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Coronavirus Disease
This page intentionally left blank
Coronavirus Disease
From Origin to Outbreak

Edited by
Adnan I. Qureshi
Zeenat Qureshi Institutes and Department of Neurology,
University of Missouri, Columbia, MO, United States

Omar Saeed
Department of Neurology, University of Tennessee Health Science Center,
Memphis, TN, United States

Uzma Syed
South Shore Infectious Diseases, Bayshore; Travel Medicine Consultants
and Antibiotic Infusion Center, Syosset, NY, United States
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright Ó 2022 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means,
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Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by
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Library of Congress Cataloging-in-Publication Data

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ISBN: 978-0-12-824409-8

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Contents

Contributors ix

1. Introduction 1
Adnan I. Qureshi
References 11

2. History of SARS-CoV-2 13
Iryna Lobanova
References 17

3. Zoonotic infections 21
Ghaida Zaid
Definition 21
Transmission 21
History of zoonoses 22
Emerging infections and virus spillover 25
Bat ecology 25
Zoonosis as relevant to SARS-CoV-1 and SARS-CoV-2 infections 26
Challenges to control outbreak 27
References 27

4. Global response 29
Ahmed A. Malik and Imaan Bashir
An enemy emerges 29
The virus marches on: East Asian countries 31
Europe will not be spared: Italy 32
Let us worship in peace: Pakistan 32
The new norm: the United States gets caught in a storm 33
The city that never sleeps 36
The dilemma of one of the largest gathering in the world 38
The search for a prevention 40
The need to monitor the cases 41

v
vi Contents

As Earth completes its revolution 41

References 44

5. Coronavirus infection outbreak: comparison with

other viral infection outbreak 47
Mohammad Rauf A. Chaudhry
Understanding SARS-CoV-2 47
Epidemic versus pandemic 49
Common features of epidemics 49
Saw tooth pattern 49
Tooth necklace pattern 49
Tooth eruption pattern 50
Why epidemics die their deaths? 50
Comparing SARS-CoV-2 with SARS-CoV and influenza
pandemics 51
Gene structure of MERS-CoV, SARS-CoV, and SARS-CoV-2 51
Transmissibility and the basic reproductive rate 52
Incubation period of SARS-CoV-2 and viral excretion 52
Case fatality and risk of severe illness 52
Population-based mortality 54
Incidence of SARS-CoV-2 infections 55
Comparing SARS-CoV-2 and SARS-CoV spread 55
SARS-CoV-2 and warmer weather 55
SARS-CoV-2 and the effect of containment measures 55
Conclusion 56
References 56

6. SARS-CoV-2 viral structure and genetics 59

Abhi Pandhi and Ishita Vasudev
Introduction 59
Viral structure 59
Molecular genetics 61
Cell entry process 61
Replication and gene expression 62
Replication transcription complexes 63
Basics of immune response 64
Viral host immune interactions 65
SARS-CoV-2 vaccines 66
Conclusions 66
References 67

7. Clinical manifestation and diagnosis 71

Yasemin Akinci
Introduction 71
Transmission of COVID-19 72
Routes of Transmission 72
 Contents vii

Timescale of transmission 75
Susceptible groups 76
Clinical manifestations 77
Initial phase 78
Pulmonary phase 78
Inflammatory phase 80
Extrapulmonary manifestations 80
Clinical classification of symptomatic patients 85
Risk factors for severe disease 85
Disease course in special groups 87
Diagnosis 89
Specific diagnostic tests 89
Laboratory findings 92
Radiological findings 94
Case definitions 97
Differential diagnosis 97
Viral persistence, convalescence, and recovery period 99
Precautionary guidelines set up by the Centers for
Disease Control and Prevention regarding the testing
process of COVID-19 and laboratory biosafety 101
Use of personal protective equipment 101
Collecting, handling, and testing clinical specimens for
COVID-19 103
COVID-19 laboratory biosafety 105
References 107

8. Treatment and therapeutic agents 121

Iqra Naveed Akhtar
Emergency use authorizations during the SARS-CoV-2
pandemic 123
What is an emergency use authorization? 123
EUA for vaccine development 124
Part I: Antiviral drug therapy 126
Drugs that inhibit SARS-CoV-2 cell entry, endocytosis, and
membrane fusion 126
Drugs that inhibit proteolysis of SARS-CoV-2 134
Drugs that inhibit the RNA-dependent RNA-polymerase
(RdRp) of SARS-CoV-2 136
Drugs with unspecified antiviral activity 142
Part II: Immunomodulatory agents 144
Corticosteroids 144
Part III: Convalescent plasma, Intravenous immunoglobulin,
and Cell-based therapies 155
Clinical Research 156
Wuhan, China 156
The Netherlands (CONCOVID) 156
viii Contents

India (PLACID) 156

United States (Mayo Clinic Expanded Access Program) 157
Part IV: Vaccine 158
Different Vaccine Platforms 159
Vaccines issued EUA by the FDA 160
Conclusion 162
References 163
Further Reading 176

9. The economic repercussions of Coronavirus

disease 2019 (COVID-19) 177
Usman Saeed
World economy December 2019 177
Major conflicts 178
Political impact of COVID-19 178
China’s economic response to COVID-19 179
What industry relied on Wuhan for trade globally 179
Governments’ economic response to COVID-19 182
A recession caused by SARS-CoV-2 183
References 185
Further Reading 186

10. Psychological and social implications of COVID-19 187

Ihtesham Qureshi
Introduction 187
Effect of quarantine and isolation on psychosocial well-being 188
Impact on healthcare providers and frontline
workersd“heal the healers” 189
Impact on the society 190
Children 190
Old age 191
Domestic caregivers 192
Neglected communitydmigrants, daily wagers,
slum dwellers, and inmate 192
General public 193
Home quarantine for “homeless”d self-contradictory 194
Impact on people with preexisting psychiatric condition 194
Role of social platforms and media 195
Role of government and political leaders 198
Conclusion 199
References 200

Index 207
Contributors

Iqra Naveed Akhtar, Zeenat Qureshi Stroke Institute, Columbia, MO, United States
Yasemin Akinci, Zeenat Qureshi Stroke Institute, University of Missouri, Columbia,
MO, United States; Istanbul University - Cerrahpasa, Cerrahpasa School of
Medicine, Department of Neurology, Istanbul, Turkey
Imaan Bashir, Albirr Medical Research Consultants, Gainesville, FL, United States
Mohammad Rauf A. Chaudhry, Department of Neurology, Texas Tech University
Health Science Center, El Paso, TX, United States; Zeenat Qureshi Stroke Institute,
St. Cloud, MN, United States
Iryna Lobanova, Zeenat Qureshi Stroke Institute and Department of Neurology,
University of Missouri, Columbia, MO, United States
Ahmed A. Malik, Department of Internal Medicine, UCF-COM/HCA GME
Consortium, North Florida Regional Medical Center, Gainesville, FL, United
States; Zeenat Qureshi Stroke Institutes, Columbia, MO, United States
Abhi Pandhi, University of Tennessee Health Science Center, Memphis, TN, United
States
Adnan I. Qureshi, Zeenat Qureshi Stroke Institute and Department of Neurology,
University of Missouri, Columbia, MO, United States
Ihtesham Qureshi, Fellowship Physician, Epilepsy, Department of Neurology,
University of Texas Health Science Center at Houston, Houston, TX, United States
Usman Saeed, Independent Advisor on Internationals Political Economy
Ishita Vasudev, Sir Ganga Ram Hospital, New Delhi, Delhi, India
Ghaida Zaid, Department of Neurology, University of Tennesse Health Science
Center, Memphis, TN, United States

ix
This page intentionally left blank
Chapter 1

Introduction
Adnan I. Qureshi
Zeenat Qureshi Stroke Institute and Department of Neurology, University of Missouri, Columbia,
MO, United States

The goal of this book is to provide a detailed description with easy-to-un-

derstand accounts of one of the fastest growing infections in the world. An
outbreak of respiratory disease was caused by a novel coronavirus that was
first detected in China and which has now been detected in almost every
location internationally. The respiratory disease caused by virus has been
named “coronavirus disease 2019” (COVID-19). An outbreak of COVID-19
began in Wuhan, Hubei Province, China, in December 2019. On January 30,
2020, the World Health Organization declared the Chinese outbreak of
COVID-19 to be a Public Health Emergency of International Concern posing a
high risk to countries with vulnerable health systems. By February 23, 2020,
there were 76,936 reported cases in mainland China and 1875 cases in loca-
tions outside mainland China. By March 5th, 2020, 360 cases of COVID- 19
were reported in the United States. As of April 2021, 136 million persons had
been infected by the novel coronavirus with 2.94 million persons dying from
the infection worldwide. Several web-based resources have been created to
provide real-time updates on the occurrence of COVID-19. One of the most
widely used is developed at Johns Hopkins University available at COVID-19
Map - Johns Hopkins Coronavirus Resource Center (jhu.edu). The interface is
shown in Fig. 1.1.
The progression of COVID-19 over time is shown in Fig. 1.2 adapted from
Wikipedia.
The top five countries with the highest rates of COVID-19 are shown in
Table 1.1 (adapted from Wikipedia):
Paradoxically, there is a disproportionately high burden faced by some of
the most developed countries in terms of both health care and economic
infrastructure in the COVID-19 pandemic. This is very different from previous
pandemics such as those caused by Ebola virus or Dengue virus. Also, there
appears to be differences in COVID-19-related mortality between countries.
The differences in rates of COVID-19-related deaths between countries are a
function of the total number of cases, the proportion of the population who are
at high risk for severe COVID-19, the implementation of precautionary

Coronavirus Disease. https://doi.org/10.1016/B978-0-12-824409-8.00010-2

Copyright © 2022 Elsevier Inc. All rights reserved. 1
 2 Coronavirus Disease
FIGURE 1.1 Interface of Johns Hopkins Coronavirus Resource Center.
 Introduction Chapter | 1 3

FIGURE 1.2 Global progression of COVID-19 over time.

measures by respective governments and populations, and effectiveness of

medical treatment. Countries can be divided based on ratio of between
observed mortality and vulnerability index to quantify how effective the pre-
ventive measures and medical treatment were in reducing mortality (measure
of performance) [1]. The three groups of countries are presented on the world
map (see Fig. 1.3) with countries depicted in green as those with high per-
formance in reducing mortality, in yellow as moderate performance, and red as
low performance. Countries for which no statistics or data was available on
COVID-19-related deaths or mortality per 1,000,000 persons have been
marked in gray on the map. Countries in the high-performance group included
several African and south-east Asian nations that are typically resource-
deprived and are thought to face the worst brunt of any infectious disease.

FIGURE 1.3 Performance of various countries in reducing COVID-19-related mortality.

4 Coronavirus Disease

TABLE 1.1 Five countries with the highest rates of cases of COVID-19 and
associated deaths.

Location Cases Deaths

31.2M 562,000

United States
13.5M 170,000

India
13.5M 353,000

Brazil
5.06M 98,750

France

4.59M 101K

Russia

Another interesting finding was that Taiwan was in the high-performance

group despite the island comprising 23 million inhabitants is located just 81
miles from mainland China. Frequent travel back and forth between China and
Taiwan occurs on a daily basis and thousands of Taiwanese nationals live and
work in China. Despite the challenges, the COVID-19-related mortality was
low in Taiwan after adjusting for vulnerability to severe COVID-19 infection.
Among countries in the low-performance tier were the wealthy and resourceful
countries of western Europe and North America, supporting the argument that
mere healthcare resources and finances are not enough when it comes to
effectively dealing with the current pandemic. These countries have high
proportion of persons at risk for severe COVID-19 and poor performance was
still identified despite adjustment for vulnerability index.
Coronaviruses are a large family of viruses that are responsible for Middle
East Respiratory Syndrome Coronavirus (MERS-CoV) and Severe Acute
Respiratory Syndrome Coronavirus (SARS-CoV). The causative agent was
identified from throat swab samples conducted by the Chinese Center for
 Introduction Chapter | 1 5

Disease Control and Prevention on January 7, 2020 and was subsequently

named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
The SARS-CoV-2 virus is a betacoronavirus, like MERS-CoV and SARS-CoV.
All three of these viruses have their origins in bats. The SARS-CoV was
transmitted from civet cats to humans and MERS-CoV from dromedary
camels to humans.
Common signs of infection include respiratory symptoms, fever, cough,
and shortness of breath. In more severe cases, infection can cause pneumonia,
severe acute respiratory syndrome, and even respiratory failure leading to
death. COVID-19 is not limited to pulmonary system but results in multiorgan
dysfunction involving gastrointestinal, cardiac, hepatic, neurologic, and renal
systems. Another feature that gained prominence was inflammatory throm-
bosis, which resulted in ischemic stroke, pulmonary embolisms, cardiac
ischemia, and peripheral venous thromboembolism. There was a secondary
component 2e4 weeks after primary infection attributed to excessive immu-
nological response (cytokine storm) resulting in multisystem inflammatory
syndrome consisting of shock, cardiac involvement, and gastrointestinal
symptoms. Anecdotal data suggests that a proportion of persons after contact
with COVID-19-infected individuals develop symptoms of COVID-19 but do
not have the disease, an entity we term as COVID-19 mimic. The pooled
prevalence of COVID-19 mimic was 16 per 100 persons under surveillance
(95% confidence interval 11e23 per 100 persons) [2]. In the analysis of a
priori subgroups, by region of the studies, prevalence of COVID-19 mimic was
16 (95% CI 11e23) in North America, 15 (95% CI 4e40) in Europe, and 15
(95% CI 7e32) per 100 persons in Asia.
The COVID-19 pandemic resulted in widespread and unprecedented
institution of mandated societal lockdown. Mandated social distancing
comprising a combination of travel restrictions, closure of nonessential group
meeting venues (restaurants, schools, shops), and steps to avoid close contact
at essential meeting venues (hospitals, food supply, pharmacies). Using
publicly available data, we had examined the effect of timing of mandated
social distancing on the rate of COVID-19 in 119 geographic regions derived
from 41 states within the United States and 78 countries [3]. The primary
outcome was the highest number of new COVID-19 cases per day recorded
within each geographic unit. We found that highest number of new COVID-19
cases per day per million persons was significantly associated with total
number of COVID-19 cases per million persons on the day before mandated
social distancing (b ¼ 0.66, P < .0001). Our findings suggested that the
initiation of mandated social distancing after doubling in number of existing
COVID-19 cases would result in eventual peak with 58% higher number of
COVID-19 cases per day. Initiating mandated social distancing with smaller
number of COVID-19 cases within a region significantly reduces the number
of daily new COVID-19 cases and perhaps also reduces the total number of
cases in the region.
6 Coronavirus Disease

Wearing facemask to cover mouths and noses with filtering materials has
been widely used to prevent inhalation of particulates containing SARS-CoV-2
virus. By February 2020, Centers for Disease Control and Prevention had
recommended that persons with suspected SARS-CoV-2 infection should wear
facemasks [4]. By July 2020, Centers for Disease Control and Prevention had
recommended facemask use during all public encounters for all persons. A
study from a large healthcare system in Massachusetts with more than 75,000
employees evaluated the effect of mandatory policy of universal masking for all
healthcare workers and for all patients [5]. After the universal masking policy
was in place, the proportion of symptomatic healthcare workers with positive
test results steadily declined, from 14.7% to 11.5% (a mean decrease of 0.49%
per day). Another study that looked at transmission among 139 clients exposed
to two hair stylist with COVID-19 found no case of SARS-CoV-2 transmission
when both hair stylists and clients were wearing facemasks [6].
One of the unique aspects of developing diagnostic tests, vaccines, and
medications for prevention and treatment of SARS-CoV-2 infection was the
use of Emergency Use Authorization (EUA) by Food and Drug Administration
(FDA). On February 4, 2020, pursuant to section 564(b)(1)(C) of the FD&C
Act (21 U.S.C. 360bbb3(b)(1)(C)), the Secretary of Health and Human Ser-
vices determined that there is a public health emergency that has a significant
potential to affect national security or the health and security of US citizens
living abroad, and that involves the virus that causes COVID-19. On the basis
of such determination, on March 27, 2020, the Secretary then declared that
circumstances exist justifying the authorization of emergency use of drugs and
biological products during the COVID-19 pandemic, pursuant to section
564(b)(1) of the FD&C Act (21 U.S.C. 360bbb-3(b)(1)). A copy of the notice
is provided in Fig. 1.4.
Several in vitro diagnostic (IVD) devices were approved under EUA for
performing tests on samples such as swabs of mucus from inside the nose or
back of the throat or blood taken from a vein or fingerstick. The FDA classifies
these IVDs as follows:
Diagnostic Tests: Molecular tests and antigen tests that detect components
of the SARS-CoV-2 to diagnose infection with the SARS-CoV-2.
Serology/Antibody and Other Adaptive Immune Response Tests: Tests
that detect IgM and IgG antibodies to the SARS-CoV-2 virus or that measure a
different adaptive immune response (such as T cell immune response) to the
SARS-CoV-2 virus. These types of tests are best suited for identifying
previous infection.
Tests for Management of COVID-19 Patients: Tests that are authorized
for use in the management of patients with COVID-19, such as to detect
biomarkers related to inflammation and guide patient management decisions.
Several medications were approved for use in patients with COVID-19
under EUA. A list is provided in Table 1.2 as adapted from https://www.fda.
gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-
authorizations-medical-devices/.
 Introduction Chapter | 1 7

FIGURE 1.4 Emergency use authorization declaration [7].

TABLE 1.2 Medications were approved for use in patients with COVID-19
under EUA.

Date of first
EUA Most recent letter of
issuance authorization (PDF) Authorized use
04/30/2020 Fresenius Medical, To provide continuous renal replacement
multiFiltrate PRO System therapy (CRRT) to treat patients in an
and multiBic/multiPlus acute care environment during the
Solutions (171 KB) [also COVID-19 pandemic
listed under Medical
Device EUAs]
January 05, Remdesivir for Certain For emergency use by licensed healthcare
2020 Hospitalized COVID-19 providers for the treatment of suspected
Patients (423 KB) or laboratory-confirmed COVID-19 in
(Reissued August 28, hospitalized pediatric patients weighing
2020, October 1, 2020, 3.5 kg to less than 40 kg or hospitalized
and October 22, 2020) pediatric patients less than 12 years of
age weighing at least 3.5 kg.
On October 22, 2020, FDA approved

Continued
8 Coronavirus Disease

TABLE 1.2 Medications were approved for use in patients with COVID-19
under EUA.dcont’d

Date of first
EUA Most recent letter of
issuance authorization (PDF) Authorized use
Veklury (remdesivir) for use in adults and
pediatric patients (12 years of age and
older and weighing at least 40 kg) for the
treatment of COVID-19 requiring
hospitalization. Veklury should only be
administered in a hospital or in a
healthcare setting capable of providing
acute care comparable to inpatient
hospital care. This approval does not
include the entire population that had
been authorized to use Veklury under an
emergency use authorization (EUA)
originally issued on May 1, 2020. In order
to ensure continued access to the
pediatric population previously covered
under the EUA, the EUA for Veklury
continues to authorize Veklury for
emergency use by licensed healthcare
providers for the treatment of suspected
or laboratory-confirmed COVID-19 in
hospitalized pediatric patients weighing
3.5 kg to less than 40 kg or hospitalized
pediatric patients less than 12 years of
age weighing at least 3.5 kg.
August 05, Fresenius Kabi Propoven To maintain sedation via continuous
2020 2% (209 KB) infusion in patients older than age 16
with suspected or confirmed COVID-19
who require mechanical ventilation in an
intensive care unit (ICU) setting
08/13/2020 REGIOCIT replacement To be used as a replacement solution only
solution that contains in adult patients treated with continuous
citrate for regional renal replacement therapy (CRRT), and
citrate anticoagulation for whom regional citrate anticoagulation
(RCA) of the is appropriate, in a critical care setting
extracorporeal circuit
(92 KB)
08/23/2020 COVID-19 convalescent For the treatment of hospitalized patients
plasma (284 KB) with coronavirus disease 2019
(Reissued February 23, (COVID-19)
2021 and March 9,
2021)

Continued
 Introduction Chapter | 1 9

TABLE 1.2 Medications were approved for use in patients with COVID-19
under EUA.dcont’d

Date of first
EUA Most recent letter of
issuance authorization (PDF) Authorized use
September Bamlanivimab (339 KB) For the treatment of mild-to-moderate
11, 2020 (reissued February 9, COVID-19 in adult and pediatric patients
2021 and March 2, with positive results of direct SARS-CoV-2
2021) viral testing who are 12 years of age and
older weighing at least 40 kg (about 88
pounds), and who are at high risk for
progressing to severe COVID-19 and/or
hospitalization.
11/19/2020 Baricitinib (Olumiant) in For emergency use by healthcare
combination with providers for the treatment of suspected
remdesivir (Veklury) or laboratory-confirmed COVID-19 in
(322 KB) hospitalized adults and pediatric patients
2 years of age or older requiring
supplemental oxygen, invasive
mechanical ventilation, or extracorporeal
membrane oxygenation (ECMO).
11/21/2020 REGEN-COV Casirivimab and imdevimab to be
(Casirivimab and administered together for the treatment of
Imdevimab) (232 KB) mild to moderate coronavirus disease
(Reissued February 3, 2019 (COVID-19) in adults and pediatric
2021 and February 25, patients (12 years of age and older
2021) weighing at least 40 kg) with positive
results of direct SARS-CoV-2 viral testing,
and who are at high risk for progressing to
severe COVID-19 and/or hospitalization.
September Bamlanivimab and For the treatment of mild-to-moderate
02, 2021 Etesevimab (344 KB) COVID-19 in adult and pediatric patients
(Reissued February 25, with positive results of direct SARS-CoV-2
2021) viral testing who are 12 years of age and
older weighing at least 40 kg (about 88
pounds), and who are at high risk for
progressing to severe COVID-19 and/or
hospitalization.
December Propofol-Lipuro To maintain sedation via continuous
03, 2021 1% (344 KB) infusion in patients greater than age 16
with suspected or confirmed COVID-19
who require mechanical ventilation in an
ICU setting.
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