HANDBOOK OF COVID 19

(Revised Edition)

Editor
Brig A S Menon

Associate Editors
Gp Capt TVSVGK Tilak
Wg Cdr Rohit Vashisht

ARMED FORCES MEDICAL COLLEGE

PUNE
 Note from Editors
The Science of COVID 19 is evolving.
Readers are advised to refer to suggested
reading for updates

2022 Edition
Published by
Armed Forces Medical College
Pune

Cover Design
Aditi Menon

This book is a training manual for officers of the Armed Forces

Medical Services and is NOT for sale
 LIST OF CONTRIBUTORS

Surg Cmde KM Adhikari Brig SK Kaushik

Professor & Head Dy Comdt
Dept of Pediatrics CH(NC)

Col S Adhya Maj Arjun Kurup

Professor Graded Spl (Paeds)
Dept. of Community Medicine MH Patiala

Maj Varun Anand Col Vikas Marwah, SM

Clinical Tutor Professor & Head
Dept of Radiodiagnosis Dept of Respiratory Medicine

Col AT Atal Brig AS Menon

Col Med, 8 Mountain Div Professor & Head
C/O 56 APO Dept of Internal Medicine

Surg Capt Kavita Bala Anand Surg Lt Cdr Kranthi K Nethi

Professor Resident
Dept of Microbiology Dept of Hospital Administration

Surg Capt V Bhaskar Maj Neelesh Patel

CO, Clinical tutor
INHS Jeevanti, Goa Dept of Hospital Administration

Surg Capt Saurabh Bobdey Col SK Patnaik

Professor Professor & Offg HOD
Dept of Community Medicine Dept of Hospital Administration

Surg Cmde K Chatterjee Maj Deepu K Peter

Professor & Head Clinical Tutor
Dept of Psychiatry Dept of Respiratory Medicine

Col Neeraj Garg Col Jyoti Prakash

Assoc Professor Professor
Dept of Hospital Administration Dept of Psychiatry

Col Nikahat Jahan Col Ravinder Sahdev

Sr Adv (Anaesthesia & Critical care) Assoc Prof
MH Secunderabad Dept of Radiodiagnosis

Air Cmde BM John Maj Apoorva Saxena

PMO, Graded Spl (Paeds)
SWAC MH Ahmedabad
Col S Karade Air Cmde Arijit Sen
CO, Professor & Head
4014 Field Hospital Dept of Pathology

Air Cmde SP Singh Col Kiran Sheshadri

Professor & Head Sr Adv(Anaesthesia & Critical Care
Dept of Microbiology Base Hospital, Delhi Cantt.

Gp Capt TVSVGK Tilak Brig Rangraj Setlur

Professor & Head Commandant
Dept of Geriatrics MH Barrackpore

Wg Cdr Rohit Vashisht Col Y Uday

Associate Professor Professor
Dept of Internal Medicine Dept of Internal Medicine

Surg Lt Cdr Shrinath V Col AK Yadav

Clinical tutor CO,
Dept of Respiratory Medicine 2 118 Field Hospital

Maj Naveen Yadav AVM Rajesh Vaidya, VSM

Gd Spl (Med) Dean & Dy Comdt
MH Chennai AFMC
 Table of Contents

Chapter Name Page No

1. Genealogy of the Pandemic 1
2. Coronaviruses & SARS-CoV-2 11
3. Immune response and Immunopathogenesis 16
4. Laboratory diagnosis of COVID 19 28
5. Role of Radiodiagnosis in Management of COVID-19 36
6. Management of Mild COVID-19 47
7. Management of Moderate and Severe COVID 54
8. Oxygen Therapy, Ventilation and ICU management 66
9. COVID-19 in Children 76
10. Complications of COVID 19 90
11. Vaccines 99
12. Adaptive immunity, Vaccine Efficacy, & Vaccination strategy 114
13. Impact on mental health of COVID 19 Pandemic 125
14. Initial response to Pandemic-AFMS perspective 134
15. Public health Challenges in COVID Pandemic 141
16. Challenges in establishing COVID Care Hospital 148
1. Genealogy of the Pandemic

Lt Col AK Yadav, Surg Capt Saurabh Bobdey,

Brig SK Kaushik

Introduction

COVID-19 (Coronavirus Disease-2019) pandemic is the worst of its kind faced

by humanity after the ‘Spanish Flu’. COVID-19 is an acute viral disease caused
by infection with Severe Acute Respiratory Syndrome - Corona Virus-2 (SARS-
CoV-2), a newly emerged zoonotic infectious disease. As the disease spread
across the globe, WHO declared COVID-19 as a Public Health Emergency of
International Concern (PHEIC) on 30 January 2020 and a pandemic on 11 March
2020.

Magnitude of the problem

World As of 04 July 2022, there have been approximately 554 million

COVID-19 cases and nearly 6.3 million worldwide. The reported case count is
an underestimate of the overall burden of COVID-19, as only a fraction of acute
infections are diagnosed and reported. Seroprevalence surveys in the United
States and Europe have suggested that after accounting for potential false
positives or negatives, the rate of prior exposure to SARS-CoV-2, as reflected by
seropositivity, exceeds the incidence of reported cases by approximately 10-fold
or more. Approximately one-third of the total cases were estimated to have
occurred in South Asia (including India). As per published literature, it is believed
that the virus originated from the seafood market of Wuhan city of Hubei
province, China. Following reports of cases from China, Thailand was the first
country to report cases, followed by Japan, South Korea, USA and European
nations (Fig 1.1 & 1.2). The virus rapidly spread across the globe, causing high
morbidity and mortality in many countries. The worst affected countries in terms
of number of cases in the world are USA (89 million cases) followed by India
(43.5 million) and Brazil (32.6 million). However, in varying proportions, this
deadly disease has affected almost the whole world.

1
 Source: Worldometer

Fig 1.1 Spread of Covid-19 Cases as on 31 Jan 2020

Source: Worldometer

Fig 1.2 Spread of Covid-19 Cases as on 29 Feb 2020

2
 India On 30 January 2020, the first case was confirmed in Kerala's
Thrissur district in a student who had returned home for a vacation from Wuhan
University in China. In February 2020, very few cases were reported from India.
However, in March 2020, COVID cases started rising in many states, and
therefore, to suppress transmission, the Union government declared a
countrywide lockdown on 24 March 20. In early Aug-Sep 2020, India
experienced a surge of cases and crossed the five million mark on 16 September
20 (‘first wave’). There was a steady decline in the number of cases reported from
the end of September 2020. However, from the middle of February 2021, a
massive upsurge started (‘second wave’), with the number of cases and deaths
reported daily showing a very steep climb (Fig 1.3). During the second wave,
more than 0.4 million new cases and 4000 deaths were reported per day. COVID
cases started declining from mid-May and continued with that trend until January
2022 when country witnessed third wave with a sudden spurt in number of daily
cases peaking at 0.35 million daily cases reported on 20 Jan following which there
was a sharp and consistent decline in daily cases. The severity during this wave
was a lot lesser which can be made out from the fact that the peak number of daily
reported deaths was 1,745 compared with 5,093 during the second wave (Fig 1.4).
The same trend was seen in terms of hospital admission too with no reported
saturation of health care facilities dedicated for Covid treatment. In the month of
June again the country witnessed a slight increase in number of daily cases with
19,118 cases reported on 30 Jun 2022 but there has been no increase in
hospitalizations or deaths.

Fig 1 .3 Daily reported Covid-19 Cases in India

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 Fig 1.4 Daily reported Covid-19 deaths in India

Agent factors

a) Morphology: The agent is a positive sense, single-stranded, enveloped

RNA virus belonging to the family Coronaviridae. The word Corona
means crown. It is so named because the virus has a shape of a crown with
small bulbar projections formed by the viral spike (s) peplomers.

b) Reservoir: Human being is the only reservoir for SARS-CoV-2

c) Source of Infection: The source of infection is an infected human

being who discharges the virus into the environment in respiratory
droplets.

d) Mode of entry: The virus gains access into the human body
primarily through the respiratory route. It establishes infection through
“spike protein” on its surface, which combines with the “ACE receptors”
present in the respiratory tract of human beings.

e) Infectivity: The virus is highly infectious, especially in a congested

environment. An infected person can transmit the virus to others before the
onset of symptoms and in the early course of illness. Peak viral shedding
seems to occur at the time of symptom onset and declines thereafter.

f) Pathogenicity: Though the infectivity is high, the pathogenicity is

low, as a large percentage of infected persons remain asymptomatic.

4
 g) Survival in nature: The COVID-19 virus is a very fragile organism
and does not survive for more than a few hours outside the human body.
However, studies have shown that the virus can survive on artificial
surfaces in the form of moist droplets for up to a few days. A study
evaluating the duration of the viability of the virus on objects and surfaces
showed that SARS-CoV-2 could be found on plastic and stainless steel for
up to 2-3 days, cardboard for up to 1 day, and similarly virus remains viable
on commonly touched items such as computer mouse, keyboard, handrails,
etc.

h) Susceptibility: The virus is quite susceptible to natural agents as

bright sunlight, heating, and drying. Direct bright sunlight and total drying
can inactivate the virus in a few hours while heating at 50OC for 10 minutes
will also inactivate it. The virus is susceptible to chemical agents, with 1%
sodium hypochlorite, 60% alcohol, and scrubbing with ordinary soap
deactivating it within a few seconds.

j) Mutant Strains: Mutations arise as a natural by-product of viral

replication and hence are bound to happen with the passage of time. RNA
viruses typically have higher mutation rates than DNA viruses.
Coronaviruses, however, make fewer mutations than most RNA viruses
because they encode an enzyme that corrects some of the errors made
during replication. In most cases, the fate of a newly arising mutation is
determined by natural selection. Those that confer a competitive advantage
for viral replication, transmission, or escape from immunity will increase
in frequency. Those that reduce viral fitness tend to disappear from the
population of circulating viruses. Multiple variants of the SARS-CoV-2
virus have emerged, which are quite different from the original Wuhan
virus. For ease and uniformity, WHO recommends that the nomenclature
of the variants be based on Greek alphabets like alpha, beta, gamma, delta,
omicron, etc.

Host Factors

(a) Age: Children less than ten years of age seem to be less susceptible.
Persons more than sixty years tend to have more severe disease and have a
higher risk of mortality than younger ones.

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 (b) Sex: The occurrence of cases shows a slightly higher preponderance
among males, but this may be due to more reporting of symptoms and
consequent testing rather than due to actual biological differences.

(c) Pre-existing diseases: Persons with co-morbidities (Diabetes,

Chronic Lung Disease, Obesity, cardiovascular disease, diseases
associated with immunosuppression like cancers) tend to have more severe
diseases and a higher risk of mortality.

(d) Occupation: Healthcare workers are at a particularly high risk of

being infected. Similarly, other frontline workers such as surveillance
workers, police, etc. are at a higher risk.

(e) Genetic & racial Factors: The role of genetic factors is not clear
but people with ACE2 polymorphism who have type 2 transmembrane
serine proteases (TMPRSS2) are at high risk of SARS-CoV-2 infection.
Besides, research has also shown that patients possessing HLA-B*15:03
genotype may become immune to the infection. Racial/ethnic minorities
who maintain livelihood as essential workers are more likely to be exposed
to the virus, whereas living in high density areas, high proportion of
homelessness and incarceration adds to the barriers to social distancing.

Environmental Factors

(a) Climate and seasons: So far, no evidence has emerged indicating

the role of climate or seasons in the transmission of COVID-19

(b) Overcrowding: The single most important social factor, which

determines the transmission of COVID-19, is overcrowding. It is primarily
a disease of ‘closely huddled humans’. Whenever a large number of
humans crowd together, COVID transmission is likely to be intense.

(c) Ventilation: An important approach to lowering the concentrations

of indoor air pollutants or contaminants including any viruses that may be
in the air is to increase ventilation – the amount of outdoor air coming
indoors. Ensuring proper ventilation with outside air can help reduce the
concentration of airborne contaminants, including viruses, indoors. Proper

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 ventilation also reduces surface contamination by removing some virus
particles before they can fall out of the air and land on surfaces. However,
by itself, increasing ventilation is not enough to protect people from
COVID-19.

Transmission dynamics

(a) Infective material: The infective material is primarily the oro-

pharyngeal secretions of an infected person.

(b) Modes of transmission: Transmission of the disease can broadly

occur by direct transmission i.e. when a susceptible individual comes in
close contact with an infected people through infected secretions such as
saliva or respiratory secretions or due to indirect transmission i.e. involving
contact of a susceptible host with a contaminated object or surface. A
detailed brief of various modes of transmission is as follows

(i) Droplet Transmission: Transmission of SARS-CoV-2 can

occur through direct, indirect, or close contact with infected people
through saliva and respiratory secretions or their droplets, which are
expelled when an infected person coughs, sneezes, talks, or sings. In
these circumstances, droplets that include viruses can reach the
mouth, nose or eyes of a susceptible person and can result in
infection.

(ii) Airborne Transmission: Airborne transmission is defined as

the spread of an infectious agent caused by the dissemination of
aerosols that remain infectious when suspended in air over long
distances and time. Airborne transmission of SARS-CoV-2 can
occur during medical procedures that generate aerosols.
Epidemiologists and scientists have been evaluating SARS-CoV-2
spread through aerosols, particularly in indoor settings with poor
ventilation. Evidence suggests that the virus spreads through
airborne transmission especially in closed areas with poor ventilation
(places of worship, marriage halls, lecture halls, theatres, restaurants
etc.), and situations where human beings are congested in a small

7
 space (religious ceremonies, marriages, business meetings, lectures,
festivals, political rallies, etc.).
(iii) Fomite Transmission: Respiratory secretions or droplets
expelled by infected individuals can contaminate surfaces and
objects, creating fomites. Viable SARS-CoV-2 virus and/or RNA
detected by RT-PCR can be found on those surfaces for periods
ranging from hours to days, depending on the ambient environment
(including temperature and humidity) and the type of surface.
Transmission may also occur indirectly through touching surfaces/
objects contaminated with virus from an infected person (e.g.,
stethoscope or thermometer), followed by touching the mouth, nose,
or eyes. Despite evidence of SARS-CoV-2 contamination and
survival of the virus on surfaces, there has been no report that
demonstrates conclusively direct fomite transmission. People
exposed to potentially infectious surfaces often also have close
contact with the infectious person, making the distinction between
respiratory droplet and fomite transmission difficult to differentiate.

(iv) Other modes of Transmission: SARS-CoV-2 RNA has also

been detected in other biological samples, including the urine and
faeces. However, there have been no published reports of
transmission of SARS-CoV-2 through faeces or urine. Current
evidence suggests that humans infected with SARS-CoV-2 can
infect other mammals, including dogs, cats, and farmed mink.
However, it remains unclear if these infected mammals pose a
significant risk for transmission to humans.

(c) Incubation period: The usual incubation period is 5 to 7 days

(range 1-14 days) and studies have shown that more than 97% of cases
experience symptoms within eleven days of contacting the virus. However,
with newer more infective variants like omicron, it has been observed that
there is reduction in incubation period as well which was 3.03 ± 1.35 days
for omicron variant.

(d) Period of communicability: The usual period of communicability

ranges from 2 days before the onset of symptoms to 5-7 days after the
onset. The infected person can shed the virus as much as twenty-eight days

8
 or more following entry of the organism into the body. Depending upon
whether the infected person develops symptoms, the potential to transmit
the disease is as follows:

(i) COVID 19 cases: They are the most important source of infection
and transmit the virus during the entire phase of symptomatic illness.

(ii) Pre-symptomatic infected persons: These are infected persons

who will develop symptoms as against asymptomatic infected persons.
These persons have an important role in transmitting the infection, as
they transmit the infection two days before the onset of symptoms.

(iii) Asymptomatic infection: These are persons who are infected but
will never develop symptoms. These persons may transmit the
infection; however, their role in the extent of transmission is debatable.
As per latest published literature 81% of people with Covid-19 had mild
or moderate disease (including people without pneumonia and people
with mild pneumonia), 14% had severe disease, and 5% had critical
illness.

Conclusion

COVID-19 is an acute infectious disease caused by SARS-CoV-2. It has spread

rapidly across the world and has affected all continents and countries. The person
is infective in asymptomatic and pre-symptomatic phase of disease, which makes
prevention and control of infection challenging. India has already seen three
waves of COVID 19, with the second wave being the most devastating in terms
of case severity where as in terms of infection transmission, omicron driven third
wave saw the most acute rise in number of cases within a short span of time
compared with other variant driven waves. The future of the pandemic will
depend on the ongoing evolution of SARS-CoV-2 virus along with behaviour of
citizens and vaccination coverage of population. In this aspect the world
governments need to respond effectively in an equitable manner which has not
been the case so far which is evident with low vaccination coverage in African
countries.

9
Suggested Reading

1. Guo ZD, Wang ZY, Zhang SF, Li X, Li L, Li C, et al. Aerosol and surface
distribution of Severe Acute Respiratory Syndrome Coronavirus 2 in
hospital wards, Wuhan, China. Emerg Infect Dis. 2020; 26(7):1583-1591.
2. Lauring AS, Hodcroft EB. Genetic Variants of SARS-CoV-2—What Do
They Mean? JAMA. 2021; 325(6):529–531.
3. WHO, scientific brief. Transmission of SARS-CoV-2: implications for
infection prevention precautions. Available at https://www.who.int/news-
room/commentaries/detail/transmission-of-sars-cov-2-implications-for-
infection-prevention-precautions (Last visited on 04 Jul 2022)

10
2. Coronaviruses & SARS-CoV-2

Air Cmde SP Singh, Surg Cdr Kavita Bala Anand, Lt Col S Karade

Introduction

Coronaviruses were first discovered in the nasal washings of a male child in 1965
by Tyrrell et al and since then a number of coronaviruses have been discovered.
Till the emergence of SARS-CoV in 2002 & 2003 in Guadong China, this group
of virus was considered innocuous only causing mild illness in the
immunocompetent individual. Ten years later in 2012, a highly pathogenic
MERS-CoV emerged in the Middle Eastern countries. In Dec 2019, a cluster of
cases of Pneumonia were reported from Wuhan, China. Next Generation
sequencing technology led to the discovery of new human Coronavirus belonging
to the Genus Beta coronavirus which was provisionally named as 2019 novel
Coronavirus (2019-nCoV) and later named as the SARS-CoV-2 by the
International Committee on Taxonomy of Viruses (ICTV) and disease caused by
it was named as COVID 19.

Classification of Coronaviruses

Corona viruses belong to the family Corona viridae. They are divided into
four genera: Alpha coronavirus, Beta coronavirus, Gamma corona virus and Delta
corona virus. The beta corona viruses are further divided into four lineages A, B,
C & D. The humans are affected by the lineage A-OC 43 & HKU1, lineage B
(SARS-CoV and SARS-CoV-2) and lineage C (MERS-CoV).

Structure of Coronaviruses

Corona viruses are named after the crown like spikes on their surface as
seen under Electron microscope. SARS-CoV-2 belongs to the genus beta corona
virus, subgenus Sarbeco virus. It is approximately 80–200 nm in size. It contains
about 30kb single stranded positive sense RNA. The 3’ end encodes for the
structural proteins including spike (S), envelope (E), membrane (M) and
nucleoprotein (N). The 5’ terminal end of this virus encodes for the non-structural
proteins polyprotein 1ab that gives rise to further 16 nonstructural proteins. (Fig
2.1 & 2.2).

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 SARS-CoV-2 contains 20 nm spike glycoproteins embedded in its
envelope, these are club shaped and are called peplomers, these help the virus
attach to host cells. The spike protein has two subunits S1 and S2. The S1 subunit
harbours the receptor binding domain (RBD). Beta coronaviruses belonging to
lineage A also harbour a hemagglutinin esterase on their surface.

Fig 2.1 Structure of SARS-CoV-2

Fig 2.2 Genome of SARS-CoV-2

UTR (Untranslated region) ORF (Open Reading Frame)

12
Origin of SARS-CoV-2

Corona viruses have been found in large number of domestic and wild
mammals and birds, suggesting that birds and bats are the natural reservoirs of
the virus. Corona viruses also have potential for interspecies transmission which
can also cause zoonotic outbreaks. The genomic characterization of the SARS-
CoV-2 from Wuhan cluster carried out by various study groups was done using
next generation sequencing of samples from bronchoalveolar lavage fluid and
cultured isolates. These studies showed that SARS-CoV-2 was related (with 88%
identity) to two bat-derived severe acute respiratory syndrome (SARS)-like
coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21 and more distant from
SARS- CoV (about 79%) and MERS-CoV (about 50%). Zhou et al. demonstrated
that the novel virus has 96.2% similarity to a bat SARS-related Coronavirus
(SARSr-CoV; RaTG13). The S1 protein, is phylogenetically closer to pangolin-
CoV than RaTG13 and the RBD region within the S1 has been found to be
conserved between Pangolin CoV and SARS-CoV2. The origins of the SARS-
CoV-2 however still remain a matter of debate.

Virus entry into host cells

Infection starts when the viral spike protein attaches to its complementary
host cell receptor. The host cellular receptor for SARS-CoV-2 is ACE-2 receptor
(Angiotensin converting enzyme 2). Initial spike protein priming
by transmembrane protease, serine 2 (TMPRSS2) is essential for entry of
SARS-CoV-2. TMPRSS2 primes the spike protein domain by cleaving the S1/S2
site, which leads to fusion of the virus to the respiratory epithelial cells by binding
to the ACE 2 receptors. The receptor for SARS-CoV is also ACE-2 receptor.
MERS-CoV binds to the Dipeptidyl peptidase 4 (DPP4).

Variants

All viruses, including SARS-CoV-2, undergo changes in their genomic

structure over time. These heritable changes in the nucleotide sequence of the
genome are called mutation. Most mutations have little to no impact on the virus’
properties. However, some of the mutations in the virus may provide survival
advantage. The original SARS-CoV-2 isolated in 2019, in Wuhan, China has

13
undergone variety of changes in different structural and functional genes due to
natural selection process or immune pressure.

A new SARS-CoV-2 variant may have different mutations that can affect
transmissibility, antigenicity, or virulence. WHO has defined a SARS-CoV-2
variant of concern (VoC) as one that has propensity of increased transmissibility,
alteration in clinical presentation as compared to the original. Rise in infections
due to VoC is a threat as it decreases the effectiveness of various public health
measures such as vaccine outreach, therapeutics and diagnostics concern. On 26
November 2021, WHO designated the variant B.1.1.529 a variant of concern,
named Omicron. The Omicron variant is the currently circulating VoC and is the
predominant variant in circulation around the world. In addition, Variant of
interest (VoI) is another term used for those variants that have caused community
transmission or cluster of cases. WHO recognized previous VoC and current VoC
are enumerated in Table 2.1 and Table 2.2

Table 2.1 WHO labelled SARS-CoV-2 previous Variants of concern.

Picture Courtesy: WHO; Tracking SARS-CoV-2 variants (who.int)

14
 Table 2.2 WHO labelled SARS-CoV-2 currently circulating Variant of concern
Picture Courtesy: WHO; Tracking SARS-CoV-2 variants (who.int)

Suggested Reading

1. Tyrrell DAJ, Bynoe ML. Cultivation of a novel type of common cold virus
in organ cultures. BMJ. 1965; 1:1467e1470.
2. Masters, P. S. & Perlman, S. in Fields Virology Vol. 2 (Eds Knipe, D. M.
& Howley, P. M.) 825–858 (Lippincott Williams & Wilkins, 2013).
3. Cui, J., Li, F. & Shi, ZL. Origin and evolution of pathogenic
coronaviruses. Nat Rev Microbiol.2019; 17:181–192.
4. Zhong NS., Zheng BJ, Li YM, Poon LLM, Xie ZH, Chan KH et al.
Epidemiology and cause of severe acute respiratory syndrome (SARS) in
Guangdong, People’s Republic of China. Lancet.2003;362:1353–1358
5. DrostenC, GuntherS, PreiserW, van den WerfS, BrodtH, Becker S et al.
Identification of a novel coronavirus in patients with severe acute
respiratory syndrome. N. Engl. J. Med.2003; 348:1967–1976.
6. Naming the coronavirus disease (COVID-19) and the virus that causes it".
https://www.who.int/emergencies/diseases/novel-coronavirus-
2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-
and-the-virus-that-causes-it (Last visited 13 Aug 2021)
7. Sturman LS, Holmes KV (1983-01-01). Lauffer MA, Maramorosch K
(eds.). The molecular biology of coronaviruses. Advances in Virus
Research. 28: 35–112
8. Gadsby NJ, Templeton KE. Coronaviruses.In: Caroll Karen C, Pfaller MA,
Landry ML, McAdam AJ, Patel R. editors. Manual of Clinical
Microbiology. 12thed. Vol. 2. Washington DC: ASM Press; Chapter 92.
9. Lu R, Zhao X, Li J, NiuP, YangB, WuH, Wang W et al. Genomic
characterisation and epidemiology of 2019 novel coronavirus: implications
for virus origins and receptor binding. Lancet. 2020;395 : 565-574.
10. https://www.who.int/news/item/28-11-2021-update-on-omicron

15
3. Immune response and Immunopathogenesis
Air Cmde Arijit Sen

The initial entry and response to the virus

The first event is the interaction of the COVID-19 virus and human cell
takes place through the Angiotensin Converting Enzyme 2 Receptor (ACE2 R).
The spike proteins of the virus attaches to the goblet and mucociliary cells of the
upper respiratory pathway. In the lower respiratory tract it attaches to type II
pneumocytes in the alveoli, macrophages and the dendritic cells. It also manages
to penetrate the endothelial lining cells. All the mentioned cells are rich in ACE2
receptors. Cellular serine protease TMPRSS2 is used by the virus to initiate this
binding. Further the virus particle enters the cell by endocytosis.
After entry of the virus into the epithelial and endothelial cells, it starts
multiplying and eventually causes pyroptosis. This is a special type of pro-
inflammatory apoptosis. This recruits macrophages which release IL-6
(interleukin), IL10 and TNFα (Tumor Necrosis Alpha). Other pro-inflammatory
cytokines are released too IL-2, IL-2R, IL-7, IL-8 and MIP1A (Macrophage
inflammatory protein 1). The more the severe infection the more the number of
macrophages and the more the amount of cytokines released. IL6 also suppresses
T Cell function. On binding of the virus the ACE2 is released from the surface of
the epithelial surface into the airway surface liquid. This is brought about by the
metallopeptidase. Metallopeptidase too processes the activation of the membrane
form of interleukin-6 (IL6) receptor to soluble form. This in turn activates the
signal transducer and activator of transcription factor 3 (STAT3) via gp130. The
STAT3 in turn activates pro-inflammatory nuclear factor kappa beta (NF-kB).
There is thickening of the interstitium over the next few days. The alveolar lining
permeability increases leading to pulmonary oedema and subsequently formation
of hyaline membrane. Neutrophils and monocytes also pour into the alveolar
space (Fig3.1).

Immune response to infection

The immune response to any infection can be divided as follows:-
Innate Immunity
Adaptive Immunity
Humoral Immunity (B Cell Response)
Cell Mediated Immunity (T Cell response)

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a) Innate Immunity
During routine viral infection the innate immunity works with Pattern
Recognition Receptors (PRR) such as TLR7 (Toll Like Receptor) and TLR8.
This further downstream activates production of antiviral interferons and
chemokines which recruit immune cells like lymphocytes and natural killer
cells. It has been found, that COVID-19 does not induce any such immune
response through the innate immunity. This suggests that unlike other
Coronaviruses, COVID-19 does not elicit adequate immune response through
the innate immunity pathway to induce an adequate adaptive immunity. This
allows the virus to continue to multiply inside the pneumocytes.

b) Adaptive Immune response

(i) Humoral Immunity (B Cells)
In the early phase of infection there is rise of IgM and IgA, which do not
appear to be protective. In 7-14 days the IgG appears against the spike
protein. The CD4+ T Helper cells present in the follicular centre induce the
naive B lymphocytes to progress towards plasma cells and produce these
antibodies. Memory B cells also get formed in response. This is supposed
to be the neutralizing antibody. They peak by 50 to 60 days post infection
and fade by around 10 months. The memory B cells generated in the
process can again produce the IgG antibody in cases of re-infection and be
protective. Two IgG antibodies have been identified which are effective
against the receptor binding domain (RBD) of the COVID-19 virus and can
be effective in preventing of binding of the virus to the ACE2 receptors
and hence are protective. The short lived existence of the neutralizing
antibodies has raised a concern against protection to re-infection of vaccine
induced protection. The memory B cells and the long lived plasma cells
will play a role in generating anti-RBD antibodies during reinfection, this
needs to be further studied. In addition, T Cell memory may help in
producing cytotoxic T cell response. The convalescent plasma therapy did
not hold ground and has been shown to have failed to have been protective
in a controlled trial. The use of monoclonal antibody has shown some
benefit when used for mild infection in OPD patients.

(ii) Cell Mediated Immunity (T Cells)

CD4 + T cells (T Helper Cells) reactive against spike protein have been
detected in most of the patients infected with COVID-19. However it has

17
 also been found in one third of non-infected normal population, suggesting
that these CD4+ cells likely developed due to seasonal Coronavirus and
are of cross reacting nature with other viruses of the Corona family. Likely
this protects the children and the young adults who are frequently exposed
to seasonal virus. This is in contrast to the antibodies which are specific
only to COVID-19.
CD8+ T cells (Cytotoxic T Cells) response in COVID is quite
heterogeneous. In mild COVID disease, the CD8+ T cell responds with
activation and clonal expansion. This results in formation of effector and
terminally differentiated T cells and also memory T cells. There number is
normal or increased. This leads to increased production of Interferon γ, IL-
2, CD107a (Cluster Differentiation), TNF α and GZMB (Granozyme B)
which have cytokine, chemokine and cytoxic function against the virus.
The co-inhibitory signals like PD1 (Programmed Cell Death Protein 1),
CD38, CD39, TIM3 (T Cell Immunoglobulin and Mucin Domain) also are
reduced in expression. Whereas in moderate to severe COVID infection
the activation factors IFNγ, IL-2, CD107a, TNFα, GZMB, Perforins, CCL
3 & 4(chemokine ligand) and IL1β are all normal or reduced and also the
co-inhibitory signals are grossly increased resulting in altered T cell
function and exhaustion (Fig2.2).

(c) Cellular response

Patients may have lymphopenia, leucopenia of leucocytosis, but the first is
most common. Lymphopenia is a poor prognostic factor in COVID infection
and correlates well with severity of the infection and levels of IL6 and IL 8
production. Both CD4+ (Thelper1 and Tregs) and CD8+ T cells reduce in
number. CD8+ (Cytotoxic T Cells) reveal abnormal function and exhaustion.
NK Cells and monocytes too reveal reduced number and abnormal function
in moderate and severe COVID -19 infection. Neutrophil to lymphocyte ratio
(NLR) is calculated for prognostication. Moderate infection usually has a
NLR of 4.8 (+/- 3.5), whereas in severe infection a NLR of 20.7 to 24.1 is
usually seen. A NLR of 3.3 is taken as a cut off for poor prognosis.

Cytokine Storm
Cytokines are a large family of small proteins. They are important in cell
signaling and play a role as immune-modulators. The family includes interferons,
interleukins, chemokines, lymphokines and tumor necrosis factor. Cytokine

18
storm is an unregulated host immune response in auto-amplifying production of
cytokines. Adaptive immunity induced by the CD4 (Th1) is the first response in
SARS COV-2 infection like in any other viral infection. However a dysregulated
and excessive adaptive immune response may be disastrous. Various Cytokines
have been found to be grossly raised in severe COVID-19 patients getting
admitted to the ICU as compared to the mild and moderate illness. They have
been found to have raised levels of granulocyte-macrophage colony-stimulating
factor (GM-CSF), interferon gamma-induced protein 10 (IP10), monocyte
chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1 alpha
(MIP1A), TNFα , IL-1βbeta, IL-8 and IL-6. The pathway initiating cytokine
storm and its effect is illustrated in (Fig3.3). High levels of IL-6 is damaging on
alveolar epithelium and the endothelium leading to severe diffuse alveolar
damage. There is multi-organ damage affecting the primarily the lungs but also
the GIT, brain, heart, liver and the eyes. IL-6 along with other pleotropic
cytokines raise the levels of other acute phase reactants like C reactive protein
(CRP), Ferritin, complement and pro-coagulant factors. The prognostic markers
used to monitor moderate and severe COVID infection are IL-6 (normal level-5-
15pg/ml), Ferritin (normal levels in males 24-336 micrograms per litre and for
females 11-307 micrograms per litre), CRP (normal levels < 3mg/L), D-dimer
(normal levels < 250ng/ml), Procalcitonin (normal levels 0.05ng/ml) and
Troponin I (Normal levels 0.04ng/ml).

Organ Involvement
The organs affected by the COVID-19 Virus.
(a) Lungs
Diffuse alveolar damage (DAD) is the most prominent pathology in the
lung. These results as a result of destruction of type 2 pneumocytes and the
endothelial cells by the virus. DAD leads to exudation of fibrin rich fluid into the
alveoli and formation of hyaline membrane. Evidence of microvasculature
thrombosis, fibrinous organizing pneumonia. Pulmonary embolism has also been
identified. Further details of findings in the lung have been brought out under the
autopsy section.

(b) Heart
Pre-existing coronary artery disease (CAD) may get complicated with
plaque rupture causing acute coronary even. However in absence of CAD an
event mimicking myocardial infarction can occur due to inadequate oxygen

19
supply, Cytokine storm may lead to myocarditis in absence of viral affection of
the myocytes. Intra-myocardial thrombosis is another important finding. In later
stages of illness heart failure may produce raised levels of Troponin and brain-
type natriuretic factor (BNP)

(c) Kidney
The virus infects the glomerular tufts, podocytes and the tubular epithelium
due to presence of ACE2 receptors. Patients present with acute kidney injury with
microvasculature thrombosis and acute tubular necrosis. Hypoperfusion of the
kidney is also a part of cytokine storm.

(d) Brain
Brain stem and the cerebral cortex have ACE2 receptors. Some patients
may present with meningitis and encephalitis. Cytokine storm may also produce
inflammation in the brain. Arterial thrombosis though rare can produce an
ischemic stroke. Olfactory nerve involvement may produce anosmia.

(e) Gastrointestinal Tract

The lower GI tract is rich in ACE 2 receptors. Patients may produce GI
symptoms in the form of loss of appetite, vomiting, abdominal pain and diarrhea.

(f) Skin
Patients having skin manifestation have an erythematous patch. They do
not correlate with severity of disease. Vesiculo-bullous eruptions like in cases of
chicken pox also have been seen. The manifestations are mainly immune
mediated and due to microangiopathy.

(g) Eye
As the cornea, sclera and the epithelium of the eyelid have ACE2 receptors.
Patients present with conjunctivitis.

Hypercoagulable State in COVID 19

The patients of COVID-19 virus infection have been seen to present with
hypercoagulable state and thrombosis in spite of anticoagulant therapy. The
whole phenomenon has been called COVID associated Coagulopathy. The
pathogenesis is still being studied. It is explained by the activation of the
Virchow’s Triad of thrombus formation in patients infected by the COVID-19

20
virus. First pillar of the triad is endothelial injury. Endothelial injury in SARS
COV-2 infection is due to the direct invasion of the virus into these cells using
the Angiotensin Converting Enzyme (ACE) 2 receptors found on the surface of
these cells. Transmission Electron Microscopy (TEM) has detected the presence
of these viruses inside the endothelium, (Fig 3.4). The COVID19 spike protein
also induces complement mediated injury of the endothelium. Endothelial injury
has also been postulated to be induced by IL 6 storm (as brought out above) and
neutrophil extracellular traps from chromatin released from dying neutrophils.
All this leads to endotheliitis and microvascular inflammation. The second pillar
of the triad is stasis and contributed by the immobilization of a patient on oxygen
therapy. The third pillar of the Virchow’s triad is the hypercoagulable state. The
changes seen in COVID-19 infection are Elevated levels of factor VIII (FVIII),
fibrinogen, von-Willebrand factor (vWF), circulating prothrombotic
microparticles, neutrophil extracellular traps (NETs) and hyper viscosity (likely
due to raised polyclonal gamma globulin levels). D-dimer a product of cross
linked fibrinogen degradation is also raised in severe illness.

Though in severe COVID-19 disease, DIC (disseminated intravascular

coagulation) does develop as a complication but the hypercoagulable state in
COVID appears different from DIC. The major effect in DIC is bleeding whereas
in COVID it is thrombosis. Though marked increase in D-dimer in severe COVID
and mild thrombocytopenia are similar to DIC but increased levels of fibrinogen
and factor VIII levels are in contrast to DIC. Hence COVID-19 does not appear
to be a case of consumption coagulopathy. So the hypercoagulable state in
COVID is more likely to be like compensated DIC and unlike decompensated
DIC where the patient is bleeding. Also usually the prothrombin time (PT),
Activated partial thromboplastin time (APTT) and platelets are usually within
normal range unlike in a decompensated DIC.

Thus the hypercoagulable state results in widespread venous thrombosis,

venous thromboembolism (VTE) and deep vein thrombosis in COVID-19
infection. The risk of VTE is about 3% in COVID-19 infection.

Cases of arterial thrombosis resulting in ischaemic stroke, thrombotic

microangiopathy in the lungs and myocardial infarction also has been reported
but cases are far and few. Finally it appears that we are dealing with situation of
inflammatory thrombosis. The inflammatory cytokines Interleukin 1, 6 and 8 are

21
produced by the inflammatory reaction induced in the respiratory pathway. The
direct infection of the endothelial cells as brought out above too activates the
endothelial cells resulting in release of von Willebrand Factor and Factor VIII.
Also it leads to activation of platelets. All this promotes fibrin clot formation and
thrombosis. Thrombosis in return induces inflammation. Thrombosis activates
the endothelium through the PAR (Protease activated receptors). The
endothelium produces C5A that activates the monocytes. The cross talk between
inflammation and thrombosis is postulated to be the mechanism as this is how the
two events are usually related. Thus as we see the whole process is initiated in
the respiratory passage by epithelial and endothelial damage both of which carry
ACE2 receptors. A local thrombo-inflammatory event in COVID-19 induces a
generalized hypercoagulable and prothrombotic state which produces thrombosis
in the micro-vasculature of the brain, kidneys and venous plexus of the prostate.

Autopsy Studies
Limited knowledge exists as autopsies are restricted due to safety concerns.
The lungs in all cases were heavy with evidence of consolidation and presence
of intravascular thrombi on gross examination. On microscopy, exudative diffuse
alveolar damage (DAD) and severe capillary congestion was found in early
disease. Tracheobronchitis and large vessel thrombi (Fig3.1b) and microthrombi
in pulmonary vasculature was a common finding. Evidence of pulmonary
embolism, alveolar haemorrhage and evidence of bronchopneumonia has also
been documented in the lung. Beside this all cases showed evidence of Type II
pneumocyte hyperplasia with atypia. The alveolar septae of the lung showed
presence of thrombi with intra-alveolar extravasated RBCs and fibrin thrombi
fibers. The bronchial lining too showed evidence of squamous metaplasia. The
immunohistochemistry (IHC) revealed presence of viral spike proteins in the
trachea-bronchial lining epithelium and the hyaline membrane in the alveoli.
Electron Microscopy (EM) revealed presence of 67 nm electron dense particles
in the cytoplasm of the pneumocytes. The understood mechanism of entry of the
COVID-19 virus in the upper respiratory epithelium and the type 2 pneumocytes
using the ACE2 and transmembrane protease serine 2 (TMPRSS2) is well
confirmed by the presence of the spike proteins of the virus as demonstrated by
IHC in both these cells. Evidence of trachea-bronchitis and DAD is well
explained by the preference of these cells by the virus due to the expression of
the ACE2 receptor. Heart commonly showed presence of intra-myocardial

22
thrombi on histology. No other specific findings were detected like coronary
thrombosis and myocarditis.

Among the other organs liver histology showed presence of peculiar

basophilic structures in the sinusoids. Likely to nuclear remnants of degenerated
cells. These could not be characterized even with IHC. Rest of the findings in the
liver has been non-specific. Lymph nodes of most cases showed large
transformed cells in the subcapsular and intra-parenchymal sinuses. These cells
showed a vesicular nuclei, prominent nucleoli and moderate amphophilic
cytoplasm and were positive for CD 20 a marker of B lymphocyte on IHC.
Kidneys in most cases at autopsy showed and acute tubular necrosis and peri-
tubular micro-angiopathy. In spite of most patients who underwent autopsy being
on anti-coagulant therapy, micro-thrombi were still detected especially in the
pulmonary vasculature. Gross and Histopathology Images of autopsy studies are
not available in open access and are listed under further studies.

23
Fig 3.1 Entry of SARS CoV2 and initial response

24
Fig 3.2 Cellular response to SARS CoV2

Fig 3.3 Pathway to cytokine storm

25
 Fig 3.4 Pathogenesis of prothrombotic state in COVID 19

Acknowledgement

Fig3.1: COVID 19 Pathology Outlines (Open Access)

Fig 3.2 :Mortaz Esmaeil, Tabarsi Payam, Varahram Mohammad, Folkerts Gert,
Adcock Ian M. The Immune Response and Immunopathology of COVID-19.
Frontiers in Immunology. 2020;11:2037. (Open Access)
Fig3.3: Bhaskar Sonu, Sinha Akansha, Banach Maciej, Mittoo Shikha, Weissert
Robert, Kass Joseph S., Rajagopal Santhosh, PaiAnupama R., Kutty Shelby.
Cytokine Storm in COVID-19—Immunopathological Mechanisms, Clinical
Considerations, and Therapeutic Approaches: The REPROGRAM Consortium
Position Paper. Frontiers in Immunology. 2020;11:1648. (Open Access)
Fig 3.4:Luis Ortega‐Paz, DavideCapodanno, Gilles Montalescot, Dominick J.
Angiolillo. Coronavirus Disease 2019–Associated Thrombosis and
Coagulopathy: Review of the Pathophysiological Characteristics and
Implications for Antithrombotic Management. J Am Heart Assoc.
2021;10:e019650. https://doi.org/10.1161/ JAHA. 120.019650 (Open Access)

26
Suggested Reading

1. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and

management. Mouhamed YazanAbou-Ismail, Akiva Diamond, Sargam
Kapoor, Yasmin Arafah and LalithaNayak. Thromb Res 2020; 194: 101–
115.
2. Uday Jain. Effect of COVID-19 on the Organs.Cureus. 2020: 12(8);e9540.
3. Alain C. Borczuk et al. COVID-19 pulmonary pathology: a multi-institutional
autopsy cohort from Italy and New York City. Modern Pathology. 2020: 33;
2156-2168.
4. Menter Tet al. Postmortem examination of COVID-19 patients reveals
diffuse alveolar damage with severe capillary congestion and variegated
findings in lungs and other organs suggesting vascular
dysfunction.Histopathology. 2020;77(2): 198.
5. Autopsy Findings in 32 Patients with COVID-19: A Single-Institution
Experience. Sarah S. Elsoukkarya Maria Mostykaa Alicia Dillarda Diana R.
Bermana Lucy X. Maa Amy Chadburnb Rhonda K. Yantissb Jose Jessurunb
Surya V. Seshanb Alain C. Borczukb Steven P. Salvatore. Pathobiology.
2021;88 :56–68.

27
4. Laboratory diagnosis of COVID 19

Col S Karade, Air Cmde SP Singh

Introduction
Laboratory plays a pivotal role in diagnosis, prognosis, and overall management
of a patient of COVID-19. Several modalities of COVID-19 diagnosis are
currently available, however reverse transcriptase based real-time polymerase
chain reaction (RT-PCR) to detect viral genetic component in respiratory samples
is considered gold standard for diagnosis of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) infection. These tests need to be conducted in an
ICMR approved molecular laboratory. A typical diagnostic cycle includes sample
collection, nucleic acid extraction, PCR, interpretation, and generation of results.
Commonly available ICMR or US-FDA approved COVID-19 diagnostic tests are
summarized in Table 4.1

Table 4.1 Diagnostic tests for COVID-19

Name of the test Sample Turn-around Remarks

requirement time and
cost/test
Generic real time OP/NP swab in 5-8 hr  Can handle 90-94 sample in one run,
RT-PCR test VTM useful for medium and high-level
450 INR BSL-2 laboratory
 Needs skilled manpower and
sophisticated equipment
GeneXpert COVID OP/NP swab in 45 min  Useful in acute health care setting and
Xpress VTM 2000 INR triage situations
 User friendly
Tru NAT (MolBio) Respiratory sample < 1 hr  Indigenous assay
in viral lysis buffer 1000 INR  Useful for low and medium level
laboratories
 User friendly
FELUDA (Tata 96% sensitivity and 45 min  Lateral flow assay-based detection of
group) 98% specificity 450 INR amplicons
 Does not require expensive Real-time
PCR instrument
Antigen detection NP swab 20-30 min  Inexpensive test
test  Positive test indicative of active
250 INR infection
 Screening tool for high-risk groups
 Low sensitivity as compared to RT-
PCR
IgG/IgM Antibody Serum 2-3 Hr  Tool to assess the prevalence of the
detection test 250 INR diseases in a specific area
 Not recommended for diagnosis by
ICMR

28
Sample Collection

Preferred sample for molecular study of SARS-COV-2 infection includes

throat swab or oropharyngeal swab (OP) and nasal swab or nasopharyngeal swab
(NP). Both NP and OP swabs are collected using a nylon flocked swab in a viral
transport medium (VTM) following appropriate biosafety precautions. Other
effective but invasive samples include bronchoalveolar lavage and endo-tracheal
aspirate collected in wide mouth sterile plastic containers. The sample should be
collected ideally within 3 days of onset of symptom and no later than 7 days,
preferably prior to initiation of antivirals. For children and uncooperative patient,
saliva or buccal swab samples are useful, however the sensitivity is compromised.
Good laboratory practices, abiding standard precautions and biosafety guidelines
including PPE kit are essential while handling patient samples.

Respiratory specimen should be transported in triple layer packaging as

early as possible from site of collection to diagnostic laboratory as per ICMR,
New Delhi and WHO guidelines. If delay is anticipated, specimen can be stored
at 4-8 degree Celsius for up to 5 days.

Reverse transcriptase based real-time PCR (RT-PCR)

PCR is a molecular tool for amplifying DNA/RNA targets in geometric

progression. In SARS-CoV-2 real-time PCR test we amplify three or more
genetic determinants of SARS-CoV-2 and detect these target amplicons using
fluorescent probes in real-time. The assay also includes a human gene component
as internal control. The typical process involves viral RNA extraction from
respiratory specimen, master-mix preparation, addition of template RNA,
amplification of target genes followed by detection of signal and analysis of the
assay. The entire process is carried out in a biosafety level two molecular
laboratory and takes 5-6 hr for a batch of 90-94 samples. The viral genetic targets
commonly used includes combination of envelope gene (E) with RNA-dependent
RNA polymerase (RDRP) or HKU open reading frame (HKU Orf 1b), or
nucleoprotein (N) or S gene target. As SARS-CoV-2 undergoes mutations, newer
variants are produced in infected individuals across the world. Use of multiple
target genes improves sensitivity and help to detect such variants. The advantage
of commercially available assay is low cost/test (approx. INR 450/test) and ability
to handle bulk samples. However, time constraint, requirement of trained staff,

29
biosafety cabinets and sophisticated equipment limits its use in emergency
setting.

Regardless of the target used for detection of SARS-CoV-2 genetic determinants,

the sensitivity and specificity of the different RT-PCR kits is estimated to be
approximately 70% and 95% respectively. The factors affecting the sensitivity of
RT-PCR includes types of starting samples (OP swab/ nasal swab/ saliva or
broncho-alveolar lavage), expertise in collection, duration, and severity of disease
etc.

Fig 4.1 Lab technician in molecular biology lab wearing PPE handling respiratory
samples in Biosafety cabinet

Interpretation of RT-PCR results

The results of COVID-19 RT-PCR is expressed as positive or negative (SARS-

CoV-2 genomic target detected or not-detected based on cycle threshold (Ct)
value. Ct value is a numerical value that refers to the number of cycles needed for
a sample to amplify the SARS-CoV-2 genomic target and cross a threshold (cut-
off). Most of the commercially available kit use Ct cutoffs of 35 cycles, i.e., any
sample with a Ct value below 35 is considered as true positive. A lower Ct value
indicates higher viral load in the given sample which changes based on the stage
of infection, as the amount of virus present in a sample can vary during the
course of their illness.
A positive SARS-CoV-2 RT-PCR indicates qualitative detection of 2 or
more virus specific sequences in the given sample. Since prolonged viral

30
shedding up to 4-8 weeks can occur in a confirmed case of COVID 19, the test
does not aid in prognostication. A false negative test can occur due to poor
specimen collection, unsatisfactory specimen transport, specimen collection too
early or too late after onset of symptoms (> 1 week) and due to technical errors
(3). RT-PCR test if negative needs to be repeated if clinical suspicion is strong.

Cartridge based Nucleic acid amplification-based tests (NAAT)

Currently, Xpert Xpress SARS-CoV-2 (Cepheid) and TrueNat™ (Molbio)

are the two Indian Council of Medical Research (ICMR) recommended cartridge-
based nucleic acid amplification tests (CBNAAT) for qualitative detection of
SARS-CoV-2 in respiratory samples. These are closed system and require
minimum handling of specimen and poses minimum biothreat to laboratory
personnel. The turn-around time is 45 min making its use suitable for emergency
setting. However, a single CBNAAT system can handle only 4 specimens in one
go.

Isothermal amplification Assay

ID NOW COVID-19 assay (Abbott) utilizes an isothermal nucleic acid

amplification technology for qualitative detection of genetic targets from the
SARS-CoV-2 viral RNA in direct nasal, naso-pharyngeal or oro-pharyngeal
samples. This platform is US FDA approved and commercially available as point
of care test as the turn-around time is just 5 min to 20 min depending upon number
of copies of target RNA present in the sample.

CRISPR/Cas9 based assay (FELUDA)

CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic

Repeats) based rapid test was recently approved by ICMR and Director General
Drug controller of India. This test is indigenously developed for COVID-19
diagnosis by Institute of Genomics and Integrative Biology (CSIR-IGIB), New
Delhi and marketed by TATA group. The test is named FELUDA, an acronym
for ‘FNCas9 Editor Limited Uniform Detection Assay’, based on fictious
detective character portrayed by renowned film director Satyajit Ray. The assay
does not require costly Real-time PCR instrument and the SARS-CoV-2 genomic
sequence can be detected by paper strip-based test. This assay takes 45 min and

31
claimed to have limit of detection of as low as 10 copies of purified viral
sequence.

Rapid antigen detection test (RAT)

These group of rapid diagnostic test (RDT) detects the presence of viral
proteins (antigens) expressed by the SARS-CoV-2 in a sample from the
respiratory tract of a person. If the target antigen is present in sufficient
concentrations in the sample, it will bind to specific antibodies fixed to a paper
strip enclosed in a plastic casing and generate a visually detectable signal in form
of a band within 20-30 minutes. The antigen(s) detected are expressed only when
the virus is actively replicating; therefore, such tests are best used to identify acute
or early infection.

Antibody based tests

Detection of antibodies against various SARS-CoV-2 antigen in the serum

sample of an individual helps us to determine evidence of past infection.
Qualitative or quantitative estimation of antibodies against nucleoprotein or
surface (S1 /S2) antigen can be done, based on Enzyme linked immune-sorbent
assay (ELISA) or chemiluminescence assay (CLIA). These tests are useful in
determining the seroprevalence of COVID-19 in given population. A positive
antibody test does not necessarily mean immunity against SARS-CoV-2 infection
as these may be non-neutralizing antibodies. Presently, quantitative antibody
estimation test following vaccination is not recommended to determine level of
protection from COVID-19.

Ancillary tests
These sets of hematological and biochemical tests are essential for clinical
monitoring and prognostication of COVID-19 cases. These tests also help in
assessing the severity of disease. The detail of these tests is shown in Table 4.2.

32
 Table 4.2 Ancillary test for management of case of COVID-19
Sample and type of Parameter Remarks
vacutainer measured
EDTA blood, purple top Total blood Essential for monitoring of neutrophilia,
vacutainer counts lymphopenia, N:L ratio and thrombocytopenia
Citrated, light-blue top D Dimer Indicator of activation of coagulation system/DIC
vacutainer
EDTA blood, purple top Prothrombin Indicator of activation of coagulation system
vacutainer time
Serum, Red top or yellow Interlukin-6 Indicative of cytokine storm
top vacutainer
Serum, Red top or yellow Ferritin Inflammatory marker
top vacutainer
Serum, Red top or yellow Procalcitonin Marker for secondary bacterial infection
top vacutainer
Serum, Red top or yellow C-reactive Inflammatory marker, also indicative of severe viral
top vacutainer protein infection
Serum, Red top or yellow Liver Function Deranged in case of end organ damage or multi-
top vacutainer test organ dysfunction syndrome
Renal function
test

SARS-CoV-2 genome sequencing

Any change in the nucleic acid sequence of the genome of an organism is

called mutation. Mutations in SARS-CoV-2 genome is common which can affect
its pathogenicity due to immune escape or increase ability for human-to-human
spread. The recent upsurge of cases in India commonly referred as second
COVID-19 wave, after initial stabilization has brought attention to role of SARS-
CoV-2 variants in fueling the pandemic. Whole genomic sequencing (WGS) is
an important tool for identification of novel SARS-CoV-2 genomic variants of
concern (VoC) and correlating with epidemiological trends. WGS is an expensive
and cumbersome process that does not benefit an infected individual; however,
the phylogenomic data is important at community level for detection of mutations
that may confer additional properties to the virus such as immune escape and
increased infectivity.

Recently a pan-India, multi-laboratory network was initiated, known as the

Indian SARS-CoV-2 Genomics Consortium (INSACOG). This joint venture by
the Union Health Ministry of Health, and Department of Biotechnology (DBT)

33
with Council for Scientific & Industrial Research (CSIR) and Indian Council of
Medical Research (ICMR), is a consortium of 38 laboratories to monitor the
genomic variations in the SARS-CoV-2.

Suggested Reading

1. Tang Y, Schmitz JE, Persing DH, Stratton CW. Laboratory Diagnosis of

COVID-19: Current Issues and Challenges. J Clin Microbiol. 2020
26;58(6):e00512-20. doi: 10.1128/JCM.00512-20.
2. Mourya DT, Sapkal G, Yadav PD, Belani SKM, Shete A, Gupta N. Biorisk
assessment for infrastructure & biosafety requirements for the laboratories
providing coronavirus SARS-CoV-2 /( COVID-19 ) diagnosis. Indian J
Med Res. 2020;151(2 & 3):172-176.
3. WHO Guidance Note. Laboratory testing for coronavirus disease (COVID-
19) in suspected human cases :interim guidance ,11 retemter2020 .World
Heal Organ [Internet .]2020;(harcM):20. moailatle irom: Mttth: // atth.
oMo. Int/ irih/Mandle/10001/ 553213( laht oihited15 mug2021(
4. Ghoshal U, Vasanth S, Tejan N. A guide to laboratory diagnosis of Corona
Virus Disease-19 for the gastroenterologists. Indian J Gastroenterol.
2020;39(3):236–42.
5. Kumar KSR, Mufti SS, Sarathy V, Hazarika D, Naik R. An Update on
Advances in COVID-19 Laboratory Diagnosis and Testing Guidelines in
India. Front Public Heal. 2021;9 :1–6.
6. Loeffelholz MJ, Alland D, Butler-Wu SM, Pandey U, Perno CF, Nava A,
et al. Multicenter evaluation of the cepheid xpert xpress sars-cov-2 test. J
Clin Microbiol. 2020;58(8):1–8.
7. Basu A, Zinger T, Inglima K, Woo KM, Atie O, Yurasits L, et al.
Performance of abbott id now COVID-19 rapid nucleic acid amplification
test using nasopharyngeal swabs transported in viral transport media and
dry nasal swabs in a New York city academic institution. J Clin Microbiol.
2020;58(8):1–7.
8. Suvvari T, Nawaz M, Mantha M. FNCas9 editor-linked uniform detection
assay: An innovative COVID-19 sleuth. Biomed Biotechnol Res J.
2020;4(4):302–4.
9. Möckel M, Corman VM, Stegemann MS, Hofmann J, Stein A, Jones TC,
et al. SARS-CoV-2 antigen rapid immunoassay for diagnosis of COVID-19
in the emergency department. Biomarkers [Internet]. 2021;26(3):213–20.

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10. Bats M-L, Rucheton B, Fleur T, Orieux A, Chemin C, Rubin S, et al.
Covichem: A biochemical severity risk score of COVID-19 upon hospital
admission. PLoS ONE 2021; 16(5): e0250956. (https://doi.org/ 10.1371/
journal.pone.0250956)
11. Singh UB, Rophina M, Chaudhry R, Senthivel V, Bala K, Rahul C. Variants
of Concern responsible for SARS-CoV-2 vaccine breakthrough infections
from India. Preprint available at https://doi.org/10.31219 /osf.io/fgd4x
12. Anand KB, Karade S, Jindamwar P, Sen S, Babu B, Bobdey S, Gupta R M.
Self-collected saliva: Diagnostic potential for severe acute respiratory
syndrome coronavirus-2 testing in a resource-limited setting. J Mar Med
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https://www.marinemedicalsociety.in/text.asp?2021/23/2/155/326274
13. K.B. Anand, S. Karade, S. Sen, R.M. Gupta, SARS-CoV-2: Camazotz's
Curse, Medical Journal Armed Forces India 2020; 76(2):136-41

35
5. Role of Radiodiagnosis in Management of COVID-19

Col Ravinder Sahdev, Maj Varun Anand

Introduction
Ever since the outbreak of the Coronavirus pandemic in March 2020, there
has been a dilemma regarding the diagnosis of the same. Even though, reverse
transcriptase polymerase chain reaction (RT-PCR) is considered as the gold
standard for diagnosis, the sensitivity of RT-PCR test is around 80-85%. Due to
suboptimal sensitivity of RT-PCR, technical errors, resource and time constraints,
imaging has played a crucial role in management of the patients via early
diagnosis and follow up. Imaging has also been crucial in diagnosis of various
lung, cardiovascular, neurological and rhino-orbito-cerebral complications.

Imaging strategy for management of COVID-19 patients

An imaging approach for diagnosis and further management of COVID-19
suspect/ diagnosed case as recommended by Indian Radiological and Imaging
association (IRIA) is at Fig 5.1.

Fig 5.1 Imaging approach for COVID 19

36
Role of Various Imaging Modalities
Chest radiograph:
It is the imaging backbone for diagnosis, follow up and assessment of
complications. Although chest radiographs are not as sensitive in diagnosis of
COVID-19 as compared to CT scan, it’s easily accessible, causes less radiation
exposure and is inexpensive.
Chest radiograph is reserved for moderate to severe cases of COVID-19
with the frequency of the radiograph to be decided clinically. It is done in mild
cases of COVID-19 when associated with high risk factors for severe disease such
as age >60yrs, cardiovascular disease, diabetes, immunocompromised states,
chronic liver/kidney/lung disease.
It is pertinent to mention that all precautions should be taken while taking
radiographs including correct use of PPE, covering cassette and detector with 2
layers of plastic, using separate machines for COVID and non-COVID patients
and if sufficient manpower is available, two technicians should be doing the
procedure.
Bedside portable ultrasound-POCUS (point of care USG) Advocated in
severely ill patient in ICU/RICU.
Lung ultrasound (LUS) has superior sensitivity when compared to chest
radiograph in patients with acute respiratory failure. It is more feasible, can be
quickly done at the bedside, is repeatable and reduces the possibility of cross-
infections.
As COVID-19 predominantly involves the periphery of the lung, POCUS
is an imaging method that classically allows the evaluation of the pulmonary
periphery. Also, used to monitor post COVID changes and see the progression
/regression of disease. POCUS is also used for investigating the potential vascular
complications associated with COVID infections like deep venous thrombosis of
lower limbs.
CT Chest assess the extent of involvement of lung by COVID-19, to detect
pulmonary embolism and other complications associated with the disease.
However, the use of CT for diagnosis and screening is not recommended.
One should only use as an adjunct. It should be performed judiciously with proper
protocol optimization to reduce radiation exposure to patients and appropriate
precautionary safety measures to decrease the exposure of health care workers to
COVID-19.
CT therefore is basically done in those patients whose clinical symptoms
are unexplained by combined use of Chest radiography and bedside portable

37
ultrasound / POCUS. One should be aware of the CT findings of chest in COVID
patients as the suspicious findings may be detected incidentally on CT done in
non-suspected/RT- PCR negative patients also. In centres where more than one
CT machine is available, a dedicated machine for COVID patient is ideal or a
mobile CT scanner can be used.

Assessment by imaging modalities

Chest Radiograph
The classical pattern is:
 Bilateral ground glass opacities /consolidation which show peripheral and
lower lobe predominance.
Other findings and distribution patterns seen are:
1. Peribronchial or diffuse consolidations:
2. Multifocal airspace opacities
3. Diffuse airspace opacities
4. Cavitations and collapse secondary to mucus plugs(rare).

A B

38
 C D

Fig 5.2 A CXR shows consolidation and ground glass opacities which show
peripheral and lower lobe predominance- classical pattern.
B Patchy areas of consolidations.
C Multifocal airspace opacities
D Diffuse air space opacities

Chest radiography based severity score

As per Borghesi A et al, severity scores are assigned where both lungs are
divided into 3 zones each (upper, middle, lower) and each zone is given a separate
score 0-3 (max score: 18)
 Score 0: no lung abnormalities.
 Score 1: interstitial infiltrates.
 Score 2: interstitial and alveolar infiltrates (interstitial predominance).
 Score 3: interstitial and alveolar infiltrates (alveolar predominance).

This score is known as the Brixia Score and a value of > 8 along with one
predictor factor (like increased age, immunosuppression and other co-
morbidities) increases the risk of in- hospital mortality.

39
Chest CT

a. CT imaging findings according to the stage of the disease

• Ultra-early stage : single or multiple focal GGO, pulmonary nodules
encircled by GGO, patchy consolidative opacities.
• Early stage: single or multiple GGOs, or GGO combined with interlobular
septal thickening.
• Rapid progression stage: large consolidative opacities with air
bronchograms.
• Consolidation stage : reduction in density and size of the consolidative
opacities.
• Resolution stage: Dispersed patchy consolidative opacities, reticular
opacities with interlobular septal thickening and bronchial wall
thickening.

Fig5.3 (A,B,C&D): CT images depict the ultra-early, early, rapid progression and
consolidation stages in the same patient..

Image courtesy: Wang, Y., Dong, C., Hu, Y., Li, C., Ren, Q., Zhang, X., Shi, H.
and Zhou, M., 2020. Temporal Changes of CT Findings in 90 Patients with
COVID-19 Pneumonia: A Longitudinal Study. Radiology, 296(2), pp.E55-E64.

40
 Fig 5.4 (A,B,C&D): CT images depict the early, rapid progression,
consolidation stages and resolution stages.

b. COVID-19 REPORTING AND DATA SYSTEM (CO-RADS)

CO-RADS is an assessment scheme developed to categorize non-enhanced CT

scans of patients with symptomatology of COVID-19 infection, depending on the
likelihood of such patients to be actually having COVID-19 infection and its
associated lung findings. It is based on the lines of other reporting and data
systems like BI-RADS, TI-RADS, PI-RADS, etc. Depending on the CT features,
patients are categorized into CO-RADS 0 to CO-RADS 6.

41
 Table 5.1 CO-RADS classification
Level of suspicion Summary
for pulmonary
involvement
CO-RADS 0 Not interpretable Scan technically insufficient for assigning
a score
CO-RADS 1 Very low Normal or non-infectious
CO-RADS 2 Low Typical for other infection but not
COVID-19
CO-RADS 3 Equivocal / unsure Features compatible with COVID-19, but
also other Diseases
CO-RADS 4 High Suspicious for COVID-19
CO-RADS 5 Very high Typical for COVID-19
CO-RADS 6 Proven RT-PCR positive for SARS-CoV-2

(Prokop, M., van Everdingen, W., van Rees Vellinga, T., Quarles van Ufford, H.,
Stöger, L., Beenen, L., Geurts, B., Gietema, H., Krdzalic, J., Schaefer-Prokop, C.,
van Ginneken, B. and Brink, M., 2020. CO-RADS: A Categorical CT Assessment
Scheme for Patients Suspected of Having COVID-19—Definition and Evaluation.
Radiology, 296(2), pp.E97-E104)

Figure 5.5 (A&B): CO-RADS 1: HRCT showing pulmonary edema.

(Non-infectious)

42
 A B

Fig 5.6 (A&B): CO-RADS 2: HRCT showing consolidation and centrilobular

nodules (features of other infections)

Fig 5.7 Fig 5.8 Fig 5.9

Fig 5.7 CO-RADS 3: HRCT showing few GGOs, not definitely in the typical
distribution seen in COVID-19 infection- (Equivocal / Unsure)
Fig 5.8 CO-RADS 4: HRCT showing subpleural GGOs, with RT-PCR negative
result. (Suspicious for COVID 19)
Fig 5.9 CO-RADS 5: Typical for COVID -19

CT severity score in COVID-19

The extent of lung involvement on the CT has a direct correlation with the
severity of the disease. The individual scores in each lung and the total CT
Severity scores are higher in severe COVID 19 as compared to the mild cases.
43
Visual Assessment The severity on CT can be assessed by visual assessment,
which is the easiest way to score the severity. It is done by determining the
percentage of each of the five lobes that is involved:
1. Less than 5% involvement
2. 5% to 25% involvement
3. 26% to 49% involvement
4. 50% to 75% involvement
5. More than 75% involvement
The total CT score is the sum of the individual lobar scores and can range
from 0 (no involvement) to 25 (maximum involvement). The optimal CT Severity
score threshold for identifying severe COVID 19 is 19.5 according to recent
researches (83.3% sensitivity and 94% specificity).

A B

Fig 5.10 (A&B): HRCT images show less than 5% involvement of at least 4
segments of RLL, LUL and LLL. CT Severity score 4/25.

A B C

Fig 5.11 (A,B&C): HRCT images showing more than 75% involvement of the
upper lobes with relatively less involvement of lower and middle lobes. CT
Severity score- 14/25

44
 A B

Fig 5.12 (A&B): HRCT showing extensive involvement (more than 75%) of all
the lobes. CT Severity score- 23/25

CT pulmonary angiography in COVID -19

Hypercoagulability is a common occurrence in COVID-19 patients. CT
progression and the rising D Dimer level are considered the most important
parameters suggesting underlying pulmonary thromboembolism in patients with
positive COVID-19 infection which is commonly seen during second week of
infection and alert the use of pulmonary angiography to exclude or confirm
pulmonary thromboembolism.

Imaging findings:
In acute pulmonary thromboembolism (PTE), there are central hypodense
filling defects seen in the pulmonary artery and/or it branches up to the sub-
segmental branches. Secondary to the thrombus, lung parenchymal and pleural
findings can also be seen in the form of wedge shaped peripheral based infarcts,
pleural effusions etc.

A B

Fig 5.13 (A&B): CT pulmonary angiography images showing acute thrombus

in the right and left main pulmonary arteries.

45
Conclusion
Imaging has a potentially important role in the diagnosis, severity
assessment and prognostication. The imaging modalities should be used as an
adjunct rather than as a primary diagnostic tool in suspected COVID patients.
However, the type of imaging modality and the frequency at which it is carried
out should solely be determined on the clinical picture. Care should be taken to
follow proper COVID appropriate behavior and disinfection protocols to avoid
cross infection to the healthcare workers and other patients.

Suggested Reading

1. IRIA COVID-19 Imaging recommendations.

2. RSNA-Use of Chest Imaging in the Diagnosis and Management of COVID-
19: A WHO Rapid Advice Guide.
3. RSNA- Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR.
4. Ahmad W, Ahmad U. Role of radiology in COVID-19 pandemic and post
COVID-19 potential effects on radiology practices. Indian J Radiol Imaging.
2021; 31(Suppl 1):S196-S197.
5. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing
for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014
Cases. Radiology. 2020; 296(2):E32-E40.
6. Vieira, A.L.S., PazeliJúnior, J.M. & Bastos, M.G. Role of point-of-care
ultrasound during the COVID-19 pandemic: our recommendations in the
management of dialytic patients. UltrasoundJ .2020; 12: 30. https://doi.org
/10.1186/s13089-020-00177-4.

46
6. Management of Mild COVID-19

Wg Cdr Rohit Vashisht, Brig AS Menon, Col Y Uday, Col AT Atal

Clinical Features

COVID-19 has variable signs and symptoms. Majority of patients present

with fever, dry cough, fatigue, loss of appetite, breathlessness and myalgias. The
presence of anosmia and ageusia preceding respiratory symptoms has been
increasingly reported. These symptoms, in the background of an ongoing
pandemic, call for a heightened suspicion of COVID-19. Occasionally, patients
present with sore throat, coryza, loose motions and headache. Elderly may have
a blunted febrile response, with fatigue, reduced alertness, gastro-intestinal
symptoms and delirium, leading to a delayed diagnosis.

Mild COVID19

The WHO defines mild disease as a patient meeting the case definition for
COVID-19 with no hypoxia or shortness of breath. The oxygen saturation (SpO2)
needs to be greater than 94% on room air. While the disease course is variable
and difficult to predict, mild disease with a self-limited course in seen in 80-85%
of patients. This figure is likely to be higher in a vaccinated population.

Vulnerable population

A subset of population have higher risk of progression to moderate or

severe disease with higher morbidity and mortality. These include the elderly,
obese, those with diabetes, hypertension, coronary artery disease, cerebro-
vascular disease, chronic kidney disease, chronic obstructive pulmonary disease
and those on immunosuppressive drugs.

Red flag signs

These signs need to be diligently looked out for, and indicate worsening
disease and progression to moderate or severe category. They include resting
tachycardia, desaturation (SpO2 < 94% on room air), fall in saturation of 3
percent or more after a 6 minute walk test, and, a neutrophil lymphocyte ratio

47
greater than 3.5. Immediate medical attention should be sought if a patient with
mild disease desaturates, complains of dyspnoea or chest pain, shows signs of
mental confusion or poor arousability, has cyanosis or oliguria and, has high
grade fever or cough persisting for five days or more.

Management

Majority (80-85%) of patients have a swift recovery without long term

sequelae. Management rests on providing symptomatic relief. Routine blood and
radiology investigations are not advised as they do not alter the course of disease
or treatment. Evaluation of comorbid conditions may be carried out if deemed
necessary. There is evidence of coinfection with Dengue, Malaria and other
seasonal outbreaks in patients with COVID19. Investigations to rule these out
should be performed when deemed necessary.

Isolation: This is the cornerstone of management of mild cases. It ensures

physical distancing, thus breaking the chain of transmission. A paradigm shift
seen during the second wave was the shift to home isolation as against the practice
of institutional isolation. This was done to take the load off an overburdened
health care system. The patient should be in a well ventilated separate room or
isolated space. In the absence of such a facility, institutional isolation is advised.

Non pharmacological intervention: The patient should practice hand hygiene,

use separate utensils and bedding and should be able to clean and disinfect
touched surfaces. A household member should be identified as a caregiver
(preferably be vaccinated and not at high risk). The caregiver must wear N-95
mask and should be well versed with practice of hand hygiene and be able to
monitor patient for any features of deterioration. Institutional isolation should be
recommended where there is no caregiver, or patient is incapable of supporting
himself or herself without assistance.

Adequate rest, nutrition and hydration are essential. Temperature and SpO2
monitoring is to be done daily and noted by the caregiver. Management of any
comorbidity is paramount and existing medication should be continued with
special emphasis on blood sugar control.

48
Symptomatic treatment: This includes warm water gargles and steam inhalation
while guarding against overzealous use which may damage mucosa. Tablet
Paracetamol may be taken in a dose of 500-650 mg QID for fever or headache.
Naproxen at a dose of 250 mg twice a day may be given in case fever persists
beyond day 5.In patients with coryza or troublesome cough, the use of cetirizine
10 mg OD or anti-tussive cough syrup is advised.

Antiviral drugs

Nirmatrelvir plus Ritonavir (Paxlovid): Nirmatrelvir is an orally administered

antiviral agent targeting the SARS CoV-2, 3-chymotrypsin–like cysteine protease
enzyme, preventing cleavage of the viral polyprotein which is required for viral
proteins to become functional. Adding a low dose of Ritonavir, a CYP3A4
inhibitor, enhances pharmacokinetics of Nirmatrelvir. Symptomatic,
unvaccinated, non-hospitalized adults at high risk for progression to severe
COVID-19 were assigned in a 1:1 ratio to receive either Nirmatrelvir (300 mg)
plus Ritonavir (100 mg) or placebo every 12 hours for 5 days. There was a relative
risk reduction of 89 % of COVID 19 related hospitalization or death at 28 days
of follow up. The most frequent adverse events in recipients of Nirmatrelvir plus
Ritonavir were dysgeusia, diarrhea, and vomiting. In individuals at high risk of
hospitalisation WHO has given a strong recommendation for its use as soon as
possible after onset of symptoms, ideally within 5 days. Dose reduction in renal
insufficiency (GFR 30–59 mL/min) is 150 mg of Nirmatrelvir and 100 mg of
Ritonavir twice a day. It is not recommended for breastfeeding or pregnant
women and children. Potential drug interactions with those metabolized by
CYP3A4 should be considered while initiating therapy. Nirmatrelvir –Ritonavir
combination has greater efficacy in preventing hospitalization and less adverse
effect than the current alternatives.

Remdesivir: Remdesivir is a nucleotide prodrug of an adenosine analog. It binds

to the viral RNA-dependent RNA polymerase and inhibits viral replication by
terminating RNA transcription prematurely. PINETREE investigators conducted
a placebo-controlled trial involving non hospitalized patients with COVID-19
who had symptom onset within the previous seven days and who had at least one
risk factor for disease progression (age ≥60 years, obesity, or certain coexisting
medical conditions).The intervention arm was given intravenous Remdesivir
(200 mg on day 1 and 100 mg on days 2 and 3). Three day course of Remdesivir
resulted in an 87% lower risk of hospitalization or death compared to placebo
49
when assessed at day 28. WHO has given a conditional recommendation for its
use in non-hypoxemic high-risk patients within seven days of onset of symptoms.
Remdesivir can cause gastrointestinal symptoms (e.g., nausea), elevated
transaminase levels, hypersensitivity reactions and an increase in prothrombin
time without a change in the international normalized ratio.

Molnupiravir: Molnupiravir is a nucleoside analogue, which inhibits viral

replication by mutagenesis. In MOVe-OUT Phase 3 RCT Molnupiravir was
started within five days after the onset of signs or symptoms in non-hospitalized,
unvaccinated adults with mild-to-moderate COVID. The risk for hospitalization
or death anytime until day 29 was lower with Molnupiravir (6.8 %) as compared
to placebo (9.7 %) Patients with evidence of previous SARS-CoV-2 infection,
low baseline viral load and diabetes did not benefit from the drug.US FDA has
given emergency use authorization (EUA) for Molnupiravir. It should be started
within five days of symptom onset and given as 800 mg twice daily for 5 days.
Molnupiravir should not be offered to patients less than 18 years of age,
breastfeeding or pregnant women. Men should be advised about the potential for
temporary genotoxic effect on sperm cell production. No data are currently
available demonstrating activity against the Omicron variants

Monoclonal Antibodies:
Monoclonal antibodies (MAbs) like Casirivimab plus Imdevimab, Bamlanivimab
plus Etesevimab received emergency use authorization (EUA) from US FDA for
use in mild to moderate COVID 19. This was based on findings in trials that
showed MAbs reduced the risk of hospitalization and death in patients with mild
to moderate disease and at high risk factors for disease progression. Due to lack
of in vitro neutralization activity against the Omicron and its subvariants current
WHO guidelines strongly recommend against their use for all patients with
COVID 19. Sotrovimab is active against the Omicron BA.1 and BA.1.1
subvariants, but it has substantially decreased in vitro neutralization activity
against the Omicron BA.2, BA.4, and BA.5 subvariants.

Bebtelovimab: Bebtelovimab is a recombinant neutralizing human MAb that

binds to the spike protein of SARS-CoV-2. In vitro neutralization studies have
shown Bebtelovimab to be effective against Omicron and all its subvariants. CDC
recommends use of Bebtelovimab for non-hospitalized adults aged ≥18 years
with mild to moderate COVID-19 who are at high risk of progressing to severe

50
disease. The panel recommends using Bebtelovimab 175 mg intravenous (IV)
injection as an alternative therapy based on in vitro studies and efficacy data of
Phase 2 trials ONLY when both Ritonavir-boosted Nirmatrelvir (Paxlovid) and
Remdesivir are not available, feasible to use, or clinically appropriate.

Ivermectin: Ivermectin is a semisynthetic anti-helminthic agent and has been

found to bind with Importin α/β1 heterodimer restricting entry of virus into the
nucleus. In vitro data first supported its use in COVID-19. Trials from
Bangladesh, Iran and India have shown reduction in mortality, intubation rate and
requirement of mechanical ventilation. This led to its inclusion in
MoHFW/AIIMS guidelines in 2020 as ‘may do’ drug therapy in mild COVID-
19. It was recommended at a dose of 200 mcg/kg once daily for 3 days. Currently,
there is a weak or conditional recommendations from WHO against use of
Ivermectin in high risk mild COVID and to be used only in the context of a
clinical trial or research settings. If oral steroids are used in the treatment of
COVID-19, empiric treatment with Ivermectin may still be considered in areas
where Strongyloidiasis is endemic, albeit not for treatment of COVID-19.

Fluvoxamine: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI)

that is approved by the Food and Drug Administration (FDA) for the treatment
of obsessive-compulsive disorder and is used for other conditions, including
depression. In murine models and human endothelial cell culture use of
Fluvoxamine resulted in reduced production of inflammatory markers.
TOGETHER was a RCT conducted in Brazil, which compared oral Fluvoxamine
100 mg twice a day versus placebo in patients who were SARS CoV2, considered
at high risk. Results showed decreased risk of hospitalization, however no benefit
was observed on incidence of mechanical ventilation or mortality. WHO
guidelines recommends its use only in research settings.

Omicron variant
On Nov 25, 2021, about 23 months since the first reported case of COVID-
19 a new SARS-CoV-2 variant of concern Omicron (B.1.1.529) was reported.
Since then the Omicron variant of concern (VOC) has become the dominant
SARS-CoV-2 variant the world over. Omicron has been divided into five distinct
sub lineages: BA.1, BA.2, BA.3, BA.4, and BA.5.1. Most circulating Omicron
variants belong to sub lineage BA.2; however, the prevalence of BA.2.12.1 (a
subvariant of BA.2), BA.4, and BA.5 is increasing rapidly in several regions of

51
the world. The trials using antiviral drugs have been conducted on variants of
SARS CoV-2 prior to emergence of Omicron. Neutralization studies however
suggest that the Remdesivir, Molnupiravir, Nirmatrelvir and Bebtelovimab have
therapeutic value against the sub lineages BA.2.12.1, BA.4, and BA.5.

Conclusion
Majority of patients not at risk for hospitalization do well with symptomatic
treatment. Currently recommended therapies are best suited for patients
considered vulnerable and with high risk of hospitalisation

Table 6.1 WHO recommendations for use of drugs in Non-Severe COVID

Recommendations Intervention
Strong recommendations in favour Nirmatrelvir and Ritonavir
Weak or conditional Molnupiravir, Remdesivir, Sotrovimab
recommendations in favour
Weak or conditional Corticosteroids, Ivermectin,
recommendation against Fluvoxamine
Strong recommendation against Convalescent plasma, Colchicine,
Hydroxychloroquine, Lopinavir-
Ritonavir

Suggested Reading

1. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J et al. Clinical characteristics of

Coronavirus disease 2019 in China. N Engl J Med 2020; 382:1708-20.
2. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of Coronavirus
Disease 2019 (COVID-19) from publicly reported confirmed cases:
Estimation and application. Ann Int Med 2020;172(9):577-82
3. Clinical Management Protocol for COVID-19 (In Adults). Government of
India, Ministry of Health and Family Welfare. Version 6, 24.05.21.
4. https://www.COVID19treatmentguidelines.nih.gov/therapies/(last accessed
on 28 Sep 2022)
5. Therapeutics and COVID-19. Living Guideline July 2022. World Health
Organisation.

52
6. www.dghs.gov.in › WriteReadData › News › 202104290258250563281Sy.
7. Hammond J, Heidi Leister‑Tebbe H, Gardner A, Abreu P, Bao W,
Wisemandle W et al. (EPIC-HR Investigators).Oral Nirmatrelvir for High-
Risk, Nonhospitalized Adults with COVID-19.N Engl J Med
2022;386:1397-408
8. Jayk Bernal A, Gomes da Silva MM, Musungaie D B, Kovalchuk E,
Gonzalez A, Delos Reyes V et al. (MOVe-OUT Study Group ) Molnupiravir
for Oral Treatment of COVID-19 in Nonhospitalized Patients . N Engl J
Med 2022; 386:509-20.
9. Gottlieb R L, Vaca C E, Paredes R, Mera J, Webb B J, Perez G.et al
(PINETREE) Investigators. Early Remdesivir to Prevent Progression to
Severe COVID-19 in Outpatients. N Engl J Med 2022; 386:305-315
10. Takashita E, Yamayoshi S, Simon V, van Bakel H, Sordillo E M, Pekosz A
et al (Letter to Editor) .Efficacy of Antibodies and Antiviral Drugs against
Omicron BA.2.12.1,BA.4, and BA.5 Subvariants (DOI:
10.1056/NEJMc2207519)
11. Gilmar Reis, Eduardo Augusto dos Santos Moreira-Silva, Daniela Carla
Medeiros Silva, Lehana Thabane, Aline Cruz Milagres et al(TOGETHER
investigators). Effect of early treatment with Fluvoxamine on risk of
emergency care and hospitalisation among patients with COVID-19: the
TOGETHER randomised, platform clinical trial. Lancet Glob Health 2022;
10: e42–51

53
7. Management of Moderate and Severe COVID

Col Vikas Marwah SM, Maj Deepu K Peter, Surg Lt Cdr Shrinath V

Introduction

COVID 19 has a diverse presentation with 81% having mild disease, 14%
develops severe form of disease and 5% will progress to have critical disease.
Past two years have seen a huge increase in data regarding this novel disease,
diagnostics and its therapy. Many of the currently accepted treatment protocols
are based on outcomes of large international multicentre randomised control trials
(RCT’s) such as RECOVERY, WHO SOLIDARITY, REMAP-CAP, ACTIV,
COV-BARRIER and ACTT2. This chapter aims at an evidence-based approach
to management of moderate to severe COVID-19 based on various international
and national recommendation.

Approach to a case of hospitalized patient with COVID-19

The management protocols of COVID-19 are evolving. Various clinical

trials are ongoing and patients are being recruited continuously in these trials.
Mortality benefit has been suggested with the use of steroids, Tocilizumab, and
Baricitinib. Remdesivir has also been found to offer some clinical benefit. It has
been emphasized in the various trials/studies that these drugs are beneficial in
only patients with moderate/severe disease. Hence, it is pivotal to assess the
disease severity when a patient is admitted with COVID-19.

Moderate COVID Severe COVID

Pneumonia with Pneumonia with
- Respiratory rate ≥ 24/min - Respiratory rate > 30/min
- SpO2 ≥ 90% to < 94% - SpO2 <90% on room air
- No features of severe disease - Accessory muscle use,
inability to complete full
sentence

54
Risk factors associated with severe disease are as follows:
1. Age more than 60 years.
2. Underlying non-communicable diseases (NCDs): diabetes, hypertension,
cardiac disease, chronic lung disease, cerebrovascular disease, dementia,
mental disorders, chronic kidney disease.
3. Immunosuppression, obesity and cancer.
4. Pregnancy- increasing maternal age, high BMI, chronic conditions and
pregnancy specific conditions such as gestational diabetes and pre-
eclampsia.
5. Smoking

Pharmacotherapy

a) Systemic corticosteroids
Multiple RCT’s have shown benefit of glucocorticoids in severe COVID-
19. Most of the efficacy data comes from the RECOVERY trial, an open labelled
RCT that showed a 28-day mortality benefit with intravenous or oral
dexamethasone among hospitalized patients. The RECOVERY trial used Inj
Dexamethasone 6 mg IV daily for up to 10 days. The total duration of regimens
evaluated in the seven other RCT’s have varied between 5 and 14 days. WHO
has strongly recommended the use of steroids for COVID-19 patients having
oxygen requirement or requiring ventilatory support. It should ideally be given
for 10 days or until discharge, whichever is shorter. In case of non-availability of
Dexamethasone, other glucocorticoids can be given at equivalent doses; however,
the data on their efficacy is limited to certain small trials. Patients on
glucocorticoids should be monitored for hyperglycemia and are at an increased
risk of infections.

b) IL- 6 pathway inhibitors

IL-6 is a cytokine, which activates and regulates the immune response to
infections. Although role of IL6 in COVID disease pathogenesis is unclear, it has
been well established that elevated IL-6 concentrations are associated with severe
outcomes in COVID-19, including respiratory failure and death.

Tocilizumab and Sarilumab are monoclonal antibodies approved for use in

rheumatoid arthritis which antagonize the membrane bound and soluble forms of
the IL-6 receptor. These IL-6 inhibitors are refurbished for use in COVID-19.

55
WHO strongly recommends the use of IL6 receptor blocker for severe COVID-
19. There is high certainty evidence that they reduce mortality and need for
mechanical ventilation. Low certainty evidence suggest that they may reduce
duration of mechanical ventilation and hospital admission. They are administered
along with corticosteroids.

Patients with severe COVID, who are progressing despite initiation of

steroids and has markedly elevated inflammatory markers (CRP ≥ 75 mg/L),
should be given a single dose of intravenous tocilizumab at 8 mg/kg (maximum
dose 800mg) over 1 hour. WHO has also recommended that a second dose may
be administered 12 to 48hrs after the first dose as per discretion of treating
physician if clinical response is inadequate. All patients should be monitored for
signs and symptoms of infection.

c) Janus Kinase (JAK) inhibitors

JAK inhibitors prevent phosphorylation of proteins, which are involved in
signal transduction, which leads to immune activation and inflammation.
Baricitinib and Tofacitinib are JAK inhibitors, which are used for
immunomodulatory effect in treatment of rheumatoid arthritis. WHO has strongly
recommended the use of Baricitinib as an alternative to IL6 receptor blocker in
severe COVID-19. Baricitinib has been shown to reduce mortality, duration of
hospitalization and mechanical ventilation. Baricitinib and Tocilizumab should
not be given together due to risk of severe immune suppression. There are no
head-to-head trials comparing Baricitinib and Tocilizumab. The selection
between the two should be based on availability, cost, route of administration and
physicians experience with the drug. It is an oral tablet and taken 4 mg once daily
for 14 days in adults with eGFR ≥ 60 mL/min/1.73 m2. Dose adjustment is
required in patients with leukopenia, renal or hepatic impairment and patients
taking strong organic anion transporter 3 inhibitors (e.g. Probenecid). WHO has
made a conditional recommendation against Tofacitinib due to adverse effects
and uncertain mortality benefit.

d) Remdesivir
Remdesivir is a novel nucleotide analogue prodrug, which is metabolized
to an active tri-phosphate form that inhibits viral RNA synthesis. It has in vitro
and in vivo anti-viral activity against several viruses, including SARS-CoV-2.
Final result of WHO solidarity trial and meta-analysis have shown that

56
Remdesivir has mortality benefit and reduces the duration of hospital stay in
patients with low flow oxygen requirement. In patients with high flow oxygen
requirement, even though there is no mortality benefit, Remdesivir reduces the
duration of hospital admission. In mechanically ventilated patients, Remdesivir
has been shown to have no mortality benefit and does not reduce the duration of
mechanical ventilation. A subgroup analysis of the data indicated that Remdesivir
treatment possibly increased mortality in the critically ill and possibly reduced
mortality in the non-severely and severely ill. ICMR and CDC guidelines
recommend use of Remdesivir for treatment of hospitalized patients with
moderate to severe COVID-19 who are within 10 days of onset of symptom.
Adults and pediatric patients 12 years of age and older and weighing at least 40
kg are recommended a single loading dose of Inj Remdesivir 200 mg on Day 1
followed by once-daily maintenance doses of 100 mg from Day 2 infused over
30 to 120 minutes from day 2-5. Its use is contraindicated in those with liver
(ALT > 5 times normal at baseline) or renal (eGFR < 30 mL/minute) dysfunction
and in critical COVID-19.

e) Monoclonal antibodies
Monoclonal antibodies (see previous chapter) bind to the SARS-CoV-2
spike protein and prevent the viral entry into the human cell. WHO has given
conditional recommendation for use of Sotrovimab and Casirivimab-Imdevimab
for outpatient patients with high risk of disease progression. The use of
monoclonal antibodies in hospitalized patients has shown mixed benefit and
requires further validation.

f) COVID convalescent plasma (CCP)

It was hypothesized that CCP would be beneficial in COVID-19 and was
used as an adjunct in the initial phase of the pandemic. Janiaud et al in a
systematic review and meta-analysis showed that CCP with high neutralizing
antibody titers might be effective when administered early in the course of disease
especially in individuals with deficit antibody production. However, there was no
reduction in all-cause mortality. PLACID trial conducted on 464 patients with
PaO2/FiO2 ratio 200-300 concluded that convalescent plasma in moderate
COVID-19 failed to prevent progression to severe disease. Based on these data,
CCP is presently not recommended for treatment on COVID-19.

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Management Protocol for Moderate and Severe COVID-19

All patients with moderate COVID-19 should be admitted in designated

COVID wards. They should be evaluated for features suggestive of severe illness
as early identification and implementation of therapy is key to the successful
management of COVID-19. They should be closely monitored for signs or
symptoms of disease progression.

On admission, complete blood counts with differential, metabolic panel,

C-reactive protein, coagulogram including D-dimer should also be performed.
These investigations should be repeated every 48 hrs or daily if the patient is in
ICU. Initial chest radiograph should be performed and it can be repeated daily in
case of severe and critical COVID-19 pneumonia patients. Chest CT should
ideally be reserved for patients where it would help change clinical management
like when there is deterioration and a pulmonary thromboembolism is suspected.
Serum IL 6 levels to be done if there is clinical deterioration. Patients should
also be screened for endemic causes of febrile illness.

Bacterial infection is an infrequent occurrence despite the use of extensive

immunosuppression. However, if secondary bacterial pneumonia is suspected in
view of clinical worsening, sputum gram stain and culture and two sets of blood
cultures are warranted. Serum procalcitonin levels can also be helpful however
they tend to rise along with progression of COVID-19 disease and levels should
be correlated clinically.

Daily ECG monitoring should be performed in patients with severe disease

to monitor ischemic changes, viral myocarditis or pulmonary embolism. Cardiac
enzymes may be measured if there is suspicion of cardiac ischemia, myocarditis
or heart failure. Closely monitor patients for complications like ARDS, acute
liver injury, acute kidney injury, acute cardiac injury, viral myocarditis, sepsis,
disseminated intravascular coagulation (DIC) and shock.

Oxygen:
Supplemental oxygen therapy to target SpO2 ≥ 94% in any patient with
emergency signs (obstructed or absent breathing, severe respiratory distress,
central cyanosis, shock, coma and/or convulsions) and target SpO2 >90% or ≥
92–95% in pregnant women if there are no red flag signs. Details of Oxygen

58
therapy, non-invasive and invasive mechanical ventilation are discussed in
subsequent chapter.

Anticoagulation

In the absence of contraindication or high risk of bleeding, all patients of

COVID 19 must be initiated on prophylactic pharmacologic anticoagulation
using unfractionated heparin or low molecular weight heparin (see chapter on
Oxygen therapy).

Antibiotics

WHO recommends against the use of routine antibiotics in COVID-19

unless there is evidence of bacterial infection. This comes in the wake of systemic
review evidence that only 8% of patients admitted with moderate COVID-19
pneumonia had concurrent bacterial infection. Patients with advanced age and
children <5 yrs may be provided with an empirical antibiotic cover.

Anti-inflammatory or immunomodulatory therapy

All patients with moderate and severe COVID-19 should be initiated on

glucocorticoids (Inj Methylprednisolone 0.5 to 1 mg/kg in two divided doses or
an equivalent dose of dexamethasone) for a duration of 5 to 10 days. Patient may
be switched to oral route if stable and improving.

Specific therapy for Moderate disease (Pneumonia with no signs of severe

disease)

At this stage of the disease, there is no role for steroids and remdesivir as
the patient is not hypoxic. This is based on studies which have shown that
remdesivir may reduce time to recovery and that steroids at this stage may cause
more harm than good and offers no mortality benefit. There is no role of other
immunomodulators (Tocilizumab, Baricitinib, Tofacitinib) at this stage of
disease.

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Severe disease with low flow supplemental oxygen requirement

When a COVID-19 patient develops oxygen requirement prompt anti-

inflammatory therapy in the form of steroids should be started. If patient is within
first 10 days of symptom onset, Remdesivir can also be administered.
RECOVERY trial has shown significant benefit of steroids in patients with
oxygen or invasive ventilation.

When a patient is on oxygen therapy, evaluation should also be done to

assess the level of inflammation. CRP levels more than 75mg/L with escalating
oxygen requirements should also prompt addition of other anti-inflammatory
therapy like Baricitinib or Tocilizumab. The decision on which drug to be started
should be made on a case-to-case basis. Studies have shown that addition of
Baricitinib or Tocilizumab to steroids can reduce mortality.

Critical COVID 19

Monitor all patients with severe COVID 19 for the development of critical
disease. For adults and children with mild ARDS, a trial of HFNC and/or NIV
can be given. All patients who are initiated on HFNC and NIV should be
monitored using ROX index and HACOR score to detect HFNC/NIV failure
under which conditions early elective intubation should be done.

For adults and children with moderate to severe ARDS requiring invasive
mechanical ventilation, ventilatory strategy should be that of conventional ARDS
ventilation as per ARDSnet. The findings of PROSEVA trial may be extrapolated
for COVID ARDS wherein there can be mortality benefit (inadequate data for
COVID ARDS) by early proning and ventilating patients who have a PaO2/FiO2
ratio < 150 when on a PEEP of at least 5 cm of H2O and FiO2 of 100%. Proning
should be given for 16-18 hrs a day. Detailed description of non-invasive and
invasive ventilatory strategy discussed in detail in subsequent chapter.

COVID specific therapy in Critical COVID-19

All patients with critical COVID-19 should be on steroids, anticoagulation

and antibiotics. Inflammatory parameters should be analyzed in these patients and
if there are features of hyper-inflammation, Baricitinib or Tocilizumab should be
instituted. Baricitinib or Tocilizumab should also be initiated in situations where
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patient requires ICU care and markers of inflammation are not available. This is
as per the evidence, which has shown that Baricitinib or Tocilizumab when added
to regimen containing steroids has proven mortality benefit. Antivirals like
remdesivir should not be routinely used in critically ill patients.

Management of Comorbidities

Patients who have comorbidities are at increased risk of developing severe

COVID-19. These patients constitute the bulk ICU admission and has a higher
mortality risk. The cytokine storm associated with severe and critical COVID as
well as the treatment imparted (e.g. corticosteroids) tend to worsen these
underlying comorbidities. Therefore, it is very much important to manage these
comorbidities along with the COVID-19.

Diabetes mellitus

COVID patients with diabetes are at high risk of developing severe disease.
Acute hyperglycaemia and glucose variability causes oxidative stress and can
cause cytokine release adding on to the cytokine storm syndrome of COVID-19.
Hypoglycaemia on the other hand also possess a high mortality risk to patient.
Corticosteroids, which are proven beneficial in COVID-19, are known to worsen
glycaemic control. Hyperglycaemia has also been proven to decrease the
effectiveness of Tocilizumab. In hospitalised patients with acute illness, oral
diabetic agents are contraindicated. SGLT2 inhibitors are associated with
increased risk of dehydration and volume contraction. Metformin causes
increased risk of lactic acidosis. GLP-1 receptor agonists often cause nausea and
are avoided in the acute care setting. All patients with known diabetes mellitus
and those with steroid induced deranged glucose levels should be managed with
a basal long-acting insulin (started at 0.2–0.3 units/kg/day and a prandial short
acting insulin (started at 0.05–0.1 units/kg/day). The dose should be titrated to
achieve the desired glycaemic target of 140–180 mg/dl for hospitalised patients.
In patients with very high glucose levels (more than 250 mg/dl), urine ketones
and arterial blood gas levels to look for metabolic acidosis should be done.
Diabetic ketoacidosis should be managed with insulin infusion (there are
recommendations suggesting the use of subcutaneous insulin in mild to moderate
DKA), and fluids (though high volume of IV fluids should be avoided as it can
worsen ARDS)

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Hypertension

Hypertension is a risk factor for development of severe disease in COVID

19. Patients receiving angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs) should continue treatment with these
agents (unless there is an indication for discontinuation such as hyperkalaemia or
hypotension). There is no evidence that stopping ACE inhibitors or ARBs reduces
the severity of COVID-19. Study of 740 hypertensive adults hospitalized for mild
or moderate COVID-19 showed that compared with those assigned to discontinue
ACE/ARB therapy, those who continued taking an ACE inhibitor or ARB had
statistically similar 30-day mortality and need for mechanical ventilation.

Kidney disease

Patients with chronic kidney disease are at increased risk of severe disease
and has increased mortality risk. Remdesivir is contraindicated in patients with
eGFR < 30 ml/min. Renal dose modification should be done for all other
supportive medications, which have renal route of excretion. CKD patients who
are on dialysis must be admitted in centres equipped with dialysis facility.
Separate negative pressure dialysis rooms to be arranged for such patients for
haemodialysis. Continuous renal replacement therapy is the preferred mode of
dialysis for critical ICU patients. All patients should be monitored for
development of acute kidney injury, which can be due to cytokines storm during
COVID, sepsis, or ventilator induced alveolar hyperinflation causing cytokine
release. Patients with AKI requiring renal replacement therapy should be
managed with haemodialysis or CRRT. Differences in management of AKI
among patients with COVID-19 is the limited use of intravenous fluids. Fluid
resuscitation should be individualized and based on trackable objective measures
like inferior vena cava collapse on ultrasound.

Cardiac diseases

ECG, troponins, serial CKMB should be used to monitor severe and critical
COVID patients suspected of having cardiac diseases. A high index of suspicion
should be kept for diagnosis of viral myocarditis, which can pose a high mortality
risk. All patients with unexplained tachycardia and cardiogenic shock should be
evaluated for viral myocarditis using cardiac enzymes and 2D ECHO. Patients

62
should also be monitored using ECG for signs of pulmonary thromboembolism,
like sinus tachycardia, right heart strain, new onset right bundle branch block,
S1Q3T3. Patients who are suspected to have pulmonary thromboembolism
should be confirmed using CT pulmonary angiography if hemodynamically
stable and can be shifted for CT or with bed side 2D ECHO and d-dimer levels if
deemed unstable to be shifted for CTPA. Statins and aspirin can be continued in
patients with severe COVID along with heparin therapy. Clopidogrel can be
discontinued in patients who are already on heparin and aspirin due to high risk
of bleeding especially in those with a moderate to high risk as per HAS-BLED
score.

Rheumatological diseases

Adjustments to medication regimens in patients with documented or

presumptive COVID-19 should be individualized with specific attention to the
severity of the infection. Temporarily discontinuing of DMARDS and biologic
agents (e.g., anti-TNF inhibitors, IL-6 receptor inhibitors), and JAK inhibitors
should be done during the period of active infection. However, in cases where
patients have active or organ threatening rheumatic disease, continuation of their
immunosuppressive therapy may be required based upon an individualized
assessment and rheumatological consultation. In patients with severe respiratory,
cardiac, or kidney involvement, NSAIDs should be discontinued. Patients treated
with glucocorticoids should maintain the same dose to avoid acute rheumatic
disease flare and the complications of adrenal insufficiency associated with
abrupt discontinuation.

PPE and Health Care Workers

Personal protective equipment (PPE) is part of infection control in COVID

19. They help to reduce infection transmission to healthcare workers who are
working for prolonged hours in high-risk aerosol generating conditions. PPE
include gloves, gown, N95 face mask and eye protection. HCWs should pay
special attention to the appropriate sequence of putting on and taking off PPE as
incorrect handling of PPE is common, even by trained clinicians, and are
associated with contamination of HCWs with pathogens. In a Cochrane review
that evaluated methods to increase compliance with donning and doffing of PPE,
several interventions appeared to have some benefit in preventing contamination,

63
including the use of CDC protocols and face-to-face training. The CDC suggests
that masks can be used for 8 to 12 hours whereas the WHO suggest use up to six
hours when caring for patients with COVID-19. The CDC states reuse of N95
respirators should be limited to no more than five uses (i.e., five donnings) per
device by the same HCW, unless otherwise specified by the manufacturer. The
WHO has issued caution regarding the potential for transmission of drug-resistant
pathogens from reuse of PPE. If strategies are needed to conserve supplies of PPE
in the setting of severe shortages, the CDC and WHO have highlighted several
methods for decontamination of respirators which include UV light, hydrogen
peroxide vapor and moist heat.

Suggested Reading

1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics

of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected
Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061–9.
2. Dexamethasone in Hospitalized Patients with COVID-19. N Engl J Med.
2020 Jul 17;384(8):693–704.
3. A Neutralizing Monoclonal Antibody for Hospitalized Patients with
COVID-19. N Engl J Med. 2020 Dec 22;384(10):905–14.
4. Investigators R-C, Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM,
Nichol AD, et al. Interleukin-6 Receptor Antagonists in Critically Ill
Patients with COVID-19. N Engl J Med. 2021/02/25. 2021 Apr
22;384(16):1491–502.
5. Therapeutics and COVID-19: living guideline [Internet]. [cited 2021 Aug
3]. Available from: https://www.who.int/publications/i/item/WHO-2019-
nCoV-therapeutics-2021.2 (last visited 13 Aug 2021)
6. Marconi VC, Ramanan A V., Bono S de, Kartman CE, Krishnan V, Liao R,
et al. Baricitinib plus Standard of Care for Hospitalized Adults with
COVID-19. medRxiv. 2021 May 3;2021.04.30.21255934.
7. Repurposed Antiviral Drugs for COVID-19 — Interim WHO Solidarity
Trial Results. N Engl J Med. 2021 Feb 11;384(6):497–511.
8. Group RC, Horby PW, Mafham M, Peto L, Campbell M, Pessoa-Amorim
G, et al. Casirivimab and imdevimab in patients admitted to hospital with
COVID-19 (RECOVERY): a randomised, controlled, open-label, platform
trial. medRxiv. 2021 Jun 16;2021.06.15.21258542.
9. Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M, et al.

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 Association of Convalescent Plasma Treatment With Clinical Outcomes in
Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA.
2021 Mar 23;325(12):1185–95.
10. Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra
P. Convalescent plasma in the management of moderate COVID-19 in
adults in India: Open label phase II multicentre randomised controlled trial
(PLACID Trial). BMJ. 2020;371.
11. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics
of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected
Pneumonia in Wuhan, China. JAMA - J Am Med Assoc. 2020;
323(11):1061–9.
12. Guérin C, Reignier J, Richard J-C, Beuret P, Gacouin A, Boulain T, et al.
Prone Positioning in Severe Acute Respiratory Distress Syndrome. N Engl
J Med. 2013;368(23):2159–68.
13. Verbeek JH, Rajamaki B, Ijaz S, Sauni R, Toomey E, Blackwood B, et al.
Personal protective equipment for preventing highly infectious diseases due
to exposure to contaminated body fluids in healthcare staff. Cochrane
database Syst Rev. 2020 ;4(4):CD011621–CD011621.
14. WHO Solidarity Trial Consortium. Remdesivir and three other drugs for
hospitalised patients with COVID-19: final results of the WHO Solidarity
randomised trial and updated meta-analyses. The Lancet. 2022 May 2.

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 8. Oxygen Therapy, Ventilation and ICU management

Brig Rangraj Setlur, Col Kiran Sheshadri, Col Nikahat Jahan

Introduction

The COVID 19 pandemic has reminded us just how important Oxygen is

for life. COVID pneumonia can cause mild to severe hypoxemia and respiratory
distress requiring oxygen therapy, ventilatory support and critical care
management of the patient. Some patients with hypoxemia can seem comfortable
even when their oxygen levels are dangerously low. This ‘Happy hypoxia’ can
mislead caregivers into believing that the patient is not very sick. Monitoring of
SpO2 and PaO2 on arterial blood gas analysis in these situations gives a more
accurate picture than the clinical appearance. There are several modes of oxygen
support such as nasal prongs, Hudson’s mask, non-rebreathing mask (NRBM),
Venturi mask and High Flow Nasal Oxygen (HFNO). When these fail to bring
up the oxygen saturation, we proceed to mechanical ventilatory support which
could be Noninvasive or Invasive. If ventilatory support also fails, Extracorporeal
Membrane Oxygenation (ECMO) can be considered.

Oxygen Therapy

When and how should oxygen be given?

Oxygen is a drug with specific indications, methods of delivery and targets.

A prescription for oxygen should reflect all these features. For instance, an
adequate prescription for a COVID pneumonia patient with mild hypoxemia in
the ward would be “Oxygen at 6 litres per minute to be given by nasal cannula
and titrated to an oxygen saturation of 92-94%. Remove when the patient is
maintaining a saturation of greater than 90 % on room air.”

Let us consider the indications, the methods of delivery and the targets in
sequence.

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Indications for oxygen delivery

Oxygen supplementation is indicated in COVID patients with hypoxemia;

there is no benefit of giving oxygen prophylactically. Hypoxemia is a low arterial
oxygen tension below the normal expected value of (85-100 mmHg). The British
Thoracic Society (BTS) guideline defines hypoxemia as PaO2 < 60 mmHg or
SaO2 < 90%. Hypoxia on the other hand, refers to oxygen lack at a tissue level,
and is generally inferred from evidence of tissue hypoperfusion (increasing serum
lactate).

Sources of Oxygen Supply

Oxygen is available in three forms; in a cylinder, which is what one sees in

smaller hospitals; from a liquid oxygen plant, generally present in larger hospitals
and from oxygen concentrators/ Oxygen generators. Oxygen cylinders are
generally available in two size- a size ‘E’ cylinder, which when full contains 680
litres of oxygen, and a type ‘F’ cylinder which contains between 1200 and 1300
litres of oxygen. It is important to know this, because when one is transporting a
patient, dividing the capacity of the cylinder by the oxygen required in litres per
minute will let one know how long the supply will last. The oxygen cylinder
manifold supply has a main bank and a reserve bank of cylinders, with a selector
switch, which the technician uses to switch from one bank to the other when the
pressure drops below a critical limit. This gives the technician time to attach filled
cylinders after removing the empty ones.

Liquid oxygen is nearly always supplied from a central location through a

system of pipeline to patient outlets. The oxygen passes through either a single
stage or a two stage pressure reducing valve before passing to a length of tubing,
which connects to an interface with the patient, which acts as an oxygen delivery
system. Oxygen concentrators have a dust filter followed by a Zeolite filter. Air
passes through the dust filter and then the Zeolite filter which adsorbs the
nitrogen, and supplies around 90% pure oxygen (Argon and Radon are not filtered
out). They are very useful in wards where patients generally do not require very
high oxygen flows.

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Types of oxygen delivery systems

a) Nasal cannula (Fig 8.1)

Nasal cannulas are extremely comfortable for the patient, as they allow the
patient to eat and drink without taking it off. However, they generally cannot
deliver oxygen at greater than 6 litres per minute as they cause drying of nasal
mucosa at higher flows. A nasal cannula increases percentage of oxygen by
around 4% per litre of flow. So, starting from a room air percentage of 21%,
6 litres per minute could be expected to deliver a FiO2 of around 40% oxygen.

b) Oxygen Masks(Fig 8.2)

The next step up in terms of delivering oxygen percentage are low flow
oxygen masks which deliver oxygen at 6-10 litres per minute and can deliver
an FiO2 of up to 60% oxygen. Nasal cannulas and low flow masks are known
as low flow oxygen enrichment devices. The oxygen concentration supplied
by them depends heavily on what percentage the oxygen flow is of the
patients’ peak inspiratory flow rate and can vary widely depending on the
patient’s inspiratory effort. In patients in whom a more reliable
concentration of oxygen is required, a venturi mask can be used which
supplies oxygen through a venturi device; the oxygen passes at high flow
through a small hole, and this entrains atmospheric air, to give a specified,
predictable FiO2 at high flows. Venturi valves designed to give specific FiO2s
at recommended flows are available. (Fig 7.3) Masks linked to anaesthesia
circuits and other masks, which have attached reservoir bags, can push the
oxygen percentage all the way up to 100%, because the patient inspires at
peak inspiratory flow not only from the oxygen tubing, but also from the
reservoir bag, which accumulates oxygen when the patient is expiring.

c) Non rebreathing masks (Fig 8.4)

NRBMs provide higher FiO2 as compared to Hudson’s mask, due to the
attached reservoir bag, for the same flow rates of oxygen. This has been found
to be extremely useful in patients with COVID who primarily have a type I
respiratory failure.

d) High Flow Nasal Oxygen (Fig 8.5)

HFNO provide very high flows of warm and humidified oxygen through a
special nasal cannula at flow rates up to 60 litres per minute and a FiO2 of

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100%. In patients with COVID, it helps in delaying or avoiding intubation
and mechanical ventilation. Patients who do not tolerate Non-invasive
ventilation, generally tolerate HFNO very well; however it consumes a very
high amount of oxygen which is not desirable in the times where oxygen may
be in short supply due to very high demand.

Fig 8.1 Nasal prongs Fig 8.2 Hudson Mask

Fig 8.3 Venturi mask Fig 8.4 Non-rebreathing

mask (NRBM)

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 Fig 8.5 High Flow Nasal Oxygen

Targets of oxygen delivery

Oxygen is generally delivered to achieve a saturation of greater than about

90% in COVID patients. However, in patients with COPD with acute hypoxemia,
a saturation of around 88-92% may be more suitable as there are concerns of
suppressing the hypoxemic drive in a patient who is no longer responding to
carbon dioxide as a means of maintaining the respiratory drive.

Ventilation

Non Invasive Ventilation (NIV)

When targets of oxygen therapy cannot be met with oxygen therapy

devices, NIV is required. NIV is mainly used for severe COVID patients with
mild to moderate ARDS. Use of NIV in severe ARDS (PaO2 /FiO2 ratio less than
150 mmHg) leads to a higher failure rate especially when compared to invasive
mechanical ventilation (IMV). Patients who fail NIV and progress to IMV have
a higher mortality. A high tidal volume, greater than 9 ml/kg, on NIV is also a
strong predictor of NIV failure. NIV therefore has to be instituted in severe
COVID under close supervision.

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 In NIV, a mixture of oxygen and air is delivered to the patient via a tight-
fitting interface like oro-nasal face mask, nasal mask, full-face mask or helmet.
The oronasal mask is most commonly used due to its availability. ICUs using the
NIV helmet have reported increased rates of success of NIV. A vented NIV mask
is to be used with single limb circuits and a non-vented NIV mask is required to
be used along with dual limb circuits.

CPAP modes available in single limb NIV machines improve hypoxemia

and decrease afterload. However, the ideal mode on NIV for severe COVID is
the BiPAP mode, which reduces work of breathing and is useful for removal of
CO2. Higher end ICU ventilators should be used for NIV whenever available, as
it can be connected to the intermediate pressure oxygen pipeline of the hospitals.
The dual limb circuit, predictable oxygen delivery and use of viral filters in
expiratory limb makes its use beneficial.

One generally starts NIV with a Pressure Support Ventilation (PSV) of 15

cm H2O, Positive End Expiratory Pressure (PEEP) of 10 cm H2O; FiO2 of 1.0 to
start with and titrate down to maintain SpO2 greater than 92%.The PEEP can also
be titrated to maintain SpO2 of around 92%. If the tidal volume is high, (more
than 8 ml/kg), the pressure support can be decreased. The respiratory rate and
pattern needs to be observed very carefully and repeated arterial blood gas
measurements are necessary.

Patients are often agitated on NIV, leading to frequent removal of NIV

mask and immediate desaturation. The causes include claustrophobia, delirium,
hypoxemia and non-compliance to NIV. The key to the treatment is proper
counselling. Mild sedation with Fentanyl or Dexmedetomidine infusions, may be
utilised, with great caution, when the patient is on NIV.

Maintaining feeds on NIV via a nasogastric tube is essential. Early enteral

feed with high proteins are necessary to improve nutrition and tackle the calorie
deficit. The patient may be taken off NIV intermittently for feeds and some
amount of leaks occurring due to the nasogastric tube may be accepted. While
feeding it is important to avoid hypoxemia by using NRBM while the patient is
off NIV.

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 It is imperative to identify failure of NIV, which may present as respiratory
rate persistently greater than 35 breaths per minute, use of accessory muscles,
increased work of breathing, persistent hypoxemia, signs of hypercarbia and
hemodynamic instability. Failure of NIV requires use of the other techniques of
oxygen therapy or ventilation.

Many studies have compared NIV with HFNO and concluded that HFNO
is a better modality for hypoxemia without respiratory distress, and is useful for
severe COVID with mild ARDS as patient tolerance is better. For severe COVID
with moderate ARDS, NIV is a better modality compared to HFNO.

Contraindications to NIV include patient non-compliance, decreased

sensorium, hemodynamic instability, increased respiratory secretions and a high
risk of aspiration.

Awake Prone Positioning

Awake prone positioning improves oxygenation, but improvement is not

sustained after turning supine. Some studies have shown no difference in
progression to ventilation rates with or without awake prone positioning.
However, it is a useful technique, which is easy to use, even when the patient is
on NIV. It may however provide a false sense of security, and it is definitely not
to be used as a rescue therapy for refractory hypoxemia or to avoid intubation in
patients who otherwise meet the indications for intubation and mechanical
ventilation.

Invasive Mechanical Ventilation

IMV is indicated when NIV is not tolerated, in patients with high work of
breathing, persistent signs of respiratory distress, impending airway obstruction,
decreased sensorium, severe hypercarbia, severe acidosis and increased minute
ventilation of more than 10 L/min. Patients with refractory profound hypoxemia
despite high PEEP, respiratory compliance < 40 ml/cm H2O and patients with
hemodynamic instability or multiorgan failure are candidates for IMV. IMV
needs to be considered early if the disease trajectory is showing a deteriorating
trend.

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 The clinician needs to weigh the risks and benefits of IMV and not go by
biomarkers of inflammation alone. It is better to plan intubation electively than
to get into a situation that necessitates emergency intubation. IMV is resource
intensive and requires closer monitoring of the patient. Intubation is to be
performed by an experienced practitioner in a controlled setting, as it is being
performed in a physiologically difficult airway on a hypoxemic tachypnoeic
patient.

The principles of mechanical ventilation include ARDSNet strategies of

low tidal volume of 6 ml/kg with a high respiratory rate to prevent hypercarbia.
A certain amount of permissive hypercarbia is acceptable. PEEP should be set
appropriately to prevent lung de-recruitment. It is ideal to limit plateau pressures
to less than 30 cm H2O. PEEP and FiO2 need to be titrated according to
oxygenation status of the patient. Either the Volume Assist Control mode or
Pressure Assist Control mode is ideal for ventilation as long as the goals of
ventilation are met.

Refractory hypoxemia may necessitate use of neuromuscular blocking

agents for up to 48 hours or recruitment manoeuvres such as inspiratory hold at
40 cm H2O for 40 seconds to recruit alveoli. Prone ventilation for 12 to 16 hours
per day is preferable, but is labour intensive. A few pitfalls of IMV include
barotrauma, pneumothorax, decreased venous return, hypotension, air trapping
and machine & circuit disconnections.

ICU management of COVID-19 patient

a) Central line/Arterial line: Central line insertion should be done after

intubation under USG guidance. Central line should be used for drug and fluid
administration and for collection of blood samples. The need for arterial line
should be decided on a case to case basis. If required it should be placed at the
same time as the central line.

b) Sedation/Analgesia/Muscle relaxation: In order to reduce the patient contact,

one option is to mix all the components of sedation analgesia and muscle
relaxation in the same syringe. One option is to mix Fentanyl 10 ml (500mcg),
Midazolam 5 ml (25mg), Atracurium 15 ml (75mg) in NS 20ml to make 50 ml
and run at 6 ml per hour. Atracurium may be omitted when the patient can be
ventilated effectively without it. The drug syringe should be prepared outside the
73
patient care area and handed over to the ICU team (stored in the refrigerator if
required), so that apart from initial central line, there are no needle changes. This
mixture has been created to allow for one syringe change per shift.

c) Hemodynamic support: Inj Noradrenaline followed by Inj Vasopressin is

used for septic shock. If very high doses are required, 8 instead of 4 Ampoules of
Noradrenaline may be added in each syringe to reduce the need for frequent
refilling.

d) LMWH: COVID being a prothrombotic state, these patients need

thromboprophylaxis as a routine. A suggested approach to anticoagulation is
depicted at Fig 7.6

Fig 8.6 Anticoagulation in patients with COVID 19

(Ref:https://emcrit.org/pulmcrit/dimer-cutoff-COVID/)

e) Fluid therapy. Restrictive fluid therapy approach is suggested however one

needs to maintain a balance. Some patients may be febrile and tachypneic, hence
suffering from higher than usual insensible fluid losses. There have been

74
numerous reports of renal failure possibly due to a cytokine storm, and a rigid
fluid restriction protocol runs the risk of worsening of renal function.

f) General Care
Place a Diaper on all patients and change once a day or on as required basis.
Foley’s catheter and Ryle’s tube should be placed for all intubated patients.
Low residue feeds to reduce stool frequency and quantity should be started as
soon as feasible. Patients on NIV should also be fed by putting them on NRBM
or HFNO during feeds, if doing so does not lead to hypoxia. Soft diet and liquid
diet is preferred for those on NIV in order to reduce the‘off’ time.

g) Investigations
Patients with COVID present with significant lymphopenia, hepatic
dysfunction, risk of thrombosis and HLH like syndrome. Keeping this in view,
the following investigations may be useful in management of cases. The list of
investigations is purely indicative.

CBC, LFT, RFT, Prothrombin time and D-Dimer, IL-6, Procalcitonin,

ferritin and Triglycerides and X Ray Chest. Other investigations are done as per
the discretion of the treating team.

Considering the logistic difficulties in performing serial X Ray Chest,

daily lung ultrasound is recommended. Whenever ordering CT Chest the
logistics, risks involved and requirement of decontamination of CT scan suite
must be taken into consideration. Daily Echocardiography to assess the cardiac
status is recommended.

If an arterial line is not present then a VBG from the central line and the
patients SpO2 may be used as an acceptable surrogate for most variables.

Suggested Reading

1. The AFMC ICU Manual

2. The ICU Book by Paul Merino,
3. Clinical Management Guidelines of the MOHFW, GoI

75
9. COVID-19 in Children

Maj Arjun Kurup, Maj Apoorv Saxena, Gp Capt BM John, Surg Cmde
KM Adhikari

Introduction

The COVID-19 pandemic has been rampant for the past two years. With
increased vaccination coverage and the emergence of variants causing less severe
disease, the disease seems to be transitioning to endemic state in our country. As
life seems to be returning to normal with easing of restrictions and opening of
schools for physical classes, children are the most vulnerable due to their
unvaccinated status. However, until date, children are relatively spared from the
disease as compared to adults. The SARS-CoV-2 virus primarily affects lungs
and causes pneumonia but can also include other systems and manifest as
Multisystem Inflammatory Syndrome in Children (MIS-C). Neonates born to
COVID-19 positive mothers are largely asymptomatic although there have been
isolated reports of such neonates requiring intensive care.

Why COVID-19 is less severe in Children?

Data available so far indicates that the COVID 19 infection in children is

mild. Less than 1% of infected children develop severe disease or MIS-C
requiring intensive care. The possible explanations for milder disease in children
are as under:
a) Differences in innate and adaptive immunity as compared to adults
b) Immaturity of ACE-2 receptors in type-II lung pneumocytes
c) Cross reactivity with other respiratory viruses (other coronaviruses) which
limit the growth of SARS-CoV-2
d) Protective efficacy of certain vaccines e.g. BCG
e) Less intensity of exposure to SARS-CoV-2, particularly with current
COVID appropriate behavior

Although the disease is mild in children, the risk of transmission of virus

to others from them is significant.

76
Clinical Features

Majority of children with COVID-19 infection are asymptomatic (15 to 42

percent) or mildly symptomatic. Commonly reported symptoms are that of any
other respiratory viral illness. Few children may also present with gastrointestinal
symptoms like diarrhea, pain abdomen and vomiting without any respiratory
symptoms. Based on the signs and symptoms, the disease can be classified into:
a) Mild – Fever, cough, rhinorrhea, loss of taste and smell sensations, sore
throat with no breathing difficulty or diarrhea, vomiting without shock.
b) Moderate – All the above symptoms may be present. In addition, child
will have tachypnea with or without hypoxemia (SpO2 90% – 94% on
room air). Tachypnea for various age groups is defined as:
 < 2 months – respiratory rate > 60 per minute
 2 months to 1 year –respiratory rate > 50 per minute
 1 year to 5 years –respiratory rate > 40 per minute
 > 5 years –respiratory rate > 30 per minute
c) Severe– Children with severe disease present with tachypnea, hypoxemia
(SpO2 < 90%), chest retractions, cyanosis, grunting, lethargy, poor oral
intake, excessive somnolence or seizures. They may progress to acute
respiratory distress syndrome (ARDS), multi-organ dysfunction syndrome
(MODS) or septic shock.

Lab Investigations

All suspected cases should be confirmed with RT-PCR or nucleic acid

amplification test (NAAT) in nasopharyngeal and/or oropharyngeal swab. A
rapid antigen test (RAT) may also be undertaken if RT-PCR is not available
although it is less sensitive than RT-PCR as discussed in chapter 4. Asymptomatic
and symptomatic cases usually do not require any investigation. A chest X-ray
and complete blood count should be done for moderate disease. All severe cases
should undergo following investigations:
 Complete blood count
 Chest X-Ray
 C-Reactive protein (CRP)
 Liver function test
 Renal function test
 D-dimer, Ferritin, Coagulation profile, LDH and IL-6 (only if available)

77
 Apart from the above-mentioned usual investigations for other common
treatable causes of fever must be done i.e. malaria, dengue, enteric fever etc.
Management

All children with COVID-19 infection must be isolated with mother/care-

giver as per isolation plan in Fig 9.1.
a) Mild disease – Symptomatic management.
 Paracetamol – 15 mg/kg/dose every 6 to 8 hourly
 Ensure hydration
 Antibiotics are not required
b) Moderate disease – Requires admission. Treatment includes:
 Oxygen supplementation via nasal prongs or facemask to maintain
SpO2 > 94%.
 Intravenous (IV) fluids if oral intake is poor
 Oral amoxycillin (30 – 50 mg/kg/day q 8 hourly) or IV Amoxycillin-
Clavulanate (60 – 80 mg/kg/day in 2 divided doses) if strong suspicion
of secondary bacterial infection.
 Paracetamol – 15 mg/kg/dose every 6 to 8 hourly
 Corticosteroids should be used in rapidly progressive disease
(Dexamethasone – 0.15 mg/kg/dose, max 6mg, once a day). Steroids
should never be started upfront for moderate disease, as it can be
detrimental.
c) Severe disease – Admit in pediatric ICU.
 Oxygen therapy – Usually requires high flow nasal oxygen device
(HFNO) or non-invasive ventilation (NIV). Infants may benefit from
continuous positive airway pressure (CPAP). A brief on oxygen therapy
in children is provided in Table 9.1.
 Fluids – IV bolus of 10-20 ml/kg of Normal saline (NS) or Ringer
lactate (RL) over 20 minutes may be required for children presenting
with shock. Repeat boluses up to 30-40 ml/kg of NS or RL may be
required if shock is not corrected with initial bolus. Early inotropic
support should be started for fluid refractory shock. Fluids should be
cautiously administered if there are features of cardiac dysfunction or
myocarditis.
 Steroids – Injectable Dexamethasone 0.15 mg/kg (Max 6 mg) in a
single dose or equivalent dose of methylprednisolone (0.75 mg/kg, Max

78
 30 mg one a day should be started as early as possible and continued
for 5 to 7 days and tapered over 14 days.
 ARDS - Mild ARDS can be managed with HFNO or NIV, however
severe ARDS will require mechanical ventilation. Principles of
ventilation are similar to any other ARDS and includes low tidal volume
(< 6 ml/kg), high positive end expiratory pressure (PEEP) of 6-8 cm
H2O. Awake prone positioning may be considered in older children.
 Organ support – e.g., Renal replacement therapy
 Remdesivir – Not recommended
 Use of Baricitinib, Hydroxychloroquine, Lopinavir-Ritonavir,
Favipiravir, Ivermectin, Tocilizumab or monoclonal antibodies are
currently not recommended.
 VTE prophylaxis should not be started routinely and should be
considered on a case-by-case basis.
Management of COVID-19 infected children is summarized in Table 9.2.

Multisystem Inflammatory Syndrome in Children (MIS-C)

In April 2020, a cluster of children in Europe presented with Kawasaki

disease (KD) and Toxic shock syndrome (TSS) like features with evidence of
prior exposure to SARS-CoV-2. This syndrome was termed as MIS-C. Over the
course of the last two years, varied presentations of this syndrome have been
reported. The pathogenesis of MIS-C is poorly understood however, immune
dysregulation and severe antibody dependent enhancement triggering the
hyperinflammatory response may have a role to play.

Clinical features

MIS-C is prevalent in older children (> 6 years of age) and adolescents as

compared to KD, which is seen in children < 5 years. Classical presentation
includes KD phenotype–fever, mucocutaneous rash, non-purulent conjunctivitis
and coronary artery abnormalities. However, KD phenotype is seen only in one
third of the patients. Severe form of MIS-C presents with life-threatening shock
and requires early recognition and prompt management. Other presentations
include gastrointestinal involvement (vomiting, diarrhea), coagulopathy
(petechiae, bleeding). It should be remembered that MIS-C is a diagnosis of
exclusion.

79
Diagnostic Criteria of MIS-C

1. Children and Adolescents 0 – 19 years with fever > 3 days AND

2. At least two of the following
• Rash/bilateral non-purulent conjunctivitis
• Hypotension or shock
• Features of myocardial dysfunction, pericarditis, valvular
dysfunction, or coronary abnormalities (including echo-
cardiographic findings or deranged NT-proBNP/ Troponin-T)
• Evidence of coagulopathy (abnormal PT/aPTT/D-dimer)
• Acute gastrointestinal problems (vomiting, diarrhoea or abdominal
pain)
3. And
• Elevated markers of inflammation such as ESR(>40mm),
CRP(>5 mg/L) or Procalcitonin
• No other obvious microbial cause of inflammation
• Evidence of COVID-19 (RT-PCR/antigen test/serology positive)
or likely contact with patients with COVID-19

Management

Early recognition is key to successful management of MIS-C and a high

index of suspicion should be kept in diagnosing this condition. If MIS-C is
suspected, then the child should undergo two-tier investigation to confirm it:

1. Tier I – CBC, LFT, RFT, blood glucose, arterial/venous blood gas,

CRP, blood culture, SARS-CoV-2 serology and RT-PCR, ICT for
malaria, dengue serology and other tests to rule out infectious etiology.
Positive Tier-1 screen includes:
a) CRP > 5 mg/dl and/or ESR > 40 mm fall in first hour AND
b) At least one of the following:
i. Absolute lymphocyte count < 1000/cmm
ii. Platelet count < 1,50,000/cmm
iii. Serum Sodium (Na) < 135 mEq/L
iv. Neutrophilia
v. Hypoalbuminemia (Serum albumin < 3 m g/dL)

80
 2. Tier-II – This includes investigations to look for presence of organ
dysfunction and includes:
a) Cardiac: ECG, echocardiography, Brain Natriuretic Peptide,
Troponin-T
b) Inflammatory markers: Procalcitonin, Ferritin, LDH
c) Coagulopathy: Increased PT/APTT/ INR/D-dimer, decreased
fibrinogen
The treatment of MIS-C involves immunomodulation using intravenous
Immunoglobulin (IVIg) and/or steroids. Both should be used upfront in case child
presents with life-threatening disease or shock. Refractory disease can be treated
with repeat dose of IVIg or biologicals like Anakinra, Infliximab and
Tocilizumab. Children with shock may require inotropic support and those with
coronary artery abnormalities should be managed with Aspirin (3-5 mg/kg/day,
maximum 75 mg/day for at least 4-6 weeks in all children with coronary
aneurysms). The stepwise investigations and management are summarized in Fig
9.2.

The long-term sequelae of MIS-C are unknown as the disease is still

evolving. In a recent study on 6 months follow-up of MIS-C children, 96% had
normal echocardiogram, 87% had no gastrointestinal abnormality, and near
complete resolution of renal, hematological, neurological and otorhinolaryngeal
abnormalities at 6 months. These findings are encouraging, however, long-term
follow-up is recommended.

Management of neonates born to COVID-19 positive mother

COVID-19 rarely affects neonates. There is no evidence of vertical

transmission of SARS-CoV-2 from COVID-19 affected mothers to neonates.
However, mothers can transmit SARS-CoV-2 to the newborn horizontally in the
postnatal period. Although disease in neonates is largely asymptomatic, there is
increased incidence of abortions, pre-term delivery, fetal distress, caesarean
sections, low birth weight babies and NICU admissions. Rarely it may manifest
with respiratory distress or shock in neonates.
Following points should be considered during the perinatal and postnatal
management of neonates born to COVID-19 affected mothers:
 MO/Pediatrician should attend delivery in full PPE
 Delayed cord clamping up to 60 seconds

81
  Room-in with mother if clinically stable and establish breast feeds
 Mother to practice respiratory hygiene while feeding
 Zero dose of vaccines (BCG, OPV and Hepatitis B) to be administered
before discharge
 Lactating mothers should be immunized against COVID-19.

Stable neonates exposed to mothers or any other person with COVID-19

should be roomed-in with mother and exclusively breastfed. Essential newborn
care and lactation support should be provided. If rooming-in is not possible
because of sickness in the mother, the newborn should be fed expressed
breastmilk (EBM) of the mother by a trained nurse or a willing healthy family
member. Breast milk has been found to have antibodies against COVID-19
following natural infection or vaccination of mother. Mother should wear mask
while breast feeding or expressing breast milk and practice hand hygiene before
and after handling the baby.

Vaccination
Multiple COVID-19 vaccines are undergoing Phase II/III trials. Although
multiple vaccines have been approved internationally for children, the DGCI have
only authorized use of Covaxin and Corbevax for use above the age of 6 years
and ZyCov-D for use above the age of 12 years.
All of these vaccines are administered in a 2 dose schedule (Day 0 and Day
28).

Conclusion

As per current evidence COVID-19 in children is mild. A child presenting

with multisystem involvement in the current pandemic should be evaluated for
MIS-C. However, children less than 18 years continue to be susceptible for
COVID-19 due to delay in their immunization and evolving host dynamics as a
result of school opening in future.

82
Suggested reading

1. Zimmermann P, Curtis N. Why is COVID-19 less severe in children? A

review of the proposed mechanisms underlying the age-related difference
in severity of SARS-CoV-2 infections. Arch Dis Child. 2021;106(5):429-
439
2. Guidelines for Management of COVID-19 in Children (below 18 years).
Ministry of Health & Family Welfare Government of India.
3. COVID-19 Management For 1 Month-19 Years Old: Statement by Indian
Academy of Pediatrics (April 2021).
4. Perinatal-Neonatal Management of COVID-19 Ver.2.0 07 Federation of
Obstetric & Gynaecological Societies of India National Neonatology
Forum, India Indian Academy of Pediatrics Replaces Ver.1.0 of 26
Mar2020. Available from: www.fogsi.org (last visited 02 Aug 2021)
5. Penner J, Abdel-Mannan O, Grant K, Maillard S, Kucera F, Hassell J, et al.
6-month multidisciplinary follow-up and outcomes of patients with
paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary
paediatric hospital: a retrospective cohort study. Lancet Child Adolesc
Health.2021 Jul;5(7):473-482

83
Fig 9.1 Isolation plan for children less than 12 years

84
 Fig 9.2 Diagnosis and management of MIS-C (Adapted from MoHFW and IAP guidelines for management of
COVID-19 in Children)
o
Unremitting Fever; > 38 C

Epidemiological link to COVID-19 No Evaluate for alternate diagnosis

Clinical features suggestive of MIS- Monitor for features of MIS-C

C
Yes

No Positive Tier-II investigations

Is Shock/ Life threatening organ Tier-I investigations
dysfunction present Work-up for common
tropical infections
Yes

Simultaneous Tier-I and Tier-II

Fulfills criteria for MIS-C
investigations
Work-up for common tropical infections

Yes

IVIg 2g/kg (max 100 gm) over 12 hours OR

Fulfills criteria for MIS-C
Methylprednisolone 1-2 mg/kg/day
Add Enoxaparin 1mg/kg BD subcutaneously if coronary artery
Yes Z-score > +10 or LVEF < 35% or thrombosis Aspirin 3-5 mg/kg/day (max 81 mg/day)

Change methylprednisolone to dexamethasone after 3 – 5

IVIg 2g/kg (max 100 gm) over 12 hours days; Taper 25% every week and stop after 3-4 weeks Repeat IVIg – 2g/kg over 12 hours
AND Methylprednisolone 10 – 30 OR
mg/kg/day (max 1gm/day) Anakinra
Empiric antibiotics No response in 48 hours OR
Aspirin 3-5 mg/kg/day (max 81 mg/day) Tocilizumab
85
Severity Clinical Investigations Management Monitoring
Features
Mild Fever Not required Home Isolation Home
Sore Throat Rest monitoring –
Rhinorrhea Paracetamol temperature,
No fast Adequate SpO2,
breathing hydration and respiratory rate
nutrition and urine output

Moderate Fever CBC Oxygen by nasal Admit in HDU –

Tachypnea Chest X-ray prongs or face respiratory rate,
SpO2 - 90 – mask SpO2, urine
94% on room air IV fluids if output, blood
Vomiting required pressure or
Loose stools Empirical capillary refill
Dehydration antibiotics time, work of
Corticosteroids in breathing
rapidly
progressive
disease

Severe Fever CBC Corticosteroids Admit in ICU –

Tachypnea Chest X-ray IV fluids incl Intensive
SpO2 - < 90% LFT/RFT bolus monitoring
on room air Blood gas Empirical including blood
ARDS Blood culture antibiotics gas analysis
Septic shock CRP Ventilation
MODS PT/aPTT
D-dimer
Ferritin

Table 9.1 Clinical features, investigations and management of COVID-19 in children

(Adapted from MoHFW and IAP guidelines for management of COVID-19 in Children)
CBC – Complete blood count ARDS – Acute respiratory distress syndrome
IV – Intravenous MODS – Multi organ dysfunction syndrome
HDU – High dependency unit CRP – C-reactive protein
86
S.N Device Description Indication Consideration
o
1 Nasal Cannula - Lightweight; two - Children who need O2 - Most
commonly used
soft prongs that fit concentrations between oxygen delivery device
in the nares 22–45%. - Maximum oxygen flow
- Different sizes are - Allows child to eat, should not exceed 4L/min
available talk and cough without - Inconsistent FiO2
interrupting oxygen depending on child’s size
- Better tolerated delivery - May cause drying of
by infants and mucous membranes
younger children - Remove nasal prongs for 2
mins after every 4 hours
(under cover of free flow
oxygen) to prevent injury to
nasal septum
2 Face Mask - Mask sits on Low flow device for - Appropriate flow rate – 6-
face over mouth children needing 35-60 % 10L/min; Minimum flow of 5
and nose; has FiO2. L/min to be maintained
elastic straps. - Inconsistent FiO2
- Available in various - Flow below 4 L/min can
sizes. cause CO2 retention
- Device of choice in - Monitor for signs
older children (>5 of hypercarbia
yrs)

87
 3 Non - Mask sits on the Children requiring - HighFiO2 of upto 90%
Rebreathing face over mouth and high amount of - Monitor for signs of
Mask (Face nose; has elastic oxygen up to 90%. hypercarbia
mask with a strap.
reservoir) - A reservoir bag is
attached which has
02 valves, one in the
exhalation port to
prevent room air
from entering during
inspiration and a one-
way valve to prevent
mixing of exhaled
gases in to the
reservoir.
4 Heated -Lightweight; two soft Children who require -Flow rate scan be adjusted
Humidified prongs that loosely fit Higher FiO2 up to -Provides PEEP
High Flow in the nares. 80% with some -Devices have humidifier
Nasal -Delivers oxygen from PEEP (use of which prevents drying of
Cannula a flow rate of 4 L/min accessory muscles of mucosal membranes
(HHHFNC) in infants to 40 L/min respiration) -Start with 2 L/kg/min flow
or more in adolescents rate and titrate as per SpO2;
generates 4-5 cm H2O of
PEEP.
-Monitor for abdominal
distension; Use OG tube to
decompress stomach.

88
5 Continuous - Has 2 limbs – - Respiratory distress - Delivers PEEP
Positive inspiratory and with increased work of - Monitor for abdominal
Airway expiratory with nasal breathing distension; Use OG tube
Pressure interface (snugly fit - Delivery of mild air to decompress stomach
(CPAP) short binasal prongs) pressure to keep the - Flow rate 0f 5–10 L/min
between them. airways open. is required
Inspiratory limb is - FiO2 can be titrated. - Remove nasal prongs for 5
connected to oxygen Delivers PEEP to a mins after every 4 hours
source and expiratory spontaneously breathing (under cover of free flow
limb is immersed in to child. oxygen) to prevent injury to
a water chamber to a nasal septum
depth in centimetres
that equals the CPAP
pressure.
- Similar to HHHFNC
except the nasal
prongs are snugly fit

Table 9.2 Oxygen therapy in children

89
10. Complications of COVID 19

Wg Cdr Rohit Vashisht, Gp Capt TVSVGK Tilak

Introduction

COVID 19 poses a risk of sequel after recovery from the acute episode.
Understanding the post covid sequelae is just like opening the pandora’s box.
Major organ systems can be affected post COVID adding up to the morbidity and
mortality. The diverse range of post COVID complications are described in this
chapter.

Long COVID syndrome

This is also known as Post-acute COVID syndrome, Long haul COVID

and Chronic COVID. Though commonly seen in moderate to severe COVID, it
has also been reported in people with mild disease or in those with asymptomatic
disease. The frequency ranges widely from 5-80%. In the absence of a universally
accepted definition, Long COVID has been described as an umbrella term for the
diverse range of physical and mental health consequences presenting four or more
weeks after acute infection. It can be further sub divided into two phases: (a)
Subacute or ongoing COVID, which include symptoms present from 4-12 weeks
beyond acute infection (b) Chronic/post COVID syndrome, which include
symptoms or abnormalities persisting, or present beyond twelve weeks after onset
and are not explained by alternative diagnosis. Common clinical features are
fatigue, post-exertional malaise, breathlessness, joint pains, chest pain, cough,
anosmia, ageusia, hair loss, insomnia, anxiety and brain fog. Less common
complications include thromboembolism, infections (mucormycosis,
aspergillosis), cardiac (myocarditis, arrhythmias, sudden death), respiratory (lung
fibrosis) and rare complications are multi-inflammatory syndromes (MIS) in
children and adults. Risk factors for developing long covid include the people
who were hospitalized or needed intensive care for severe covid 19, who had
underlying health conditions, unvaccinated individuals, who experience MIS
during or after the covid illness and some people affected by health inequities like
minority groups and people with disabilities.

90
Delayed thromboembolic disease

The pathogenesis of procoagulant state induced by COVID 19 has been

described in a previous chapter and manifests as deep vein thrombosis, pulmonary
embolism, thrombotic and embolic strokes, myocardial infarction and limb
gangrene. The prevalence of thromboembolic events has been reported to be 5%
in previous retrospective studies. Current literature shows that the 90-day
incidence of thromboembolism in COVID-19 patients was 7%, but <1% after
discharge. Male sex, elderly patients with high d-dimer (>2 times the normal) are
at increased risk for developing DVT. The risk is also high in ICU patients with
moderate to severe COVID even when on anticoagulants. Elevation in d-dimer
levels has a sensitivity, specificity and negative predictive value of 85%, 88.5%
and 94.7% respectively in the prediction of venous thromboembolism. A recent
study found an increased risk of a first deep vein thrombosis up to three months
after covid-19, pulmonary embolism up to six months, and a bleeding event up to
two months, with the risk of pulmonary embolism in the acute phase being
especially high. The incidence of pulmonary embolism is also about nine times
higher in COVID 19 patients as compared to the general population. Strokes and
myocardial infarction have been reported in young patients with no apparent risk
factors.

Direct oral anticoagulants like Apixaban, Rivaroxaban have been used

successfully for DVT prophylaxis post COVID. Post discharge, prophylaxis is
indicated in the following subset of patients:
o Modified IMPROVE-VTE score ≥4
o Modified IMPROVE-VTE score ≥2 and D-dimer level > 2 times the upper
limit of normal.
o Age ≥75 years
o Age >60 years and D-dimer level >2 times the upper limit of normal

Routine post-discharge thromboprophylaxis is not recommended. Most

outpatients also do not warrant thromboprophylaxis. Therapy such as
rivaroxaban 10 mg daily is recommended for minimum 4 weeks only in high-risk
patients. In a proven DVT/PE case, anticoagulation is advised for 3-6 months.
The patients should be monitored for any bleeding manifestations during follow
up visits. Available data do not support use of aspirin or other antiplatelet agents
in outpatients.

91
Infectious complications

Bacterial and fungal infections are known to complicate viral infections.

COVID 19 is no exception. There has been a surge of opportunistic infections
especially fungal post COVID.

(a) Covid associated Mucormycosis (CAM)

Mucor has shown a steep rise in incidence, especially so after the second
wave in India. Mucor is a filamentous opportunistic fungus, which is ubiquitous
in nature and owing to its angio-invasive nature, causes life threatening infection
in patients of diabetes & those who are immunocompromised. Indiscriminate
steroid use with poor glycemic control is a major risk factor for this invasive
fungal infection. A systematic review showed that the majority of patients were
male (78%) and had diabetes mellitus (85%). A prior history of COVID-19 was
present in 37% patients with mucormycosis. The median time interval between
COVID-19 diagnosis and the first evidence of CAM diagnosis was 15 days.
Glucocorticoid use was reported in 85% of cases. Rhino-orbital mucormycosis
(ROCM) was most common (42%), followed by rhino-orbito-cerebral
mucormycosis (24%). Pulmonary mucormycosis was observed in 10 patients
(10%). Overall mortality ranges from 15 to 31 percent. Mucormycosis, post
COVID results from interplay of multiple factors. COVID 19 causes endothelitis,
endothelial damage, thrombosis, lymphopenia, and reduction in CD4 + and
CD8+ level and has been hypothesized to predispose to mucormycosis.
Dysregulation of iron metabolism in COVID 19 may also contribute to the
pathogenesis. ROCM is the predominant mucor syndrome post COVID. The
patients present with facial pain/numbness, maxillary swelling, black, necrotic
eschars in nasal turbinates and hard palate, extraocular muscle involvement
leading to proptosis and chemosis. The patients may have intracranial spread in
the form of cavernous sinus thrombosis. MRI is the preferred modality for
imaging brain and orbital disease. The diagnosis is established by growing mucor
on culture from a sterile site or histopathological evidence of invasive
mucormycosis. The latter shows classically wide (≥ 6 to 30-μm), thick-walled,
ribbon like, aseptate hyphal elements branching at right angles.

The principles of management of invasive mucor are

• Extensive surgical debridement

92
 • Reversing underlying predisposing cause
• Medical therapy: Drug of choice is Liposomal Amphotericin B 5mg/kg/d
(3-6 weeks). Duration of therapy should be guided by clinico-radiological
resolution and preferably by a repeat biopsy showing normal
histopathology. The alternative drugs are oral Posaconazole 400 mg BD
(with high fat meal). Isavuconazole is another effective alternative reserved
for patients with renal dysfunction. It is dosed as 200 mg iv/po q 8h x 6
doses followed by 200 mg OD.

(b) COVID 19 associated Pulmonary Aspergillosis (CAPA)

Moderate to severe COVID 19 patients with a history of ICU stay/ assisted
ventilation or who have received prolonged steroids or Tocilizumab are at
increased risk of CAPA. Presentation may be in the later part of acute COVID
illness or early phase post COVID. It has been reported to occur in 10.2% of
patients admitted to an ICU. It was diagnosed a median of 11 days after symptom
onset of COVID-19 and 9 days after ICU admission in one case series. Patients
usually present with new onset fever, productive cough, hypoxia and new or
worsening lung infiltrates. Besides the typical radiographic features suggestive of
invasive aspergillosis, it should also be suspected in patients with prolonged or
relapsing respiratory failure, particularly in those with structural lung disease, age
>65 years, and/or immunocompromising conditions. Diagnosis is made by chest
imaging and bronchoscopic alveolar lavage (BAL). CT chest usually shows
cavitary or nodular infiltrates and sometimes classic ‘halo sign’ (consolidation
surrounded by ground glass opacities). BAL fluid shows septate hyphae on fungal
stain and growth of aspergillus can be seen in culture. Aspergillus galactomannan
in BAL fluid is a useful biomarker and value >1 is a strong pointer towards the
diagnosis of CAPA. Therapy should be instituted after microbiological diagnosis
and consists of Voriconazole in a dose of 6 mg/kg i.v /oral q 12 hrly x 2 doses,
followed by 4 mg/kg q12 hrly. Duration of therapy is usually 2-4 weeks and is
guided by clinical and radiological improvement.

Post COVID Pulmonary Fibrosis:

Residual pulmonary disease is an important complication seen in post

COVID and significantly affects quality of life. A recent meta-analysis showed
the prevalence of post covid lung fibrosis of 44.9% without a significant gender
preponderance. The risk was 2.8 times more in patients with chronic obstructive

93
pulmonary disease. Persisting cough is a frequently reported sequel, usually last
for few weeks after the discharge, and may even occur in those with mild disease.
Dyspnea is the most common respiratory symptom post COVID with prevalence
of 42–66% at 60–100 days of follow-up. Parenchymal involvement of the lungs
is usually the main cause for breathlessness. Neuromuscular deconditioning and
resulting weakness due to prolonged ICU stay in severe COVID illness also
contribute to persisting dyspnea. A significant number of patients are discharged
on domiciliary oxygen support due to partial recovery of lung function. A US
based study reported 6.6% of patients required supplemental oxygen two months
post discharge. Alveolar injuries, endothelial injuries along with
microthrombosis, cytokines such as IL-6 and transforming growth factor (TGF)
play an important role in causation of pulmonary fibrosis.

A decrease in the diffusion capacity is a common physiological impairment

especially post severe COVID. In an Indian study, restrictive impairment with
FEV <80% was found in half of the patients at 6-8 weeks, with significant
improvement on follow-up. Residual CT abnormalities like ground glass
opacities, fibrous stripes, bronchovascular bundle disruption are commonly seen
post COVID. Patients with persistent hypoxia should be clinically assessed with
spirometry, six-minute walk test, chest X ray and/or CT chest at 12 weeks, 24
weeks and at one year. Pulmonary rehabilitation is an important component of
management. Antifibrotic agents like Pirfenidone and Nintedanib have been tried
with varied success and are under clinical trials. A recent open-label randomized
trial support the efficacy of low-dose corticosteroid regimens in patients with
COVID-19-related organizing pneumonia with improvements in respiratory
symptoms, lung imaging and pulmonary function.

Cardiovascular complications

About twenty percent of COVID 19 patients report chest pain at two

months follow up. Palpitation is another common symptom reported in about
10% of the survivors. There is increased risk of stress cardiomyopathy and
myocarditis post COVID. A study revealed findings of myocarditis on cardiac
MRI in fifteen athletes who suffered from mild or asymptomatic COVID. Cardiac
troponin levels may be elevated without ECG changes. Elevated troponin predicts
a poor outcome and higher risk of mortality. The prothrombotic and hyper
inflammatory state can cause impairment of coronary flow and acute myocardial

94
infarction. Patients may also present with arrhythmias due to myocarditis and
cytokine induced catecholamine surge. Sudden death has also been reported in
survivors of COVID.

Patients, who develop cardiac complications during acute COVID, should

be followed up by repeat ECG and Echocardiographic evaluation at 1-3 months.
Renin angiotensin aldosterone system (RAAS) inhibitors have been found to be
safe and should not be stopped in patients with pre-existing hypertension. Low
dose beta blockers may be useful for rate control in sinus tachycardia.

Multi-inflammatory syndrome in adults (MIS-A)

MIS was initially described in children with features mimicking Kawasaki

disease, a medium vessel vasculitis. Though rare, it has been documented in
adults as well. It occurs in adults two to six weeks after COVID irrespective of
severity of disease. Immune dysregulation or aberrant immune response may be
the trigger. Centre for disease control and prevention (CDC) defines MIS-A as
follows:
A person aged ≥21 years hospitalized for ≥24 hours who meets the
following clinical and laboratory criteria.
(A) Clinical Criteria
Fever (≥38.0 C) for ≥24 hours and at least three of the following clinical
criteria occurring prior to hospitalization or within the first three days of
hospitalization. At least 1 must be a primary clinical criterion.
a. Primary clinical criteria
i. Severe cardiac illness (Includes myocarditis, pericarditis, coronary
artery dilatation or new-onset ventricular dysfunction, A-V block, or
ventricular tachycardia).
ii. Rash AND non-purulent conjunctivitis
b. Secondary clinical criteria
i. New-onset neurologic signs and symptoms (Includes encephalopathy,
seizures, meningeal signs, or peripheral neuropathy (including
Guillain-Barré syndrome)
ii. Shock or hypotension
iii. Abdominal pain, vomiting, or diarrhoea
iv. Thrombocytopenia

95
 (B) Laboratory evidence
The presence of laboratory evidence of inflammation and SARS-CoV-2
infection.
a. Elevated levels of at least 2 of the following: C-reactive protein, ferritin, IL-6,
erythrocyte sedimentation rate, procalcitonin
b. A positive SARS-CoV-2 test for current or recent infection by RT-PCR,
serology, or antigen detection

Infectious causes like bacterial sepsis, toxic shock syndrome, severe

tropical infections should be ruled out before labelling a post COVID survivor to
be having MIS-A. One point to distinguish MIS-A patients from severe COVID
19 is that the former is not accompanied by respiratory failure and has minimal
respiratory symptoms unlike the presentation seen in hospitalized patients with
severe COVID. Treatment is admission for intensive care and administration of
corticosteroids and/or intravenous immunoglobulin (IVIG). Most (88.8 %) of the
patients described in CDC case series survived after treatment in an intensive care
setting.

Other Post COVID sequelae:

a) Persistent fatigue
About 16-55% of the patients may have persistent fatigue week to months
after recovery. It resembles other post viral syndrome with muscle aches,
chronic malaise. It is self-limiting and does not require any specific
therapy. If the symptoms are persisting for more than 6 months, chronic
fatigue syndrome should be ruled out.

b) Neuropsychiatric sequelae
A Chinese study reported anxiety, depressive symptoms and sleep
disturbances in about 25% of patients at six months follow up. Headaches
resembling migraine that do not respond to usual analgesics and persisting
headaches have been reported in small studies. ‘Brain fog’ a term used to
describe symptoms of difficulty to concentrate, memory or cognition
impairments have also been reported. Smell and taste dysfunction usually
recover at a median duration of 31 days, however, persistent anosmia and
ageusia may persist in about 10% of patients even up to six months.

96
 c) Dermatologic sequelae
Significant hair loss (up to 20%) especially in women has been reported. It
is hypothesized to be secondary to viral infection and/or a stress generated
by the hospitalization and the disease. It resolves in 3-4 months.

d) Endocrine sequelae
SARS-CoV-2 has been demonstrated to cause pancreatic β-cell damage
which can persist in post covid period and cause insulin resistance. In a
retrospective study from England, diabetes was diagnosed in 4.9% of
COVID-19 survivors after discharge. Cases of diabetic ketoacidosis
(DKA) have been reported in those with no previous history of diabetes
mellitus, weeks to months after initial illness. Thyroid abnormalities such
as subacute thyroiditis have been reported post COVID. Decreased sperm
concentration and motility have also been reported post COVID.

Impact of vaccination and variants on Persistent symptoms

A recent observational study of 2560 patients with mild COVID-19 shows
that COVID-19 vaccination was associated with a dose-dependent decreased
prevalence of long covid symptoms (three doses 16 percent, two doses 17.4
percent, and one dose 30 percent) compared with unvaccinated individuals (42.8
percent).
Omicron variant was associated with a lower risk of developing persistent
symptoms compared with the Delta variant (4.5 versus 10.8 percent).
Observational data from non-hospitalized health care workers also suggest that
the prevalence of persistent symptoms waned with each successive COVID-19
wave (48 percent in wave 1 [wild-type variant], 36 percent in wave 2 [alpha
variant], and 17 percent in wave 3 [Delta and Omicron]). Though, there is a
possibility of results being influenced by the impact of vaccination status.

Conclusion:

COVID 19 carries a varying degree of risk of complications weeks or

months after the initial insult. However, the risk is less with newer milder variants
and in vaccinated individuals. Serious post COVID manifestations are
mucormycosis, thromboembolic episodes and MIS-A. It is important for
physicians to be aware and regularly monitor these patients.

97
Suggested reading:

1. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGruder C, Stevens

Jacob S.et al et al. Post-acute COVID 19 syndrome. Nature Medicine.2021;
27 (Apr): 601–615
2. BMJ best practice. Coronavirus disease 2019.
https://bestpractice.bmj.com/topics/en-us/3000168 (Last updated 08 Jul,
2022)
3. Multisystem Inflammatory Syndrome in Adults - Case Definition
information for health care providers. Centre for Disease Control and
Prevention (CDC).
4. Singhal T. The Chronic Effects of COVID-19 or “Long COVID”. The
Indian Practitioner.2021; 74(4): 24-31.
5. COVID-19: Evaluation and management of adults with persistent
symptoms following acute illness ("Long COVID")- UpToDate.

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11. Vaccines

Surg Cdr Kavita B Anand, Air Cmde SP Singh

Introduction
Since the publication of the whole genome sequence of the SARS-CoV-2
virus on 11 Jan 2020, the race for development of vaccines that began against
COVID 19 has progressed with unprecedented pace and magnitude. Around the
world, there are now 137 COVID-19 vaccine candidates undergoing clinical trials
and 194 candidates in pre-clinical development. There are different technologies
for development of vaccines. Currently ten platforms are being used for the
development of vaccine. Many candidate vaccines are in various phases of trial,
and some have been granted emergency use approval (EUA) by US Food and
Drug Administration (FDA). Pfizer/BioNTech obtained EUA for its vaccine in
December 2020, Moderna a week later and Johnson & Johnson in February 2021.
Covaxin and Covishield were granted EUA in India on 03 Jan 2020. The four
vaccines, which have been given EUA in India are Covaxin, Covishield, Sputnik
V, Moderna, ZyCOV DNA vaccine and Corbevax at the time of writing this
article.

Fig 11.1 Vaccines based on Inactivated Virus

1. Covaxin (BBV152)

COVAXIN® (BBV152) is an inactivated virus vaccine developed by

Bharat Biotech in collaboration with ICMR. Covaxin uses traditional technology.
It is based on a novel Algel+IMDG adjuvant. IMDG is a TLR7/8 agonist, which
induces memory T cell responses as well as strong neutralizing antibodies. This

99
vaccine is a multi-epitope vaccine and can cause activation of cell mediated
immune responses; the immune protection can be achieved from S, RBD and N
proteins similarly. The vaccine received the Emergency use approval in India on
03 Jan 21. (8) It has to be stored at 2-80C.

2. COVID-19 Vaccine (Vero Cell), Inactivated (Sinopharm)

It is an inactivated vaccine produced by the Beijing Institute of Biological
Products Co Ltd. This vaccine is adjuvanted (with aluminium hydroxide), to
increase the response of the immune system. The unopened vials and monodose
prefilled syringes have to be stored between 2 to 8 °C for 24 months or until
expiry date stated on the label.

Vaccines bases on Virus vector non replicating technology

1. Covishield
Oxford–AstraZeneca COVID19 vaccine, codenamed AZD1222 is also
marketed under the name Vaxzevria in Europe. It is a viral vector vaccine
developed by Oxford University and AstraZeneca. It is a recombinant,
replication-deficient chimpanzee adenovirus vector encoding the SARS -CoV-2
Spike (S) glycoprotein (Abbreviated as ChAdOX1-S). Produced in genetically
modified human embryonic kidney (HEK) 293 cells. The vaccination course
consists of two separate doses. The second dose being administered at 4-6 weeks.
However, ICMR has suggested administration of the second dose up to 12 weeks
after the first dose to give a robust immune response. It needs to be stored at 2-80
C for up to 6 months.

2. Sputnik V (Gam-COVID-Vac)
Sputnik V (Gam-COVID-Vac) is a combined vector vaccine. It contains
two components. Component I contains- recombinant adenovirus serotype 26
particles containing the SARS-CoV-2 protein S gene and component II contains
recombinant adenovirus serotype 5 particles containing the SARS-CoV-2 protein
S gene. Component I and II are administered on Day 0 and Day 21 respectively.
No serious adverse effects have been reported for Sputnik V. The vaccine has to
be stored at -180C or below in a lightproof place. The thawed vaccine can be
stored at room temperature (15-250C) for no more than 2 hours.

100
3. COVID19 vaccine Janssen
COVID19 vaccine Janssen contains Adenovirus type 26 encoding the
SARS-CoV-2 spike glycoprotein (Ad26.COV2-S). It is produced in the PER.C6
TetR cell line using recombinant DNA technology. It is a single dose vaccine and
approved for individuals more than 18 years of age. Vaccine needs to be stored
at 2-80C. Once opened the vial can be stored at 2 to 8 0C for six hours or at room
temperature (maximally 250C) for two hours.

Vaccines based on RNA technology

1. Pfizer-BioNTech (Comirnaty)

Pfizer-BioNTech COVID-19 was the first vaccine to be granted EUA by

US FDA. The vaccine is based on mRNA based vaccine technology. It is
composed of nucleoside-modified mRNA (modRNA) which encodes the spike
protein of SARS-CoV-2, encapsulated in lipid nanoparticles. The mRNA
vaccines are a favourable choice to conventional vaccine platforms because of
their high potency, capability for rapid development, low side effects and
possibility for low-cost of production. It is safe for use in more than twelve years
old. It has to be stored at -800 to -600C for six months and then at 2 to 80C for five
days prior to administration.

2. Moderna COVID-19 vaccine

Moderna COVID19 vaccine is the second vaccine to receive EUA from

US FDA. It uses technology similar to Pfizer BioNTech. It has to be stored at -25
to -150C for 6 months and 2-80C for 30 days.

Indigenous COVID Vaccines under development

1. ZyCoV-D

This Indian vaccine, manufactured by Zydus Cadila is based on DNA

technology and is currently in Phase III clinical trials. It follows a three dose
protocol and has applied for EUA.

101
2. Novavax

Novavax COVID-19 vaccine (NVX-CoV2373) is a subunit vaccine being

manufactured by Novavax and is undergoing Phase III trials in India.

3. BBV 154

Bharat Biotech BBV 154 is an intranasal vaccine based on viral vector non
replicating technology and currently in Phase I clinical trial. BBV 154 is a single
dose vaccine.

4. COVI-VAC

Codagenix is manufacturing this vaccine in partnership with Serum

Institute of India. COVI-VAC is a single dose intranasally administered live
attenuated vaccine. It will provide immunity against all antigens of SARS-CoV-
2 and is expected to provide protection against a range of SARS-CoV-2 strains.
The vaccine has been found safe in animal studies and is presently being
evaluated in the Phase I clinical trials.

102
 Table 11.1: COVID19 vaccines based on various platforms

Vaccine Type of vaccine No of Dose Developers Phase

platform candidate Days of Of Trial
administration
Route
Inactivated (BBV152); Covaxin Two Bharat Biotech Phase 3
Virus Day 0,28 International Limited
IM
CoronaVac; Two Sinovac Research and Phase 4
(vero cell) Day 0,14 Development Co., Ltd
IM
Viral Vector ` One/Two AstraZeneca +University Phase 4
(non- Day 0 ± 28 of Oxford
replicating) Sputnik Two Gamaleya research Phase 3
Day 0, 21 Institute; Health Ministry
IM of Russian Federation
BBV154, One Bharat Biotech Phase 1
Day 0 International Limited
IN
Live COVI-VAC One/Two Codagenix/Serum Phase 1
Attenuated Day 0±28 Institute of India
Virus IN

RNA mRNA-1273 Two Moderna + National Phase 4

Moderna Day 0, 28 Institute of Allergy and
IM Infectious Diseases
(NIAID)
BNT162b2 Two Pfizer/BioNTech + Phase 4
(3 LNP-mRNAs ), Day 0, 21 Fosun Pharma
also known as IM
"Comirnaty"
DNA nCoV Vaccine Three Zydus Cadila Phase 3
Day 0,28,56
ID
Viral Vector DelNS1-2019- Two University of Hong Phase 2
(replicating) nCoV-RBD-OPT1 Day 0, 28 Kong, Xiamen University
(Intranasal flu- IN and Beijing Wantai
based-RBD) Biological Pharmacy

103
 Vaccine Type of vaccine No of Dose Developers Phase
platform candidate Days of Of Trial
administration
Route
Protein SARS-CoV-2 Two Novavax Phase3
subunit rS/Matrix M1- Day 0, 21
Adjuvant IM
(Full length
recombinant SARS
CoV-2 glycoprotein
nanoparticle vaccine
adjuvanted with
Matrix M)
NVX-CoV2373
Virus Like RBD SARS-CoV-2 Two Serum Institute of India + Phase 1/2
Particle HBsAg VLP vaccine Day 0,28 Accelagen Pty +
IM SpyBiotech
VVr Dendritic cell One Aivita Biomedical, Inc. Phase 1/2
+ Antigen vaccine AV- Day 0 National Institute of
Presenting COVID-19. A IM Health Research and
Cell vaccine consisting of Development, Ministry of
autologous dendritic Health Republic of
cells loaded with Indonesia
antigens from
SARS-CoV-2, with
or without GM-CSF
Live COVI-VAC One/Two Codagenix/Serum Phase 1
Attenuated Day 0 ± 28 Institute of India
Virus IN
VVnr LV-SMENP-DC One Shenzhen Geno-Immune Phase 1/2
+ Antigen vaccine. Dendritic Day 0 Medical Institute
Presenting cells are modified SC/IV
Cell with lentivirus
vectors expressing
COVID-19
minigene SMENP
and immune
modulatory genes.
CTLs are activated
by LV-DC
presenting COVID-
19 specific antigens.

104
 Table 11.2 Newer vaccines under development

Vaccine
platform Type of No of Dose Days of Developers Phase
candidate vaccine administration of Trial

CORBEVAX 02 28 Biological Phase 4

Protein IM E. Limited
subunit (BioE)
CoV2- 1-2 Day 0 +/- 14, USSF/Vaxf Phase 1
OGEN1, Oral orm
protein-based
vaccine
ACM-SARS- 2 Day 0 + 28, ACM Phase 1
CoV-2-beta IN/IM Biolabs
ACM-CpG
vaccine
candidate
(ACM-001)
Live COVI-VAC 1-2 Day 0 ,IN Codagenix/ Phase 3
attenuated Serum
virus Institute of
India
MV-014-212, 1 Day 0,IN Meissa Vacc Phase 1
a live ines, Inc.
attenuated
vaccine that
expresses the
spike (S)
protein of
SARS-CoV-2
DNA based INO- 2 Day 0 + 28, ID Inovio Phase 3
vaccine 4800+electro Pharmaceuti
poration cals +
International
Vaccine
Institute +
Advaccine
AG0301- 2 Day 0 + 14, IM AnGes + Phase 2/3
COVID19 Takara Bio
+ Osaka
University
nCov vaccine 3 Day 0+ 28 + 56, Zydus Phase 3
ID Cadila
GX-19N 2 Day 0 + 28, IM Genexine Phase 2/3
Consortium
Covigenix 2 Day 0 + 14, IM Entos Phase 1
VAX-001 - Pharmaceuti
DNA cals Inc.
vaccines +
proteo-lipid

105
vehicle (PLV)
formulation
CORVax12 - 2 Day 0 + 14, ID OncoSec Phase 1
Spike (S) Immunother
Protein apies;
Plasmid DNA Providence
Vaccine Health &
Services
bacTRL- 1 Day 0, Oral Symvivo Phase 1
Spike oral Corporation
DNA vaccine
GLS-5310 2 Day 0 + 56 or, GeneOne Phase 1/2
ID Life
Science, Inc.
COVIGEN 2 Day 0 + 28, University Phase 1
ID/IM of Sydney,
Bionet Co.,
Ltd
Technovalia
COVID- 2 Day 0 + 28,IM Takis + Phase 1/2
eVax, a Rottapharm
candidate Biotech
plasmid DNA
vaccine of the
Spike protein
AG0302- 2-3 Day 0 + 14 + AnGes, Phase 1/2
COVID19 28, IM Inc/Osaka
University
Plasmid DNA 2 Day 0 + 28, ID Scancell Ltd Phase 1
vaccine
SCOV1 +
SCOV2.
COVIDITY
VB10.2129, a 1-2 Day 0 + 21, IM Vaccibody Phase 1/2
DNA plasmid AS
vaccine,
encoding the
receptor
binding
domain
(RBD)
VB10.2210, 1-2 Day 0 + 21, IM Vaccibody Phase 1/2
DNA plasmid AS
vaccine,
encodes
multiple
immunogenic
and conserved
T cell
epitopes
spanning
multiple

106
 antigens
across the
SARS-CoV-2
genome.
SARS-CoV-2 2 Day 0 + 21, IM
The Phase 1
DNA vaccine University
(delivered IM of Hong
followed by Kong;
electroporatio Immuno
n) Cure 3
Limited
Prophylactic 3 Day 0 + 21 + Imam Phase 1
pDNA 42, IM Abdulrahma
Vaccine n Bin Faisal
Candidate University
Against
COVID-19
Inactivated Adjuvanted 2 Day 0 + 21 , SC The Phase 1
Virus inactivated Scientific
vaccine and
against Technologic
SARS-CoV-2 al Research
Council of
Turkey
(TÜBITAK)
Inactivated Inactivated 2 Day 0 + 28, IM KM Phase 3
Virus COVID-19 Biologics
vaccine Co., Ltd.
Live 2 Day 0 + 21, IM Laboratorio Phase 2/3
recombinant Avi-Mex
Newcastle
Disease Virus
(rNDV)
vector
vaccine
Inactivated 2 Day 0 + 14, IM Chumakov Phase 3
Whole Virion Federal
Concentrated Scientific
Purified Center for
Vaccine
(CoviVac)
Covi Vax, 2 Day 0 + 28, IM National Phase 1
inactivated Research
coronavirus Centre,
vaccine Egypt
Osvid-19 2 Day 0 + 28, IM Osve Phase 1
inactivated Pharmaceuti
vaccine for cal
Covid-19 Company
RNA based mRNA-1273 2 Day 0 + 28, IM Moderna + Phase 4
vaccine National
Institute of

107
 Allergy and
Infectious
Diseases
(NIAID)
BNT162b2 (3 2 Day 0 + 21, IM Pfizer/BioN Phase 4
LNP-mRNAs Tech +
), also known Fosun
as Pharma
"Comirnaty"
CVnCoV 2 Day 0 + 28, IM CureVac Phase 3
Vaccine AG
ARCT-021 NR NR,IM Arcturus Phase 2
Therapeutic
s
LNP- 2 NR,IM Imperial Phase 1
nCoVsaRNA College
London
SARS-CoV-2 2 Day 0 + 14 or Academy of Phase 3
mRNA Day 0 + 28, IM Military
vaccine Science
(ARCoV) (AMS),
Walvax
Biotechnolo
gy and
Suzhou
Abogen
Biosciences
Viral vector AAV5-RBD- 1 Day 0, IM Biocad Phase 1/2
(Replicating) S vaccine
(BCD-250),
A
recombinant
Adenovirus-
Associated
viral Vector
(AAV-5)
encoding
spike protein
Ad26.cov2.s+ 1 Day 0, ID Han Xu, Phase 1
bcg vaccine. M.D., Ph.D.,
AD26-BCG FAPCR,
Sponsor-
Investigator,
IRB Chai
MVA-SARS- 1 Day 0, IH Hannover Phase 1
2-ST Vaccine Medical
School
V591-001 - 1-2 Day 0 + 28 ,IM Merck & Phase 1/2
Measles- Co. +
vector based Themis +
(TMV-o38) Sharp &
Dohme +

108
 Institute
Pasteur
DelNS1- 2 Day 0 + 28, IN University Phase 3
2019-nCoV- of Hong
RBD-OPT1 Kong,
(Intranasal Xiamen
flu-based- University
RBD ) and Beijing
Wantai
Biological
Pharmacy
Covid- 3 Day 0 + 14 + Shenzhen Phase 1
19/aAPC 28, SC Geno-
vaccine. The Immune
Covid- Medical
19/aAPC Institute
vaccine is
prepared by
applying
lentivirus
modification
with immune
modulatory
genes and the
viral
minigenes to
the artificial
antigen
presenting
cells
(aAPCs).
rVSV-SARS- 1 Day 0, IM Israel Phase 2/3
CoV-2-S Institute for
Vaccine (IIB Biological
R-100) Research
Dendritic cell 1 Day 0, IM Aivita Phase 2
vaccine AV- Biomedical,
COVID-19. Inc;
A vaccine
consisting of
autologous
dendritic cells
loaded
COVIVAC. 2 Day 0 + 28, IM Institute of Phase 1/2
Newcastle Vaccines
Disease Virus and Medical
(NDV) Biologicals,
expressing Vietnam
membrane-
anchored pre-
fusion-
stabilized

109
 NDV-HXP-S; 1 Day 0, IN/IM Sean Liu, Phase 2/3
A Live Icahn
Recombinant School of
Newcastle Medicine at
Disease Mount Sinai
Virus-
vectored
COVID-19
Vaccine
Viral vector AAV5-RBD- 1 Day 0, IM Biocad Phase 1/2
(Replicating) S vaccine
(BCD-250),
A
recombinant
Adenovirus-
Associated
viral Vector
(AAV-5)
encoding
spike protein
Ad26.cov2.s+ 1 Day 0, ID Han Xu, Phase 1
bcg vaccine. M.D., Ph.D.,
AD26-BCG FAPCR,
Sponsor-
Investigator,
IRB Chai
MVA-SARS- 1 Day 0, IH Hannover Phase 1
2-ST Vaccine Medical
School
V591-001 - 1-2 Day 0 + 28 ,IM Merck & Phase 1/2
Measles- Co. +
vector based Themis +
(TMV-o38) Sharp &
Dohme +
Institute
Pasteur
DelNS1- 2 Day 0 + 28, IN University Phase 3
2019-nCoV- of Hong
RBD-OPT1 Kong,
(Intranasal Xiamen
flu-based- University
RBD ) and Beijing
Wantai
Biological
Pharmacy
Covid- 3 Day 0 + 14 + Shenzhen Phase 1
19/aAPC 28, SC Geno-
vaccine. The Immune
Covid- Medical
19/aAPC Institute
vaccine is
prepared by
applying

110
 lentivirus
modification
with immune
modulatory
genes and the
viral
minigenes to
the artificial
antigen
presenting
cells
(aAPCs).
rVSV-SARS- 1 Day 0, IM Israel Phase 2/3
CoV-2-S Institute for
Vaccine (IIB Biological
R-100) Research
Dendritic cell 1 Day 0, IM Aivita Phase 2
vaccine AV- Biomedical,
COVID-19. Inc;
A vaccine
consisting of
autologous
dendritic cells
loaded
COVIVAC. 2 Day 0 + 28, IM Institute of Phase 1/2
Newcastle Vaccines
Disease Virus and Medical
(NDV) Biologicals,
expressing Vietnam
membrane-
anchored pre-
fusion-
stabilized
NDV-HXP-S; 1 Day 0, IN/IM Sean Liu, Phase 2/3
A Live Icahn
Recombinant School of
Newcastle Medicine at
Disease Mount Sinai
Virus-
vectored
COVID-19
Vaccine
Virus like RBD SARS- 2 Day 0 + 28, IM Serum Phase 1/2
particle CoV-2 Institute of
HBsAg VLP India +
vaccine Accelagen
Pty +
SpyBiotech
Coronavirus- 2 Day 0 + 21, IM Medicago Phase 3
Like Particle Inc.
COVID-19
(CoVLP)

111
VBI-2902a. 2 Day 0 + 28, IM VBI Phase 1/2
An enveloped Vaccines
virus-like Inc.
particle
(eVLP) of
SARS-CoV-2
spike (S)
glycoprotein
and
aluminium
phosphate
adjuvant.
SARS-CoV-2 2 Day 0, SC The Phase 2
VLP Vaccine Scientific
and
Technologic
al Research
Council of
Turkey
ABNCoV2 2 Day 0 + 28, IM Radboud Phase 3
capsid virus- University
like particle
(cVLP) +/-
adjuvant
MF59
SARS-CoV-2 3 Day 0 + 28 + Yantai Phase 1
Vaccine 56, IM Patronus
LYB001, a Biotech Co.,
receptor- Ltd.
binding
domain
(RBD) from
SARS-CoV-2
and virus-like
particle
(VLP) vector,
adjuvanted
with
aluminium
hydroxide.

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Suggested Reading

1. COVID-19 - Landscape of novel coronavirus candidate vaccine

development https://www.who.int/publications/m/item/draft-landscape-
of-COVID-19-candidate-vaccines(Last visited 13 Aug 2021)
2. Pfizer BioNTech Vaccine. https://www.fda.gov/emergency-preparedness-
and-response/coronavirus-disease-2019-COVID-19/pfizer-biontech-
COVID-19-vaccine (last visited 13 Aug 2021)
3. Moderna COVID 19 vaccine https://www.fda.gov/emergency-
preparedness-and-response/coronavirus-disease-2019-COVID-
19/moderna-COVID-19-vaccine (last visited 13 Aug 2021)
4. When-will-COVID-19-vaccines-be-fully-approved-and-does-it-matter-if-
they-are.https://www.sciencemag.org/news/2021/07/(last visited 13 Aug
2021)
5. https://www.bharatbiotech.com/images/press/barat-biotech-bbv152-
covaxin-phase3-final-analysis-03July2021.pdf
6. Vaxzevria (previously COVID-19 Vaccine Astra Zeneca)
https://www.ema.europa.eu/en/medicines/human/EPAR/vaxzevria-
previously-COVID-19-vaccine-astrazeneca.(last visited 13 Aug 2021)
7. Factsheet of Gam-COVID-Vac Combined vector vaccine (Component I &
II) SPUTNIK V of Dr. Reddy's Laboratories Ltd. Downloaded from
https://cdsco.gov.in/opencms/opencms/en/biologicals/Vaccines/(Last
visited on 1 Aug 2021)
8. Pardi, N., Hogan, M., Porter, F.W., Weissman D. mRNA vaccines — a
new era in vaccinology. Nat Rev Drug Discov 2018; 17:261–279

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 12 Adaptive Immunity, Vaccine Efficacy, &
Vaccination strategy

Surg Capt Saurabh Bobdey, Lt Col AK Yadav, Brig SK Kaushik

Brig A S Menon, Col Y Uday

Protective immunity against Covid 19

The immune mechanisms preventing severe disease is layered one and can
be likened to a Swiss cheese. Both natural infection and vaccines trigger an
adaptive immune response in the host. Adaptive immune responses, which
protect against Covid 19 are a combination of circulating (Ig G) and local
antibodies (Ig A), memory B Cells, CD4 T cell and CD8 T cell. Antibodies can
protect against COVID 19 if present before infection by neutralizing them.
Observational studies have confirmed that there is gradual decline in neutralisng
antibodies with time. However, the cell-mediated immunity may still be
preserved. It is postulated that local site specific T cell response (e.g. lung) may
protect against severe disease even if infection occurs. Variants of concern,
(mutant strains of the original SARS CoV 2) are able to evade the antibody
response and is an important reason for persistence of SARS CoV2 in the
community and various waves of the current pandemic, Omicron being the latest.
There is substantial immunological and epidemiological evidence that hybrid
immunity (infection plus vaccine) provides the most robust immunity against
COVID-19. Booster doses if adequately spaced after last dose of vaccine or
infection increase the repertoire of memory B cell to respond to the variant strains
and may reduce the severity of illness.

Vaccine Efficacy & Effectiveness

Vaccine efficacy is the degree to which a vaccine prevents a disease or
transmission as compared to a placebo. Efficacy is calculated in a setting of
clinical trial. The earliest efficacy data, which became available, was for mRNA
vaccines. Both mRNA-1273 Moderna and BNT162b2 (Pfizer, BioNTech)
showed efficacy up to 95 % in preventing symptomatic disease when compared
with placebo. The efficacy was also demonstrable in those greater than 65 years
old. Since then Pfizer BioNTech vaccine has received approval for use in more
than 90 countries. ChAdOX1-S vaccine (Covishield, India) was found to have a

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vaccine efficacy of 70.1 % in an interim analysis of clinical trials conducted in
Brazil, South Africa and UK leading to its emergency use authorization in India.
BBV 152 (Covaxin, Bharat Biotech) has been reported to have an efficacy of
77.8% in preprint version published on medRxiv. Preliminary results from
interim analysis of Gam-COVID-Vac (Sputnik V) reported of vaccine efficacy of
91.6 %. The vaccine trials have been carried out at different times during the
pandemic. There has been change in the prevalence of disease in the population
and new variants have emerged, hence direct comparisons of efficacy results are
likely to be fallacious.

Effectiveness on the other hand is obtained from surveillance data obtained

from real world setting after vaccine administration; hence, the terms efficacy and
effectiveness are not to be used interchangeably. VIN WIN studied a cohort of
one and half million HCW and frontline workers of Indian Armed Forces who
were administered Covishield in the first phase of vaccination in India. The
vaccine effectiveness was found to be 91.8-94.9 % against breakthrough
infections. All vaccines presently used in India have shown high effectiveness
against hospitalisation, severe disease and death against all variants.

The BNT162b2 (Pfizer) and ChAdOx1 nCoV-19 both had shown reduced
effectiveness against Delta variant of 88 % and 67 % respectively. Another
notable difference was that the effectiveness was 30.7 % after one dose of vaccine
(pooled data for both vaccines) arguing that both doses of vaccine should be taken
for maximum effect.

No official data or large-scale study on efficacy of Corbevax is available

presently, but a randomised control trial conducted in paediatric age groups with
312 participants shows vaccinated subjects having significant improvement in
humoral immune responses in terms of anti RBD-IgG concentrations, anti-RBD-
IgG1 titres, neutralizing antibody (nAb)-titres against Ancestral Wuhan and Delta
strains. CORBEVAX vaccinated subjects with minimal effect on IL-4 cytokine
secretion elicited significantly high interferon gamma immune response
(cellular).

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Precautionary/Booster dose
With the increasing evidence of waning of immunity after second dose and
emergence of Omicron variant, immunisation with booster dose is started by
countries by latter half of 2021. Countries like Israel, USA and UK were the first
ones to announce Booster for high-risk populations. A systematic review done on
efficacy of COVID booster shots based on studies done in UK and US have
shown the effectiveness of booster dose vaccination, significant increase in
neutralizing immunity, and higher levels of antibody titres against the new
COVID‐19 variant Omicron. In India, free precautionary dose for high-risk
groups was announced in Jan 2022 and for all eligible population in Apr 2022
through private vaccination centres. In India presently nine months gap is
recommended between booster dose and second dose. Presently as of Jun 2022,
only 2 percent of the eligible people in India have taken the precautionary dose.

Vaccination Strategy of India

A Ministerial Advisory Committee on COVID-19 Vaccines has been
constituted with experts in the field of vaccines as advisors. They have made a
strategy to ensure equitable access to vaccines. This strategy includes the various
purchasing mechanisms, funding implications, local manufacturing
opportunities, and identifying priority groups for vaccination. India began
administration of COVID-19 vaccines on 16 January 2021. As of 17 June 2022,
India has administered over 1.9 billion doses overall, including first, second and
precautionary (booster) doses of the currently approved vaccines. In India, 93%
of the eligible population (12+) has received at least one shot, and 83% of the
eligible population (12+) is fully vaccinated

Prioritization for vaccination

As per Ministry of Health & Family welfare guidelines (MoHFW), in the
first phase, COVID-19 vaccine was given to priority groups i.e., health care and
frontline workers. In the second phase of vaccination, which started on 01 March
2021 vaccination was started for all Indians of age more than 60 years and those
between 45 - 59 years of age with comorbidities. From 01 April 2021, people
older than 45 years of age without comorbidities were also made eligible and on
01 May 2021, vaccination was started for eligible citizens above 18 years. From
21 Jun 21 vaccination for free was announced for all personnel above 18 years
was announced. On 3rd Jan 22 vaccination for children aged 15-18 years started.
On 10 Jan 22 the precautionary dose for HCW, FLW and personnel aged > 60

116
years and with comorbidity was announced. The precautionary dose for the age
group 18-60 without any comorbidity is available on payment basis presently.

Fig 12.1 National COVID 19 vaccination policy

The flow of vaccine from manufacture to user

India has up-scaled its cold chain infrastructure to facilitate smooth

transportation of vaccines across the length and breadth of the country. The
manufacturers of COVID-19 vaccine dispatches consignments via air or by road
to four designated Government medical store depots (GMSD) located in Mumbai,
Chennai, Kolkata, and Karnal. From these GMSDs, the vaccines are transported
in refrigerated or insulated vans to States and UTs. Centre and state governments
co-ordinate and monitor their transportation and maintenance of cold chain.
There are thirty seven state vaccine stores meant for bulk vaccine stores. It is the
responsibility of the state to safely transport vaccines to various districts, sub-
districts, and Primary health centres (PHCs) with minimal or zero wastage. PHCs
with Ice Lined Refrigerators are the final point of vaccine storage. The movement
of vaccines is regularly updated on the CO-WIN digital platform.

Planning and conduct of vaccination

Infrastructure.
Following are infrastructure norms for vaccination centre-
(a) The vaccination centre should have three demarcated rooms/ areas namely
waiting room, vaccination room and observation room

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(b) These rooms should have a minimum of two doors, one for entry and one
for the exit as shown in Fig 1. A physical distance of at least two meters should
be maintained between chairs/seats in the waiting and observation rooms.

(c) The waiting room should have a facility for hand washing/ sanitization and
display IEC materials on COVID-appropriate behaviour.

(d) The vaccination room should have a table of at least 4 feet x 2 feet and two
chairs. Hand washing/ sanitization arrangement and following logistics should
be made available in the vaccination room:
(i) Adequate COVID-19 vaccine
(ii) Adequate numbers of syringes
(iii) Hand sanitizer and masks
(iv) Needle destroyer/ Hub cutter
(v) If the room is not separate, then use of a screen to be done
(vi) Cotton
(vii) Anaphylaxis/AEFI kit
(viii) Separate color-coded waste bags for waste segregation

(e) The observation room should have space for waiting and observation of
AEFIs following immunization. IEC materials on COVID appropriate
behaviour may be displayed in the area.

Fig 12.2 Layout of vaccination Centre

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AEFI
As of January 30, 2022, India has reported at least 70,102 cases of Adverse
Events Following Immunization (AEFI), and 1,013 fatalities following the
COVID-19 vaccines, the Ministry of Health and Family Welfare informed the
Parliament. Majority of studies conducted has shown Fever and Myalgia as the
most common adverse effects following vaccination. The rate of serious health
effects for all vaccines used in India were very low considering the large number
of doses administered. AEFI data in India showed that there is a very miniscule
but definitive risk of thromboembolic events. The reporting rate of these events
in India is around 0.61/million doses, which is much lower than the four
cases/million reported by UK’s regulator Medical and Health Regulatory
Authority (MHRA). Germany has reported 10 events per million doses.

Management of AEFI.

An adverse event following immunization (AEFI) is any untoward medical

occurrence that follows immunization, and which may not necessarily be a direct
side effect of the vaccine. The most common effects reported post ChAdOx1
vaccination are pain at local site lasting 12 to 24 h, fever, fatigue, chills, myalgia
and arthralgia, they usually respond to Acetaminophen and NSAIDS. Similar
effects are reported after m-RNA vaccines. Events like transverse myelitis,
venous thrombosis and thromboembolic events have been reported post
ChAdOx1, however with millions of doses administered till date the absolute
risks is small and beneficial effects outweigh the risk. An observation period of
thirty minutes is recommended post vaccination. The guidelines for the
management of AEFI on site are as follows:
(a) All beneficiaries must be counselled about the adverse events such
as local pain and swelling and mild to moderate fever, etc. which
may occur post COVID-19 vaccine.
(b) An AEFI management kit should be available for use at all
vaccination sites.
(c) All vaccinators should be trained to recognise symptoms and signs
of anaphylaxis and on use of anaphylaxis kit. Vaccinators are also
responsible for arranging transportation of the patient to the nearest
identified AEFI management centre/hospital for management of
severe/serious AEFIs.

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 (d) In case of any type of discomfort or illness post-COVID vaccination
and after the vaccine beneficiary leaves the vaccination centre he/
she should be advised to report to the nearest health care facility for
treatment.

Vaccine Induced Thrombotic Thrombocytopenia (VITT)

In February 2021, a prothrombotic syndrome was reported in a small

number of individuals who received the ChAdOx1 CoV-19 vaccine. This
syndrome has been designated vaccine-induced immune thrombotic
thrombocytopenia (VITT) and has also been reported with adenovirus vector
vaccine (Janssen). The exact incidence of VITT is unknown, but it appears to be
rare. Serious AEFI cases following Covid 19 vaccination (as reported to MoHFW
until May 22) shows two cases of thrombosis with thrombocytopenia and one
case of intracranial haemorrhage with thrombocytopenia. The lower reported
cases in India could be due to stringent case definition of VITT or lack of
diagnostic facility. VITT is caused by antibodies that recognize platelet factor 4
(PF4,) bound to platelets, leading to their activation via low affinity platelet
FcγIIa receptors and stimulation of coagulation system and thromboembolic
complications. VITT strongly mimics autoimmune heparin-induced
thrombocytopenia (aHIT). Pooled data from cases of VITT have shown median
age of cases to be 48 years(18-79), slight female preponderance
(M:F::45:55),median time to occurrence 14 days (5-48);sites of thrombosis
[(cerebral veins, deep veins of the leg, pulmonary arteries, and splanchnic vessels,
multiple sites (fifty percent of cases)].The treatment offered include
anticoagulation, intravenous immune globulin [IVIG], therapeutic plasma
exchange [TPE] and transfusions.

Waste management

(a) After administering the injection, with help of the hub cutter cut the
hub of the syringe.
(b) Cut needles in the hub cutter will get collected in the puncture-proof
container.
(c) The plastic portion of the cut syringes should be put into a red bag.
(d) The plastic wrapper and the cap of the syringe should be treated as
Municipal general waste.

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 (e) After administering the injection cotton swab should be put in a
yellow bag.
(f) Broken vials should be put into a puncture-proof blue container after
use.

Vaccination Certificate.

The vaccination centre is responsible for the registration of the vaccine

beneficiary and generation of vaccination certificate from the Co-WIN portal.
The registration of the vaccination centre on the Co-WIN portal has to be done
through District Immunization officer and should be completed before
commencement of the vaccination drive. As per GoI guidelines, it is mandatory
to complete the vaccination certification process on the spot at the vaccination
centre.

Vaccination in special groups

Occurrence of COVID19 in special groups like pregnancy, lactating

mothers, or individuals with co-morbidities may result in rapid deterioration of
health of individuals. Hence, experts are of the view that the benefits of
vaccination to the special group outweigh its potential risks. The National
Technical Advisory Group on Immunization (NTAGI), Ministry of Health &
Family Welfare (MoHFW) has advised COVID19 vaccination for individuals
with co-morbidities. COVID19 vaccination has now been also advised for
lactating and pregnant women. The operational guidelines issued by MoHFW
mandates that the women should be informed about the risks of exposure to
COVID19 infection along with the risks and benefits associated with the COVID-
19 vaccines available in the country. Based on the information provided, the
individuals will have the choice to take the vaccination.

Contraindication to vaccination

COVID Vaccine is contraindicated in individuals with history of:

(a) Anaphylactic or allergic reaction to a previous dose of COVID-19
vaccine
(b) Immediate or delayed-onset anaphylaxis or allergic reaction to
vaccines or injectable therapies, pharmaceutical products, food items, etc.

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Provisional/temporary contraindications: In these conditions, COVID
vaccination is to be deferred for 12 weeks after recovery
(a) Persons having active symptoms of SARS-CoV-2 infection.
(b) SARS-CoV-2 patients who have been given anti-SARS-CoV-2
monoclonal antibodies or convalescent plasma
(c) Acutely unwell and hospitalized (with or without intensive care) patients
due to any illness

Vaccine hesitancy
Even though COVID vaccine is well accepted in India unlike USA and
where there is adverse public reaction towards compulsory vaccination, some
studies have shown that 7-12% of eligible population in India are hesitant to take
COVID vaccination. The major barriers towards vaccination identified were fear
of side effects, low digital literacy, misinformation, and economic vulnerability.

Suggested Reading

1. Sette S, Crotte S. Immunological memory to SARS-CoV- 2 infection and

COVID-19 vaccines. Immunological Reviews. 2022; 310:27–46.
2. Interim statement on hybrid immunity and increasing population
seroprevalence rates [Internet]. [cited 2022 Jul 4]. Available from:
https://www.who.int/news/item/01-06-2022-interim-statement-on-hybrid-
immunity-and-increasing-population-seroprevalence-rates
3. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al.
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J
Med 2021; 384:403-416
4. Victoria Jane Hall, Sarah Foulkes, Ayoub Saei, Nick Andrews, Blanche
Oguti, Andre Charlett et al COVID-19 vaccine coverage in health-care
workers in England and effectiveness of BNT162b2 mRNA vaccine
against infection (SIREN): a prospective, multicentre, cohort study. Lancet
2021; 397: 1725–35
5. Jeewandara C, Fernando S, Pushpakumara PD, Ramu ST, Kamaladasa A,
Gunasekara B, et al. Immune responses following the first dose of the
Sputnik V (Gam-COVID-Vac). Sci Rep [Internet]. 2022 Feb 2 [cited 2022
Jul 6]; 12(1):1727. Available from:
https://www.nature.com/articles/s41598-022-05788-6

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6. MOHFW, GoI, COVID-19 vaccines - operational guidelines.
https://www.mohfw.gov.in/pdf/COVID19VaccineOG111Chapter16.pdf
(Last visited 13 Aug 2021)
7. Ghosh S, Subramanian Shankar, Chatterjee Kaustuv, Chatterjee Kaushik,
Yadav A K, Pandya K et al. COVISHIELD (AZD1222) VaccINe
effectiveness among healthcare and frontline Workers of INdian Armed
Forces: Interim results of VIN-WIN cohort study. MJAFI 2021; 77 S 2 6
4eS270
8. Bernaz JL, Andrews N, Gower C, Gallagher E, Simmons R et al .
Effectiveness of COVID-19 vaccines against the B.1.617.2 N Engl J Med
2021; 385:585-594
9. WHO, Evaluation of COVID-19 vaccine effectiveness (along with
addendum). https://www.who.int/publications/i/item/WHO-2019-nCoV-
vaccine effectiveness measurement-2021.1(Last visited 13 Aug 2022)
10. CorbeVax COVID-19 Vaccine [Internet]. [cited 2022 Jul 4]. Available
from: https://www.precisionvaccinations.com/vaccines/corbevax-covid-
19-vaccine
11. Chenchula S, Karunakaran P, Sharma S, Chavan M. Current evidence on
efficacy of COVID-19 booster dose vaccination against the Omicron
variant: A systematic review. J Med Virol. 2022 Jul; 94(7):2969–76.
12. Parida SP, Sahu DP, Singh AK, Alekhya G, Subba SH, Mishra A, et al.
Adverse events following immunization of COVID-19 (Covaxin) vaccine
at a tertiary care centre of India. J Med Virol. 2022 Jun;94(6):2453–9.
13. COVID-19 vaccine tracker and landscape [Internet]. [cited 2022 Jul 4].
Available from: https://www.who.int/publications/m/item/draft-
landscape-of-covid-19-candidate-vaccines
14. The COVID-19 vaccine race [Internet]. [cited 2022 Jul 4]. Available from:
https://www.gavi.org/vaccineswork/covid-19-vaccine-race
15. Thuluva S, Paradkar V, Gunneri S, Yerroju V, Mogulla R, Suneetha PV,
et al. Safety, tolerability and immunogenicity of Biological E’s
CORBEVAX™ vaccine in children and adolescents: A Prospective,
Randomised, Double-blind, Placebo controlled, Phase-2/3 Study
[Internet]. Infectious Diseases (except HIV/AIDS); 2022 Apr [cited 2022
Jul 6].
http://medrxiv.org/lookup/doi/10.1101/2022.04.20.22274076
16. MoHFW: Guidelines to COVID vaccination children 12-14 yrs.
,March2022

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17. https://www.mygov.in/COVID-19 (Last visited 13 Aug 2022)
18. http://www.gavi.org/COVID19 (Last visited 13 Aug 2022)
19. https://www.nejm.org/COVID-vaccine (Last visited 13 Aug 2022)

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13. Impact on mental health of COVID 19 Pandemic

Col Jyoti Prakash, Surg Cmde K Chatterjee

Introduction

COVID pandemic has adversely impacted our life and living conditions.
The unprecedented circumstances have spared none and has led to widespread
emotional and behavioural reaction in many. There is a need to understand these
behavioural and emotional reactions and implement appropriate remedial and
preventive measures to bolster mental well-being.

Common mental health issues in general population

a) Anxiety and worry about uncertain future

b) Fear of contamination and infection
c) Over-reaction to symptoms like cough, sore throat or fever
d) Hoarding of protective equipment, medicine and survival items
e) Anger/ irritation regarding irresponsible behaviour of people in society
related to spread of infection
f) Undue attention to unsubstantiated facts being shown in news and social
media
g) Irresistible urge to touch mouth/face

Common mental health issues in people infected with COVID 19

a) Fear of ostracization by people and avoidance of reporting due to

stigma/isolation
b) Undue guilt about having indulged in behaviour leading to the infection
c) Guilt about being responsible for spread of infection to near and dear ones
d) Anxiety and panic about worst possible outcomes
e) Worry about safety and well-being of family members
f) Undue fatigue and weakness

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Common mental health issues among health care workers

a) Anxiety about magnitude of cases and working environment inadequate to

handle load
b) Anxiety about individual role and competence/training for such role
c) Burnout due to long working hours, critically ill-patients and witnessing
deaths
d) Sense of failure, frustration, poor self-care, blaming, irritability, giving up,
etc
e) Secondary traumatic stress: Undue worry about something bad happening,
exaggerated startle, anxiety, nightmares etc.
f) Lack of adequate caution due to altruistic zeal

Table 13.1 General mental health management (ABC)

A Acknowledge feelings and share them with others

Awareness of realistic information and reliable sources like CDC, WHO,
ICMR etc
Avoid speculation and rumours
Adherence to hand hygiene, social distancing, vaccination protocol etc
Avoid excessive time in social media/ TV news
Arrange for periodic breaks with music, meditation or yoga
B Be physically active. Do regular exercises.
Balanced diet
Be a role model
Break chain of rumours
Balance work and leisure
Breaks are essential
C Communicate to people with empathy and allow expression of feelings
Care for elderly (more risk of infection)
Cultivate hobbies and routine to tide through tough times
Cautious approach towards spread of infection
Chat and e-socialize for continued connect with people
Commit yourself towards some noble cause, altruism, societal welfare,
larger goal

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Additional measures as a health care worker

a) Prepare in advance, conduct mock training and drill

b) Have clarity of role and realistic management goals
c) Conduct regular risk assessment and critical incident debriefing
d) Have effective buddy system to ventilate and express emotions and
concerns
e) Take healthy breaks and healthy diet
f) Look for signs of burn out and stress. Intervene early
g) Cultivate cautious calmness in the hospital and at work
h) Avoid/limit use of caffeine and alcohol
i) Keep an eye out for each other

Self-reminders for health care workers

a) Protect yourself.
b) It is NOT SELFISH to take breaks
c) Needs of your well-being is important for the patient under your care
d) Working all the time is NOT your best contribution
e) There are other people who can help

Management of specific mental health issues

Handling distress- Emotional distress during pandemic is widely prevalent.

Affected individual should be assured that given these exceptional circumstances,
the distress is normal and many are going through it. Anxiety is further allayed
by reliable information on these concerns. Empathetic communication and
support of the family is important. They are asked to focus on routines and invest
on healthy coping strategies like exercises, hobby, relaxation training etc.

Breaking bad news- Significant empathy and skill is needed to break bad news,
given the growing number of COVID related complications and mortality.
SPIKES is a mnemonic for intervention, which can be used by medical
professionals to deliver bad news to a patient or their relatives. (Table 11.2)

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SPIKES stands for:
 S – Setting
 P – Perception/Perspective
 I – Invitation
 K – Knowledge
 E – Empathy/Emotion
 S – Summary/Strategy

Table 13.2 SPIKES protocol for breaking bad news

Setting It is important to select the right setting and time to talk to the
patient or relatives. Therapist should not be in a rush and ensure
privacy in the selected room. There should be minimum
interruption. Ensure that the next of kin and vital member of care
team is present during the session. Take some time to introduce
each other and offer place to sit, so that all are comfortable in the
room
Perspective/ Explore what the patient/ family member already knows about the
Perception situation. Some questions which may be asked are:
 Tell me, what you know about your/your husbands’
illness?
 Do you know why you have been called here?
 How do you think the illness is affecting you or the patient?
Above questions provides a baseline of the knowledge, patient or
their family has and how they might react to the news. Some
patient/ relatives may lack understanding or be in denial of the
illness being serious. Depending on the baseline, the extent of
information to be given and nature of delivery is decided
Invitation Find out how much they desire to know about the situation. Some
people may want specific details where as some would prefer
broad description only. Asking these simple questions might help
that-
 Would you like to know what to expect in future with
regard to the illness of your loved ones?
 Would it be fine, if we discuss some important issues about
the illness?
 We have test results here. Can we discuss them?
Knowledge After having found out baseline knowledge and what the patient /
family member wants, it is time to explain them the current health
status and deliver the news. Keep it simple to understand. Be direct
but communicate empathically. You can prepare them with some

128
 advance warning, of what they are going to hear. Useful sentences
are
 This is looking more serious than we originally expected.
 The condition may be a little more serious than that.
Give the information slowly for them to process and give some
time to let it sink in or clarify doubts if any. Repeat important
points of the agenda and check they have understood the
information well
Empathy/Emotion Be empathetic throughout, while imparting information and
addressing relevant concerns. Address the emotional response
during the session with genuine concern and understanding. Help
them normalize the way they are feeling and render necessary
support
Summary/Strategy Support is the last step of SPIKES. Let them know in simple and
clear words that the whole team is there doing their best, is ever
there to support and that they are not alone. Work out a plan with
them for moving forward and answer any query they have

Handling grief- Many families have suffered loss of near and dear ones during
current COVID crisis. There has been restriction on meeting the dead,
performance of final rites and proper burial or cremation. All these are likely to
complicate the grieving process and may require mental health intervention.
Acknowledge their feeling of loss, allow ventilation of their emotions. Be with
the individual, give him time / opportunity to talk about his/her loved ones. Offer
assistance and help them connect with their social network. Give space to the
grieved family, if needed. Guilt of not having been able to give the due to the
departed soul can be addressed by universalization of the issue, helping them
connect with people in general and those who went through this phase
successfully, assisting in ventilation of emotion and rest.

Special considerations

Mentally ill person- There has been increase in relapse/ severity of illness or
psychiatric emergencies because of lockdown, lack of accessible health care,
nonavailability of medications, expressed emotions of caregiver because of
increased together time, irregular compliance, boredom etc. Use of
telepsychiatry, prescribing easily available medication and for longer period,
maintaining contact with caregivers, activity scheduling, avoiding triggers and
anticipating early warning signs is useful.
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Worried well- There may be undue fear in some people of having contracted the
disease and they may frequently report sick with various complaints, which do
not turn out to be COVID. They are likely to increase burden to health care system
and expose them to increase risk to infection due to frequent visit to health care
services. Hearing them out, validating their feeling, imparting appropriate
knowledge of illness & preventive strategies thereof may allay anxiety.
Relaxation exercise or short course of anxiolytics may be required at times.

Suicidality- There has been increased suicidality due to isolation, boredom, sense
of despair, lack of goal and continued crisis overshadowing the optimism. There
would be sense of hopelessness/ helplessness, suicidal ideas or plan, mood swing
or associated substance use. Management aims at addressing current emotion,
risk assessment and provision/ emotional support to tide the crisis. Short time
anxiolytic may be required. Underlying psychiatric illness, if found, is treated as
per existing guidelines.

Violence and aggression- Given the constraining environment and limited

option a person may get angry and resort to violence. These may be seen in
patients and the family looking after them. The brunt may be borne by the health
care worker/ facility. It is therefore important to anticipate likely situations and
take timely actions. However, in case of person with manifest violence, first make
oneself safe. Keep safe distance and calm composure. Assess situation and risk
involved. Avoid confrontational stance and call for help. Try to understand the
cause of his behaviour. Rephrase his words back to him in a manner which bring
his/ her focus to the anger. Suggest a non-violent approach for the same problem
and ensure support throughout, given that he/she behaves in socially appropriate
manner. Additionally, the surrounding environment may be made more harm
proof (bereft of items which can be used as instrument of violence) with soothing
ambience.

Substance use- Increase in substance use has been seen both in general
population as well as those afflicted with mental illness/ addiction. Because of
restrictions and lockdown, a patient of dependence may suffer from significant
withdrawal feature requiring definitive interventions. Avoiding the triggers,
preparing in advance to curtail drinking and relying on alternate source of
enjoyment, helps.

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Domestic violence- There have been increased incidence of domestic violence
and substance abuse because of being together in confined space for long,
financial crisis and lack of creative utilization of time. Allowing separate
emotional space, defining separate/ together times and lowering expectations
from others who are also in similar crisis, helps.

COVID medication and psychiatric treatment- There are significant

interaction with COVID related medicine and psychiatric medication. Antivirals
increases the level of Olanzapine, Quetiapine and Haloperidol.
Hydroxychloroquine and azithromycin when given with haloperidol may prolong
QT interval. Most SSRI increases toxicity of antiviral drugs. Sertraline and
Escitalopram are safer amongst them. Ritonavir may decrease concentration of
Lamotrigine and Valproate. Benzodiazepines can increase the risk of respiratory
depression in delirium.

Moderate and severe COVID patient- These patients may have delirium due to
hypoxemia and other metabolic disturbance. Anxiety features may be there while
weaning off ventilator. Reorientation, good sleep, pain management, adequate
nutrition & hydration and early mobilization will reduce/ prevent delirium. Low
dose antipsychotics may be required for behavioural control. Olanzapine,
quetiapine, haloperidol has been used.

Children- Avoid information load, it may confuse them. Provide balanced level
of information. Do activity scheduling at home to keep them occupied at home or
involved. Cater to some family time for communication and expression of
feelings. Be a role model for them to emulate right coping behaviour.

Adolescents- There is increased likelihood of perceive invincibility and

experimentation with substance of abuse. Activity scheduling helps. Have
positive interaction and provide stroke for good behaviour. Avoid behavioural
addiction like video games, social media, unhealth food etc

Elderly- Geriatric population is likely to have more comorbidities thus exposing

them to higher risk to COVID infection. They are not that apt with technology to
be in communication with people on internet, mobile or social media, which is
important during current crisis. Risk of delirium is also higher. There is need for

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extra precaution and structuring of routine. Regular health review, medication for
comorbidities, adequate nutritional balance etc is important.

Pregnancy- There may be additional concerns related to effect of virus on baby,

use of sanitizer, breast feeding following infection etc. Positive birth related
stories and minimizing contact with anxiety provoking stimuli will help.

Disabled person- There is additional concerns of being a burden to others during

crisis time and fear of care giver falling ill. Continued access to health care,
allaying of these concerns and enlisting support system/ services helps.

Other mental health interventions

Softwares & applications- The current COVID crisis has given lot of avenues
for digital mental health intervention. Currently there are many free and paid
software and apps which addresses various mental health issue. There are
facilities available for both evaluation and management of mental health
problems. Various measure available are chatbot, pep-talk, community
discussion, life coach, booster buddy, relaxing task, professional supports etc.

Helplines-There are many international and national helplines available, which

are dedicated to addressing COVID related mental health issues. In Armed Forces
there is helpline available in Base Hospital Delhi and Command Hospital (EC)
Kolkata.

Summary

The COVID 19 Pandemic is associated with significant psychosocial issues.

Health care workers have additional issues of ‘burn out’ and ‘secondary
traumatization’. Primary prevention and early intervention reduce mental health
morbidity. ABC of general mental health measures help us to handle this crisis
more effectively. Specific management approaches are required for individual
emotional distress, handling grief and breaking bad news

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Suggested reading

1. Mental Health in the times of COVID-19 Pandemic: Guidance for

General Medical and Specialised Mental Health Care Settings.
https://nimhans.ac.in/health-information-nimhans/COVID19-information/
(Last visited 15 Aug 2021)
2. Looking after our mental health.
https://www.who.int/campaigns/connecting-the-world-to-combat-
coronavirus/healthyathome/healthyathome---mental-health (Last visited
15 Aug 2021)
3. Minding our minds during the COVID-19.
https://www.mohfw.gov.in/pdf/MindingourmindsduringCoronaeditedat.p
df (Last visited 15 Aug 2021)

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14. Initial response to Pandemic-AFMS perspective

Air Vice Marshal R Vaidya VSM, Col S Adhya, Brig A S Menon

In late January 2020, India reported the first case of COVID 19 in a

student who had returned from Wuhan City a week ago. Travel advisories were
issued for screening and quarantine of travelers returning from countries where
cases were being reported. Government of India on 23 Mar 2020 placed a ban on
international travel to and from the country. A nationwide lockdown was
announced on 25 Mar 2021, which continued until 31 May 2020, after which
lockdown was lifted in a phased manner.

SQTI measures in an operational area

The following is a brief account of the Screening, Quarantine, Testing &

Isolation (SQTI) measures carried out in an operational area. Once the lockdown
was announced, it was estimated that 30,000 troops from the op area were at their
home station waiting for return to duty. During the lockdown period, special
military trains carried troops to select destinations. The troops were mandatorily
quarantined at entraining stations before boarding the trains. On arrival pool
testing was done; out of 10,000 arrivals in the afore mentioned area, none were
found to be positive.

After lifting of lockdown and resumption of public transport, the troops

were advised to report to designated SQTI facilities in the area. Central quarantine
facilities were established at these designated places. Adhoc isolation facility
were created next to hospitals. The lone testing facility was provided with
additional funding to boost testing capacity. Twenty-seven medical teams
consisting of one medical officer and one nursing assistant each were deployed
at various facilities for daily screening, documentation, collection of
nasal/oropharyngeal swabs and transport of viral transport medium to the testing
facility while maintaining a cold chain. Though the national guidelines
recommended testing only symptomatic individuals, a policy of 100 % testing of
returning troops was implemented. This was done in view of sensitive nature of
deployment and practical difficulty in maintaining Covid appropriate behavior in
forward areas. They were tested after completing five days of quarantine. Pooled

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sample (sample size of five) were tested; those returning positive were retested,
and the deconvoluted samples were sent back to the lab to know their individual
COVID status. Individuals who were SARS CoV2 positive were admitted to
isolation facilities. Those found negative were send to their parent formations for
completing fourteen days quarantine thus decongesting the reporting facility.
This procedure was followed for forty-five days post lifting of lock down during
which more than 21,000 troops were tested. Nine hundred and ninety one (4.6 %)
of the troops were detected to be positive of which only 20 % were symptomatic
at the time of testing. The state authorities screened 10,000 troops at arrival
stations of whom 21 were reported to be positive. The strategy of screening all
troops during the initial rush back from leave, post lockdown, permitted large-
scale movement of troops to forward echelons. Thereafter the process was
streamlined with setting up of additional testing centers and systematic contact
tracing protocols drawn up to limit the spread of the pandemic.

Armed Forces –a vulnerable population

Many diseases, especially airborne, food and water borne, as well as vector
borne diseases have been shown to spread readily in the military due to the close
communal living and training quarters. An outbreak of COVID-19 occurred on
the U.S.S. Theodore Roosevelt, a nuclear-powered aircraft carrier with a crew of
4779 personnel. Over the course of the outbreak, 1271 crew members (26.6% of
the crew) tested positive for severe acute respiratory syndrome coronavirus 2
(SARS-CoV2).

Developing a surveillance system

Emerging and re-emerging infectious diseases are threats that military

organisations have to guard against, as they cause substantial impact to training
and operations. Emerging infectious diseases (EID) are defined as infectious
diseases that are newly recognized in a population or have existed but are rapidly
increasing in incidence or geographic range. Military organisations can develop
surveillance systems for early identification of diseases. French Military
Influenza Surveillance System (MISS) is an example of one such. It is integrated
with French national surveillance system and includes epidemiological and
virological surveillance.

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Quarantine

Ideally, immunizations and chemoprophylaxis for those exposed should be

available assuming early identification of a known agent with treatment options.
When this is not possible, quarantine is at the heart of an effective disease
containment strategy. Quarantine involves the separation and restriction of
movement of persons who are not yet ill, but have been exposed to an infectious
agent and therefore may become infectious. The purpose of quarantine is to
reduce the incidence of new cases, resulting in an expectation that the number of
infected individuals will peak, decline, and then reach zero if effective.

Quarantine as public health measure to prevent spread of the disease was

enforced during Severe Acute Respiratory Syndrome (SARS) pandemic of 2003.
Early on during Covid 19 pandemic the Government of India enforced a
quarantine on travelers returning from select countries before international travel
was suspended.6 The impact of quarantine measures on preventing spread of
infection has received very little attention; no studies are available documenting
its effect in Indian Armed Forces. Two studies have documented the results of
quarantine on freshly inducted recruits in US Armed Forces. In one of the studies
conducted from May to July 2020, recruits completed a 2-week self-quarantine
period at home, followed by a 2-week supervised quarantine on a college campus
after assignment to platoons, which consisted of 50 to 60 recruits. Study
volunteers were tested for SARS CoV-2 by means of quantitative polymerase-
chain-reaction (qPCR) assay of nares swab specimens obtained between the time
of arrival and the second day of supervised quarantine and on days 7 and 14. Of
the 1884 recruits who volunteered for the study 16 (0.9%) tested positive for
SARS-CoV-2 on initial testing, 15 of whom were asymptomatic. An additional
35 participants (1.9%) tested positive on day 7 or on day 14.Five of the 51
participants (9.8%) who tested positive at any time had symptoms in the week
before a positive qPCR test. Analysis of 36 SARS-CoV-2 genomes obtained from
32 participants revealed six transmission clusters among 18 participants. Most
recruits who tested positive were asymptomatic, and no infections were detected
through daily symptom monitoring. Relying solely on symptom screening could
lead to missing out on cases. Strict enforcement of Non Pharmacological
Intervention (physical distancing, hand hygiene, wearing of mask) will prevent
local spread in inmates in quarantine.

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Optimum time of Quarantine

Duration of quarantine is subject to maximum incubation period of the

contagion in the initial part of pandemic, later revisions are subject to better
elucidation of transmission dynamics, availability of rapid and cost effective
point of care diagnostics and population immunity. Quarantine leads to loss of
productivity and testing can be used to allow individuals to return to productive
life early. At the beginning of the COVID 19 pandemic, a fourteen-day quarantine
period was followed as it was estimated that 99 % of individuals would develop
symptoms by then. Modelling studies during the Covid pandemic indicated that
testing on exit (or entry and exit) could reduce the duration of a 14-day quarantine
by 50%, while testing on entry could shorten quarantine by at most one day. With
availability of widespread testing and better understanding of the viral dynamics
and symptomatology, health monitoring agencies recommended reduction of
quarantine to 10 days if individual remained asymptomatic and 7 days if
screening test was negative.

Contact tracing

Contact tracing for contagious disease is the process of identifying,

assessing, and managing people who have been exposed to someone who has
been infected with the contagion, while quarantine is the separation of contacts
from other people after exposure to a probable or confirmed case. Contact tracing
should be conducted for all contacts during periods characterized by uncertainty
such as the emergence of new infectious disease. Supported quarantine measures
should be applied for (i) contacts at high risk, (ii) in high-risk settings and (iii)
uncertain situations (such as the emergence of a new variant of concern as in the
current pandemic). During COVID 19 the initial period of quarantine was as
detailed above but with growing population immunity with vaccination and prior
infections the period of quarantine was reduced. Aggressive contact tracing was
resorted to in Armed Forces during the pandemic and relaxed later to conform
with national guidelines.

Laboratory Facilities

Questionnaires and thermal screening do not reliably detect all cases.

Reliable diagnostic tests are necessary to conduct screening of individuals

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suspected to be affected by the pathogen. Advances in molecular diagnostics like
nucleic acid amplification test (NAAT) and miniaturization have made it possible
to use them as point of care (PoC) diagnostic test. These tests would be required
when there is a requirement of rapid diagnosis of common diseases especially
during field deployments where full laboratory facilities may be unavailable.
Establishing PoC testing facilities as forward as possible would help decentralize
quarantine of troops nearer to areas of deployment.

Use of pooled testing

Pooled testing means combining the same type of specimen from several
people and conducting one NAAT on the combined pool of specimens to detect
the pathogen. During a pandemic, a high load of samples requires to be tested,
especially for containment measures, but the positivity rates are low or show a
wide variation from place to place. The high sensitivity of real-time RT-PCR
based tests and the low prevalence of COVID-19 during the initial part of
pandemic, allowed pooled testing of respiratory samples. Pooling preserves
testing reagents and resources, reducing the amount of time required to test large
numbers of specimens (increasing throughput), and lowering the overall cost of
testing. The optimal pooling strategy depends on the incidence of infection in the
community, and pool size will need to be adjusted accordingly. A multi-site
evaluation compared 5- to 10- sample pooling with a presumed population
positivity of 2%. Five samples for SARS-CoV-2 detection by real-time RT-PCR
was found to be an acceptable strategy without much loss of sensitivity even for
low viral loads, while with 10-sample pools, there were considerably higher
numbers of false negatives. Before pooling is resorted to, it is recommended that
the laboratory conduct validation study with the RNA extraction and RT PCR
kits. Pooling sizes will differ by the populations and group of individuals being
tested as well as the positivity rates.

Creating a Biobubble

A bio-bubble is a safe and secure environment isolated from the outside

world to minimise the risk of infection. This concept though popularized in sports
during the pandemic is a mandatory drill for sailors on board ships and troops
deployed in forward areas.

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Conclusion

Screening for symptoms may underestimate the number of cases in

illnesses with long incubation period or illnesses with high proportion of
asymptomatic cases. Pooling of samples for testing by NAAT should be resorted
when the incidence is low and resources are scarce. Quarantine with enforcement
of Non Pharmacological Intervention should be used to break the chain of
transmission.

Suggested Reading

1. Korzenewski K, Nitsch-Onush A, Chcialowski A, Korsak J.

Environmental factors, immune changes and respiratory diseases in troops
during military activities Respir Physiol Neurobiol 2013, 187(1):118–122
2. Kasper Matthew R, Geibe Jesse R, Sears Christine L., Riegodedios Asha J
, Luse T, Von Thun A M et al. An Outbreak of Covid-19 on an Aircraft
Carrier. N Engl J Med 2020; 383:2417-26
3. Lindahl F L. The consequences of human actions on risk for infectious
diseases: a review. Infection Ecology and Epidemiology 2015, 5: 30048 -
http://dx.doi.org/10.3402/iee.v5.30048
4. Duron S , Mayet A, Lienhard F, Haus-Cheymol R, Verret C, Védy S et al.
The French Military influenza surveillance system (MISS): overview of
epidemiological and virological results during four influenza seasons--
2008-2012. Swiss Med Wkly. 2013 Oct 2; 143:w13848
5. https://stacks.cdc.gov/view/cdc/11429 (last visited 12 Sep 2022)
6. https:// www. civilaviation. gov.in /sites /default/ files/ State_ wise_
quarantine_ regulation-converted.pdf (last visited 12 Sep 2022)
7. Marcus JE, Frankel DN, Pawlak MT, Casey TM, Blackwell RS, Tran FV
et al. COVID-19 monitoring and response among U.S. Air Force Basic
Military Trainees - Texas, March-April 2020 .MMWR Morb Mortal Wkly
Rep. 2020 Jun 5; 69(22):685-688.
8. Letizia A G, Ramos I, Obla A, Goforth C, Weir D L, Ge Y, et al. SARS-
CoV-2 Transmission among Marine recruits during quarantine. N Engl J
Med 2020; 383:2407-2416
9. Wells CD , Townsend JP, Pandey A , Moghadas SM, Krieger G, Singer B,
et al. Optimal COVID-19 quarantine and testing strategies. Nature

139
 Communications https://doi.org/10.1038/s41467-020-20742-8 (last visited
12 Sep 2022)
10. https://www.who.int/publications/i/item/WHO-2019-nCoV-
Contact_tracing_and_quarantine-2022.1 (last accessed on 14/10/22)
11. Praharaj I, Jain A, Singh M, Balakrishnan A, Dhodapkar R, Borkakoty B
et al. Pooled testing for COVID-19 diagnosis by real-time RT-PCR: A
multi-site comparative evaluation of 5- & 10-sample pooling. Indian J Med
Res.2020; 152: 88-94

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15. Public health Challenges in COVID Pandemic

Surg Capt Vijay Bhaskar, Surg Capt Saurabh Bobdey, Lt Col AK Yadav,
Brig SK Kaushik

Introduction

COVID-19 was declared a pandemic on 11 March 2020 and since then the world
is struggling in its war against SARS CoV2. This disease came as a complete
surprise to most of the world as the etiological agent was a novel virus about
which very little was known. Those with severe disease had a high mortality. The
pandemic led to collapse of public health infrastructure in many countries. The
economic and social disruption caused by the pandemic has been devastating.
Disruption of daily life, loss of livelihood, closure of educational institutions,
shops, restaurants, recreational facilities, restrictions on social functions,
restriction to go outdoors for children and elderly, and travel restrictions are
amongst many such fallouts of the pandemic. Parents have concerns about loss of
structured education and minimal social interaction of children and uncertainty
about re-opening of schools or colleges. Isolation and fear of contracting the disease
have had an impact on mental health. The COVID-19 pandemic has driven us to
change the very definition of social norms and adapting to the new normal.

The novel nature of the virus, its mode of transmission, lack of effective
treatment modalities and lack of effective vaccine (during the initial phase) have
left both developed and developing nations struggling to control the pandemic.

Challenges in adopting Non-Pharmacological interventions (NPI)

The COVID appropriate behaviour which consist of wearing a face mask,

maintaining physical distance and hand hygiene have been found to be effective
in preventing the transmission. Although some countries like Japan and south
Asian countries already have the norm of use of facemask by an individual having
flu; these measures were new to rest of the world and it took them some time to
accept.

Mankind is resistant to any kind of change. Making the public accept the
new norm of use of facemask and maintaining physical distance was a
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challenging task for every public health professional. During the initial phase of
the pandemic the literature and advisories from the technical bodies were wide
and varied. This too was a hindrance in implementation of the NPIs. In addition
to the self-motivation on the part of the general population, these preventive
measures had to be enforced by the governments across the world by formulation
of new laws and imposing heavy monetary fines if anyone found flouting these
measures.

The face mask has become an integral part of our dress code and even small
children can be seen wearing them. The face mask has become mandatory in all
the public spaces, offices, and gatherings all over the globe. Although some
countries have relaxed the mandate on face mask for completely vaccinated
individuals but they are forced to rethink this decision due to the rise in number
of COVID-19 cases because of the newer variants presently in circulation.

Another facet of COVID appropriate behaviour is maintaining physical

distance of at least 1 to 2 meters when venturing out in public places or in
confined spaces such as offices or classrooms. This preventive measure is easier
said than done as the need to socialise is deeply rooted in everyone across the
world. The physical distancing is much more difficult to maintain in developing
and under developed nations simply due to the huge population and living in
confined spaces. Although there are laws set by the government for physical
distancing, but they are being flouted at level of the individual itself. There is a
need to be more compliant towards these measures and try to adapt to this new
normal of COVID appropriate behaviour. As the pandemic unfolds and continues
to spread globally it is becoming more and more apparent that behaviour change
is the only way forward if we want to survive and thrive.

Challenges faced by the Healthcare workers

COVID-19 exposed health care workers (HCWs) and their families to

unprecedented levels of risk. Data from many countries indicate that COVID-19
infections among health workers are far greater than those in the general
population. Pandemic has placed psychological stress on HCWs working in high-
demand settings for long hours. They have to work with constant fear of exposure,
separation from family members and facing stigmatization in few places. Unlike
other diseases, the HCWs were managing patients with COVID 19 in the initial

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phase of the pandemic with limited knowledge about the virus, treatment
protocols, and prevention modalities. The magnitude of cases reported
overwhelmed the scarce medical resources. The HCWs had to multitask while
treating the patients at the same time ensuring keeping themselves and family
members safe. Even one HCW getting infected causes a cascading effect wherein
the high risk contacts too needs to be quarantined leading to disruption of
functioning of the healthcare facilities.

Achieving herd immunity

The concept of achieving herd immunity is a known approach in control of

the disease progression. The indirect protection happens when a population is
immune to an infectious disease either through vaccination or through previous
natural infection. In a population where all the individuals are susceptible, a
pathogen will spread in an unchecked manner. The chance of an effective contact
between infected and susceptible host is reduced if a certain fraction of the
population is immune to that same pathogen. The point at which the percentage
of susceptible individuals falls below the threshold needed for transmission is
known as the Herd Immunity Threshold (HIT). HIT value varies with the
virulence of the disease, the efficacy of the vaccine and the contact rate within
the population. HIT mainly depends on a single parameter known as R 0, or the
basic reproduction number. R0 refers to the average number of secondary
infections caused by a single infectious individual introduced into a completely
susceptible population. If an infectious disease has high R0 it leads to a higher
rate of transmission in a susceptible population e.g.; if R0 of a disease introduced
in a susceptible population is three, it implies that, the disease is likely to be
transmitted by an infected individual to three susceptible hosts.

In present COVID pandemic, herd immunity against the virus is expected

to be achieved by vaccinating maximum percentage of the population to reduce
the number of susceptible individuals. The percentage of people who need to be
immune to achieve herd immunity varies with each disease, for example, herd
immunity against measles requires about 95% of a population to be vaccinated
and for polio, the threshold is about 80%. The available literature suggests that
most of the individuals infected with COVID-19 develop an immune response
within the first few weeks after infection, but the strength of immunity and the
duration for which the immunity will last is still a topic of research. The

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vaccination strategy to achieve herd immunity is surrounded by some serious
concerns such as the duration of immunity provided by the currently available
vaccines.

Another factor, which might influence herd immunity against the SARS
CoV2, is the rapid and frequent mutation of the virus and appearance of new
strains. It is of concern whether currently available vaccines will impart immunity
against these mutant strains. Immune escape by these newer strains leading to
breakthrough infections or reinfections is being reported worldwide.

Role of Serosurvey

Serosurvey is the procedure of testing the body fluids mainly blood or any
specimen such as saliva for IgG antibody to estimate the burden of disease or
exposure and to know the extent of herd immunity. In the present pandemic, it is
crucial to estimate and predict whether seroprevalence is conferring protection to
the individual or the group as a whole in terms of herd immunity. Serosurveys are
undertaken to access the specific protective value in a population. It is well
understood now that the population remains susceptible to SARS-CoV-2
infection as long as the seroprevalence is low whether it pertains to a particular
geographical region or a particular age group. Transmission is expected to
increase whenever there is lower seroprevalence.

The knowledge about the extent of immunity and the duration of immunity
induced by natural infection or vaccination is limited. The nature of immune
response in the body is again a point of contention. Dedicated research in this
field will clear the unanswered questions. Various surveys have been undertaken
at multiple locations in India. The results of these surveys vary from each other
and need to be interpreted carefully. The procedure of the survey, sample size,
the kits used and the team undertaking the survey do have an impact on the results.
However, these surveys give a fair idea about the susceptible population in a
geographical area.

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Challenges in implementing lockdown, travel restrictions and other
restrictive measures

Globally, most of the countries have used nationwide lockdown as a

strategy to tackle the pandemic. Lockdown was announced in India on evening
of 24 Mar 2020 for 21 days and the numbers of confirmed cases were 500 at that
time. Lockdown was envisaged as a requirement to break the chain of
transmission of the virus. The nationwide lockdown did help the Government to
tackle the first wave given the limited resources. However, it had an unintended
impact, the lower socioeconomic strata were affected with loss of daily wage and
employment, and the resulting migration of workers from cities according to
many experts was the numerically largest since partition of India in 1947.

Total lockdown is unlikely to be accepted voluntarily by a majority of the

population, owing to its highly disruptive nature. In the absence of clear support
strategy for vulnerable sections, implementation of a total lockdown becomes
difficult. A major impact on global economy, food supply, trade and others was
visible in many countries during the lockdown period.

The international and domestic travel restrictions definitely had a positive

influence in halting the transmission of the virus between geographical areas.
With emergence of variants of the virus and their distinct epidemiological profile,
partial lockdown & travel restrictions appear to be an important strategy in
tackling the pandemic.

Managing misinformation and Risk communication

There are around 600 million internet users in India and this number is
likely to grow to 900 million by 2025. This has led to increasing use of social and
messaging platforms like WhatsApp, Facebook and twitter. During the present
pandemic, it was evident how social media platforms can lead to sharing of
misinformation. Misinformation breeds uncertainty, which fuels skepticism and
distrust for health authorities. Environment of fear and anxiety in the public
makes it impervious to sound scientific advice and dismissal of public health
measures. This has been a direct reason for increasing vaccine hesitancy the world
over. Misinformation also triggers individual fears and anxieties leading to social
stigmatization that might even progress to aggression and violence.

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 Though it is difficult to block the virtual flow of information over internet,
it is possible to issue clarification on social networking sites and popular search
engines. Information should be made available on government websites like
MoHW and ICMR

Challenges with regard to the existing public health resources

The response to any pandemic, should be driven by public health and

epidemiological experts trained in this field. In the present pandemic, it is
apparent that many decisions were taken without consultation with public health
specialist and lacked scientific evidence. Countries with best of the health care
facilities were found struggling to tackle the surge in cases. In India the same was
witnessed both during first and second wave. Countries globally have now
realised the importance of having dedicated public health work force, which is
equipped with latest technology and protocols for control of any pandemic of
such a magnitude.

This is an opportunity to invest in the public health infrastructure in India,

which have suffered systemic neglect over the past few decades. It is time to
reinforce online technologies and digital tools to institute timely response for
control of pandemics. Digital surveillance systems, machine learning,
telemedicine, rapid case identification and diagnosis, apps for public
communication and hybrid models are some of the tools which have to be in fore
for effective management of any such pandemic. Expansion of public health
infrastructure must remain the mainstay for wider access to health care for all.
Existing set of public hospitals should be supported by good management and
funding.

India should augment its resources in public health sector if it wants to

provide the best healthcare at the remotest location to every individual. The
pandemic should be a strong reminder to public and policymaker alike that the
economy will keep slipping if we do not invest in strong public health system.

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Improved Monitoring and Early Warning Systems

For any country to respond to an event like the COVID-19 pandemic a

well-established surveillance systems acts as early warning system. Many
countries have put such systems in place. It is amply clear that there is a need for
a robust infectious disease surveillance system in India. Harnessing technology
to integrate indicator-based, event-based and syndromic surveillance systems will
be the key in early detection of infectious diseases and timely implementation of
control measures.

Conclusion

World stands at an important turning point. The capability to prevent and

manage such global pandemics needs to be incorporated in its policies. The
pandemic has offered multitude of challenges to the global community. The
countries with better public health care fared better as compared to others. For
countries with insufficient health infrastructure, health and economic impact of
the present pandemic offers an opportunity to rethink their approach to public
health. A much-needed public investment in health, a well-equipped workforce
to respond to future pandemics, and system capacity for surveillance, contact
tracing, research and disease modelling amongst others will be most crucial for
the future generations. With concerted and comprehensive efforts, we should
hope that the present pandemic is controlled and the world reverts to normalcy.
The world needs to learn from the challenges being faced during the pandemic
and prepare well for any such event in future.

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16. Challenges in establishing COVID Care Hospital

Col S K Patnaik, Col Neeraj Garg, Surg Lt Cdr Kranthi K Nethi,

Maj Neelesh Patel

Introduction

The COVID-19 pandemic has presented an exceptional challenge to public

health and medical care systems around the world. As the virus is spreading, it
has threatened public health, straining medical facilities and healthcare providers.
Across the globe, political, financial and technical resources have been mobilized
to contain the COVID-19 pandemic. The impact of this pandemic shall be long
lasting and will influence all spheres of human lives and slow all developmental
activities.

The Global response to the COVID-19 pandemic has exposed inherent

flaws in our preparedness and response. The health systems have been
overwhelmed by the pandemic, posing enormous challenges to healthcare
facilities. It has been challenging to transform the existing hospitals to a dedicated
COVID care facility as a Brown Field Project, or developing a facility providing
COVID care facilities as well to continue to provide non-COVID services
through the existing staff and equipments. At some places, the rapid increase in
caseload has forced the creation of Green Field temporary projects with urgent
procurement of various equipment and deployment of trained manpower from
elsewhere. The illness has had a significant impact on the deliveryof non-COVID
hospital services, logistic supply chain management and utilization of
information technology to deal with the massive data generated at these facilities.

Brown field project

The difficulties associated with the conversion of an existing facility to a

COVID care facility primarily include addition/ alteration, structural
modifications, earmarking of red and green zones, provisioning of donning area
with strict adherence to infection control practices, adherence to standards
precaution with full PPE gear while carrying out duties are some to mention.
These challenges have been elaborated below-.

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a) Planning: Planning for a COVID care facility requires detailed deliberations
on manpower, resources, and Infrastructure. A very important aspect is to
create SOPs with respect to entry, screening, testing, admission, discharge,
death, etc for the hospital. The supportive services for COVID-19 patient
care need to be made available or should be tied up in the vicinity like RT-
PCR, CT scan, etc. A Nodal officer needs to be appointed for the elaborate
planning and coordination for establishing a COVID care facility within the
existing hospital.

b) Entry & Exit of the hospital: Designated entry and exit point to the hospital
require to be earmarked. The number of entries and exits should be such that
parallel defence screens can be set up at the entry gate round the clock.

c) Control room: A dedicated control room should be established for handling

all COVID and non-COVID queries through helpline nos. for the patients as
well as relatives.

d) Influenza Clinic: Influenza clinic or Flu clinic should be established, in a

separate OPD location, for screening patients with influenza-like illness
(ILI) and severe acute respiratory illness (SARI). Specialty and subspecialty
OPD consult should be done after the mandatory clinical screening. A
separate outpatient department (OPD) complex should be identified within
the main hospital building, or the existing OPDs can be re-structured using
screen/physical barriers between healthcare workers and patients. The
waiting area for the OPD should be such that overcrowding can be avoided.
Certain engineering modifications of existing inpatient infrastructure can be
done to ensure better ventilation, increased air changes and air filters.

e) Isolation Ward: The next important aspect is to establish a functional

isolation ward. The following aspects are critical in the planning of the
isolation ward:-

(i) Separate Donning/Doffing Room for wearing personal protective

equipment (PPE) and removing before leaving the isolated
contamination area. Practice of hand hygiene with an alcohol-based
hand rub should be ensured. Adequate storage cabinets should be made
available in the donning room for storage of PPE.

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 (ii) Air conditioning- Since the isolation ward would cater to COVID
patients with mild or moderate symptoms, modification to air
conditioning should be done to provide a comfortable environment to
the patient as well as removal of contaminants from the environment.
It should be ensured that the airflow is non-turbulent, unidirectional
and there is no leakage of contaminated air to surrounding non-infected
areas. Where the wards cannot be air-conditioned, additional exhaust
fans can be installed to create dilution and removal of contaminated
air. A negative pressure area in critical care set ups is required

f) Intensive Care Unit: A separate triage intensive care unit (ICU) should be
set up where all critical patients and unstable SARIs can be admitted. Also other
than the triage, ICU a separate dedicated COVID ICU should be established.

g) Miscellaneous Challenges:
(i) Training of the manpower and emphasizing adherence to standard
SOPs.
(ii) Procurement of non-expendables and expendables. A robust
supply chain management is required for the efficient delivery of
patient care.
(iii) Health and safety of healthcare workers should be ensured to
preserve the valuable workforce.

Green field project

If there is an acute surge in the number of cases, the need to cater for more
beds dedicated for COVID patients can only be achieved by creating temporary
hospitals in a shorter period. These facilities must be sited away from the
population however still accessible to the needy. It should be ensured that the
hospital building should be in zones, facilitating effective infection control
practices and preventing community spread of virus within the healthcare facility
or staff. Challenges in establishing a Greenfield hospital are as follows:-

a) Identifying are as, which are large, enough to establish a hospital and retain
accessibility is a challenge. The provisioning of facilities like MRI/CT, a
blood bank within the facility mandates regulatory licenses, which are
often quite difficult. MoUs with other centres are required for shifting

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 critical patients requiring subspecialty care such as dialysis, ECMO and
labour rooms. Arrangements for providing blood components should be
made through a certified blood bank.

b) Ensuring adequate and uninterrupted electric supply, piped potable water

supply, piped medical gas supply to each of the patient beds and climate
control of patient care areas are continuing challenges for a temporary
facility tiding over the seasonal variations. Apart from the generator
supply, a UPS facility is required for critical lifesaving equipment and
patient monitors to continue functioning in the event of a power outage.

c) Due to the construction of the facility with flammable materials in a short

time, the risk of fire and other issues such as ingress of water and
waterlogging during monsoons need to be addressed. Fire safety is of
paramount importance and involves with adequate and trained manpower,
firefighting equipment and active surveillance.

d) The equipment-related issues are non-availability, calibration difficulties,

technical glitches, faulty equipment, equipment not up to specifications
and lack of training of operators. Equipment maintenance also is
challenging, with company engineers often finding it difficult to work in
full PPE.

e) The greatest challenge in operating a COVID hospital is the availability of

trained manpower. Managing patients of COVID poses risk of infection to
Health Care Workers (HCWs). Hence, it is imperative to train HCWs in
personal protective measures and reinforcing them by conducting regular
training sessions by experts in the field of infectious diseases and critical
care. HCWs also need to be trained in donning and doffing of PPE,
sanitation drills, fire safety and evacuation drills etc.
f) Provisioning of basic diagnostic imaging, laboratory, and pharmacy services
through outsourcing requires coordination and best achieved by
establishing a hospital informatics system.

g) The catering services should be capable of providing nutritious diet as well

as special diets if required.

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 h) Laundry and linen services should provide uninterrupted supply to meet the
demands and requires detailed planning and coordination.

j) Safe biomedical waste (BMW) disposal is essential, since improper

handling of the waste could also lead to spread of infections to the
community. The outsourced agency should have a certificate issued by
local pollution control board and should regularly carry the BMW waste
from kerb site.

k) Attrition of trained personnel results in a greater workload for the personnel

already trained and directly relates to increased stress levels apart from
hectic work among the healthcare workers.

j) Provisioning of accommodation for HCWs, maintaining a social bubble in

transport, logistics and supply chain management, concerns from patients
related to gender segregation, lack of variety in the hospital diet, difficulty
in communicating with families, and the non-availability of avenues for
entertainment are few of the other issues.

Logistic challenges
The outbreak of COVID 19 compelled Governments to impose restrictions
on all kinds of travel within or outside the country to contain the spread. Primarily
issues are related to facilities, their location and capacities, selection and
utilization of transportation as well as distribution modes, and restocking the
stock capacities across the whole supply chain. The supply chain should be
strengthened by:

a) Identification of the source for essential goods.

b) Management of contracts and development of inventories for the
procured commodities.
c) Medical equipment including personal protective kits are periodically
analysed and updated.
d) Stockpiling warehouses are located, and their capacities assessed.
e) Transportation network systems are planned for optimised dissemination
of essential commodities.
f) Expansion of the existing healthcare capacities.

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 g) Guaranteeing the sufficient provision of direct as well as indirect
financial resources.

The importance of logistic supply chain management has been brought

forth due to requirement of maintaining uninterrupted supply of personal
protective equipment (PPE) for HCWs to goods at as upper market.

Challenges faced by COVID hospitals.

Following logistic challenges have been identified by various COVID care

facilities:-
a) Acute shortages of PPE
b) Severe deficiencies of testing supplies and undue delay in obtaining
results
c) Difficulty maintaining adequate staffing and supporting Staff
d) Shortages of critical supplies, materials, and logistic support
e) Anticipated shortages of ventilators

Following mitigation strategies can be adopted by the hospitals:-

a) PPE: Equipment, and Supplies. Hospitals should plan well in time to

ensure supply of PPEs and use them with prudence.

b) Training: Hospitals should train maximum number of Medics and

paramedics to help care for patients on ventilators

c) Support Staff: All the other staff should also be trained to perform the
non-core services and other operational tasks to make the hospital
function at its highest potential.

d) Patient Flow and Hospital Capacity: To manage patient flow and

hospital capacity, some hospitals may provide ambulatory care for
patients with less severe symptoms, offering telehealth services when
possible and setting up alternate facilities such as fairgrounds, vacant
college dorms and closed correctional facilities as additional spaces for
patient care.

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e) Ventilators and Alternative Equipment: In anticipation of enhanced
requirement for ventilators, hospitals may acquire supplementary
machines by renting ventilators, buying emergency transport ventilators,
or obtaining ventilators through an allied facility.

f) Testing, Supplies, and Equipment: The hospitals have requested the

government for uninterrupted supply of PPE kits, medicines, electro
medical equipment like ventilators and testing kits for augmentation of
testing, seamless health care delivery to critical patients.

g) Financial Assistance: Enhanced financial assistance to hospitals

particularly rural establishments, in terms of loans, grants, including
increased reimbursements of govt schemes to run their hospitals at
maximum capacity should be given. The emergency financial powers
were granted to the Govt hospitals for speedy procurement of critical life
saving equipment.

h) Communication and Information: There should be unified

communication and public information, including evidence-based
guidance, reliable data and predictive models, and a central repository for
all COVID-19-related guidance, data, and information.

i) Oxygen Management: While the ‘second wave’ of the pandemic spread

across India, hospitals in many urban settings were striving to treat
COVID patients because of an acute scarcity of oxygen. While the timely
Liquid Medical Oxygen (LMO) production has offered some, albeit
limited, relief to meet the demand, transporting the produced oxygen to
demand sites continued to be a logistical challenge. With the growing
COVID cases, the need for shipping LMO has risen significantly, almost
heading to an oxygen logistics crisis. The specialized cryogenic oxygen
tankers met this transportation challenge. LMO is hazardous to transport
due to its flammability. A possible way to reduce is to relocate some of
the “demand” closer to the supply settings. The options can be
i) Use of oxygen concentrators
ii) Installation of PSA plants within the hospital premises
iii) Installation of LMO storage tanks in hospital premises

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Impact of hospital and other healthcare services

Due to the COVID pandemic following hospital services got affected in

most of the countries
a) Outpatient services
b) Elective surgeries
c) Dental health services, rehabilitation services, and palliative care
services
d) Inpatient treatment for communicable diseases and other ailments
e) Medical tourism due to international travel restrictions

Periodic surveys conducted by WHO has brought out that the following
services were disrupted to varying degree significantly due to the pandemic.
Maximum disruption has been reported in middle and low-income countries.

Mental, neurological and substance use disorders

Neglected tropical diseases
Non communicable diseases
Immunisation services
Reproductive, maternal, new born, child and adolescent health and nutrition
services
Survey also has brought out reasons for disruption of health care services (Fig
13.1).

During the pandemic, huge out-of-pocket expense for COVID treatment as well
as other non-COVID illnesses has increased awareness about health insurance.

Impact on Clinical Research and professional services

a) Research: The current pandemic has enormously affected ongoing

research, including the outcomes; these effects need to be accounted during
data analysis and interpretation. However, the measures taken to tackle
COVID pandemic will advance the conduct of clinical research.

b) Telemedicine: Guidelines for telemedicine services that have been

promulgated by the Ministry of Health and Family Welfare along with

155
 NITI Aayog l facilitate utilisation of telemedicine by registered medical
practitioners to provide professional services.

Fig 15.1 Reasons for disruption of hospital services (WHO second round of
national pulse survey)

IT Challenges during COVID-19

The existing IT network infrastructure of hospitals has come under intense

strain due to additional requirement posed by the pandemic. Consequently, to
support the implementation of digital technology, investments to combat the
COVID-19 pandemic had to be diverted to expenses concerning network
communication and electrical infrastructures.

Hospital Information Management system (HIMS)

Development of a HIMS fora hospital to maintain a strict barrier between

the red zones and the green zones is a minimum inescapable requirement. Besides

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providing storage of medical records, it provides update of the patients to the
nodal centre of the green zone who in turn can inform patients' relatives.

Telemedicine

Setting up a telemedicine centre to decrease the contact of patients with

healthcare facilities, other patients and healthcare staff to reduce the risk of
COVID-19 infection.

Training of IT

The most important challenge is to train the healthcare workers to work on

HMIS and procedures to utilize Telemedicine for consultation. Since most of the
senior healthcare workers are of the era, where traditional methods were used to
deliver healthcare and they are not pro with working on IT platforms.

Conclusion
The challenges faced in establishing a make shift facility or transforming
an existing facility with adequately trained staff in such a short time frame with
good coordination between all the stake holders would help in ensuring a healthy
balance between the needs of the clinician and the requirements of the other
collaborators. The involvement of ground-level workers during the designing
process could also help reap rewards, as they are often best placed to provide an
insight into the patient perspective. The initial trends of facility performance also
showed that while concerns over the effectiveness of makeshift hospitals do still
exist, when executed well, they have the potential to significantly augment the
healthcare facilities in the event of disasters.

Suggested Reading
1. Operational considerations for case management of COVID-19 in health
facility and community. WHO/2019-nCoV/HCF_operations/2020.1
(accessed from https://apps.who.int/iris/handle/10665/331492. (Last
visited 13 Aug 2021)
2. Singh S , Ambooken GC , Setlur R , Paul SK , Kanitkar M , Bhatia SS,
Kanwar RS. Challenges faced in establishing a dedicated 250 bed COVID-
19 intensive care unit in a temporary structure. Trends Anaesth Crit Care.
2020;14(4):337–9.

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3. Converting a British-era hospital into a state-of-the-art COVID-19
care centre. Dawra S, Patnaik S, Tevatia MS, Hasnain S, Patnaik U,
Srivastava S, et al.BMJ Mil Health 2021;0:1–3.doi:10.1136/bmjmilitary-
2021-001895
5. COVID-19: guidelines on dead body management, 2020.(accessed from
https://www.mohfw.gov.in/pdf/1584423700568_COVID19Guidelineson
Deadbodymanagement.pdf last visited 13 Aug 2021)
7. Moynihan R, Sanders S, Michaleff ZA, Scott AM, Clark J, To EJ, et al.
Impact of COVID-19 pandemic on utilisation of healthcare services: A
systematic review. BMJ Open.2021;11:e045343. doi:10.1136/bmjopen-
2020-0453438.
8. Lalit Mistry. India ’ s healthcare sector transformation in the post COVID-
19 era.https://home.kpmg/in/en/home/insights.html (last accessed 13 Aug
2021)
9. Tuttle KR. Impact of the COVID-19 pandemic on clinical research. Vol.
16, Nature Reviews Nephrology. 2020;16: 562–4
10. Information technology challenges in a public hospital during the COVID-
19 pandemic. Yamamoto JF, I, de SouzaIOM, Letaif LSH., Cobello-Junior
V.CLINICS 2021; 76:e2648
11. Buntin MB, Burke MF, Hoaglin MC, Blumenthal D. The benefits of health
information technology: a review of the recent literature shows
predominantly positive results. Health Affairs (Millwood). 2011;
30(3):464-71.
12. Telemedicine: Embracing virtual care during COVID-19 pandemic
Garg S, Gangadharan N, Bhatnagar N, Singh MM, Raina SK, Galwankar
S.J Family Med Prim Care. 2020; 9(9): 4516-4520
13. Second round of the national pulse survey on continuity of essential health
services during the COVID-19 pandemic. WHO Interim report 23 April
2021https://www.who.int/publications/i/item/WHO-2019-nCoV-EHS-
continuity-survey-(lastaccessed on 13 Aug 2021)

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 NORMAL LAB VALUES FOR REFERENCE

1. CRP < 10 mg/L

2. LDH 85-227 U/L

3. D-dimer < 0.5 mcg/ml

4. Procalcitonin < 0.05 ng/ml

5. IL-6 5-15 pg/ml

6. PT 11-16 sec

7. T bilirubin 0.2-1 mg/dl

8. Direct bilirubin 0- 0.2 mg/dl

9. AST 15-37 U/L

10. ALT 16-63 U/L

11. Urea 6-20 mg/dl

12. Creatinine

Male 0.9-1.3 mg/dl

Female 0.6- 1.1 mg/dl

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Notes

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COVID 19 HANDBOOK (REVISED EDITION)