Coronavirus Disease: From Origin to Outbreak [1 ed.] 0128244097, 9780128244098

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Coronavirus Disease

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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, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright 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 the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-824409-8 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisitions Editor: Kattie Washington Editorial Project Manager: Pat Gonzalez Production Project Manager: Maria Bernard Cover Designer: Matthew Limbert Typeset by TNQ Technologies

Contents Contributors

1.

Introduction

ix

1

Adnan I. Qureshi

2.

References

11

History of SARS-CoV-2

13

Iryna Lobanova

3.

References

17

Zoonotic infections

21

Ghaida Zaid

4.

Definition Transmission History of zoonoses Emerging infections and virus spillover Bat ecology Zoonosis as relevant to SARS-CoV-1 and SARS-CoV-2 infections Challenges to control outbreak References

21 21 22 25 25 26 27 27

Global response

29

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

29 31 32 32 33 36 38 40 41

v

vi Contents

5.

As Earth completes its revolution References

41 44

Coronavirus infection outbreak: comparison with other viral infection outbreak

47

Mohammad Rauf A. Chaudhry

6.

Understanding SARS-CoV-2 Epidemic versus pandemic Common features of epidemics Saw tooth pattern Tooth necklace pattern Tooth eruption pattern Why epidemics die their deaths? Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics Gene structure of MERS-CoV, SARS-CoV, and SARS-CoV-2 Transmissibility and the basic reproductive rate Incubation period of SARS-CoV-2 and viral excretion Case fatality and risk of severe illness Population-based mortality Incidence of SARS-CoV-2 infections Comparing SARS-CoV-2 and SARS-CoV spread SARS-CoV-2 and warmer weather SARS-CoV-2 and the effect of containment measures Conclusion References

51 51 52 52 52 54 55 55 55 55 56 56

SARS-CoV-2 viral structure and genetics

59

47 49 49 49 49 50 50

Abhi Pandhi and Ishita Vasudev

7.

Introduction Viral structure Molecular genetics Cell entry process Replication and gene expression Replication transcription complexes Basics of immune response Viral host immune interactions SARS-CoV-2 vaccines Conclusions References

59 59 61 61 62 63 64 65 66 66 67

Clinical manifestation and diagnosis

71

Yasemin Akinci Introduction Transmission of COVID-19 Routes of Transmission

71 72 72

Contents vii

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

8.

Treatment and therapeutic agents

75 76 77 78 78 80 80 85 85 87 89 89 92 94 97 97 99

101 101 103 105 107 121

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

123 123 124 126 126 134 136 142 144 144 155 156 156 156

viii Contents

9.

India (PLACID) United States (Mayo Clinic Expanded Access Program) Part IV: Vaccine Different Vaccine Platforms Vaccines issued EUA by the FDA Conclusion References Further Reading

156 157 158 159 160 162 163 176

The economic repercussions of Coronavirus disease 2019 (COVID-19)

177

Usman Saeed

10.

World economy December 2019 Major conflicts Political impact of COVID-19 China’s economic response to COVID-19 What industry relied on Wuhan for trade globally Governments’ economic response to COVID-19 A recession caused by SARS-CoV-2 References Further Reading

177 178 178 179 179 182 183 185 186

Psychological and social implications of COVID-19

187

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

Index

187 188 189 190 190 191 192 192 193 194 194 195 198 199 200 207

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

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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-understand 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 locations 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 preventive 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 performance 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 resourcedeprived 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

13.5M

170,000

13.5M

353,000

5.06M

98,750

4.59M

101K

United States

India

Brazil

France

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 thrombosis, 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 immunological 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 Services 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-useauthorizations-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 issuance

Most recent letter of authorization (PDF)

Authorized use

04/30/2020

Fresenius Medical, multiFiltrate PRO System and multiBic/multiPlus Solutions (171 KB) [also listed under Medical Device EUAs]

To provide continuous renal replacement therapy (CRRT) to treat patients in an acute care environment during the COVID-19 pandemic

January 05, 2020

Remdesivir for Certain Hospitalized COVID-19 Patients (423 KB) (Reissued August 28, 2020, October 1, 2020, and October 22, 2020)

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. 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 issuance

Most recent letter of 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, 2020

Fresenius Kabi Propoven 2% (209 KB)

To maintain sedation via continuous 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 solution that contains citrate for regional citrate anticoagulation (RCA) of the extracorporeal circuit (92 KB)

To be used as a replacement solution only in adult patients treated with continuous renal replacement therapy (CRRT), and for whom regional citrate anticoagulation is appropriate, in a critical care setting

08/23/2020

COVID-19 convalescent plasma (284 KB) (Reissued February 23, 2021 and March 9, 2021)

For the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19)

Continued

Introduction Chapter | 1

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

Most recent letter of authorization (PDF)

Authorized use

September 11, 2020

Bamlanivimab (339 KB) (reissued February 9, 2021 and March 2, 2021)

For the treatment of mild-to-moderate COVID-19 in adult and pediatric patients with positive results of direct SARS-CoV-2 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 combination with remdesivir (Veklury) (322 KB)

For emergency use by healthcare providers for the treatment of suspected or laboratory-confirmed COVID-19 in 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) (232 KB) (Reissued February 3, 2021 and February 25, 2021)

Casirivimab and imdevimab to be administered together for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age and older 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 02, 2021

Bamlanivimab and Etesevimab (344 KB) (Reissued February 25, 2021)

For the treatment of mild-to-moderate COVID-19 in adult and pediatric patients with positive results of direct SARS-CoV-2 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 03, 2021

Propofol-Lipuro 1% (344 KB)

To maintain sedation via continuous infusion in patients greater than age 16 with suspected or confirmed COVID-19 who require mechanical ventilation in an ICU setting.

9

10 Coronavirus Disease

Development of vaccine for prevention of SARS-CoV-2 infection was a healthcare priority with the first clinical trial of a vaccine candidate for SARSCoV-2 beginning in March 2020 [8]. The FDA prespecified some of the requirements for approval under “Development and Licensure of Vaccines to Prevent COVID-19” guidance, which included a point estimate for a placebocontrolled efficacy trial of at least 50%, with a lower bound of the appropriately alpha-adjusted confidence interval around the primary efficacy endpoint point estimate of >30% with additional safety and effectiveness data. Messenger ribonucleic acid (mRNA)-based vaccines assumed a major role in vaccine candidates for SARS-CoV-2. The genetic information for the antigen is delivered by mRNA (with modifications) or a self-replicating RNA. The antigen is then expressed in the cells of the vaccinated individual invoking an immune response. Several vaccines were approved for use under EUA. A list is provided in Table 1.3 as adapted from https://www.fda.gov/medical-devices/coronavirusdisease-2019-covid-19-emergency-use-authorizations-medical-devices/. TABLE 1.3 Vaccines approved for use for prevention of SARS-CoV-2 infection under EUA. Date of first EUA issuance

Most recent letter of authorization (PDF)

Authorized use

November 12, 2020

Pfizer-BioNTech COVID-19 Vaccine (455 KB) (Reissued February 25, 2021) Letter Granting EUA Amendment (January 6, 2021) (164 KB) Letter Granting EUA Amendment (January 22, 2021) (190 KB) Letter Granting EUA Amendment (April 6, 2021) (166 KB)

For the prevention of 2019 coronavirus disease (COVID-19) for individuals 16 years of age and older

12/18/2020

Moderna COVID-19 Vaccine (392 KB) (Reissued February 25, 2021) Letter Granting EUA Amendment (April 1, 2021) (193 KB)

For the prevention of coronavirus disease 2019 (COVID-19) for individuals 18 years of age and older

02/27/2021

Janssen COVID-19 Vaccine (183 KB) Letter Granting EUA Amendment (March 29, 2021) (152 KB)

For the prevention of coronavirus disease 2019 (COVID-19) for individuals 18 years of age and older

Introduction Chapter | 1

11

Another issue that is gaining importance is reinfection. A better understanding of reinfection became one of the priorities for Centers for Disease Control and Prevention to inform public health action [9]. and the European Centre for Disease Prevention and Control [10] due to implications for duration of acquired immunity. The European Centre for Disease Prevention and Control [10] and Centers for Disease Control and Prevention [11] emphasize that individuals that have been infected once with SARS-CoV-2 are not always immune and infection prevention/control and contact principles should be followed even after the infection. By October 2020, five cases of reinfection with SARS-CoV-2 had been reported from Hong Kong, Belgium, the Netherlands, Ecuador, and the United States [12e16] when over 37 million SARS-CoV-2-infected persons had been reported worldwide [17]. Reinfection was identified in 0.7% (n ¼ 63, 95% confidence interval 0.5%e0.9%) during follow-up of 9119 patients with SARS-CoV-2 infection among 62 healthcare facilities in the United States between December 1, 2019 and November 13, 2020 [18]. The mean period (standard deviation [SD]) between two positive tests was 116  21 days. Similar results were reported by SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) [19] The study identified 44 reinfections (two probable, 42 possible) in the baseline positive cohort of 6614 healthcare workers. These observations strongly suggest that survivors from SARS-CoV-2 infection must not relax compliance with proven interventions in prevention of SARS-CoV-2 transmission such as social distancing [3] and universal face mask use [20]. Due to concerns for reinfection, the Centers for Disease Control and Prevention [11] currently recommends vaccination for patients who had SARS-CoV-2 infection after 90 days but acknowledges the limited data is available to support the recommendation.

References [1] [2]

[3]

[4]

[5]

Qureshi AI, Jilani T, Huang W, et al. Performance of various countries in reducing COVID19 mortality after adjustment for vulnerability. HealthCare Res J 2020;1(1):9e10. Qureshi AI, Jani V, Akhtar I, et al. Occurrence of COVID-19 mimic in persons under surveillance after COVID-19 exposure: a systematic review. HealthCare Res J 2020;1(1):2e8. Qureshi AI, Suri MFK, Chu H, Suri HK, Suri AK. Early mandated social distancing is a strong predictor of reduction in peak daily new COVID-19 cases. Public Health 2021;190:160e7. Patel A, Jernigan DB, nCoV CDC Response Team. Initial public health response and interim clinical guidance for the 2019 novel coronavirus outbreak - United States, December 31, 2019eFebruary 4, 2020. MMWR Morb Mortal Wkly Rep 2020;69(5):140e6. Wang X, Ferro EG, Zhou G, Hashimoto D, Bhatt DL. Association between universal masking in a health care system and SARS-CoV-2 positivity among health care workers. J Am Med Assoc 2020;324(7):703e4.

12 Coronavirus Disease [6] Hendrix MJ, Walde C, Findley K, R Trotman. Absence of apparent transmission of SARS-CoV-2 from two stylists after exposure at a hair salon with a universal face covering policy d Springfield, Missouri, May 2020. MMWR (Morb Mortal Wkly Rep). 2020;69(28):930-932. [7] Department of Health and Human Services. Emergency use authorization declaration. 2020. Updated April 1, 2020. [Accessed 13 April 2021], https://www.federalregister.gov/ documents/2020/04/01/2020-06905/emergency-use-authorization-declaration. [8] Krammer F. SARS-CoV-2 vaccines in development. Nature 2020;586(7830):516e27. [9] Reinfection with COVID-19. 2020. Updated October 27, 2020. [Accessed 7 Febaruary 2021], https://www.cdc.gov/coronavirus/2019-ncov/your-health/reinfection.html. [10] European Center for Disease Prevention and Control. Reinfection with SARS-CoV-2: considerations for public health response. 2020. Accessed April 4, 2021, https://www.ecdc. europa.eu/sites/default/files/documents/Re-infection-and-viral-shedding-threat-assessmentbrief.pdf. [11] Frequently asked questions about COVID-19 vaccination. 2021. Accessed Febaruary 10, 2021, https://www.cdc.gov/coronavirus/2019-ncov/vaccines/faq.html#:w:text¼Yes.,already %20had%20COVID%2D19%20infection. [12] First case of covid-19 reinfection detected in the us; n.d. https://www.ajmc.com/view/firstcase-of-covid-19-reinfection-detected-in-the-us. [Accessed 7 February 2021]. [13] Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARSCoV-2: a case study. Lancet Infect Dis 2021;21(1):52e8. [14] Prado-Vivar B, Becerra-Wong M, Guadalupe JJ, et al. COVID-19 re-infection by a phylogenetically distinct SARS-CoV-2 variant, first confirmed event in South America. September 3, 2020. [15] To KK, Hung IF, Ip JD, et al. COVID-19 re-infection by a phylogenetically distinct SARScoronavirus-2 strain confirmed by whole genome sequencing. Clin Infect Dis 2020:ciaa1275. [16] Van Elslande J, Vermeersch P, Vandervoort K, et al. Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain. Clin Infect Dis 2020;73(2):354e6. [17] Coronavirus disease (COVID-19). 2020. Updated October 11, 2020. Accessed Febaruary 7, 2021, https://www.who.int/docs/default-source/coronaviruse/situation-reports/20201012weekly-epi-update-9.pdf. [18] Qureshi AI, Baskett WI, Haung W, et al. Re-infection with SARS-CoV-2 in patients undergoing serial laboratory testing. Clin Infect Dis 2021:ciab345. [19] Hall V, Foulkes S, Charlett A, et al. Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020. medRxiv 2021;01.13.21249642. https://doi.org/10.1101/2021.01.13.21249642. [20] Brooks JT, Butler JC, Redfield RR. Universal masking to prevent SARS-CoV-2 transmission-the time is now. J Am Med Assoc 2020;324(7):635e7.

Chapter 2

History of SARS-CoV-2 Iryna Lobanova Zeenat Qureshi Stroke Institute and Department of Neurology, University of Missouri, Columbia, MO, United States

On December 31, 2019, the World Health Organization (WHO) was formally notified about a cluster of cases of pneumonia in Wuhan City, home to 11 million people and the cultural and economic hub of central China [1]. By January 5th, 59 cases were identified and none had been fatal [1,2]. Ten days later, WHO was aware of 282 confirmed cases, of which four were in Japan, South Korea, and Thailand [1,3]. There had been six deaths in Wuhan, 51 people were severely ill, and 12 were in a critical condition. The virus responsible was isolated on January 7th and its genome shared on January 12th [1,4]. The cause of the severe acute respiratory syndrome that became known as coronavirus disease 2019 (COVID-19) was a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Phylogenetic analysis suggests that SARS-CoV-2 originated in animals, probably bats, and was transmitted to other animals before crossing into humans at the Huanan wet market in Wuhan City [1,5e7]. As of February 22, 2021, more than 111 million cases have been confirmed, with more than 2.46 million deaths attributed to COVID-19 [8]. The history of human coronaviruses began in 1965 after Tyrrell and Bynoe [9,10] identified a virus named B814. The virus was found in human embryonic tracheal organ cultures obtained from the respiratory tract of an adult with a common cold. At about the same time, Hamre and Procknow [9,11] were able to grow a virus with unusual properties in tissue culture from samples obtained from medical students with colds. Both B814 and Hamre’s virus, which she called 229E, were ether-sensitive and therefore presumably required a lipid-containing coat for infectivity. While working in the laboratory of Robert Chanock at the National Institutes of Health, McIntosh et al. [9,12] reported the recovery of multiple strains of ether-sensitive agents from the human respiratory tract by using a technique similar to that of Tyrrell and Bynoe [9,12]. These viruses were termed “OC” to designate that they were grown in organ cultures. Within the same time frame, Almeida and Tyrrell [9,13] performed electron microscopy on fluids from organ cultures infected Coronavirus Disease. https://doi.org/10.1016/B978-0-12-824409-8.00007-2 Copyright © 2022 Elsevier Inc. All rights reserved.

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14 Coronavirus Disease

with B814 and found particles that resembled the infectious bronchitis virus of chickens. In the late 1960s, Tyrrell was leading a group of virologists working with the human strains and a number of animal viruses. This new group of viruses was named coronavirus (corona denoting the crown-like appearance of the surface projections) and was later officially accepted as a new genus of viruses [9,14]. Epidemiologic and volunteer inoculation studies found that respiratory coronaviruses were associated with a variety of respiratory illnesses; however, their pathogenicity was considered to be low [9,11,15e17]. The predominant illness associated with infections was an upper respiratory infection with occasional cases of pneumonia in infants and young adults [9,18,19]. These viruses were also shown to be able to produce asthma exacerbations in children as well as chronic bronchitis in adults and the elderly [20e22]. In 2004, van der Hoek et al. [9,23] reported the discovery of a new human coronavirus, NL63, isolated from a 7-month-old girl with coryza, conjunctivitis, fever, and bronchiolitis. Using a novel genomic amplification technique, these investigators were able to sequence the entire viral genome. Phylogenetic analysis demonstrated that this virus was a group I coronavirus related to 229E and transmissible gastroenteritis virus, a virus of pigs. Screening of 614 respiratory specimens collected between December 2002 and April 2003 identified seven additional individuals with upper or lower respiratory tract disease or both. Shortly after, Fouchier et al. [9,24] reported the identification of a coronavirus, named NL, isolated from an 8-month-old boy with pneumonia and grown from a clinical specimen that was obtained in April 1988. Full genomic sequence analysis of NL showed that this virus was also a group I coronavirus and closely related to NL63. The discovery of both NL63 and NL depended on the propagation of the viruses in cell culture. With the use of molecular probes that targeted conserved regions of the coronavirus genome, months later, Esper et al. [9]. found evidence of a human respiratory coronavirus in respiratory specimens obtained from children younger than 5 years of age, which was designated the New Haven coronavirus (HCoVeNH). Graf [25] detected the presence of a peptide corresponding to the spike glycoprotein of NL63, the closely related virus identified in the Netherlands, in tissue from individuals with Kawasaki disease. The summation of these findings suggests that HCoV-NH may play a role in the pathogenesis of Kawasaki disease. Two nonendemic coronaviruses have caused serious disease. A very new coronavirus, severe acute respiratory syndrome, called severe acute respiratory syndrome (SARS), emerged in 2002e03 as a coronavirus from southern China and spread throughout the world with quantifiable speed [9,26,27]. During the 2002e03 outbreak, SARS-CoV infection was reported in 29 countries in North America, South America, Europe, and Asia. This virus was responsible for SARS, a flu-like illness, though diarrhea was common. It could progress to pneumonia and respiratory failure in 2 weeks, and 25% of people infected required intensive care [1]. SARS-CoV was transmitted via

History of SARS-CoV-2 Chapter | 2

15

droplets in respiratory aerosol, contact with surfaces, and possibly via fecaleoral contact [28]. Within 1 month of 55 index cases being recognized in Hong Kong, Hanoi, and Singapore, a total of 3000 cases had been confirmed globally with a peak reporting rate of 200 new cases per day [29]. Overall, 8098 infected individuals were identified, with 774 SARS-related fatalities [30]. It is still unclear how the virus entered the human population and whether the Himalayan palm civets were the natural reservoir for the virus. Sequence analysis of the virus isolated from the Himalayan palm civets revealed that this virus contained a 29-nucleotide sequence not found in most human isolates, in particular those involved in the worldwide spread of the epidemic [31]. The SARS epidemic gave the world of coronaviruses research an enormous infusion of energy and activity that contributed to the large amount already known about the virology and pathogenesis of coronavirus infections from the expanding area of veterinary virology [32]. The second serious infection due to a coronavirus was Middle Eastern respiratory syndrome (MERS). The MERS-CoV virus was first identified as the cause of a fatal infection in Saudi Arabia in 2012 [9,33]. It spread to 27 countries. Unlike SARS, MERS is still prevalent, and as of November 2019, 2494 infections had been notified, of which 858 proved fatal [9,34]. Like SARS, MERS causes a flu-like illness with symptoms ranging from mild (with about one-quarter of people also having diarrhea) to severe pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan failure. MERS-CoV is believed to have reached humans via dromedary camels, which appear to be a reservoir in several Middle East states. The original source species is not known, but bats are the most likely. SARS-CoV-2 more closely resembles the bat wild virus than it does either SARS-CoV or MERSCoV, strongly suggesting that it is a novel coronavirus in humans [6,9]. Outbreaks of MERS-CoV infection now occur mostly due to animal-to-human transmission (probably during the camel calving season) [9,35]. Personto-person spread seems to depend on close contact, such as providing care to an infected person or within a hospital setting. In all, 40% of confirmed cases have been acquired nosocomiallydon 1 day in May 2015, an individual with MERS visited several hospitals in Korea and infected 186 people [9,33]. No vaccines are yet available that can protect against MERS-CoV infection [33]. A study of the first 41 cases of confirmed COVID-19, published in January 2020 in The Lancet, reported the earliest date of onset of symptoms as December 1, 2019 [36]. Official publications from the WHO reported the earliest onset of symptoms as December 8, 2019 [37]. Human-to-human transmission was confirmed by the WHO and Chinese authorities by January 20, 2020 [38]. During the early stages of the outbreak, the number of cases doubled approximately every seven and a half days [39]. In early and mid-January 2020, the virus spread to other Chinese provinces, helped by the Chinese New Year migration and Wuhan being a transport hub and major rail

16 Coronavirus Disease

interchange [40]. A report in The Lancet on January 24th indicated human transmission was possible and strongly recommended personal protective equipment for health workers, and said testing for the virus was essential due to its “pandemic potential” [41]. On January 30, the WHO declared the coronavirus a public health emergency of international concern [42]. By this time, the outbreak spread by a factor of 100e200 times [43]. On January 31, 2020, Italy had its first confirmed cases, two tourists from China [44]. As of March 13, 2020, the WHO considered Europe the active center of the pandemic [45]. On March 19, 2020, Italy overtook China as the country with the most deaths [46]. By March 26, the United States had overtaken China and Italy with the highest number of confirmed cases in the world [47]. Research on coronavirus genomes indicates that the majority of COVID-19 cases in New York came from European travelers, rather than directly from China or any other Asian country [48]. Retesting of prior samples found a person in France who had the virus on December 27, 2019 [49] and a person in the United States who died from the disease on February 6, 2020 [50]. The field of corona virology has advanced significantly in recent years. The SARS epidemic was a dramatic reminder that animal coronaviruses are potential threats to the human population, although the exact mechanism of species-to-species spread of the SARS coronavirus remains obscure. NL63 has been identified in many countries [9]. This virus and the related viruses NL and HCoV-NH are likely the cause of a substantial proportion of respiratory tract disease in infants and children [9]. It seems clear that the coronaviruses infecting humans and causing respiratory disease are heterogeneous and quite widely distributed throughout the world. It may be that some of the newer coronaviruses represent strains similar to the original B814 and OC strains that could not be further characterized in the 1960s [9]. Additional human coronavirus strains will very likely be discovered, which stresses the need for further investigation into the virology and etiology of these infectious organisms [9]. COVID-19 presents an enormous global challenge that has required levels of intervention on a scale that is unprecedented [1]. In one sense, it is a new threat: SARS-CoV-2 emerged as a novel virus to which humans had no immunity, it spreads exceptionally quickly, carries a high mortality, and can overwhelm the capacity of health services to treat the most seriously ill [1]. But it is not incomparable: similarities with other coronaviruses and recent epidemics mean that infection control measures are well rehearsed and existing technologies can be deployed to speed the development of new vaccines and treatments. In recent months, several new strains of SARS-CoV-2, the causative agent of COVID-19, have emerged. These variants have evolved an increased transmission rate compared with the original strains, which makes controlling this virus even more challenging [51]. One straindUK B.1.1.7 lineage (variant

History of SARS-CoV-2 Chapter | 2

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of concern 202012/1) has a significantly higher potential rate of transmission (R0) compared with previous variants [51,52]. Genomic analysis of the strain found substantial novel sequence variation caused by mutations, which may provide a biological reason for the observed increase in transmissibility. Initial assessments suggest that the novel variants show an improved interaction with host cell receptors, such as Angiotensin-converting enzyme II (ACE2) on epithelial cells [51,53]. This enables the virus to better establish and propagate infections, resulting in higher levels of virus in the host and increased rate of transmission [51,54,55]. A threat to COVID-19 vaccine effectiveness comes from other emergent strains, both existing and yet to come. For example, another highly virulent SARS-CoV-2 variant has been identified in South Africa (SouthAfricaV501.V2 clade), which like B.1.1.7 appears to be transmitting more quickly than other strains. This lineage has rapidly become the dominant circulating strain, and it too is mutated in several areas of the viral spike protein [51,53] as are a group of Brazilian (B 1.1.28) variants now predominating in Amazonas state [51,56]. The fear is that variation generated by mutation could give rise to vaccine-resistant strains in the long term. Such vaccine-escaped mutants can potentially be favored during protracted infections in patients with a weakened immune response and longer transmission chains. A sufficient level of vaccination coverage will reduce the number of contacts between susceptible hosts, and hence, selection pressures for increased R0 are likely to involve adaptations that prolong the infection. Finally, strains evolving independently in reservoir hosts (e.g., mink) have also been shown to contain viral spike protein mutations and be less readily neutralized by immune serum [51,57]. New virus variants are likely to continue to evolve that have the potential to sweep through the human population [51]. However, as long as vaccines remain effective, a higher uptake of the vaccines will: (1) reduce the number of COVID-19-related deaths, (2) block the spread of the transmissible strain of the virus, and (3) reduce risk of the evolution of other, even more, virulent strains [51].

References [1] [2]

[3]

Chaplin S. COVID-19: a brief history and treatments in development. Prescriber 2020;31(5):23e8. World Health Organization. GCM teleconference e Note for the Records. Subject: Pneumonia in Wuhan, China. 10 January 2020. Available from: https://www.who.int/blueprint/ 10-01-2020-nfr-gcm. World Health Organization. Teleconference of the R&D blueprint GCM. Pneumonia of unknown etiology in Wuhan China. 20 January 2020. Available from: https://www.who.int/ blueprint/prioritydiseases/key-action/20-01-2020-nfr-gcm.pdf?ua¼1.

18 Coronavirus Disease [4] World Health Organization. Novel coronavirus (2019-nCoV). Situation report e 1. January 21, 2020. Available from: https://www.who.int/docs/default-source/coronaviruse/situationreports/20200121-sitrep-1-2019-ncov.pdf?sfvrsn¼20a99c10_4%20. [5] World Health Organization. Coronavirus disease 2019 (COVID-19). Situation report e 113. May 12, 2020. Available from: https://www.who.int/emergencies/diseases/novelcoronavirus-2019/situationreports. [6] Lu R, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020;395:565e74. [7] Andersen KG, et al. The proximal origin of SARS-CoV-2. Nat Med 2020, 17 March;26:450e2. https://doi.org/10.1038/s41591-020-0820-9. [8] COVID-19 pandemic. 2021. https://en.wikipedia.org/wiki/COVID-19_pandemic. [9] Kahn JS, McIntosh K. History and recent advances in coronavirus discovery. Pediatr Infect Dis J 2005;24:S223e7. [10] Tyrrell DA, Bynoe ML. Cultivation of viruses from a high proportion of patients with colds. Lancet 1966;1:76e7. [11] Hamre D, Procknow JJ. A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med 1966;121:190e3. [12] McIntosh K, Dees JH, Becker WB, Kapikian AZ, Chanock RM. Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease. Proc Natl Acad Sci USA 1967;57:933e40. [13] Almeida JD, Tyrrell DA. The morphology of three previously uncharacterized human respiratory viruses that grow in organ culture. J Gen Virol 1967;1:175e8. [14] Tyrrell DA, Almeida JD, Cunningham CH, et al. Coronaviridae. Intervirology 1975;5:76e82. [15] McIntosh K, Kapikian AZ, Turner HC, Hartley JW, Parrott RH, Chanock RM. Seroepidemiologic studies of coronavirus infection in adults and children. Am J Epidemiol 1970;91:585e92. [16] Bradburne AF, Bynoe ML, Tyrrell DA. Effects of a “new” human respiratory virus in volunteers. Br Med J 1967;3:767e9. [17] Bradburne AF, Somerset BA. Coronative antibody tires in sera of healthy adults and experimentally infected volunteers. J Hyg 1972;70:235e44. [18] McIntosh K, Chao RK, Krause HE, Wasil R, Mocega HE. Coronavirus infection in acute lower respiratory tract disease of infants. J Infect Dis 1974;130:502e7. [19] Wenzel RP, Hendley JO, Davies JA, Gwaltney Jr JM, Mufson MA. Coronavirus infections in military recruits. Three-year study with coronavirus strains OC43 and 229E. Am Rev Respir Dis 1974;109:621e4. [20] McIntosh K, Ellis EF, Hoffman LS, Lybass TG, Eller JJ, Fulginiti VA. Association of viral and bacterial respiratory infection with exacerbations of wheezing in young asthmatic children. Chest 1973;63(Suppl. l):43S. [21] Falsey AR, McCann RM, Hall WJ, et al. The “common cold” in frail older persons: impact of rhinovirus and coronavirus in a senior daycare center. J Am Geriatr Soc 1997;45:706e11. [22] Falsey AR, Walsh EE, Hayden FG, et al. Rhinovirus and coronavirus infection-associated hospitalizations among older adults. J Infect Dis 2002;185:1338e41. [23] van der Hoek L, Pyrc K, Jebbink MF, et al. Identification of a new human coronavirus. Nat Med 2004;10:368e73. [24] Fouchier RA, Hartwig NG, Bestebroer TM, et al. A previously undescribed coronavirus associated with respiratory disease in humans. Proc Natl Acad Sci USA 2004;101:6212e6.

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Graf JD. Identification of peptide epitopes recognized by antibodies in untreated acute Kawasaki disease. Presented at the eighth International Kawasaki disease symposium, San Diego, CA. 2005. Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. Engl J Med 2003;348:1953e66. Peiris JS, Lai ST, Poon LL, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003;361:1319e25. Hui DSC, Zumla A. Severe Acute Respiratory Syndrome: historical, epidemiologic, and clinical features. Infect Dis Clin 2019;33:869e89. World Health Organization. Emergency preparedness, response. Update 83 e One hundred days into the [SARS] outbreak. June 18, 2003. Available from: https://www.who.int/csr/don/ 2003_06_18/e. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/ncidod/sars/ index.htm. Guan Y, Zheng BJ, He YQ, et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 2003;302:276e8. Lai MM, Holmes KV. Coronaviridae: the viruses and their replication. In: Knipe DM, Howley PM, editors. Fields virology. Philadelphia, PA: Lippincott-Raven; 2001. Azhar EI, et al. The Middle East respiratory syndrome (MERS). Infect Dis Clin 2019;33:891e905. World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV). November 2019. Available from: https://www.who.int/emergencies/mers-cov/en. Dudas G, et al. MERS-CoV spillover at the camel-human interface. eLife 2018;7:e31257. https://doi.org/10.7554/eLife.31257. Wu YC, Chen CS, Chan YJ, March. The outbreak of COVID-19: an overview. J Chin Med Assoc 2020;83(3):217e20. Novel coronavirusdChina. World Health Organization (WHO); January 12, 2020. Kessler G. Trump’s false claim that the WHO said the coronavirus was ’not communicable. The Washington Post; April 17, 2020. Archived from the original on 17 April 2020. Retrieved 17 April 2020. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. March 2020;382(13):1199e207. Report of the WHO-China joint mission on coronavirus disease 2019 (COVID-19) (PDF) (report). World Health Organization (WHO); February 24, 2020. Archived (PDF) from the original on 29 February 2020. Retrieved 21 March 2020. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet January 24, 2020;395(10223):497e506. Flattery and foot dragging. China’s influence over the WHO under scrutiny. The Globe and Mail April 25, 2020. China delayed releasing coronavirus info, frustrating WHO. AP NEWS; June 2, 2020. Retrieved 3 June 2020. Coronavirus: primi due casi in Italia [Coronavirus: First two cases in Italy]. Corriere della sera (in Italian); January 31, 2020. Retrieved 31 January 2020. Fredericks B. WHO says Europe is new epicenter of coronavirus pandemic. New York Post; March 13, 2020. Retrieved 9 May 2020. Coronavirus: number of COVID-19 deaths in Italy surpasses China as total reaches 3,405". Sky News. Retrieved 7 May 2020.

20 Coronavirus Disease [47] McNeil Jr DG. The U.S. Now leads the world in confirmed coronavirus cases. The New York Times; March 26, 2020. Retrieved 27 March 2020. [48] Studies show N.Y. Outbreak originated in Europe. The New York Times; April 8, 2020. [49] Deslandes A, Berti V, Tandjaoui-Lambotte Y, Alloui C, Carbonnelle E, Zahar JR, Brichler S, Cohen Y. SARS-COV-2 was already spreading in France in late December 2019. Int J Antimicrob Agents May 3, 2020;55(6):106006. [50] 2 died with coronavirus weeks before 1st U.S. virus death. PBS NewsHour; April 22, 2020. Retrieved 23 April 2020. [51] Oosterhout C, Hall N, Ly H, Tyler KM. COVID-19 evolution during the pandemic e implications of new SARS-CoV-2 variants on disease control and public health policies. Virulence 2021;12(1):507e8. [52] Volz E, Mishra S, Chand M, et al. Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: insights from linking epidemiological and genetic data. medRxiv 2021. https:// doi.org/10.1101/2020.12.30.20249034. [53] Tegally H, Wilkinson E, Lessells RR, et al. Major new lineages of SARS-CoV-2 emerge and spread in South Africa during lockdown. medRxiv 2020. https://doi.org/10.1101/ 2020.10.28.20221143. [54] Starr TN, Greaney AJ, Hilton SK, et al. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. Cell 2020;182(5):1295e310. [55] Gu H, Chen Q, Yang G, et al. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science 2020;369(6511):1603e7. [56] Naveca F, Nascimento V, Souza V, et al. Phylogenetic relationship of SARS-CoV-2 sequences from Amazonas with emerging Brazilian variants harboring mutations E484K and N501Y in the Spike protein. 2021. Available from: https://virological.org/t/phylogenetic-relationship-ofsars-cov-2-sequences-from-amazonas-with-emerging-brazilian-var iants-harboring-mutationse484k-and-n501y-in-the-spike-protein/585. [57] Koopmans M. SARS-CoV-2 and the human-animal interface: outbreaks on mink farms. Lancet Infect Dis 2021;21:18e9.

Chapter 3

Zoonotic infections Ghaida Zaid Department of Neurology, University of Tennesse Health Science Center, Memphis, TN, United States

Definition Zoonosis is a Greek word of two parts: zoo means animal and (sis) is indication of a state of condition. The term identifies the diseases that are transmitted from animal to human and can be caused by variant microorganisms including bacteria, viruses, microparasites, macroparasites, fungi, protozoa, flea, worms, and ticks. It is categorized according to the route of transmission, i.e., vector borne, foodborne, and airborne. Zoonotic infection can spread between animals and animals to humans, and some of them spread widely between people and are important source for epidemics. About two-thirds of human infections arise from wild or domestic animals, and pose a global threat to health and economics [1,2].

Transmission In zoonotic infections, a nonhuman host is the primary reservoir of the infection, and humans are usually involved accidently when they come in contact with the material passed from the host. Human infection is not essential for the pathogens’ s life cycle or for its transmission in nature. Mechanisms of transmission of zoonotic pathogen vary widely. Many are linked to food collection, processing, or consumption. Consumption of wild animals’ meat is responsible for the most devastating epidemics in the history including Ebola virus disease, severe acute respiratory syndrome, Middle East respiratory syndrome, monkeypox, tularemia, and Marburg virus infection. Not only wild animal meat carry risk for infection, domestic pets can transmit many other infections such as Salmonella, Escherichia coli, and Prion disease. Other modality of transmission is via arthropods such as mosquitos, ticks and flies, which serve to transmit different bacteria and viruses from birds and mammals to humans, such as malaria, dengue fever, Lyme disease, West Nile virus, St. Louis encephalitis virus, and Zika virus. Direct transmission through exposure to infected urine or feces can occur and examples include Coronavirus Disease. https://doi.org/10.1016/B978-0-12-824409-8.00008-4 Copyright © 2022 Elsevier Inc. All rights reserved.

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Toxoplasmosis, and lymphocytic choriomeningitis. Other ways of contact are animal bites or scratches. For instance, dog and bat bites can transmit rabies, cat bites can transmit cat scratch fever, monkey bites can transmit Hepatitis B, and rat bites can transmit different infections such as leptospirosis, bubonic plague, salmonellosis, and rat-bite fever. Deforestation, the expansion of agriculture, and the extractive industries, particularly in tropical regions with high wildlife biodiversity, have led directly or indirectly to the emergence of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), Nipah virus, and filoviruses. Examples of different pets that are considered hosts for zoonotic infections include horses, deers, rabbits, sheep, cattle, goats, dogs, cats, rodents, birds, reptiles, and amphibians. Exotic pets such as hedgehogs, ferrets, flying squirrels, and monkeys can also seve as hosts. Other viruses can be transmitted via orthopods or bats. Wild animals that are hosts for zoonotic infections most commonly involve bats and rodents (Table 3.1) [4].

History of zoonoses Zoonosis importance has emerged throughout the history, the first known pandemic was Plague of Justinian (541e543 AD). In 541 AD, the disease spread from central Asia or Africa across the Mediterranean basin into Europe, killing an estimated 100 million people and the end of Roman empire. Black death continued to threaten humanity until the 18th century. Many European cities were frequently affected by the other great plague epidemics, and world wide spread of the third pandemic began when the plague reached Hong Long and Canton in the year 1894. The responsible organism was later found to be Yersinia Pestis. During World War I (WWI) in 1917 after US soldiers joined the war, there was report of a pulmonary illness spreading among soldiers that continued to claim many lives, and around 1918 there were upwards of 100,000 fatalities, and it rendered millions infective. The 1918 Influenza pandemic occurred in waves of varying lethality, the first wave was relatively mild in the spring of 1918, and then in the beginning of the summer the virus reemerged in the extremely virulent fashion and caused tens of millions of deaths throughout the world. In the Autumn months of 1918 to winter 1919, a third wave of infection emerged. It was not until 1933 when the influenza virus was isolated as the cause of the mysterious WWI pandemic [5]. The most devastating pandemic of human diseases is smallpox. The disease occurred from ancient times and continued into recent human history. The disease was caused by Variola virus from Ruminants, which thought to be from camels. Ancient history showed that Mummies of Egyptians exhibited physical findings of smallpox-like rash; however, histopathological studies failed to reveal the virus in the vesicles. After emerging in human populations, it was transmitted between people through increased population densities, wars, and

TABLE 3.1 Examples of zoonotic disease: agents and vectors. Vector Arthropod

Mosquito

Agent

Disease

Bunyaviridae

La crosse encephalitis virus, California encephalitis virus

Encephalitis

Rift valley virus

Hemorrhagic fever

Japanese encephalitis virus, St. Louis encephalitis virus, West Nile virus

Encephalitis

Dengue virus, yellow fever virus, Zika virus

Hemorrhagic fever

Togaviridae

Eastern equine encephalitis, western equine encephalitis, Venezuelan equine encephalitis virus, chikungunya virus, o’nyong-nyong fever virus

Encephalitis

Bunyaviridae

Crimean-Congo hemorrhagic fever virus

Hemorrhagic fever

Flaviviridae

Tick-borne encephalitis virus, Powassan encephalitis virus

Encephalitis

Omsk hemorrhagic fever virus, Kyasanur forest virus, Langat virus

Hemorrhagic fever

Spirochaetaceae

Borrelia

Lyme disease

Enterobacteriaceae

Yersinia pestis

Hemorraghic fever (plague)

Flaviviridae

Tick

Flea

23

Continued

Zoonotic infections Chapter | 3

Agent family

Vector Mammal

Agent family

Agent

Disease

Arenaviridae

Lassa fever virus, Guanarito virus, Junin virus, Machupo virus, Sabia virus, Lujo virus

Hemorrhagic fever

Lymphocytic choriomeningitis virus

Meningitis, encephalitis

Dobrava-Belgrade virus, Hantaan virus, Puumala virus, Seoul virus

Hemorrhagic fever

Sin Nombre virus

Pulmonary

Spirochaetaceae

Leptospira

Leptospirosis

Rabbit

Francisellaceae

Francissella Tularensis

Tularemia

Bat

Filoviridae

Ebola virus, Bundibugyo virus, Sudan virus, Tai forest virus, Marburg virus

Hemorrhagic fever

Rhabdoviridae

Rabies virus, Chandipura virus

Encephalitis

Paramyxoviridae

Hendra virus, Nipha virus

Pulmonary, encephalitis

Coronaviridae

Severe acute respiratory syndrome (SARS) coronavirus, middle eastern coronavirus

Pulmonary

Cattle

Prions

Bovine spongiform encephalopathy prion

Neurodegeneration

Cat

Bartonellaceae

Bartonelia

Hemorraghic fever

Sarcocystidae

Toxoplasma

Toxoplasmosis

Orthomyxovirus

Influenza virus

Pulmonary

Rodent

Bunyaviridae

Avian

Bird

W.I. Lipkin, Zoonoses, Mandell, Douglas, and Bennett’s principles and practice of infectious diseases (2015) 3554e3558.

24 Coronavirus Disease

TABLE 3.1 Examples of zoonotic disease: agents and vectors.dcont’d

Zoonotic infections Chapter | 3

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trades. Severe epidemic episodes were, however, still observed in the 1800s (e.g., in European and North American cities), and the disease was also present during the Franco-Prussian War of 1870e71. Smallpox was still endemic in many countries at the beginning of the 20th century. In 1959, WHO initiated an eradication program targeting smallpox. The mass eradication program from 1967 to 1980 resulted in mass vaccination campaigns and the development of surveillance system, and by 1979, WHO officially declared smallpox was eradicated [6]. Simian immunodeficiency virus infects nonhuman primates and evolved to infect humans, such as human immune deficiency viruses: human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2). There have been many theories behind the route of transmission, one such theroy was thought to be through contaminated blood of hunted chimpanzees. In the summer of 1981, AIDS was first recognized, it was initially thought to affect homosexuals and intravenous drug abusers. In 1983, it was found that heterosexual transmission was responsible for more than 80% of the cases worldwide. By 1994, there were 23 million HIV-infected people worldwide. Human immunodeficiency virus/acquired immunodeficiency syndrome continued to be a major global public health issue. According to the last World Health Organization epidemiological data, human immunodeficiency virus has claimed almost 33 million lives. And by the end of 2019, there were estimated 38 million people living with HIV [7,8]. Over the years, pandemics have continued; in 1997, avian flu (H5N1) was responsible for more than 371 deaths, and 2013 H7 N9 avian flu cost the lives of 44 human. The 2009 swine flu H1N1 caused more than 15,000 deaths [1]. Between 2013 and 2016, Western Africa had one of the most widespread outbreak of Ebola virus disease in history. It caused major loss of life and devastated the West African region. It was not just an endemic outbreak, and in March 2014, the World Health Organization deemed it a global pandemic. Although West Africa was hardest hit, there were reported cases in United States, Italy, United Kingdom, and Spain. As of May 2016, according to the Centers for Disease Control and Prevention, there were a total of 28,646 total cases of Ebola virus disease with a total of 11,323 reported deaths. The prime vector for this virus was thought to be bats [9].

Emerging infections and virus spillover Changes in the environment and human behavior affect biodiversity and relations between animal hosts, people immunity, and pathogens. These changes, including agriculture, food handling, defrosting, and change in water ecosystem, lead to the contact with nature and host and to the emerging of different zoonotic infections [2,10].

Bat ecology It is the second most diverse mammalian order on earth after rodent, and they reside on every continent except Antarctica; they can fly and aggregate at high

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density. Bats are divided into two suborders: the Megachiroptera (fruits bats and flying foxes) and the Microchiroptera (insectivorous and vampire bats). Bats are the hosts for many different ribonucleic acid (RNA) viruses and played important role in most of the pandemics including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Ebola virus, Hendra virus, and Nipah virus. Bats have the ability to harbor most of the viruses without evidence of any clinical disease. That phenomenon is attributed to intrinsic bat resistance as they are refractory to viral pathogenesis. Clinical data showed that bat’s highenergy metabolic demands of flight leads to elevated body temperature, which mimics fever in other animals during immune activation. Another theory suggested that bats lack the immune response to the virus, which is responsible for the clinical disease in other animals. The levels of immune interferon alpha, beta, and gamma vary in bats compared with humans in response to viral infection. One great interesting finding is the adaptive immunity in the bats. Egyptian fruit bats were challenged with Marburg virus; antibodies formed against the viruses were undetectable after 5 months. But of more interest, rechallenge with the virus resulted in drastic reduction in viral replication within the bats. The spillover of bat-associated viruses depends on many ecological, host, and viral factors. Many spillovers pass undetected and other causes disease by direct bat-to-human spillover such as Nipah virus in Bangladesh in 2001 and several Marburg virus outbreaks across Africa and subsequent Rabies outbreaks. Other indirect bat-to-human spillover via intermediate host includes Hendra virus in 1994 via horses and Nipah virus in Malaysia in 1997 via pigs.

Zoonosis as relevant to SARS-CoV-1 and SARS-CoV-2 infections Severe acute respiratory syndromeeassociated coronavirus 1 and 2 were thought to be connected to bats via intermediate hosts and also were directly found in animals isolated in the wet markets in China. Severe acute respiratory syndromeeassociated coronavirus crossed species barriers over the years when changes in the viral reservoir and humans’ eating habits resulted in an ability to transmit to, and between, humans. In 2002e03, SARS-CoV outbreak in southern China caused 774 deaths and was thought to originate from palm civets, and then in 2005, it was isolated from horseshoe bats. In 2013, middle eastern respiratory syndrome (MERS) outbreak in the Middle East caused about 74 deaths and was thought to originate from camels. The latest outbreak in Wuhan, China, SARS-CoV-2 is the current pandemic. Various SARS-CoV viruses were detected in several wildlife species including horseshoe bats, Himalayan masked palm civet cats, Chinese ferret badgers, raccoons, and dogs. Initially, news regarding pangolins which can be described as scaly ant eating creature, were thought be the soruce of the current SARS-CoV-2 pandemic [12]. There was also some evidenc of SARS-CoV-2 ciruclating antibodies identified in Pangolins at wildlife checkpoints in Southern Thailand

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FIGURE 3.1 https://commons.wikimedia.org/wiki/File:Pangolin_brought_to_the_Range_office,_ KMTR_AJTJ_cropped.jpg.

although further analysis of both pangolins and bats suggest the later to be the likley culprit [13,14] (Fig. 3.1). These animals were incidental hosts, and bats were found to be the reservoir of not just SARS-CoV but also a number of other coronaviruses [4,11]. Questions remian regarding the zoonotic source of SARS-CoV-2 and whether this is a true zoonotic infections or should this instead be clasified into an emerging infectious disese of probable animal origin which has now spread due to an evolutionalry jump [14].

Challenges to control outbreak The way to control zoonotic infections and the pandemic is by vaccinating the wildlife, which is not feasible. Throughout history, humanity has faced pandemics with strict quarantine polices to limit the spread of the disease and by working on preventive measures to decrease the disease incidence. The development of any vaccine is very costly and depends on many factors such as global hazards, the rate of transmission between humans, and the mortality rate. Many successful vaccines have been established against influenza, Ebola virus, and now SARS-CoV-2 vaccine, which could change the course of current pandemic [3,11].

References [1] [2]

Bean AG, Baker ML, Stewart CR, et al. Studying immunity to zoonotic diseases in the natural host - keeping it real. Nat Rev Immunol 2013;13(12):851e61. Lai AL, Millet JK, Daniel S, Freed JH, Whittaker GR. The SARS-CoV fusion peptide forms an extended bipartite fusion platform that perturbs membrane order in a calcium-dependent manner. J Mol Biol 2017;429(24):3875e92.

28 Coronavirus Disease [3] Lipkin WI. Zoonoses. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases 2015:3554e8. [4] Relman DA HM, Eileen R, Mack A. Microbial Evolution and Co-Adaptation: A Tribute to the Life and Scientific Legacies of Joshua Lederberg. http://www.nap.edu/catalog/12586/ microbial-evolution-and-co-adaptation-a-tribute-to-the-life. [5] Wever PC, van Bergen L. Death from 1918 pandemic influenza during the First World War: a perspective from personal and anecdotal evidence. Influenza Other Respir Viruses 2014;8(5):538e46. [6] The`ves C, Crube´zy E, Biagini P. History of smallpox and its spread in human populations. Microbiol Spectr 2016;4(4). [7] Greene WC. A history of AIDS: looking back to see ahead. Eur J Immunol 2007;37(Suppl. 1):S94e102. [8] Deeks SG, Overbaugh J, Phillips A, Buchbinder S. HIV infection. Nat Rev Dis Primers 2015;1:15035. [9] Centers for Disease Control and Prevention (CDC)> Viral hemorrhagic fevers> Ebola virus diseaes>Outbreaks. 2014-2016 Ebola outbreak in West Africa Web site. https://www.cdc. gov/vhf/ebola/history/2014-2016-outbreak/index.html#anchor_1515001427541. Published 2019. Accessed: 2020. [10] Kreuder Johnson C, Hitchens PL, Smiley Evans T, et al. Spillover and pandemic properties of zoonotic viruses with high host plasticity. Sci Rep 2015;5:14830. [11] Letko M, Seifert SN, Olival KJ, Plowright RK, Munster VJ. Bat-borne virus diversity, spillover and emergence. Nat Rev Microbiol 2020;18(8):461e71. [12] Cyranoski D. Mystery deepens over animal source of coronavirus. Nature 2020;579:18e9. https://doi.org/10.1038/d41586-020-00548-w. [13] Wacharapluesadee S, Tan CW, Maneeorn P, et al. Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast. Asia. Nat Commun 2021;12:972. https://doi.org/10.1038/s41467-021-21240-1. [14] Haider N, Rothman-Ostrow P, Osman AY, et al. COVID-19-Zoonosis or Emerging Infectious Disease? Front Public Health 2020;8:596944. https://doi.org/10.3389/fpubh.2020.596944.

Chapter 4

Global response Ahmed A. Malik1, 2, Imaan Bashir3 1 Department of Internal Medicine, UCF-COM/HCA GME Consortium, North Florida Regional Medical Center, Gainesville, FL, United States; 2Zeenat Qureshi Stroke Institutes, Columbia, MO, United States; 3Albirr Medical Research Consultants, Gainesville, FL, United States

An enemy emerges Wuhan, the very city in China that saw the initial protests leading to the downfall of the mighty Qing Dynasty in 1912, once again became the center of world attention overnight in the year 2019. It seems as if Wuhan has been destined to be in the spotlight for the citizens of China; this time, it would become so for citizens of the entire world. It was in the month of December 2019 that a new cold enemy emerged in Wuhan, China, in the form of an unknown virus. Physicians began seeing many patients with symptoms they could only diagnose as those related to pneumonia. Dr. Li Wenliang, an ophthalmologist at the Wuhan Central Hospital, noticed several patients with a virus infection he thought resembled severe acute respiratory syndrome (SARS), one of whom initially did not have any symptoms [1] Chinese officials informed the World Health Organization (WHO) about the possibility of detecting a new virus on December 31st, 2019. However, they had ruled out human-to-human transmission of the virus [2]. Dr. Li, nonetheless, was concerned about the possibility of human-to-human transmission of this new virus. On December 30th, 2019, he had warned his fellow medics about the potential outbreak and requested them to wear protective gear when dealing with patients suspected of having the new viral illness. Since Chinese officials had ruled out the human route of transmission and in order to maintain, what they viewed as “social order,” authorities in Wuhan warned Dr. Li to stop spreading “rumors” and obliged him to sign a statement denouncing his concerns. Dr. Li was among eight other doctors who were being investigated for “spreading rumors.” [1] At this stage in the appearance of the virus, it seems that Chinese officials were more concerned about animal-to-human transmission of the 2019-novel coronavirus (2019-nCoV). They were thus maximizing their efforts on controlling animal vectors. On

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January 1, 2020, authorities closed Wuhan’s Huanan Seafood Wholesale Market. They also banned the sale of live animals to restaurants, wet markets, or individuals online [2]. Let down by the authorities, and with the several warnings in mind, Dr. Li returned to work and continued treating his patients. In the first week of January, he was treating a patient with glaucoma but was unaware that she had been infected with the 2019 novel coronavirus. On January 10, 2020, Dr. Li started coughing, developed a fever the next day, and was hospitalized 2 days later. Interestingly, it was on January 9th, 2020, that Chinese officials informed the WHO that they had identified the virus [2]. Chinese scientists had isolated the virus from a patient in Wuhan on January 7th, 2020 and had shared the genome sequence with the National Institutes of Health (NIH) public genetic sequence database and the Global Initiative on Sharing All Influenza Data” (GISAID) [2]. During this time, cases in Wuhan, China, continued to rise and finally on January 20th, 2020, China declared the outbreak an emergency [1]. Dr. Li was tested several times for the coronavirus, but persistently tested negative. Ten days later, on January 30, 2020, Dr. Li reported that nucleic acid testing revealed that he had indeed contracted the virus and had developed the Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) infection, also known as Coronavirus disease 2019 (COVID-19) [1]. Sadly, on February 7, 2020, the 34-year-old Dr. Li passed away. It was only after his death, when the virus had reached the level of a pandemic that the veracity of his warnings had become clear. The people who had been following Dr. Li’s social media updates regarding the potential outbreak and need for preventive measures were outraged that the Chinese government had not handled the situation responsibly and had initially ignored the warnings of Dr. Li and the other doctors [2]. The first SARS-CoV-2 infection-related death was reported on January 11th, 2020. The patient was reported to be an elderly man of 61 years of age who happened to be a frequent buyer at the Wuhan wet market. His underlying conditions included “liver disease and abdominal tumors.” Ultimately he had suffered “respiratory failure and severe pneumonia, septic shock, and multiple organ failure.” [3] Interestingly, the very next day another man in his mid-30’s who had returned to Washington D.C from Wuhan developed symptoms of the SARS-CoV-2 infection. This was the first reported case in the United States. Due to the rise in the number of cases around the world, the WHO declared the SARS-CoV-2 infection a Global Health Emergency on January 30th, 2020. China initiated a lockdown within Wuhan by canceling all flights to and from Wuhan, and all public transport was closed. Around the world, this new virus began to be known as the “Wuhan coronavirus” or the “Chinese coronavirus.” On February 11, 2020, however, the WHO

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announced an official new name for the virusdSARS-CoV-2din line with agreed upon guidelines to choose a name “that did not refer to a geographical location, an animal, an individual or group of people.” [4].

The virus marches on: East Asian countries Experience, whether with something good or bad, teaches one to be smarter and better equipped for the next interaction. Most East Asian countries were ready to deal with SARS-CoV-2 infection more efficiently and effectively due to having dealt with pandemics in the past such as severe acute respiratory syndrome (SARS) in 2003, H1N1 Influenza (swine flu) in 2009, and Middle East respiratory syndrome (MERS) in 2015. In an attempt to curb the virus “China, Hong Kong and Vietnam used aggressive lockdowns, border closures and other social control measures .” [5] South Korea and Singapore focused more on self-isolation and developing tests instead of implementing countrywide lockdowns. Kang Kyung Wa, South Korea’s Foreign Minister, stated that a “key lesson” that could be learned from her country was that “it developed testing for the virus even before it had a significant number of cases.” [6]. Japan, known as the country with the largest elderly population and the largest suicide rates in the world, detected its first SARS-CoV-2 infection case on January 16th, 2020. Japan experienced a different outcome compared with its fellow East Asian countries. It fared much better in terms of fatality and number of patients infected when compared with the United States and Europe. However, when compared with its fellow East Asian countries, it fared worse in both areas [7]. The main reason for Japan’s high death rates was due to the lack of aggressive lockdowns unlike its neighboring countries. Lockdowns were not enforced because the Japanese government is not allowed to implement policies that may be perceived as preventing one from practicing constitutional rights. However, social distancing, working from home, and the closure of essential businesses was encouraged [7]. There happens to be a sad twist of events that occurred in Japan. In addition to the SARS-CoV-2 infection related deaths, there was another set of deaths that had nothing to do with being infected with the virus. The toll that SARSCoV-2 took on Japan’s economy, like many other countries, was by far not a very unusual one. The weak and the poor always get afflicted in the worst possible way. Women took a very dreadful hit, more from socioeconomic factors than from SARS-CoV-2 pandemic itself. Twenty-seven percent of the women compared with 10% of the men in Japan experienced serious mental health challenges due to lay-offs caused by the SARS-CoV-2 pandemic [8]. The number of suicides in women also rose to 83% in October 2020 in comparison to the previous year [8]. Due to the stigma and shame attached to discussing mental health issues, many men and women suffer silently. This factor likely contributed to a rise in suicide rates.

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Europe will not be spared: Italy Most of Europe had implemented lockdown measures along with social distancing. Among the seven hardest hit European countries, Italy had suffered the worst consequences of the SARS-CoV-2 pandemic and the infection spread rapidly from there to other parts of the world. Cases from 27 countries around the world were traced back to Italy or to people of Italian origin. Once again, the origin of the SARS-CoV-2 infection in Italy could be traced back to China. On January 30th, 2020, two Chinese tourists were diagnosed with the SARSCoV-2 infection and thus became the first known cases in Italy [9]. By March 23rd, 2020, the number of cases in Italy had risen to 59,138. Italy reported about 800 deaths per day and became the second largest country after China to be hit the hardest. It is speculated that the cause of the fast-spreading virus and the mass numbers of cases were associated with frequent air travel between China and Italy. A nationwide quarantine and complete shutdown were initiated in order to curb the SARS-CoV-2 pandemic [9]. As rationing food and sanitary items became a policy, so did rationing of healthcare at most hospitals across the world. Nursing homes across the world became hotspots for the SARS-CoV-2 infection as it consumed the lives of the elderly without any remorse. Such became an acceptable excuse for Italy to deny hospital beds to its senior citizens. An unnamed doctor stated that one of the tough decisions healthcare providers had to make was to deny care to the elderly based on their age and their age-related conditions [10].

Let us worship in peace: Pakistan The Islamic Republic of Pakistan faced an issue unique to the country. As the initial lockdown was imposed, nationwide masjids (mosques) were not exempted from this rule. The imams and the local leaders agreed to comply with the rule. However, as the holy month of Ramadan approached toward the end of April 2020, a vast majority of civilians as well as imams and local leaders demanded that the masjids be reopened for the holy month. The Pakistani government had to give in to the request and pleas of the masses and “signed an agreement that let mosques stay open for Ramadan as long as they followed 20 rules,” some of which included maintaining a 6 foot social distance, wearing masks, and limiting capacity [11]. As the virus spread like wildfire, Pakistan decided to take preventive measures before it discovered any cases of the SARS-CoV-2 infection within the country. Eight hundred Pakistani students, who were in Wuhan, China, were not allowed to return to Pakistan in order to prevent the spread of the virus. The quick spread of the SARS-CoV-2 infection within the country was associated with travel. The vast majority of those who traveled in and out of the country were people associated with the Tableeghi Jamaat, a missionary

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movement that tries to promote the development of moral values through an emphasis on communal gatherings of learning and interaction. A mass gathering of 150,000 people, who had gathered for their annual meeting in a city in Pakistan, left for their homes after the meeting, unaware of any precautions needed before, during, or after the gathering. A large number of these people later tested positive for the SARS-CoV-2 infection [11]. The first known death in Pakistan was of a man who had just returned from the Hajj pilgrimage from Makkah, Saudi Arabia. According to Brookings, his family “held a 2000person feast to commemorate his pilgrimage, during which many people embraced him.” [12] It is unclear whether one of the guests passed on the SARS-CoV-2 infection to this man or if he contracted it elsewhere. Nonetheless, many were exposed at this gathering [12]. Emergency relief funds were taken out by the Pakistani government in order to provide temporary relief for the people. Among the recipients of such aid were the underprivileged, wage workers. They took a hit bigger than anyone else, as it became impossible for these workers to feed their families. Pakistan initially took out a stimulus package of 200 billion Pakistani rupees (PKR) in order to give them temporary relief. This relief package also included support for those who were laid off from work [11]. Prime Minister Imran Khan insisted on only a partial lockdown to allow the possibility of continued work for the poor and underprivileged wage workers. Taxes were temporarily removed on food and groceries. A total of 1.13 trillion PKR was taken out as part of the rescue stimulus package. Additionally, a package of 50 billion PKR was reserved for obtaining medical equipment [12].

The new norm: the United States gets caught in a storm In the book, Zika Virus Disease: From Origin To Outbreak, after concluding that the United States Centers for Disease Control and Prevention (CDC) and local health authorities had some semblance of preparedness, which helped control the Zika virus disease epidemic, the authors made an ominous prediction: “Time will tell if the public health efforts were truly successful in stamping out the epidemic and if the United States will be prepared to deal with other emerging infectious diseases.” [13] As the world scrambled to shop for essentials, sanitary products became scarce. Bare shelves mocked those who did not bother to stock up on toilet paper, paper towels, hand soap, and disinfectant wipes. Panic buying caused store owners to make amends to the shopping and return policies. No returns were allowed for products purchased during the pandemic. Karestan Koenen, professor of psychiatric epidemiology at the Harvard T.H. Chan School of Public Health, states that panic buying can be a source of psychological relief and gives one a sense of security that they have at least some “control” over their situation during the pandemic [14]. One could only wonder: just how long would this new norm last?

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Little did the world know that the SARS-CoV-2 pandemic would turn everyone into an untouchable. On January 8th, 2020, The CDC informed healthcare providers to look out for patients with symptoms of a respiratory illness and whether they had traveled to Wuhan, China, in the past [15]. The first known case of the SARS-CoV-2 infection was of a 30-year-old man from Washington. He had flown in from Wuhan, China, on January 15th, 2020 [16]. However, he had no symptoms of the virus upon his arrival. He had heard about the new virus and had read about its symptoms. When he suspected that his symptoms may be similar to those of COVID-19, he reported his symptoms to healthcare providers [16]. Initially, the CDC required all SARS-CoV-2 tests to be run at CDC, but later it extended the tests out to other facilities. On January 17th, 2020, the CDC started to recommend public health entry screenings at major airports in San Francisco, New York, Los Angeles, Atlanta, and Chicago [15]. Any passenger who had traveled to Wuhan, China, had to be rerouted to any of these five airports [16]. On their website, the CDC listed a few ways that the virus can spread. It is commonly spread through airborne transmission. Contaminated surfaces, however, are not a very common cause for the spread of the virus. To prevent exposure from person to person, the CDC recommended that everyone wear face masks covering the face and the mouth, stay 6 feet apart from one another, and wash hands with warm water and soap for 20 seconds. However, children under the age of 2, people who may have breathing problems, and those who may have trouble in removing the mask from their face were exempted from this recommendation [17]. Despite having to lead the public health response in the United States, the CDC quickly saw their task become fraught with controversy. The CDC had initially stated that healthy individuals who stand 6 feet apart may need no mask to protect themselves, because the 6 feet distance may be enough to prevent the spread of germs from one person to another [18]. Another issue was changes in their statements regarding how the virus could be spread. On September 21, 2020, it was reported that the CDC initially stated that the virus can “hang in the air and spread over an extended distance.” [18] This statement was later deleted from the CDC official website. The CDC’s deputy director for infectious diseases stated that the post was published without any editing and it was a mistake on their behalf. They continued to maintain, though, that droplets from sneezing and coughing may be the primary cause of transmitting the virus from one person to another [18]. The CDC discouraged the general public from wearing N-95 and surgical masks, which are required for healthcare workers. Instead, cloth masks were encouraged for the general public with few guidelines explaining how to select and wear the cloth mask. It was emphasized that the cloth mask should be made out of two or more layers of washable fabric [19]. The CDC remained persistent with encouraging people to wear masks when in public. Despite these and other recommendations, the number of SARS-CoV-2

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infection cases in the United States continued to rise. By December 19, 2020, the CDC reported that the number of cases had risen to 1,672,460 within just a week [20]. Unfortunately, the changing statements of the CDC were not the only obstacles to generating a sustained and effective response to the SARS-CoV-2 pandemic. As the encouragement to wear face masks increased, so did the number of people who refused to wear them. One reason that some people might have refused to wear a mask was that they were in denial about the existence of the virus and its potentially deadly effects. Such denial can lead to the burgeoning of conspiracy theories and spread of information that can convince people to believe that even the most ill-conceived beliefs are correct [21]. As one expert put it, “denial leads to avoidance, and then leads to not hearing the facts, which in turn leads to not following safe measures to prevent the thing they fear.” [21]. A very widely believed conspiracy theory was that SARS-CoV-2 was a man-made virus. However, as scientists raced to find out the origins of SARSCoV-2, they learned that it indeed had a zoonotic animal origin and was not created in a laboratory [22]. Furthermore, they learned that the virus originally spread from animals to humans. In fact, 75% of all new viruses that infect humans are known to have zoonotic origins. However, to this point there was no clear answer on whether SARS-CoV-2 could also be transmitted from humans to humans. Then, on January 21, 2021, China confirmed that SARSCoV-2 could be transmitted via the human-to-human route. SARS-CoV-2 is among the seven of the known corona viruses that originated from animals; most of these originate from mice and bats. SARS-CoV-2 is believed to have originated from bats [22]. Despite these revelations, there were people who tried to avoid wearing a mask or outright refused to follow recommendations. These people had to face consequences when they refused to wear the mask. Air travel became especially difficult for them as well as for those who tried to abide by the CDC guidelines when the frequent disputes about masks would lead to delayed flight departures. Many airlines required crew members and passengers to wear face masks during flights. When some passengers refused to wear the mask, these airlines felt compelled to deny them services. Those who refused to wear a mask were either escorted off the plane or were banned from future travel with the airlines [23]. Delta Airlines had 460 people on nofly list, and by September, 2020, it had banned 350 people from flying with the airline in the future [24]. On June 24th, 2020, it was reported that 500 members of Delta’s staff got infected with SARS-CoV-2 and 10 of them died. Like many other airlines, Delta tried to reduce exposure to the virus by taking precautionary steps. It sanitized the aircraft and disinfected all handles that required touching. American, Southwest, and United Airlines were some of the other airlines that also enforced the wearing of masks and faced similar problems.

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Such measures may seem drastic, but in order to avoid exposure to the SARS-CoV-2, every such measure is indeed justified when we take into consideration the consequences of unawareness. On March 10th, 2020, with a sore throat and consistent cough, a 27-year-old Vietnamese businesswoman boarded a flight bound for Vietnam from London. Her symptoms of “fever, sore throat, fatigue, and shortness of breath” only worsened by the time the flight arrived at its destination [25]. She went to a hospital on March 5th, 2020 and tested positive for SARS-CoV-2. Upon contact tracing it was learned that in February, she had traveled to Italy and France with her sister and from there back to London, where her sister resided. Her sister later tested positive for SARS-CoV-2 in London. The woman stayed two more nights with her sister before departing for Vietnam. She had officially started to experience symptoms of SARS-CoV-2 infection on February 29th, 2020. Three of the woman’s family members and 14 of the flight passengers whom she had flown with also tested positive for SARS-CoV-2 [25]. Another mystery surrounding the spread of SARS-CoV-2 was the continued disagreement about the actual origin of the virus despite the fact that Wuhan, China, was already deemed the culprit by many. As president Trump continued to refer to the SARS-CoV-2 as the “China Virus,” the Chinese government became more determined to prove that it was not a virus native to their country [26]. Experts at University of Cambridge stated that there appeared to be “substantial evidence” that the virus had been around way before it was discovered in Wuhan. One expert found three strains of the virus, which he labeled as A, B, and C. He stated that in China, type A was the predominant one and yet, out of 23 samples of the virus that came from Wuhan, only three were type A, the rest were type B [27]. His research further indicated that the virus may have been circulating among humans way before it was first reported in China on December 1, 2019 [27]. Considering that the first few cases of SARS-CoV-2 infection in the United States were traced back to China, however, a majority of the scientific community concluded that SARS-CoV-2 had indeed originated from Wuhan, China. Nonetheless on February 26th, 2020, the CDC reported the United States’ first nontravelrelated SARS-CoV-2 infection case in California [28]. It is postulated that by this time, through enough travel, the SARS-CoV-2 infection could now easily be community acquired in the United States.

The city that never sleeps New York City (NYC), known as the city that never sleeps, became deserted as the SARS-CoV-2 pandemic took over. NYC reported its first SARS-CoV-2 case on March 1st, 2020. The 39-year-old female healthcare worker, who had traveled to Iran, was believed to have been exposed to the virus during her travel even though she had tried to avoid congested spaces [41]. The patient did take precautions after she returned to the United States.

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By March 7th, 2020, the statewide total of positive SARS-CoV-2 infection cases reached 76. Five months later, Governor Andrew M. Cuomo declared that NY state “conducted 82,737 SARS-CoV-2 tests,” 91% of the test results came out positive [29]. To prevent the spread of SARS-CoV-2 infections, Governor Cuomo declared a state of emergency. Amidst the chaos, businesses started indulging in unfair practices sometimes taking advantage of the limitation of people. Governor Cuomo instructed the New York State Department of State’s Consumer Protection Division to investigate a number of complaints about unfair price increases on essentials such as household cleaning supplies and hand sanitizers [29]. A toll-free hotline and an online complaint form were launched where consumers could directly lodge complaints about any unfair price increases during the pandemic. Any substantive report was directed to the New York State’s Attorney General’s office [29]. As the number of cases surged in NYC, it came to be known as the epicenter of the United States. On March 10th, 2020, Governor Cuomo ordered a containment zone for an area in New Rochelle that lasted from the March 12, 2020 to March 25, 2020 [30]. A containment zone was identified as the place where the largest numbers of SARS-CoV-2 infection cases were found [29]. New Rochelle became the epicenter within an epicenter for NYC. The National Guard was deployed to the city to disinfect and sanitize schools and deliver food to quarantined residents. Any place where a large gathering was unavoidable, such as schools and houses of worship, were closed for 2 weeks [30]. Eventually as the virus raged on, New York state began facing a shortage of hospital beds and ventilators. On March 18th, 2020, it was reported that Governor Cuomo stated that at the rate that SARS-CoV-2 infection cases were rising, they could end up needing “110,000 beds, 37,000 ICU units . 3000 ventilators”. [31]. He further stated that that very morning, the cases had doubled and about 23% of the patients were hospitalized. The percentage of the cases rising that required hospitalization was 10% more than the global average. Starting from mid-April 2020, the number of cases spiked exponentially. For a week straight, 700e800 people had died from the SARS-CoV2 infection [32]. In order to reduce the number of cases that may require hospitalization, Governor Cuomo mandated that schools and other nonessential businesses remain closed [31]. Nursing homes across the state were also badly hit. More than 6300 nursing home residents died of SARS-CoV-2 infection [32]. New York, along with three other states, was sent letters from the United States Department of Justice to explain why SARS-CoV-2 infection-related deaths in nursing homes were so high [32]. This pattern of high deaths in nursing homes was not unique to the United States, however. It has been reported that 46% of the reported SARS-CoV-2 infection deaths in other high-income countries were of nursing home residents. In the continued effort to try to control the spread of SARSCoV-2 infections, Governor Cuomo mandated the wearing of masks in public

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places, put in place strict screening and quarantine measures for all travelers to New York state, and kept restaurants and bars closed. These aggressive measures helped bring the New York epidemic under control and helped to flatten the epidemiological curve. However, there were some unintended consequences of all these stringent measures. Many people were put out of work due to the statewide lockdown in New York. Following weeks of protests, where people demanded the reopening of workplaces, Phase One of four phases of economic reopening was initiated in Upstate, New York. Businesses slowly reopened biweekly. The goal was to have all businesses and schools reopened by July 20th, 2020 [32].

The dilemma of one of the largest gathering in the world As most countries across the world struggled to contain SARS-CoV-2, Saudi Arabia had to respond to the SARS-CoV-2 pandemic with extraordinary actions and precautionary measures. The first case of SARS-CoV-2 infection in Saudi Arabia was reported on March 2nd, 2020. Within a week of the emergence of the first case in the country, by March 9th, 2020, Saudi Arabia had put in place intense lockdown measures [33]. Initially, a partial curfew that lasted from 6 a.m. until 7 p.m. was mandated for 21 days. A 24-h curfew was later placed in major cities such as Riyadh, Jeddah, and Taif. The 24-h curfew was mandated until May 23rd, 2020 [33]. Local restrictions included limited time windows when people could complete grocery shopping and other essential outdoor tasks; then too, they were required to complete these tasks only within their own neighborhoods. Police checkpoints were set up to ensure that people did not venture outside of their neighborhoods without a legitimate emergent need. These measures seemed draconian, but Saudi Arabia had an immense task at hand: they had to find a way to prepare the country for the annual Hajj. Travel restrictions included suspension of all types of domestic and air travels and suspension of all types of public transportation. Even days before the discovery of the first case in the country, on February 7th, 2020, Saudi Arabia had already banned the entry of travelers with visitor visas and those who had Hajj and Umrah Visas [33]. Umrah is a religious mini pilgrimage that Muslims, followers of the religion of Islam, can perform at any time throughout the year. Hajj, however, is the major pilgrimage that every Muslim, who is in stable health and has the financial means, must perform at least once in his or her lifetime. Unlike Umrah, Hajj takes place only once every year. The Hajj, one of the largest gatherings in the world, is attended by 2 million people each year; in 2018, it was attended by 2.5 million people [34]. Muslims from all around the world travel to Makkah, Saudi Arabia, each year at Hajj time to complete the rituals of Hajj, which commemorate the patience, sacrifice, and devotion to God that the Prophet Abraham practiced in his life

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and that the Prophet Muhammad emulated and encouraged as well. These rituals include staying in a tented area outside Makkah for the purpose of thought, prayer, and contemplation; walking seven times around the cubical structure in the Holy Mosque (Al-Masjid Al-Haram) called the K’abah (believed to be built by the Prophet Abraham and, his son, the Prophet Ishmael) in prayer, thought, and contemplation; and casting seven pebbles at each of three stone pillars of increasing size in succession, commemorating and internalizing Prophet Abraham’s successful repelling of the devil and devil’s whispering in trying to prevent him from fulfilling the commandments of God. As one can imagine, these rituals can bring people into close proximity, which would be a recipe for disaster in the raging SARS-CoV-2 pandemic. The solution, however, could not be to simply halt the Hajj. For many people it takes months, if not years, in savings and planning to prepare for this once in a lifetime journey; for others it is a relatively frequent journey of personal spiritual rejuvenation. Additionally, the Hajj, as a whole, has never been suspended since its institution and, for most Muslims, the determination to start or stop the Hajj would be a prerogative of God only. As such, shutting down the Hajj could cause the stirring of raw emotions. Saudi authorities, therefore, had to work diligently to control the spread of the SARS-CoV-2 infection and devise a strategy to allow a safe and peaceful Hajj. On June 18, 2020, the daily confirmed SARS-CoV-2 infection cases were 4919. However, by July 28th, 2020, the start of Hajj, the confirmed daily cases had dropped to 1993 [35]. Eventually, Saudi authorities decided to keep the Hajj open limiting it to only 10,000 people already living in Saudi Arabia. People were selected by a special lottery system and those selected had to be tested for the coronavirus infection prior to arriving in Makkah. Additionally, all pilgrims had to wear masks and observe social distancing during the rituals described above. In fact, rows were demarcated around the K’abah to help people maintain social distancing. Pilgrims were also subject to temperature checks and mobile clinics and ambulances were set up to cater to the pilgrims. The K’abah was cordoned off so people could see it but could not touch it to limit the chances of spreading infection. Pilgrims were given special amenity kits that included sterilized pebbles for the stoning ritual described above, disinfectants, masks, and a prayer rug. According to reports, workers could be seen cleaning and disinfecting high contact areas quite frequently. The pilgrims were also instructed to quarantine after the Hajj upon returning home. The Hajj was completed without reports of any major events, and there were no reports of a spike in cases during or immediately after the Hajj. Overall, according to the WHO, Saudi Arabia has had 361,010 cases of SARS-CoV-2 infection and 6122 deaths [35] compared with the more than 17 million cases and more than the 300,000 deaths in the United States, as of this writing [36].

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The search for a prevention Since no cure was in sight and prevention is always better, scientists began to race against time to produce a coronavirus vaccine [37]. There are six stages to the production of a vaccine. In the first three stages, a vaccine is tested for safety and dosage. These stages are referred to as Phase 1, Phase 2, and Phase 3. The other three stages are known as Limited, Approved, and Abandoned. In the Approved stage, a vaccine is in early or limited use, in the Approved stage a vaccine is approved for full use, and in the Abandoned stage, a vaccine is abandoned after proven to be inefficient. On December 18th, 2020, it was reported that 6 vaccines were in limited use, two vaccines were approved for full use, and just one vaccine was abandoned [37]. Early in the initial quest for a vaccine, a total of 148 vaccines were in trials; 63 of these vaccines were in clinical trials on humans, and 85 of them were in the preclinical phases in trials on animals. As countries raced against the ravaing pandemic, they were faced with the dilemma of balancing the need for following established policies for the evaluation of vaccines prior to approval and making them available to the public in a timely manner. The compromise seemed to be offering emergency use authorization. One such vaccine, BNT162b2, a vaccine that was produced by Pfizer, a New Yorkebased company, in collaboration with a German company named BioNtech, received emergency use authorization from the United States Food and Drug Administration (FDA). On November 9th, 2020, they presented data that showed that the vaccine they developed had over 90% efficacy [37]. Based on tests, Pfizer and BioNtech claimed that their vaccine created antibodies by allowing immune cells, called T cells, to respond to a component of the virus [37]. On December 11th, 2020, BNT162b2, referred to as Pfizer, was approved in Canada and other countries. In the United States, however, Pfizer only received emergency use authorization. On December 18th, 2020, Moderna was another vaccine that received emergency use authorization in the United States [37]. Side effects can be expected with most medications; Pfizer was no different. On December 21st, 2020, it was reported that eight people had experienced allergic reactions to Pfizer [38]. The allergic reactions seem to be related to polyethylene glycol (PEG), a compound used to make the main ingredient of the vaccines Pfizer-BioNTech and Moderna. PEG has never been approved for a vaccine before, although it can be found in many drugs and, in those drugs, it is well known for triggering an allergic reaction, known as anaphylaxis. Anaphylaxis can cause “a potentially life-threatening reaction that can cause rashes, a plummeting blood pressure,” [38] and an inability to breathe. Anaphylaxis can be triggered by any vaccine. However, it is not very common. The United States National Institute of Allergy and Infectious Diseases (NIAID) became concerned about these reactions and called for meetings with the FDA, independent scientists and physicians, and the

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producers of the vaccine [38]. Discussions are ongoing and only time will tell if there are other side effects that people will experience and if people will receive effective protection from these fast-tracked, albeit immensely necessary, vaccines.

The need to monitor the cases In the midst of the rapid spread of the SARS-CoV-2 pandemic, the necessity to track cases became obvious. Several different organizations, some functioning under the auspices of governmental oversight and others created by private entities, undertook the task of tracking and reporting cases around the world. One of the most prominent organizations was the Johns Hopkins Coronavirus Resource Center (CRC). Experts from the Johns Hopkins CRC began collecting data on SARS-CoV-2 infection cases and deaths since the beginning of the pandemic and became one of the first to provide global maps to track this information. It then evolved beyond a data repository to a resource of expert guidance to help policymakers and healthcare professionals respond to the pandemic [39]. As the cases raged on, and agencies such as the CDC became shrouded with controversies, more and more people began relying on data from the Johns Hopkins CRC. However, it is interesting to note that on the website of publicly available raw data that has been used to create these graphs and maps, the Johns Hopkins University Hospital states, “Website relies upon publicly available data from multiple sources that do not always agree.” [39]. The WHO also provided a vast depository of data on global cases and deaths. A WHO Coronavirus (COVID-19) Dashboard was created to track global cases and deaths. Data were presented based on WHO region and country, area, or territory [40]. Additionally, the WHO created an interactive "COVID-19 Explorer" where one could view the global epidemic curve of COVID-19 over a desired number of time (i.e., one month to a year) by WHO region or country (Fig. 4.1). Another feature of the COVID-19 Explorer was that it gave users the capability to select countries and compare the number of COVID-19 cases and form a graphical representation of the data (Fig. 4.2). Aside from tracking the number of cases, the WHO’s COVID-19 Explorer also provided data on the number of deaths. Again, users could select the timeframe over which to compare the number of COVID-19 deaths between various WHO regions (Fig. 4.3) [40].

As Earth completes its revolution As the SARS-CoV-2 pandemic has been a testament, emerging infectious diseases may be one of the greatest threats to public health. As the Earth completes its revolution around the sun, and the year 2020 comes to a tumultuous end, scientists, physicians, and common people will have to band

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FIGURE 4.1 Data on the number of confirmed new cases by WHO region from the WHO’s COVID-19 Explorer from January 2020 to January 2021.

FIGURE 4.2 Data on number of new cases per 1 million population in select countries from the WHO’s COVID-19 Explorer.

together to mount and sustain effective public health responses to such diseases. Being a pandemic of colossal proportions, possibly comparable to the Spanish flu in many ways, and despite not being the first pandemic to ravage the world, not all countries were able to successfully control the spread of the

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FIGURE 4.3 Data on the number of deaths by WHO regions from the WHO’s COVID-19 Explorer from January 2020 to January 2021.

SARS-CoV-2 infection. As soon as cases would seemingly begin to decrease, another spike would appear and throw everything into a repetitive loop. Interestingly some of the most advanced and industrialized nations struggled to bring down cases and stem mortality. For some, this was due to a lackadaisical attitude on the part of authorities and reluctance to accept the reality of the consequences of the pandemic. For others, there was trepidation to enact regulations that could be viewed by citizens as restricting of their individual rights. Still, for others, safety measures were enacted too little, too late. The ramifications of both, the effective measures and lack thereof, were evident. Around the world people could see heart-wrenching pictures of completely empty streets of once-bustling metropolises turned into ghost towns; grandparents limited to seeing their grandchildren from behind glass barriers and only during limited rare occasions; family members of critically ill patients only being able to see their loved ones through computer or cell phone screens; family members of terminally ill patients only being able to bid their final farewells from behind glass doors; overworked healthcare workers struggling to find adequate protective gear to carry out their frontline mandate to care for those devastated by the pandemic; or of the final moments of a healthcare worker who had put his or her life on the line without a second thought to help the ill who had walked through his or her hospital doors. Through all of this, some could find solace in the fact that there was yet humanity left when various individuals, nonprofits, and businesses came together to support each

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other. Gestures such as free coffee, free crocs, or extra protective gear for healthcare workers on the frontlines provided an expression of appreciation for the work that healthcare providers were always prepared to do even if they could never imagine that they would one day be called on to do so in the midst of a ravaging pandemic of the magnitude of the SARS-CoV-2 pandemic. Only time will tell if this will cause people, public health authorities, and governments to become numb to future such dangers or if the SARS-CoV-2 pandemic will have taught us valuable lessons that we can carry forward in our preparedness for future emerging infectious diseases. Disclaimer: This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

References [1] Hegarty S. The Chinese doctor who tried to warn others about coronavirus. BBC News. https://www.bbc.com/news/world-asia-china-51364382. Published February 6 A. [2] Allam Z. The first 50 days of COVID-19: A detailed chronological timeline and extensive review of literature documenting the pandemic. Surveying the Covid-19 Pandemic and its Implications. Elsevier Public Health Emergency Collection; 2020. p. 1e7. [3] Taylor DB. A Timeline of the Coronavirus Pandemic. The New York Times. https://www. nytimes.com/article/coronavirus-timeline.html. Published February 13 AD. [4] Forster V. Coronavirus gets a new name: COVID-19. Here’s why that is important. Forbes. https://www.forbes.com/sites/victoriaforster/2020/02/11/coronavirus-gets-a-new-name-covid19-heres-why-renaming-it-is-important/?sh¼59cdb933548e. Published February 12, 2020. Accessed August 19, 2021. [5] https://globalhealth.duke.edu/news/how-some-asian-countries-beat-back-covid-19. Accessed December 17, 2020. [6] Beaubien J. How South Korea reined in the outbreak without shutting everything down. NPR. https://www.npr.org/sections/goatsandsoda/2020/03/26/821688981/how-south-koreareigned-in-the-outbreak-without-shutting-everything-down. Published March 26, 2020. Accessed August 19, 2021. [7] The National Bureau of Asian Research (NBR). Masked success: Japan’s response to Covid-19. https://www.nbr.org/publication/masked-success-japans-response-to-covid-19/. Accessed December 17, 2020. [8] Wang S WR, Wakatsuki Y. In Japan, more people died from suicide last month than from Covid in all of 2020. CNN. https://www.cnn.com/2020/11/28/asia/japan-suicide-womencovid-dst-intl-hnk/index.html. Published November 30, 2020. Accessed December 17, 2020. [9] Duddu P. Coronavirus in Italy: Outbreak, measures and impact. pharmaceutical technology. https://www.pharmaceutical-technology.com/features/covid-19-italy-coronavirus-deathsmeasures-airports-tourism/. Accessed August 19, 2021. [10] https://www.independent.co.uk/news/health/coronavirus-italy-hospitals-doctor-lockdownquarantine-intensive-care-a9401186.html. Published March 13, 2020. Accessed December 17, 2020.

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tests ever conducted in the State 2020. https://www.governor.ny.gov/news/five-months-firstconfirmed-covid-19-case-new-york-governor-cuomo-announces-highest-number. Accessed December 2020. https://www.nytimes.com/2020/03/10/nyregion/coronavirus-new-york-update.html. Published March 10, 2020. Accessed December 22, 2020. Noah Higgins-Dunn WF. Cuomo: New York needs 110,000 hospital beds for coronavirus patients in 45 days and we only have 53,000. CNBC. https://www.cnbc.com/2020/03/18/ cuomo-says-trump-is-dispatching-a-floating-hospital-to-new-york-state.html. Published March 18, 2020. Accessed December 22, 2020. New York State. Governor Andrew Cuomo Website. At novel coronavirus briefing, Governor Cuomo declares state of emergency to contain spread of virus. https://www. governor.ny.gov/news/novel-coronavirus-briefing-governor-cuomo-declares-state-emergencycontain-spread-virus. Published March 11, 2020. Accessed December 22, 2020. Nurunnabi M. The preventive strategies of COVID-19 pandemic in Saudi Arabia. J Microbiol Immunol Infect 2021;54(1):127e8. Published August 7, 2020, https://www. ncbi.nlm.nih.gov/pmc/articles/PMC7411502/. [Accessed 22 December 2020]. AFP. Muslims begin downsized hajj pilgrimage. https://www.bangkokpost.com. https://www. bangkokpost.com/world/1959259/muslims-begin-downsized-hajj-pilgrimage. Published 2020. Accessed December 22. Saudi Arabia: WHO coronavirus disease (COVID-19) dashboard. Covid19.who.int. https:// covid19.who.int/region/emro/country/sa. Published 2020. Accessed December 22. United States of America: WHO coronavirus disease (COVID-19) dashboard. Covid19.who.int. https://covid19.who.int/region/amro/country/us. Published 2020. Accessed December 22. Zimmer C Jonathan C, Sui-lee W. Coronavirus vaccine tracker. The New York times. https:// www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html. Published June 10, 2020. Accessed December 22, 2020. Vrieze J. Suspicions grow that nanoparticles in Pfizer’s COVID-19 vaccine trigger rare allergic reactions. 2020. https://www.sciencemag.org/news/2020/12/suspicions-grownanoparticles-pfizer-s-covid-19-vaccine-trigger-rare-allergic-reactions. Johns Hopkins university of medicine coronavirus resource center. 2020. https:// coronavirus.jhu.edu/. [Accessed 12 December 2020]. Organization WHO COVID-19 explorer. 2021. https://worldhealthorg.shinyapps.io/covid/. Goldstein J, Mckinley J. Coronavirus in N.y.: Manhattan woman is first confirmed case in state. The New York Times. https://www.nytimes.com/2020/03/01/nyregion/new-yorkcoronvirus-confirmed.html. Published March 2, 2020. Accessed August 19, 2021.

Chapter 5

Coronavirus infection outbreak: comparison with other viral infection outbreak Mohammad Rauf A. Chaudhry1, 2 1 Department of Neurology, Texas Tech University Health Science Center, El Paso, TX, United States; 2Zeenat Qureshi Stroke Institute, St. Cloud, MN, United States

The novel coronavirus disease 2019 (COVID-19) was declared as pandemic in March 2020 by World Health Organization (WHO). Initial rapid global dissemination was contributed by a cruise ship in Japan, mass getting of a religious group in South Korea, skiing resorts in Italy and Australia, and popular scrimmage city (Iran). [1] In December 2019, Wuhan, Hubei province, China, the virus originated in bats and was transmitted to humans through yet unknown intermediary animals and transmitted by inhalation or contact with infected droplets, incubation period ranges from 2 to 14 days. The usual symptoms are fever, cough, sore throat, breathlessness, fatigue, and malaise. The disease is mild mostly but in some elderly patients and those with multiple medical comorbidities, it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multiorgan dysfunction. However, in many people it is completely asymptomatic [2]. We provide a comparison of the COVID-19 with past pandemics severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), and pandemic influenza viruses in terms of transmissibility, hospitalization, and mortality rates.

Understanding SARS-CoV-2 Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invades the cell and uses cell’s biologic machinery for reproduction and releases multiple daughter virions. Six steps in the life cycle of SARS-CoV-2 have uncovered by research: (1) attachment and entry; (2) uncoating; (3) guide ribonucleic acid (gRNA) replication; (4) translation in the endoplasmic reticulum and Golgi

Coronavirus Disease. https://doi.org/10.1016/B978-0-12-824409-8.00009-6 Copyright © 2022 Elsevier Inc. All rights reserved.

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apparatus; (5) assembly; and (6) virion release [3,4]. Fig. 5.1 The life cycle of SARS-CoV-2 in host cells; begins its life cycle when S protein binds to the cellular receptor ACE2. After receptor binding, the conformation change in the S protein facilitates viral envelope fusion with the cell membrane through the endosomal pathway. Then SARS-CoV-2 releases RNA into the host cell. Genome RNA is translated into viral replicase polyproteins pp1a and 1ab, which are then cleaved into small products by viral proteinases. The polymerase produces a series of subgenomic mRNAs by discontinuous transcription and finally translated into relevant viral proteins. Viral proteins and genome RNA are subsequently assembled into virions in the ER and Golgi and then transported via vesicles and released out of the cell. ACE2, angiotensinconverting enzyme 2; ER, endoplasmic reticulum; ERGIC, EReGolgi intermediate compartment.

There are multiple protruding elements called spike proteins present on the external surface of SARS-CoV-2. These spike proteins are manipulated by host cell enzymes (furin and TMPRSS2) and function as anchors for attachment to the host cells [5,6]. Angiotensin-converting enzyme-2 (ACE2) receptors, which are physiologically involved in blood pressure regulation, are present on cell surfaces of the upper and lower respiratory tracts. Presence of these receptors in other body tissues help explain the extrapulmonary manifestations of COVID-19 [7]. After attaching to the external surface, SARSCoV-2 covers itself with a portion of the host cell membrane and becomes an intracellular endosome. The structure undergoes modification and releases strands of gRNA. Guide ribonucleic acid (gRNA) attaches to host ribosomes,

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RNA-dependent RNA polymerase (RdRp), and together activates the gRNA replication mechanism. The different basic blocks of reproduced virus are assembled into multiple virions that are expelled to the extracellular space of the host [8].

Epidemic versus pandemic Epidemic and pandemic are primarily different in terms of spread of contagious, infectious, or viral illness. Epidemic is limited to one specific region and is an event in which a disease is actively spreading while pandemic describes a disease affecting the whole country or the entire world. In simple words, when epidemics falls short in describing the scale of a problem, it is better to use pandemic [9].

Common features of epidemics According to the previous work on Ebola virus epidemic by Qureshi et al. [10], there are several factors that can start an epidemic listed below: 1. 2. 3. 4. 5.

Disasters (e.g., wars, famine, floods, and earthquakes) Temporary population settlements Preexisting diseases in the population Ecological changes such as floods and cyclones Resistance potential of the host (i.e., nutritional and immunization status of the host) 6. Damage to public utility and interruption of public health services Qureshi et al. [10] mentioned that there are three patterns of disease continuity: 1: Saw tooth pattern 2: Tooth necklace pattern 3: Tooth eruption pattern.

Saw tooth pattern It represents an intermittent outbreak of a disease that recedes in intensity, but the disease is not eradicated from the population. The smallpox epidemics in Africa during 1920se1950s would be an example of such a pattern.

Tooth necklace pattern It constitutes where the disease is eradicated from the population, but pathogen species is kept alive under controlled circumstances for preparation of vaccines and biological studies. While the escape of pathogen from confinements of laboratories has been the subject of numerous conspiracy theories, vaccination with live attenuated viruses is more likely to be the string to maintain the continuity.

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Tooth eruption pattern It constitutes where, like the tooth hidden within the gums and emerging independent of other teeth, the pathogen emerges and is exterminated without any relation to previous occurrences. The Dengue virus infection epidemic follows the “tooth eruption” pattern.

Why epidemics die their deaths? It is generally believed that measures such as vaccination of at-risk individuals, quarantine of diseased persons, and acute and timely treatment help to control all the epidemics. However, facts do not support this conclusion. In fact, the largest epidemics, such as the Peloponnesian War Pestilence, Antonine Plague, Plague of Justinian, Black Death of the 14th century, and Spanish flu, came to an end without widespread use of any of these strategies mentioned above. Qureshi et al. [10] came up with three theories for spontaneous remission of epidemics, which are mentioned below: 1. There are two types of people within the exposed population: some more vulnerable and some more resistant. The people who may be resistant to the disease may be so because of previous exposure to viruses with similar structures, resulting in the development of immune responses that are adequate for multiple pathogens. They might also be resistant due to superior health, including age, nutritional status, and occupational advantages. The virus might eventually be faced with a population that is completely resistant to the infection. 2. Changing environment within habitats that is not conducive to the survival or propagation of viruses or other pathogens. Weather changes, including temperature and humidity fluctuations, may significantly influence the survival or propagation of a virus outside the body. Elimination of reservoirs that carry pathogens including animals, insects, food, or water, by chance or design may disrupt the cycle of propagation. Such elimination of infection is less likely to occur within an epidemic because of diverse factors and geographical areas involved. 3. The most likely explanation is the “Sand Filter Theory,” a term coined by Adnan I. Qureshi, MD. This theory reflects the similarity between retention of particulate matter during filtration based on density of sand particles, which can be compared with pathogens within a population based on population density. Most epidemics are composed of diseases that require close contact between diseased and healthy individuals for continued propagation of pathogens. Unlike natural disasters, such as hurricanes, floods, volcanoes, and changes in climate that exist independent of population density, epidemics depend upon population density, a feature shared with reproduction rates, migrations, and predation. After population density reduces below a critical limit, such contact may not be available enough for continued propagation of pathogens.

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Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics SARS-CoV-2 is genetically related to SARS-CoV. SARS-CoV caused the first pandemic of deadly coronavirus in late 2000s. It was highly lethal but faded out due to intense public health mitigation measures. But in contrast, novel SARS-CoV-2 caused a global pandemic, which emerged in December 2019. The SARS 2003 global outbreak ceased in June 2003, caused 8098 cases and 774 deaths, and a case fatality rate of 9.7%, while Middle East respiratory syndrome coronavirus (MERS-CoV)danother deadly coronavirus, emerged in 2012, caused 2494 reported cases and 858 deaths in 27 countries with high case fatality rate of 34%. The current coronavirus, SARS-CoV-2, is less deadly but far more transmissible than MERS-CoV or SARS-CoV. As of April 2021, the global count is approaching 10 million known cases and has passed 500,000 deaths. Due to its broad clinical spectrum, and high transmissibility, eradicating corona virus completely does not look like a realistic goal in short term at least [1]. Now, we will study what makes SARS-CoV-2 different from pandemic influenza virus and the other epidemic severe coronaviruses.

Gene structure of MERS-CoV, SARS-CoV, and SARS-CoV-2 Fig. 5.1.

FIGURE 5.1 Black boxes represent the most critical differences between the viruses. The open reading frames (ORFs)1a produce polypeptide 1a (pp1a, 440e500 kDa), which is cleaved into 11 nsps. A frameshift occurs immediately upstream of the ORF1a stop codon, which allows continued translation of ORF1ab to yield a large polypeptide (pp1ab, 740e810 kDa), which is cleaved into 15 nsps. The proteolytic cleavage is mediated by viral proteases nsp3 and nsp5, which harbor a papain-like protease domain and a 3C-like protease (3CLpro), respectively. The viral genome is also used as the template for replication and transcription, which is mediated by nsp12, which harbors RNA-dependent RNA polymerase (RdRp) activity. [11]

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Transmissibility and the basic reproductive rate Basic reproductive rate (R0) is the key measure in estimating the ability of a new pathogen to spread. It is defined as the average number of secondary transmissions from one infected person; when R0 is greater than 1, the epidemic is growing. The R0 values have important implications for disease control. It indicates level of mitigation efforts needed to bring an epidemic under control. Mitigation measures include rapid case identification, quarantine measures, and physical distancing to prevent secondary transmissions. It brings down the effective transmission coefficient, called Re. Re needs to be reduced to less than 1 to ensure cessation of an epidemic. For SARS-CoV-2 with an R0 value of approximately 25, transmission would need to be reduced by more than 60% through mitigation measures for Re to be less than 1. MERS-CoV caused several limited nosocomial outbreaks since 2012, in hospitals in Saudi Arabia, Jordan, and South Korea due to fact that it has limited transmissibility in contrast with SARS-CoV and SARS-CoV-2 [1].

Incubation period of SARS-CoV-2 and viral excretion Incubation period is defined as the time from infection to symptom onset. All the three coronaviruses have longer incubation period than influenza virus. SARS-CoV and MERS-CoV have tropism for lower airways, but in contrast SARS-CoV-2 has tropism for upper respiratory airways. Two studies [12,13] in Hong Kong and China found the presence of high viral loads in the first samples obtained from patients with SARS-CoV-2 at the time of symptoms onset, which declined rapidly declined in the following 5e6 days. This rapid decline in viral load makes isolation and quarantine of patients and their contacts challenging and less effective as it needs to be done as soon possible to reduce the transmission. But in contrast, in patients with SARS-CoV, it takes 6e11 days [14,15] for viral loads to peak after the symptoms onset. This almost an extra week to identify and isolate cases before transmission occurred. This can potentially explain why SARS-CoV pandemic in 2003 was eradicated in contrast to the trajectory seen in current SARS-CoV-2 pandemic. There is increasing evidence that transmission from asymptomatic people, but proportion of presymptomatic individuals is unknown. Studies from Iceland and China found that between 43% and 78% cases of SARS-CoV-2 were asymptomatic [15,16].

Case fatality and risk of severe illness Mortality rate in SARS-CoV-2 patients increases steeply with age, and fatality is seen almost exclusively in people older than 50 years [1] (Table 5.1). Similar trend of increase in morbidity and mortality was also seen in SARS-CoV. A study in Hong Kong reported a case fatality as 0% for age

TABLE 5.1 COVID-19 age-specific case morbidity and fatality rates. Morbidity, % of positive tests China

South Korea

Italy (Lombardy)

Fatality rates, % China

South Korea

Italy (Lombardy)

0.9

1.0

0.4

0.0

0.0

0.0

10e19 years

1.2

5.2

0.8

0.2

0.0

0.0

20e29 years

8.1

28.0

2.7

0.2

0.0

0.0

30e39 years

17

10.3

5.1

0.2

0.1

0.0

40e49 years

19.2

14.0

9.4

0.4

0.1

0.1

50e59 years

22.4

19.3

16.6

1.3

0.4

0.6

60e69 years

19.2

12.4

17.5

17.5

1.6

2.7

70e79 years

8.8

6.5

23.2

8.0

5.4

9.6

80 years

3.2

3.3

19.7

14.8

10.2

16.6

Data for China, South Korea, 43 and Italy. Average age of death in Italy is 81 years, and mortality in Italy in people older than 90 years was 19%. (Redrawn with permission).

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0e9 years

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group 0e24 years, 6% for those aged 25e44 years, 15% for those aged 45e64 years, and 52% for people who were 65 years and older [17,18]. Children suffer rarely a severe disease in both SARS-CoV-2 and SARS-CoV, but recently a rare hyperinflammatory syndrome reported in children. The rate of secondary attack for children and adults has been reported as 15% but whether the children transmit the virus as effectively as adults is not known. In United States, case fatality rates among patients with COVID-19 were less than 1% for people aged 20e54 years, 1%e5% in those aged 55e64 years, 3%e11% in those aged 65e84 years, and 10%e27% in people aged 85 years and older. Considerable subset of COVID-19 patients develop respiratory failure, which requires intensive care unit is higher compared with the influenza pandemic in 2009. One study reported that about 14% of patients with COVID-19 admitted in New York, NY, USA, required intensive care unit with about 85.7% requiring mechanical ventilation, and mortality in those requiring mechanical ventilation was 88.1% [19] Table 5.2.

Population-based mortality Excess mortality is defined as count of all deaths relative to what would normally had been expected. In a pandemic, death rate rises sharply but exact cause of cause of death is not known as reliable diagnostic tests are not widely available. Ideally, excess mortality is estimated from a mortality time series one time per week, during or at the end of a pandemic [20,21]. The mean excess mortality in 2009 influenza pandemic for different age groups was reported as 0.1e6.4 per 100,000 people younger than 65 years, 2.9e44.0 per 100,000 people aged 65e74 years, and 17.9e223.5 per 100,000 people aged 75 years and older. As of June 8, 2020, mortality rate of COVID-19 has reached up to 159 per 100,000 population, but these numbers are not from the end of pandemic and numbers are expected to increase. For accurate comparison of COVID-19 pandemic with past pandemics, more data and time are needed [21].

TABLE 5.2 Transmissibility, incubation period, viability on surface, mortality for SARS 1-2 and MERS. SARS-CoV-2

SARS-CoV

MERS-CoV

Transmissibility (R0)

2.5

2.4

0.69

Incubation period, days

4e12

2e7

6e7

Viability on surface (stainless steel)

2 days

5 days

3 days

Mortality

7.70%

10.2%

47.2%

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Incidence of SARS-CoV-2 infections To find out the true attack rate of SARS-CoV-2, serological studies are needed. As of February 16th, 2020, 0.11% of the population was affected and a mortality rate of 4.8 per 100,000 population in Hubei, the earliest affected province in China low compared with certain countries in Europe as few people might have been tested due to mild symptoms. While in comparison, annual attack rate of seasonal influenza is 10%e20% every winter [22].

Comparing SARS-CoV-2 and SARS-CoV spread In comparison to SARS-CoV, it is not clear what characteristics SARS-CoV-2 possess that led to the SAR-CoV-2 outbreak evolving into a global pandemic. In 2003, SARS spread globally after one person traveled from mainland China to Hong Kong. Since 2003, international traffic from China has increased 10 times, and high-speed train network connects eastern China and Wuhan where the COVID-19 outbreak began in 2019. In addition, COVID-19 patients begin viral shedding a few days before symptom onset, which makes quarantine difficult.

SARS-CoV-2 and warmer weather Temperature and humidity play an important role for viral survival in the environment. A study [23] that used enveloped virus Phi6 as a surrogate virus showed that infectivity is sensitive to temperature and decreases by two orders of magnitude between 19 C and 25 C. Similarly, another study [24] showed a two-log reduction in viral titer of SARS-CoV after 7 h at 38 C and 95% humidity. These experimental data suggest that SARS-CoV-2 might be less susceptible to warmer weather.

SARS-CoV-2 and the effect of containment measures A mortality study about 1918 influenza pandemic showed that cities in United States, which implemented mitigation measures early, have delayed and flatter epidemic curve with a 50% lower peak mortality and a 20% lower overall mortality [25]. This analysis demonstrated that implementing the mitigation measures is of paramount importance to keep the burden on the healthcare system manageable. The control of spread of COVIT-19 in China and South Korea through mitigation measures is a promising example, but the socioeconomic cost of this is enormous, which will last for a long time. Approach applied in South Korea was through extensive testing quarantine and contact tracing in early stages of outbreak. In addition, schools were closed, and persons with international arrivals were quarantined for 2 weeks [1].

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Conclusion Morbidity and mortality in older adults caused by SARS-CoV-2 pandemic are much higher compared with pandemic influenza. Clearly children are less affected in SARS-CoV-2 pandemic their role to transmission needs to be studied. At this early stage of pandemic, there are no effective treatments such as antivirals or passive immunizations. Only supportive treatment is provided in the hospitals, and efforts are to limit the spread of virus and continue to reduce the impact of virus and to prevent overwhelming the healthcare system. Historic study of influenza pandemic shows that the pandemics come in spike for first few years until population builds immunity through exposure or vaccination and then the numbers start decreasing. This observation implies that in near future we need to adjust to new norms in which combination of physical distancing, enhanced testing, quarantine, and contact tracing will be needed for a protracted period. It is likely after the end of current pandemic, there will be another pandemic. It could be another coronavirus, an influenza virus, a paramyxovirus, or a completely new disease. Critical lessons need to be learned from current pandemic so that we can meet future pandemic with far better preparation in terms of testing, adequate stocks of personal protective equipment, and critical care capability [1].

References [1] Petersen E, Koopmans M, Go U, Hamer DH, Petrosillo N, Castelli F, Storgaard M, Al Khalili S, Simonsen L. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis July 3, 2020;20(9):e238e44. [2] Singhal T. A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr April 2020;87(4):281e6. [3] Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. J Adv Res July 1, 2020;24:91e8. [4] Sternberg A, McKee DL, Naujokat C. Novel drugs targeting the SARS-CoV-2/COVID-19 machinery. Curr Top Med Chem June 1, 2020;20(16):1423e33. [5] Hussain M, Jabeen N, Amanullah A, Baig AA, Aziz B, Shabbir S, et al. Structural basis of SARS-CoV-2 spike protein priming by TMPRSS2. AIMS Microbiol. 2020;6(3):350e60. https://doi.org/10.3934/microbiol.2020021. [6] Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, Zhou Y, Du L. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol June 2020;17(6):613e20. [7] Li Y, Zhou W, Yang L, You R. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res April 14, 2020;157:104833. [8] Kim D, Lee JY, Yang JS, Kim JW, Kim VN, Chang H. The architecture of SARS-CoV-2 transcriptome. Cell May 14, 2020;181(4):914e21. [9] Torrey T. Difference between an epidemic and a pandemic. 2020, Apil 13. https://www. verywellhealth.com/difference-between-epidemic-and-pandemic-2615168. [10] Qureshi AI. Ebola virus disease: from origin to outbreak. Academic Press; January 9, 2016.

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Hatmal MM, Alshaer W, Al-Hatamleh MA, Hatmal M, Smadi O, Taha MO, Oweida AJ, Boer JC, Mohamud R, Plebanski M. Comprehensive structural and molecular comparison of spike proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and their interactions with ACE2. Cells December 2020;9(12):2638. To KK, Tsang OT, Yip CC, Chan KH, Wu TC, Chan JM, Leung WS, Chik TS, Choi CY, Kandamby DH, Lung DC. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis July 28, 2020;71(15):841e3. Wang FS, Zhang C. What to do next to control the 2019-nCoV epidemic? Lancet February 8, 2020;395(10222):391e3. Cheng PK, Wong DA, Tong LK, Ip SM, Lo AC, Lau CS, Yeung EY, Lim WW. Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome. Lancet May 22, 2004;363(9422):1699e700. Pan Y, Zhang D, Yang P, Poon LL, Wang Q. Viral load of SARS-CoV-2 in clinical samples. Lancet Infect Dis April 1, 2020;20(4):411e2. Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. 2020. Peiris JS, Guan Y, Yuen K. Severe acute respiratory syndrome. Nat Med December 2004;10(12):S88e97. World Health Organization. Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). 2003. World Health Organization; 2005. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA May 26, 2020;323(20):2052e9. Viboud C, Miller M, Olson DR, Osterholm M, Simonsen L. Preliminary estimates of mortality and years of life lost associated with the 2009 A/H1N1 pandemic in the US and comparison with past influenza seasons. PLoS Curr March 20, 2010;2:RRN1153. Simonsen L, Spreeuwenberg P, Lustig R, Taylor RJ, Fleming DM, Kroneman M, Van Kerkhove MD, Mounts AW, Paget WJ. Global mortality estimates for the 2009 Influenza Pandemic from the GLaMOR project: a modeling study. PLoS Med November 26, 2013;10(11):e1001558. Somes MP, Turner RM, Dwyer LJ, Newall AT. Estimating the annual attack rate of seasonal influenza among unvaccinated individuals: a systematic review and meta-analysis. Vaccine May 31, 2018;36(23):3199e207. Prussin AJ, Schwake DO, Lin K, Gallagher DL, Buttling L, Marr LC. Survival of the enveloped virus Phi6 in droplets as a function of relative humidity, absolute humidity, and temperature. Appl Environ Microbiol June 15, 2018;84(12):e00551. Chan KH, Peiris JM, Lam SY, Poon LL, Yuen KY, Seto WH. The effects of temperature and relative humidity on the viability of the SARS coronavirus. Advances in virology 2011;2011:734690. Hatchett RJ, Mecher CE, Lipsitch M. Public health interventions and epidemic intensity during the 1918 influenza pandemic. Proc Natl Acad Sci Unit States Am May 1, 2007;104(18):7582e7.

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Chapter 6

SARS-CoV-2 viral structure and genetics Abhi Pandhi1, Ishita Vasudev2 1 University of Tennessee Health Science Center, Memphis, TN, United States; 2Sir Ganga Ram Hospital, New Delhi, Delhi, India

Introduction Coronaviruses are a large family of common viruses that are found in humans and animals especially birds and bats. Many cases of the common cold are attributed to these viruses. There are seven human coronaviruses including alpha and beta [1]. Prior outbreaks due to these included severe acute respiratory distress syndrome in 2002 and Middle Eastern respiratory syndrome in 2012. Previous studies have shown that these viruses can evolve in animals such as bats and transmit to humans via an intermediate host (such as palm civets, raccoon dogs for above) [2]. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible for the ongoing pandemic referred to as the COVID 19 pandemic (intermediate hosts include bats and pangolins) [1].

Viral structure SARS-Cov-2 appears as a viral particle with multiple protein spikes on the surface (Fig. 6.1) When seen under an electron microscope, crown-like (Corona means crown) protein spikes on the surface of the virus are seen. There are four main types of proteins seen on the surface, which include: S (Spike), E (Envelope), M (Membrane), and N (Nucleocapsid) [3]. S protein contains a receptor-binding domain (RBD), which recognizes and binds to a specific receptor, angiotensin-converting enzyme receptor, which is found in the lung, heart, kidneys, and intestines. SARS-Cov-2 potentially has over 20 times more affinity for the above receptor than the SARS-Cov-1, which could explain the worsening widespread pandemic [4,5]. S protein has two components S1 and S2. S1 is the most genetically variable part and binds the host cell receptor, and S2 mediates the fusion of viral and cellular membranes (Fig. 6.2) [3]. Coronavirus Disease. https://doi.org/10.1016/B978-0-12-824409-8.00001-1 Copyright © 2022 Elsevier Inc. All rights reserved.

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60 Coronavirus Disease

FIGURE 6.1 Viral particle with various surface proteins including S (Spike), E (Envelope), M (Membrane), N (Nucelocapsid).

FIGURE 6.2 S or Spike protein structure.

M protein is the most abundant protein on the viral surface. It defines the shape of the viral envelope and works as a structural organizer with other viral proteins. It connects the viral membrane with the nucleic acids via a dominant C-terminal domain. E protein is the smallest of all proteins. It is integral in the assembly and releases the virus from host cells. E protein is largely localized in the endoplasmic reticulum and the Golgi apparatus of host cells during viral replication. Underneath the surface proteins is the virus envelope or capsid. This is the outer layer and derived from the host cell membrane. It is a fatty bilayer, and when in contact with soap, it breaks down and thus killing the virus. Underneath this layer is the capsid, which harbors N protein or nucleocapsid, which binds to the viral genetic material (i.e., single-stranded RNA of the virus) and thus helps in replication (Fig. 6.3). Also, N protein assists

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FIGURE 6.3 N or Nucleocapsid protein structure.

in overcoming the host’s defense mechanisms. SARS-CoV-2 are pleomorphic and have a helical nucleocapsid with a 125 nm diameter and 30 Kb (þ) RNA genome [3].

Molecular genetics Cell entry process Spike (S) protein on the viral surface interacts with the host cell surface angiotensin-converting enzyme-2 receptor. At that time, a host membrane protease, i.e., Transmembrane serine protease 2 (TMPRSS2) cleaves the spike protein such that the host binding component of spike protein (S1) is separated from the rest of the spike protein [4]. The protease is also responsible for a second cleavage event, which activates the fusogenic state of this protein and then the subsequent entry, which can be direct via plasma membrane or endocytosis or both [4]. S protein is a class 1 fusion protein. Other similar protein examples include hemagglutinin in influenza, Ebola protein, Human Immunodeficiency Virus (HIV) fusion protein [5]. Various conformations of S protein in the process of cell entry include prefusion, open, extended, trimerized, fold back, hemifusion, and fusion. Recent studies show that inhibition of endosomal cathepsins reduces the efficiency of SARS-CoV-2 entry, suggesting that this virus also exploits endocytosis as another route of entry in addition to direct membrane fusion [4,6,7]. There are six critical amino acids in the receptor-binding domain, which interact with angiotensin-converting enzyme 2 for coronaviruses. However, five out of six amino acids are different in SARS-CoV-2 compared with coronavirus. Uniquely, SARS-CoV-2 acquires a polybasic cleavage site that enables cleavage to other cellular proteases (in addition to TMPRS22) [6,8]. This has been seen in other viruses to increase transmissibility, particularly in influenza viruses.

62 Coronavirus Disease * Multiple studies are looking to target the process of SARS-CoV2 entry, including blocking ACE2 engagement, inactivating host proteases, and inhibiting S2-mediated membrane fusion [4,9]. A recent study isolated neutralizing antibodies capable of blocking the interaction between S and ACE2 from convalescent SARS-CoV2 patients and demonstrated that they effectively reduce viral load in a mouse model [10]. Other strategies include the development of lipopeptides that block S2-mediated membrane fusion [11] and the use of a clinically tested TMPRSS2 inhibitor [4]. Vaccine directed against S protein includes the production of recombinant S protein, use of nonpathogenic viral vectors to direct expression of S, and nucleic-acid-based vaccines in which sequence encoding the S protein is delivered as a messenger RNA (mRNA) or on a DNA backbone. The viral vector and nucleic acid vaccine strategies rely on host ribosomes to translate the S sequence into a protein, which would then be subsequently presented to the immune system [12].

Replication and gene expression SARS-CoV-2 genome constitutes an ssRNA (30 Kb) and has 14 open reading frames, encoding 27 proteins. Large segment 1 (1a,1b) of ssRNA or 50 end, which encodes nonstructural proteins, is formed from 50 end directly from genomic RNA forming polyprotein. Two proteases within SARS-CoV-2 cleave polyproteins into individual proteins which include nonshock proteins that have cell function and replication properties. Additionally, programmed ribosomal frameshifting, which is increased in SARS-CoV-2, generates the rest of the polyproteins [13]. 30 end genes for structural proteins are translated directly from subgenomic mRNAs with shared 50 and 30 sequences. Subgenomic mRNA transcription is discontinuous and is facilitated by shared transcription regulatory sequences, which are fairly stable throughout, thus explaining high recombination rates within SARS-CoV-2 [14]. Several proteins have also been implicated in regulating the levels of subgenomic mRNAs and the switch between full-length negative-strand synthesis and subgenomic RNA synthesis such as viral N protein, Glycogen synthase kinase 3 (GSK 3) and helicase. These proteins are important in producing full-length ns gRNA, long sgRNAs, and N protein. N protein has helicase-like properties and appears to be vital for replication as well. * Frameshifting has been explored as a novel drug target. These drugs typically prevent frameshifting by binding to RNA structures that are required for frameshifting [15,16].

The SARS-CoV-2 replicase requires functional integration of RNA polymerase, capping (nsp 16), and proofreading activities (nsp 7,8,12,14) [4]. Exonuclease is present only in viruses with genomes over 20 Kb such as in SARS-CoV-2. This confers the proofreading function on the RNA-dependent RNA polymerase. However, the loss of exonuclease activity dramatically increases the sensitivity of SARS-CoV-2 to RNA mutagens [17,18].

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* Studies on murine coronavirus exonuclease mutant showed promise as a vaccine strategy [19]. Exonuclease nonshock protein 14 is a bimodular protein of exonuclease and N7 MTase domains (mRNA capping) [20]. It interacts with the nonshock proteins 12-8-7 tripartite complex providing biochemical evidence for its role in proofreading during transcription/replication. Coronavirus nsp 10/ Exonuclease works as a heterodimer in a mismatch repair mechanism. * Exonuclease can efficiently excise ribavirin 50 MP (i.e., proofreading activity) [21,22]. Therefore, the above can explain why ribavirin does not work against SARS-CoV-2. Replication of MHV-Exonuclease 1 knockout was inhibited more efficiently than wild-type virus by remdesivir, suggesting ExoN may reduce its incorporation; thus trying simultaneous targeting of RNA-dependent RNA polymerase (with Remdesivir) and ExoN with nucleoside analog þ some specific exoribonuclease inhibitor [23e25].

In coronaviruses, recombination occurs as a part of the replication cycle during the synthesis of subgenomic mRNAs and due to the RNA-dependent RNA polymerase to switch templates from the transcription regulatory-B sequence to the -L sequence to copy the leader sequence from the 50 end of the genome. Such recombination events can also occur between coinfecting coronaviruses with different genotypes, thus leading to a potential for new outbreaks [26]. * Use of live attenuated vaccines could be challenging due to potential for mutational recombination potential as described above. Examples of therapeutic targets include studying nonshock protein 14-Exonuclease in vaccine development [27] * Given that translation of coronavirus mRNAs relies on host cap-dependent translation machinery, several cellular cap-binding complex factors are candidates for therapeutic targeting [28]

Replication transcription complexes These complexes are interconnected double-membrane vesicles inside the host cell, where viral replication and transcription can occur [29]. These are derived from the endoplasmic reticulum of the host cell. This protects the viral genome from nucleases and concentrates factors necessary for replication. Also, these complexes carry out the synthesis of subgenomic mRNAs, which encode for the open reading frames located in the 30 -proximal one-third of the genome [29]. Integral membrane replicase proteins function in vesicle biogenesis. Nonstructural proteins such as nonshock protein 3,4 and 6 are involved in vesicle formation [30]. These complexes are potential treatment targets.

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Nonshock 1 protein is not a part of the vesicles. It is a host shutoff factor as it inhibits host gene expression (not viral) by blocking the ribosome directly [31]. Inhibition of host gene expression helps the virus delay the interferon response [32e34]. * Mutation of this factor has also been explored as a potential vaccine strategy.

Assembly and virion proteins are not present in the vesicles (i.e., 2a, HE, S, ORF4, 5a, E, and M) [26]. Accessory genes are also not present in vesicles. These are species-specific and are usually dispensable for viral replication. Both SARS-CoV-1 and SARS-CoV-2 may have a similar set of accessory genes with some differences among the interferon antagonists (3a, 3b, 6, 8) as discussed below [35,36].

Basics of immune response Innate response is the first response to the viral invasion in the first 2 days. This response includes interferons such as type 1 interferons and result in activation of antiviral pathways. The majority of patients have a mild case with rapid clearance of viral titers early on which goes along with a good innate immune response. However, there is a minority of patients get more severe disease from SARS-CoV-2 infection and require intensive unit care. More severe infection can occur due to reduced clearance or there is a dysregulated immune response. This leads to amplification of response with release of interferons, interleukins rapidly, which can have systemic consequences including fever, pneumonia, hypoxic respiratory failure, myocardial infarction, acute myocarditis, muscle aches, acute renal failure, nausea, diarrhea, heart, kidney, gastrointestinal, anosmia, headaches, and confusion [37]. Adaptive immunity response constitutes humoral and cell responses. In theory, humoral immunity includes B cell activated by virus and antibodies are formed, which will neutralize the virus binding to the receptors and thus preventing further infection from taking place. These are referred to as neutralizing antibodies [37]. Cellular immunity is provided by T cells, helper, and cytotoxic. T cells in severe SARS-CoV-2 infection result in activation of cytotoxic rather than helper T cells. The response may exhibit a trend toward exhaustion based on continuous expression of inhibitory markers such as programmed death 1 (PD 1) and T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM 3) as well as overall reduced polyfunctionality and cytotoxicity. Conversely, recovering patients have an increase in helper CD4 T cells with decreasing levels of inhibitory markers [38]. One study reported a population of polyfunctional SARS-CoV-2-specific T cells with a stem-like memory phenotype in the circulation of antibody-seronegative convalescent individuals presenting asymptomatic and mild SARS-CoV-2. The observation suggested that in the absence of antibodies, a robust and broad T-cell response might be sufficient to

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provide immune protection against SARS-CoV-2 [39]. A small study of 10 patients demonstrated that all patients expressed helper T cells that responded to the Spike protein on the surface of the virus, and 70% of these patients had cytotoxic T cells. Even 11 healthy patients/controls had those helper T cells. Latter observation can be explained by an innate T-cell response to common coronaviruses in the past instead of the novel coronavirus [39].

Viral host immune interactions SARS-CoV-1 and Middle Eastern Respiratory Syndrome induce very little if any interferon in most cells. This is because there are several putative interferon antagonists including some accessory proteins in the their viral genome i.e., nonshock proteins 1, 3,7,15, 16, open reading frame 3a (ORF 3a), 3b, 6, M, and nucleocapsid protein (NP protein) [35]. Some differences noted between SARSCoV-2 and above mentioned viruses especially among the interferon signaling antagonists include a premature stop codon in ORF3b resulting in a truncated and likely nonfunctional 20 amino acid protein and relatively lower (69%) amino acid similar to the ORF6 protein [40]. This observation may suggest differences in the susceptibility of SARS-CoV-1 compared with SARS-CoV-2 to host interferon responses. These viruses have a multipronged approach to dampen early interferon response to the viral invasion, thus contributing to viral pathogenesis. The latter is linked to delayed interferon signaling and subsequent immune toxicity. Murine experiments with a group of mice with interferon knockout do not die of coronavirus infection compared with wild type with normal interferon expression. The hypothesis is that virus can replicate to higher initial factors due to the above multipronged approach and accessory factors and the delayed interferon response. Then interferon response comes a later time and leads to aberrant activation of the innate immune response leading to cytotoxicity such as acute lung injury and acute respiratory distress syndrome [41]. The strong down regulation of type I interferon during coronavirus infection suggests that these viruses are highly sensitive to the presence of interferon, and administration of interferons has been discussed as a therapeutic strategy for SARS-CoV-2 as well. * Antiviral effects of type I interferon treatment were recently described in tissue culture models with SARS-CoV-2 [40,42], highlighting the potential for the rational design of a live attenuated vaccine with mutations in key immune agonist genes. Genetic knockout of the interferon-ab receptor during infection protected coronavirus-infected mice, demonstrating the role of a vigorous proinflammatory response in lethal coronavirus infection and identifying these pathways as potential therapeutic targets in patients infected with a highly pathogenic coronavirus.

SARS-CoV-2 patients exhibit a similar pattern of immune dysregulation similar to SARS-CoV-1 with elevated levels of interleukin 6 which correlates

66 Coronavirus Disease

with severe disease pathology and mortality [39]. Murine studies showed that elevated interleukin 6 levels play a major role in predisposing to acute lung injury similar to that observed in both SARS-CoV-1 and SARS-CoV-2 infected patients, and reduction of interleukin 6 reduces the severity of acute lung injury [43]. Furthermore, necroptosis and pyroptosis are forms of highly inflammatory cell death that are observed during infection with cytopathic viruses and likely contribute to the molecular mechanisms underlying the severe lung pathology associated with SARS-CoV-1 and SARS-CoV-2 and Middle Eastern respiratory syndrome virus with elevated interleukin-1B and ORF 3a and 3b expression, leading to necrotic cell death in latter [44]. * Multiple coronavirus proteins antagonize the host innate immune response, including ORF3b, ORF6, nsp1, N, M, and PLpro. Murine studies showed that the deletion of nsp1 severely attenuates infection in vivo and rendered mice immune to a subsequent challenge with wild-type virus [32].

SARS-CoV-1 and SARS-CoV-2 infection mounts a robust antibody response (neutralizing antibody) within 2e3 weeks for SARS-CoV-1 and likely earlier in SARS-CoV-2 (due to earlier viral titers peak) [45e47]. The target for neutralizing antibody is S protein specifically the S1 portion, which differs significantly between SARS-CoV-1 and SARS-CoV-2 thus explaining why only a small number of SARS-CoV-1 antibodies bind and neutralize SARS-CoV-2 [48,49]. Neutralizing antibodies assay has been developed, which can detect various neutralizing antibodies in serum.

SARS-CoV-2 vaccines Multiple vaccines against SARS-CoV-2 have been approved now. Majority of vaccine candidates to date are targeting the spike protein, receptor-binding domain of SARS-CoV-2 using either mRNA or adenoviral vector DNA or protein adjuvant itself. Two of the mRNA-based vaccines, include Pfizer and Moderna, some of the adenoviral vector DNA-based include Astra Zeneca, Sputnik, and Janssen vaccines. Last type is the protein adjuvant, which is the Novavax vaccine. Strong T-cell responses especially T helper cell responses were seen. Only Pfizer, Moderna, and Janssen vaccines have been granted emergency use authorization in the United States so far [50e55].

Conclusions SARS-CoV-2 virus shares various molecular and genetic similarities with SARS-CoV-1 and yet differs in many ways which is discussed above in this chapter. We discuss various genomic targets for both current and future treatments and vaccine development. Our understanding of the pathologic processes involved in SARS-CoV-2 infection will continue to evolve with time.

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70 Coronavirus Disease [51] Anderson EJ, Rouphael NG, Widge AT, et al. mRNA-1273 study group. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med December 17, 2020;383(25):2427e38. https://doi.org/10.1056/NEJMoa2028436. Epub 2020 Sep 29. PMID: 32991794; PMCID: PMC7556339. [52] Livingston EH, Malani PN, Creech CB. The Johnson & Johnson vaccine for COVID-19. J Am Med Assoc 2021;325(15):1575. https://doi.org/10.1001/jama.2021.2927. Published online March 01. [53] Ramasamy MN, Minassian AM, Ewer KJ, et al., Oxford COVID Vaccine Trial Group. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet December 19, 2021;396(10267):1979e93. https://doi.org/10.1016/S01406736(20)32466-1. Epub 2020 Nov 19. Erratum in: Lancet. 2021 Dec 19;396(10267):1978. PMID: 33220855; PMCID: PMC7674972. [54] Keech C, Albert G, Cho I, et al. Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med December 10, 2020;383(24):2320e32. https://doi.org/ 10.1056/NEJMoa2026920. Epub 2020 Sep 2. PMID: 32877576; PMCID: PMC7494251. [55] Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Gam-COVID-Vac vaccine trial group. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet February 20, 2021;397(10275):671e81. https://doi.org/10.1016/S0140-6736(21)00234-8. Epub 2021 Feb 2. Erratum in: Lancet. 2021 Feb 20;397(10275):670. PMID: 33545094; PMCID: PMC7852454.

Chapter 7

Clinical manifestation and diagnosis Yasemin Akinci1, 2 1 Zeenat Qureshi Stroke Institute, University of Missouri, Columbia, MO, United States; 2Istanbul University - Cerrahpasa, Cerrahpasa School of Medicine, Department of Neurology, Istanbul, Turkey

Introduction The novel coronavirus disease 2019 (COVID-19) caused by the newly identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), first reported in Wuhan, a city in the Hubei Province of China in early December 2019. COVID-19 quickly spread and was declared a pandemic by the World Health Organization on March 11, 2020. Coronaviruses are known human pathogens. Although they have traditionally been considered as benign respiratory pathogens, they started to be recognized as serious respiratory pathogens after the emergence of the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). SARS led to the deaths of 916 people in 2002, while MERS has led to the deaths of 858 people between September 2012 and November 2019 [1,2]. SARS-CoV-2 is a b-coronavirus similar to causative viruses of MERS and SARS. However, SARS-CoV-2 is more rapidly spreading across the globe. In about 11 months since December 2019, 49,578,590 confirmed cases of COVID-19 have been reported worldwide, including 1,245,717 deaths and death toll continues to rise in many countries. (World Health Organization Coronavirus Disease (COVID-19) Dashboard, Health Emergency as of 4:07 pm CET, November 08, 2020). Due to rapid transmission of the disease and the increasing number of the cases, several research reports, case reports, editorials, letters, and reviews were published in a short period of time. Our knowledge of the disease has increased along with the increasing number of cases and publications; however, there are many undefined aspects of the disease. Based on the published data, this chapter systematically discusses transmission and clinical manifestations of COVID-19, current diagnostic methods, differential diagnosis from other infectious diseases, recovery period, and measures to be taken by Coronavirus Disease. https://doi.org/10.1016/B978-0-12-824409-8.00006-0 Copyright © 2022 Elsevier Inc. All rights reserved.

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healthcare providers. The chapter will provide a comprehensive understanding of strategies to reduce the spread of SARS-CoV-2 and describes various manifestations of COVID-19.

Transmission of COVID-19 Routes of Transmission Within the Coronaviridae family and Orthocoronavirinae subfamily, the Alphacoronavirus and Betacoronavirus mainly infect mammals and are transmissible to humans. The Alpha- and Betacoronavirus strains are thought to have originated from the bat species (Rousettus leschenaultii) [3e5]. SARSCoV-2 is a distinct class of the beta coronaviruses. Genomic analyses showed that SARS-CoV-2 is 96.2% identical to a bat CoV (RaTG13) and shares 79.5% of its identity with SARS-CoV, suggesting the bat as the most probable original reservoir of the virus. The fact that the first cases were related to fish market in Wuhan supports this information though the exact host of the novel SARS-CoV-2 virus is not yet identified [6]. Due to its genetic similarity with pangolin-derived CoVs, pangolins are thought to be intermediate host; however, the possibility of multiple intermediate hosts is considered [7]. Although transmission from the bat to human via carrier animals seemed to be the main transmission route at first, human-to-human transmission played an important role in the spread of the disease and is now considered as the main form of transmission. Human-to-human transmission occurs mainly through family members, friends, coworkers, healthcare providers (probably as a result of cross-contamination in donning and doffing and/or insufficient measures), and other close contacts. SARS-CoV and MERS-CoV transmission has been reported to occur mainly through nosocomial transmission (33%e42% of SARS cases were healthcare providers (HCPs) and transmission between patients was responsible for 62%e79% of MERS cases) [8,9]. Nosocomial transmission is also an important form of transmission for SARS-CoV-2, though to a lesser extent than seen in these two. In a study of 138 hospitalized patients in Wuhan, in 57 patients (41.3%), 40 of whom were healthcare professionals, hospital-associated transmission was thought to be the default mechanism of infection [10]. In a retrospective study of 435 polymerase chain reaction positive COVID-19 inpatients from London, hospital-associated transmission was reported as definite source of infection in 47 patients (11%) and as a possible source of infection in 19 patients (4%) [11]. Cats, dogs, lions, tigers, and minks in contact with infected humans have been reported to be tested positive for SARS-CoV-2 after showing signs of illness. Of these animals only minks that were infected by humans in a farm in the Netherlands have been reported to infect other people. There is still no evidence that other ones can transmit the disease to humans [12e14].

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The virus primarily causes respiratory illness, and like other respiratory pathogens, the transmission is thought to occur through saliva, respiratory secretions, droplets (particles >5e10 mm in diameter), and droplet nuclei or aerosols (particles 30 breaths/min). The immune system becomes strongly affected by the infection, and inflammatory response (vasodilation, endothelial permeability, leukocyte recruitment) leads to lung injury and hypoxia (PaO2/ FiO2 < 300 mm Hg) along with tissue damage. At this stage, most patients need to be admitted to hospital for close observation and management. Bilateral patchy infiltrates and/or ground glass opacities become visible on chest X-ray and chest computed tomography. With the progression of damage, respiratory failure and COVID-19-related acute respiratory distress syndrome

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develop, which has been observed to show different characteristics from acute respiratory distress syndrome caused by other factors [72,79]. These differences include: 1. In typical acute respiratory distress syndrome, the alveolus is primarily involved with destruction of epithelial and endothelial cells, while injury to the alveolar epithelial cells has been cited as the main cause of COVID-19related acute respiratory distress syndrome. It is suggested that endothelial cells were less damaged with therefore resulted in less exudation. 2. Clinical symptoms were inconsistent with the severity of imaging findings in some patients. Although the computed tomography results indicated diffuse and severe lung injury, clinical findings in some patients were relatively mild. However, it was also observed that these patients can rapidly deteriorate. 3. According to Berlin Criteria for acute respiratory distress syndrome, respiratory symptoms must have begun within 1 week of a known clinical insult or patients must have new or worsening respiratory symptoms during the past week [80]. However, the median time from onset of symptoms to COVID-19-related acute respiratory distress syndrome was reported as 8e12 days. 4. Pulmonary compliance might slightly be reduced in some intubated COVID-19 patients compared to acute respiratory distress syndrome in which the combination of severe hypoxemia is rarely observed without significant reduction in compliance. Ventilation is therefore easier, and patients benefit from low-to-moderate levels of positive end expiratory pressure (8e10 cm H2O) and prone positioning. COVID-19-related acute respiratory distress syndrome was divided into three categories based on oxygenation index (arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2)) on positive end expiratory pressure
5 cm H2O by the experts from the National Health Commission of China [81]: l l l

Mild (200 mm Hg  PaO2/FiO2 < 300 mm Hg) Mildemoderate (150 mm Hg  PaO2/FiO2 < 200 mm Hg) Moderateesevere (PaO2/FiO2 < 150 mm Hg)

The disease can activate the coagulation cascade, cause rise in D-dimer levels and widespread micro- and macro-thromboses. Uncontrolled endothelial damage and associated hypoxic pulmonary vasoconstriction failure favor ventilation-perfusion mismatch, hypoxemia, and thrombogenesis. Lung vascular thrombosis from thrombotic microangiopathy and/or pulmonary embolism results in increased respiratory dead space. As edema increases and lung damage progresses, some patients develop a phenotype more consistent with classical acute respiratory distress syndrome in the following phase.

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Treatment in the second phase mainly consists of supportive measures, antiviral therapies that prevent the entry of the virus into the host cell and inhibit virus replication, and anticoagulant prophylaxis. The development of hypoxia in the pulmonary phase can be accepted as evidence that progress requiring mechanical ventilation will be seen. Therefore, antiinflammatory therapies such as corticosteroids may be initiated in patients who develop hypoxia at this stage [72,73].

Inflammatory phase Some COVID-19 patients will transition into this critical phase, which is the most severe stage of the illness. The main feature of this phase is the uncontrolled increased inflammatory response (cytokine storm) resulting from the release of proinflammatory cytokines and chemokines rather than the virus load itself, which has already begun to decrease. High levels of interleukin-1 beta, interleukin-1RA/2/6e10, basic fibroblast growth factor 2, granulocytecolony stimulating factor, interferon-g, interferon-g inducible protein 10, monocyte chemoattractant protein-1, macrophage inflammatory protein 1a, macrophage inflammatory protein 1b, platelet-derived growth factor subunit B, tumor necrosis factor-a, and vascular endothelial growth factor A have been detected in patients with COVID-19. The effect of exaggerated inflammatory immune response is extensive tissue damage with predisposition to venous and arterial thromboembolic events. Hypoxia and immobilization that occur with disease progression also contribute to the development of thromboembolic events. Multiorgan failure, acute respiratory distress syndrome, septic shock, refractory metabolic acidosis, disseminated intravascular coagulopathy, acute heart/liver/kidney injury, and secondary bacterial/fungal infections constitute the main clinical characteristics of this most severe phase of the disease. However, the respiratory and cardiac systems are the most commonly involved. The main cause of death can be cardiopulmonary arrest, myocardial infarction, arrhythmias, pulmonary embolism, and acute respiratory distress syndrome [72,73]. Under the prevailing circumstances, treatment in the third phase relies on the use of immunomodulatory agents to reduce systemic inflammation, antithrombotics to prevent thromboembolic events, respiratory and circulatory support, renal replacement therapy, and antibiotics for secondary infections.

Extrapulmonary manifestations Despite being known as a respiratory illness, the impact of the disease extends far beyond the respiratory system and the involvement of the other organs is an important factor influencing mortality and morbidity. Expression of angiotensin-converting enzyme 2 in multiple extrapulmonary tissues, endothelial damage and thrombo inflammation, erratic and overactive immune

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responses, damage in angiotensin-converting enzyme 2-related pathways and dysregulation of renin-angiotensin-aldosterone system, which is responsible for the regulation of key physiological processes including fluid and electrolyte balance, blood-pressure regulation, vascular permeability, and tissue growth, contribute to the occurrence of extrapulmonary manifestations during the course of COVID-19. The extrapulmonary manifestations appear to occur more frequently in patients with severe disease forms and more likely to be associated with worse outcomes. Some of them may be seen in the early stages of the disease when the disease is not yet severe, or may even be the presenting symptom. Vesicular rashes, for example, have been found to occur early in the course of the disease, before other symptoms, chilblain-like lesions usually occur late during the course of the disease, while remaining cutaneous findings tend to develop during the disease stage [82]. Another example is the timing of ischemic stroke, which is one of the extrapulmonary manifestations of COVID-19. Determination of higher incidence of cerebrovascular events in patients with severe disease (those needing mechanical ventilation and basic life support) suggests that stroke occurs more frequently in the second stage of the disease. However, in case series, it is reported that cerebrovascular events may also occur in the early stage of the disease [83]. It should also be taken into account that patients can only be presented with severe extrapulmonary manifestations such as stroke and acute coronary syndrome without showing classic symptoms of the illness (fever, cough, or loss of appetite) [83,84]. Frequently reported extrapulmonary manifestations of COVID-19 are summarized in Table 7.1.

TABLE 7.1 Frequently reported extrapulmonary manifestations of COVID-19. Organ system Cardiovascular manifestations [85e87]

Manifestation

Frequency

Heart failure/cardiogenic shock

8%

Arrhythmias (with a general trend of tachyarrhythmias including atrial fibrillation, atrial flutter, ventricular tachycardia/fibrillation)

14%

Myocarditis

12.5% (unconfirmed by ECG/echocardiogram)

Acute coronary syndrome

Unknown

Venous thromboembolism

22.7%

Pericarditis

Pericardial effusion frequency was 4.8% in severe cases Continued

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TABLE 7.1 Frequently reported extrapulmonary manifestations of COVID-19.dcont’d Organ system

Manifestation

Frequency

Acute kidney injury

7.58%e11.0%

Electrolyte disturbance (particularly hyperkalaemia)

12.5%

Proteinuria

57.2% (95% CI 40.6% e73.8%)

Hematuria

36% and 26% (>5 or 10 RBC per field) 13% (in patients without UC, >10 RBC per field)

Acidosis

12.5% (10.1e15.0)

Alkalosis

6.9% (4.5e10.6)

Anorexia

26.8%

Nausea/vomiting

10.3%e26.4%

Diarrhea

10.4%e33.7%

Abdominal pain

8.8%e14.5%

Hemorrhagic colitis

At least 2 cases have been reported

Mild pancreatic injury

Elevated levels of amylase and lipase in 1.85% of mild cases, the proportion of increased amylase and lipase were 17.91% and 16.41% respectively in severe cases

Hepatobiliary manifestations [93]

Abnormal liver chemistries (including decreased albumin, increased serum levels of AST, ALT, bilirubin)

43%

Endocrinologic manifestations [40,94]

Disruption of insulin production, hyperglycemia and diabetic ketoacidosis

6.4% (with 64% patient rate without underlying DM)

Possible leydig cell damage (higher serum LH with low T:LH ratio compared to healthy individuals)

Unknown

Renal manifestations [23,88,89]

Gastrointestinal manifestations [90e92]

Continued

Clinical manifestation and diagnosis Chapter | 7

83

TABLE 7.1 Frequently reported extrapulmonary manifestations of COVID-19.dcont’d Organ system Neurologic manifestations [40,95e126]

Manifestation Central nervous system manifestations

Peripheral nervous system manifestations

Skeletal muscle manifestations

Frequency

Headache

19.88%

Encephalopathy

8%e8.8%

Ischemic stroke

2.8%e5%

Intracerebral hemorrhage

0.45%

Cerebral venous sinus thrombosis

At least 11 patients have been reported, including 13year-old pediatric case

Encephalitis

At least 8 cases were reported

Acute myelitis

At least 11 patients have been reported, including 3year-old pediatric case

Acute necrotizing myelitis

At least 2 cases have been reported

Acute necrotizing encephalopathy

At least 3 cases have been reported

Posterior reversible encephalopathy syndrome

At least 7 patients have been reported, including a hemorrhagic PRES case

Seizure

0.5%

Cytotoxic lesion of the corpus callosum

In 4.1% of COVID-19 patients presented with acute neurological symptoms

Anosmia and ageusia

59.45% and 56.48% respectively

Guillain-Barre´ syndrome and its variants

At least 19 cases have been reported

Bell’s palsy

At least 2 cases have been reported

Myalgia and myositis

25.1% for myalgia, 10.7% for myositis

Rhabdomyolysis

0.2% Continued

84 Coronavirus Disease

TABLE 7.1 Frequently reported extrapulmonary manifestations of COVID-19.dcont’d Organ system

Manifestation

Ophtalmologic manifestations [76]

Conjunctivitis (along with sore eye, increased eye secretions, dry eye, foreign body sensation, itching, redness)

0.8%e31.6%

Dermatologic manifestations [78,127e130]

Erythema

44.18%a

Systemic manifestations [131e135]

Frequency

a

0.19% e20.45%

Chilblain-like lesions “covid toe”

19.72%

Urticaria

16.37%a

Vesicular lesions

13.20%a

Livedo/necrosis

6.1%a

Petechiae

1.58%a

Pruritus

44.77%a

Angioedema

At least 3 cases have been reported

COVID-19 Kawasaki-like disease (Kawa-COVID-19)

Frequency is unknown but at least two adult patients have been reported and Verdoni et al. [131] found 30-fold increase in the Kawasaki-like disease in children after COVID-19 epidemics

Hyperinflammation and extrapulmonary organ dysfunction without respiratory failure

Multisystem inflammatory syndrome in adults (MIS-A)

At least 27 cases have been reported

Multisystem inflammatory syndrome in cchildren (MIS-C)

2 per 100,000

ALT, alanine transaminase; AST, aspartate transaminase; DM, diabetes mellitus; ECG, electrocardiogram; LH, luteinizing hormone; PRES, posterior reversible encephalopathy syndrome; RBC, red blood cell; T, testosterone; UC, urinary catheter. a It represents the proportion within all skin manifestations.

Clinical manifestation and diagnosis Chapter | 7

85

Clinical classification of symptomatic patients A clinical classification has been made by the National Health Commission of China that gives some information about the prognosis and mortality of COVID-19 [136]. According to this classification, COVID-19 severity is classified as follows: 1. Mild Cases: Those with mild clinical symptoms and with no abnormal radiological findings of pneumonia. 2. Moderate Cases: Those showing fever and respiratory symptoms with radiological findings of pneumonia. 3. Severe Cases: a. Adult cases that meet at least one of the following criteria: l Respiratory distress (
30 breaths/min) l Low resting oxygen saturation (93%) l PaO2/FiO2 & 300 mm Hg (in high-altitude areas, PaO2/FiO2  [atmospheric pressure (mm Hg)/760]) shall be used. And cases with obvious pulmonary lesion progression within 24e48 h > 50% in chest imaging. b. Pediatric cases that meet at least one of the following criteria: l Tachypnea (independent of fever and crying) l Low oxygen saturation at rest on finger pulse oximeter (92%) l Labored breathing, cyanosis, and intermittent apnea l Lethargy and convulsion l Difficulty feeding and signs of dehydration 4. Critical Cases: Those meeting any of the following criteria: l Respiratory failure and requiring mechanical ventilation l Shock l With other organ failure that requires intensive care unit The Chinese Center for Disease Control and Prevention announced that most COVID-19 cases were mild (81%), 14% were severe, and 5% were critical. In the same report, the case-fatality rate in confirmed cases and critical cases declared as 2.3% and 49%, respectively [137]. Although we do not have the opportunity to compare exactly, we can say that similar results have been obtained in the United States. In total, 14% of patients were hospitalized, 2% were admitted to an intensive care unit, and 5% died [138].

Risk factors for severe disease Older people who are infected with the SARS-CoV-2 have a high risk of developing severe illness and with aging, the risk of death increases. In a metaanalysis with 611,583 subjects from different countries, mortality rate was found to be