HANDBOOK OF COVID 19

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

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

FOREWARD

The world has been in the grip of COVID Pandemic since end of 2019. Such has been the impact of the disease, that the very behaviour of humankind has been altered with respect to awareness, hygiene, travel and working atmosphere etc. Despite the nationwide approach of lockdowns and restrictions, cases and mortality due to the disease continue to occur.

There has been an exponential growth in the literature on various aspects of the disease and the pandemic. A search on Pubmed with the terms ‘COVID/Therapy’ revealed more than seventeen thousand articles. Multiple agencies are issuing guidelines on all aspects of the disease. There is a need to distil the knowledge and make it available to Health Care Workers of the Armed Forces. The ‘Handbook of COVID-19’ is an attempt to make available information that is relevant in a concise manner.

I compliment the authors as well as the editorial team for the effort taken in putting together the Handbook of COVID-19.

PREFACE

1. Ever since the onset of COVID pandemic, the Armed Forces Medical College has been actively involved in the nation’s response to tackling the pandemic. AFMC was identified as a nodal centre for mentoring of institutions in setting up RT-PCR laboratories. Faculty from the college have been co-opted in state task force and have conducted online training for HCW’s of Armed Forces and civil alike. Hospitals affiliated to AFMC have participated in clinical trials on patients with COVID. Faculty, residents, nursing and paramedical staff were deployed at various ‘BROWNFIELD’ and ‘GREENFIELD’ COVID hospitals across the country during the first and second wave. The faculty has been actively involved in research about disease prediction models, epidemiology, immune response and have numerous publications in this regard.

2. It is but natural that the vast experience of AFMC in handling COVID-19, both administrative as well as clinical, would be useful in bringing about the handbook. The chapters in handbook are designed to provide the reader a quick reference without burdening them with details. The various departments of AFMC have endeavoured to bring forth latest information as available, however as the editor’s note states that the knowledge is accruing and readers should refer to suggested reading at end of each chapter for updates.

3. I compliment the authors as well as the editorial team for the effort taken in bringing about the Handbook of COVID-19 at short notice.

Best Wishes Jai hind

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CONTENTS Chapter

Genealogy of COVID 19 Pandemic…………………………….. Coronavirus and SARS CoV2……………………………………… Immune response and Immunopathogenesis ……………………… Laboratory Diagnosis of COVID 19………………………………. Role of Radiodiagnosis in Management of COVID-19…………… Management of Mild COVID 19………………………………….. Management of Moderate and Severe COVID 19………………… Oxygen therapy, ventilation & ICU management…………………. COVID 19 in Children…………………………………………….. Complications of COVID 19……………………………………… Vaccines……………………………………………………………. Impact of COVID 19 Pandemic on mental health………………… Public Health challenges in COVID 19 Pandemic………………… Challenges in establishing COVID Care Hospital…………………

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LIST OF CONTRIBUTORS

Surg Cmde KM Adhikari

Professor & Head Dept of Pediatrics

Maj Varun Anand

Clinical tutor

Dept of Radiodiagnosis

Col A T Atal

Assistant Prof

Dept of Internal Medicine

Surg Cdr Kavita Bala Anand

Assoc Prof

Dept of Microbiology

Surg Capt V Bhaskar

Professor

Dept of Community Medicine

Surg Capt Saurabh Bobdey

Professor

Dept of Community Medicine

Surg Cmde K Chatterjee

Professor & Head Dept of Psychiatry

Col Neeraj Garg

Assoc Professor

Dept of Hospital Administration

Col Nikahat Jahan

Professor

Dept of Anaesthesiology& Critical Care

Gp Capt BM John

Professor

Dept of Pediatrics

Lt Col S Karade

Assoc Prof

Dept of Microbiology

Brig SK Kaushik

Professor & Head

Dept of Community Medicine

Col Vikas Marwah

Professor & Head

Dept of Respiratory Medicine

Brig A S Menon

Professor & Head

Dept of Internal Medicine

Surg Lt Cdr Kranthi K Nethi

Resident

Dept of Hospital Administration

Maj Neelesh Patel

Clinical tutor

Dept of Hospital Administration

Col S K Patnaik

Professor & Offg HOD

Dept of Hospital Administration

Maj Deepu K Peter

Clinical tutor

Dept of Respiratory Medicine

Col Jyoti Prakash

Professor

Dept of Psychiatry

Col Ravinder Sahdev

Assoc Prof

Dept of Radiodiagnosis

Maj Apoorv Saxena

Clinical tutor Dept ofPediatrics

Air Cmde Arijit Sen

Professor & Head Dept of Pathology

Col Kiran Sheshadri

Professor

Dept of Anaesthesiology & Critical Care

Brig Rangraj Setlur

Professor & Head

Dept of Anaesthesiology & Critical Care

Air Cmde SP Singh

Professor & Head Dept of Microbiology

Gp Capt TVSVGK Tilak

Professor

Dept of Internal Medicine

Wg Cdr Rohit Vashisht

Assistant Prof

Dept of Internal Medicine

Surg Lt Cdr Shrinath V

Resident

Dept of Respiratory Medicine

Lt Col AK Yadav

Assoc Prof

Dept of Community Medicine

Maj Naveen Yadav

Clinical tutor

Dept of Internal Medicine

Lt Col Y Uday

Assoc Professor

Dept of Internal Medicine

1. Genealogy of the Pandemic

Lt Col AK Yadav, Surg Capt Saurabh Bobdey, Surg Capt V Bhaskar, 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 30 July 2021, there have been approximately 19.4 crores COVID-19 cases and nearly 41.6 lakh deaths worldwide. As per published literature, it is believed that the virus originated from the seafood market of Wuhan city of Hubei province, China. However, it was soon brought under control in China by strict lockdown in the affected areas. Nevertheless, the virus rapidly spread across the globe, causing high morbidity and mortality in many countries. A few of the worst affected countries are the USA, United Kingdom, Italy, Brazil, Russia, France and India. However, in varying proportions,this deadly disease has affected almost the whole world.

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

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reported daily showing a very steep climb (Fig1.1). During the second wave, more than four lakh new cases and 4000 deaths were reported per day. COVID cases started declining from mid-May, but India continues to simmer with almost forty thousand new cases and more than 500 deaths per day till 30 July 2021.

Fig 1.1 Graph of occurrence of new COVID cases 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.

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Num bers per day

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.

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

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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, 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.

(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. 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.

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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 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

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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.

(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 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.

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(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.

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 two waves of COVID 19, with the second wave more devastating than the

first. The future of the pandemic will depend on the ongoing evolution of

SARS-CoV-2 besides the behaviour of citizens, governmental efforts to respond

effectively including rapid vaccination and the extent to which the international

community can cooperate in these efforts.

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 13 Aug 2021)

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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.

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

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).

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structural proteins polyprotein 1ab that gives rise to further 16 non structural proteins.(Fig 2.1 & 2.2).

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). Betacoronaviruses 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)

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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

The host cellular receptor for SARS-CoV-2 is ACE-2 receptor (Angiotensin convertase enzyme 2). I

bytransmembrane protease, serine 2

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 Dipeptydyl 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,

Infection starts when the viral spike protein attaches to its complementary

host cell receptor.

nitial spike protein priming

(TMPRSS2) is essential for entry of

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China has 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. Currently SARS-CoV-2 Delta variant, first reported from India, is considered an important VoC that has spread to over 100 countries till now. In addition, Variant of interest (VoI) is another term used for those variants that have caused community transmission or cluster of cases. WHO recognized VoI and VoC are enumerated in Table 2.1 and Table2.2

Table 2.1 WHO labelled SARS-CoV-2 Variant of concern. Picture Courtesy: WHO; Tracking SARS-CoV-2 variants (who.int)

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Table 2.2 WHO labelled SARS-CoV-2 Variant of interest. 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. Fields Virology

3.

Nat Rev Microbiol.2019; 17:

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)

Masters, P. S. & Perlman, S. in

Vol. 2 (Eds Knipe, D. M.

& Howley, P. M.) 825–858 (Lippincott Williams & Wilkins, 2013).

Cui, J., Li, F. & Shi, ZL. Origin and evolution of pathogenic

coronaviruses.

181–192.

7.

Research. 28: 35–112

Sturman LS, Holmes KV (1983-01-01). Lauffer MA, Maramorosch K

(eds.).

The molecular biology of coronaviruses.Advances in Virus

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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.

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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

the upper respiratory pathway. In the lower respiratory tract it attaches to type II

goblet and mucociliary cells of

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

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Adaptive Immunity

Humoral Immunity (B Cell Response) Cell Mediated Immunity (T Cell response)

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

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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

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

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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 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).

17

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 microvasulature

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

supply, Cytokine storm may lead to myocarditis in absence of viral affection of

the myocytes. Intra-mycocardial 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 a

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.

18

(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 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 inspite 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 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 hyperviscosity (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

19

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 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

20

found in early disease. Tracheo-bronchtis and large vessel thrombi (Fig3.1b) and microthorombi 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

Heart commonly showed presence of intra-myocardial 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. Inspite of most patients who underwent autopsy were on anti-coagulant therapy still micro-thrombi were 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.

proteins of the virus as demonstrated by IHC in both these cells. Evidence of

ACE2 and transmembrane

protease serine 2 (TMPRSS2) is well confirmed by the presence of the spike

trachea-bronchitis and DAD is well explained by the preference of these cells

by the virus due to the expression of the ACE2 receptor.

21

Fig 3.1 Entry of SARS CoV2 and initial response

22

Fig 3.2 Cellular response to SARS CoV2

23

Fig 3.3 Pathway to cytokine storm

24

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)

25

Suggested Reading

1.

2. 3.

4.

5.

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

115.

Uday Jain. Effect of COVID-19 on the Organs.Cureus. 2020: 12(8);e9540.

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.

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.

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.

Mouhamed YazanAbou-Ismail, Akiva Diamond, Sargam

Kapoor, Yasmin Arafah and LalithaNayak. Thromb Res 2020; 194: 101–

26

4. Laboratory diagnosis of COVID 19

Lt 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 requirement

Turn-around time and cost/test

Remarks

 Can handle 90-94 sample in one run, useful for medium and high-level BSL-2 laboratory

 Needs skilled manpower and sophisticated equipment

Generic real time RT-PCR test

OP/NP swab in VTM

5-8 hr 450 INR

 Useful in acute health care setting and triage situations

 User friendly

GeneXpert COVID Xpress

OP/NP swab in VTM

45 min 2000 INR

 Indigenous assay

 Useful for low and medium level

laboratories

 User friendly

Tru NAT (MolBio)

Respiratory sample in viral lysis buffer

< 1 hr 1000 INR

 Lateral flow assay-based detection of amplicons

 Does not require expensive Real-time PCR instrument

FELUDA (Tata group)

96% sensitivity and 98% specificity

45 min 450 INR

 Inexpensive test

 Positive test indicative of active infection

 Screening tool for high-risk groups

 Low sensitivity as compared to RT-PCR

Antigen detection

NP swab

20-30 min

test

250 INR

 Tool to assess the prevalence of the diseases in a specific area

 Not recommended for diagnosis by ICMR

IgG/IgM Antibody detection test

Serum

2-3 Hr 250 INR

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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

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constraint, requirement of trained staff, biosafety cabinets and sophisticated equipment limits its use in emergency setting.

Interpretation of RT-PCR results

A positive SARS-CoV-2 RT-PCR indicates qualitative detection of 2 or

more virus specific sequences in the given sample. Since prolonged viral

shedding upto 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 TrueNatTM (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

29

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 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 haematological and biochemical tests are essential for clinical monitoring and prognostication of COVID-19 cases. These tests also

30

help in assessing the severity of disease. The detail of these tests is shown in Table 4.2.

Table 4.2 Ancillary test for management of case of COVID-19

Sample and type of vacutainer

Parameter measured

Remarks

EDTA blood, purple top vacutainer

Total blood counts

Essential for monitoring of neutrophilia, Lymphopenia, N:L ratio and thrombocytopenia:

Citrated, light-blue top vacutainer

D Dimer

Indicator of activation of coagulation system/DIC

EDTA blood, purple top vacutainer

Prothrombin time

Indicator of activation of coagulation system

Serum, Red top or yellow top vacutainer

Interlukin-6

Indicative of cytokine storm

Serum, Red top or yellow top vacutainer

ferritin

Inflammatory marker

Serum, Red top or yellow top vacutainer

Procalcitonin

Marker for secondary bacterial infection

Serum, Red top or yellow top vacutainer

C-reactive protein

Inflammatory marker, also indicative of severe viral infection

Serum, Red top or yellow top vacutainer

Liver Function test

Deranged in case of end organ damage or multi-organ dysfunction syndrome

Renal function test

SARS-CoV-2 genome sequencing

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 fuelling 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.

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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 Setember 2020. World Heal Organ [Internet]. 2020;(March):20. Available from : https : // apps . who. Int / iris/handle/10665/334254 (last visited 13 Aug 2021)

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.

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

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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

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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

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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 radiographis 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.

35

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 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).

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A

B

CD

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.

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 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.

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.

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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.

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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.

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Table 5.1 CO-RADS classification

Level of suspicion for pulmonary involvement

Summary

CO-RADS 0

Not interpretable

Scan technically insufficient for assigning a score

CO-RADS 1

CO-RADS 4 CO-RADS 5 CO-RADS 6

Very low

High Very high Proven

Normal or non-infectious

Suspicious for COVID-19

Typical for COVID-19

RT-PCR positive for SARS-CoV-2

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

(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)

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

A

B

Fig 5.6 (A&B): CO-RADS 2: HRCT showing consolidation and centrilobular nodules (features of other infections)

42

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.

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%to49%involvement

4. 50%to75%involvement

5. Morethan75%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).

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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.

ABC

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

A

B

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

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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 upto 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.

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

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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.

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.

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.

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6. Management of Mild COVID-19

Col AT Atal, Maj Naveen Yadav

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 COVID 19

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

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percent or more after a 6 minute walk test, and, a neutrophil lymphocyte ratio 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.

Investigations

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 COVID 19. Investigations to rule these out should be performed when deemed necessary.

Management

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

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special emphasis on blood sugar control. It is vital to stay in contact with a doctor who would be better able to interpret red flag signs.

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.

Inhaled steroids: Inhaled Budesonide at a dose of 800 mcg twice a day for 5 days is recommended in patients more than 65 years of age and those aged 50- 64 years with co-morbidies and have fever and cough persisting more than 5 days. The ‘STOIC’ Phase-2 Randomised Clinical Trial (RCT) demonstrated reduction in COVID-19 related Emergency Department visits as well as reduced antipyretic use. This was followed by the PRINCIPLE trial, a phase 3 RCT, which, in its interim results, demonstrated median time to self recovery 3 days shorter in patients > 65 years of age or those 50-64 years with co-morbidities. Budesonide is safe, inexpensive, well studied and widely available. Additionally, it avoids the adverse effects of oral steroids, and, its efficacy is unlikely to be affected by a variant.

Vitamins/ Supplements: Vitamin C, Vitamin D and Zinc are being widely used as a cocktail in patients with mild disease. COVID A to Z randomized clinical trial conducted in US found that, treatment with high doses of Zinc gluconate and Ascorbic acid did not shorten the duration of illness in patients with mild COVID 19.

Oral Steroids: Oral steroids are not indicated as risk of complications increase and adverse effects have been shown to occur in trials on patients with mild disease. Systemic steroids are only advocated in patients with falling oxygen saturation requiring supplemental oxygen. They have been shown to have a definite mortality benefit in this group.

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 (low quality evidence) have shown reduction in

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mortality, intubation rate and requirement of mechanical ventilation. This led to its inclusion in MoHFW/AIIMS guidelines as ‘may do’ drug therapy in mild COVID-19. It was recommended at a dose of 200 mcg/kg once daily for 3 days. The Director General Health Services (DGHS) in its guidelines of May 2021 however does not recommend its use. 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.

Favipiravir: This Pyrazine carboxamide derivative causes selective inhibition of viral RNA dependent RNA Polymerase. It finds place in Maharashtra guidelines for mild-moderate COVID 19, largely based on a pharma sponsored open label Phase 3 RCT. The trial of 150 patients demonstrated lack of statistical significance on achieving the primary endpoint (cessation of viral shedding). The DGHS guidelines no longer recommends it use.

Hydroxychloroquine(HCQ): This antimalarial and disease modifying anti rheumatic drug was observed in-vitro studies to have antiviral effect and immunomodulatory effects (impaired terminal glycosylation of ACE2 receptor). It was introduced for managing mild COVID-19 at an initial dose of 400 mg BID and then, 400 mg OD for 4 days (low certainty of evidence). On 22 March 2020, National COVID 19 Task Force, constituted by ICMR, taking cognizance of in vitro studies empirically recommended HCQ prophylaxis in India to cover added risk to Health Care Workers (HCWs) at high risk of acquiring infection. On 17 June 2020, WHO announced that the hydroxychloroquine (HCQ) arm of the Solidarity Trial to find an effective COVID-19 treatment was being stopped. This decision was based on evidence from the Solidarity trial, UK’s Recovery trial and a Cochrane review of other evidence on HCQ, which showed that it does not result in the reduction of mortality of hospitalized COVID-19 patients, when compared with standard of care. DGHS guidelines mentioned above no longer recommend its use in COVID 19

Antibiotics: No antibiotic is advised for mild COVID-19. Its use should be restricted only to those who have a complicating bacterial infection.

Monoclonal Antibodies: Combination monoclonal antibodies (Casirivimab plus imdevimab) and single monoclonal antibody (sotorivimab) targeting spike protein have received emergency use authorization (EUA) from US FDA for use in mild to moderate COVID 19. This is based on findings in trials that the

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monoclonal antibodies reduced the risk of hospitalization and death in patients with mild to moderate disease and risk factors for disease progression (see section on vulnerable population). Both companies manufacturing above monoclonal antibodies have received EUA for its use in India. Recently Subject Expert Committee (SEC) of Central Drugs Standard Control Organisation (CDSCO), India has given permission to Zydus Cadila to conduct Phase 1 & 2 trials for its antibody cocktail (ZRC 3308).

Conclusion

It is ironic that the self limited mild form of COVID-19 has seen more polypharmacy and therapeutic misadventures than some of the more serious forms. As we have learnt from trials over the last one year, basic measures as advocated for viral upper respiratory infection, hold true for this disease as well. In the absence of an effective anti-viral, observing non pharmacologic measures and vaccination remains our best protection from contracting this disease.

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. Therapeutics and COVID-19. Living Guideline 06 July 2021. World Health Organisation.

4. Clinical Management Protocol for COVID-19 (In Adults). Government of India, Ministry of Health and Family Welfare. Version 6, 24.05.21.

5. Ramakrishnan S, Nicolau Jr DV, Langford B, Mahdi M, Jeffers H, Mwasuku C et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open label, randomised control trial. Lancet Respir Med 2021. doi.org/10.1016/S2213-2600(21)00171-5.

6. Alam MT, Murshed R, Bhiuyan E, Saber S, Alam RF, Robin RC. A case series of 100 COVID-19 positive patients treated with combination of ivermectin and doxycycline. J Bangladesh Coll Physician Surg 2020;38:10-5.

7. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with COVID-19-Preliminary report. N Engl J Med 2021;384(8):693-704.

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8. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med 2020; 383:517-25.

9. https://www.COVID19treatmentguidelines.nih.gov/therapies/anti-sars-cov- 2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/ (last accessed on 13 Aug 2021)

10. http://www.dghs.gov.in › WriteReadData › News › 202104290258250563281Sy.

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7. Management of Moderate and Severe COVID

Col Vikas Marwah, 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 year and half has 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 and ACTIV. 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 hospitalised 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, Baricitinib and Tofacitinib. 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.

The presence of fever, cough, sore throat, without the presence of dyspnea will be classified as having mild disease and they seldom require hospitalisation. COVID-19 patients with non-severe disease requires only supportive care and management of underlying comorbidities.

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.

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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

COVID-19 patient with clinical signs of pneumonia (fever, cough, dyspnoea, tachypnoea) but without any features of severe pneumonia and maintaining a saturation of ≥ 90% is said to have moderate disease. If the patient develops tachypnoea more than 30/min, severe respiratory distress and has a SpO2 <90% on room air, he/she is said to have severe disease. Critical COVID-19 disease consists of ARDS, sepsis and septic shock.

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 hospitalised 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. Dexamethasone should be initiated 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 hyperglycaemia 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.

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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. The current pool of evidence suggests that in severe and critical COVID-19, IL-6 receptor blockers reduce mortality and reduced the need and duration of invasive mechanical ventilation. A subgroup analysis of these data has suggested that steroids did not abolish and may even enhance the beneficial effect of IL-6 receptor blockers on mortality. Head-to-head data from REMAP- CAP trial has demonstrated no difference between Tocilizumab and Sarilumab in a population of patients all receiving corticosteroids.

Patients with severe COVID, which is 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. All patients should be monitored for signs and symptoms of infection, given the increased risk with immunosuppression in addition to systemic corticosteroids.

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. Barcitinib has been found to have an antiviral action in that it interferes with the viral entry into the cell. A multinational controlled randomized trial comparing Barcitinib in patients with COVID-19 not on mechanical ventilation showed a reduction in 28-day mortality seen with Baricitinib when compared with placebo. Baricitinib can be offered to patients with or progressing towards high flow oxygen or non invasive ventilation despite being on glucocorticoids. It is an oral tablet and taken 4 mg once daily for 14 days. It should however be not used in individuals who have already received IL-6 pathway inhibitor as there are no studies on co- administration of these drugs.

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. A panel review of evidences done by WHO found lack of evidence that

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Remdesivir improved outcomes which matter to patients such as reduced mortality, need for mechanical ventilation and time to clinical improvement. 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. WHO has given a conditional recommendation for using Remdesivir for treatment of hospitalized patients with COVID-19. In 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. It can be used within ten days of symptom onset in patients with moderate to severe disease (requiring supplemental oxygen). If a patient does not demonstrate clinical improvement, treatment may be extended for up to five additional days for a total treatment duration of up to 10 days. Its use is contraindicated in those with liver (ALT > 5 times normal at baseline) or renal (eGFR < 30 mL/minute) dysfunction.

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. In patients of moderate disease who are at high risk, monoclonal antibodies to neutralize SARS-CoV-2 are being administered on an outpatient basis. The use of monoclonal antibodies in hospitalised 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 titres 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 grams 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 ischaemic changes, viral myocarditis or pulmonary embolism. Cardiac enzymes may be measured if there is suspicion of cardiac ischaemia, 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 ≥

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92–95% in pregnant women if there are no red flag signs. Details of Oxygen 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 has 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 does 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 75/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 analysed in these patients and if there are features of hyper-inflammation, Baricitinib or

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Tocilizumab should be instituted. Baricitinib or Tocilizumab should also be initiated in situations where 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 these 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

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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)

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 hyperkalemia 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.

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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 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) are part of infection control in COVID 19. They help to reduce infection transmission to healthcare workers

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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, 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 CDCand WHOhave 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

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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.

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.

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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 Non invasive 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’smask, 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.

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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 liters per minute and a FiO2 of 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 8.2 Hudson’s Mask

Fig 8.1 Nasal Prongs

Fig 8.3 Venturi mask

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Fig 8.4 Non-rebreathing mask (NRBM)

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

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prepared outside the patient care area and handed over to the ICU team (stored in the refrigerator if required), so that apart from initial central Iine, 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 toanticoagulation 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

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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

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9. COVID-19 in Children

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

India has battled out the first and second waves of COVID 19 infections. The possibility of a third wave of COVID 19 is being widely modelled and discussed with the inference of possible increased number of cases in the pediatric population. 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.

Clinical Features

Majority of children with COVID-19 infection are asymptomatic or symptomatic. Commonly reported symptoms are that of any other respiratory

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viral illness. Few children may also present with gastrointestinal symptoms like diarrhea, pain abdomen and vomiting. 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 if available

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

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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 in 2 divided doses). 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 20 ml/kg of Normal saline (NS) or Ringer lactate (RL) over 20 – 30 minutes may be required for children presenting with shock. Repeat boluses up to 60 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/dose in two divided doses or equivalent dose of methylprednisolone should be started as early as possible and continued for 5 to 14 days.

 ARDS – Mild ARDS can be managed with HFNO or NIV, however severe ARDS will require mechanical ventilation. Principles of

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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 Hydroxychloroquine, Lopinavir-Ritonavir, Favipiravir,

Ivermectin, Tocilizumab or monoclonal antibodies are currently

not recommended.

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 an evidence of prior exposure to SARS-CoV-2. This syndrome was termed as MIS-C. Over the course of last year and half, 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.

Diagnostic Criteria of MIS-C

1. Children and Adolescents 0 – 19 years with fever > 3 days AND 2. At least two of the following

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• Rash/non-purulentconjunctivitis

• Hypotensionorshock

• Features of myocardial dysfunction, pericarditis, valvular

dysfunction or coronary abnormalities (including echo-

cardiographic findings and deranged BNP/Troponin-T)

• Evidence of coagulopathy (abnormal PT/aPTT/D-dimer)

• Acutegastrointestinalproblems(vomiting,diarrhoeaorabdominal

pain)

3. Elevated markers of inflammation (ESR, CRP, Procalcitonin)

4. No other obvious microbial cause of inflammation

5. 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 to diagnose 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. Plateletcount<1,50,000/cmm

iii. Serum Sodium (Na) < 135 mEq/L

iv. Neutrophilia

v. Hypoalbuminemia (Serum albumin < 3 m g/dL)

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

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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 ionotropic support and those with coronary artery abnormalities should be managed with Aspirin. 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

 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

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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.

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.

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: http://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

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Fig9.1 Isolation plan for children less than 12 years

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Fig 9.2 Diagnosis and management of MIS-C (Adapted from MoHFW and IAP guidelines for management of COVID-19 in Children)

Unremitting Fever; > 38oC Epidemiological link to COVID-19

Clinical features suggestive of MIS- C

Yes

Yes

No

No

Tier-I investigations

Positive

Is Shock/ Life threatening organ dysfunction present

Evaluate for alternate diagnosis Monitor for features of MIS-C

Tier-II investigations Work-up for common

Simultaneous Tier-I and Tier-II investigations

Work-up for common tropical infections

IVIg 2g/kg (max 100 gm) over 12 hours OR Methylprednisolone 10 – 30 mg/kg/day (max 1gm/day)

Fulfills criteria for MIS-C

Yes

tropical infections

Fulfills criteria for MIS-C

Yes

Aspirin 3-5 mg/kg/day (max 81 mg/day)

Add Enoxaparin 1mg/kg BD subcutaneously if coronary artery Z-score > +10 or LVEF < 35% or thrombosis

Change methylprednisolone to dexamethasone after 3 – 5 days; Taper 25% every week and stop after 3-4 weeks

IVIg 2g/kg (max 100 gm) over 12 hours AND Methylprednisolone 10 – 30 mg/kg/day (max 1gm/day)

Empiric antibiotics

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Repeat IVIg – 2g/kg over 12 hours OR

Anakinra

No response in 48 hours

OR

Aspirin 3-5 mg/kg/day (max 81 mg/day)

Severity Clinical Investigations Management Monitoring Features

Mild

Fever

Sore Throat Rhinorrhea

No fast breathing

Not required

Home Isolation Rest Paracetamol Adequate hydration and nutrition

Home monitoring – temperature, SpO2, respiratory rate and urine output

Moderate

Fever Tachypnea

SpO2 – 90 – 94% on room air Vomiting

Loose stools Dehydration

CBC

Chest X-ray

Oxygen by nasal prongs or face mask

IV fluids if required Empirical antibiotics Corticosteroids in rapidly progressive disease

Admit in HDU – respiratory rate, SpO2, urine output, blood pressure or capillary refill time, work of breathing

Severe

Fever Tachypnea SpO2 – < 90% on room air ARDS

Septic shock MODS

CBC

Chest X-ray LFT/RFT Blood gas Blood culture CRP PT/aPTT D-dimer Ferritin

Corticosteroids IV fluids incl bolus Empirical antibiotics Ventilation

Admit in ICU – Intensive monitoring including blood gas analysis

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 IV – Intravenous

HDU – High dependency unit

ARDS – Acute respiratory distress syndrome MODS – Multi organ dysfunction syndrome CRP – C-reactive protein

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Device

Description

Indication

Consideration

NasalCannula

– Lightweight; two soft prongs that fit in the nares

– Different sizes are

available

– Better tolerated by infants and younger children

– Children who need O2 concentrations between 22–45%.

– Allows child to eat, talk and cough without interrupting oxygen delivery

– Most commonly used oxygen delivery device

– Maximum oxygen flow should not exceed 4L/min

– Inconsistent FiO2 depending on child’s size

– May cause drying of mucous membranes

– Remove nasal prongs for 2 mins after every 4 hours (under cover of free flow oxygen) to prevent injury to nasal septum

Face Mask

– Mask sits on face over mouth and nose; has elastic straps.

– Available in various sizes.

– Device of choice in older children (>5 yrs)

Low flow device for children needing 35-60 % FiO2.

– Appropriate flow rate – 6- 10L/min; Minimum flow of 5 L/min to be maintained

– Inconsistent FiO2

– Flow below 4 L/min can cause CO2 retention

– Monitor for signs

of hypercarbia

S.N o

1

2

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Non Rebreathing Mask (Face mask with a reservoir)

– Mask sits on the face over mouth and nose; has elastic strap.

– 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.

Children requiring high amount of oxygen up to 90%.

– High FiO2 of upto 90% – Monitor for signs of hypercarbia

Heated Humidified High Flow Nasal Cannula (HHHFNC)

-Light weight; two soft prongs that loosely fit in the nares.

-Delivers oxygen from a flow rate of 4 L/min in infants to 40 L/min or more in adolescents

Children who require Higher FiO2 up to 80% with some PEEP (use of accessory muscles of respiration)

-Flow rate scan be adjusted -Provides PEEP

-Devices have humidifier which prevents drying of mucosal membranes

-Start with 2 L/kg/min flow rate and titrate as per SpO2; generates 4-5 cm H2O of PEEP.

-Monitor for abdominal distension; Use OG tube to decompress stomach.

3

4

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Continuous Positive Airway Pressure (CPAP)

– Has 2 limbs – inspiratory and expiratory with nasal interface (snugly fit short binasal prongs) between them. Inspiratory limb is connected to oxygen source and expiratory limb is immersed in to a water chamber to a depth in centimetres that equals the CPAP pressure.

– Similar to HHHFNC except the nasal prongs are snugly fit

– Respiratory distress with increased work of breathing

– Delivery of mild air pressure to keep the airways open.

– FiO2 can be titrated. Delivers PEEP to a spontaneously breathing child.

– Delivers PEEP

– Monitor for abdominal distension; Use OG tube

to decompress stomach

– Flow rate 0f 5–10 L/min

is required

– Remove nasal prongs for 5 mins after every 4 hours (under cover of free flow oxygen) to prevent injury to nasal septum

5

Table 9.2 Oxygen therapy in children

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10. Complications of COVID 19

Wg Cdr Rohit Vashisht, Gp Capt TVSVGK Tilak Introduction

Moderate to severe COVID 19 poses a risk of sequel after recovery from the acute episode. 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. The prevalence ranges from 10-80%. In absence of a standard case definition, Long COVID is best defined as symptoms persisting beyond four weeks. 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. Alternative diagnosis explaining these symptoms should be excluded. Common clinical features are fatigue, 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 in children and adults.

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 retrospective studies. Elderly patients with high d-dimer (>2 times

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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. 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

Therapy is recommended for minimum 4 weeks 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. The role of antiplatelet such as aspirin for thromboprophylaxis is currently under investigation.

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) Invasive Mucormycosis

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. Majority of the cases post COVID have been documented in patients of diabetes

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with uncontrolled hyperglycemia. Indiscriminate steroid use with poor glycemic control is a major risk factor for this invasive fungal infection. In a large series of 2826, COVID with rhino-orbital cerebral mucormycosis (ROCM) reported from India; 78% had diabetes and 87% had received steroids. 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

(b)

• • •

Extensive surgical debridement

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.

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. Patients usually present with new onset fever, productive cough, hypoxia and new or worsening lung infiltrates.

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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. Persisting cough is a frequently reported sequel, usually last for few weeks after the discharge, and may even occur in those with mild disease. Dyspnoea 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 dyspnoea. 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 have

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been tried with varied success. A small study from UK found steroids to be useful in some patients with post COVID organizing pneumonia; however, more research is required to validate these therapies.

Cardiovascular complications

About twenty percent of COVID 19 patients report chest pain at two months follow up. Palpitation is another common symptom seen in some 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. The prothrombotic and hyper inflammatory state can cause impairment of coronary flow and acute myocardial 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) case definition for MIS-A includes five criteria:

a) Severe illness which requires a person aged ≥21 years to be hospitalized b) Evidence of current or previous SARS-CoV-2 infection by a positive test result (RT PCR/ antigen or COVID antibodies) while admission or in the

last 12 weeks;

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c) Severe extra pulmonary dysfunction involving ≥ 1 organ system (e.g., cardiac dysfunction, hypotension/shock, arterio-venous thrombosis or embolic manifestations, or acute hepatic dysfunction);

d) Severe inflammation as evidenced by lab parameters (e.g., raised ferritin, D-dimer, CRP or interleukin-6) AND

e) Severe respiratory illness should be absent.

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 50% 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.

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. Persistent anosmia and ageusia may persist in about 10% of patients even up to six months.

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

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generated by the hospitalization and the disease. It resolves in 3-4 months.

d) Endocrine sequelae

Cases of diabetic ketoacidosis (DKA) have been reported in those with no previous history of diabetes mellitus, weeks to months after initial illness. Possible mechanisms may be direct viral or immune mediated damage to islet cells. Thyroid abnormalities such as subacute thyroiditis have been reported post COVID. Decreased sperm concentration and motility for have also been reported post COVID.

Conclusion:

COVID 19 carries a varying degree of risk of complications weeks or months after the initial insult. Serious post COVID manifestations are mucormycosis, thromboembolic episodes and MIS-A It is important for physicians to be aware and regularly monitor these patients.

Further 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 accessed22 Jul, 2021)

3. Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection. Centre of Disease Control .Morbidity and Mortality Weekly Report 2020/ 69(40); 1450–1456 October 9, 2020 / Vol. 69 / No. 40.

4. Singhal T. The Chronic Effects of COVID-19 or “Long COVID”. The Indian Practitioner.2021; 74(4): 24-31.

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11. Vaccines

Surg Cdr Kavita B Anand, Air Cmde SP Singh,

Brig A S Menon, Lt Col Y Uday

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

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. As of July 2021, one hundred and eight vaccines are in clinical development and one hundred and eighty four are 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 Administeration (FDA).

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 and Moderna at the time of writing this article.

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 vaccine is a multi-epitope vaccine 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.

its vaccine in December 2020, Moderna a week later and Johnson & Johnson in

Pfizer/BioNTech obtained EUA for

February 2021.

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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.

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.

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.

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.

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 than18 years of age. Vaccine needs to be

96

2-80C. Once opened the vial can be stored at 2 to 80C for six hours or

stored at

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.

2. Novavax

at room temperature (maximally 250C) for two hours.

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

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

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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.

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Table 11.1: COVID19 vaccines based on various platforms

Vaccine platform

Type of vaccine candidate

No of Dose Developers Days of

administration Route

Phase Of Trial

Inactivated Virus

(BBV152); Covaxin

Two Bharat Biotech

Day 0,28 International Limited IM

Phase 3

CoronaVac;

Two Sinovac Research and Day 0,14 Development Co., Ltd IM

Phase 4

(vero cell)

Viral Vector (non- replicating)

`

One/Two AstraZeneca +University Day 0 ± 28 of Oxford

Phase 4

Sputnik

Two

Day 0, 21 IM

Gamaleya research Institute; Health Ministry of Russian Federation

Phase 3

BBV154,

One Bharat Biotech

Day 0 International Limited IN

Phase 1

Live Attenuated Virus

COVI-VAC

One/Two Codagenix/Serum Day 0±28 Institute of India IN

Phase 1

RNA

mRNA-1273 Two Moderna Day 0, 28

IM

Moderna + National Institute of Allergy and Infectious Diseases (NIAID)

Phase 4

BNT162b2

(3 LNP-mRNAs ), also known as “Comirnaty”

Two Pfizer/BioNTech + Day 0, 21 Fosun Pharma

IM

Phase 4

DNA

nCoV Vaccine Three Zydus Cadila Day 0,28,56

ID

Phase 3

Viral Vector (replicating)

DelNS1-2019- nCoV-RBD-OPT1 (Intranasal flu- based-RBD )

Two

Day 0, 28 IN

University of Hong Kong, Xiamen University and Beijing Wantai Biological Pharmacy

Phase 2

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Vaccine platform

Type of vaccine candidate

No of Dose Days of administration Route

Developers

Phase Of Trial

Protein subunit

SARS-CoV-2 rS/Matrix M1- Adjuvant (Full length recombinant SARS CoV-2

Two

Day 0, 21 IM

Novavax

Phase3

glycoprotein nanoparticle vaccine adjuvanted with Matrix M) NVX-CoV2373

Virus Like Particle

RBD SARS-CoV- 2 HBsAg VLP vaccine

Two Day 0,28 IM

Serum Institute of India + Accelagen Pty + SpyBiotech

Phase 1/2

VVr

+ Antigen Presenting Cell

Dendritic cell vaccine AV- COVID-19. A vaccine consisting of autologous dendritic cells loaded with antigens from SARS-CoV-2, with or without GM-CSF

One Day 0 IM

Aivita Biomedical, Inc. National Institute of Health Research and Development, Ministry of Health Republic of Indonesia

Phase 1/2

Live Attenuated

COVI-VAC

One/Two Day 0 ± 28

Codagenix/Serum Institute of India

Phase 1

Virus

IN

VVnr

+ Antigen Presenting Cell

LV-SMENP-DC vaccine.

Dendritic cells are modified with lentivirus vectors expressing COVID-19 minigene SMENP and immune modulatory genes. CTLs are activated

One Day 0 SC/IV

Shenzhen Geno-Immune Medical Institute

Phase 1/2

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by LV-DC presenting COVID-19 specific antigens.

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 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. Study on UK Health care workers who received BNT162b2 mRNA (Pfizer, BioNTech) showed vaccine effectiveness of 85 % seven days after the second dose.

Emergence of highly transmissible variants of concern like the Delta variants have raised the possibility of breakthrough infections in previously

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vaccinated individuals. The BNT162b2 (Pfizer) and ChAdOx1 nCoV-19 both have shown reduced effectiveness against Delta variant of 88 % and 67 % respectively. Another notable difference was 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.

Durability of protection

The question of durability of protection is an unanswered one. Lancet

reported that antibody elicited by against Spike (S) glycoprotein of SARS CoV2 in patients vaccinated by both BNT162b2 (Pfizer) and ChAdOx1 nCoV-19 show waning titre if followed up serially. Cell mediated response to vaccines have been reported in trials and may explain protection against disease despite falling antibody titres. There are no guidelines yet for any additional booster dose administration after prime & boost dose.

Evaluation of COVID-19 vaccine effectiveness

In response to the pandemic, there has been an unparalleled global effort for the development of a vaccine against COVID-19, and many vaccines were given EUA by many countries worldwide. Considering the rapid development and implementation of vaccination, it is important for each nation to evaluate the effectiveness of the vaccine in preventing morbidity and mortality due to COVID-19. However, vaccine effectiveness studies need to be conducted using a sound methodology to provide scientific evidence for policy-makers. WHO have provided the guidelines for the conduct of vaccine studies. (Refer to

suggested reading section for further guidance).

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.

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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.

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 manufactures 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

(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

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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 11.1: Layout of vaccination Centre

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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 recognisesymptoms 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.

(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.

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, COVIDvaccination 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

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

9. 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

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10. MOHFW, GoI, COVID-19 vaccines – operational guidelines. Available online:

Click to access COVID19VaccineOG111Chapter16.pdf

(Last visited 13 Aug 2021)

11. https://www.mygov.in/COVID-19 (Last visited 13 Aug 2021)

12. http://www.gavi.org/COVID19 (Last visited 13 Aug 2021)

13. https://www.nejm.org/COVID-vaccine (Last visited 13 Aug 2021)

14. 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

15. 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

16. 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

17. 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 2021)

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12. 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 12.1 General mental health management (ABC) A

B

C

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

Be physically active. Do regular exercises. Balanced diet

Be a role model

Break chain of rumours

Balance work and leisure Breaks are essential

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 12.2 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/ Perception

Explore what the patient/ family member already knows about the 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 advance warning, of what they are going to hear. Useful sentences are

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 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 extra precaution and structuring of routine. Regular health

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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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13. 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. P

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.

arents 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.

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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 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

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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 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 R0, 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

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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 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

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.

provide the best healthcare at the remotest location to every individual.

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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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14. 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

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precaution with full PPE gear while carrying out duties are some to mention. These challenges have been elaborated below-.

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.

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.

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.

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.

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:-

b)

c)

d)

e)

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(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.

(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

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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 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)

c)

d)

e)

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.

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.

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.

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

128

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.

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:

129

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.

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

130

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.

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,

131

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

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).

132

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

Fig 14.1 Reasons for disruption of hospital services (WHO second round of national pulse survey)

133

IT Challenges during COVID-19

The existing IT network infrastructure of hospitals has come under intense straindue 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 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

Training of IT

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

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.

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.

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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.

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.

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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)

136

1. CRP

2. LDH

3. D-dimer

4. Procalcitonin

5. IL-6

6. PT

7. T bilirubin

8. Direct bilirubin

9. AST

10. ALT

11. Urea

12. Creatinine

Male Female

< 10 mg/L 85-227 U/L

< 0.5 mcg/ml < 0.05 ng/ml

5-15 pg/ml 11-16 sec 0.2-1 mg/dl 0- 0.2 mg/dl 15-37 U/L 16-63U/L 6-20mg/dl

0.9-1.3 mg/dl 0.6- 1.1 mg/dl

NORMAL LAB VALUES FOR REFERENCE

137

Notes

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