replicating
• Best used to identify acute or early infection.

30
ANG, D.K.
 COVID-19
Asymptomatic Symptomatic Symptomatic E. Timeline of Antigen-Antibody Detection
Median 3 days 5 days
Interval
from
symptom
onset
Sensitivity 41.2% 80.0% 74.2%
Specificity 98.4% 98.9% 99.2%
Positive 33.3% 94.1%
Predictive
Negative 98.8% 95.9%
Predictive

F. Relationship between Pre-Test Probability and the

Likelihood of Positive and Negative Predictive
Values
Pretest- Negative Positive Impact on Test
Probability Predictive Predictive Results
Value Value
Low High Low Increased likelihood
of False Positives or
True Negatives
High Low High Increased likelihood
of True Positives or
False Negatives

G. Sensitivity and Specificity of Tests in correlation with

Day of Exposure and Symptom Onset
Day of Day of RT-PCR Rapid Rapid
Exposure Symptom Antigen Antibody
Onset Test Test
Day 1 100% False 100% False 100% False
Negative Negative Negative
D. Algorithm for Testing Day 4 68% False 80% False 100% False
1. For Congregate Living Negative Negative Negative
Day 5 Day 1 62% True 50% True 100% False
Positive Positive Negative
Day 8 Day 3-4 80% True 62% True 100% False
Positive Positive Negative
Day 12 Day 5-7 70% True 71% True 30% True
Positive Positive Positive
Day 21 Day 16 66% False 100% False 30-88%
Negative Negative True
Positive

H. Difference of RT- PCR and Antigen Tests

RT-pCR Test Antigen Test
Intended Use Detect current Detect current
2. For Community Settings
infection infection
Analyte Detected Viral RNA Viral Antigens
Specimen Type Nasal Swab, Nasal Swab
BAL, Saliva,
Sputum
Sensitivity High Moderate
Specificity High High
Test Complexity Varies Relatively easy
Authorized for Use at Most devices Yes
the Point-of-Care are not
Turn-around-time 15 minutes to 2 15 mins
days approx.
Cost/Time Moderate Low

31
ANG, D.K.
 COVID-19
B. Chest CT Scan
I. Quantitative Anti-SARS-CoV-2 IgG Antibodies • >1000 patients shows >95% sensitivity
• Brand Specificity o <1 missed diagnosed case
o Abbott 99.6% Specificity o In Asymptomatic or Mild cases = 50% sensitivity when
o Euroimmun IgG 91.5% Specificity done during the first 48 hours of symptom onset
o Euroimmun IgA 71.5% Specificity - suboptimal • CT should be used sparingly and only when impacting
management
J. Testing Strategies for SARS-CoV-2 • No longer part of the diagnostic criteria
Diagnostic Screening Surveillance • High sensitivity in severe COVID-19 cases
Symptomatic or Yes No N/A • Can be used to identify patients for further testing and isolation
Known or and inform treatment
Suspected • Role of CT findings depend on:
Exposure o Severity of infection
Asymptomatic No Yes N/A o Prevalence of COVID-19 in the community
without known or § Low sensitivities in countries with very low
Suspected prevalence
Exposure
• Most useful in acutely ill and symptomatic patients with high
Characterize N/A N/A Yes burden of disease
Incidence and
Prevalence in the • Advantage: If accessible CT-scan but no access to RT-PCR or
Community long turn-around-time for RT-PCR
Results may be Yes Yes No • Not very specific
returned to • Findings include:
Individuals
Results Returned No No Yes 1. Ground Glass Opacities (GGO)
in Aggregate to • Represents tiny alveoli filled with fluids turning gray in CT-
Requesting scans
Results Reported Yes Yes Only if
to State Public
• Parenchymal opacification of the lungs which produces a
requested;
Health smaller increase in attenuation compared to consolidation
must be in
• First sign to appear and is usually followed by one of the other
aggregate
two findings
Testing can be Yes Yes Yes
performed in a • Usually occurs in:
CLIA-Certified Lab o Multiple lobes of the lung
Testing can be No No Yes o Both lungs (bilateral)
performed in a o Periphery of the lung
Non-CLIA-Certified • In Mild, or Recovering patients,
Lab findings can be isolated in just
Testing can be Yes Yes No one lobe
FDA authorized or
offered under the 2. Peri-lobular patterns
policies of FDA’s 3. Revere Halo (Atoll sign)
Guidance
4. Solid White Consolidation
XII. Ancillary Imaging • Seen in severe cases
• Increased fluid accumulation in lung alveoli
A. Chest X-ray
• Occupation of airspace by pathological products (pus, water,
• Typically done first in patients blood, etc)
presenting with fever, cough, and
• Homogenous increase in pulmonary parenchymal attenuation
dyspnea to exclude pneumonia that obscures the margins of vessels and airway walls
• Easier, and cheaper • May exhibit air bronchogram sign
• Low sensitivity for COVID-19
• Yields false negatives
• Ground-glass opacities = most
common abnormality seen
o Looks like frosted glass
• Bilateral interstitial opacification
• Dense peripheral and lower lung
zones = severe covid cases
• A patient highly suspicious for COVID-19 SHOULD GET a
chest-CT even in the presence of a negative X-ray finding.
5. Crazy Paving Pattern
• Swelling of the interstitial space
along the lung lobule
• Makes the walls look thicker
• Appearance looks like pavings in
the street
• Inter and intralobular septal
thickening superimposed on
ground glass opacities
From Left to Right (Photo of Mild, Moderate, Severe COVID)

32
ANG, D.K.
 COVID-19
6. Peripheral Halo in a COVID-19 (+) Pneumonia 2. Advantages
• (+) Pulmonary nodule in right lower lobe on Chest X-ray • High sensitivity (93-98%)
• CT-scan revealing solid nodule with faint peripheral halo of • Correlate fairly with those of chest CT scan
ground glass density located in the superior aspect of the right • Advantages:
lower lobe o Lack of exposure to radiation
• Patients presenting with a pulmonary nodule accompanied by o Bedside repeatability during follow-up
a peripheral halo on CT scan should be evaluated for the o Low cost and easier application in low-resource settings.
possibility of COVID-19 infection especially on the background • Consequently, LUS may decrease utilization of conventional
of chronic immunosuppression diagnostic imaging resources (CT scan and chest X-ray
• Presence of peripheral halo on CT-Scan with initial negative • May help in early diagnosis, therapeutic decisions and follow-up
result of rT-PCR may mislead the physicians in suspicion of monitoring of COVID-19 pneumonia, particularly in the critical
care setting and in pregnant women, children and patients in
metastasis rather than COVID-19 pulmonary involvement
areas with high rates of community transmission.

3. Findings
• COVID-19 Ultrasound Findings:
o Focal B lines
o Irregular pleura
o Multi-focal B-lines
o Fragmented pleura
o Coalescing B-lines
o Subpleural consolidations
o a typical pattern of diffuse interstitial lung syndrome
o multiple or confluent bilateral B-lines with spared areas
o thickening of the pleural line with pleural line irregularity
and peripheral consolidations
a. Ground Glass Opacities, b. consolidation, c. consolidations with ground glass
opacities, d. solid nodules

C. Key findings
• These CT-findings can be seen in isolation or in combination
• Disease severity is proportionate according to the lung findings
• As patients improves, there is gradual resolution of the lung
findings
• Can also be seen in other viral pneumonias like influenza and (a) A-Lines: Lines horizontal to the pleura. (b–e). B-Lines: Linear vertical
adenovirus and other non-infectious conditions artifacts that arise from pleural lines (a) with different B-line shapes, for
• Interpretation: example, a single cone-shaped line (b), a single thin line (c), a single thick
line (d) and a subpleural consolidation without air bronchogram (e).
o If High prevalence of disease in the country:
+ CT findings even if – PCR = PRESUMPTIVE INFECTION
(Higher prevalence in the area = higher LR of CT findings
representing COVID-19 that will eventually turn out + in RT-
PCR)

D. Lung findings typically ABSENT in COVID-19

• Pleural effusions = more common in congestive heart failure
and bacterial pneumonia
• Large lymph nodes in the mediastinum or near the hilum
(more common in other types of pneumonia) (a) Normal sonographic lung appearance. Pleural line (hyper-echoic
horizontal line, green arrowhead) and multiple horizontal reverberations of
• Lung cavities (develops in bacterial and fungal pneumonia the pleural line (A-lines). (b) Severe interstitial pneumonia and acute
due to necrosis of the tissues turning into an air-filled cavity) respiratory distress syndrome sonographic appearance. Green
arrowhead indicates irregular pleural line; vertical lines indicate multiple
blurred B-lines.

4. Equipment Protection and Decontamination

• Use of 70% Isopropyl Alcohol
• Use of Quaternary Ammonium compound

E. Point-of-care Lung Ultrasound (US)

• Contentious and evidence still evolving
• Role in assessment of covid-19 particularly in an intensive care
setting
1. Probes
• Probes:
o Curvilinear = first choice
o Phased Array = second choice
o Linear = last choice
o Positioning: Cephalad to Caudad

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ANG, D.K.
 COVID-19

H. Summary of Official Guidelines regarding imaging of

COVID-19 patients
Lung
Chest-Xray Chest CT
Ultrasound
For critically ill Suggested to
British
patients; Only for critically ill be used as a
society of
For stable patients who have monitoring tool
Thoracic
patients, only if inconclusive CXR for critically ill
Imaging
clinically required patients
European
society of
Radiology/ Restricted use of Suggested to
For imaging
European chest CT is be used at the
within ICU units
Society of recommended bedside
Thoracic
Imaging
Not
recommended
for diagnosis. No Not recommended
American impact on clinical unless imaging
College of outcomes, will have an No information
Different Scoring Systems used to quantify the extent and Radiology Mobile CXR is impact on
characterize the different patterns of lung involvement suggested when management
clinically
necessary
F. MRI Canadian
Limited use has
• Not relevant for evaluation of lung disease Association
been suggested
• Contributes to the diagnostic pathway of COVID-19 patients of
to those in whom Not recommended
Radiologist/
with neurological manifestations Canadian
results will unless clinically No information
• Significant in diagnosis of COVID-19 complications such as change the requried
Society of
management
acute stroke, skeletal muscle injuries, consciousness Thoracic
plan
impairment, or acute necrotizing hemorrhagic encephalopathy, Radiology
cardiac complications of persistent myositis Suggested to be
used only in
Royal critically ill
G. COVID-19 Imaging Technical Considerations For critically ill
College of patients, and No information
patients
• Performed with portable equipment within specifically Radiologists when is likely to
change the
designated isolated rooms for eliminating the risks of cross management plan
infections Fleishner Not
Not recommended
• AP chest radiograph performed on patient’s bed Society (an recommended in
in patients with
• PA chest radiograph performed on radiology international patients with mild
mild symptoms.
consortium of symptoms. No information
Indicated for
medical Indicated for
critically ill
imaging of critically ill
patients.
the lungs) patients,
Royal
Only when it is
College of No information
likely change the No information
Surgeons of included
management
Edinbrugh
Royal
Recommended
Australian
for hospitalized
and New
patients and Not recommended No information
Zealand
monitoring of the
College of
disease
Radiologists
International
Society of Mobile
Not recommended
Radiographe Mobile CXR equipment is
for diagnosis or as
rs and recommended suggested to
a first line tool
Radiological be used
technologists

34
ANG, D.K.
 COVID-19
XIII. Diagnostic Tests for Suspected, Probable or A. Tests to request
Confirmed COVID-19 cases • Complete Blood Count
Baseline Frequency o Lymphopenia with leukocytosis/leukopenia (>80%)
Risk Other
Diagnos Findings of o Critically ill patients in the ICU – developing more severe
Factors Comments
tics Monitoring lymphopenia compared to those not in the ICU
Low risk (Mild disease) = Mild Symptoms o Has been associated with poor prognosis for patients with
Strict home isolation or COVID-19
No co- None
quarantine in a designated o Median 1 vs 0.4cells/mm3
morbids needed
COVID facility
• Arterial Blood Gas = mild acidosis
High risk (Severe or Critically ill) : Fever with or without respiratory symptoms
with SpO2 <92, RR >30, SBP <90 • LDH = elevated
ALC <0.8, • BUN/Crea = elevated
Leukopenia or poor • D-dimer = elevated >1000ng/mL
CBC Daily or as
normal
frequent as
prognostic • Procalcitonin = elevated
marker • CRP = markedly elevated >125mg/L
possible
ALT/AST • Ferritin = elevated >300ug/L
CMP
elevated
• Prothrombin = prolonged
If elevated,
Procalcit Low or normal consider • Liver enzymes = elevated
onin (10) other • Respiratory tract specimen = to determine other co-infections
causes through standard bacterial tests (Gram stain and culture) or
If low or N = Use to track respiratory panels (Respiratory Film Array)
consider other mortality risk • Quick Flu test
causes or mild w/ median • Respiratory Viral Panel
disease 40mg/L;
CRP
If mean 66 non-
mg/L (IQR 48- survivors w/ 1. D-dimer tests
98) = high risk median 125 • Increase risk for coagulopathy has been associated with
of hypoxemia mg/L COVID-19
• Repeat q2-3 If >2.4 = • D-dimer levels > 1ug/L at admission predicted an 18-fold
days to increased increase in odds of dying before discharge
D-dimer
evaluate risk of ICU
2. ECG
Age >60; trend and/or stay
pre- when If >400 = • ST-changes mimicking STEMI
If >245 = poor
existing patient increased
LDH prognostic
pulmona deteriorates risk of ICU 3. Cardiac Markers in COVID-19
marker
ry stay
disease; If >1000
• Troponin I = may be increased over 10,000 ng/L
CKD; ng/mL • CK-MB = > 100ng/L
DM; Ferritin watch out
HTN; or for cytokine XIV. Collection and Handling of Specimens
CVD storm
transpla
A. Collection of Respiratory Tract Specimen
May be
nt CK 1. Personal Protective Equipment (PPE) for collecting and
elevated
Sputum Evaluate for handling respiratory tract specimens
Usually As clinically
or ETA bacterial • Use the following for safety protection
normal flora needed
GS/CS cause o Eye protection
Influenza Usually o Surgical mask
No need
A/B negative
o Double gloves
Respirat Rule out
ory viral
Usually
No need other viral
o A disposable impermeable, breathable, long-sleeved,
negative laboratory gown fasted at the back
panel causes
Blood & • Aerosol-generating procedure: wear a particulate respirator at
Usually As clinically least as protective as a NIOSH-certified N95, EU standard
Urine
negative indicated
Cultures FFP2
May be Repeat in 3
CXR normal; days or if
PA/Lat bilateral patient
infiltrates deteriorates
Ground glass
Detect early
opacities;
pneumonia
typically Repeat
CT Chest before
bilateral but periodically
symptom
may be
onset
unilateral

35
ANG, D.K.
 COVID-19
2. Procedure for collecting respiratory specimen D. Virus Isolation
• Use sterile dacron or rayon viral swabs for both specimens • In-vitro and in-vivo culture of the 2019 Novel
from nasopharynx and the oropharynx Coronavirus/SARS-CoV-2 is STRONGLY DISCOURAGED
• Do not use calcium alginate swabs • Laboratories must strictly enforce compliance with Biosafety
a. Lower respiratory tract specimens should be collected in Level 2 laboratory guidelines for facility, equipment and
sterile containers practices
b. Avoid sputum induction to reduce the risk of aerosol • No potentially contaminated PPE shall be taken out of the
transmission laboratory for washing and reuse
c. Collecting the Nasopharyngeal Swab
o Insert flexible wire shaft swab through nares parallel to the E. Timing of Specimen Collection
palate (NOT UPWARDS) until resistance is encountered
or the distance is equivalent from the ear to the nostril of
the patient indicating contact with the nasopharynx
o Rub and roll the swab
o Leave the swab in place for several
seconds to absorb secretions before
removing
o Do not sample the nostrils

d. Collecting the Oropharyngeal Swab

o Insert swab into posterior pharynx and tonsillar areas
o Rub swab over both tonsillar pillars and posterior
oropharynx
o Avoid touching the tongue, teeth, and gums
o Do not sample the tonsils XV. Equipment needed in Units Managing COVID Patients
• Personal Protective Equipment
• Detachment equipment including thermometer, stethoscope,
and blood pressure apparatus
• Pulse Oximeter
• Functioning Oxygen System
• Disposable, single-use, oxygen-delivering interfaces (nasal
cannula, simple face mask, and mask with reservoir bag)
• Video laryngoscopes
• Closed Suction System

XVI. COVID-19 in Pediatric patients

A. Epidemiological
B. Specimen Handling • Low incidence and prevalence rate in children
• Place NP and OP swabs immediately into a sterile vial • Low case fatality rate in children
containing 2 ml of viral transport media without antibiotics. Age in Years Case Fatality Rate in %
• Both swabs can be placed in the same vial, if desired. 0-9 ---
• Aseptically, cut or break applicator sticks off near the tip to 10-19 0.2%
permit tightening of the cap.
• Risk factors for severe COVID-19 in Children and Infants
• Label the vial with the patient’s name, specimen type, date
among children with co-morbid conditions
collected and other required information.
o Obesity 38%
• If specimens will be examined within 48 hours after collection, o Prematurity 15%
keep specimen at 4oC and ship on wet ice or refrigerant gel-
• < 2 years of age
packs
o Chronic pulmonary disease 18%
• Otherwise store frozen at ≤-70oC and ship on dry ice.
• Including Asthma
• Avoid freezing and thawing specimens
B. Clinical Findings
C. Specimens Packaging
• Symptoms in children were non-specific
• Using the triple packaging system
• Most common presentation in children:
• Seal the primary receptacle containing the swabs and viral o Coughing (>50%)
transport media using Parafilm. Wrap the primary receptacle
o Sore throat
with an absorbent material e.g., gauze.
o Nasal congestion
• Place the primary receptacle into the second container. o Rhinorrhea
• The second container should be durable and leak-proof. o Diarrhea
• Place the second container into the outer container e.g., ice • Symptoms commonly seen in adults like lethargy, dyspnea,
box. muscle ache, headache, nausea, vomiting, and disorientation
• Ensure that the required temperature is maintained in the outer are not common
container through the use of wet ice or refrigerant packs. • No children required respiratory support or intensive care
36
ANG, D.K.
 COVID-19
C. Procedures and Ancillaries Findings B. Key Considerations regarding Management of COVID-
• Chest X-ray lacked definite signs of pneumonia 19 in Pregnancy
o either normal or showed only coarse lung markings • Pregnant women should be counseled about the potential for
without unilateral or bilateral pneumonia severe disease from SARS-CoV-2 infection and the
• 80% children persistently tested positive rectal swabs even recommended measures to take to protect themselves and
after nasopharyngeal testing was negative their families from infection.
o Possibility of fecal oral transmission • Hospitalization for COVID-19 is indicated in a pregnant
• Chest CT-scan woman, care should be provided in a facility that can conduct
o isolated or multiple patchy ground-glass opacities maternal and fetal monitoring, when appropriate.
o outer lung fields and few patients had subpleural bands or • Management of COVID-19 in the pregnant patient should
strips include:
• There was no pleural effusion, enlarged lymph nodes or other o Fetal and uterine contraction monitoring, when
changes that are typically seen in the critically ill adult patients appropriate, based on gestational age
• Few cases had leukopenia, leukocytosis, lymphopenia or o Individualized delivery planning
elevated transaminase, which in contrast are frequently seen o Multispecialty, team-based approach that may include
in adult patients consultation with obstetric, maternal-fetal medicine,
• Viral Respiratory panel (Influenza etc) were often negative infectious disease, pulmonary and critical care, and
• IL-17F are elevated with concurrent elevation of IL-22 pediatric specialists, as appropriate
• IL-6 were elevated in 50% of patients • The COVID-19 Treatment Guidelines Panel recommends that
potentially effective treatment for COVID-19 should not be
D. Treatment withheld from pregnant women because of theoretical
• Antiviral therapy with α-interferon oral spray initiated from concerns related to the safety of therapeutic agents in
admission (8,000 U, two sprays, three times a day). pregnancy
• No patient required respiratory support or intensive care unit • In most cases, the timing of delivery should be dictated by
care. obstetric indications rather than maternal diagnosis of COVID-
19. For women who had suspected or confirmed COVID-19
XVII. COVID-19 in Pregnant Patients early in pregnancy who recover, no alteration to the usual
timing of delivery is indicated.
• Limited data at this time
• Vertical transmission of SARS-CoV-2 via the transplacental
• Treatment for suspected or confirmed with COVID-19
route appears to be rare but possible
o Supportive therapies
o Take into account the physiologic adaptations of
C. Breastfeeding
pregnancy
• Determine severity of illness and imminence of delivery • Unknown whether virus can be transmitted to breast milk
• If needs to be admitted à Isolation Unit • No sufficient evidence suggesting it can be transferred via
• If imminent delivery à observe transmission-based breastfeeding
precautions • Droplet transmission could occur during breastfeeding
• Pregnant women who have common health conditions such as • Mothers with confirmed COVID-19 or symptomatic mothers
obesity and asthma may be at a greater risk for severe suspected with COVID-19 = should take precaution and
COVID-19 and medically indicated preterm delivery to prevent transmission to infant during breastfeeding
improve lung function • Consider having a different individual feed expressed
• Recommended for women at 37-38 weeks prior to delivery breast milk to infant
• Intrauterine transmission has been documented but appears
to be rare
o MOA: Unknown
o May be related to lower expression of the ACE2 receptor
and serine protease TMPRSS2 à which are necessary
for SARS-CoV-2 cell entry
• Transmission via breastmilk is unlikely
o In a study using 64 breastmilk samples with 18 mothers,
only 1 tested positive.
o No replication-competent virus was detected

A. Pathway of Pregnant Patients

37
ANG, D.K.
 COVID-19
D. American College of Obstetricians and Gynecologists • Testing should be done first at approximately 24 hours of age
Guidance for Pregnant Women with COVID-19 and again at approximately 48 hours of age. Some infants
have had a negative test at 24 hours only to have a positive
test at a later time
• For infants who are positive on their initial testing, consider
follow-up testing at 48-72 hour intervals until two consecutive
negative tests are obtained to establish that the infant has
cleared the virus from mucosal sites

F. Thromboprophylaxis in Pregnant Patients with COVID-

19
• Pregnant women do not appear to have a substantially
increased risk of thrombotic complications related to
COVID-19
• Currently no evidence to recommend the use of intermediate
or therapeutic doses of LMWH in thromboprophylaxis, which
may increase bleeding risk without reducing thrombotic risk in
pregnant patients with COVID-19.
• There is no evidence to comment on the role of low- dose
aspirin in thromboprophylaxis or of anti-cytokine and antiviral
agents in preventing immunothrombosis

XVIII. Treatment
A. Mainstay Supportive Treatment
• Oral Fluids for hydration
• Anti-pyretics for fever
• Oxygen
• Ventilatory Support
• Routine empiric antibiotics and anti-influenza drugs are NOT
recommended for mild COVID disease

1. NSAIDS
• Can be used as anti-pyretics
E. Infants born to Mothers with confirmed COVID-19 • DO NOT give to COVID-19 patients with signs of kidney injury
• Based on American College of Obstetricians and (known kidney disease/elevated creatinine)
Gynecologists (ACOG) and American Academy of Pediatrics
• Should be considered a patient under investigation 2. Antibiotics
• Appropriately isolated and evaluated • Can be given if with superimposed bacterial infection
• Currently no evidence for intrauterine infection caused by • Avoid Vancomycin
vertical transmission in women who develop COVID-19 • Stop using if with clear signs of kidney injury
pneumonia in late pregnancy
• Risk that a newborn tests positive for SARS-CoV-2 in the hours 3. ACEI/ARBs
or days after birth to a mother with COVID-19 at the time of • Can be used continuously
delivery is informed both by published case series and over • DO NOT give to COVID-19 patients with signs of kidney injury
3,000 cases reported to date to the Perinatal COVID-19 (known kidney disease/elevated creatinine)
Registry
• Approximately 2% of infants born to women who test positive
for SARS-CoV-2 near the time of delivery have tested positive
in the first 24-96 hours after birth
• Delayed cord clamping practices and skin-to-skin care in the
delivery room should continue per usual center practice.
Mothers with COVID-19 should use a mask while holding their
baby.
• no published report has identified an infant who has died
during the initial birth hospitalization as a direct result of SARS-
CoV-2 infection
• Mothers and newborns may room-in according to usual center
practice.
• Infants born to mothers with confirmed or suspected COVID-
19 should be bathed after birth to remove virus potentially
present on skin surfaces
• Obtain either a single swab of the nasopharynx; or a single 4. Albuterol/Ipratropium
swab of the throat followed by the nasopharynx; or two
separate swabs from each of these sites, and submit for a • Given for patients with COPD/Asthma in acute exacerbation
single test. The specifics of testing will depend on the • Metered dose inhaler are preferred over nebulizers
requirements of local testing platforms • Nebulizers must avoided since it aerosolizes the viral particles
• 8 puffs of MDI = 1 nebulizer treatment (wait 1 minute in
between each puff)

38
ANG, D.K.
 COVID-19
B. Investigational Pharmacologic Treatment
1. Hydroxychloroquine/Chloroquine + Any Macrolide
• NO LONGER RECOMMENDED
• Chloroquine (CQ) or hydroxychloroquine (HCQ) as
monotherapy or in combination with a macrolide (e.g.
azithromycin) or an antiviral agent (lopinavir-ritonavir,
favipiravir) among hospitalized patients with probable or
confirmed COVID-19 pneumonia is NOT recommended.
• Chloroquine or hydroxychloroquine is not recommended for
outpatients with early or mild COVID- 19 disease except in the
context of a clinical trial.
• Chloroquine or hydroxychloroquine is not recommended for
prophylaxis or prevention of COVID- 19 except in the context
of a clinical trial.
• Hospitalized with mild-to-moderate Covid-19, the use of
hydroxychloroquine, alone or with azithromycin, did not
improve clinical status at 15 days as compared with standard
care
• Rationale for its use: increases endosomal pH, inhibits fusion
of sever acute respiratory syndrome coronavirus 2 and host
cell membranes and could have immunomodulatory effects
• No difference in viral clearance between hydroxychloroquine
and placebo
• Higher risk for its known side effects: Cardiac arrhythmia,
retinopathy, bone marrow suppression

2. Remdesivir
• Being tested in large scale clinical trials in US and China
• Drug used against Ebola Virus Outbreak in 2014
• Novel nucleotide analogue in vitro SARS-CoV-2, (in vitro and
in animal studies: SARS-CoV-1; MERS-CoV) 3. Tocilizumab
• Formerly GS-5734
• MOA: inhibitor of the viral RNA and RNA dependent • IL-6 inhibitor
polymerase with inhibitory activity against SARS-CoV and • Used to treat patients in China with severe COVID-19 and
MERS-CoV elevated IL-6 levels (Treatment guidelines from China’s
• Median recovery time of 11 days as compared with 15 days in National Health Commission)
those who received placebo • Observational retrospective study (43), a single infusion of
• Believed to be efficacious in moderate to severe COVID-19 Tocilizumab given to severely or critically ill COVID-19 patients
resulted in prompt
• Intravenous Remdesivir (unknown dose)
o First initiated for compassionate use on day 7 of • Given to patients with severe to critical COVID-19
hospitalization based on the patient’s worsening condition. • Resulted in shorter duration of vasopressor support, resulted
The patient’s condition improved the next day in shorter median time to clinical improvement and shorter
• 200 mg IV loading dose on Day 1 duration of invasive ventilation
o followed by 100 mg IV once a day for 5-10 days • Improvement in clinical, inflammatory and radiologic markers.
• For hospitalized patients with severe COVID-19 who are not • Adverse effects:
intubated, a 5-day regimen of remdesivir may be given. o Hypertension
• Remdesivir therapy may be extended to up to 10 days if no o Diarrhea
substantial clinical improvement is seen at Day 5. o Abdominal Pain
o Increase in ALT/AST
• The combination of remdesivir and dexamethasone has not
o Dizziness
been studied in clinical trials; however, there are theoretical
o Headache
reasons for combining these drugs.
o Pharyngitis
• The Panel recognizes there are theoretical reasons for adding
o Infusion reactions
dexamethasone to the drug regimen of patients who are
currently receiving remdesivir but who are clinically • Serious side effects:
o Thrombocytopenia
deteriorating.
o Neutropenia
• If dexamethasone is not available, an alternative corticosteroid
o GI perforation
such as prednisone, methylprednisolone,
o Pancreatitis
or hydrocortisone can be used
o Hepatotoxicity
• A combination of remdesivir (dose and duration as above)
o Anaphylaxis
plus dexamethasone 6 mg IV or orally for up to 10 days or
o URTI
until hospital discharge
o Severe infections
• Adverse effect: Hypotension, Elevated Creatinine, ALT/AST
• Monitoring:
• Clinical Monitoring: Liver Enzymes and Creatinine o Evaluate for latent/active TB prior to initiation
• Undergoing clinical trials for COVID-19 o Check for baseline CBC, ALT/AST and monitor
• There is insufficient evidence to recommend the routine use of periodically
remdesivir among hospitalized patients with mild to moderate o Check baseline lipid panel and monitor periodically
COVID disease except in the context of a clinical trial. o Do Hepatitis B and TB screening at the minimum
• Kaplan-Meier estimates mortality by 14 days were 7.1% with • Undergoing clinical trials for COVID-19
remdesivir and 11.9% with placebo

39
ANG, D.K.
 COVID-19
• Can be distributed into the sperm
• Male patients should be informed the risk associated with the
use of this product
• Male patients using this product are advised the following:
o Do not have sexual intercourse with pregnant women
o Advise the use of condom
o Should be advised to use most effective contraceptive
method while using the drug and after 7 days of the last
dose
• Benefit-risk balance should be carefully assessed prior to
considering the use of this drug

7. Ivermectin
• COVID-19 inhibitor in vitro
• Single treatment able to effect ~5000-fold reduction in virus at
48h in cell culture
• Potential role for IMPa/b1 during infection in signal-dependent
• There is insufficient evidence to recommend the use of nucleocytoplasmic shutting of the SARS-CoV Nucleocapsid
tocilizumab and other IL-6 inhibitors for the management of protein 16,17,18
COVID-19 in severe hospitalized patients with suspected • Recommends against the use of ivermectin for the
cytokine storm except in the context of a clinical trial or for treatment of COVID-19
compassionate use. o Based on the latest PSMID guidelines for COVID-19
treatment guidelines
4. Lopinavir-Ritonavir
• NO LONGER RECOMMENDED
• Lopinavir-ritonavir (LPV/r) as monotherapy or in combination
with hydroxychloroquine or other immunomodulators is NOT
recommended among hospitalized patients with probable or
confirmed COVID-19 pneumonia.
• Rationale for use: inhibitor of SARS-CoV 3CL pro in-vitro
• a human immunodeficiency virus 1 (HIV-1) protease inhibitor
administered in fixed-dose combination with ritonavir (LPV/r),
a potent CYP3A4 inhibitor that increases lopinavir
concentration
• No difference in viral clearance
• No benefit was observed with lopinavir–ritonavir treatment
beyond standard care
• Did not significantly accelerate clinical improvement, reduce a. Based on PSMID newest joint statement with FDA
mortality, or diminish throat viral RNA detectability in patients o On in vitro studies, it prevents viruses from suppressing
with serious Covid-19 the host’s anti-viral response
• Dose: 200/50mg twice daily orally o May reduce cytokine secretion
o Use of ivermectin for the treatment of COVID-19 does not
5. Zinc reduce mortality risk
o NOT ASSOCIATED with a definite benefit in terms of other
• No current clinical evidence that zinc or zinc supplements are
clinically important outcomes such as improvement at Day
effective adjunctive treatment for COVID-19
6-10, clinical deterioration, nor need for mechanical
ventilation
6. Favipiravir
o It does not significantly reduce the duration of
• 6-fluoro-3-hydroxy-2pyrazinecarboxamide, Avigan) is a hospitalization and time to resolution of symptoms
prodrug of a purine nucleotide, favipiravir ribofuranosyl-5′- o Rate of hospital discharge at Day 10-14 DOES NOT
triphosphate DIFFER SIGNIFICANTLY between those given ivermectin
• Mechanism of action: inhibitor of the RNA-polymerase by and those who received standard of care or placebo
resembling the endogenous guanine o The use of Ivermectin for the treatment of COVID-19 has
• Use of favipavir led to shorter latencies to relief both pyrexia not been proven to significantly reduce mortality or
by 1.7 days and cough by 1.75 improve other clinical outcomes.
• Associated with shorter viral clearance time
• There is insufficient evidence to recommend the routine use of b. Based on FLCCC Alliance guidelines
favipiravir in the treatment of COVID-19 except in the context o Inhibits SAR-CoV-2 replication and binding to host tissue
of a clinical trial or for compassionate use among patients with via several observed and proposed mechanisms
moderate COVID-19 disease. o Significantly diminishes viral load and protects against
• Clinical trial dosage is 1800 mg 2x/day loading dose then organ damage in multiple animal models when infected
800 mg 2x/day for 13 days. with SARS-CoV-2 or similar coronaviruses
• Side effects: o Prevents transmission and development of COVID-19
o Mild diarrhea and Nausea disease in those exposed to infected patients
o Elevated serum uric acid o Hastens recovery and prevents deterioration in patients
o Elevated ALT/AST with mild to moderate disease treated early after
o Elevated Bilirubin symptoms
• Contraindicated in known or suspected pregnancy o Hastens recovery and avoidance of ICU admission and
o Teratogenic and Embryogenic death in hospitalized patients
• Can only be used in women in the child-bearing age after o Reduces mortality in critically ill patients with COVID-19
confirming a negative pregnancy test

40
ANG, D.K.
 COVID-19
o Leads to striking reduction in case-fatality rates in regions 12. Hemoperfusion
with widespread use • There is insufficient evidence to support the routine use of
o I-MASK+ Prophylaxis and Early Outpatient Treatment hemoperfusion as adjunctive management for severe COVID-
Protocol for COVID-19 19 patients suspected to have cytokine storm except for
• Prophylaxis for high risk individuals compassionate use.
o 0.2mg/kg per dose – one dose today, 2nd in 48 hours, • Cytokine release syndrome is prevalent in severe cases of
then one dose every 2 weeks COVID-19.
• Post-COVID-19 exposure prophylaxis • Hemoperfusion devices or extracorporeal blood purification
o 0.2mg/kg per dose – one dose today, 2nd dose in 48 has been proven to effectively remove the released
hours inflammatory cytokines.
• Early Outpatient Treatment Protocol
o 0.2mg/kg per dose – one dose daily for minimum of a. Algorithm for Hemoperfusion
2 days, continue daily until recovered (max 5 days)

c. Based on other literatures

o Associated with lower mortality during treatment of
COVID-19, especially in patients with severe pulmonary
involvement
o ivermectin's activity against SARS-CoV-2 is currently
under investigation in patients
o 5-day course of ivermectin was found to be safe and
effective in treating adult patients with mild COVID-19

8. Camostat Mesylate
• Inhibits serine protease TMPRSS2 activity
• Blocks cellular entry of SARS-CoV-2
• In mice, dosed concentration similar to clinically achievable
concentration in humans reduced mortality from 100 to 30-
35%
• On Phase 1 Clinical Trial b. Other Indications for Hemoperfusion
• Nafamostat (IV form) o High SOFA Score
o Hemodynamic instability
9. Intravenous Immunoglobulin o High level of pro-inflammatory parameters
• There is insufficient evidence to support the use of intravenous
immunoglobulin (IVIg) for the management of COVID-19
among severe hospitalized patients except in the context of a
clinical trial.
13. Dexamethasone
• Mixture of polyclonal immunoglobulin and proteins pooled from
healthy donors. • the use of dexamethasone resulted in lower 28-day mortality
• MOA: twofold – one, as a neutralizing antibody and second as among those who were receiving either invasive mechanical
an anti-inflammatory or immunomodulator of the cytokine ventilation or oxygen alone at randomization but not among
response (e.g. IL-1 or TNF-α). those receiving no respiratory support.
• High dose of IVIg at 0.3-0.5 g/kg BW daily for 5 days • The RECOVERY trial provides evidence that treatment with
dexamethasone at a dose of 6 mg once daily for up to 10 days
10. Interferon reduces 28-day mortality in patients with Covid-19 who are
receiving respiratory support
• There is insufficient evidence to support the routine use of
interferon (IFN) for patients hospitalized patients with COVID-
14. Heparin
19 except in the context of a clinical trial or for compassionate
use. • an initial strategy of therapeutic-dose anticoagulation with
• Refer to innate cytokines that make host cells refractory to heparin did not result in a greater probability of survival to
virus replication. hospital discharge or a greater number of days free of
• Clinical studies on the efficacy of type I interferons, alfa and cardiovascular or respiratory organ support than did usual-
beta, in the treatment of SARS-CoV with variable results care pharmacologic thromboprophylaxis
• Dosage:
o Intravenously: Dose of 10 μg once daily for 6 days
o Subcutaneously at the dose of 44 μg on Day 1, Day 3 and 15. Bamlanivimab
Day 6 (total: 3 doses) • LY-CoV555 and LY3819253
§ Should be given at the same time each day. • EUA pulled out due to evidence of INSIGNIFICANT
o No dosage adjustment is required for renal or hepatic BENEFIT
impairment. • a neutralizing monoclonal antibody that targets the receptor-
binding domain of the spike protein of severe acute respiratory
11. Vitamin C syndrome coronavirus 2 (SARS-CoV-2)
• There is no direct evidence available at this time on the • Because this drug may block SARS-CoV-2 entry into host
efficacy/effectiveness of intravenous vitamin C in reducing cells, it is being evaluated for the treatment of COVID-19
mortality or shortening disease course among adults • November 9, 2020, FDA and EUA make bamlanivimab
suspected of, or positive for COVID-19. available for the treatment of non-hospitalized patients with
• Indirect evidence from studies in sepsis and ARDS do not mild to moderate COVID-19 who are at high risk for
show any benefit. progressing to severe disease and/or hospitalization
• There is insufficient evidence to support the use of vitamin C
as adjunctive treatment for COVID-19.

41
ANG, D.K.
 COVID-19
• insufficient data to recommend either for or against the use of 16. Etesivimab (+Bamlanivimab)
bamlanivimab for the treatment of outpatients with mild to • FDA approved for use in combination with Bamlanivimab for
moderate COVID-19 treatment of mild-to-moderate COVID-19 in patients aged >12
• should not be considered the standard of care for the • Etesevimab 1400mg + Bamlanivimab 700mg as a single IV
treatment of patients with COVID-19 infusion
• should not be withheld from a pregnant individual who has a • Manufactured by Eli Lilly and Co
condition that poses a high risk of progression to severe • Must not be given in hospitalized patients due to COVID-19
COVID-19, and the clinician thinks that the potential benefit of • May be associated with worse clinical outcomes when
the drug outweighs potential risk administered to hospitalized COVID-19 patients with high-flow
• hospitalized for COVID-19 should not receive bamlanivimab oxygen or mechanical ventilation
outside of a clinical trial • Given to patients immediately diagnosed with a positive
• Use of bamlanivimab for the treatment of non-hospitalized SARS-CoV-2 and within 10 days of symptoms onset
adults and children aged ≥12 years and weighing ≥40 kg who • Given to non-hospitalized high risk patients with one of the
have a high risk for progressing to severe COVID-19 or following criteria:
hospitalization o BMI >35
• High Risk specified are: o Chronic kidney disease
o Individuals aged ≥12 years who have one of the following o Diabetes
conditions: o Immunosuppressive disease
• BMI ≥35 o Receiving immunosuppressive treatment
• Chronic kidney disease o Age >65
• Diabetes mellitus o Age >55 with cardiovascular disease, hypertension, or
• Immunosuppressive disease COPD/chronic respiratory disease
• Currently receiving immunosuppressive treatment • For patients 12-17 years old:
o Individuals aged ≥65 years o BMI >85th percentile
o Individuals aged ≥55 years who have: o Sickle cell disease
• Cardiovascular disease, or o Congenital or acquired heart disease
• Hypertension, or o Neurodevelopmental disorders
• Chronic obstructive pulmonary disease/other chronic o Medical-related technological dependence
respiratory disease o Asthma, reactive-airway disease, or other respiratory
• Monoclonal antibody LY-CoV555, when coadministered with disease requiring maintenance medications
remdesivir, did not demonstrate efficacy among hospitalized • Not authorized for use as preventive measure
patients who had Covid-19 without end-organ failure. • Side effect when co-administered with Bamlanivimab
• Slight decrease in the mean serum creatinine level from o Nausea; Dizziness; Rash
baseline to day 5 in the LY-CoV555 group as compared with • COVID-19 vaccine can be deferred or atleast 90 days following
no change in the placebo group, no significant between-group treatment with monoclonal antibody for COVID-19
differences were seen with respect to intrapatient changes in • Bamlanivimab plus etesevimab led to a lower incidence of
key laboratory values Covid-19–related hospitalization and death than did placebo
• Relative side effects: (accdg to studies, these side effects are and accelerated the decline in the SARS-CoV-2 viral load.
unclear and cannot be differentiated with disease progression) • At day 7, a greater reduction from baseline in the log viral load
o Fever was observed among patients who received bamlanivimab
o Hypoxia plus etesevimab than among those who received placebo
o Increased respiratory difficulty
o Arrhythmia 17. Molnupiravir
o Fatigue • EIDD-2801/MK-4482
o Altered mental status • the prodrug of the active antiviral ribonucleoside analog ß-d-
• Primarily based on the Phase2/3 data of BLAZE-1 trial N4-hydroxycytidine (NHC; EIDD-1931)
• Cannot be used as a preventive measure for COVID-19 • Appeared rapidly in plasma, with a median time of maximum
observed concentration of 1.00 to 1.75 hours,
• Targets the viral polymerase, an enzyme needed to make
copies of the virus
• Declined with a geometric half-life of approximately 1 hour,
• Slower elimination phase apparent following multiple doses or
higher single doses (7.1 hours at the highest dose tested)
• When administered in a fed state, there was a decrease in the
rate of absorption, but no decrease in overall exposure
• Therapeutic treatment of infected animals with twice-daily MK-
4482/EIDD-2801 significantly reduced upper respiratory tract
SARS-CoV-2 load and completely suppressed spread to
untreated contact animals.
• Ferrets and related members of the weasel genus transmit
SARS-CoV-2 efficiently with minimal clinical signs, resembling
spread in the young-adult population.
• Promising antiviral countermeasure to break SARS-CoV-2
community transmission chains.
• The potency of NHC/EIDD-2801 against multiple CoVs and
oral bioavailability highlights its potential utility as an effective
antiviral against SARS-CoV-2 and other future zoonotic CoVs.
• Mid-stage trial found that treatment after 5 days of
molnupiravir, none of the various doses of the drug tested
positive for infectious virus, while 24% of placebo did.

42
ANG, D.K.
 COVID-19
18. Umifenovir (Arbidol Hydrochloride) 20. Regdanvimab
• Indole-derivative broad-spectrum drug against wide range of • Celltrion’s monoclonal antibody treatment
enveloped and non-enveloped viruses interacts preferentially • CT-P59 showed the antiviral effect but reduced susceptibility
with aromatic amino acids against authentic Gamma, Delta, Epsilon and Kappa variants
• Inhibits replication of influenza virus in-vitro in cell experiments
• Affects multiple stage of virus life cycle by either direct • CT-P59 showed neutralizing activity against pseudo
targeting viral proteins or virus-associated host factors virus variants: Gamma, Delta, Epsilon, Kappa, K417T,
• Licensed to use in Russia and China as an anti-influenza drug E484K, N501Y, L452R, T478K and P681H
• Proposed mechanism against SARS-CoV-2: • Clinically relevant dose of CT-P59 showed in vivo protection
o Interferes with SARS-CoV-2 binding against Gamma and Delta variants in hACE2-expressing
o Interferes with intracellular vesicle trafficking mice challenge experiments
o Identifies the spike glycoprotein essential for cell • clinical dosage of CT-P59 could overcome a certain level of
adherence and entry as the target of the drug reduction in in vitro antiviral activity, as long as it is not a
• May be associated with lower incidence of SARS-CoV-2 complete loss in neutralizing activity.
infection • The therapeutic ability of Regdanvimab (40 mg/kg dosage and
• No effect in hospitalization rate in health professionals 6.76 ng/mL IC50) could come to approx. 70-fold over that of
• Selective prophylaxis for high-risk populations Sotrovimab (500 mg dosage and 100 ng/mL IC50)
• Dosed at 200mg 3x/day for 10-18 days – although dosage
must be elevated 21. Casirivimab and Imdevimab
• Substantial evidence associated with reduction in mortality • REGEN-CoV combination of Casirivimab and Imdevimab
among hospitalized COVID-19 patients reduced the viral load and number of medical visits in patients
• Combination of Arbidol and Oseltamivir may be further with coronavirus disease
associated with a reduction in mortality • REGEN-COV has activity in vitro against current severe acute
• Criteria of improvement: respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of
o Relief of cough concern
o Dyspnea • REGEN-COV reduced the risk of Covid-19–related
o Fever hospitalization or death from any cause, and it resolved
• Peripheral oxygen saturation rate was significantly different symptoms and reduced the SARS-CoV-2 viral load more
after 7 days of admission across two groups rapidly than placebo.
• Based on 2 unpublished clinical trials. LOW TO MODERATE • The median time to resolution of symptoms was 4 days shorter
QUALITY OF EVIDENCE with each REGEN-COV dose than with placebo
• INSUFFICIENT EVIDENCE TO SUPPORT THE USE FOR • Serious adverse events occurred more frequently in the
COVID PATIENTS placebo group (4.0%) than in the 1200-mg group (1.1%) and
• No significant difference in clinical recovery rate in the the 2400-mg group (1.3%)
subgroup of moderate COVID-19 patients
• No significant difference compared to lopinavir/ritonavir and 22. Tofacitinib
supportive care alone in the viral clearance, disease
•A Janus kinase
progression, clinical status on days 7 and 14
inhibitor
• Adverse effects:
o Mild diarrhea
• Tofacitinib led to a
o Nausea
lower risk of death or
o Elevated serum uric acid
respiratory failure
o Elevated ALT/AST
through day 28 than
o Elevated Bilirubin
placebo.
• 10 ongoing trials and results are
• The cumulative
expected to be released by
incidence of death or
February 2021
respiratory failure
through day 28 was
18.1% in the tofacitinib group and 29.0% in the placebo group
19. Leronlimab
• The proportional odds of having a worse score on the eight-
• A monoclonal antibody blocker of C-C chemokine receptor level ordinal scale with tofacitinib, as compared with placebo,
type 5 originally developed to treat human immunodeficiency was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI,
virus infection 0.27 to 1.06) at day 28.
• 700mg Leronlimab subcutaneously after 7 days • Serious adverse events:
• 23 patients were given o Deep vein thrombosis
o 17 recovered o Myocardial infarction
o 2 still hospitalized o Myocarditis
o 4 died o Ventricular tachycardia
• Given to patients whose clinical and laboratory parameters
reflected severely ill cohort
• Well tolerated by most patients except for 1
o Developed a maculopapular rash
• Examination of disease markers in 10 days after treatment
o D-dimer remained stable during dosing
o CRP dropped after 2nd dosing
o Il-6 consistentnly dropped
• Substantially higher survival rate than other reports of critically
ill COVID-19 patients
• CCR5 occupancy – may be determinant or marker for
leronlimab responsiveness

43
ANG, D.K.
 COVID-19
23. List of all anti-cytokine receptor antagonists being tested • Early administration of high-titer convalescent plasma against
for COVID-19 SARS-CoV-2 to mildly ill infected older adults reduced the
progression of Covid-19.
• interleukin-1 and interleukin-6 receptor antagonists
(e.g., anakinra, tocilizumab, sarilumab, and siltuximab)
• tumor necrosis factor inhibitors
(e.g., adalimumab and infliximab)
• granulocyte–macrophage colony-stimulating factors
(e.g., gimsilumab, lenzilumab, and namilumab)

C. Convalescent Plasma Therapy

• Has not yet been shown to be effective in COVID-19 (FDA Apr
3,2020)
• Several studies showed a shorter hospital stay and lower
mortality in patients treated with convalescent plasma
• Possible rationale: antibodies from convalescent plasma might
suppress viremia
• FDA Considerations for eligibility of plasma donors
o Evidence of COVID-19 documented by a laboratory test
• Diagnostic test at time of illness; OR
• + serological test for SARS-CoV-2 antibodies after
recovery, if prior diagnostic testing was not performed
at the time of COVID-19 was suspected
o Either one of the following:
• Complete resolution of symptoms >28 days prior to
donation; OR
• Complete resolution of symptoms >14 days prior to
donation; AND
• Negative result for COVID-19 either from one or more
nasopharyngeal swab specimens or by molecular
diagnostic test from blood
o Male donors or Female donors who have not been
pregnant
o Defined SARS-CoV-2 neutralizing antibody titers (>1:80)
• There is insufficient evidence to support the use of
convalescent plasma (CP) for hospitalized COVID-19 patients
except in the context of a clinical trial.
• CP may be considered for patients with severe COVID-19
under compassionate use or for eligible patients with moderate
to severe COVID-19 in institutions where there is an ongoing
clinical trial, duly approved by the appropriate corresponding
Institutional Regulatory Board.
• It is a means of antibody transfer to provide passive immunity D. Role of Traditional Chinese Medicine (Lianhua
(through neutralizing antibodies or possibly other immune
Qingwen)
mediators directed against the infectious pathogen) until the
individual can develop an active immune response, with the 1. LianHua QingWen (连花清瘟胶囊)
hope that clinical outcomes can be improved in the recipient. • Capsule Type or Granule Types
• Use of convalescent plasma as treatment for patients with • Consists of 11 herbs, gypsum, and menthol
severe COVID-19 • Components of CM formula reportedly exerting activity
• May provide immunity by giving patients neutralizing o Forsythia suspensa (Thunb.)
antibodies for SARS-CoV-2 o Vahl. (Lianqiao)
• The efficacy of this therapy has been associated with the o Lonicera japonica Thunb. (Jinyinhua)
concentration of neutralizing antibodies (Nabs) in plasma from o Ephedra sinica Stapf (Mahuang)
o Armeniacae Amarum Semen (Kuxingren)
recovered donors. o Gypsum Fibrosuum (Shigao)
• NAbs bind to spike1-receptor binding protein (S1-RBD), S1-N- o Isatis tinctoria L. (Banlangen)
terminal domain and S2, thus inhibiting their entry, limiting viral o Dryopteridis
amplification Crassirhizomatis Rhizoma
• No statistically significant benefit in clinical improvement at 28 (Mianmaguanzhong)
days or mortality among all randomized patients o Houttuynia cordata Thunb.
(Yuxingcao)
• Death within 30 days after plasma transfusion occurred in o Pogostemon cablin (Blanco)
26.9% of all the patients o Benth. (Guanghuoxiang)
• Patients in the high-titer group had a lower relative risk of death o Rheum palmatum L. (Dahuang)
within 30 days after transfusion than patients in the low-titer o Rhodiola rosea Linn. (Hongjingtian)
group (relative risk, 0.75; 95% CI, 0.61 to 0.93) o Mentha haplocalyx Briq. (Bohe)
• Patients who received plasma within 3 days after the diagnosis o Glycyrrhiza uralensis Fisch. (Gancao)
o Herbal ratio of 170 g: 170 g: 57 g: 57 g: 170 g: 170 g: 170 g: 170
of Covid-19 had a lower risk of death than those who received
g: 57 g: 34 g: 57 g: 5 g: 57 g,
a transfusion later in the disease course o Recorded in Chinese Pharmacopeia (2015)
• Benefit of convalescent plasma was most apparent in patients • Combination of TCM with western medicine has a potential
who received plasma transfusions containing higher levels of advantage in improving the prognosis of patients with COVID-
anti–SARS-CoV-2 IgG antibodies early in the disease course 19
• It has been used for fighting against the epidemic in China

44
ANG, D.K.
 COVID-19
• There have been some relevant clinical reports on COVID-19 F. Pre-exposure or Post-exposure Prophylaxis
treated with Lianhua Qingwen • Chloroquine and Hydroxychloroquine is NOT recommended to
• MOA: prevent COVID-19
o Direct pathway mainly affects the function of the viral • There are no high-quality direct evidence supporting the use of
envelope, inhibits virus adsorption and penetration into these drugs for prophylaxis
cells, and inhibits viral transcription and replication • At least 4 clinical trials are on-going for the effectiveness of
processes. HCD as prophylaxis
o Indirect pathways include improving body immunity, • Proper use of good-quality PPEs should be ensured
improving immunoglobulin levels, regulating cytokine • After high-risk or moderate-risk exposure to Covid-19,
synthesis and release, and inhibiting oxidative stress hydroxychloroquine did not prevent illness compatible with
damage caused by viruses Covid-19 or confirmed infection when used as post-exposure
• Lianhua Qingwen combined with conventional drugs can prophylaxis within 4 days after exposure
better alleviate the clinical symptoms of ordinary patients, has
good safety, and has important clinical application value
G. Management Algorithm
• Not enough randomized control trials to prove significant
evidences regarding efficacy and safety.
• Side effects: Abnormal Liver Function Tests

E. Mechanism of Action of Drugs

45
ANG, D.K.
 COVID-19
H. Additional Supportive Therapy and Monitoring for
Patients with Pneumonia
1. Supplemental Oxygen Therapy
• Patient Positioning:
o Upright – improves lung capacity
o Prone – awake proning for 5-10 mins
• Give supplemental oxygen therapy
o Especially to patients with pneumonia and respiratory
distress, hypoxemia, or shock
o Initiate 5 L/min
o titrate flow rates to reach target:
§ SpO2 ≥90% in non-pregnant adults
§ SpO2 ≥92-95 % in pregnant patients
• Children with emergency signs should receive oxygen therapy 2. Fluid Resuscitation
during resuscitation to target SpO2 ≥94%; • Conservative fluid management in patients with pneumonia
• Children without signs SpO2 is ≥90% when there is no evidence of shock
• If patient has pneumonia, should be equipped with: • If with pneumonia, treat cautiously
o pulse oximeters o Aggressive resuscitation = worsens oxygenation
o functioning oxygen systems
o disposable, single-use, oxygen-delivering interfaces 3. Antimicrobials
(nasal cannula, simple face mask, and mask with reservoir • Give appropriate empiric antimicrobials if patient has
bag) concomitant CAP
• Delivery Devices • Empiric antimicrobials within ONE hour of identification of
Device Flow Rate O2 Concentration sepsis
Nasal Cannula 1-6L/min 24-44% FiO2 • Give oseltamivir for 5 to 10 days for patients who are
Simple Facemask 6-10L/min 40-60% FiO2 confirmed to have influenza A or B infection
Non-Rebreather 12-15L/min 90-100% FiO2 o 75 mg per tab BID for adults
o 3mg/kg per dose BID for pediatric patients
• Empiric therapy with Oseltamivir when there is local circulation
or other risk factors, including travel history

4. Steroids
• DO NOT routinely give systemic corticosteroids for treatment
of viral pneumonia or ARDS outside of clinical trials unless they
are indicated for another reason
• There is insufficient evidence to support the use of steroids in
• Assess the need for intubation and mechanical ventilation the management of patients with confirmed or suspected
• Avoiding pitfalls 2019-nCoV infection with acute lung injury and ARDS
o Avoid Benzodiazepines or narcotics in agitated patients • May provide little benefit and cause more harm among these
o Be careful with COPD or chronic respiratory insufficiency patients.
§ Might result into hypercarbia • Corticosteroid therapy (dexamethasone) is recommended as
o Ensure oxygen is flowing adjunctive treatment for COVID-19 patients requiring oxygen
support and for patients on mechanical ventilation.
• Aerosolization risk • The recommended dose for dexamethasone is 6 mg IV for
10 days.
• Corticosteroid therapy (dexamethasone) is not recommended
for COVID-19 patients who do not require oxygen support (mild
to moderate disease severity).
• Inhaled steroids are NOT recommended for the treatment of
COVID-19 pending the results of ongoing studies.
• Oral, inhaled or IV steroids are NOT recommended for
prophylaxis or prevention of COVID-19.
• Use of dexamethasone resulted in lower 28-day mortality
among those who were receiving either invasive mechanical
ventilation or oxygen alone at randomization but not among
those receiving no respiratory support
• Interfaces for Non-invasive Positive Pressure Ventilation
5. Intubation Sedation
Drug Dose Onset Side effects
Etomidate 0.3mg/kg 15-45 secs
Hypotension;
Midazolam 0.2mg/kg 30-60 secs
ICU Delirium
Hypotension;
Propofol 1.5-3mg/kg 15-45 secs
Bradycardia;
Chest wall
• Different Types of Non-invasive Ventilation Ketamine 1-2mg/kg 45-60 secs rigidity;
Hypotension
Succinylcholine 1.5mg/kg Hyperkalemia
Rocuronium 1-1.2mg/kg

46
ANG, D.K.
 COVID-19
I. Management of Sepsis and Septic Shock K. Management of Acute Respiratory Distress Syndrome
• Admit the patient to designated COVID-19 isolation room/ICU • Recognize severe hypoxemic respiratory failure when a
1. Antimicrobials patient with respiratory distress is failing standard oxygen
• Give appropriate antimicrobials within one hour, DO NOT therapy
DELAY antimicrobials
• Blood cultures should be collected prior to antimicrobial 1. Signs and Symptoms
treatment • Onset: new or worsening respiratory symptoms within 1 week
• Determine if infection was acquired in the community or in the of known clinical insult
hospital setting and provide appropriate empiric therapy • Chest imaging (radiograph, CT scan, or lung ultrasound):
o bilateral opacities, not fully explained by effusions,
2. Dobutamine o lobar or lung collapse, or nodules.
• consider an inotrope if signs of poor perfusion and cardiac • Origin of edema: respiratory failure not fully explained by
dysfunction persist despite achieving MAP target with fluids cardiac failure or fluid overload.
and vasopressors • Need objective assessment (e.g. echocardiography) to
exclude hydrostatic cause of edema if no risk factor present.
3. Fluid resuscitation
2. Classification of ARDS among adults:
• Early effective fluid resuscitation as follows:
• Fluids of Choice: Crystalloids (NSS/LRS) Classification
200 mmHg < PaO2/FiO2 ≤ 300 mmHg
• In adults, administer at least 30 ml/kg of balanced crystalloid
Mild ARDS (with PEEP or CPAP ≥5 cmH2O, or non-
or normal saline solution within 1 hours if with signs of sepsis-
ventilated)
induced hypoperfusion
Moderate ARDS 100 mmHg < PaO2/FiO2 ≤200 mmHg
• In children in well-resourced settings, give 20 ml/kg as a rapid with PEEP ≥5 cmH2O, or non- ventilated)
bolus and up to 40-60 ml/kg in the first 1hr PaO2/FiO2 ≤ 100 mmHg
• Do not use hypotonic crystalloids, starches, or gelatins for Severe ARDS with PEEP ≥5 cmH2O, or non-ventilated)
resuscitation. When PaO2 is not available,
• Monitor for volume overload during resuscitation SpO2/FiO2 ≤315 suggests ARDS
(including in non-ventilated patients)

3. Classification of ARDS among children:

Classification
Bilevel NIV PaO2/FiO2 ≤ 300 mmHg or
CPAP ≥5 cmH2O SpO2/FiO2 ≤264
via full face mask
Invasively ventilated
Mild ARDS 4 ≤ OI < 8 or 5 ≤ OSI < 7.5
Moderate ARDS 8 ≤ OI < 16 or 7.5 ≤ OSI < 12.3
Severe ARDS OI ≥ 16 or OSI ≥ 12.3

4. Management
• Admit the patient to the ICU.
4. Vasopressors • Recognize severe hypoxemic respiratory failure when a
patient with respiratory distress is failing standard oxygen
• If still hypotensive à assess fluid responsiveness therapy.
o If fluid unresponsive,
§ Initiate vasopressors: target MAP ≥65 mmHg in a. Hypoxemic patients without ARDS
adults.
o may benefit from high flow nasal oxygen (HFNO) therapy
§ If with pre-existing hypertension, MAP of 75 to 85
or non-invasive ventilation.
mmHg is suggested
o monitor closely in an ICU
§ Use of vasopressors should not be delayed.
o assess on need for escalation to invasive mechanical
• given through a peripheral IV ventilation with intubation
• closely monitor for signs of extravasation and local tissue
necrosis. b. ARDS is present
o If extravasation occurs, stop infusion.
o Referral to appropriate specialists (e.g. Pulmonologist
• Central venous pressure (CVP) should not be used to assess
and/or Intensivist)
fluid responsiveness.
o Endotracheal intubation – under airborne precautions
o Implement lung protection strategy with initial tidal
J. Non-sedation in Critically-ill or Mechanically Intubated
volumes at 6-8 ml/kg of predicted body weight
• Mortality at 90 days did not differ significantly between those o Limit inspiratory pressures (plateau pressures) below 30
assigned to a plan of no sedation and to those assigned to a cmH2O
plan of light sedation with daily interruption. o In patients with moderate or severe ARDS, higher PEEP
• The patients in the non-sedation group had a median of 27 instead of lower PEEP is suggested.
days free from coma or delirium, and those in the sedation
group had a median of 26 days free from coma or delirium. c. ARDS patients who remain hypoxemic
• In critically ill, mechanically ventilated patients, daily o ARDS patients who remain hypoxemic despite lung
interruption of sedation has been shown to reduce the time on protection strategy – immediately placed prone for no < 12
ventilation and the length of stay in the intensive care unit hours
(ICU). § goal of lung recruitment
• Data on whether a plan of no sedation, as compared with a o Termination of prone positioning after 12 hours
plan of light sedation, has an effect on mortality are lacking. § Consult with a pulmonologist and/or an intensivist

47
ANG, D.K.
 COVID-19
d. Fluid management
o conservative fluid management strategy for ARDS
patients without tissue hypoperfusion
o Main effect: to shorten the duration of ventilation

e. Moderate-Severe ARDS
o PaO2/FiO2 <150
o Use of neuromuscular blockade by continuous infusion
should NOT be routinely used

f. Extracorporeal life support (ECLS)

• Ventilator Problems: Use the DOPES Checklist
o should be considered when the above measures are o Displaced Endotracheal Tube or Deflated Cuff
unable to provide adequate oxygenation o Obstruction
o Pneumothorax
L. Management for Discharged Patients o Equipment malfunction
• For discharged patients, close follow-up is still required. o Breath Stacking
• When a patient is discharged from the hospital, his place of
residence and address should be recorded.
• Patients should rest at home for 2 weeks after leaving the
hospital, avoid activities in public places, and must wear masks
when going out.
• Monitor the patient’s temperature and health status for 2
weeks.
• If fever and / or respiratory symptoms recur, the corresponding
primary health care facility should assist in sending them to the
designated medical institutions in the area for treatment.
• This should be reported to the corresponding surveillance units
of the Department of Health.

M. Ventilator Management
• Post-intubation management starts before intubation • Troubleshoot: DOTTS Checklist
o place EtCO2 monitor, if available, on vent tubing before o Disconnect patient from the ventilator
intubation o Oxygenate the patient with a bag-valve and feel for
o place viral filter if available, on vent tubing before resistance to bagging
intubation o Tube position (kinking/obstruction)
o post-intubation sedation medication should be drawn and o Tweak the vent settings
ready prior to intubation o Sonogram: look for pneumothorax or a mainstem
o Post-intubation confirmation with EtCO2 waveform intubation
• Initial Ventilator Setting: Assists Control Setting • Pressure Assessments
• Ideal Tidal Volume for patients with COVID-19: 8mL/kg PIP PPLAT Problems
• TV 8mL/kg of Ideal Body Weight High Normal
Resistance; Bronchospasms; Obstruction;
o (men): 50kg + [2.3kg x (height inches - 60)] Secretions
o (women): 45.5 kg + [2.3kg x (height inches - 60)] Lung compliance; Patient positioning; Body
High High
• Positive End Expiratory Pressure: 8cc habitus; Auto-PEEP; Pneumothorax
• Optimal Initial Respiratory Rate: 16 breaths per minute Leak in the system; Hole in the ventilator tubing;
Low
• After intubation, initial FiO2 is set at 100% or endotracheal tube; or a deflated balloon
• After choosing initial ventilator settings; plateau pressure
<30mmHg XIX. Management for Asymptomatic COVID-19 Positive
• After setting ventilator • Immunocompetent Individuals
o If patient is stable: acquire initial ABG o These asymptomatic individuals should remain under
home (or community facility) quarantine for 10 days from
the time they tested positive for COVID-19.
o There is no need for a COVID-19 test (i.e. PCR, or
serology) at end of quarantine.
• Immunocompromised Individuals
o Repeat RT PCR as early as 10 days from the initial
positive RT PCR.
o A single negative RT PCR can be used to discontinue
transmission-based precautions (including isolation).
o If still positive, repeat RT PCR at least 24 hours apart until
there is documentation of at least one negative RT PCR.
• Should asymptomatic individuals develop fever or respiratory
symptoms within this 10-day quarantine period, quarantine
should be extended for 10 days after the first day of symptoms.

48
ANG, D.K.
 COVID-19
XX. Prevention of Complications XXII. Main Goal VS the Pandemic
• Reduce days of invasive Mechanical Ventilation A. Flattening the curve
• Reduce incidence of: • X axis = time since outbreak; Y axis = daily number of cases
o ventilator-associated pneumonia • When an outbreaks hit, number of cases will sky rocket since
§ oral intubation preferred than nasal intubation there are not enough public measures in placed
§ semi-recumbent position • The spike = means that a lot of people are getting sick all at
§ closed suctioning system once and there will not be enough hospitals, hospital beds,
o venous thromboembolism heath care workers, ventilators for everyone who needs them
§ low molecular-weight heparin or heparin 5000 units • Country’s healthcare system will get overwhelmed and that
subcutaneous twice daily capacity (example: Italy)
§ given if without contraindications • The graph will show the importance of flattening the curve
§ if with contraindications = use mechanical prophylaxis
• Goal: INCREASE SOCIAL DISTANCING
(intermittent pneumatic compression devices)
o in order to slow down the spread of the virus
o catheter-related bloodstream infection
o so that you don’t get a huge spike in the number of people
o pressure ulcers = turn every 2 hours
getting sick all at once
o stress ulcers and GI bleeding
o the following recommended measures will help flatten the
§ give enteral nutrition
curve
§ histamine-2 receptor blockers or proton-pump
inhibitors
o ICU-related weakness

XXI. Outcomes
• Majority of patients seem to recover
• Patients developing ARDS worsened in a short period of time
and died of multiple organ failure
• ARDS – most common cause of death in patients infected with
COVID-19
• Elderly and individuals with underlying co-morbidities have
higher case fatality rate compared to younger and healthier
patients B. Raising the Line
• Other complications and outcomes: • Raising the line means meeting the increase in demand
o Septic shock • Increase number of beds
o Invasive ventilation • increase staffing
o ECMO • cancelling elective procedures
o Death • online health education
o Recovery • home care and telemedicine
A. Clinical Course • avoid intra hospital spread
Clinical course of Survivors VS Non-survivors
• Sepsis – developed at median of 9.0 days (7-13 days) C. Spread Prevention
• ARDS - developed at median of 12 days (8-15 days) SOCIAL QUARANTINE SELF-ISOLATION
• Acute cardiac injury - developed at median of 15 days (10-17 DISTANCING
days) WHO People with a People with People who have
• Acute kidney injury - developed at median of 15 days (13-19.5 is it LOW chance HIGH chance of been exposed to
days) fore? of having been having been COVID-19 and
• Secondary infections - developed at median of 17 days (13-19 exposed to exposed to Showing
days) COVID-19 COVID-19 symptoms
What Go out as little Avoid direct Avoid direct contact;
do as possible; contact; Maintain 6-foot
you Do not shake Maintain 6-foot distance from
do? hands; Avoid distance from others
crowds of 50+ others 7 days minimum and
people 3 days fever-free
For Indefinitely 14 days without fever-
How minimum reducing medication
long? + improvement of
symptoms

D. Recommendations
B. Risk Factors for Poor Outcome 1. General Recommendations
• Higher in patients with diabetes or coronary heart disease • To prevent and/or contain the virus, some schools, offices,
• Associated with death on univariate analysis events, conferences, and mass gatherings have been
o Age postponed
o Lymphopenia • Avoid person-person transmission
o Leukocytosis • Avoid travel to disease with outbreaks
o Elevated ALT, LDH. TropI, CK, d-dimer, serum ferritin, IL- • Stay away from crowded places
6, PT, Creatinine, procalcitonin • Stay at least 6 FEET (2 meters) away from someone with
• Factors with increased odds of death symptoms “Social Distancing”
o Older age • Surgical mask or N95 not recommended
o Higher SOFA score • Clean and sterilize surfaces
o D-dimer greater than 1ug/mL • Proper hand washing with soap and alcohol based

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• Avoid touching the T-zone (area of eyes, nose, and mouth) 6. Any person >60 or have chronic disease/s WITHOUT
o Entry point for virus in the body symptoms
• Are in high risk
• Do self-quarantine
• Few weeks supply of medications, groceries, household items
and emergency contact person

7. Classification of PPEs
CLASSFICIATON WHERE WHAT
MINIMAL All health care staff working with Triple layer medical
patients mask; Gloves
MODERATE ED: all patients N95 + gloves + eye
IN-patients: isolation protection
OUT-patients: respiratory areas
MAXIMAL ED & ICU: critically ill COVID-19 N95 + gloves + eye
Anywhere intubation/ protection + body
aerosolization is occuring covering

8. Proper Donning of PPE

• Wash hands with soap and water
• Put on disposable laboratory gowns
• Wear inner glove
• Put-on N95 masks (proper donning)
• Wear eyeglasses + eye protection
• Wear Hairnet
2. For Healthcare workers • Wear Outer Gloves
• DROPLET and CONTACT precaution
o Includes wearing of surgical mask, gloves, long-sleeved 9. Proper Doffing of PPE
gowns, eye protection • Remove disposable laboratory gowns at the same time as the
• Procedures that produce aerosols (Intubation, Bronchoscopy, outer gloves
CPR, Non-invasive mechanical ventilation) - AIRBORNE • Sanitize the inner glove
o Use N95 mask respirator (prevents 95% aerosol from • Remove hairnet and eye protection
passing through) • Remove inner glove
• Wash your hands again
3. For Radiologic Technologist • Remove your masks à Wash hands again
• When performing CXR on a possible COVID-19 patient, do so
from a distance
• While wearing a full protective equipment, clean and
decontaminate all surfaces using EPA approved cleaning
materials after imaging
• Based on air exchange rate of the room, determine if room
needs to be completely avoided for up to an hour between
imaging infected patients.

4. Anyone with MILD symptoms

• must wear a mask
• self-quarantine within their homes
o If symptoms worsen, seek medical consult
• Must not attend school, work, and in-person gatherings
• AVOID TRAVEL

5. If person with SYMPTOMS + LIVE with Others

• Self-quarantine in Separate room
• Use separate bathrooms
• Avoid sharing household items (beddings, utensils, etc)

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 COVID-19
10. Checklist of Home Care Supplies XXIII. Guidelines for Advance Directives
• Tissues *Do Not Resuscitate or Allow Natural Death Orders for patients
• Acetaminophen (avoid Ibuprofen) with Severe COVID-19 Infections*
• Cough medicine (cough suppressant and expectorant) • The medical team may withhold cardiopulmonary resuscitation
• A working thermometer on critically ill patients with NO reasonable chance of recovery:
• Hand sanitizer with 60-95% alcohol these include COVID-19 ARDS secondary to High-Risk
• Humidifier Pneumonia & not responding to treatment, refractory septic
• Supply of clear fluids like water and broth shock, or multi-organ failure
• The free and informed decision not to resuscitate made by a
11. Home treatment competent patient through an advanced directive should be
followed.
• Drink plenty of clear fluids like water and broth
• Without the patient’s advanced directive, the free and informed
• Run a humidifier or breathe in steam from the shower
decision of an appropriate proxy of an incompetent patient
• Wear a mask if sick, or temporarily if entering the room of should be followed.
someone who is being treated
• Without a patient’s or a proxy’s decision, the medical team can
• Maintain 6 feet distance from other people, animals, be make the decision based on futility, the best interest of the
isolated in a separate room, and use a separate bathroom if patient, and scarcity of resources
possible
• Efforts must be made to provide spiritual care and
• Handwashing is paramount counseling for the patient and family.
• Use soap and water for at least 20 seconds each time

12. When to go to the clinic XXIV. Recommendations for Repeat Testing

• Rising fever A. Repeat Testing after a POSITIVE test
• Worsening cough
• Repeat testing after a positive COVID-19 test is no longer
• Increased difficulty of breathing
recommended at this time. A time or symptom-based
strategy for discharge and return to work are preferred.
13. Disinfectant
• Need for documenting 2 consecutive PCRs is being
• These disinfectants that have been proven effective at killing questioned in light of recent evidence showing that although
coronaviruses include : viral shedding can last several weeks
o 0.1% bleach • The virus is likely non-viable by day 8 as demonstrated in viral
§ 1:50 dilution or cultures
§ 1/3 cup in 1 gallon of household bleach • US-CDC acknowledges that detecting viral RNA via PCR does
o 60% ethanol not necessarily mean that infectious virus is present
• RT-PCR positivity persists significantly beyond infectivity,
14. Proper use of N95 routine repeat testing or a test-based approach may lead to
unnecessary isolation and use of PPE and testing resources.
• Another study showed that no positive viral cultures were seen
at a Cycle Threshold Value of > 24
• No positive viral cultures were documented in symptom to test
days of greater than 8 DAYS

B. Repeat Testing after an initial NEGATIVE test

• Repeat testing for patients with an initial negative COVID-19
test result may be performed ONLY if there is a high index
for suspicion for COVID infection despite an initial negative
test result. Such conditions include, but are not limited, to the
following:
15. Proper doning and doffing of the PPEs
1. Clinical deterioration in the presence of an established
disease etiology and with adequate treatment.
• A single negative test result, particularly if this is from an upper
respiratory tract specimen, DOES NOT exclude infection.
• Repeat sampling and testing, preferably of lower respiratory
specimen, is strongly recommended in severe or progressive
disease.
• Consider a possible co-infection with COVID-19

2. No other etiology for the patient's signs and symptoms has

been identified despite work-up
3. Clinical specimen/s initially sent was/were deemed to be
unsatisfactory or insufficient

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XXV. Criteria for Discontinuation of Transmission-based 2. Symptom-based Strategy
• Transmission-based precautions and isolation of hospitalized o at least 3 days (72 hours) have passed since recovery
patients under an institutional COVID-19 care pathway may be defined as resolution of fever without the use of fever-
discontinued 10-14 days after symptom onset, plus at least reducing medications and
3 days without symptoms (no fever and respiratory o continuous improvement in respiratory symptoms for at
symptoms). least 3 days (e.g., no cough, no shortness of breath, non-
• Release from a COVID-19 care pathway is NOT the same as oxygen requiring, radiographic improvement); and atleast
clinical discharge from a facility or from one ward to another. 10-14 days have passed since symptoms first appeared.
• Test-based strategy for specific patient groups
o Persons who could pose a risk of transmitting infection to B. Asymptomatic HCW
vulnerable individuals at high risk for morbidity or mortality 1. Time-based Strategy
from SARS-CoV-2 infection, or who support critical o 10-14 days have passed since the date of their first
infrastructure (for continuing critical operations). positive COVID-19 diagnostic test assuming they have not
o Persons normally residing in congregate living facilities subsequently developed symptoms since their positive
(e.g., correctional/detention facilities, retirement test.
communities, ships) where there might be increased risk o If they develop symptoms, then the symptom-based or
of rapid spread and morbidity or mortality if spread were test-based strategy should be used.
to occur.
o Persons who are immunocompromised as we do not know 2. Test-based Strategy
yet the transmission dynamics and if prolonged viral
o Negative results of COVID-19 molecular assay for SARS-
shedding equates to infectivity in this population. These
CoV-2 RNA RT PCR from at least two consecutive
conditions include patients on chemotherapy for cancer,
respiratory specimens collected ≥24 hours apart (total of
untreated HIV infection with CD4 T lymphocyte count <
two negative specimens)
200, combined primary immunodeficiency disorder, and
o Qualitative reporting of results of SARS-CoV-2 RT-PCR
receipt of prednisone >20mg/day for more than 14 days.
as positive or negative is sufficient for diagnosis but may
o Other less immunocompromising conditions such as end-
be supplemented by reporting the cycle threshold (Ct), a
stage renal disease, diabetes mellitus, advanced age may
semi- quantitative value, as well as time of symptom onset
be considered depending on the patient’s circumstances
to guide duration of isolation or quarantine and clearance
and assessment of the health care provider
for work, return to school, clearance for medical or surgical
• A negative RT PCR test done on day 14 from the date of onset procedures.
of symptoms.
o If still positive, repeat RT PCR at least 24 hours apart until
XXVIII. DOH Guidelines for Triaging COVID-19 patients
there is documentation of at least one negative RT PCR.
o Consultation with an ID specialist may be considered including PUM/PUIs
for persistently positive PCR results.

XXVI. Criteria for Discharge

• A repeat negative RT-PCR test is no longer needed for
discharge of immunocompetent patients with suspect,
probable or confirmed COVID-19 regardless of severity.
• Patients who have clinically recovered (with resolution of
symptoms) may be discharged from the hospital at the
discretion of the healthcare team, once all of the following
conditions are met:
o No fever or use of antipyretic medications for at least 3
days (>72 hours)
o Clinical improvement for at least 3 days (e.g. no longer
oxygen-requiring, improvement of respiratory symptoms)
o At least 10-14 days have passed since the first symptoms
appeared for patients with mild-moderate illness
o For severe and critical patients, at least 21 days have
passed since the first symptoms appeared
• Consultation with an infectious disease specialist is
recommended if there are concerns that patients may be
infectious beyond 21 days.

XXVII. Recommendations for Confirmed COVID-19

Healthcare Workers Returning to Work
A. Symptomatic HCW
1. Test-based Strategy
o Resolution of fever without the use of fever-reducing
medications and
o Improvement in respiratory symptoms (e.g., cough,
shortness of breath), and
o Negative Results of COVID-19 molecular assay for
detection of SARS-CoV-2 RNA from at least two
consecutive respiratory specimens collected ≥24 hours
apart

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1. mRNA-1273
• encodes the stabilized prefusion SARS-CoV-2 spike protein
• Solicited adverse events that occurred in more than half the
participants included fatigue, chills, headache, myalgia, and
pain at the injection site
• administered as a 0.5-ml injection in the deltoid muscle on
days 1 and 29;
• Follow-up visits were scheduled for 7 and 14 days after each
vaccination and on days 57, 119, 209, and 394.
• 100-μg dose elicits high neutralization responses and Th1-
skewed CD4 T cell responses, coupled with a reactogenicity
profile that is more favorable than that of the higher dose

B. Phases of Clinical Trials

1. Phase 1 Clinical Studies
o Test the safety of a product.
o Seeing if there are side effects, and whether the human
body can tolerate the vaccine or antibody.
o The experimental product is often compared to a group
that receives a placebo, a substance such as sterile
saltwater that has no active ingredients.
o These studies are conducted with a small group of people
(usually less than 100)
o Typically last 12 to 18 months.

2. Phase 2 Clinical Studies

o Questions such as the maximum tolerated dose,
o Optimal schedule for giving the product (how many doses,
and at what time intervals),
o Check for responses à can include the production of
antibodies, the production of T cells, and other immune
system markers
o Conducted with a medium-size population of volunteers
(usually a few hundred to 1000)
o Can last up to 2 years.
3. Phase 2b Clinical Studies
o Early look at whether the product is effective at preventing
infection or disease
o Sometimes known as Proof of Concept or Test of Concept
studies
o Several thousand people who are at increased risk for
infection or disease are enrolled
o Studies can last about 2-5 years.
o Researchers can see whether the results seem favorable,
supporting moving ahead to Phase 3.
o If the results are less favorable, it means that researchers
can redirect their efforts and save the expenses of large
Phase 3 studies.

4. Phase 3 Clinical Studies

o Questions, “Does this product prevent new infections? Or
if people do become infected, does the product help them
XXIX. COVID-19 Vaccines
control the infection so that it doesn’t become severe
A. Vaccine disease?”
• First dose for possible coronavirus vaccine to be trialed on US o Studies involve many thousands of people
on March 17,2020 EST (will likely be ready by 2021) o Includes some participants who are at increased risk for
• Mechanism studied: mRNA vaccine injected into cell infected infection.
with SARS-CoV-2 à mRNA stimulates cells to transcribe new
antigen presenting cell à newly formed APC stimulates 5. Phase 4 Clinical Studies
antibody production in human body o Take place after a product has been found to be effective
• Currently, 62 vaccines are being explored and developed in some populations, and are utilized to gather additional
worldwide information about safety and effectiveness by testing the
• Most vaccines target the trimeric spike protein (S) with the goal product in additional populations such as children or
of eliciting protective neutralizing antibodies pregnant women. They are sometimes known as bridging
studies, or post-licensure studies. These studies may be
conducted in anyone seeking a prevention option from
their physician.

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C. COVAX Initiative o The current product manufacturer will ensure the
• The vaccines pillar of the Access to COVID-19 Tools (ACT) completion of the product development and will apply for
Accelerator pre-qualification the license has been given.
• Ground-breaking global collaboration to accelerate the
development, production, and equitable access to COVID-19 F. COVID-19 Vaccines Tracker
tests, treatments, and vaccines. 1. COVID-19 Vaccine in Trials
• Co-led by Gavi, the Coalition for Epidemic Preparedness
Innovations (CEPI) and WHO.
• Aims to accelerate the development and manufacture of
COVID-19 vaccines, and to guarantee fair and equitable
access for every country in the world
• It is supporting the building of manufacturing capabilities, and
buying supply, ahead of time so that 2 billion doses can
be fairly distributed by the end of 2021
• Most countries cannot secure their own supplies if government
compete with each other in obtaining vaccines
• NO ONE IS SAFE UNTIL EVERYONE IS SAFE
• Ethical Principle: EQUITABLE ACCESS

D. Emergency Use Listing

• Global Advisory Committee on Vaccine Safety
• Related to safety issues relevant to all vaccines such as
adjuvants as well as to a number of vaccine-specific issues
pertaining to long-standing vaccines, new vaccines and
vaccines still under development.
• Established in 1999 by the World Health Organization to
respond promptly, efficiently, and with scientific rigor to vaccine
safety issues of potential global importance
• objective is to make medicines, vaccines and diagnostics (as of Oct,4,2021)
available as rapidly as possible to address the emergency
while adhering to stringent criteria of safety, efficacy and 2. Summary Information on Vaccine Products in Clinical
quality Development
• assessment weighs the threat posed by the emergency as well
• Number of Vaccines in Clinical Development 121
as the benefit that would accrue from the use of the product
against any potential risks • Number of Vaccines in Pre-Clinical Development 194
(as of Oct,4,2021)
• rigorous assessment of late phase II and phase III clinical trial
data as well as substantial additional data on safety, efficacy, 3. Candidates in Clinical Phase
quality and a risk management plan
• addition to the global, regional, and country regulatory
procedures for emergency use, each country undertakes a
policy process to decide whether and in whom to use the
vaccine, with prioritization specified for the earliest use
• WHO prequalification process will assess additional clinical
data generated from vaccine trials and deployment on a rolling
basis to ensure the vaccine meets the necessary standards of
quality, safety and efficacy for broader availability

E. Emergency Use Authorization in the Philippines

• Conditions in Giving EUA according to Executive Order No.
121
o The product has been proven safe, and effective against
COVID-19 based on the available evidence
o If the benefit of taking the vaccines outweighs the risks
o If there are no other efficient, approved, and effective
alternative in preventing or treating COVID-19
• World Health Organization Recommendation for Regulatory
Preparedness and Response of the Pandemic
o There should be a policy that would grant EUA for
vaccines and treatment
o There should be reliance and recognition from the
authority for the emergency use authorization
o There should be a monitoring team responsible for post-
marketing surveillance or risk marketing plan
• Criteria for applying EUA
o A disease that could cause an outbreak, epidemic, or
pandemic
o There’s no available product that could stop the spread of
the disease
o The product is made with Good Manufacturing Practices

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4. Number of Doses, Schedule and Routes of Administration G. COVID-19 Vaccine Types
of Candidates in Clinical Phase

1. Inactivated Vaccines
• use a weakened (attenuated) or deactivated form of the
pathogen that causes a disease to trigger protective
immunity to it.
• There are two types of whole virus vaccines.
o Live attenuated vaccines use a weakened form of the
virus, which can still grow and replicate, but does not
cause illness.
o Inactivated vaccines contain viruses whose genetic
material has been destroyed by heat, chemicals or
radiation so they cannot infect cells and replicate, but can
still trigger an immune response.
• Both are tried and tested vaccination strategies, which
form the basis of many existing vaccines – including those
for yellow fever and measles (live attenuated vaccines), or
seasonal influenza and hepatitis A (inactivated vaccines).
• Advantages and disadvantages
Live Attenuated Vaccine Inactivated Virus Vaccine
5. Approved Vaccines by at least One Country § Well-established
technology § Well-established
§ Strong immune response technology
§ Immune response involves § Suitable for people with
B cells and T cells compromised immune
§ Relatively simple to systems
manufacture § No live components, so
§ Unsuitable for people with no risk of the vaccine
compromised immune triggering disease
systems § Relatively simple to
§ May trigger disease in very manufacture
rare cases § Relatively stable
§ Relatively temperature § Booster shots may be
sensitive, so careful required
storage necessary
• may be unsuitable for people with compromised immune
systems (e.g. those with HIV) and pregnant women
• mobilising a range of defences against it, including killer T
cells (which identify and destroy infected cells), helper T
cells (which support antibody production) and antibody-
producing B cells (which target pathogens lurking
elsewhere in the body, e.g. the blood).
• inactivated vaccines only stimulate antibody-mediated
responses, and this response may be weaker and less
long-lived

2. Protein-Based Vaccines
• sometimes called acellular vaccines
• contain purified pieces of it, which have been specially
selected for their ability to stimulate immune cells.
• fragments are incapable of causing disease, subunit
vaccines are considered very safe.
• conjugate subunit vaccines bind a polysaccharide chain to
a carrier protein to try and boost the immune response.
• Only protein subunit vaccines are being developed against
the virus that causes COVID-19.
• restricting the immune system’s access to the pathogen in
this way, the risk of side effects is minimised.

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• relatively cheap and easy to produce, and more stable o Non-replicating vector vaccines are unable to make
than those containing whole viruses or bacteria. new viral particles; they only produce the vaccine
antigen.
• downside of this precision is that the antigens used to elicit
o Replicating vector vaccines also produce new viral
an immune response may lack molecular structures called
pathogen-associated molecular patterns particles in the cells they infect, which then go on to
infect new cells that will also make the vaccine
• antigens do not infect cells, subunit vaccines mainly only antigen.
trigger antibody-mediated immune responses.
• The COVID-19 viral vector vaccines under development
• immune response may be weaker than with other types of use non-replicating viral vectors.
vaccines.
• This response includes antibody-producing B cells, as well
• subunit vaccines are sometimes delivered as T cells, which seek out and destroy infected cells. T
alongside adjuvants (agents that stimulate the immune cells do this by examining the repertoire of proteins
system) expressed on the surfaces of cells.
• booster doses may be required • Challenge of this approach is that people may previously
• Advantages and Disadvantages have been exposed to the virus vector and raise an
o Well-established technology immune response against it, reducing the effectiveness of
o Suitable for people with compromised immune the vaccine.
systems • “Anti-vector immunity” makes delivering a second dose of
o No live components, so no risk of the vaccine the vaccine challenging, unless this second dose is
triggering disease delivered using a different virus vector.
o Relatively stable
o Relatively complex to manufacture 4. Nucleic Acid (mRNA) Vaccines
o Adjuvants and booster shots may be required
o Determining the best antigen combination takes time • Nucleic acid vaccines use genetic material from a disease-
• Examples include hepatitis B and acellular pertussis causing virus or bacterium (a pathogen) to stimulate an
vaccines (protein subunit), the pneumococcal immune response against it.
polysaccharide vaccine (polysaccharide) • Genetic material could be DNA or RNA; in both cases it
provides the instructions for making a specific protein from
3. Viral Vector Vaccine the pathogen, which the immune system will recognise as
foreign (an antigen).
• differ from most conventional vaccines - don’t actually
contain antigens, but rather use the body’s own cells to • Once inserted into host cells, this genetic material is read
produce them. by the cell’s own protein-making machinery and used to
manufacture antigens, which then trigger an immune
• using a modified virus (the vector) to deliver genetic code response.
for antigen, in the case of COVID-19 spike proteins found
on the surface of the virus, into human cells. • Relatively new technology, so although DNA and RNA
vaccines are being developed against various diseases,
• By infecting cells and instructing them to make large including HIV, Zika virus and COVID-19, so far none of
amounts of antigen, then trigger an immune response, the them have yet been approved for human use.
vaccine mimics what happens during natural infection with
certain pathogens - especially viruses. • Several DNA vaccines are licenced for animal use,
including a horse vaccine against West Nile virus.
• Has the advantage of triggering a strong cellular immune
response by T cells as well the production of antibodies by • Advantages And Disadvantages of Nucleic Acid Vaccines
o Immune response involves B cells and T cell
B cells.
o No live components, so no risk of the vaccine
• Example of a viral vector vaccine is the rVSV-ZEBOV triggering disease
vaccine against Ebola. o Relatively easy to manufacture
• Advantage and Disadvantages of Viral Vector-Based o Some RNA vaccines require ultra-cold storage
Vaccines o Never been licensed in humans
o Well-established technolog o Booster shots may be required
o Strong immune response • DNA plasmids carrying the antigen are usually injected
o Immune response involves B cells and T cell into the muscle, but a key challenge is getting them to
o Previous exposure to the vector could reduce cross into people’s cells.
effectiveness
o Relatively complex to manufacture • machinery which enables the antigen to be translated into
protein is located inside cells.
• Viruses survive and replicate by invading their host’s cells
and hijacking their protein-making machinery, so it reads • RNA vaccines encode the antigen of interest in
the virus’ genetic code and makes new viruses. messenger RNA (mRNA) or self-amplifying RNA (saRNA)
– molecular templates used by cellular factories to
• Virus particles contain antigens, molecules that can trigger produce proteins.
an immune response.
• Because of its transitory nature, there is zero risk of it
• A similar principle underpins viral vector vaccines - only in integrating with our own genetic material.
this case, the host cells only receive code to make
antigens. The viral vector acts as a delivery system, • The RNA can be injected by itself, encapsulated within
nanoparticles (as Pfizer’s mRNA-based Covid vaccine is),
providing a means to invade the cell and insert the code
for a different virus’ antigens (the pathogen you’re trying or driven into cells using some of the same techniques
to vaccinate against). being developed for DNA vaccines.
• The virus itself is harmless, and by getting the cells only to • Once the DNA or RNA is inside the cell and it starts
produce antigens the body can mount an immune producing antigens à displayed on its surface, where they
response safely, without developing disease. can be detected by the immune system à triggering a
response.
• There are two main types of viral vector-based vaccines.
• Response includes killer T cells, à seek out and destroy
infected cells, antibody-producing B cells and helper T
cells which support antibody production.
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H. General Guidelines for Vaccination

1. MODERNA
• mRNA-1273 vaccine, The COVE Study
• see if it can prevent illness if people are exposed to
SARS-CoV-2 in their everyday lives
• not made from SARS-CoV-2 but made from mRNA
• Site: Intramuscular
• Current participants 30,000
• Start Date: July 27,2020
• Estimated Primary Completion: October 27,2022
• final trial results confirm this vaccine has a 94% efficacy
• need to be kept in ultra-cold freezers.
• developed by Moderna, in Cambridge, Massachusetts,
and funded by the National Institute of Allergy and
Infectious Diseases (NIAID), which is part of the US
National Institutes of Health.
I. Vaccines Against Variants • The vaccine was tested in phase 1 trials on volunteers at
the Kaiser Permanente Washington Health Research
Institute in Seattle.
• Phase 2 trials on participants of a wide range of ages and
started phase 3 trials in July 2020.
• The final trial enrolled 30,000 healthy people from across
the United States.
• In February, a phase 4 trial was launched as part of a
national cohort study in collaboration with the Danish
Ministry of the Interior and Health.
• Moderna vaccine compared to the Pfizer vaccine is easier
to transport and store because it is less temperature
sensitive.
• Recommended to people 18 years of age and older, with
a dose of 50 μg (0.5 mL)
• Both the full panel of mutations in S and a subset of
mutations affecting the receptor-binding domain (RBD)
region of the B.1.1.7 variant had no significant effect on
neutralization by serum obtained from participants who
had received the mRNA-1273 vaccine in the phase 1 trial
J. Vaccines Currently in Approved for Use and in Phase 4 • significant reduction in neutralizing titers when the E484K
Clinical Trials mutation was presen
• Protection conferred by the mRNA-1273 vaccine against
the P.1, B.1.427/B.1.429, and B.1.351 variants remains to
be determined.

a. Phase I Trial in Older Adults (56-70 and >71 y/o )

• All the participants were assigned sequentially to receive
two doses of either 25 μg or 100 μg of vaccine
administered 28 days apart.
• adverse events associated with the mRNA-1273 vaccine
were mainly mild or moderate
• 100-μg dose induced higher binding- and neutralizing-
antibody titers than the 25-μg dose, which supports the
use of the 100-μg dose in a phase 3 vaccine trial.

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b. Phase III Trials in US b. Phase III Trials in South Africa
• mRNA-1273 vaccine showed 94.1% efficacy at preventing • Start of October 2020, BioNTech and Pfizer started
Covid-19 illness, including severe disease recruiting for a phase 3 trial in South Africa and by early
• Solicited adverse events at the injection site occurred November had reported promising interim results.
more frequently in the mRNA-1273 group than in the • Data showed a vaccine efficacy rate of 95% (even in
placebo group after both the first dose (84.2%, vs. 19.8%) adults over 65 years efficacy was more than 94%, which
and the second dose (88.6%, vs. 18.8%) is reassuring as older people don’t always have a strong
• The most common injection-site event was pain after immune response to vaccines)
injection • 95% effective in preventing Covid-19 (95% credible
• Moderate-to-severe systemic side effects: interval, 90.3 to 97.6)
o Fatigue • Similar vaccine efficacy (generally 90 to 100%) was
o Myalgia observed across subgroups defined by age, sex, race,
o Arthralgia ethnicity, baseline body-mass index, and the presence of
o Headache coexisting conditions
o Noted in about 50% of participants in the mRNA-
1273 group after the second dose c. Trials in the US
• Anecdotal finding of a slight excess of Bell’s palsy in this • Two-dose regimen of BNT162b2 conferred 95%
trial and in the BNT162b2 vaccine trial arouses concern protection against Covid-19 in persons 16 years of age or
that it may be more than a chance event, and the older
possibility bears close monitoring.
• Safety over a median of 2 months was similar to that of
other viral vaccines.
c. Trial in COVID-Variants
• Estimated effectiveness in preventing death from Covid-
• Significant Neutralization in Variants B.1.1.7, B.1.1.429, 19 was 72% (95% CI, 19 to 100) for days 14 through 20
and B.1.1.298 after the first dose.
• No significant neutralization in Variants P.1, P.2, and • Estimated vaccine effectiveness for the study outcomes at
B.1.351 days 14 through 20 after the first dose and at 7 or more
• B.1.1.7 remains sensitive to neutralization, albeit at days after the second dose was as follows:
moderately reduced levels (∼sim;2-fold), by serum o Documented Infection 46% 92%
samples from convalescent individuals and recipients of o Symptomatic COVID 57% 94%
an mRNA vaccine (mRNA-1273, Moderna) and a protein o Hospitalization 74% 87%
nanoparticle vaccine (NVX-CoV2373, Novavax) o Severe Disease 62% 92%
• Estimated for age >65 after second dose was 94-97%
• Interval between the first and second doses, the observed
2. Pfizer/BioNTech’s mRNA vaccine efficacy against Covid-19 was 52%, and in the first
• BNT162b2 – investigational mRNA vaccine 7 days after dose 2, it was 91%, reaching full efficacy
• Contains small part of the genetic code of SARS-CoV-2 against disease with onset at least 7 days after dose 2.
Spike Protein • Adverse Effects:
• BNT162b2 does not contain any live virus o Mild-to-moderate pain at the injection site
o Fatigue
• lipid nanoparticle-formulated, nucleoside-modified mRNA
o Headache
vaccine encoding the prefusion spike glycoprotein of
o Chills
SARS-CoV-2
o Muscle pain
• Experimental doses: (low dose, mid-dose, high-dose, o Joint pain
placebo) 2 doses
• consists of 2 doses (30 μg, 0.3 mL each) administered d. Neutralization of N501Y mutant
intramuscularly, 3 weeks apart
• Sera of 20 participants in a previously reported trial of the
• Site: Intramuscular Injection mRNA-based COVID-19 vaccine had equivalent
• Outcome measures: pain at injection sites, redness, neutralizing titers to the N501 and Y501 viruse
swelling, fever, headache, chills, vomiting, diarrhea,
myalgia e. Dose from previously infected individuals
• Participants: 43,998 • Among those with a previous SARS-CoV-2 infection,
• Start Date: April 29,2020 vaccination increased anti-S titres more than 140-fold from
• Estimated Primary End: June 13,2021 peak pre-vaccine levels
• Estimated Completion Date: December 11,2022 • Among previously uninfected, seronegative individuals,
• recommended to people 16 years of age and older, with a anti-S titres after one vaccine dose were comparable to
dose of 30 μg (0.3 m) peak anti-S titres in individuals with a previous natural
infection who had not yet been vaccinated.
• occurrence of adverse effects is reported to be lower in the
Pfizer/BioNTech vaccine compared to the Moderna
vaccine

a. Phase I trial of 2 mRNA prototype

• Trial of two vaccine candidates in younger and older
adults, added to earlier interim safety and immunogenicity
data regarding BNT162b1 in younger adults from trials in
Germany and the United States
• BNT162b2 was associated with a lower incidence and
severity of systemic reactions than BNT162b1, particularly
in older adults.
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f. Trials in Variants i. Assessment of Humoral Response after a dose
• K417N/T, E484K, and N501Y, were highly resistant to • Increase levels of IgG levels between 91-368 folds until 21
neutralization days if first vaccine dose
• relatively small number of mutations can mediate potent • Levels furthers raise to 8-30 fold post 2nd dose
escape from vaccine responses • Antibodies peak at 35 days and declines and stabilizes at
• B.1.351 neutralization titer reduced 8- to 9-fold for Pfizer day 50
and AstraZeneca vaccines
• Significant Neutralization in Variants B.1.1.7, B.1.1.429, j. Neutralization against new SARS-CoV-2 Spike Variants
and B.1.1.298 • Variants B.1.526, B.1.429, B.1.1.7+E484K variants
• No significant neutralization in Variants P.1, P.2, and remain susceptible to an important vaccine-elicited
B.1.351 immune effector
• Serum samples neutralized USA-WA1/2020 and variant
g. Short Term Efficacy in Cancer Patients treated with viruses at titers of 1:80 or higher
Immune Checkpoint Inhibitors
• E484K mutation, found in variants B.1.1.7, B.1.351, and
• 170 patients in total B.1.526 lineages, caused little compromise to
o 33 refused vaccination neutralization
o 137 received 1st dose
o 134 received 2nd dose k. Vaccine Effectiveness against B.1.1.7 and B.1.351
o 3 died after 1st dose • Estimated effectiveness of the vaccine against any
• 1 due to COVID documented infection with B.1.1.7 was 89.5% at 14 days
• 2 due to disease progression or more after second dose
o 4/134 were admitted • Effectiveness against any documented infection against
• 3 due to cancer complications B.1.351 was 75.0%
• 1 due to fever • Vaccine effectiveness against severe, critical, fatal
• Most common side effects disease due to COVID B.1.1.7 and B.1.351 was 97.4%
o Local pain on injection sites • The reduced protection against infection with the B.1.351
o Fatigue variant did not seem to translate into poor protection
o Headache against the most severe forms of infection, which was at
o Muscle Pain greater than 90%
o Chills
o Local Rash l. Vaccine Effectiveness against other variants
• Reassuring safety signal in cancer patients treated with • newly emerged B.1.526, B.1.429, and B.1.1.7+E484K
immune checkpoint inhibitors
variants remain susceptible to an important vaccine-
• No immune-related myositis observed post-vaccination elicited immune effector (neutralizing antibody)
• Third limitation is that BNT162b2 elicits multiple immune
effectors, including SARS-CoV-2 spike-specific CD4+ and
CD8+ T cells and nonneutralizing antibodies that mediate
antibody-dependent cytotoxicity
• Additional E484K mutation, which is also found in the
B.1.351 and B.1.526 lineages, caused little compromise to
neutralization

m. Safety, Immunogenicity, and Efficacy on Adolescents

• BNT162b2 vaccine in 12-to-15-year-old recipients had a
favorable safety profile, produced a greater immune
response than in young adults, and was highly effective
against Covid-19.
• mainly transient mild-to-moderate reactogenicity
(predominantly injection-site pain [in 79 to 86% of
participants], fatigue [in 60 to 66%], and headache [in 55
to 65%])
• The geometric mean ratio of SARS-CoV-2 50%
neutralizing titers after dose 2 in 12-to-15-year-old
participants relative to 16-to-25-year-old participants was
h. Increased adverse reactions from patients with previous 1.76
COVID-19 infection
• 265 out of 974 reported prior positive SARS-CoV-2 3. Astra-Zeneca
• Symptoms:
o Fever • Viral Vector Vaccine
o Fatigue • Vaxzevria
o Myalgia-Arthralgia • AZD1222
o Lymphadenopathy • ChAdOx1 vaccine developed by the University of Oxford
• No relation between illness-vaccine interval and symptom • Based on weakened version of common cold adenovirus
composite score • Presents part of COVID-19 spike protein to the body
• Long-COVID was not associated with worse AEs • Test how well the investigational vaccine works

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ANG, D.K.
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• Site: Intramuscular d. Statement of European Medicines Agency regarding
“supposed” adverse events
• Doses: 2 Doses
• Participants: 40,051 • The European Medicines Agency’s (EMA)
Pharmacovigilance Risk Assessment Committee (PRAC)
• Start Date: August 28,2020
“There is currently no indication that vaccination has
• Primary Completion: December 22,2020 caused these conditions, which are not listed as side
• Study Completion: October 25,2022 effects with this vaccine”
• granted emergency use authorization by the European • Reported to have caused rare blood coagulation disorders
Medicines Agency, National regulators in the UK, in a person in Denmark and another in Austria
Argentina, India, Mexico, Brazil and Pakistan. • As of 10 March 2021, 30 cases of thromboembolic events
• Fridge-stable – means can be easily transported had been reported among close to 5 million people
anywhere in the world vaccinated with COVID-19 Vaccine AstraZeneca in the
• Exploratory analyses of the immune responses in adults, European Economic Area
aged 18-55 years, up to 8 weeks after vaccination with a
single dose of ChAdOx1 nCoV-19 in this trial, e. Trial against Variant B.1.351
demonstrating an induction of a Th1-biased response • Two-dose regimen of the ChAdOx1 nCoV-19 vaccine did
characterized by interferon-γ and tumor necrosis factor-α not show protection against mild-to-moderate Covid-19
cytokine secretion by CD4+ T cells and antibody due to the B.1.351 variant
production predominantly of IgG1 and IgG3 subclasses.
• Vaccine efficacy against this B.1.351 variant was 10.4%
• Efficacy of 42-89% against B.1.1.7
• B.1.351 neutralization titer reduced 8- to 9-fold for Pfizer
• Efficacy of 71-91% against non-B.1.1.7 and AstraZeneca vaccines
a. Trial in Timing of Prime-Boosting
• A 3-month dose interval might have advantages over a
programme with a short dose interval for roll-out of a
pandemic vaccine to protect the largest number of
individuals in the population as early as possible
• These observations are supported by immunogenicity
data that showed binding antibody responses more than
two-fold higher after an interval of 12 or more weeks
compared with an interval of less than 6 weeks in those
who were aged 18–55 years
• Overall vaccine efficacy more than 14 days after the
second dose was 66·7% (95% CI 57·4–74·0), with 84
(1·0%) cases in the 8597 participants in the ChAdOx1
nCoV-19 group and 248 (2·9%) in the 8581 participants in
the control group
f. Phase II Trial in Older Adults (>70 y/o)
• Efficacy was higher in those with a longer prime-boost
interval (vaccine efficacy 81·3% [95% CI 60·3–91·2] at • T-cell responses peaked at day 14 after a single standard
≥12 weeks) than in those with a short interval (vaccine dose of ChAdOx1 nCoV-19
efficacy 55·1% [33·0–69·9] at <6 weeks). • ChAdOx1 nCoV-19 appears to be better tolerated in older
adults than in younger adults and has similar
b. Trial in Europe (Age >60y/o) immunogenicity across all age groups after a boost dose
• Sparse data from Phase II trials suggest a reduction in
4. Sinovac (CoronaVac)
both antibody response and mild to moderate adverse
events in well older people • Inactivated Vaccine
• Overall vaccine efficacy across both groups was 70·4% • Sinovac conducted phase 3 trials involving volunteers in
Brazil, Indonesia and Turkey.
• Chinese government has given the Sinovac vaccine
c. Phase III Trial in UK, Brazil, South Africa emergency approval for limited use
• efficacy is slightly lower than the Moderna and Pfizer • City of Jiaxing has reportedly offered the vaccine to health
vaccines, workers and other high-risk groups for US$ 60.
• Vaccine efficacy of up to 90% • The company began phase 4 trials in February 2021
• 100% effective against severe disease • Level of neutralization for the CoronaVac with 501.V2
• tested in phase 3 clinical trials with more than 10,000 variant was 30% effective in comparison with original
people from across the UK, including children and older Wuhan Strain
people. o Same study analyze found that convalescent (5
months since contraction) B.1.351 neutralization
• tested in Brazil, the United States and India and South
was 50% effective
Africa started the first COVID-19 vaccine trial in Africa.
• Neutralization against B.1.1.7 is 50% effective in
• In February, a phase 4 trial was launched as part of a comparison with the original Wuhan Strain (April 2021
national cohort study in collaboration with the Danish letter to NEJM)
Ministry of the Interior and Health.

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a. Phase I/II Trials in China (18-59 y/o) o No studies reported vaccine effectiveness of any
• The primary immunogenicity endpoint was seroconversion vaccine reducing the risk of infection or disease among
rate at 28 days after the second injection individuals exposed to P.1 transmission
• Seroconversion was defined as a change from
seronegative at baseline to seropositive for neutralising
antibodies to live SARS-CoV-2 (positive cutoff titre 1/8), or
a four-fold titre increase if the participant was seropositive
at baseline.
• 3ug dose of CoronaVac as suggested dose for efficacy
assessment
• Seroconversion of neutralizing antibodies was seen in:
o Day 14 92% in 3ug and 98% in 6ug
o Day 28 97% in 3ug and 100% in 6ug

b. Phase I/II Trails in China (Healthy >60y/o adults)

e. Real-World Trial in Chile
• Mean age of 60-68 years old
• 9% adverse events including pain at injection site, • Study covered 10.5 millions of Chilean who had received
• Seroconversion occurred after second dose in 100% of the doses, largest ever study in a real-world trial
the 3ug group and 95.7% in the 6ug group. • Efficacy
• Relatively low efficacy rate of 50% was due to more o 67% effective against symptoms
rigorous standards for what counts as an infection among o 80% against death
trial participants o 85% reduction against hospitalization
o 89% reduction in ICU visit
• Among the three doses evaluated, the neutralising
antibody titres induced by the 3 μg dose were similar to • New Adjusted Effectiveness
those of the 6 μg dose, and higher than those of the 1·5 o 65.9% for the prevention of COVID-19
μg dos o 87.5% for the prevention of hospitalization
o 90.3% for the prevention of ICU admission
c. Phase III Trials in Turkey o 86.3% against prevention of Death
• Final Phase III results from Turkey showed an efficacy of • Seroconversion rates for adults 14-28 days after the
83.5%. second dose were 95.6% for the IgG specific against S1-
• The final efficacy rate was based on 41 infections, 32 of RBD and 96% for neutralizing anti-S1 RBD IgG
which had received a placebo, said Murat Akova, head of • Moderate seroconversion noted at 42 days
the Phase III trials in Turkey. • For >60 years old – seroconversion rate was:
• Prevented hospitalization and severe illness in 100% of o 18.1% at Day 14
cases, saying six people who were hospitalized were all in o 100% at Day 28
the placebo group. o 87.5% at Day 42
• Final results were based on a 10,216 participants, 6,648
of whom received the vaccine as part of the Phase III study f. Real-World Trial in Indonesia
that began mid-September.
• Turkey announced the interim resulted to vaccine efficacy
• 128,290 healthcare workers
at 91.25% • 96% protection against hospitalization
• 98% protection against death
d. Phase III Trials in Brazil • 94% protection against symptomatic infection
• results from Phase III trials in Brazil among 13,000
volunteers revealed the vaccine was 78% effective in g. Susceptibility of Circulating Variants to Neutralization
preventing symptomatic cases of COVID-19 requiring • B.1.1.7 showed little to no resistance to the neutralizing
medical assistance (grade 3 on the WHO Clinical activity of convalescent or vaccinee serum
Progression Scale) • B.1.351 showed more resistance to neutralizing activity of
• 100% effective against moderate and severe infections convalescent serum (2x) and vaccinee serum (2.5-3.3x)
• The relatively low efficacy rate of 50.7-51.8% was due to • CoronaVac Vaccinee Serum Samples showed marked
more rigorous standards for what counts as an infection decrease in the seru, neutralization of B.1.1.7 and
among trial participants which included very mild complete or partial loss of neutralization against B.1.351
infections
• 50.65% efficacy at preventing symptomatic infections h. Safety, Tolerability, and Immunogenicity in Healthy
• 83.7% in preventing mild cases needing treatment Children and Adolescents
• 100% against severe, hospitalised and fatal cases • CoronaVac was well tolerated and safe and induced
• March 10, Instituto Butantan Director Dimas Covas said humoral responses in children and adolescents aged 3–
CoronaVac was efficient against three variants of COVID- 17 years.
19 in the country; • Neutralising antibody titres induced by the 3·0 μg dose
o British B.1.1.7 were higher than those of the 1·5 μg dose.
o South African 501.V2, • The results support the use of 3·0 μg dose with a two-
o Brazil’s P.1, of which are derived variants P.1 from immunisation schedule for further studies in children and
Manaus state, and P.2 from Rio de Janeiro adolescents.
• Vaccine effectiveness was seen 9-12 weeks or (2-5 weeks • Most adverse reactions were mild and moderate in
after 2nd dose) severity. Injection site pain was the most frequently
• 49.6% effective at preventing COVID-19 in a setting with reported event
high prevalence of P.1 variant
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5. Sinopharm 7. Janssen/Johnson & Johnson (USA)
• Inactivated Vaccine • Viral Vector Vaccine
• Beijing Institute of Biological Products • J&J has developed vaccines for Ebola and other
• The Beijing Institute is part of China’s state-run Sinopharm diseases with Recombinant Adenovirus Serotype 26
Group, and developed its vaccine called BBIBP-CorV in (Ad26)
collaboration with the Chinese Center for Disease Control • Ad26.COV2.S, is a recombinant, replication-incompetent
and Prevention. adenovirus serotype 26 (Ad26) vector encoding a full-
• In phase 3 trials in the UAE, 5,000 people received BBIBP- length and stabilized SARS-CoV-2 spike protein.
CorV. • launched phase 1/2 trials in July 2020, and launched
• The Institute has now begun a phase 4 trial for the vaccine a phase 3 trial with 60,000 participants in September
• 78.1% effective against symptomatic COVID-19 in Latin America
• began phase 3 trials in the UK in November last year.
a. Real World Study in Bahrain • committed 500 million doses of this vaccine to the
COVAX initiative for distribution worldwide
• Vaccine effectiveness of 90% for adults 18-59 y/o • Trial vaccine in South Africa reported level of protection
• 91% for those 60 years and older against moderate to severe COVID-19 infection was
• UAE announced interim results of 86% efficacy o 72% in US
• 93% effective in preventing hospitalization
o 57% in South Africa
• 95% effective in against COVID-19 infection
• vaccine efficacy of:
o 66% in Latin America,
o 57% in South Africa
b. Susceptibility of Circulating Variants to Neutralization
o 72% in the United States,
• B.1.1.7 showed little to no resistance to the neutralizing o 100% efficacy against severe disease in all trials
activity of convalescent or vaccinee serum • ENSEMBLE Study with Janssen’s Ad26.COV2.S
Investigational Vaccine
• B.1.351 showed more resistance to neutralizing activity of • Develop to prevent or lessen the severity of COVID-19
convalescent serum (2x) and vaccinee serum (2.5-3.3x) • Participants: 60,000
• BBIBP-CorV Vaccinee Serum Samples did not show • Start Date: September 7,2020
significant difference in neutralization against B.1.1.7 • Primary Completion: March 10,202
• BBIBP-CorV Vaccinee Serum Samples showed complete • Study Completion: March 10,2023
or partial loss of neutralization against B.1.351 • Most common adverse events:
o Fever
o Fatigue
c. Phase I/II in Henan Province, China o Headache
o Myalgia
• Fever – most common side effect noted o Injection-site pain
• Neutralizing antibody geometric mean titers were higher at
Day 42 in both age groups 18-59 and age >60 a. Phase I/II Trials
• Neutralizing-antibody titers against wild-type virus were
6. Gamaleya Research Institute detected in 90% or more of all participants on day 29 after the
• Viral Vector Vaccine first vaccine dose
• Regardless of vaccine dose or age group, and reached 100%
• started a phase 1 clinical trial on this non-replicating viral
by day 57 with a further increase in titers
vector vaccine candidate (known as Sputnik V) with two
sets of volunteers receiving vaccination since mid-June. • On day 15, CD4+ T-cell responses were detected in 76 to 83%
of the participants in cohort 1 and in 60 to 67% of those in
• Before the vaccine went on to later cohort 3, with a clear skewing toward type 1 helper T cells.
trials Russia announced that it would be approved for use.
• The local and systemic reactions occurred on the day of
immunization or the next day and generally resolved within 24
a. Phase III Trials in Russia
hours.
• More than 2,000 people in Russia, Latin America and the • A single dose of Ad26.COV2.S elicited a strong humoral
Middle East, and then expanded to 40,000. Volunteers response in a majority of vaccine recipients, with the presence
were also recruited in Belarus, the UAE and Venezuela. of S-binding and neutralizing antibodies in more than 90% of
• Results of their Phase 3 trial showed vaccine efficacy rate the participants, regardless of either age group or vaccine dose
of 91.6%. • During 71 days of follow-up after the first dose, antibody titers
• Heterologous recombinant adenovirus (rad26 and rad25)- further increased and stabilized, which suggests durability of
based vaccine, Gam-COVID-Vac (Sputnik V) the Ad26.COV2.S-elicited immune response.
• Interim analysis of the phase 3 trial of Gam-COVID-Vac • single immunization with Ad26.COV2.S induced rapid binding
showed 91·6% efficacy against COVID-19 and neutralization antibody responses as well as cellular
immune responses
• Carry the gene for SARS-cov-2 full-length glycoprotein S
(rAd26-S and rAd5-S) b. Phase III ENSEMBLE Trial
• rAd26-S and rAd5-S are administered intramuscularly • Efficacy against moderate to severe-critical COVID :
separately with a 21-day interval. o 67% against disease w/ onset after 14 days administration
• Vaccine efficacy was 91·8% (67·1–98·3) in participants o 66% against disease w/ onset 28 days after administration
older than 60 years • Efficacy against severe-critical COVID :
• Vaccine efficacy against moderate or severe COVID-19 o 77% against disease w/ onset after 14 days administration
was 100% o 85% against disease w/ onset 28 days after administration
• Estimated vaccine efficacy against confirmed COVID-19 • Efficacy against hospitalisation :
occurring at any time after dose 1 was 73·1% o 93% against disease w/ onset after 14 days administration

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o 100% against disease w/ onset 28 days after K. Other Vaccines in Development in Phase 3
administration
• 66% protection against serologically confirmed asymptomatic
infection
• Efficacy against symptomatic infection was similar among
younger and older participants and participants with coexisting
conditions

1. Wuhan Institute of Biological Products

• Inactivated Vaccine
• United Arab Emirates became the first foreign country to
approve this vaccine,
• interim phase 3 trials showed 86% efficacy
• The Wuhan Institute launched phase 3 trials in July 2020
in the UAE, and in Peru and Morocco in August 2020.
• The state-owned Chinese company Sinopharm has been
putting the vaccine through clinical tests.
• On 14 Sept, the UAE gave emergency approval for the
vaccine to be given to health care workers.

2. Bharat Biotech International Ltd (India)

• Inactivated Vaccine
• BBV152 Vaccine
• Indian Council of Medical Research and the National
Institute of Virology, Bharat Biotech designed a vaccine
called Covaxin
• The company is conducting phase 3 trials in 25 centres
across India, and is seeking emergency authorisation
based on promising phase 1 and 2 results.
• Were able to neutralize VUI B.1.617 although with lower
efficacy

a. Phase II Trial in India

• Whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6
μg) formulated with a toll-like receptor 7/8 agonist
molecule (IMDG) adsorbed to alum (Algel).
• The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG
formulations elicited T-cell responses that were biased to
a Th1 phenotype at day 42.
• At day 104 (3 months after the second dose), there was
observed detectable humoral and cell-mediated
responses to SARS-CoV-2.
• Seroconversion based on MNT50 at day 56 was reported
in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in
the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–
98·8]) of 177 participants in the 6 μg with Algel-IMDG
group.

3. Cansino Biologics Inc. (China)

• Viral Vector Vaccine
• Ad5-nCoV vaccine candidate uses a harmless non-
replicating viral vector to carry vaccine antigens into the
human body
• One Dose only
• same platform that the vaccine developer CanSino
Biologics Inc, used for its Ebola vaccine.
• jointly developed with the Institute of Biotechnology of the
Academy of Military Medical Sciences.

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• On 25 June 2020, the Chinese military approved the 7. Chinese Academy of Medical Science
vaccine for a year as a “specially needed drug”, which is • INACTIVATED VACCINE
unusual given that at that point phase 2 results hadn’t
been collated.
• Institute of Medical Biology at the Chinese Academy of
Medical Sciences (IMBCAMS) has previously developed
• On 9 August 2020, the Saudi health ministry announced inactivated vaccines for polio and hand-foot-and-mouth
that CanSino would run a phase 3 trial in Saudi Arabia; disease.
• also started a trial in Pakistan and Russia. • Phase 2 trials began in July 2020 and was followed by a
phase 3 trial in 29,000 participants in December 2020.
a. Phase III Trial Globally
• 65.7% efficacy in preventing moderate symptoms 8. Research Institute for Biological Safety Problems
• 90.98% efficacy in preventing severe symptoms (Kazakstan)
• Inactivated Vaccine
b. Phase III in Pakistan • On 1 September 2020 it started phase 2 trials of its
• 74.8% efficacy in preventing symptomatic diseases vaccine known as QazCovid.
• 100% efficacy in preventing severe disease • On 19 December, it reported that phase 2 trials had been
completed, with participants producing an immune
4. Novavax (USA-India) response.
• Protein Subunit Vaccine • The researchers launched a phase 3 trial, and expect to
get approval by March 2021.
• NVX-CoV2373
• a nanoparticle technology platform to generate antigens 9. Curevac (Germany)
from the spike protein found on the outer shell of the
coronavirus. • Rna Vaccine
• SARS-CoV-rS protein nanoparticle Matrix-M1 adjuvant • Phase 2 trials began in Panama and Peru in July 2020,
using baculovirus (a genetically engineered virus) • phase 3 trials launched in Germany in December 2020
• Phase 2 trials started in August in South Africa and phase with around 36,500 volunteers.
3 trials started in the UK in September as well as in the • collaborated with Elon Musk’s company Tesla to develop
USA in December last year mRNA “micro-factories,” which could be sent worldwide
• vaccine had an efficacy rate of 89.3% based on trials in to make billions of doses of the vaccine.
the United Kingdom
10. Sanofi Pasteur/GSK (USA)
• In South Africa, Novavax’s vaccine efficacy rate was lower
at below 50%, potentially due to the dominance of the • Protein Subunit Vaccine
COVID-19 variant in South Africa, which can evade the • vaccine is based on the same design Sanofi used to create
antibodies stimulated by the vaccine. Flublok, an approved vaccine for influenza.
• In both cases the vaccine was found to be 100% effective • launched a phase 1/2 clinical trial in September 2020.
against severe disease. • Following the announcement on 11 December 2020 that
• B.1.1.7 remains sensitive to neutralization, albeit at older people were not responding as strongly as expected
moderately reduced levels (∼sim;2-fold), by serum to the vaccine, the companies began phase 2 trials in
samples from convalescent individuals and recipients of February 2021 with a different formulation of their vaccine
an mRNA vaccine (mRNA-1273, Moderna) and a protein and if successful, this study will support the selection of
nanoparticle vaccine (NVX-CoV2373, Novavax) the most appropriate antigen dosage for phase 3.
• Preliminary data for clinical trials show: • Phase 3 is projected to begin in the second quarter of 2021
o 96.4% efficacy against the original variant if trial data is positive.
o 86.3% against B.1.1.7
o 51-55% against B.1.351 for mild, moderate, severe 11. Insituto Finlay De Vacunas (Cuba)
COVID-19
o 100% effective at preventing severe illness • Protein Subunit Vaccine
• October 2020, launched trials on its second COVID-19
vaccine, Soberana 2.
a. Phase II Study in South Africa against B.1.351
• In December 2020, it launched a phase 2 trial and reached
• Vaccine efficacy was 60.1% an agreement with the Pasteur Institute of Iran in January
• Posthoc vaccine efficacy against B.1.351 was 51.0% 2021 to test the vaccine in phase 3 trials.
• Efficacious against COVID-19 with higher efficacy in HIV- • In March, a phase 3 trial was registered for Soberana 2.
negative participants
12. Vector Institute (Russia)
5. Anhui Zhifei Longcom Biopharmaceutical & Institute of
• Protein Subunit Vaccine
Microbiology, Chinese Academy of Sciences
• Russian biological research centre known as the Vector
• PROTEIN SUBUNIT VACCINE Institute registered a phase 1/2 trial for a coronavirus
• Tested in collaboration with the Second Affiliated vaccine called EpiVacCorona.
Hospital of Chongqing Medical University and Beijing • On 14 October 2020, Vladimir Putin announced that
Chao Yang Hospital. Russia had granted regulatory approval for this vaccine,
• Phase 3 trials are being conducted across China. even though phase 3 trials had not yet begun.
• has since launched a phase 3 trial
6. Zydus Cadila (India)
• DNA VACCINE
• Phase 2 trials launched in August 2020.
• now initiating a phase 3 trial with 300,000 participants.

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L. Other Vaccines in Development in Phase 2 4. Inovio Pharmaceutical (USA)
• Protein Subunit Vaccine
• Inovio put its INO-4800 DNA vaccine into human trials
early in April 2020.
• it is the only company with a phase 2/3 vaccine against the
related MERS-CoV coronavirus.
• The company has begun human clinical trials in the USA,
China and South Korea.

5. COVAXX (USA)
• DNA Vaccine
• a subsidiary of United Biomedical
• registered a phase 1 trial on 11 September 2020 in
Taiwan
• plans to run its phase 2/3 trial from February 2021 in Brazil
• the company announced plans to begin pre-clinical
research on a vaccine specifically against newly emerging
COVID-19 variants.

6. Reithera (Italy)
• Viral Vector Vaccine
• has developed a COVID-19 vaccine, called GRAd-COV2,
• based on an adenovirus that infects gorillas
• In collaboration with the Lazzaro Spallanzani National
Institute for Infectious Diseases it launched a phase 1 trial
1. Medicago (Canada) at the end of July 2020, with subsequent results indicating
that participants produced antibodies.
• Virus-like-particle vaccine
• The company has launched a phase 2/3 trial.
• Plant-based Virus-like Particle
• Partly funded by the cigarette manufacturer Philip Morris, 7. Beijing Wantai Biological Pharmacy (China)
• uses a species of tobacco to make vaccines • Viral Vector Vaccine
• Virus genes are delivered into leaves, and then plant cells • made a two-dose vaccine made of a combination of spike
create proteins that mimic those found on viruses. proteins and an adjuvant from Dynavax
• launched phase 1 trials on a plant-based COVID-19
vaccine in combination with adjuvants 8. West China Hospital of Sichuan University (China)
from GSK and Dynavax.
• Protein Subunit Vaccine
• Phase 2/3 trails started in November and the company
• vaccine incorporates recombinant protein grown in insect
cells
2. Osaka University/Anges (Japan)
• To make the vaccine, researchers encode the receptor-
• DNA Vaccine binding domain (RBD) in a gene, which they then insert
• Japanese biotechnology company AnGes announced it into a virus.
had started safety trials (phase 1) on a DNA-based • They then infect insect cells with the virus, triggering them
vaccine to make the molecule in huge amounts.
• developed in partnership with Osaka University and • The hospital’s State Key Laboratory of Biological Therapy
Takara Bio. developed the “insect vaccine,” which seems to stop
infection in monkeys without showing any apparent side
3. Clover Biopharmaceuticals Inc., GSK & Dynavax effects.
(Australia)
• Protein Subunit Vaccine 9. Arcturus/Duke-Nus (USA/Singapore)
• The protein-based COVID-19 S-Trimer vaccine, which • RNA Vaccine
uses GSK’s adjuvant system, is now being tested in
human clinical trials. 10. Shenzhen Kangtai Biological Products/Beijing Minhai
• After announcing that phase 1 trial participants produced Biotechnology Co., LTD (China)
a high level of antibodies, Clover began phase 2/3 trials • Inactivated Vaccine
with the GSK adjuvant in December 2020.
• SCB-2019 vaccine, comprising S-Trimer protein 11. Medigen (Taiwan)
formulated with either AS03 or CpG/Alum adjuvants,
elicited robust humoral and cellular immune responses • Protein Subunit vaccine
against SARS-CoV-2, with high viral neutralising activity.
12. People’s Liberation Army (PLA) Academy of Military
• Both adjuvanted vaccine formulations were well tolerated Sciences/Suzhou Abogen Biosciences/Walvax
and are suitable for further clinical development. Biotechnology (China)
• RNA Vaccine
• launched a phase 2 trial for their mRNA-based vaccine,
called ARCoV, with participants aged 18-59 years.

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M. Other Vaccines in Development in Phase 1 O. Vaccine Rollout Recommendations
1. Recommendations were made with these goals:
o Decrease death and serious disease as much as possible
o Preserve functioning of society
o Reduce the extra burden COVID-19 is having on people
already facing disparities

2. Phases of Rollout
a. Phase 1a
• Healthcare personnel
• Residents of long-term care facilities

b. Phase 1b
• Frontline Essential Workers
• People aged >75 years

c. Phase 1c
• People aged 65-74 years
• People aged 16-64 years with underlying medical
conditions
• Other essential workers

3. Prioritization of Roll-out in the Philippines in the Context

of Scarcity
o Objectives
• Reduce mortality
N. Other Vaccines in Development • Preserve the health
1. Monoclonal Antibodies Studies – Actively Recruiting system capacity
a. Regeneron;s 10933 and 10987 Antibodies; The REGN o Criterion
COV2 Study
o Testing combination of 2 antibodies
• REGN10933
• REGN10987
o Whether they prevent acquisition of SARS-CoV-2
o Recruiting 2000 adults in US living in the same household
as a person who recently tested positive for SARS-CoV-2
o Designed to bind SARS-CoV-2 and prevent virus from
entering the healthy cells
o Antibodies made in a lab by Regeneron
o Site: Subcutaneous
o Participants: 2000
o Start Date: July 13,2020
o Primary Completion: June 15,2021
o Estimated Completion: August 15,2021 4. Cold Chain Storage
• From national central cold storage à brought to regional e-
b. Eli Lily’s LY3819253 Antibody, The BLAZE-2 Study Hubs- Center for Health Development (CHDs) or regional DOH
o Testing the LY3819253 antibody office à delivered to Rural Health Unit, Main Health Center, or
o Residents in skilled nursing and assisted living facilities Hospital
o Study questions: • Temperature for Vaccine Storage
• Does the antibody prevent the acquisition? o +2 to + 8 C
• Does the antibody help to prevent the development of o -20 C
more severe COVID-19 or does it reduce the o -70 C
symptoms?
o Designed to bind SARS-CoV-2 and prevent the virus from P. Special Considerations in COVID-19 Vaccines
entering healthy cells 1. Pregnant
o Developed in lab by company Eli Lilly
o The American College of Obstetricians and Gynecologists
o Cannot give you SARS-CoV-2 or make you sick of COVD-
(ACOG) recommends that all eligible persons greater than
19
age 12 years, including pregnant and lactating individuals,
o Site: Intravenous
receive a COVID-19 vaccine or vaccine series.
o Participants: 2400
o COVID-19 vaccines may be administered simultaneously
o Study Start: August 2,2020
with other vaccines, including within 14 days of receipt of
o Primary Completion: March 8,2021
another vaccine. This includes vaccines routinely
o Study Completion: June 29,2020
administered during pregnancy, such as influenza and
Tdap.
o Moderately to severely immunocompromised people
should receive a third dose of the Pfizer-BioNTech and
Moderna mRNA COVID-19 vaccines at least 28 days after
the completion of the initial mRNA COVID-19 vaccine
series.

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o There is insufficient data to determine whether received a COVID-19 vaccine as it will not interfere with
immunocompromised people who received the Johnson & the immune response to the vaccine.
Johnson’s Janssen COVID-19 vaccine also have an
improved antibody response following an additional dose
of the same vaccine.
o Individuals aged 18 through 64 years at high risk of severe
COVID-19 are eligible for a COVID booster.
o ACOG recommends that pregnant people, including
pregnant health care workers, receive a booster dose of
the Pfizer-BioNTech COVID-19 vaccine at least 6 months
following the completion of their initial Pfizer-BioNTech
COVID-19 vaccine series.
o Data from Developmental and Reproductive Toxicity
(DART) studies for the Pfizer-BioNTech COVID-19
vaccine have been reported in Europe presented to the
European Medicines Agency, suggests that animal
studies using the Pfizer/BioNTech COVID-19 vaccine do
not indicate direct or indirect harmful effects with respect
to pregnancy, embryo/fetal development, parturition, or
postnatal development
o Any of the currently authorized COVID-19 vaccines can be
administered to pregnant, recently pregnant, or lactating
people; ACIP does not state a product preference.
However, pregnant, lactating, and recently pregnant
people aged <50 years should be aware of the rare risk of 2. Breastfeeding Women
TTS after receipt of the Janssen COVID-19 vaccine and • There are neither data on the safety of COVID-19 vaccines in
that other FDA-authorized COVID-19 vaccines (i.e., lactating women nor on the effects of mRNA vaccines on the
mRNA vaccines) are available. breastfed infant or on milk production/excretion.
o No safety concerns were found in animal studies: Studies • mRNA vaccines are not thought to be a risk to the
in animals receiving a Moderna, Pfizer-BioNTech, breastfeeding infant.
or Johnson & Johnson (J&J)/Janssen COVID-19 vaccine • People who are breastfeeding and are part of a group
before or during pregnancy found no safety concerns in recommended to receive a COVID-19 vaccine
pregnant animals or their babies. • ACOG recommends that lactating individuals be vaccinated
o No adverse pregnancy-related outcomes occurred in against COVID-19. While lactating individuals were not
previous clinical trials that used the same vaccine platform included in most clinical trials, COVID-19 vaccines should not
as the J&J/Janssen COVID-19 vaccine be withheld from lactating individuals who otherwise meet
o Another report looked at pregnant people enrolled in the v- criteria for vaccination.
safe pregnancy registry who were vaccinated before 20
weeks of pregnancy. Scientists did not find an increased 3. People with Weakened Immune System
risk for miscarriage among people who received an mRNA
• People with HIV and those with weakened immune systems
COVID-19 vaccine during pregnancy
due to other illnesses or medication might be at increased risk
o Pregnant people with COVID-19 have an increased risk of
for severe COVID-19
severe illness, including illness that results in ICU
• They may receive the vaccines but they should be aware of
admission, mechanical ventilation, and death compared
the limited safety data:
with non-pregnant women of reproductive age
o Information about the safety of mRNA COVID-19 vaccines
o Pregnant people with COVID-19 might be at increased
for people who have weakened immune systems in this
risk of adverse pregnancy outcomes, such as preterm
group is not yet available.
birth, compared with pregnant women without COVID-19.
o People living with HIV were included in clinical trials,
o Routine testing for pregnancy before COVID-19
though safety data specific to this group are not yet
vaccination is not recommended.
available at this time
o Women who are trying to become pregnant do not need
to avoid pregnancy after receiving an mRNA COVID-19
4. People with Autoimmune Conditions
vaccine.
o ACOG recommends that pregnant people, including • May receive an mRNA COVID-19 vaccine.
pregnant health care workers, receive a booster dose of • They should be aware that no data are currently available on
the Pfizer-BioNTech COVID-19 vaccine at least 6 months the safety of mRNA COVID-19 vaccines for them.
following the completion of their initial Pfizer-BioNTech • Individuals from this group were eligible for enrollment in
COVID-19 vaccine series. This recommendation also clinical trials.
applies to pregnant individuals who completed their initial
Pfizer-BioNTech COVID-19 vaccine series prior to 5. People who have previously had Guillain-Barre Syndrome
pregnancy. Importantly, currently booster doses are only • May receive an mRNA COVID-19 vaccine.
authorized for the Pfizer-BioNTech COVID-19 vaccine, • No cases of Guillain-Barre syndrome (GBS) have been
and only individuals who completed their initial COVID-19 reported following vaccination among participants in the
vaccine series with the Pfizer-BioNTech vaccine can mRNA COVID-19 vaccine clinical trials.
receive a booster. • With few exceptions, the independent Advisory Committee on
o Pregnant individuals who experience fever following Immunization Practices (ACIP) general best practice
vaccination should be counseled to take acetaminophen. guidelines for immunization do not include a history of GBS as
Acetaminophen has been proven to be safe for use in a precaution to vaccination with other vaccines.
pregnancy and does not appear to impact antibody
response to COVID-19 vaccines.
o Anti-D immunoglobulin (i.e. Rhogam) should not be
withheld from an individual who is planning or has recently

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6. People who have Bell’s Palsy S. Side Effects of COVID-19 Vaccination
• Cases of Bell’s palsy were reported in participants in the • Common Local Side Effects
mRNA COVID-19 vaccine clinical trials. o Pain, Redness, Swelling
• However, the Food and Drug Administration (FDA) does not o Management: Paracetamol, Pain Reliever, Cold
consider these to be above the rate expected in the general Compress at Injection Site
population. They have not concluded these cases were • Common Systemic Side Effects
caused by vaccination. o Headache, Fatigue, Fever and Chills, Muscle Pain and
• Persons who have previously had Bell’s Palsy may receive an Tiredness
mRNA COVID-19 vaccine. o Management: Paracetamol, Pain Reliever, Cold
Compress at Injection Site, Fluids
7. People who have Allergies • Less Common (Only one of the following):
• If you have had a severe allergic reaction or an immediate o Hives/Swelling
allergic reaction—even if it was not severe—to any ingredient o Coughing/Sneezing
in an mRNA COVID-19 vaccine, you should not get either of o Itchy Nose/Itchy and Red Eyes
the currently available mRNA COVID-19 vaccines. o Management: Anti-allergy medicine (Anti-Histamines);
Continue Maintenance Medicine for Asthma and Allergic
• Person needs to be treated with epinephrine or EpiPen© or if
they must go to the hospital. Experts refer to severe allergic Rhinitis
reactions as anaphylaxis. • Rare (Anaphylaxis) (2 or more of the following)
o Hives/Swelling
• Immediate allergic reaction happens within 4 hours after
getting vaccinated and may include symptoms such as hives, o Coughing/Sneezing
swelling, and wheezing (respiratory distress) o Itchy Nose/Itchy and Red Eyes
o Fainting or Low Blood Pressure
• Polysorbate is not an ingredient in either mRNA COVID-19
o Choking
vaccine but is closely related to PEG, which is in the vaccines.
o Difficulty Breathing
• People who are allergic to PEG or polysorbate should not
• Immediate Treatment for Anaphylaxis:
get an mRNA COVID-19 vaccine.
o 1mg/mL Epinephrine 0.3-0.5 mL Intramuscular Mid-Outer
• CDC recommends that people with a history of severe allergic
Thigh
reactions not related to vaccines or injectable medications—
such as food, pet, venom, environmental, or latex allergies—
1. Vaccine-Induced Prothrombotic Immune
get vaccinated.
Thrombocytopenia
• People with a history of allergies to oral medications or a family
history of severe allergic reactions may also get vaccinated. • May lead to Vaccine-induced immune thrombotic
thrombocytopenia (VITT)
Q. What to Expect after receiving COVID-19 Vaccines • Condition of blood clots associated with low platelet counts that
occurs following receipt of the vaccine
• Severe venous thromboembolism in unusual sites and
concomitant thrombocytopenia
• Mimics heparin-induced thrombocytopenia
• Mainly observed in ChAdhOx1 vaccine
o Total of 169 cases
• 3 reported cases with Johnson and Johnson’s Vaccine
• Median age 46 years old
• 82 million doses given in the European Union
• Incidence 1 in 100,000 to 1 in 1,000,000
• occurring 5-7 days until 16-28 days after COVID-vaccination
(5-28 days median 12 days)
• Post-vaccination status common denominator: High levels of
• When to Call the doctor? antibodies to platelet-factor 4-polyanion complexes
o If the redness or tenderness where you got the shot • 1-2% mortality and potential long-term sequelae
increases after 24 hours
o If your side effects are worrying you or do not seem to be a. Hypothesis theory:
going away after a few days o Vaccine-related variant of spontaneous heparin-induced
thrombocytopenia
R. Reasons for Deferral of COVID-19 Vaccination
• If you have had a severe allergic reaction or an immediate b. Pathomechanism:
allergic reaction—even if it was not severe—to any ingredient o Platelet-levels were decreased and less dependent on
in an mRNA COVID-19 vaccine, you should not get either of physiologic levels of heparin and less sensitive to
the currently available mRNA COVID-19 vaccines inhibition with high-dose heparin compared to heparin-
• People who are allergic to PEG or polysorbate should not get induced thrombocytopenia
an mRNA COVID-19 vaccine. o Pathogenic PF4-dependent syndrome
• If you had a severe allergic reaction—also known as o Antibodies that induce massive platelet activation,
anaphylaxis—after getting the first shot of an mRNA COVID- reducing platelet count, and causing thrombosis
19 vaccine (either Pfizer-BioNTech or Moderna), CDC
recommends that you not get a second shot of that c. Presentation:
vaccine. Learn which COVID-19 vaccines need a second o Severe persistent headache after vaccination
shot. o Fever
• If you had an immediate (within 4 hours) allergic reaction after o Focal neurologic symptoms
getting a shot of an mRNA COVID-19 vaccine (either Pfizer- o Seizures or blurred or double vision à may suggest CSVT
BioNTech or Moderna) COVID-19 vaccine, you should not or arterial stroke
get a second shot of that vaccine, even if your allergic o Shortness of breath/chest pain à suggests pulmonary
reaction was not severe enough to require emergency care. embolism or acute coronary syndrome

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 COVID-19
o Abdominal pain à suggesting portal vein thrombosis
o limb swelling, redness, pallor, or coldness à suggesting
deep vein thrombosis or acute limb ischemia
o Reduced consciousness
o Thrombocytopenia (low platelet count)
o Stroke symptoms (hemiparesis)
o Chills
o Nausea/vomiting
o Epigastric discomfort

d. Probable Risk factors:

o No previous exposure to heparin
o Estrogen-replacement therapy or oral contraceptives
o Pre-existing thrombotic conditions

e. Most common sites reported

o Cerebral hemorrhage
o Cerebral venous thrombosis 44
o Splanchnic vein thrombosis 53
o Pulmonary embolism
o Other thrombosis 35

f. Diagnostic Criteria to suspect VIPIT:

o 5-28 days after vaccination
o Any of the above symptoms occurring within this time
frame
o Platelets <150 x 109/ L

g. Diagnostics:
o Platelet count ranges from 20,000-30,000 cubic mm
o High levels of D-dimer >4000 mcg/L
o Low levels of fibrinogen
o PF4 antibody assay (ELISA HIT assay)
o Imaging (Ct Scan/MRI) to rule out CSVT

h. Possible Treatment:
o DO NOT GIVE HEPARIN (both unfractionated heparin
and LMWH)
o AVOID PLATELET TRANSFUSION
o Consult a hematologist
o IVIG 1g/kg/day
• Inhibits Fcy receptor-mediated platelet activation
• For life-threatening ones: High-dose IVIG for 2 days e
o Methylprednisolone 1mg/kg/BW
o First line anti-coagulants: Direct anti-Xa Inhibitors
o Deltaparin 200IU/Kg/day
o Enoxaparin 4000 units/dosee
• Complications of overtreating:
o Aggravation of ongoing intracerebral hemorrhage

i. Recommendations
o Germany and Netherlands
• Limited the vaccine over age of 60
o France
• >55y/o
o Britain’s Joint Committee on Vaccination and
Immunisation <30 y/o should receive other brand
o Norway
• Halted vaccinations
o Other countries imposing age restrictions: Philippines,
Canada, Australia,

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Figure above: Hematoxylin–eosin stains of heart-tissue specimens obtained

by means of endomyocardial biopsy in patient 1 (Panel A) and autopsy in
patient 2 (Panel B) showed myocarditis in both patients, with multifocal
cardiomyocyte damage (arrows) associated with mixed inflammatory
infiltration. Scattered eosinophils were noted (arrowheads). The images of
the hematoxylin–eosin stains were obtained with 10× eyepieces and 40× or
60× objectives.
2. Cardiac Myositis
• Temporal relation between BNT162b2 mRNA 3. Vaccine-Induced Axillary Lymphadenopathy
• Potential relation between second dose of COVID19 vaccine
• Swollen lymph nodes after a dose of vaccine indicates
and mild cardiac involvement with acute myocarditis in
previously infected COVID-19 infection without
otherwise healthy patient with previous exposure to SARS- documentation
CoV-2
• In a study with 947 healthworkers,
• Timing of onset and inflammatory nature of the event make the o 265 participants had tested positive for the virus
relationship plausible
previously
• 4 serious events in trial o 4% with COVID-19 history experienced
• Ventricular arrhythmia was observed lymphadenopathy
• Concerns raised as it can occur after vaccination similar to • 11.6% after 1st dose
smallpox vaccination (eosinophilic myocarditis) • 16% after 2nd dose
• Proposed mechanism: • Usually at the ipsilateral side of the injection site
o Possible molecular mimicry between viral proteins of
• Commonly found in the axillary node
SARS-CoV-2 and Cardiac structures
• Pathology: Benign reactive lymphadenopathy secondary
o Could derive from a nonspecific inflammatory response
to vaccination
secondary to vaccination
• Biopsy result: Reactive Follicular Hyperplasia without
• Systemic reactogenicity – leading to systemic adverse events
Evidence of malignancy
often occurred after dose 2 and within 2 days to 10-14 days
post-vaccination
• Symptoms:
o Acute onset of chest pain
o Chest pain resolved spontaneously within 4h
• Findings:
o Minimal ST elevation on precordial leads with peak T
waves
o Elevated levels of biomarkers
o Increased Troponin T – normalized after Day 7
o Increased CRP
o Increased CKMB – normalized after Day 5

4. Timing of Mammography
• Mammograms should be conducted prior to COVID-19
vaccination or postponed, if possible, for 4–6 weeks
following the second vaccine dose to avoid uncertainty in
interpretation of mammogram results.
• If a mammogram is performed fewer than 4–6 weeks
after COVID-19 vaccination, patients should inform the
mammogram technologist or radiologist when the
vaccine was administered, which vaccine was received,
and in which arm to aid in interpretation of screening
results.
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5. Bell’s Palsy U. Vaccine in Pregnancy
• Bell's palsy is a rare adverse event reported in clinical a. V-Safe Pregnancy Registry
trials of COVID-19 vaccines • Preliminary findings of mRNA COVID Vaccine Safety in
• overall increased risk of Bell's palsy after CoronaVac Pregnant women
vaccination
• Both Pfizer and Moderna vaccines
• 28 clinically confirmed cases of Bell's palsy were reported
following CoronaVac and 16 cases were reported • Participants 15-64 years of age
following BNT162b2 after 451 939 individuals received the • Most common adverse reactions:
first dose of CoronaVac and 537 205 individuals received o Pain on injection site
the first dose of BNT162b2 o Headache
• The age-standardised difference for the incidence o Myalgia
compared with the background population was 41·5 (95% o Chills
CI 11·7 to 71·4) for CoronaVac and 17·0 (−6·6 to 40·6) for o Fever
BNT162b2 • Among 3958 participants enrolled
o 827 had completed pregnancy
6. Menstrual Disturbance § 712 had live births
• ACOG will continue to monitor and evaluate available § 115 had pregnancy loss
evidence on this issue. The National Institutes of Health § Adverse neonatal outcomes include:
has funded institutions to explore potential links between o Preterm birth 9.4%
COVID-19 vaccination and menstrual changes (NIH o Small size for gestational age 3.2%
2021). • Most frequently reported event was spontaneous abortion
• There is no reason for individuals to schedule their (46 cases)
vaccinations based on their menstrual cycles; vaccines • Preliminary finding: did not show obvious safety signals
can be given to those currently menstruating. among pregnant person who received mRNA vaccine
• They reported that among 827 participants with a
7. COVID arm completed pregnancy, the pregnancy resulted in
• A common COVID-19 vaccination side effect after few spontaneous abortion by week 20 in 104 (12.6%)
days of inoculation • the risk of spontaneous abortion after mRNA Covid-19
o Sore arm vaccination either before conception or during pregnancy
o General fatigue is consistent with the expected risk of spontaneous
• Red swollen area at the site of the shot abortion
• If you had an immediate allergic reaction after getting a • In the sensitivity analysis, under the extreme assumption
shot of an mRNA COVID-19 vaccine that all 65 participants with most recent contact during the
• COVID-19 vaccine, you should not get a second shot of first trimester had a spontaneous abortion, the cumulative
that vaccine, even if your allergic reaction was not severe risk of spontaneous abortion from 6 to less than 20 weeks
enough to require emergency care. of gestation was 18.8% (95% CI, 16.6 to 20.9); after age
• These rashes can start a few days to more than a week standardization, the cumulative risk was 18.5% (95% CI,
after the first shot and are sometimes quite large. These 16.1 to 20.8)
rashes are also known as “COVID arm.” Tell your
vaccination provider that you experienced a rash or
“COVID arm” after the first shot. Your vaccination provider
may recommend that you get the second shot in the
opposite arm.
• If the rash is itchy, you can take an antihistamine. If it is
painful, you can take a pain medication like
acetaminophen or a non-steroidal anti-inflammatory drug
(NSAID).

T. Antibodies in Human Breast Milk Post-vaccination

• Significantly elevated levels of SARS-CoV-2 specific IgG and
IgA antibodies in breast milk beginning Day 7 after initial
vaccine dose with IgG-dominant response
• Maternal vaccination results in SARS-CoV-2 specific
immunoglobulins in breast milk
• Increased anti-spike serum IgG was seen at Day 15
• IgG increase to convalescent-equivalent was seen at Day 21
• IgG and IgA levels broadly decreased prior to administration of
the 2nd dose vaccine and sharply increased in the timepoints
after the booster
• No significant detectable difference in levels of antibody
produced between the two vaccines (Pfizer BioNTech and
Moderna)
• Post-vaccine antibody response to SARS-CoV-2 in breast milk
is IgG Dominant
• Further research needed on longevity of antibody response in
breast milk as well as the magnitude and duration of effect on
infant immunity to the virus
• Further characterization of breast milk immune response
including IgG antibody subtypes, IgM and Spike protein
blocking assay is warranted

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X. Diagnosis and Management of Severe Allergic
Reactions after COVID-19

V. Timing of Co-Administration of Other Vaccines

• Previous recommendation of CDC stated that minimum
interval of 14 days between COVID and non-COVID
vaccines was out of abundance of caution and not
because of safety or immunogenicity concerns
• Co-administration or Simultaneous administration may be
performed without regard of timing
• Australian Technical Advisory Group on Immunization
recommends that a minimum of 7 days be observed as
between receipt of COVID vaccines and other vaccines
• 7-day interval should be observed as well with the receipt
of live shingles vaccine because of a possibility of an
inflammatory response to COVID-19 vaccine to reduce the
response to live virus
• Co-administration of <7 days can be done when there is
an increased risk of COVID or another vaccine-
preventable disease or logistical issues anticipated

W. Even After Getting COVID-19 Vaccines, You Should

Still:
• wear a well-fitting mask that covers your nose and mouth when
around others
• stay at least 6 feet away from others
• avoid crowds
• avoid poorly ventilated spaces
• wash your hands often

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Y. Health Worker Communication For COVID-19
Vaccination

Z. Interim Public Health Recommendations for Fully

Vaccinated People
1. Fully Vaccinated People Can
• Visit with other fully vaccinated people indoors without wearing
masks or physical distancing
• Visit with unvaccinated people from a single household who
are at low risk for severe COVID-19 disease indoors without
wearing masks or physical distancing
• Refrain from quarantine and testing following a known
exposure if asymptomatic

2. Fully Vaccinated People Should Continue:

• Take precautions in public like wearing a well-fitted mask and
physical distancing
• Wear masks, practice physical distancing, and adhere to other
prevention measures when visiting with unvaccinated people
who are at increased risk for severe COVID-19 disease or who
have an unvaccinated household member who is at increased
risk for severe COVID-19 disease
• Wear masks, maintain physical distance, and practice other
prevention measures when visiting with unvaccinated people
from multiple households
• Avoid medium- and large-sized in-person gatherings
• Get tested if experiencing COVID-19 symptoms
• Follow guidance issued by individual employers
• Follow CDC and health department travel requirements and
recommendations

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 COVID-19
3. Recommendation for Visiting with Others in Private 7. Vaccinated people visiting with unvaccinated people from
Settings a single household that has individuals at risk of
• Visits or small gatherings likely represent minimal risk to fully severe COVID-19
vaccinated people. • If any of the unvaccinated people or their household members
• Medium or large-sized gatherings and those including are at increased risk of severe COVID-19, all attendees should
unvaccinated people from multiple households increase the take precautions including wearing a well-fitted mask, staying
risk of SARS-CoV-2 transmission. at least 6 feet away from others, and visiting outdoors or in a
• Though the risk of disease may be minimal to the fully well-ventilated space.
vaccinated person themselves, they should be mindful of their o For example, if a fully vaccinated individual visits with an
potential risk of transmitting the virus to others if they become unvaccinated friend who is seventy years old and
infected, especially if they are visiting with unvaccinated therefore at risk of severe disease, the visit should take
people at increased risk for severe illness from COVID-19 or place outdoors, wearing well-fitted masks, and
who have unvaccinated people at increased risk for severe maintaining physical distance (at least 6 feet).
disease in their own households.
• Fully vaccinated people should not visit or attend a gathering 8. Vaccinated people visiting with unvaccinated people from
if they have tested positive for COVID-19 in the prior 10 days multiple households at the same time
or are experiencing COVID-19 symptoms, regardless of • If the unvaccinated people come from multiple households,
vaccination status of the other people at the gathering. there is a higher risk of SARS-CoV-2 transmission among
them. Therefore, all people involved should take precautions
4. Visits between Fully Vaccinated People including wearing a well-fitted mask, staying at least 6 feet
away from others, and visiting outdoors or in a well-ventilated
• Indoor visits between fully vaccinated people who do not wear space.
masks or physically distance from one another are likely low
• Continuing the example from above, if fully vaccinated
risk.
grandparents are visiting with their unvaccinated daughter and
o For example, if you are fully vaccinated, it is likely a low
her children and the daughter’s unvaccinated neighbors also
risk for you to invite other fully vaccinated friends to dinner
come over, the visit should then take place outdoors, wearing
inside your private residence.
well-fitted masks, and maintaining physical distance (at least 6
feet).
5. Visits Between Fully Vaccinated People and Unvaccinated • This is due to the risk the two unvaccinated households pose
People to one another.
• Indoor visits between fully vaccinated people and
unvaccinated people who do not wear masks or physically 9. Medium or Large Sized Gatherings
distance from one another are likely low risk for the vaccinated • All people, regardless of vaccination status, should adhere to
people. current guidance to avoid medium- or large-sized in-person
• Therefore, the level of precautions taken should be gatherings and to follow any applicable local guidance
determined by the characteristics of restricting the size of gatherings.
the unvaccinated people, who remain unprotected against • If they choose to participate, fully vaccinated people should
COVID-19. continue to adhere to prevention measures that reduce
spread, including wearing a well-fitted mask, maintaining
6. Vaccinated people visiting with unvaccinated people from physical distance from others, and washing hands frequently.
a single household that does not have individuals at
risk of severe COVID-19 10. Other personal or social activities outside the home
• If the unvaccinated people are from a single household that • Risk of SARS-CoV-2 infection during public social activities
does not have individuals at risk of severe COVID-19, they can such as dining indoors at a restaurant or going to the gym is
visit with fully vaccinated people indoors, without anyone lower for fully vaccinated people.
wearing masks, with a low risk of SARS-CoV-2 transmission. • However, precautions should still be taken as transmission risk
o For example, fully vaccinated grandparents can visit in these settings is higher and likely increases with the number
indoors with their unvaccinated healthy daughter and her of unvaccinated people present.
healthy children without wearing masks or physical • Thus, fully vaccinated people engaging in social activities
distancing, provided none of the unvaccinated family in public settings should continue to follow all guidance for
members are at risk of severe COVID-19 these settings including wearing a well-fitted mask,
maintaining physical distance (at least 6 feet), avoiding
crowds, avoiding poorly ventilated spaces, covering coughs
and sneezes, and washing hands frequently.

AA. Recommendations for Isolation, Quarantine, and

Testing
1. Fully Vaccinated People with COVID-19 Symptoms
• Risk of SARS-CoV-2 infection during public social activities
such as dining indoors at a restaurant or going to the gym is
lower for fully vaccinated people.
• Precautions should still be taken as transmission risk in these
settings is higher and likely increases with the number of
unvaccinated people present.
• Fully vaccinated people engaging in social activities in public
settings should continue to follow all guidance for these
settings including wearing a well-fitted mask, maintaining
physical distance (at least 6 feet), avoiding crowds, avoiding
poorly ventilated spaces, covering coughs and sneezes, and
washing hands frequently.

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2. Fully Vaccinated People with No COVID-19 symptoms
following an exposure
• Fully vaccinated people with no COVID-like symptoms do not
need to quarantine or be tested following an exposure to
someone with suspected or confirmed COVID-19, as their risk
of infection is low.
• Fully vaccinated people who do not quarantine should still
monitor for symptoms of COVID-19 for 14 days following an
exposure. If they experience symptoms, they should isolate
themselves from others, be clinically evaluated for COVID-19,
including SARS-CoV-2 testing, if indicated, and inform their
health care provider of their vaccination status at the time of
presentation to care.

3. Fully Vaccinated Residents of Non-Healthcare Congregate

settings
• Fully vaccinated residents of non-healthcare congregate
settings (e.g., correctional and detention facilities, group
homes) should continue to quarantine for 14 days and be
tested for SARS-CoV-2 following an exposure to someone with
suspected or confirmed COVID-19.
• This is because residential congregate settings may face high
turnover of residents, a higher risk of transmission, and
challenges in maintaining recommended physical distancing.

4. Fully vaccinated employees of non-healthcare congregate

settings and other high-density workplaces
• Fully vaccinated employees of non-healthcare congregate
settings and other high-density workplaces (e.g., meat and
poultry processing and manufacturing plants) with no COVID-
like symptoms do not need to quarantine following an
exposure; however testing following an exposure and through
routine workplace screening programs (if present) is still
recommended.

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 COVID-19
C. Summary of Evidence Effectiveness and
Immunogenicity
1. For HOMOLOGOUS BOOSTERS

XXX. COVID-19 Third Dose VS Boosters

2. Safety for HOMOLOGOUS BOOSTERS
A. Definition of Terms
1. Boosters VS Third Dose
• Booster Shots – A Dose of vaccine administered when
the initial sufficient immune response to a primary
vaccine series is likely to have waned over time
• Third Dose or Additional Dose after an initial primary
vaccine series – Administration of additional vaccine
dose when the initial primary vaccine series is likely to be
insufficient

2. Differentiating booster sequence

• Homologous Booster – using the same vaccine type as
the initial primary series 3. For HETEROLOGOUS BOOSTERS
• Heterologous Booster – using a different vaccine type
as a booster to the initial booster series

B. Eligibility for a Booster Shot

1. Criteria
• available for the following Pfizer-BioNTech vaccine
recipients who completed their initial series at least 6
months ago and are
o 65 years and older
o Age 18+ who live in long-term care settings
o Age 18+ who have underlying medical conditions
o Age 18+ who work in high-risk settings D. Evidences
o Age 18+ who live in high-risk settings 1. Pfizer BioNTech
2. People in High-risk Settings a. Israeli Study
o July 30,2021 – Israeli Ministry of Health approved the
• First responders (healthcare workers, firefighters, police, administration of booster shots for >60 y/o
congregate care staff)
o After administering for at least 5 months earlier = rates
• Education staff (teachers, support staff, daycare workers) of confirmed COVID-19 and severe illness were
• Food and agriculture workers substantially lower among those who received a third
• Manufacturing workers dose
• Corrections workers o 12 days after the confirmed booster,
§ the rate of confirmed infection was lower in the
• U.S. Postal Service workers booster group by a factor of 11.3
• Public transit workers § rate of severe illness was lower by factor of
• Grocery store workers 19.5
§ rate of confirmed infection after 4-6 days was
lower by a factor of 5.4

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ANG, D.K.
 COVID-19
b. Global Study 2. Astrazeneca
o Efficacy waned to 84% between 4 and approximately a. UK Trial
6 months after dose 2 o response to a third dose as a booster given 28-38
o administered a third 30-μg BNT162b2 dose 7.9 to 8.8 weeks after the second dose
months after dose 2 to 11 participants 18 to 55 years o An extended interval before the second dose of
of age and to 12 participants 65 to 85 years of age ChAdOx1 nCoV-19 leads to increased antibody titres.
from U.S o A third dose of ChAdOx1 nCoV-19 induces antibodies
o Local reactions and systemic events after dose 3 were to a level that correlates with high efficacy after second
predominantly mild to moderate and were similar to dose and boosts T-cell responses.
those after dose 2 o Antibody titres were higher 28 days after vaccination in
o by 1 month after dose 3, neutralization GMTs against those with a longer interval between first and second
wild-type virus increased to more than 5 times as high dose than for those with a short interval
(in 18-to-55-year-olds) and to more than 7 times as o Among participants who received a third dose of
high (in 65-to-85-year-olds) as the GMTs 1 month after vaccine, antibody titres were significantly higher 28
dose 2 days after a third dose than 28 days after a second dose
o during the approximately 8 months from 7 days after
dose 2 to before dose 3, SARS-CoV-2 neutralization 3. Moderna
geometric mean titers (GMTs) in this subgroup of
a. For Organ Transplant Recipients
participants from phase 1 of the trial declined far more
rapidly than vaccine efficacy declined in participants in o We enrolled 120 organ-transplant recipients. No patient
the phase 2–3 pivotal trial had a previous diagnosis of Covid-19.
o neutralization GMTs against the beta variant o The median age of the patients was 66.6 years
increased more after dose 3 than did GMTs against (interquartile range, 63.3 to 71.4), and the median time
wild-type virus, to more than 15 times as high (in from transplantation to the third dose was 3.16 years
younger adults) and more than 20 times as high (in o A third dose of mRNA vaccine in transplant recipients
older adults) as those after dose 2, reducing the gap had substantially higher immunogenicity than placebo,
between neutralization of wild-type virus and the beta as determined in our analysis of both primary and
variant secondary trial end points.
o neutralization GMTs decreased from 7 days to 1 o After the third dose, the median percent virus
month after dose 2 but increased from 7 days to 1 neutralization was 71% in the mRNA-1273 group and
month after dose 3 13% in the placebo group (95% CI for the between-
group difference, 11 to 76 percentage points), and the
c. Among Immunocompromised individuals and Seniors percentage of patients above the 30% threshold for
neutralizing antibody positivity was 60% and 25%,
o Local and systemic reactions after third vaccination
respectively
with SARS-CoV-2 vaccine BNT162b2, reported by ICI
and adults 60 years and older, were similar to those
4. Sinovac CoronaVac
observed following administration of the previous
vaccines and mostly self-resolved. a. China Trial
o Fatigue, myalgia and fever were the most frequent o Scheduled Dosing
systemic side effects reported • Schedule 1 0, 14, 42
o Women and younger age groups reported systemic • Schedule 2 0, 14, 54
reactions more commonly.
o Most of immunocompromised individuals and seniors • Schedule 3 0, 28, 56
reported experiencing a better or a similar response to • Schedule 4 0, 28, 268
the third dose, compared to the second. o 3ug group, neutralizing antibody titers induced by the
2 doses declined after 6-8 months to below the
d. Among Heart Transplant Recipients seropositive cut-off for Schedule 2 and Schedule 4
o A homologous third booster dose of the BNT162b2 o When a third dose was given 6-8 months after a
vaccine gave overall consistent tolerability and a good second dose, GMTs assessed 14 days later increased
safety profile, while eliciting humoral and cellular to 137.9 for Schedule 2 and 143.1 for Schedule 4,
immune responses approximately 3 fold above Schedule 1 and Schedule
3 after Third Doses
o 96 adult HT patients who received a third homologous
dose of the BNT162b2 vaccine 168 days after the
second dose
o third dose was associated with a low rate of adverse
events, mostly mild pain at the injection site
o At 18 days following the third dose of the vaccine, the
positive antibody response increased from 23% to 67%,
with a corresponding increase in neutralizing capacity.
o The third dose elicited SARS-CoV-2 neutralization
titers >9-fold and IgG anti-RBD antibodies >3-fold of the
range achieved after the two primary doses.
o Mycophenolate use, lower eGFR and higher C-reactive
protein were independently associated with a reduced
likelihood of generating an immune response.

77
ANG, D.K.
 COVID-19
5. Heterologous VS Homologous Prime Boost Schedules
with an Adenoviral Vectored and mRNA COVID-19
Vaccine (Com-COV)
• SARS-CoV-2 anti-spike IgG concentrations of both
heterologous schedules were higher than that of a
licensed vaccine schedule (ChAd/ChAd) with proven
efficacy against COVID-19 disease and hospitalization
• At day 28 post boost, the geometric mean concentration
of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients
(12 906 ELU/mL) was non-inferior to that in ChAd/ChAd
recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided
97·5% CI 7·5 to ∞)
• Four serious adverse events occurred across all groups,
none of which were considered to be related to
immunisation
o Antibody level declined to a low level 6 months after
2nd dose
o Antibody level declined but remained a relatively high
level 6 months after the boosting dose
o Boosting 6 m after 2-dose vaccination increases
neutralizing antibodies by 20x in adults immediately
after 7 days and 30x in elderly
o Neutralizing antibody maintained 14-28 days after
boosting with a significant dose-response relationship

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