Traditional Chinese and Western Medicine for Diagnosis and Treatment of Coronavirus Disease 2019 (COVID-19) [Team-IRA] 9811228051, 9789811228056

Table of contents :
Contents
Editorial Board
About the Editors
Foreword by Zhong Nanshan
Foreword by Wang Chen
Foreword by Li Lanjuan
Preface
Chapter 1 General Introduction
1. An Overview
1.1 Etiological characteristics
1.2 Pathogenesis
1.3 TCM understanding of COVID-19
2. Epidemiological Characteristics
2.1 Source of infection
2.2 Route of transmission
2.2.1 Respiratory droplet transmission
2.2.2 Indirect transmission
2.2.3 Faecal–oral transmission
2.2.4 Aerosol transmission
2.2.5 Vertical transmission
2.3 Susceptible population
2.4 Incubation and infectious period
2.5 Demographic characteristics
2.5.1 Age distribution and sex ratio
2.5.2 Distribution of the stage of disease
2.5.3 Mortality rate
2.5.4 Global or regional distribution
2.5.5 Epidemic outbreak
2.5.6 Nucleic acid testing mass screening in Wuhan
2.6 Correlation and distinction between SARS and COVID-19
3. Clinical Characteristics
3.1 Clinical manifestations
3.2 Laboratory examination
3.3 Imaging findings
3.4 Pathological characteristics
3.4.1 Lung
3.4.2 Spleen, hilar lymph nodes, and bone marrow
3.4.3 Heart and blood vessels
3.4.4 Liver and gallbladder
3.4.5 Kidney
3.4.6 Other organs
Chapter 2 Clinical Diagnosis
1. Diagnostic Criteria and Clinical Classification
1.1 Diagnostic testing and inspection technology
1.1.1 Conventional laboratory examination technology
1.1.2 Etiology and serological detection technology
1.1.3 Imaging examination method
1.2 Diagnostic criteria
1.2.1 Suspected case
1.2.2 Clinical manifestations
1.2.3 Confirmed cases
1.3 Clinical classification
1.3.1 Clinical classification based on severity of the disease
1.3.2 Clinical classification of COVID-19 in children
1.3.3 Classification based on the Clinical Management of COVID-19: Interim Guidance
1.4 Early warning indicators for severe/critical illnesses
1.5 Differential diagnosis
1.6 Diagnostic procedure
2. Nucleic Acid Testing
2.1 Testing principle
2.2 Sample collection
2.2.1 Collection of upper respiratory tract specimens
2.2.2 Collection of lower respiratory tract secretions
2.2.3 Collection of urine and fecal specimens
2.3 Diagnostic criteria
2.4 Limitations of nucleic acid test
3. Serological Testing
3.1 Testing principle and method
3.2 Sample collection
3.3 Diagnostic criteria
3.4 Interpretation of the joint test results of nucleic acid and serology
3.4.1 Nucleic acid (+), antibody test (+)/(–)
3.4.2 Nucleic acid testing (–), antibody test (+)/(–)
3.5 Limitations of serological testing
4. Re-positive Patients, Persistent Positive Patients, Asymptomatic Patients, and Reinfected Patients
4.1 Re-positive COVID-19 patients
4.2 Persistent positive COVID-19 patients
4.3 Asymptomatic COVID-19 patients
4.4 Reinfected COVID-19 patients
Chapter 3 Western Medicine Treatment
1. Principles of Treatment
1.1 Determining the treatment site according to the condition
1.2 Treatment principles of mild and moderate cases
1.3 Treatment principles of severe and critical cases
1.4 Treatment principles of special populations
2. Western Medicine Treatment
2.1 Supportive treatment
2.1.1 Respiratory support treatment
2.1.1.1 General oxygen therapy
2.1.1.2 High-flow nasal cannula
2.1.1.3 Non-invasive positive pressure ventilation
2.1.1.4 Prone ventilation
2.1.1.5 Invasive positive pressure ventilation
2.1.1.6 Extracorporeal membrane oxygenation
2.1.2 Circulatory support treatment
2.1.3 Nutritional support treatment
2.2 Antiviral treatment
2.2.1 Interferon
2.2.2 Lopinavir and ritonavir
2.2.3 Ribavirin
2.2.4 Arbidol
2.2.5 Chloroquine phosphate
2.3 Antimicrobial treatment
2.4 Hormone therapy
2.5 Intestinal microecologics
2.6 Convalescent plasma therapy
2.7 Artificial liver treatment
2.8 Immunotherapy
2.8.1 Tocilizumab therapy
2.8.2 Intravenous infusion of immunoglobulin
2.9 Continuous renal replacement therapy
2.10 Notes for medication use for special population
2.10.1 Pregnant patients
2.10.2 Newborns
2.10.3 Children and adolescents
2.10.4 The elderly
Chapter 4 TCM Treatment
1. An Overview
1.1 Basic understanding
1.2 Etiology
1.3 Pathogenesis and nature of the disease
1.4 Syndrome characteristics
1.5 Treatment principles
1.6 The dominant role of TCM
2. TCM Treatment
2.1 During medical observation
2.2 During clinical treatment (confirmed cases)
2.2.1 Mild and moderate cases
2.2.2 Severe and critical cases
Chapter 5 Complications, Sequelae, and Long-Term Symptoms
1. Mechanisms of Injury
2. Relevant Organ and System Injury
2.1 Immune dysfunction and coagulation disorder
2.1.1 Syndromes caused by cytokine release
2.1.2 Coagulation disorder
2.2 Cardiovascular injury
2.3 Pulmonary dysfunction
2.4 Neurosystem influence
2.5 Liver and kidney function injury
2.5.1 Liver injury
2.5.2 Renal injury
2.6 Reproductive system injury
2.7 Psychological disorders
2.8 Special groups
2.8.1 Pregnant women
2.8.2 Children
3. Long-Term Symptoms
4. Understanding and Effect of TCM on the Complications, Sequelae, and Long-Term COVID
Chapter 6 The Rehabilitation Treatment of Integrated Traditional and Western Medicine
1. An Overview
2. Management Objectives and Principles
2.1 Objective of rehabilitation
2.2 Object and place of rehabilitation
2.3 Principles of rehabilitation diagnosis and treatment
3. Rehabilitation Diagnosis and Treatment Procedures and Evaluation
3.1 Rehabilitation diagnosis and treatment procedures
3.1.1 Inpatient rehabilitation procedure for COVID-19 patients
3.1.2 Outpatient rehabilitation procedure for COVID-19 patients
3.1.3 Home rehabilitation procedure for COVID-19 patients
3.2 Rehabilitation assessment
3.2.1 Respiratory function assessment
3.2.2 Assessment of free-hand cardiopulmonary function
3.2.3 Assessment of free-hand muscle strength
3.2.4 Assessment of free-hand flexibility
3.2.5 Assessment of free-hand balance
3.2.6 Assessment of psychological function
3.2.7 Assessment of the ability of daily life activities
3.2.8 Assessment of quality of life
4. Rehabilitation Treatment
4.1 Rehabilitation interventions
4.1.1 Western medicine interventions
4.2. TCM rehabilitation
4.2.1 Rehabilitation treatment of TCM medicinals
4.2.2 Rehabilitation of TCM physiotherapy
4.3 Psychological rehabilitation treatment
4.3.1 Self-psychological regulation
4.3.2 Professional psychological intervention
4.3.3 TCM mental therapy
4.3.4 Home rehabilitation guidance
4.3.5 Reasonable diet
4.4 Notes
Chapter 7 Prevention
1. Lifestyle
1.1 Pay attention to personal protection and achieve two “less”, two “frequently”, and two “smooth”
1.2 Maintain a healthy lifestyle and improve resistance
1.3 Health monitoring and timely medical treatment
2. Comprehensive Prevention of TCM
2.1 Acupoint application
2.2 Acupuncture treatment
2.3 Auricular therapy
2.4 Massage and scrapping therapy
2.5 Traditional health-maintaining method
2.6 Medicinal diet therapy
2.7 Mental guidance
3. The Prevention of Chinese Medicinals
3.1 Decoction or substitute of tea
3.2 Prescriptions for external use
4. Vaccine Development
4.1 What is a vaccine?
4.2 Progress in the research and development of COVID-19 vaccines in China
Chapter 8 Diagnosis and Treatment Standards of Traditional Chinese and Western Medicine in a Makeshift Hospital
1. An Overview of Makeshift Hospital
2. Management Principles
3. Standards for Admission and Pre-examination and Triage of Patients
3.1 Standards for admission of patients in the makeshift hospital
3.2 Admission process of the makeshift hospital
3.3 Pre-examination and triage of the makeshift hospital
4. Treatment Measures
4.1 Closely monitor the vital signs and oxygen saturation
4.2 General treatment
4.3 Oxygen therapy
4.4 Drug treatment
4.4.1 Antiviral therapy
4.4.2. Antibiotic therapy
4.4.3. Infusion support treatment
4.4.4. TCM treatment
4.5 Management of severe patients
4.5.1 Treatment measures that should be available in the observation and treatment area for severe patients
4.5.2 Indications for starting consultation and transferring to severe patient observation and treatment area
4.5.3 Rescue procedure
5. Standards and Procedures for Transfer and Discharge
5.1 Transfer standards for severe patients in the makeshift hospital
5.2 Transfer procedure of severe patients
5.3 Discharge standards
5.4 Discharge procedure
5.5 Disinfection procedure of discharged patients
6. Introduction of TCM Model of Jiangxia Makeshift Hospital
6.1 Organizational structure and management mode
6.2 Treatment methods
6.2.1 The comprehensive treatment of TCM measures is rich and diverse, covering the whole process
6.2.2 Great doctors should have exquisite expertise and sincere attitude, treat patients as family, and treat both body and mind
6.2.3. Teach health-maintaining skills at different levels and give full play to the specialty of TCM in promoting rehabilitation
6.3 Summary of curative effect
Chapter 9 Introduction to Clinical Drug Research
1. Traditional Chinese Medicine
1.1 Screening of listed Chinese patent medicines
1.2 Construction of the core outcome set for clinical trials on COVID-19
1.3 The “three TCM drugs and three herbal formulas” recommended by the Diagnosis and Treatment Protocol
1.3.1 Jinhua Qinggan Granules
1.3.2 Lianhua Qingwen Capsules (Granules)
1.3.3 Xuebijing Injection
1.3.4 Qingfei Paidu Decoction
1.3.5 Huashi Baidu Decoction
1.3.6 Xuanfei Baidu Decoction
1.4 Other recommended Chinese patent medicines
1.4.1 Huoxiang Zhengqi Capsules (Pills, Liquid, and Oral Liquid)
1.4.2 Shufeng Jiedu Capsules
1.4.3 Xiyanping Injection
1.4.4 Reduning Injection
1.4.5 Tanreqing Injection
1.4.6 Xingnaojing Injection
2. Chemicals
2.1 Anti-viral drugs
2.1.1 Interferon
2.1.2 Favipiravir
2.1.3 Arbidol
2.1.4 Ribavirin
2.2 Anti-malaria drugs
2.2.1 Chloroquine
2.2.2 Hydroxychloroquine
2.3 Anti-HIV drugs
2.3.1 Lopinavir/ritonavir
2.3.2 Darunavir
2.4 Antibiotics
2.5 Immunotherapy drugs
2.5.1 Tocilizumab
2.5.2 Methylprednisolone
2.5.3 Convalescent plasma therapy
Chapter 10 International Progress
1. An Overview of the International Popularity
1.1 The comparison between Spanish flu and COVID-19
1.2 Timeline of the overseas epidemic
1.3 Local epidemic control situation
1.3.1 Epidemic situation in North America
1.3.2 Epidemic situation in South America
1.3.3 Epidemic situation in Africa
1.3.4 Epidemic situation in Europe and Asia
1.3.5 Epidemic prevention and control measures
2. International Assistance
3. Research on SARS-CoV-2 Characteristics
3.1 The virus structure
3.2 Virus mutation
3.3 Exploration of the origin of the virus
4. Drugs, Vaccines, and Other Therapies
4.1 Drug research and development
4.2 Stem cell therapy
4.3 Vaccine research and development
4.4 Plasma therapy
4.5 Application of traditional Chinese medicine
5. The Clinical Treatment of COVID-19
5.1 “Cytokine storm”
5.2 Prediction of disease development
5.3 Herd immunity and ADE
5.4 Other clinical findings
6. Related Clinical Studies of COVID-19
7. Clinical Drug Research
7.1 Remdesivir
7.1.1 Safety of drugs
7.1.2 Clinical evaluation indicators
Appendix A: Diagnosis and Treatment Protocol for COVID-19 Patients
1. Etiological Characteristics
2. Epidemiological Characteristics
2.1 Source of infection
2.2 Route of transmission
2.3. Susceptible population
3. Pathological Changes
3.1 Lungs
3.2. Spleen, hilar lymph nodes, and bone marrow
3.3. Heart and blood vessels
3.4. Liver and gallbladder
3.5. Kidneys
3.6. Other organs
4. Clinical Features
4.1. Clinical manifestations
4.2. Laboratory testing
4.2.1 General testing
4.2.2 Etiology and serological examination
5. Diagnostic Criteria
5.1. Suspected cases
5.1.1 Epidemiological history
5.1.2 Clinical manifestations
5.2. Confirmed cases
6. Clinical Classification
6.1. Mild
6.2. Moderate
6.3. Severe
6.4. Critical
7. Groups at High Risk of Severe/Critical Illnesses
8. Early Warning Indicators for Severe/Critical Illnesses
8.1. Adults
8.2. Children
9. Differential Diagnosis
10. Case Finding and Reporting
11. Treatment
11.1. Determining the treatment site according to the condition
11.2. General treatment
11.3. Antiviral treatment
11.4. Immunotherapy
11.5. Glucocorticoid therapy
11.6. Treatment of severe and critical cases
11.7. Traditional Chinese medicine (TCM) therapy
11.8. Early rehabilitation therapy
12. Nursing
13. Discharge Criteria and Precautions after Discharge
14. Patient Transfer
15. Control of Nosocomial Infection in Medical Institutions
16. Prevention
Appendix B: COVID-19 TCM Syndrome Research and Analysis
1. General Information
2. “Dampness Toxin Stagnation of the Lungs” is the Core Pathogenesis
3. Composite Onset of Disease as Regional Characteristics
4. Clinical Manifestation and Evolutionary Pattern of “Dampness-Toxin Pestilence”
Appendix C: The Roles of TCM in the Prevention and Treatment of COVID-19
1. TCM can Play a Role in the Whole Process of Anti-epidemic
1.1 Quarantine of the “4 categories of people” and the general application of TCM decoction
1.2 Undertaking of makeshift hospitals — TCM as the main force
1.3 TCM, as an adjuvant treatment, can also turn the tide for patients with severe symptoms
1.4 Promote recovery and reduce sequelae during rehabilitation period
1.4.1 Science and technology supported TCM in the fight against COVID-19
Appendix D: Hot Issues Related to COVID-19 TCM Treatment (Questions & Answers)
Bibliography

Citation preview

Diagnosis and Treatment of COVID-19 with Integrated Chinese and Western Medicine

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Diagnosis and Treatment of COVID-19 with Integrated Chinese and Western Medicine 主编 Editors-in-Chief

张伯礼 Boli Zhang Tianjin University of Traditional Chinese Medicine, China 刘清泉 Qingquan Liu Beijing Hospital of Traditional Chinese Medicine, China 副主编 Associate Editors

张俊华 Zhang Jun hua 夏文广 Xia Wen Guang 黄明 Huang Ming 杨丰文 Yang Feng Wen 李霄 Li Xiao 郑文科 Zheng Wen Ke 张磊 Zhang Lei 编委 Editorial Board

于亚君 Yu Ya Jun 王玉光 Wang Yu Guang 王佳宝 Wang Jia Bao 冯睿 Feng Rui 吕玲 Lv Ling 乔晨曦 Qiao Chen Xi 安长青 An Chang Qing 江丰 Liu Feng 刘静 Liu Jing 张军 Zhang Jun 张晗 Zhang Han 李旭成 Li Xu Cheng 李霖 Li Lin 苗青 Miao Qing 金鑫瑶 Jin Xin Yao 郑承红 Zheng Cheng Hong 昝树杰 Zan Shu Jie 夏文广 Xia wen Guang 高丹 Gao Dan 黄敏 Huang Min 黄湘龙 Huang Xiang Long 雷伟 Lei Wei 熊可 Xiong Ke 蔡慧姿 Hui Zi Chua

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Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE

Library of Congress Cataloging-in-Publication Data Names: Zhang, Boli (Professor of Chinese medicine), editor. | Liu, Qingquan, 1965– editor. Title: Diagnosis and treatment of COVID-19 with integrated Chinese and Western medicine / Editors-in-Chief Boli Zhang (Tianjin University of Traditional Chinese Medicine, China), Qingquan Liu (Beijing Hospital of Traditional Chinese Medicine, China). Description: New Jersey : World Scientific, [2023] | Includes bibliographical references and index. Identifiers: LCCN 2023015002 | ISBN 9789811228056 (hardcover) | ISBN 9789811228063 (ebook for institutions) | ISBN 9789811228070 (ebook for individuals) Subjects: LCSH: COVID-19 (Disease)--Alternative treatment. | Medicine, Chinese. | COVID-19 (Disease)--Diagnosis. | COVID-19 (Disease)--Treatment. Classification: LCC RA644.C67 D525 2023 | DDC 616.2/4144--dc23/eng/20230527 LC record available at https://lccn.loc.gov/2023015002

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.

Copyright © 2023 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher.

For any available supplementary material, please visit https://www.worldscientific.com/worldscibooks/10.1142/12034#t=suppl Desk Editor: Carmen Chan Typeset by Stallion Press Email: [email protected] Printed in Singapore

Editorial Board Editorial Committee Chief Editors: Zhang Boli, Liu Qingquan Associate Editors: Zhang Junhua, Xia Wenguang, Huang Ming, Yang Fengwen, Li Xiao, Zheng Wenke, Zhang Lei Editorial board (sorted by surname strokes) Yu Yajun, Wang Yuguang, Wang Jiabao, Feng Rui, LYU Ling Qiao Chenxi, Liu Jing, Jiang Feng, An Changqing, Li Lin Li Xucheng, Zhang Jun, Zhang Han, Miao Qing, Jin Xinyao Zheng Chenghong, Zan Shujie, Gao Dan, Huang Min, Huang Xianglong Chua Hui Zi, Xiong Ke

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About the Editors Zhang Boli holds the following positions: Academician of the Chinese Academy of Engineering, Honorary Principal of Tianjin University of Traditional Chinese Medicine (TCM), Honorary President of the China Academy of Chinese Medical Sciences, Member of the Expert and Central Steering Group to Hubei Province, National Famous Doctors of TCM, Director of the Department of Medicine and Health of the Chinese Academy of Engineering, Director of the State Key Laboratory of Component-based Chinese Medicine, awarded National Excellent Communist Party Member, Deputy Chief Engineer of National Major Scientific and Technological Special Project for “Innovation and Formulation of Significant Novel Medicine”, Academic Leader of National Key Disciplines of Internal Medicine of TCM, Vice Chairman of Medical Education Expert Committee, Ministry of Education (China), Deputy Director of the Eleventh Pharmacopoeia Committee, Vice Chairman of the World Federation of Chinese Medicine Society (WFCMS), Director Committee Member of TCM Education Steering Committee

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(WFCMS), Honorary President of the Chinese Association of Integrative Medicine, Vice President of Chinese Medical Association, Vice President of China Association of Chinese Medicine, and President of World Association of Chinese Doctors. He has been engaged in clinical practice, scientific research, and educational work relating to TCM for decades. He has won 7 National Science and Technology Awards, including first prize for National Science and Technology Progress, 10 provincial and ministerial Science and Technology Progress Awards, and first prize at the National Teaching Achievement Awards on two occasions. He has published more than 400 papers, and mentored over 300 postdoctoral fellows, PhD and Master’s students. He has been awarded special government allowances issued by the State Council and has won the National Innovation Award, Guanghua Engineering Science and Technology Prize, Ho Leung Ho Lee Foundation Award, Wu Jieping Medicine Prize, the Shulan Medical Prize, and the Tianjin Municipal Science and Technology Achievement Award. His awards also include honorary titles of National Outstanding Professional and Technical Talent, National Advanced Workers, National Outstanding Scientific and Technological Workers, and National-level Young and Middle-aged Experts with Outstanding Contributions. He was an expert committee member of the Central Steering Group that went to Wuhan to participate in the 82-day quest against the epidemic, during which time he chaired the group as it formulated the treatment plan of integrated traditional Chinese and Western medicine and guided the whole process of TCM to intervene in the treatment of COVID-19. In 2020, he was awarded the honorary title of the national honorary title, “The People’s Hero”. Moreover, he also fought the epidemic in Hebei for 20 days, where he summarized the characteristics and measures of epidemic prevention and control in rural areas, which provided a basis for decision-making in the formulation of a rehabilitation plan using integrated traditional Chinese and Western medicine.

About the Editors  ix

Liu Qingquan holds the following positions: President of Beijing Hospital of Traditional Chinese Medicine, Chief Physician and Supervisor for doctoral students, Deputy Leader of the Expert Group of National Administration of TCM for the Joint Prevention and Control of COVID-19 epidemic, Chairman of Emergency Professional Committee of China Association of Chinese Medicine, and President of WFCMS for Infectious Control Committee. He has presided over 10 projects such as the 13th Five-Year Plan, Science and Technology Support Program of the 12th FiveYear Plan, the “Major New Drug Creation and Development” project, and the projects of the National Natural Science Foundation of China. He has published more than 100 papers as the first author or corresponding author, including 14 SCI papers and 11 monographs, and he has also won 23 patents. He has edited the planning textbooks for national institutions of higher education for TCM in the New Century, the 10th Five-Year plan, Emergency Medicine of TCM, the 12th Five-Year plan for the former National Health Commission, and the teaching materials of national universities for TCM Emergency and Critical Care Medicine of TCM. He won the first prize of the Beijing Science and Technology award and the third prize at the Science and Technology Progress of China Association of Chinese Medicine Program.

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Foreword by Zhong Nanshan The sudden COVID-19 outbreak at the end of 2019 has evolved into a “global pandemic” due to its widespread infectivity and strong pathogenicity. At present, the number of people infected with SARSCoV-2 worldwide has exceeded 100 million, marking the largest public health crisis facing mankind in the last hundred years, which is of unprecedented difficulty. Since the outbreak of the epidemic, the Party and the Government have made protecting the people’s lives and health the top priority. They have accurately judged, taken decisive decisions, and united the whole nation to work together in the fight against the epidemic. At present, China’s epidemic prevention and control has achieved phased victory, and the situation of accelerating the recovery of the production and life order has been continuously consolidated and expanded. TCM has played an outstanding role in the history of the Chinese nation in the battle against epidemics. This has allowed China to accumulate a rich experience in prevention and control and form a unique theoretical system which is of great value in the fight against infectious diseases. In recent years, TCM has played an irreplaceable role in addressing respiratory public health events caused by viruses such as Severe Acute Respiratory Syndrome (SARS) in 2003 and Influenza A virus subtype H1N1 in 2009. In the course of battling the COVID-19 epidemic, TCM intervened early, thoroughly, and deeply in the prevention, control, and treatment of the epidemic, and

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the intensity and breadth of its participation were also unprecedented. Traditional Chinese and Western medicine fought the epidemic side by side and complemented each other with their advantages, jointly improving the treatment concept and plan of integrated traditional Chinese and Western medicine for COVID-19. The integration of TCM and Western medicine has become a distinctive characteristic in China’s anti-epidemic treatment experience and has thus developed a mechanism for further integration of TCM and Western medicine in the prevention and control of major epidemics and in maintaining and assuring the health and life of the people. Academician Zhang Boli and Professor Liu Qingquan led the TCM team to Wuhan for medical support, and devoted themselves on the front line to Wuhan’s fight against COVID-19. The early intervention of TCM and its participation throughout the whole process were actively promoted by Academician Zhang Boli and Professor Liu Qingquan. Both were personally involved in winning the battle against COVID-19 and achieved conclusive results at Wuhan and Hubei. The book Diagnosis and treatment of COVID-19 with Integrated Chinese and Western Medicine is based on the clinical anti-epidemic data from the front line, which combines theory with practical experience, and especially highlights the characteristics of combining TCM and Western medicine. This book not only elaborates on the etiological characteristics, pathogenesis, epidemiological characteristics, clinical diagnosis, treatment, prevention, rehabilitation, clinical drugs, and research progress of COVID-19 but also summarizes the fundamentals, syndrome differentiation, treatment principles, and prescriptions of COVID-19 from a TCM perspective. The book also summarizes the advantages of integrated Chinese and Western medicine, the diagnosis and treatment mode in TCM makeshift hospitals, and discusses the organically combined mode of TCM and Western medicine from multiple perspectives of prevention, diagnosis, treatment, rehabilitation, prevention, and control management in treatment and prevention of COVID-19. Against the background of the current global pandemic of COVID-19, this book summarizes the clinical experience of China’s fight against COVID-19, improves and optimizes Chinese treatment

Foreword by Zhong Nanshan  xiii

featuring integrated traditional Chinese and Western medicine, placing equal emphasis on both, and helps to consolidate China’s experience in the global fight against the epidemic. We also look forward to TCM making greater contributions to the fight against the epidemic globally! Zhong Nanshan Academician of the Chinese Academy of Engineering Head of the Senior Expert Group of the National Health Commission Director of National Clinical Research Center for Respiratory Disease March, 2021

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Foreword by Wang Chen In the millennia of developmental history of human society, infectious diseases have always profoundly affected human beings and the evolution of civilization. Since ancient times, infectious diseases have constantly threatened human survival, transformed historical ruts, reshaped human social structure, impacted economic and cultural foundations, and affected the prosperity or decline of nations, included victories and defeat in wars, political reformation, the development of civilizations, and scientific and technological advances. Although the 20th century is an era of rapid development for modern medicine and technology, novel infectious diseases such as influenza, bubonic plague, malaria, HIV/AIDS, SARS, and Ebola have never been far away from humans. The mortality caused by various infectious diseases was greater than the deaths caused by wars. The history of human development, in a manner, is a history of the continuous struggle and battle against infectious diseases. We still vividly remember the SARS epidemic in 2003, when SARSCoV-2 arrived abruptly at the beginning of the Gengzi Year. Within a few months, the epidemic intensified and rapidly exploded worldwide. The sudden COVID-19 outbreak became the worst global crisis faced by human society in the 21st century, of unprecedented breadth and depth. Even today, the COVID-19 epidemic is still raging around the world, and its impact is still being felt. In the face of such a novel disease, we should be fully prepared to coexist with it,

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and plan for long-term prevention and control with a positive attitude. As the first country to experience the outbreak of COVID-19, China adopted unprecedented and strict measures to achieve effective control of the epidemic by the courageous devotion of all, under the strong deployment of the Party and the government. As Director-General Tedros Adhanom Ghebreyesus of the World Health Organization (WHO) pointed out, China has contained 99% of the disease within the country, which has created a valuable window for the international community to jointly tackle the epidemic and also set a new benchmark internationally in the field of epidemic prevention. This extraordinary experience and the achievement of fighting the epidemic reflect the immense respect of Chinese culture for life and health and highlight the advantages of the Chinese system and national power. At the same time, the actions and noble professionalism of the medical personnel as well as the adamant pursuit of scientific researchers greatly contributed to the battle against COVID-19. TCM and Western medicine battled alongside on the front line of COVID-19 toward a common goal and belief in saving lives, as well as realizing their complementary benefits, strengths, and interactions. This displayed the positive impact that the integrated Chinese and Western medicine had on major epidemic treatment, and this profoundly enlightened China on the future of medical defense. The complementary and coordinated development of TCM and Western medicine is an important feature of China’s medical and health undertakings. Academician Zhang Boli and Professor Liu Qingquan led the TCM team to make great efforts in the treatment protocol during the epidemic in Wuhan and actively promoted the work of TCM in the prevention and control mechanism, diagnosis, treatment, protocol formulation, emergency management, scientific research, and development of the epidemic. This has noted down a very important piece of experience for China’s anti-epidemic rescue and treatment. Based on various aspects of prevention, diagnosis, treatment, and

Foreword by Wang Chen  xvii

rehabilitation, this new book Diagnosis and Treatment of COVID-19 with Integrated Chinese and Western Medicine expounds the basic concept, epidemiological research, diagnosis methods, studies on prevention, research and development on drugs and vaccines, and the progress of medical development to systematically and thoroughly interpret the fundamentals, diagnosis, treatment methods, clinical experience, drug research, and development of TCM during the COVID-19 pandemic. This book is a phased summary of China’s current anti-epidemic work. I believe that the compilation and publication of the book will contribute to the prevention and control of the ongoing COVID-19 epidemic. Wang Chen Academician of the Chinese Academy of Engineering Vice-president of Chinese Academy of Engineering President and Principal of Chinese Academy of Medical Sciences & Peking Union Medical College March, 2021

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Foreword by Li Lanjuan Under the wise decision-making and strong leadership of the Party and the government, and with the support and cooperation of the country, we have currently achieved a phased victory in the prevention and control of the COVID-19 epidemic in China. During the epidemic, the participation of TCM was unprecedented. More than 4,900 TCM medical personnel were on the front line. These frontline workers treated COVID-19 patients, set up TCM wards, and determined designated hospitals such as Hubei Provincial Hospital of Integrated Chinese and Western Medicine and Wuhan Hospital of TCM. The Jiangxia Makeshift Hospital was built to provide patients with systematic and standardized TCM treatment, and has achieved satisfying results. In the absence of specific drugs and vaccines, the early intervention of TCM was carried out in an orderly manner on a large scale for the first time. These inaugural events include the comprehensive management of a hospital, the takeover of the hospital wards, using both TCM and Western medicine throughout inspection and ward rounds, as well as thorough intervention in the treatment of severe and critical patients. All this helped in the exploration and formulation of a systematic treatment plan using a combination of traditional Chinese and Western medicine and screening of the “three medicines and three formulas”. TCM service covered the whole process of prevention, treatment, and rehabilitation. This is a vivid practice of the inheritance and innovation of TCM, and using integrated traditional Chinese and xix

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Western medicine as a treatment plan has also become the highlight of China! The sole purpose of both TCM and Western in the treatment of COVID-19 is to cure and save the lives of people. There is implicit understanding between the complementary aspects of traditional Chinese and Western medicine, which has proved that traditional Chinese and Western medicine can be well combined in the treatment of a major epidemic. It is China’s national healthcare policy to apply both traditional Chinese and Western medicine and to put equal emphasis on them. Both sets of medicine have their own merits, which can complement each other, and one cannot be replaced by the other. Utilizing the strengths of the two sets of medicine is the basis of the health care system with Chinese characteristics, for the well-being of China’s population. Academician Zhang Boli and Professor Liu Qingquan, experts from the Central Steering Group and leading figures in the field of TCM, fought the epidemic in Wuhan for more than 80 days and witnessed the whole development process of the epidemic. Academician Zhang first proposed an approach involving the integration of TCM and Western medicine as the way forward for the treatment of the COVID-19 epidemic. The two experts actively offered suggestions to the Central Steering Group, participated in the formulation of the country’s national version of the diagnosis and treatment plan, and went into the “Red Zone” to personally provide diagnosis and treatment for COVID-19 patients. The Jiangxia Makeshift Hospital, which they led, received a total of 564 mild and moderate patients. The comprehensive integrated TCM treatment was adopted, which achieved remarkable results in improving symptoms, promoting immune function repair, and shortening the time of nucleic acid tests turning negative, and achieved zero cases of mild cases turning severe. From the fundamental concept, epidemiology, clinical diagnosis, treatment, rehabilitation, and prevention to the introduction of makeshift hospitals, drug research, and international progress, the book Diagnosis and Treatment of COVID-19 with Integrated Chinese and Western Medicine illustrates the in-depth knowledge of

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COVID-19 and the combined treatment of TCM and Western medicine from multiple aspects in a simple way. In particular, it introduces in detail how the advantages of TCM can be fully utilized as treatment in all stages of COVID-19 so as to present readers with a brilliant view of TCM’s anti-epidemic fight, which is an alternative “paradigm” of anti-COVID-19 work. Li Lanjuan Academician of the Chinese Academy of Engineering Director of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases March, 2021

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Preface At the end of the Yihai Year and in the early days of the Gengzi Year, the COVID-19 epidemic spread rapidly around the world. Due to its strong infectivity, extraordinary concealment, rapid transmission speed, multiple transmission routes, and the general susceptibility of the population, COVID-19 became the most urgent and serious challenge to human health and the world’s peace. At present, COVID-19 has spread across more than 200 countries and regions, and the global epidemic is characterized as a “pandemic”, with its transmission degree and severity far exceeding expectation. The World Health Organization (WHO) has pointed out that the COVID-19 epidemic is a once-in-a-century health crisis, and its impact will linger for decades. China, being the first country to be impacted by the COVID-19 epidemic, faced an unprecedented challenge. Under the strong leadership of the Party and the government, China was able to form an accurate and objective judgment of the epidemic situation, with a series of targeted, effective, and strict prevention and control measures implemented, alongside national unity and solidarity in the fight against COVID-19. The resolution to curb the spread of the epidemic was fully affirmed by the international community. At present, China’s situation has entered a normalcy phase of “preventing recurrence internally, preventing imported cases externally”. However, the global epidemic situation is still extremely grim.

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TCM has a long history in the fight against epidemics. In the centuries of Chinese civilization, the Chinese nation has experienced more than 300 epidemic ordeals and has accumulated a rich experience in prevention and control. In this fight against the epidemic, TCM has intervened in the early stage and participated throughout the whole process, playing an important role in every stage and becoming the highlight of China’s fight against the epidemic. The TCM team of nearly 5,000 medical personnel rushed to support Hubei Province in administering treatment plans upon clinical classification, supplementing manpower in hospitals, setting up makeshift hospitals, taking over the intensive care units as an organizational system, and intervening thoroughly in the treatment of patients who had severe or critical symptoms under the guidance of the Central Steering Group and the national emergency deployment of administering TCM. This groomed a team of accountable and responsible TCM practitioners. At the same time, integrated traditional Chinese and Western medicine was explored as a new path in dealing with public health emergencies, that is, to intervene in the early stage, adopt treatment plans based on clinical classifications, and apply strategies based on scientific evidence aimed at the prevention, treatment, and rehabilitation of COVID-19 patients. The simultaneous focus on the development of clinical treatment, new drug discovery, and scientific and technological breakthroughs was realized by the coordinated efforts of the frontline and technical backend personnel, as well as the “three medicines and three formulas” as proposed for the prevention and control of COVID-19. As the epidemic heats up overseas, TCM is actively supporting the global fight against the epidemic, by taking the initiative to cooperate with the World Health Organization (WHO), sharing the experience of TCM in the fight against the epidemic, donating Chinese medicines, and sending TCM practitioners to participate in medical expert teams overseas to assist in the fight against the epidemic. This also contributed to the world the wisdom of TCM and allowed the voice of TCM to be heard. The COVID-19 epidemic is a practical test for TCM, and its advantages in the prevention and control of major epidemics have once again gained the attention of the world. President Xi Jinping

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indicated, “Applying and integrating traditional Chinese and Western medicine is a major feature of the prevention and control of the epidemic, as well as a vivid practice of the inheritance of TCM essence and innovation.” Under the increasingly complex situation of the global epidemic at present, there is much practical significance in summarizing the existing research progress and fundamental understanding of COVID-19, as well as in sorting out the measures, experiences, and achievements of using integrated traditional Chinese and Western medicine. Academician Zhang Boli and Professor Liu Qingquan, chief editors of this book and experts of the Central Steering Group, led the TCM national team to fight against the epidemic on the front line in Wuhan for more than 80 days. They took on the responsibility of multiple tasks, which included administering TCM and integrated traditional Chinese and Western medicine treatments, formulation of the treatment protocol, and guidance and management of COVID-19 patients. They also undertook multiple clinical and basic studies in the prevention and control of COVID-19. The editorial board of the book includes numerous frontline clinical experts and scientific research team members. Based on the existing medical evidence, combined with the anti-epidemic experience on the front line, we collated the etiological, epidemiological, and clinical characteristics of COVID-19, as well as the diagnostic methods and clinical classification, Western medicine treatment modalities, and its application from a professional perspective. We introduced the fundamental understanding of COVID-19 in a systematic manner from the TCM perspective, such as etiological characteristics and pathogenesis, syndrome characteristics, clinical stages, main points of syndrome differentiation, prognosis, and sequelae. We paid attention to and tracked the hot spots and new progress of COVID-19 from the point of view of prevention studies, clinical drugs and emerging therapies, disease complications and sequelae, international epidemic prevention, and other aspects. Based on first-hand information, we introduced and presented the treatment of integrated traditional Chinese and Western medicine in rehabilitation care, as well as the diagnosis, treatment, and management modes of

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COVID-19 patients in makeshift hospitals. At the same time, this book also introduces our team’s experience in drug evaluation and new drug research and development, in an objective manner clearly based on scientific evidence. We have a long way to go in addressing the global public health crisis of the COVID-19 pandemic. Mankind may face the new norm of long-term coexistence with COVID-19 in the future, and this highlights the urgency and importance of building a community of shared future for mankind. The final victory can only be realized by the joint response, mutual support, unity and cooperation, and timely sharing of resources, experiences, and lessons. In China’s unprecedented battle in the overall prevention and control of the epidemic, TCM has effectively played an important role and is a major feature and highlight. The preparation of this book started on the front line in Wuhan, and it took several months and several drafts to summarize and sort out a great deal of experience and achievements of integrated traditional Chinese and Western medicine as we hoped to provide valuable references for the fight against the COVID-19 epidemic in China. Despite careful preparation and multiple discussions and exchanges of ideas, due to the time constraint and the limited research and understanding of COVID-19, we are afraid that there are inevitable shortcomings and omissions. We sincerely hope that our peers will send us their criticisms and corrections! Here, we sincerely thank academicians Zhong Nanshan, Wang Chen, and Li Lanjuan who have worked on the front line in fighting the epidemic and have graciously provided the prefaces to this book. We also want to express our gratitude to the frontline medical staff and Wuhan medical staff, who have accumulated practical experience through their hard work, and the Ministry of Science and Technology for approval of the project “Clinical Research on Integrated Traditional Chinese and Western Medicine Prevention and Control of COVID-19”, which is the basis for this book. A special thanks also to our frontline and technical backend teams for their excellent work!

Contents Editorial Boardv About the Editorsvii Foreword by Zhong Nanshanxi Foreword by Wang Chenxv Foreword by Li Lanjuanxix Prefacexxiii Chapter 1  General Introduction

1

1.  An Overview 1 1.1  Etiological characteristics 5 1.2 Pathogenesis 6 1.3  TCM understanding of COVID-19 9 2.  Epidemiological Characteristics 10 2.1  Source of infection 10 2.2  Route of transmission 10 2.3  Susceptible population  12 2.4  Incubation and infectious period 12 2.5  Demographic characteristics 13 2.6 Correlation and distinction between SARS and COVID-1917 3.  Clinical Characteristics 20 3.1  Clinical manifestations 20 3.2  Laboratory examination 21

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3.3  Imaging findings 3.4  Pathological characteristics Chapter 2  Clinical Diagnosis 1.  Diagnostic Criteria and Clinical Classification 1.1  Diagnostic testing and inspection technology 1.2  Diagnostic criteria 1.3  Clinical classification 1.4 Early warning indicators for severe/critical illnesses 1.5  Differential diagnosis 1.6  Diagnostic procedure 2.  Nucleic Acid Testing 2.1  Testing principle 2.2  Sample collection 2.3  Diagnostic criteria 2.4  Limitations of nucleic acid test 3.  Serological Testing 3.1  Testing principle and method 3.2  Sample collection 3.3  Diagnostic criteria 3.4 Interpretation of the joint test results of nucleic acid and serology 3.5  Limitations of serological testing 4. Re-positive Patients, Persistent Positive Patients, Asymptomatic Patients, and Reinfected Patients 4.1  Re-positive COVID-19 patients 4.2  Persistent positive COVID-19 patients 4.3  Asymptomatic COVID-19 patients 4.4  Reinfected COVID-19 patients Chapter 3  Western Medicine Treatment

22 23 27 27 27 29 30 32 36 38 39 40 41 42 43 44 44 46 46 47 49 50 50 52 53 56 59

1.  Principles of Treatment 59 1.1 Determining the treatment site according to the condition59 1.2 Treatment principles of mild and moderate cases 59

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1.3 Treatment principles of severe and critical cases 1.4  Treatment principles of special populations 2.  Western Medicine Treatment   2.1  Supportive treatment   2.2  Antiviral treatment   2.3  Antimicrobial treatment   2.4  Hormone therapy   2.5  Intestinal microecologics   2.6  Convalescent plasma therapy   2.7  Artificial liver treatment   2.8 Immunotherapy   2.9 Continuous renal replacement therapy 2.10  Notes for medication use for special population Chapter 4  TCM Treatment 1.  An Overview 1.1  Basic understanding 1.2 Etiology 1.3  Pathogenesis and nature of the disease 1.4  Syndrome characteristics 1.5  Treatment principles 1.6  The dominant role of TCM 2.  TCM Treatment 2.1  During medical observation 2.2  During clinical treatment (confirmed cases)

61 63 64 64 72 77 78 79 79 84 86 88 90 95 95 95 96 97 98 101 104 109 109 114

Chapter 5  Complications, Sequelae, and Long-Term Symptoms135 1.  Mechanisms of Injury 2.  Relevant Organ and System Injury 2.1  Immune dysfunction and coagulation disorder 2.2  Cardiovascular injury 2.3  Pulmonary dysfunction 2.4  Neurosystem influence 2.5  Liver and kidney function injury

136 137 137 140 141 142 143

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2.6  Reproductive system injury 145 2.7  Psychological disorders 146 2.8  Special groups 147 3.  Long-Term Symptoms 150 4. Understanding and Effect of TCM on the Complications, Sequelae, and Long-Term COVID 152 Chapter 6  The Rehabilitation Treatment of Integrated Traditional and Western Medicine

157

1.  An Overview 157 2.  Management Objectives and Principles 159 2.1  Objective of rehabilitation 159 2.2  Object and place of rehabilitation 160 2.3 Principles of rehabilitation diagnosis and treatment160 3. Rehabilitation Diagnosis and Treatment Procedures and Evaluation 161 3.1 Rehabilitation diagnosis and treatment procedures161 3.2  Rehabilitation assessment 162 4.  Rehabilitation Treatment 164 4.1  Rehabilitation interventions 164 4.2.  TCM rehabilitation 175 4.3  Psychological rehabilitation treatment 181 4.4 Notes 184 Chapter 7  Prevention185 1. Lifestyle 185 1.1 Pay attention to personal protection and achieve two “less”, two “frequently”, and two “smooth” 185 1.2 Maintain a healthy lifestyle and improve resistance187 1.3  Health monitoring and timely medical treatment 189 2.  Comprehensive Prevention of TCM 189 2.1  Acupoint application 189

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2.2  Acupuncture treatment 2.3  Auricular therapy 2.4  Massage and scrapping therapy 2.5  Traditional health-maintaining method 2.6  Medicinal diet therapy 2.7  Mental guidance 3.  The Prevention of Chinese Medicinals 3.1  Decoction or substitute of tea 3.2  Prescriptions for external use 4.  Vaccine Development 4.1  What is a vaccine? 4.2 Progress in the research and development of COVID-19 vaccines in China

189 190 190 192 192 193 193 194 196 198 198 199

Chapter 8 Diagnosis and Treatment Standards of Traditional Chinese and Western Medicine in a Makeshift Hospital205 1.  An Overview of Makeshift Hospital 205 2.  Management Principles 206 3. Standards for Admission and Pre-examination and Triage of Patients 207 3.1 Standards for admission of patients in the makeshift hospital 207 3.2  Admission process of the makeshift hospital 207 3.3 Pre-examination and triage of the makeshift hospital208 4.  Treatment Measures 209 4.1 Closely monitor the vital signs and oxygen saturation209 4.2  General treatment 209 4.3  Oxygen therapy 210 4.4  Drug treatment 210 4.5  Management of severe patients 215 5. Standards and Procedures for Transfer and Discharge216

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5.1 Transfer standards for severe patients in the makeshift hospital 216 5.2  Transfer procedure of severe patients 217 5.3  Discharge standards 217 5.4  Discharge procedure 218 5.5  Disinfection procedure of discharged patients 218 6. Introduction of TCM Model of Jiangxia Makeshift Hospital219 6.1  Organizational structure and management mode 219 6.2  Treatment methods 222 6.3  Summary of curative effect  224 Chapter 9  Introduction to Clinical Drug Research 1.  Traditional Chinese Medicine 1.1  Screening of listed Chinese patent medicines 1.2 Construction of the core outcome set for clinical trials on COVID-19 1.3 The “three TCM drugs and three herbal formulas” recommended by the Diagnosis and Treatment Protocol 1.4  Other recommended Chinese patent medicines 2. Chemicals 2.1  Anti-viral drugs 2.2  Anti-malaria drugs 2.3  Anti-HIV drugs 2.4 Antibiotics 2.5  Immunotherapy drugs Chapter 10  International Progress

231 232 233 234

235 245 251 251 256 259 261 262 267

1.  An Overview of the International Popularity 267 1.1 The comparison between Spanish flu and COVID-19267 1.2  Timeline of the overseas epidemic 269 1.3  Local epidemic control situation 271 2.  International Assistance 279

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3.  Research on SARS-CoV-2 Characteristics  3.1  The virus structure 3.2  Virus mutation 3.3 Exploration of the origin of the virus 4.  Drugs, Vaccines, and Other Therapies 4.1  Drug research and development 4.2  Stem cell therapy 4.3  Vaccine research and development 4.4  Plasma therapy 4.5  Application of traditional Chinese medicine 5.  The Clinical Treatment of COVID-19 5.1  “Cytokine storm” 5.2  Prediction of disease development 5.3  Herd immunity and ADE 5.4  Other clinical findings 6.  Related Clinical Studies of COVID-19 7.  Clinical Drug Research 7.1 Remdesivir

283 283 285 286 288 288 288 289 292 293 294 294 297 298 300 302 303 303

Appendix A: Diagnosis and Treatment Protocol for COVID-19 Patients307 Appendix B:  COVID-19 TCM Syndrome Research and Analysis337 Appendix C: The Roles of TCM in the Prevention and Treatment of COVID-19345 Appendix D: Hot Issues Related to COVID-19 TCM Treatment (Questions & Answers) by Prof. Zhang Boli353 Bibliography 365

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Chapter 1

General Introduction 1.  An Overview The coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by an infection of SARS-CoV-2. As an acute respiratory infectious disease, it has been included in the Class B infectious diseases stipulated in the Law of the People’s Republic of China on Prevention and Control of Infectious Diseases and is managed as a Class A infectious disease. On March 11, 2020, the World Health Organization (WHO) declared COVID-19 as a global pandemic. As of December 2020, the COVID-19 epidemic had spread across more than 200 countries and regions, with over 80 million confirmed cases worldwide, causing nearly 600,000 deaths. Since December 27, 2019, when Hubei Provincial Hospital of Integrative Medicine reported unexplained pneumonia cases to Wuhan Jianghan District Center for Disease Control and Prevention (CDC), the National Health Commission had organized several visits to Wuhan by sending a national high-level medical expert group for onsite inspection of the epidemic prevention and control work. On January 19, the human-to-human transmission of SARS-CoV-2 was confirmed. China took key measures to curb the transmission of the virus, and resolutely and decisively closed the borders of Wuhan and Hubei to protect the city and province in an all-round approach. On January 27, 2020, the Central Steering Group was stationed in

1

2  Diagnosis and Treatment of COVID-19

Wuhan to reinforce the guidance on epidemic prevention and control at the front line in a comprehensive manner. Since February 2, 2020, under the guidance of the Central Steering Group, patients were triaged and classified into four categories. Patients were managed centrally according to the “Four response” requirements, i.e., all suspected and confirmed patients should be (i) admitted to the hospital; (ii) treated; (iii) screened; and (iv) quarantine. This was in coordination with the strict implementation of the “Four early” measures, i.e., early detection, early reporting, early quarantine and early treatment, whereby the three tough battles of mass screening, centralized admissions and treatment, and thorough investigation were continuously carried out. The national emergency medical rescue team has been mobilized successively to establish makeshift hospitals. Suspected cases of patients who developed a fever or were close contacts of COVID-19-infected patients were placed under centralized quarantine. This effectively suppressed the spread of the epidemic. For the confirmed cases, the treatment sites were determined according to the clinical classification and severity of illness, to be treated in either designated hospitals or makeshift hospitals. People who were well could prevent the spread of COVID-19 by taking active preventive measures and maintaining a healthy lifestyle such as having fewer social gatherings, maskwearing, frequent handwashing, and keeping the area well-ventilated. By February 18, 2020, the number of newly confirmed cases began to decline nationwide, and in mid-March, the daily number of newly confirmed local cases reported progressively declined and reached single digits. On April 10, patients treated in Hubei Province who were severely ill or in critical condition decreased to double digits for the first time. All hospitalized cases of COVID-19 in Wuhan were discharged by April 26, 2020, and the national epidemic prevention and control was normalized. Since the epidemic outbreak in Wuhan, the local epidemic was brought under control and achieved phased strategic results. However, the cluster outbreak at the Beijing Xinfadi Wholesale Market on June 11, 2020, led to local sporadic cases and more cluster outbreaks in various parts of China, such as Heilongjiang, Jilin,

General Introduction  3

Liaoning, Dalian, Beijing, Qingdao, Xinjiang, Shanghai, Tianjin, Anhui, Inner Mongolia, and Chengdu. The characteristics of the epidemic situation in various places encompassed a broad scope, presented by multi-point distribution, localized outbreaks, and the ability to transmit rapidly. The cases were mainly imported and appeared to have human-to-human transmission. The transmission became prevalent in rural areas of Hebei, Jilin, Heilongjiang, and other regions at the end of 2020, affecting a large group of elderly people and children. In some areas, community and multi-generation transmission had occurred. There was an increase in asymptomatic COVID-19-infected patients and a prolonged incubation period of SARS-CoV-2. This resulted in some patients initially testing negative for the nucleic acid test, but later testing positive after related symptoms appeared or subsequently testing positive with SARS-CoV-2 antibodies. As the current detection technology, i.e., Polymerase Chain Reaction (PCR) test, cannot achieve 100% accuracy, it suggests the complexity of the SARS-CoV-2 infection. However, by combining nucleic acid and COVID-19 serology detection tests, the accuracy of SARS-CoV-2. being detected can be improved to reduce the risk of false negative or false positive results from nucleic acid PCR tests. This has contributed to the prevention and control of the epidemic. The epidemic situation in other countries worldwide were of high severity, as compared to the local sporadic infection situation. On January 13, 2020, the first COVID-19 confirmed case was reported overseas. In February, a collective outbreak and transmission occurred in cruise ships from Japan and church organizations in Korea, followed by community-transmitted infections that occurred in Iran and Southeast Asian countries. Italy was the first European country to have a massive COVID-19 outbreak. In late March 2020, the United States (US) reported more than 10,000 confirmed COVID-19 cases, and by this time, all European countries had reported confirmed COVID-19 cases. Although the first wave of the epidemic overseas subsided in June 2020 due to stringent prevention and control measures, many countries rushed to reopen their borders in order to restore economic activities, leading to the second wave of

4  Diagnosis and Treatment of COVID-19

the epidemic in August and September of the same year with a higher infection rate than the first epidemic wave. Countries affected by the second wave included the US, France, Spain, Italy, Belgium, Germany, the Czech Republic, the United Kingdom, Australia, Japan, South Korea, Vietnam, Malaysia, and Thailand. “Dampness-toxin pestilence” makes up the main understanding of COVID-19 from the traditional Chinese Medicine (TCM) perspective. COVID-19 presents the characteristics of concealment at the onset of the disease, has a lingering effect, and is constantly changing. In terms of treatment, TCM is offered to all suspected cases under centralized quarantine. For confirmed COVID-19 cases, treatment plans of integrated traditional and Western medicine are formulated according to the clinical classification and the degree of disease severity. The therapeutic effect is optimized by giving full play to the respective advantages of TCM and Western medicine. During this epidemic, the Jiangxia Makeshift Hospital was established, which was dominated by TCM treatment, admitting mild and moderate COVID-19 patients, and it achieved excellent records of zero COVID-19 cases turning severe, zero re-positivity, and zero medical staff being infected with COVID-19. Starting from the third edition of the Diagnosis and Treatment Protocol for COVID-19 Patients, the National Administration of TCM participated in organizing the compilation of the guiding principles of TCM diagnosis and treatment. It was later revised and improved when more information were shared and COVID-19 was better understood, and was subsequently updated to the 8th edition. Each edition of the diagnosis and treatment protocol has played an important role in guiding the treatment of COVID-19. The guidelines of the third edition are relatively simple, easy to flexibly adjust and modify according to different syndromes, and can be used for reference. The several editions of TCM protocol refined the application scope of prescriptions and dosages, but did not account for the differences in climate and geographical environment and the changes in syndrome characteristics derived from it. Therefore, their clinical applications were consolidated and recognized to lack

General Introduction  5

flexibility, which led to some difficulties in promoting implementation across the country. With the advancement of research, there is a deeper understanding of COVID-19, such as its etiological characteristics and pathogenesis. A series of clinical studies on the effectiveness and safety of COVID-19 treatment have also been actively conducted.

1.1  Etiological characteristics SARS-CoV-2 is a novel variant of the coronavirus family that has been proven to belong to the Sarbecovirus subgenus of type b coronavirus through genome sequencing analysis. SARS-CoV-2 has an envelope, its particles are round or oval, measuring 60–140 nm in diameter, and its genome length is about 29 kb, which is similar to that of the Severe Acute Respiratory Syndrome Coronavirus (SARSCoV) from 2003 and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) from 2012. SARS-CoV-2 has an 85% homology with SARS-CoV (bat-SL-CoVZC 45), separated from Rhinolophus sinicus (a species of Chinese Horseshoe Bat), and even 96% homology with the genome-wide nucleotides of the SARS-CoV RaTG13 strain. But it is unclear whether SARS-CoV-2 has other possible wildlife hosts and it is still under investigation. When separated and cultured in vitro, it was noticed that SARSCoV-2 could be found in human respiratory epithelial cells in around 96 h, while it took about 6 days to separate and culture SARS-CoV-2 in African green monkey kidney cells (Vero E6) and the human hepatoma cell line (Huh-7). Based on the understanding of the physicochemical properties of SARS-CoV and MERS-CoV, it is currently believed that SARS-CoV-2 is sensitive to ultraviolet and heat, i.e., 56°C for 30 min, ether, 75% ethanol, chlorine-containing disinfectants, peracetic acid, and chloroform, which can effectively inactivate the virus. However, chlorhexidine cannot effectively inactivate the virus. Although the nucleotide homology between SARS-CoV-2 and human SARS-CoV is less than 80%, the amino acid similarity of seven conserved replicase domains in the open reading frame lab

6  Diagnosis and Treatment of COVID-19

(ORF lab) of coronavirus classification is 94.6%, indicating that SARS-CoV-2 and SARS-CoV may belong to the same species. In a study, 56 genomes of SARS-CoV-2 had low variability (>99% sequence consistency). However, because SARS-CoV-2 is a single positive-strand RNA virus, mutation and recombination may still occur in the environment or in vivo, and the toxicity may be enhanced or weakened during the mutation process. SARS-CoV-2 is the seventh coronavirus found to infect humans, and the viral genome sequence has been mapped (NCBI BioProject: PR-JNA485481), with 14 gene mutations as of August 2020. Through the study of the SARS-CoV-2 gene, it was found that the virus has mainly mutated into three different strains (type A, type B, and type C) during its transmission worldwide, with obvious regional population distribution characteristics. Among them, type A exists in the US, Australia, and in Americans living in Wuhan; type B mainly exists in Wuhan and other parts of China and East Asia; and type C mainly exists in European countries and other regions, and is also found in Hong Kong, Singapore, and South Korea. Based on published clinical gene data, the SARS-CoV-2 single-nucleotide polymorphism (SNP) differences show that new haplotypes (types L and S) may be formed, which can be used to distinguish clinical patients. Based on the different clinical phenotypes, high-throughput digital PCR technology and whole genome sequencing technology can obtain more subtype sequence data and establish subtypes corresponding to disease subtypes, which will be of great value for guiding clinical treatment.

1.2  Pathogenesis SARS-CoV-2, like SARS-CoV, enters the cell by binding to the angiotensin-converting enzyme 2 (ACE2) of the host cell. The spike protein binding region on the surface of SARS-CoV-2 has 73–76% similarity with the genome of SARS-CoV. Among them, the asparagine mutation of SARS-CoV-2 into threonine is one of the reasons for the significant improvement of the binding ability of SARS-CoV-2 to human ACE2 receptors. The team led by McLellan analyzed the

General Introduction  7

spike protein and ACE2 using surface plasmon resonance (SPR) technology and found that the equilibrium dissociation constant (15 nmol/l) between SARS-CoV-2 surface spike protein and ACE2 was much lesser than that of SARS-CoV (325.8 nmol/l), and the affinity of ACE2 protein to SARS-CoV-2 surface spine protein was 20 times higher than that of SARS-CoV. This was further proven by SPR analysis, suggesting that the infectivity of COVID-19 in human-tohuman transmission was significantly higher than that of SARS. ACE2 is commonly expressed in alveolar epithelial cells. During a viral infection, the expression of ACE2 is down-regulated by a combination of virus S protein and ACE2, leading to elevated angiotensin II (Ang II) levels. The signal is transmitted by Ang II type 1 receptor (AT1R), which increases pulmonary vascular permeability, leading to lung damage, and causing acute respiratory distress syndrome (ARDS). Due to the high expression of ACE2 in myocardial cells, renal proximal convoluted tubule epithelial cells, bladder epithelial cells, and even the esophagus and ileum, the latest research showed that SARS-CoV-2 might also affect circulation, and the urinary and digestive systems, resulting in multiple-organ dysfunction and even organ failure in critical patients. At present, patients with underlying condition of renal insufficiency are more common among the COVID-19 confirmed cases, and they are prone to kidney failure and death. Patients with myocardial injury may be associated with hypoxemia, respiratory failure, inflammation, and viral infection, causing direct damage to the myocardium. Recently, cardiovascular complications have also become a major threat to COVID-19 patients. In COVID-19 patients, 8–28% of them had troponin release in the early stage of onset, which is associated with myocardial injury. Due to the binding of the virus to the ACE2 receptor, it leads to the activation and damage of endothelial cells, which may eventually lead to the destruction of the antithrombotic state. Endothelial cells release pro-inflammatory cytokines, leading to microcirculation disorders. Proinflammatory cytokines associated with COVID-19 and the activation of the coagulation mechanism and elevated plasma concentrations may be

8  Diagnosis and Treatment of COVID-19

reasons for the increase in the D-dimer level. An elevated D-dimer level can be seen in many diseases other than thromboembolism. Endothelial dysfunction is a major factor in microvascular dysfunction, whereby the altering of vascular homeostasis causes vasoconstriction, followed by organ ischemia, inflammation, edema of relevant tissues, and a procoagulant state. The existence of microangiopathy and microthrombosis will also make patients prone to microinfarction in the liver, heart, kidneys, and other organs, further aggravating the state of multiple-organ damage and failure. It has been found in the analysis of blood samples from COVID19 patients that SARS-CoV-2 is similar to SARS and MERS in that they can cause Th1 response and proinflammatory release in patients. However, increased levels of interleukin-4 (IL-4) and interleukin-10 (IL-10) are also found in COVID-19 patients, indicating that their Th2 response inhibiting inflammation is also enhanced to some extent. Clinical studies have shown higher levels of inflammatory factors (such as interferon, interleukin, colony-stimulating factor, and tumor necrosis factor) in the plasma of COVID-19 patients. The COVID-19 infection also initiate a “cytokine storm” and over-activation of immune cells, which is activated and recruited in the lungs, causing diffuse damage to pulmonary capillary endothelial cells and alveolar epithelial cells. The accumulation of a large amount of exudate blocks the airway, causing the rapid deterioration of the pulmonary function and leading to ARDS and respiratory circulatory failure. The analysis of blood samples of critical COVID-19 patients also showed a reduction of T lymphocytes in peripheral blood, mainly CD4+ T lymphocytes and CD8+ T lymphocytes in vivo. Injury to T lymphocytes can cause viral particles to spread through the respiratory mucosa and infect target cells, triggering “cytokine storms” and a series of immune responses, which rapidly develop into uncontrolled systemic inflammatory response syndrome (SIRS), accompanied by shock, vascular leakage, disseminated intravascular coagulation (DIC), and multiple-organ failure (MOF). Hence, it is an important factor leading to the death of COVID-19 patients with severe illness.

General Introduction  9

1.3  TCM understanding of COVID-19 COVID-19 infection has the characteristics of rapid onset, rapid transmission, strong susceptibility, and epidemic, and belongs to the category of “pestilence” from the TCM perspective. Elements of the main syndrome comprise of “dampness”, “heat”, “toxin”, “blood stasis”, and “deficiency”, which may also be accompanied by “wind” and “cold” at the beginning stage of the disease. Among them, “dampness” is the first syndrome element of COVID-19, which is reflected in the Diagnosis and Treatment Protocol for COVID-19 issued by the National Administration of TCM and the TCM diagnosis and treatment plans issued by various provinces and cities. The disease is located in the lungs, followed by the spleen, stomach, and in severe cases in the heart and kidneys. As China has a vast territory, the climate conditions, as well as the lifestyles and physical characteristics of the people living in the north and south part differ greatly. Adhering to the principle of “treatment in accordance with three factors”, each region has combined local characteristics to refine the classification of syndrome elements of COVID-19 from different perspectives. For example, the protocol used in Shanxi Province defined the basic pathogenesis of COVID-19 as “cold, dampness, heat, and toxicity” and proposed to fully consider the cold and dry local climate at that time, hence “cold” should be one of the factors of pathogenesis. However, in Shanghai, Hainan, Guangdong, Sichuan, and other regions with a humid and hot climate, it was considered that the main pathogenesis of COVID-19 was “heat and dampness”. In addition, the pathogenesis of COVID-19 was affected by a variety of factors, with variability and complexity, and the syndrome type at different stages of the disease course was also different. At the beginning of the disease, the dampness pathogen can be accompanied by wind, cold, and heat. In the process of disease development, manifestations such as heat, cold and dryness formation may occur, and syndromes of blockade, collapse, and deficiency can be seen in critical cases. Therefore, the dynamic changes of “dampness, toxicity, cold, heat, blood stasis, and

10  Diagnosis and Treatment of COVID-19

deficiency” in different stages of COVID-19 should be fully considered. The corresponding laws were summarized with guidelines from the “treatment in accordance with three factors”, which is of great significance in the prevention and treatment of epidemics such as COVID-19.

2.  Epidemiological Characteristics 2.1  Source of infection The source of infection is mainly persons infected with SARS-CoV-2 and asymptomatic patients. Persons with latent infection who are asymptomatic are infectious during the incubation period and are highly contagious within five days after onset. Among them, specimens collected from the upper respiratory tract of prodromal and asymptomatic patients were tested PCR positive, and infectious viruses can be cultured six days before typical symptoms appear. The amount and duration of viral RNA in the upper respiratory tract of asymptomatic patients are similar to those of patients with distinct symptoms. In addition, the virus transmission from convalescent patients and re-positive patients is low. A study showed that viral RNA clearance in patients retested positive again was intermittent and unstable at a low level. After investigation of 96 close contacts of the 23 patients who retested positive again, all of the 96 close contacts were tested negative for SARS-CoV-2, hence it can be proven that the risk of COVID-19 transmission in patients retested positive again is low.

2.2  Route of transmission 2.2.1  Respiratory droplet transmission Transmission via respiratory droplets, particularly in direct close contact with infected persons is the main mode of transmission of COVID-19. Droplets from infected persons during coughing, sneezing, and talking can be transmitted to susceptible persons, resulting in infection after inhalation through the mouth and nose.

General Introduction  11

2.2.2  Indirect transmission Indirect transmission may occur when droplets containing the virus are deposited on surfaces, such as tables, chairs, mobile phones, and door handles and when a person touches the contaminated surfaces contaminated and his or her hand coming in contact with the mucosa membranes in the oral cavity, nasal cavity and eyes, resulting in an infection.

2.2.3  Faecal–oral transmission The route of faecal–oral transmission remains to be validated. Several COVID-19 patients in Wuhan and Shenzhen, and the first case in the US tested SARS-CoV-2 positive in their stool samples, suggesting the possibility of fecal-oral transmission. Since SARS-CoV-2 can be isolated from faeces and urine, contact transmission caused by its environmental contamination, or its re-transmission in aerosol form through droplets containing the virus, should be studied.

2.2.4  Aerosol transmission Aerosol transmission refers to the formation of droplet nuclei composed of proteins and pathogens due to the loss of water during the airborne suspension process, which float in the air in the form of aerosols and can spread over long distances. Under the condition of long-term exposure to high concentrations of aerosol in a relatively enclosed environment, may result in aerosol transmission. A study showed that the stability of SARS-CoV-2 and SARS-CoV is similar in aerosols, with a median half-life of 1.1–1.2 hours. Nevertheless, the overall transmission rate and secondary incidence of SARSCoV-2 suggest that aerosol or long-range airborne transmission is not the primary mode of transmission.

2.2.5  Vertical transmission It has been reported that while the throat swabs of newborns for COVID-19 were positive, whose mothers were diagnosed for

12  Diagnosis and Treatment of COVID-19

COVID-19 infection, the fetal tissue samples (such as amniotic fluid, umbilical cord blood, or placenta) were not directly detected for SARS-CoV-2, and it could not be confirmed that the COVID-19 infection of the newborn was caused by vertical transmitted infection. In a systematic review of 936 infants whose mothers have COVID-19 infections, only 27/936 (2.9%) of the nasopharyngeal specimens collected after birth or within 48 hours after birth were positive for neonatal viral RNA, indicating that congenital infection is rare. Another more common source of infection is the SARSCoV-2 shedding from maternal faeces (see “faecal–oral transmission” section), resulting in COVID-19 infection in infants. Postpartum transmission refers to the transmission from infected mothers (or other caregivers) to infants through breast milk intake or respiratory or other infectious secretions.

2.3  Susceptible population General susceptibility of the population: On 20 February 2020, the WHO report showed that among 55,924 confirmed COVID-19 patients, the age range was from two days old to 100 years old. The elderly and persons with underlying conditions such as asthma, diabetes, and heart disease had an increased risk of death after contracting the virus. High-risk population: Persons in close contact with COVID-19 patients and persons with latent infection are at high risk of SARSCoV-2 infection. Medical staff and family members of patients who are in close contact with infected patients involved in treatment, nursing and caring for the patients have a higher risk of infection.

2.4  Incubation and infectious period Based on a current epidemiological study, the incubation period is 1–14 days, typically 3–7 days. COVID-19 patients have a large quantities of viruses in the upper respiratory tract even when there are no distinct symptoms in the prodromal or early stage. During this period, the virus is highly infectious and toxic, and also highly

General Introduction  13

contagious. A study reported the temporal pattern of virus shedding in 94 laboratory-confirmed COVID-19 patients in China and simulated the infectious profile of COVID-19 using individual sample of 77 infector-infectee pairs. The results showed that the average sequence interval between the onset of symptoms was 5.8 days. The infectivity started 2-3 days and reached its peak at 0.7 days before the onset of symptoms respectively, and subsequently decreased within seven days. The infectious period can persist for about 7–10 days after the onset of symptoms. According to a multicenter study of 73 COVID-19 patients in Singapore, although the COVID-19 patients tested PCR positive on the 11th day after the onset of symptoms, the viral RNA could not be isolated or cultured into live viruses, suggesting that COVID-19 patients may no longer be infectious on the 11th day after the onset of symptoms.

2.5  Demographic characteristics 2.5.1  Age distribution and sex ratio According to a summary report from the Chinese Centre for Disease Control (CDC) on February 11, 2020, among the 72,314 cases in China, there were 44,672 confirmed cases (61.8%), 16,186 suspected cases (22.4%), 10,567 clinically diagnosed cases (14.6%), and 889 asymptomatic infected cases (1.2%). Among the confirmed cases, the age of patients ranged between 30 and 79 years old. The proportion of this age group in the total confirmed cases was 89.8% in Wuhan, 88.6% in Hubei (including Wuhan), and 86.6% in the whole country (including Hubei). The number of cases in the elderly group over the age of 60 was 44.1% in Wuhan, 35.1% in Hubei (including Wuhan), and 31.2% in the whole country (including Hubei). The ratio of male to female in these confirmed cases was 0.99:1 in Wuhan, 1.04:1 in Hubei, and 1.06:1 in China.

2.5.2  Distribution of the stage of disease COVID-19 can be categorised into mild, moderate, severe and critical stages. At present, it has been found that patients with mild or

14  Diagnosis and Treatment of COVID-19

moderate symptoms in China account for about 81% of COVID-19 confirmed cases, while patients with severe illness and in critical stage account for about 14% and 5% respectively.

2.5.3  Mortality rate As of December 31, 2020, there were 87,071 confirmed cases and 4,634 deaths in China, with a total mortality rate of 5.32% in the entire country, 2.08% in all regions except for Wuhan, and 0.64% in all regions except Hubei. According to the analysis at different time stages, the mortality rates in January and February (early stages of the outbreak) were higher than in March and April, and few deaths were reported after June. The total mortality rates in Wuhan and Hubei Province were 7.69% and 6.62%, respectively. According to a report from the WHO on February 20, 2020, the mortality rate increased with age, and the mortality rate of people above 80 years old was the highest (21.9%). The mortality rate of males was higher than that of females (4.7% and 2.8%, respectively). The mortality rate of retirees at 8.9%, was the highest among all occupational groups. The mortality rate of patients without complications was 1.4%, while that of patients with complications was significantly higher (13.2% in patients with cardiovascular disease, 9.2% in patients with diabetes, 8.4% in patients with hypertension, 8.0% in patients with chronic respiratory diseases, and 7.6% in patients with cancer). In the second half of 2020, with no sign of the epidemic situation fo COVID-19 recovering, a second and a third wave occurred, with a significant increase in incidence rate as compared with the initial epidemic situation. As of December 27, 2020, since the COVID-19 outbreak, over 79 million confirmed cases of COVID-19 were reported worldwide, and the death toll exceeded 1.7 million. The US and India still have the highest confirmed cases and deaths in America and Asia, respectively.

2.5.4  Global or regional distribution On June 30, 2020, the WHO reported total confirmed cases of 10 million worldwide, and confirmed cases of COVID-19 were

General Introduction  15

reported in 215 countries or regions outside China. There were more than 230,000 confirmed cases in the top four countries with high incidence of COVID-19, such as Russia, Britain, Spain, and Italy. The cumulative number of confirmed cases in the US exceeded 2.53 million, making it the country with the highest number of confirmed COVID-19 cases in the world. The epidemic also spread rapidly in other countries with high incidence such as Brazil (South America), Iran (Middle East), and India (South Asia). In the second half of 2020, the Americas remained the region with the highest incidence of COVID-19 in the world, with more than 3.44 million confirmed cases, while the US accounted for 68% of the whole Americas, with a total of 1.86 million confirmed cases. Europe and Asia were the regions with the second and third highest incidences, with total confirmed cases exceeding 25.27 million and 11.84 million, respectively. Russia, the UK, and Germany were the top three countries with high incidences in Europe, with total confirmed cases of 3.05 million, 2.25 million, and 1.64 million, respectively. India, Indonesia, and Bangladesh were the top three countries with high incidences in Asia, with total confirmed cases of 10.18 million, 700,000, and 500,000, respectively.

2.5.5  Epidemic outbreak At a certain point in the early stage of the COVID-19 epidemic, human-to-human transmission occurred among some cases, followed by a community outbreak and a large scale population movement. A series of control measures were implemented to limit the spread of human to human transmission. A retrospective study of 425 COVID-19 patients in the early stage of the epidemic in China showed that the average incubation period was 5.2 days (95% CI: 4.1–7.0) and P95 was 12.5 days. In the early stage, the epidemic doubling time was 7.4 days, i.e., the number of infected people doubled every 7.4 days. The average continuous interval (average time between one person and another) was 7.5 days (95% CI: 5.3–19). The estimated R0 was 2.2 (95% CI: 1.4–3.9), i.e., every patient would infect 2.2 people on average. The basic reproduction number R0 estimated by the WHO ranges

16  Diagnosis and Treatment of COVID-19

from 1.4 to 2.5. R0 usually changes with the implementation of prevention and control measures. At present, there have been reports of the fourth generation transmission of SARS-CoV-2, indicating that the virus can achieve continuous human-to-human transmission.

2.5.6  Nucleic acid testing mass screening in Wuhan At present, the detection of SARS-CoV-2 mainly focuses on nucleic acid testing and antibody testing. A positive nucleic acid test result indicates the existence of viral nucleic acid in the specimen, which means that the infected person may be infectious. Therefore, nucleic acid testing, which is more sensitive than antibody testing, is helpful to determine whether the patient within the exposure period is infected or not. Nucleic acid testing can screen for infections in asymptomatic persons, thereby impeding the source of infection. By combining antibody testing and clinical symptoms, patients can be explicitly classified have to provide the etiology basis for subsequent classification and treatment. In order to fully grasp the situation of asymptomatic persons infected with COVID-19 in Wuhan, mass screening to test 9,899,828 people in Wuhan were conducted from May 14, 2020, 0000Hr to June 1, 2020, 0000Hr to eliminate COVID-19 transmission to the maximum extent in order to provide assurance for the well-being of the people. Together with persons who have undergone testing, a total of 10.909 million people have completed nucleic acid testing, in order to achieve full coverage screening for the population. No confirmed cases were detected in the nucleic acid testing mass screening. However, 300 asymptomatic patients were detected for COVID-19 infection, with a detection rate of 0.303/10,000, while all 1,174 close contacts were tested negative for COVID-19. The proportion of asymptomatic patients in the whole population of Wuhan was extremely low. After the viral isolation, culture and sequencing analysis, no live virus was cultivated in the samples of asymptomatic patients, and no asymptomatic patients were found

General Introduction  17

to be infectious. However, a strict prevention strategy implementing a closed loop management of the entire process of detecting, reporting and isolating asymptomatic patients was still adopted. A team of clinical experts and psychologists was formed to achieve a “one person, one plan” for the diagnosis and treatment of asymptomatic patients. The nucleic acid testing mass screening reflects the principle of testing all, which played an important role in screening and eliminating the recurrence of COVID-19, and also a valuable reference for Wuhan and the whole country to adjust the next step of prevention and control measures.

2.6  Correlation and distinction between SARS and COVID-19 As for the SARS epidemic in 2003, the total number of infections in China was 8,098 and the mortality rate was about 11%. By July 2003, the epidemic was under control within eight months. At that time, cases were reported in 26 countries or regions around the world, and a vast majority of the cases were concentrated in four countries or regions: China, Taiwan, Singapore, and Canada, in the city of Toronto. As for COVID-19, as of June 16, 2020, the total number of confirmed cases had exceeded 7.94 million worldwide. A total of 86,469 confirmed cases were recorded in China, with a mortality rate of about 5.37%. A study in February 2020 found that the average R0 of COVID-19 was 3.28, the median R0 was 2.79, while the average R0 of SARS was 3.0, indicating that the transmission rate and infectivity of COVID-19 were significantly higher than those of SARS. The main route of transmission of SARS-CoV and SARS-CoV-2 is transmitted via respiratory droplets, while some reported that the viruses can also be transmitted through faeces. Both viruses can bind to ACE2 receptors on the surface of the human lower respiratory tract to invade cells. The median incubation period for SARS-CoV-2 and SARS-CoV is about five days, while the average interval time for SARS-CoV-2 and SARS-CoV is 7.5 days and 8.4 days, respectively.

18  Diagnosis and Treatment of COVID-19

Disease progression of the two viruses in patients with severe illness follows a similar pattern, and a small number of patients may progress to acute respiratory distress syndrome (ARDS) 8–20 days after the onset of symptoms. About 10 days after the onset of symptoms, lung abnormalities can be shown on chest CT. Organ damage caused by COVID-19 and SARS mainly resides in the lungs. COVID-19 mainly leads to distal respiratory tract and alveolar injury, and the presence of mucinous secretions, and even attacks multiple organs, while SARS is mainly characterized by pulmonary fibrosis and consolidation. As the SARS viral load peaks when patients already had respiratory symptoms and could be easily identified, the quarantine measures had been effective during the SARS epidemic. In contrast, COVID-19 has begun to spread in the early stage of the disease even without any significant respiratory symptoms. This had delayed the diagnosis time and made timely and early quarantine more difficult. This is also in line with the “dampness-toxin pestilence” characteristics of SARS-CoV-2, which is lingering, everchanging in nature and significantly different from the high fever symptom of SARS-CoV. Under experimental conditions, the stability of SARS-CoV-2 is similar to that of SARS-CoV. This suggests that differences in epidemiological characteristics of the two viruses may be related to the differences in gene phenotype. It may also be caused by other factors, including the high viral load in the upper respiratory tract and the possibility that people infected with SARS-CoV-2 can shed and transmit the virus under asymptomatic conditions. In terms of clinical manifestations, COVID-19 patients usually presents with a low fever or a normal body temperature, while SARS patients mainly develop a high fever, indicating that the virulence of COVID-19 is weaker. While the impairment to immune function in SARS-CoV-2 is more severe than in SARS-CoV, infected persons who are asymptomatic and retested positive again can also be seen. Comparison of COVID-19 and SARS (Table 1).

General Introduction  19 Table 1.    Comparison of COVID-19 and SARS Distinguishing points

COVID-19

SARS

TCM name

Dampness-toxin pestilence

Pestilence

Disease characteristics

Dampness pathogen is heavy, turbid, sticky, and stagnant, the course of disease is lingering, and the condition of the disease is changeable

Exuberance of heat toxin

Epidemiology

Infectivity

Strong

Relatively weak

Virulence

Relatively weak

Strong

Number of infected patients in China

85,000+

7,000+

Mortality rate

About 5.45%

about 11%

Fever

Mostly low fever or normal body temperature

Mostly high fever

Organ damage

Mainly in the lungs and multiple organs

Mainly in the lungs

Impairment of immune function

Severe

Relatively mild

“Re-positivity”

Patient who retested positive again and persistently tested positive for extended period are often seen.

Almost no patients retested positive again

Asymptomatic patients

Yes

No

Autopsy

Deep respiratory tract and alveolar lesions, mucinous secretion

Mainly pulmonary fibrosis and consolidation

Clinical features

20  Diagnosis and Treatment of COVID-19

3.  Clinical Characteristics 3.1  Clinical manifestations COVID-19 can be clinically divided into mild, moderate, severe, and critical cases. Based on the current epidemiological study, the majority of COVID-19 patients are mild and moderate cases. COVID-19 mainly presents with fever, dry cough, and fatigue. A small number of patients have accompanying symptoms such as blocked nose, runny nose, sore throat and myalgia. However, in some clinical cases, patients had no typical respiratory symptoms such as fever and cough when they sought treatment, such as mild poor appetite, fatigue, lack of vigour, nausea, vomiting, and diarrhea; or neurological symptoms, such as headache; or cardiovascular symptoms, such as palpitation, chest tightness; or ophthalmic symptoms, such as conjunctivitis. Another study involving 1,099 COVID19 patients also showed that only 43.8% of patients in the early stage of the disease had fever symptoms, hence the diagnosis of COVID-19 patients should not focus too much on fever. Mild and moderate patients only show symptoms such as low grade fever and mild fatigue, with no clinical manifestation such as pneumonia, red tongue with thin or yellow and thin fur, and a floating and rapid pulse. Patients with severe illness mostly develop dyspnea and/or hypoxemia one week after onset, with red tongue, greasy and yellow fur, and rapid/rapid slippery/surging pulse. The disease progression of critically ill patients is rapid, which include ARDS, septic shock, difficulty in metabolic acidosis correction, coagulation dysfunction, and multiple organ failure, with mostly dark purple/ deep red and dry tongue, combined with a deep rapid/deep thin/ floating and rapid pulse. It is worth noting that patients with severe illness or in critical condition can have moderate to low fever in the course of the disease, or even no significant fever symptom. According to the current admitted cases, most patients have a good prognosis while a few are in critical condition. Elderly population and those with underlying conditions such as chronic illness have poorer prognoses. Among the deaths of COVID-19 in China, Hubei Province accounted for 95.8%, and more than 80% were

General Introduction  21

Figure 1.    Clinical classification and transformation of COVID-19.

over the age of 60. More than 75% suffered from comorbidities such as cardiovascular disease, cerebrovascular disease and diabetes. The symptoms in children are relatively mild. The severity of COVID-19 clinical cases can change during the course of the disease. The prognosis of patients with mild and moderate symptoms is favourable as they are able to recover within one week after diagnosis and receiving timely treatment. In the event the diagnosis and treatment are not timely, the symptoms of the clinical case can easily turn severe or even become critically ill, developing respiratory distress and even multiple organ failure. Therefore, patients should seek treatment immediately. Timely diagnosis and treatment can effectively halt the progress of the disease. Otherwise, the disease progresses rapidly and result in poor clinical prognosis. Convalescent patients should also have adequate rest, maintain selfquarantine, and seek medical treatment if necessary to prevent recurrence of illness and affecting the prognosis (Figure 1).

3.2  Laboratory examination Peripheral blood examination: In the early stage of disease onset, the total number of peripheral blood leukocytes and the lymphocyte count is normal or decreased.

22  Diagnosis and Treatment of COVID-19

Blood biochemical examination: Some patients showed increased level of liver enzymes, lactate dehydrogenase (LDH), creatine kinase, and myoglobin, while some critically ill patients might have increased level of troponin. In the majority of patients, the level of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were elevated while the level of procalcitonin (PCT) remained normal. In patients who are severely ill, there was an increase in the level of D-dimer and a decrease in the number of peripheral blood lymphocytes. Compared with mild and moderate cases, patients who are severely ill and in critical condition often have a more significant increase in inflammatory factors which resulted in leukocytopenia, lymphocytopenia, thrombocytopenia, and a significant increase in CRP level. Pathological and serological examination: 1. Pathologic examination: SARS-CoV-2 nucleic acid can be detected in nasopharyngeal swabs, sputum, lower respiratory tract secretions, blood, faeces, and other specimens. False negative result of nucleic acid testing may occur when there are problems in specimen sampling and reagent kit testing, making it more accurate to test lower respiratory tract samples (sputum or respiratory tract extracts). Specimens are collected for analysis as soon as possible. 2. Serological examination: SARS-CoV-2 specific immunoglobulin M (IgM) antibodies mostly begin to appear 3–5 days after disease onset, and the specific immunoglobulin G (IgG) antibody titer increases four times or higher in convalescence than in the acute phase.

3.3  Imaging findings Due to the high incidence of missed diagnosis with chest radiography, a chest computed tomography (CT) examination is recommended. Chest CT examination displayed localized early lesions, displaying patchy, subsegmental, or segmental ground-glass opacity,

General Introduction  23

with or without interlobular septal thickening. In the advanced stage, the lesions increase and expand, involving multiple lung lobes, and some lesions show consolidation, with ground-glass opacity coexisting with consolidation opacity or pulmonary fibro stripes. In the severe stage when there are diffuse lesions in both lungs, a few cases show “white lung” manifestation, mainly showing consolidation opacity combined with ground-glass opacity, and most of them are accompanied by pulmonary fibro stripes and air bronchogram signs. Pleural effusion or swollen lymph nodes are rare. Chest CT in convalescence shows that ground-glass-like lesions and consolidation areas are gradually absorbed and reduced, and their density decreases until they gradually disappear. Some patients have pulmonary fibro stripes in the primary lesion area. This characteristic is more pronounced than pneumonia due to other causes. A study in early February 2020 showed that 76.4% of 840 patients admitted to hospitals showed pneumonia on chest CT, indicating that COVID19 cannot be completely ruled out by CT alone. Therefore, the diagnosis of COVID-19 should be considered from multiple perspectives.

3.4  Pathological characteristics The pathological characteristics of COVID-19 are very similar to those caused by SARS and MERS coronavirus. Some patients have rapid progress of the lung lesions and displayed ARDS. The pathological characteristics of COVID-19 are as follows:

3.4.1 Lung Lung via naked eye: Lung damage is significant, showing patchy, gray-white lesions (inflammatory lesions) and dark red bleeding. Plenty of viscous secretions can be seen overflowing from the alveoli on the plane of section. It is suggested that COVID-19 mainly causes inflammatory responses characterized by distal respiratory tract and alveolar injury.

24  Diagnosis and Treatment of COVID-19

Lung via histological examination: Bilateral alveolar injury with cellular fibromucinous exudate and massive pulmonary interstitial fibrosis with partial hyaline degeneration and pulmonary hemorrhagic infarction are visible. Small blood vessels proliferate, and the blood vessel wall thickens with lumen stenosis and occlusion, presenting ARDS. Infiltration of interstitial mononuclear inflammatory cells, mainly lymphocytes, can be seen in both lungs. Multinucleated syncytial cells can be seen in the alveolar cavity, showing viral cytopathic changes. The positive expression of immune cells is mainly concentrated in the pulmonary interstitium and near blood vessels. The “cytokine storm” is associated with excessive immune responses and uncontrolled proinflammatory responses, which can lead to severe organ disorders, including lung damage. Coronavirus particles can be found in the cytoplasm of the bronchial mucosal epithelium and type II alveolar epithelium under an electron microscope. The SARS-CoV-2 antigen is positive in some alveolar epithelium and macrophages via immunohistochemical staining.

3.4.2  Spleen, hilar lymph nodes, and bone marrow The size of the spleen is significantly reduced, showing focal hemorrhage and necrosis. Macrophages proliferate and phagocytosis can be seen in the spleen, and there is a significant decrease in the number of lymphocytes. The number of lymphocytes in the lymph nodes is small, and lymphocyte degeneration, necrosis, and macrophage proliferation can be seen. Immunohistochemical staining shows that CD4 + T cells and CD8 + T cells decrease in the spleen and lymph nodes. SARS-CoV-2 nucleic acid testing is positive in lymph node tissue, and SARS-CoV-2 antigen immunostaining of macrophages is positive. The numbers of trilineage of bone marrow cells decrease.

3.4.3  Heart and blood vessels Degeneration and necrosis can be observed in myocardial cells, with edema and infiltration of a few monocytes, lymphocytes, and/or

General Introduction  25

neutrophils in the interstitium. Occasionally, a positive result of SARS-CoV-2 nucleic acid testing can be seen. Endothelial cell shedding and intimal or full layer inflammation can be seen in small blood vessels in the main parts of the whole body; intravascular mixed thrombosis, thromboembolism, and infarction in corresponding parts can be seen. Hyaline thrombus can be seen in the microvessels of the main organs.

3.4.4  Liver and gallbladder The liver can be seen increasing in volume and appeared as dark red. Hepatocyte degeneration and focal necrosis are accompanied by neutrophil infiltration; hepatic sinusoidal congestion can be seen, and lymphocytes and monocyte infiltration with the formation of microthrombus can be found in the portal area. The gallbladder is highly filled. The liver and gallbladder is tested positive for SARS-CoV-2.

3.4.5 Kidney Glomerular hyperemia, segmental hyperplasia, or necrosis can be seen in the kidneys. Proteinaceous exudate can be seen in the glomerular capsule cavity. The renal tubular epithelium degenerates and sheds, and a hyaline cast can be seen. Interstitial hyperemia, microthrombosis, and focal fibrosis can be seen. Focal necrosis is found in the adrenal gland, and the renal tissue occasionally tests positive for SARS-CoV-2.

3.4.6  Other organs Hyperemia and edema of brain tissue, partial neuronal degeneration, ischemic changes and loss, and occasional phagocytosis can be seen; monocyte and lymphocyte infiltration can be seen in the perivascular space. Focal necrosis of the adrenal gland can be seen. Degeneration, necrosis and shedding of esophageal, gastric and intestinal mucosa

26  Diagnosis and Treatment of COVID-19

epithelium in varying degrees, as well as infiltration of monocytes and lymphocytes in the lamina propria and submucosa can be seen. Degeneration, focal hemorrhage, and necrosis of the cortical cells can be seen in the adrenal gland. The number of spermatogenic cells decreases in varying degrees, which includes the degeneration of the Sertoli and Leydig cells. SARS-CoV-2 can be detected in the nasopharynx, gastrointestinal mucosa, testicles, and salivary glands.

Chapter 2

Clinical Diagnosis 1.  Diagnostic Criteria and Clinical Classification 1.1  Diagnostic testing and inspection technology 1.1.1  Conventional laboratory examination technology According to the patient’s condition, blood routine, urine routine, liver and kidney function, blood gas analysis, blood coagulation function, C-reactive protein (CRP), creatine kinase (CK), myoglobin, troponin, PCT, ESR, fungal G test, bacterial/fungal culture, and other indicators can be detected. For mild and moderate cases, blood routine and CRP are the primary indicators of concern. In addition, inflammatory cytokines [IL-6, IL-10, tumor necrosis factor-α (TNF-α )], T/B lymphocyte subsets, and complement detection can be determined as appropriate, especially in severe or critical cases.

1.1.2 Etiology and serological detection technology This technology mainly includes viral quarantine and culture, viral nucleic acid test, viral gene sequencing, and serological antigen (antibody) detection. The aim of viral quarantine and culture is to isolate and culture SARS-CoV-2 particles from respiratory tract samples

27

28  Diagnosis and Treatment of COVID-19

and observe them with electron microscope technology. Since this is the gold standard for laboratory detection and has high requirements for the biosafety level of the laboratory, it cannot be carried out in general laboratories. Viral nucleic acid testing is the main method of laboratory diagnosis of COVID-19. The detection of SARS-CoV-2 nucleic acids in the respiratory tract, feces, blood, eye secretion, and other samples is achieved by real-time quantitative polymerase chain reaction (PCR). However, the detection of viral nucleic acid is greatly affected by factors, such as specimen collection and methodological sensitivity. When the detection result is negative, it cannot be used as the basis for the exclusion of infection. Viral gene sequencing is used to detect whether the samples have homology with known SARS-CoV-2. Genome sequencing is highly accurate in diagnosing SARS-CoV-2 infected patients, but it takes a longer time to sequence and requires more testing equipment. Therefore, it is suitable for the initial identification of the virus and further study at a later stage and is not suitable for clinical rapid mass diagnosis. Serological detection is mainly used to detect the specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in serum. It can be used as one of the bases for the diagnosis of COVID19. The operation is simple and convenient, and the results can be obtained quickly. Serological detection can make up for the low detection rate of nucleic acid testing, which is easy to cause the defect of missed diagnosis.

1.1.3  Imaging examination method X-ray examination of the chest has a rather high false-negative rate with regard to disease in the early stage or mainly manifests groundglass opacity in the lungs. CT examination of the chest, especially high-resolution CT (HRCT), has a high spatial resolution and is not interfered with by the structure beyond the slice. It has become the main screening and auxiliary diagnosis means by post-processing technology to display the details of the focus in multiple slices and

Clinical Diagnosis  29

directions. However, imaging examination is not specific for newborns, especially premature infants. At the same time, other viral pneumonia, mycoplasma pneumonia, chlamydia pneumonia, and bacterial pneumonia may have similar imaging manifestations. Therefore, it is imperative to combine imaging examination with laboratory examination technology to improve the sensitivity and specificity of detection.

1.2  Diagnostic criteria The diagnostic criteria covered in the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 8) are elaborated on in the following sections.

1.2.1  Suspected case The case should be comprehensively analyzed by combining the following epidemiological history criteria with clinical manifestations. It should meet one of the epidemiological history criteria and show two clinical manifestations. If there is no clear epidemiological history, then it should meet any two of the clinical manifestations, and the novel coronavirusspecific IgM antibody should be positive, or else patients should show at least three of the clinical manifestations. The epidemiological history criteria are as follows: 1. Travel or residence history of the community with reported cases within 14 days before onset. 2. Contact history with SARS-CoV-2-infected patients or asymptomatic patients within 14 days before onset. 3. Contact history of patients with fever or respiratory symptoms from the community where cases have been reported within 14 days before onset. 4. Aggregation cases, involving two or more cases of fever and/or respiratory symptoms in a small area, such as family, office, school class, within two weeks.

30  Diagnosis and Treatment of COVID-19

1.2.2  Clinical manifestations 1. COVID-19-related clinical manifestations, such as fever and/or respiratory symptoms. 2. With the above-mentioned COVID-19 imaging features. 3. In the early stage of the disease, the total number of leukocytes was normal or decreased, and the lymphocyte count was normal or decreased.

1.2.3  Confirmed cases Suspected cases should show at least one of the following pathogenic or serological evidence: 1. A positive real-time RT-PCR detection of the novel coronavirus nucleic acid. 2. Viral gene sequencing, highly homologous to the known novel coronavirus. 3. The novel coronavirus-specific IgM antibody and IgG antibody test is positive. The novel coronavirus-specific IgG antibody changes from negative to positive or the IgG antibody titer in the recovery phase is 4 times or higher than that in the acute phase.

1.3  Clinical classification 1.3.1  Clinical classification based on severity of the disease Based on the severity of the disease, the cases can be divided into mild, moderate, severe, and critical cases. 1. Mild cases: The clinical symptoms are mild, and there are no signs of pneumonia on imaging. 2. Moderate cases: Fever, respiratory symptoms, other clinical manifestations, and pneumonia can be seen on imaging. 3. Severe cases: These include cases meeting any of the following criteria: (a) shortness of breath with respiratory rate (RR) ≥30

Clinical Diagnosis  31

times/min; (b) in the resting state, during inhalation, oxygen saturation ≤ 93% at rest; (c) arterial partial pressure of oxygen (PaO2)/ fraction of inspired oxygen (FiO2) ≤ 300 mmHg (1 mmHg = 0.133 kPa); in areas with high altitude (more than 1,000 meters above the sea level), PaO2/FiO2 should be adjusted according to the following formula: PaO2/FiO2 × [760/atmospheric pressure (mmHg)]; (d) the clinical symptoms are progressively worsening, and lung imaging shows that within 24–48 hours, the lesion has progressed significantly >50%. 4. Critical cases: These include cases meeting any of the following criteria: (a) respiratory failure requiring mechanical ventilation; (b) shock; (c) other organ failures that require ICU care.

1.3.2  Clinical classification of COVID-19 in children Pediatric COVID-19 is classified according to the Diagnosis and Treatment Recommendation for Pediatric COVID-19 (the Second Edition). 1. Mild cases: The symptoms include only nasal obstruction, sore throat, fever and other symptoms of upper respiratory tract infection and a short course of the disease. Some of the children have no symptoms, and only SARS-CoV-2 nucleic acid throat swabs are found positive. 2. Moderate cases: There may be fever, cough, fatigue, headache, myalgia, and other symptoms. There are manifestations of pneumonia in imaging, but no manifestations and complications related to severe or critical cases. 3. Severe cases: The cases are noted to be with one of the following conditions in the course of the disease: tachypnea (70 times/min or more for infants, 50 times/min or more for children over 1 year), hypoxia, unconsciousness, listlessness, lethargy, coma, convulsion, difficulty feeding, and even signs of dehydration, coagulation disorder, myocardial damage, gastrointestinal dysfunction, significant elevation of liver enzymes, rhabdomyolysis, etc.

32  Diagnosis and Treatment of COVID-19

4. Critical cases: These involve rapid progress of the disease, showing organ failure, in line with any one of the following: (a) respiratory failure requiring mechanical ventilation, manifesting acute respiratory distress syndrome, which is characterized by intractable hypoxemia and cannot be relieved by routine oxygen therapy such as nasal catheter or face mask; (b) septic shock, sepsis and septic shock may occur when the functions of extrapulmonary systems such as circulation, blood, digestion, central nervous system, liver, and kidney are impaired; (c) other organ failure requiring ICU care.

1.3.3 Classification based on the Clinical Management of COVID-19: Interim Guidance According to the Clinical Management of COVID-19: Interim Guidance, May 27, 2020, the condition of COVID-19 can be categorized as mild, moderate, severe, and critical diseases, and critical diseases include ARDS, sepsis, and septic shock (Table 1).

1.4  Early warning indicators for severe/critical illnesses Adults: The following indicators may indicate disease deterioration: (a) progressive exacerbation of hypoxemia or respiratory distress; (b) deterioration of tissue oxygenation index or progressive increase of lactic acid; (c) progressive decrease in peripheral blood lymphocyte count or an increase in peripheral blood inflammatory markers such as IL-6, CRP, and ferritin; (d) significant increase of D-dimer and other related indexes of coagulation function; (e) chest imaging showing obvious progression of lung disease. Children: The following indicators can be noted: (a) increased respiratory rate; (b) poor mental response and lethargy; (c) progressive elevation of lactic acid; (d) significant elevation of inflammatory markers, such as CRP, PCT, and ferritin; (e) imaging showing

Table 1.    COVID-19 disease severity Mild disease

Symptomatic patients (Table 1) meeting the case definition for COVID-19 without evidence of viral pneumonia or hypoxia. Children with clinical signs of non-severe pneumonia with cough or dyspnea + fast breathing. Fast breathing (in breaths/min): < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40, without signs of severe pneumonia.

Moderate disease

Pneumonia

Adolescents or adults with clinical signs of pneumonia (fever, cough, dyspnoea, fast breathing) but no signs of severe pneumonia, including SpO2 ≥ 90% on room air. Children with clinical signs of non-severe pneumonia (cough or dyspnea + fast breathing and/or chest indrawing) and no signs of severe pneumonia. Fast breathing (in breaths/min): < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40. While the diagnosis can be made on clinical grounds, chest imaging (radiograph, CT scan, and ultrasound) may assist in diagnosis and identify or exclude pulmonary complications.

Severe disease

Severe pneumonia

Adolescents or adults with clinical signs of pneumonia (fever, cough, dyspnea, fast breathing), plus one of the following: RR > 30 breaths/min; severe respiratory distress; or SpO2 < 90% on room air.

(Continued)

Clinical Diagnosis  33

Children with clinical signs of pneumonia (cough or difficulty in breathing) + at least one of the following: · Central cyanosis or SpO2 < 90%; severe respiratory distress (e.g., fast breathing, grunting, very severe chest indrawing); general danger signs: inability to breastfeed or drink, lethargy, unconsciousness, or convulsions. · Fast breathing (in breaths/min): < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40.

While the diagnosis can be made on clinical grounds, chest imaging (radiograph, CT scan, and ultrasound) may assist in diagnosis and identify or exclude pulmonary complications. Critical disease

Acute respiratory distress syndrome (ARDS)

Onset: Within one week of a known clinical insult (i.e., pneumonia) or new or worsening respiratory symptoms. Chest imaging: Bilateral opacity, not fully explained by volume overload, lobar or lung collapse, or nodules; chest imaging performed using radiograph, CT scan, or lung ultrasound. Origin of pulmonary infiltrates: Respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g., echocardiography) to exclude hydrostatic cause of infiltrates/edema if no risk factor is present. Oxygenation impairment in adults: · Mild ARDS: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg (with PEEP or CPAP ≥ 5 cmH2O). · Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg (with PEEP or CPAP ≥ 5 cmH2O). · Severe ARDS: PaO2/FiO2 ≤ 100 mmHg (with PEEP ≥ 5 cmH2O). Oxygenation impairment in children: (OI = oxygenation index, OSI = oxygenation index calculated by SPO2). Use OI when available. If PaO2 is not available, wean FiO2 to maintain SpO2 ≤ 97%; to calculate OSI or SpO2/FiO2 ratio: · Bilevel (NIV or CPAP) ≥ 5 cmH2O via full face mask: PaO2/FiO2 ≤ 300 mmHg or SpO2/ FiO2 ≤ 264. · Mild ARDS (invasively ventilated): 4 ≤ OI < 8 or 5 ≤ OSI < 7.5. · Moderate ARDS (invasively ventilated): 8 ≤ OI < 16 or 7.5 ≤ OSI < 12.3. · Severe ARDS (invasively ventilated): OI ≥ 16 or OSI ≥ 12.3.

34  Diagnosis and Treatment of COVID-19

Table 1.   (Continued)

Table 1.   (Continued) Sepsis

Adults: Acute life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. Signs of organ dysfunction include altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, and laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate, or hyperbilirubinemia. Children: Suspected or proven infection and ≥ 2 age-based systemic SIRS criteria, of which one must be abnormal temperature or leukocyte count.

Septic Shock

Adults: Persistent hypotension despite volume resuscitation, requiring vasopressors to maintain mean arterial pressure (MAP) ≥ 65 mmHg and serum lactate level > 2 mmol/L. Children: Any hypotension (SBP < 5th centile or > 2 SD below normal for age) or two or three of the following: altered mental status; bradycardia or tachycardia (HR < 90 bpm or > 160 bpm in infants and heart rate < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or weak pulse; fast breathing; mottled or cool skin or petechial or purpuric rash; high lactate; reduced urine output; hyperthermia or hypothermia.

Clinical Diagnosis  35

Note: BP — blood pressure; BPM — times per minute; CT — tomography; FiO2 — fraction of inhaled oxygen; MAP — mean arterial pressure; NIV — non-invasive mechanical ventilation; OI — oxygenation index; OSI SpO2 — alternative oxygenation index; PaO2 — arterial oxygen partial pressure; PEEP — positive end expiratory pressure ventilation; CPAP — continuous positive airway pressure ventilation; BiPAP — biphasic positive airway pressure; SIRS — systemic inflammatory response syndrome; SBP — systolic blood pressure; SD — standard deviation; SOFA — organ failure assessment; SpO2 — blood oxygen saturation; HR — heart rate; 1 cmH2O = 0.098 kPa.

36  Diagnosis and Treatment of COVID-19

bilateral or multiple lung lobes infiltration, pleural effusion or rapid progression of the disease in a short period of time; (f) underlying diseases (congenital heart disease, bronchopulmonary dysplasia, respiratory malformations, abnormal hemoglobin, severe malnutrition, etc.) and immunodeficiency (long-term use of immunosuppressive agents) in newborns.

1.5  Differential diagnosis COVID-19 needs to be differentiated from influenza virus, SARS coronavirus, MERS coronavirus, adenovirus, human highly pathogenic avian influenza virus, respiratory syncytial virus and rhinovirus, other known viral pneumonia, bacterial pneumonia, mycoplasma pneumonia, and chlamydia pneumonia. In addition, it should also be differentiated from non-infectious diseases, such as vasculitis, dermatomyositis, and organized pneumonia. Influenza virus pneumonia: Influenza virus pneumonia refers to respiratory diseases caused by influenza virus infection. Influenza is often prevalent in winter and spring, usually from the end of November to the end of February in the north of China. There is another peak in the south of China from May to August. There are two types of influenza: influenza A and influenza B. Patients with influenza have urgent onset, serious symptoms, various systemic symptoms, fever, with the body temperature rising to over 39°C within 1–2 days, and they also have obvious symptoms, such as headache, muscle weakness, and decreased appetite. The high-risk group includes the elderly, people with underlying diseases, obese people, immunosuppressive people, and pregnant women. The virus is spread through the air, droplet transmission, and direct contact transmission. The incubation period in general is 1–7 days and specifically 2–4 days. Severe acute respiratory syndrome (SARS): Severe acute respiratory syndrome is caused by the SARS coronavirus. The main symptoms of SARS are fever, cough, headache, muscle pain, and symptoms of

Clinical Diagnosis  37

respiratory infections. Most patients with SARS can self-heal or be cured, with a mortality rate of about 14%. A higher mortality rate can be found in those aged over 40 years or with basic diseases (e.g., coronary heart disease, diabetes, asthma, and chronic lung disease). The symptoms of COVID-19 are mild, but the virus is more transmissible, which is the biggest difference between COVID-19 and the SARS outbreak in 2003, and it is also a difficult point in the prevention and control of the outbreak. Middle East respiratory syndrome (MERS): In 2015–2016, the MERS outbreak was concentrated in Asia and had many similarities with the SARS outbreak in 2003. The population is generally susceptible to MERS, so people with a history of working or traveling in epidemic areas such as Saudi Arabia and the United Arab Emirates should be closely noted. The incubation period is 2–14 days. It is generally believed that the MERS coronavirus is not easily spread from person to person, while SARS-CoV-2 can spread rapidly between people through droplet transmission and contact transmission. Human highly pathogenic avian influenza virus: It is a human disease caused by an avian influenza virus. People lack immunity to the avian influenza virus, and those in close contact with unidentified dead poultry, live poultry markets, or confirmed avian influenza patients are the most highly exposed people. It is mainly spread through contact with dead poultry and their contaminated articles and through environmental transmission. There are a few non-sustainable human transmissions of the H5N1 avian influenza virus. The incubation period is generally within seven days. Based on the epidemiological contact history, clinical performance, and laboratory examination results, the differential diagnosis of human highly pathogenic avian influenza and COVID-19 can be achieved. Adenovirus infection: It is an acute infectious disease caused by adenovirus, which is easy to invade the respiratory tract and digestive tract mucosa, eye conjunctiva, urinary tract, and lymph nodes. The main symptoms are acute upper respiratory tract infections,

38  Diagnosis and Treatment of COVID-19

followed by eye and gastrointestinal infections. Generally, it is spread through air and droplet transmission, close contact transmission, and fecal–oral transmission. The epidemical season is from February to May every year, mainly infecting children and young adults without basic diseases. Its incubation period is 3–8 days. Bacterial pneumonia: Its common symptoms are acute onset high fever, and can be accompanied by shivering, cough, expectoration, or aggravation of original respiratory symptoms with purulent sputum or blood sputum, with or without chest pain. Significant increased peripheral blood leukocytes, elevated CRP, and signs of pulmonary consolidation or moist rale can be seen. Imaging evidence shows alveolar infiltration or pulmonary consolidation of pulmonary lobes and segments. Generally, it is not an infectious disease. Mycoplasma pneumonia: It is a respiratory disease caused by Mycoplasma pneumoniae. The main pathological change of mycoplasma pneumonia is interstitial pneumonia, sometimes complicated with bronchopneumonia. Its onset is slow, and clinical symptoms are mild. Sometimes, it is asymptomatic. Its epidemical seasons are autumn and winter, and it is mainly transmitted through droplets. The incubation period is 1–3 weeks, with the highest incidence rate in adolescents. In the early stage of onset, fever, sore throat, nausea, vomiting, headache, muscle soreness and pain, fatigue, loss of appetite, and other symptoms can be seen. The fever is generally moderate. Obvious respiratory symptoms will appear after 2–3 days, manifesting paroxysmal and irritable cough that is aggravated at night, a small amount of sticky phlegm or mucopurulent sputum, and sputum with blood at times. It can also present breathing difficulties and chest pain. The fever usually lasts for 2–3 weeks, but there still might be a cough after the fever comes down.

1.6  Diagnostic procedure The COVID-19 diagnostic procedure is shown in Figure 1.

Clinical Diagnosis  39

Figure 1.    The diagnostic procedure for COVID-19.

2.  Nucleic Acid Testing Nucleic acid testing is the primary means of pathogen examination. Once a virus infection occurs, the genetic substance RNA of the virus can be detected first. According to the diagnostic standard in the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 8) issued by the National Health Commission, the diagnosis of COVID19 mainly depends on the positive result of SARS-CoV-2 nucleic acid testing tested by real-time fluorescence RT-PCR of respiratory specimens or blood specimens, the high homology of known SARSCoV-2 with the virus gene sequencing of respiratory specimens or blood specimens, and the positivity of test serum SARS-CoV-2specific IgM antibody and IgG antibody. However, the pathological process of the disease caused by SARS-CoV-2 has not been fully clarified, and the laboratory test path is not standardized. Therefore,

40  Diagnosis and Treatment of COVID-19

many links may affect the accuracy of the nucleic acid testing results. Thus, many scholars pointed out that the negative or single-gene positive samples of clinical SARS-CoV-2 nucleic acid testing need to be treated with caution. In addition, many research teams and laboratories have focused on exploring more efficient and accurate laboratory diagnostic methods and technologies for SARS-CoV-2, which is expected to provide better and faster technical support for the clinical diagnosis of COVID-19.

2.1  Testing principle SARS-CoV-2 is a single-chain RNA virus. The goal of nucleic acid testing is to find the RNA of SARS-CoV-2 in the patient specimens. At present, SARS-CoV-2 nucleic acid testing is performed mainly by fluorescence quantitative RT-PCR method and gene sequencing. In the fluorescence quantitative RT-PCR method, the nucleic acid sequence of SARS-CoV-2 needs to be determined first through sequencing technology. Then, the specific RNA sequence in the specimen is reversed to cDNA for the following amplification testing. Theoretically, the number of viral gene fragments after each amplification is multiplied. After more than 30 times of amplification, the target gene fragments will reach a certain number. The sample Ct value obtained by fluorescence quantitative RT-PCR method determines whether the patient’s sample contains SARS-CoV-2. Currently, SARS-CoV-2 nucleic acid testing mainly targets three conserved sequences in the viral genome, namely, the ORFlab, the nucleocapsid protein (N), and the envelope protein (E) genes. On February 21, 2020, the National Health Commission issued the Prevention and Control of COVID-19 (5th Edition). It emphasized that a confirmed case should meet one of the following conditions: ORF1ab and N genes of the same samples were both positive; RT-PCR of two types of samples showed single-target positive at the same time; RT-PCR of the same type of samples showed single-target positive for two times.

Clinical Diagnosis  41

Viral gene sequencing directly uses next-generation sequencing (NGS) to detect the genome in clinical samples. The aim is to realize the rapid identification, performance identification, and functional research of pathogenic microorganisms. The method of viral gene sequencing can identify the homology of different strains, analyze the evolution process, and track their mutations, thus providing a basis for the control of the epidemic. In addition, viral gene sequencing can be used to detect early low virus content samples and the confirmation of suspicious or gray zone results of real-time fluorescence RT-PCR detection, making up for the shortcomings of RT-PCR. However, most hospitals lack sequencing equipment and professionals at present. Also, the NGS is costly and requires a long testing cycle, which is not suitable for routine clinical testing. This method can be considered for cases that are difficult to diagnose.

2.2  Sample collection 2.2.1  Collection of upper respiratory tract specimens 1. Nasopharyngeal swab: The swab is placed on the patient’s nostril wall. When the tip of the swab reaches the posterior wall of the nasopharyngeal cavity, a full rotation is completed. Then, the tip of the swab is soaked in 2–3 ml of virus preservation fluid. 2. Throat swab: The patient is asked to rinse their mouth with water. The swab is inserted into the nostrils or retropharyngeal uvula and both sides of the tonsils. The swab repeatedly scrapes the local area or rests for a few seconds, and then it is put into a sterile tube containing 2–3 ml virus preservation fluid.

2.2.2  Collection of lower respiratory tract secretions Specimens collected from deep cough sputum, alveolar lavage fluid, bronchial lavage fluid, respiratory tract absorption, etc. have the highest detection rate and hence are preferred for testing severe cases.

42  Diagnosis and Treatment of COVID-19

1. Deep cough sputum: After the patient is asked to perform a deep cough, the sputum is collected in a sampling tube containing 3 ml of sample fluid. 2. Bronchial lavage fluid: The head of the collector is inserted from the nostrils or tracheal stoma. After injecting saline, the collector is connected with the negative pressure and is rotated to collect the extracted mucus. 3. Alveolar lavage fluid: After local anesthesia, the fiber bronchoscope is inserted into the mouth or nose through the pharynx to the bronchus of the middle lobe of the right lung or the lingular segment of the left lung. Sterilized saline is slowly added through the tracheal biopsy hole. The volume of saline is 30–50 ml each time and 100–250 ml in total. The total volume should not exceed 300 ml.

2.2.3  Collection of urine and fecal specimens Urine and fecal specimens can be collected and used for testing but are not as sensitive as the above two. So, they are not widely used in clinical practice. Specimens shall be tested immediately after collection, and the transit time shall not exceed 72 hours under the condition of 2–8 °C. The patient’s personal information (e.g., gender, ID number, medical record number, address), specimen number, specimen type (such as urine and feces), and collection date should be marked on the specimen container. Then, the specimen will be sent to the CDC for testing as soon as possible. The collection should be performed with caution to avoid infection.

2.3  Diagnostic criteria According to the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 8) issued by the National Health Commission, clinically diagnosed or suspected cases have the following etiological evidence:

Clinical Diagnosis  43

1. Positive SARS-CoV-2 nucleic acid testing results by real-time fluorescence RT-PCR in respiratory or blood specimens are noted. 2. Gene sequencing of respiratory or blood specimens is highly homologous with the known SARS-CoV-2. Due to the possibility of false-negative nucleic acid testing results, the infection can be confirmed if it is positive. If it is negative, the possibility of infection cannot be completely ruled out. Clinically, the patient’s epidemiological history, clinical manifestation, imaging examination, and serological testing should be considered. Diagnosis or elimination should be comprehensively judged after collecting multiple specimens for inspection.

2.4  Limitations of nucleic acid test The RT-PCR method for the detection of SARS-CoV-2 in respiratory specimens, which generally yields results within 4–6 hours, plays an important role in the current diagnosis of COVID-19. However, since the virus nucleic acid testing mostly adopts throat swab specimens, the collection site and wipe technique in the specimen collection process, specimen preservation, and delivery process can affect the quality of the specimen. In addition, since the patient’s own virus distribution is not linearly and positively correlated with the clinical symptoms as well as the differences in personnel operation, the accuracy of the nucleic acid testing results will be affected and is prone to be false-negative. Gene sequencing technology can directly detect the nucleic acid sequence; due to its high costs of the required time, technology, and equipment conditions, it is not yet suitable for batch diagnosis. There are also other testing techniques. For example, isothermal amplification technology has high detection sensitivity and requires a short time. But the technical difficulty of the primer design is more difficult and may cause false-positive results due to the operational technology and other reasons. Another

44  Diagnosis and Treatment of COVID-19

example is point-of-care testing (POCT) technology. This technique is time-saving, portable, and simple to operate. But it has low sensitivity, so it is still not suitable for widespread clinical use.

3.  Serological Testing With the deepening understanding of SARS-CoV-2, the treatment plan for COVID-19 has been further improved. The accuracy of the nucleic acid assay is affected by the collection and storage of specimens, RNA extraction method, and quality problems of the detection kit. At the same time, the operation is relatively cumbersome and time-consuming, and the testing personnel have a high risk of infection. It is also often restricted by the experimental site and personnel operation, and thus cannot well meet the needs of screening, bringing inconvenience to the diagnosis of COVID-19 and prevention and control of the epidemic. When a pathogen infects the body, as an important effect molecule of the body’s immune system against the virus, serologically specific antibodies form another key evidence to diagnose the infection. Serological antibody test only needs to collect blood samples, which is convenient and simple. Also, it does not have very harsh requirements on the experimental environment and personnel. At the same time, it has a high timeliness, a small workload, and a low risk of infection among the testing personnel, and so it is a powerful supplement to the SARS-CoV-2 nucleic acid testing. In the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 8), the National Health Commission officially emphasized the importance of dynamic detection of serologically specific antibodies in the diagnosis and treatment of COVID-19. So, on the basis of the original nucleic acid testing and sequencing, serological testing has been included as one of the diagnostic criteria.

3.1  Testing principle and method After infection with SARS-CoV-2, the body conducts an immune defense against the virus and produces specific antibodies. Among

Clinical Diagnosis  45

them, IgM is the early antibody produced after the body infection and the diagnosis index of acute infection. However, it has the drawbacks of low concentration, low maintenance time, and low affinity. IgG is the main antibody produced by the secondary immune response, so it is produced late. But it has the advantages of high concentration, long maintenance time, and high affinity, indicating a recovery period or previous infection. The joint test of IgM and IgG not only contributes to the diagnosis of the disease but also evaluates the infection stage of the body. The three main serological testing methods commonly used clinically at present are as follows: 1. Enzyme-linked immunosorbent assay (ELISA) is a qualitative or semi-quantitative test method. The antigen or antibody is coated on the surface of a solid phase carrier, and an enzyme-labeled antibody or antigen is used to bind the object to be examined. Then, the analysis is conducted based on whether there is any product and the shade of colored products produced by the enzyme catalyzing the substrate. The test method has high sensitivity, rather low difficulty in carrier standardization, and the operation time is 1–2 hours. It is suitable for panel testing and has the advantages of low cost and fast testing speed, which is suitable to be launched in grassroots or large and medium-sized hospitals. 2. Chemiluminescent immunoassay (CLIA) combines high-sensitivity chemiluminescence determination techniques with high-specific immune reactions, and it is used for various antigens, antibodies, hormones, etc. It has higher sensitivity than ELISA and has the characteristics of high specificity, wide linear range, stable results, and simplified operation, so it is widely used in the test of clinical specimens. 3. Colloidal gold immunochromatographic assay (GICA), using colloidal gold as a tracer marker, is a novel immunolabeling technique used for the test of antigens and antibodies. It requires no special treatment on the specimen. It only needs a drop of blood, and the testing results can be obtained visually within 15

46  Diagnosis and Treatment of COVID-19

minutes. The method breaks the personnel and site restrictions of existing testing technologies and shortens the detection time with convenient and rapid operation. The test specimens can be whole blood, serum, or plasma, so it is more suitable for grassroots hospitals.

3.2  Sample collection It is best to collect two serum specimens during the acute period and the recovery period. The first serum should be collected early (preferably within seven days after onset), and the second should be collected at 3–4 weeks after onset. The acquisition volume is 5 ml. A vacuum tube without anti-coagulant is recommended. Serum specimens are mainly used for antibody tests, not for nucleic acid testing.

3.3  Diagnostic criteria The Diagnosis and Treatment Protocol for COVID-19 (Trial Version 8) issued by the National Health Commission listed serological diagnosis as one of the diagnostic criteria: serum SARS-CoV-2-specific IgM antibody and IgG antibody is positive; serum SARS-CoV-2specific IgG antibody turns from negative to positive, or it is four times higher in the recovery period than that in the acute period. Acute anti-coagulation blood within seven days after onset is used for IgM and IgG tests. If the test results are negative, it is recommended to collect again within 10 days after onset. The serum of 3–4 weeks recovery period is used for IgG test. If the commercialization kit is used, the manufacturer’s instructions shall prevail. At the same time, it should be stressed that for the diagnosis of COVID-19 patients, the epidemiological history, clinical manifestation, imaging examination, nucleic acid testing, serologically specific antibody testing, and other clinical data should be considered, and a comprehensive judgment should be made.

Clinical Diagnosis  47

3.4  Interpretation of the joint test results of nucleic acid and serology Joint tests of nucleic acid and serologically specific antibody can complement each other to improve diagnostic efficiency and monitor disease progression. However, in the different stages of SARS-CoV-2 infection, the efficiencies of nucleic acid and antibody testing are not the same. A comprehensive analysis and correct interpretation should be conducted for the joint test results, so as to better guide the clinical diagnosis and treatment.

3.4.1  Nucleic acid (+), antibody test (+)/(–) 1. Nucleic acids (+), IgM and IgG are all (–): It suggests that patients may be in the early stage of the SARS-CoV-2 infection, namely, the window phase, generally two weeks after the virus infection. In this phase, viral antibodies cannot be detected in the blood. 2. Nucleic acid (+), IgM (+), IgG (–): It indicates that patients may be in the early stage or the stage of precursor symptoms of SARSCoV-2 infection. Since the body’s immune response produces IgM antibodies at the earliest, no IgG is produced or IgG content does not reach the lower detection limit of the diagnostic reagents. 3. Nucleic acid (+), IgM (–), IgG (+): It suggests that patients may be in the late and middle stage or recurrent stage of SARS-CoV-2 infection. IgM antibody peaks about 1 month after the virus invades the human body, and then it gradually decreases until below the lower detection limit; IgG antibody is the main force of body immunity in the middle and late stages and can be detected. Recurrent infection can be diagnosed if the IgG in the recovery period is four times or higher than that in the acute period. 4. Nucleic acids (+), both IgM and IgG (+): It suggests that patients are in the symptomatic or active period of SARS-CoV-2 infection, but the human body has produced a certain immunity to

48  Diagnosis and Treatment of COVID-19

the virus (the persistent antibody IgG has been produced). Or it indicates that patients show recurrent infections, and the diagnostic standard is that the titer of IgG in the recovery period is 4 times higher than that in the acute period.

3.4.2  Nucleic acid testing (–), antibody test (+)/(–) 1. Nucleic acid (–), IgM (+), IgG (-): It suggests that patients are highly likely to be in the acute stage of SARS-CoV-2 infection, or that patients have other diseases that can cause weak positive or positive results of IgM. At this time, one should be doubtful about the nucleic acid testing results. It is suggested to consider the reasons for false-negative nucleic acid testing results. Therefore, the test results can only be reported as negative. SARS-CoV-2 infection cannot be excluded, and it needs to be confirmed repeatedly. 2. Nucleic acid (–), IgM (–), IgG (+): It suggests that patients may have once been infected with SARS-CoV-2, but have recovered, or the virus has been removed. Since the IgG produced in the immune response has long maintenance, it is still detectable in the blood. 3. Nucleic acid (–), IgM weak (+), IgG (–): It suggests that patients may be infected with SARS-CoV-2 for the first time and are in the early stage. The viral load is lower than the lower limit of nucleic acid testing. The body produces a small amount of IgM and has not produced IgG. Or the false-positive IgM is caused by the patient’s own positive rheumatoid factors. 4. Nucleic acids (–), both IgM, and IgG (+): It suggests that patients have been infected with SARS-CoV-2 recently and are in the recovery period. The virus is removed from the body, and the IgM has not been reduced to the lower test limit, or the nucleic acid testing results are false-negative. The patients are in the active period of infection and need follow-up nucleic acid testing to confirm.

Clinical Diagnosis  49

3.5  Limitations of serological testing The sensitivity of serologically specific antibody detection mainly depends on the affinity, testing methods, and operation of the antigens and antibodies. With the popularization and application of SARS-CoV-2 IgM and IgG testing reagents, more false-positive or false-negative phenomena have also appeared. First, since there is a window phase after the virus enters the body before producing specific antibodies, antibody serological testing may also have falsenegative results. Second, antibody serological testing based on N or S protein may have cross-reactions affected by other coronavirus infections. Third, antibody tests may show false-positive results due to endogenous or exogenous disturbances, such as rheumatoid factors, heterophil antibodies, supplements, specimen hemolysis, bacterial contamination, long storage time, and incomplete coagulation. In addition, the differences in the selection and preparation of the recombinant antigen in the different kits may affect the antigenicity of the recombinant antigen, and the differences in the different detection methods may also affect the sensitivity and specificity of the kits. Therefore, serological antibody testing should be applied in combination with nucleic acid testing. IgM and IgG levels should be analyzed at the same time, and multiple dynamic tests should be conducted to make the final diagnosis. Since the problem of falsepositive results for SARS-CoV-2 antibodies testing cannot be completely avoided, National Medical Products Administration especially stressed that the antibody testing of SARS-CoV-2 is not applicable to the large-scale screening of the general population. The nowapproved antibody testing kits are mostly used for supplementary testing for negative nucleic acid testing results or in conjunction with nucleic acid testing in the diagnosis of suspected cases. Of course, various detection methods for SARS-CoV-2 all have their corresponding methodology limitations. Therefore, the test results obtained from different experimental methods should be closely combined with clinical symptoms and should be analyzed with

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caution, so as to provide scientific and reliable experimental diagnostic results for epidemic prevention and control.

4. Re-positive Patients, Persistent Positive Patients, Asymptomatic Patients, and Reinfected Patients Since the outbreak of COVID-19, re-positive patients, persistent positive patients, and asymptomatic patients have received more and more attention, bringing new challenges to the prevention, control, and management of the epidemic. As COVID-19 is a novel infectious disease, the understanding of its pathogenic mechanism, disease course characteristics, and detoxification rules are still insufficient. A joint effort is needed for global scientists to further carry out continuous scientific research.

4.1  Re-positive COVID-19 patients The re-positive COVID-19 patients refer to the diagnosed patients whose SARS-CoV-2 nucleic acid testing results are still positive during the post-discharge quarantine period after being cured and reaching the discharge standard under standardized treatment. It has been found in the 14 days of follow-up of 672 discharged COVID19 patients in Shiyan, Hubei Province, that 65 cases (9.67%) tested positive for nucleic acid; the Third People’s Hospital of Shenzhen conducted a retrospective analysis of 262 discharged patients and found that the re-positivity rate was 14.5% (38 re-positive cases), and the re-positivity rate of the 109 discharged COVID-19 patients in Tianjin was 7.34% (eight re-positive cases). The current clinical observation showed that re-positive COVID-19 patients presented a few clinical symptoms and mild disease conditions when returning to the hospitals. Laboratory results showed that after readmission, laboratory indicators such as lactate dehydrogenase (LDH), CK, D-dimer, leukocytes, lymphocytes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactic acid were mostly normal. However, the detection of peripheral

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blood lymphocytes subgroups of re-positive patients showed that the number and morphology of lymphocytes were roughly normal, and L cells, CD8+ T cells, and B cells were significantly reduced, suggesting the decrease in immune response caused by cellular immune deficiency or response disorders after SARS-CoV-2 infection. In addition, CT imaging of re-positive patients presented no obvious aggravation than before, showing mostly continuous absorption of inflammation or improved conditions. At present, observations show that the clinical symptoms, laboratory results, and lung imaging of re-positive patients do not support the diagnosis of reinfection temporarily, and most cases show recovery signs. Combined with literature and clinical observation, the reasons for the re-positivity of discharged COVID-19 patients are speculated as follows: 1. False-negative situation of nucleic acid testing: SARS-CoV-2 nucleic acid RT-PCR testing is currently one of the most common coronavirus testing methods in the world. A study conducted by researchers at Johns Hopkins University found large differences in the effectiveness of nucleic acid testing in the process of detection of SARS-CoV-2 infection. Usually, several days before the symptoms start to manifest, the probability of falsenegative results can vary from 100% on the first day to 67% on the fourth day. After the symptoms began to appear, the incidence of false-negative results decreased to 38% on the fifth day and 20% on the eighth day. But it began to rise daily thereafter. False-negative results of nucleic acid testing are mainly caused by the performance of the kit, sampling and testing methods, sampling sites, etc. Inaccurate diagnosis and testing bring challenges to curbing the epidemic. 2. Intermittent detoxification in cured COVID-19 patients: There are differences in viral load in COVID-19 patients with different disease courses and different conditions. Most patients who meet the COVID-19 discharge criteria are in the recovery period of the self-limited disease, with a low viral load and intermittent detoxification. After the recovery period of the disease, the viral

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nucleic acid often shows low titers, but the current nucleic acid testing results are qualitative rather than quantitative results, so individual patients may have positive nucleic acid testing results during the recovery period. 3. The discharge criteria are not strict: Lax discharge criteria can lead to re-positivity in COVID-19 patients who may not be fully cured for a period of time after discharge. In view of this situation, the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 8) issued by the National Health Commission strictly standardized the discharge criteria and adopted the criteria of “wide entry and strict exit”. The nucleic acid testing of whole blood and feces need to be carried out at the same time. Once the results are both negative, the patient can be discharged. In addition, in view of the re-positivity situation, it is also required to “continue to conduct 14 days of quarantine management and monitoring of health status”. Sampling and monitoring before the expiration of the observation period are needed to find out the detoxification situation. One can only be released from quarantine when all the requirements are met, so as to minimize the risk of transmission. On the whole, the re-positivity of nucleic acid testing does not equal reinfection. There has been no report about discharge cases reinfecting others in China, so the risk of transmission is very low. At present, the pathological mechanism of the re-positive phenomenon is still under study, and whether re-positive patients are infectious needs further clinical research demonstration and observation.

4.2  Persistent positive COVID-19 patients Persistent positive COVID-19 patients refer to patients who meet the COVID-19 discharge criteria but are tested positive for a long time. On April 24, 2020, Wuhan was cleared of severe cases of COVID19, but more than 30 of these patients did not convert to negative nucleic acid results for a long period of time and were “COVID-19 persistent positive patients”. Also, at present, there is no clear definition of how long the nucleic acid persistent positivity should last

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before being confirmed as persistent positive. COVID-19 persistent positive patients have a long detoxification period, which is generally believed to be related to the patient’s immune response. Observation found that after being infected with SARS-CoV-2, there was no strong immune response in some patients. The reason it took long for the results to turn negative might be that a certain balance between human immunity and the virus had been achieved. Normally, even if the respiratory specimen nucleic acid testing results are positive, COVID-19 patients still have very low infectivity if they manifest normal body temperature over 10 days, disappearance of all symptoms, obvious inflammation absorption suggested by lung CT, and IgG positive. COVID-19 persistent positive patients are theoretically infectious but are currently of little significance as a source of infection. Since the residual viral load in the patients is generally low, it cannot be bred and cultivated even if it can be detected through genetic amplification means, which belongs to the “wreckage” of the virus. At present, observation shows that protective IgG antibodies are found in most COVID-19 persistent positive patients. Those patients need no special treatment but close followup and hospital observation.

4.3  Asymptomatic COVID-19 patients Asymptomatic COVID-19 patients refer to people who have no relevant clinical symptoms, such as fever, cough, sore throat, and other self-perceivable or clinically recognizable symptoms and signs but are tested positive for viral etiology or serologically specific antibody testing of specimens of the respiratory tract. The first occurrence of asymptomatic infection in China can be dated back to the end of January 2020, when Henan, Zhejiang, and Guangdong provinces reported asymptomatic infections one after another. With the implementation of large-scale nucleic acid testing in key populations, more and more asymptomatic patients have been screened out starting in March 2020. The Diagnosis and Treatment Protocol for COVID-19 (Trial Version 8) issued by the National Health Commission clearly points out that asymptomatic patients are one of

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the sources of infection. Since the epidemic prevention and control in China has entered the normalization stage, there have been multiple scattered epidemics in Qingdao, Shandong Province, Shunyi, Beijing, and other places, which were mostly caused by asymptomatic patients, and had brought severe challenges to epidemic prevention and control. The incidence of asymptomatic patients varies in different regions, different gathering patterns, different groups of people, and case reports at different stages of epidemic development. On April 15, 2020, the National Health Commission announced for the first time that there were 6,764 asymptomatic patients nationwide as of April 14. For the nucleic acid testing results and modeling analysis statistics of the Diamond Princess Cruise Ship passengers, the proportion of asymptomatic infections is estimated to be 17.9%. In addition, a comprehensive analysis of a cohort study (from April 19 to May 26, 2020) of 16 asymptomatic patients infected with SARSCoV-2 worldwide found that the proportion of asymptomatic patients infected with SARS-CoV-2 was up to 40–45%. During the nationwide nucleic acid screening after the Wuhan epidemic, from May 14, 0:00 to June 1, 24:00, 2020, 9899,828 people were concentratively tested for nucleic acid testing, among which there were 300 asymptomatic patients, and the detection rate was only 0.303/10000. The infectivity and epidemiological significance of asymptomatic patients need to be assessed based on the circumstances that can be divided as follows. The first category is newly infected patients of SARS-CoV-2 who have a history of living in epidemic areas or are discovered through close contact screening, clustered epidemic investigation, and tracking investigation of sources of infection. The patient tested positive for nucleic acid, and the IgM antibody test could also be positive, being in the precursor or incubation period of the disease without showing any clinical symptoms or signs. Subsequently, COVID-19 symptoms such as fever and cough can occur at 3–7 days or even about 14 days after the infection. Such patients are under asymptomatic infection conditions in the incubation period, and they can lead to further transmission of SARS-CoV-2. Therefore, they should

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be screened, closely focused on, and included in the management of confirmed cases as soon as possible. The second category is nucleic acid test and/or serological antibody test showing positive results of the infected patients. Patients, observed after a 14-day incubation period, showed no self-perceived or clinically-recognizable signs and symptoms, or only very minor diseases, which can be easily ignored and are usually asymptomatic. But the infected person carries the SARS-CoV-2, which belongs to an inapparent infection in lemology. Such infected patients have no cough, sneezing, and other respiratory symptoms and have relatively low virus detoxification volume, hence the transmission ability is relatively weak. The third category is similar to re-positivity. After patients are infected with SARS-CoV-2, typical COVID-19 symptoms are shown. The patient reaches the discharge criteria after treatment, but still tests positive for nucleic acid at the post-discharge review. Or, in areas closed-off by the epidemic like Wuhan, the infected patient has self-healed after SARS-CoV-2 infection, yet the test results are still positive at screening. Such patients have a low virus load, most of which are the “corpses” and “debris” of the virus, so the risk of virus transmission is very low. Since the worldwide spread of the COVID-19 epidemic, there have been a large number of reports on asymptomatic patients. Asymptomatic infection has become one of the biggest threats to epidemic prevention and control. Based on the current research and observations, asymptomatic patients are infectious and can carry out silent and deep virus transmission in the population, which is very likely to become the source of infection and cause the occurrence of a clustered epidemic. Especially for countries where the epidemic has been contained, asymptomatic patients may become one of the key factors for the epidemic to rebound again and increase the difficulty in epidemic prevention and control. Therefore, the safe and scientific screening of asymptomatic patients can help significantly improve the predictability of the pandemic and evaluate the effect of control strategies and measures in real-time, which is crucial to the prevention and control of the COVID-19 epidemic.

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The State Council issued the Management Code for the SARSCoV-2 Asymptomatic Patients on April 6, 2020, requiring risk assessment, prevention, and control management for the asymptomatic patients with SARS-CoV-2. First of all, it is necessary to highlight the monitoring of asymptomatic patients and to target and step up screening efforts to test everyone in the key groups and to test everyone who is willing to be tested. The screened asymptomatic patients will be under concentrated medical observation for 14 days, referring to the confirmed case mode. During observation, if the patients show related clinical symptoms and signs of COVID-19, they will be regarded as confirmed cases. In addition, close contact with asymptomatic patients should adopt the medical observation mode of single centralized quarantine. The observation period is 14 days after the last contact with the asymptomatic patients. If the test results of nucleic acid testing are negative during the medical observation, the observation should continue until the expiration of the observation period. Finally, the epidemiological investigation should be strengthened to find out the track of asymptomatic patients, accurately determine close contacts, and strictly implement medical quarantine and observation. All the epidemiological investigations of new asymptomatic patients should be completed within 24 hours, and the epidemiological investigation information should be filled in on the epidemic direct report network.

4.4  Reinfected COVID-19 patients The virus will mutate naturally during its life cycle. The problems associated with the SARS-CoV-2 mutation mainly include the change of the virus infectivity and the possibility of recovered patients being reinfected. In lemology, reinfection refers to the phenomenon of the recovered patient being infected with the same pathogen. In late August 2020, researchers at the University of Hong Kong reported the world’s first officially confirmed case of SARSCoV-2 reinfection. The male patient diagnosed with COVID-19 at the end of March 2020 was discharged from the hospital and then he traveled to Europe in August 2020. He tested positive for nucleic

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acid after returning to Hong Kong. Through genome sequencing of the strains of the two infections, significant differences in genetic genealogy were found in the viruses of the two infections. The second infection of the patient belongs to reinfection rather than the continuous presence of the first infecting virus. Subsequently, the United States, Brazil, and the Netherlands also reported reinfected cases one after another. According to the statistics of Science, at least 24 cases of reinfection have been officially confirmed and reported worldwide by November 2020. Whether the recovered patients will have reinfection is mainly determined by the immune system and the mutation site of the virus. When the human body is infected with the virus, it first conducts a non-specific innate immune response, playing the role of resisting the virus invasion and activating the specific immune response. Meanwhile, after the innate immune system processing and antigen presentation, the adaptive immune system composed of B cells and T cells is also activated. Adaptive immune responses produce antibodies that can specifically bind to the virus and cellular immunity that identifies and removes infected cells. In addition, the adaptive immune system also forms immunological memory. Once the same virus infection occurs, the corresponding neutralizing antibodies in the serum can effectively remove the pathogens and prevent reinfection of the same strain. Since SARS-CoV-2 is a single-stranded negative-strand RNA, its RNA polymerase has the limitation in correcting self-replication errors. The viral mutation becomes inevitable as the epidemic time extends. No reinfection will occur when the virus mutation site is different from the sites that memory T cells and B cells recognize or the body-neutralizing antibody is still effective. However, when the mutation site of the virus includes both the antibody-recognized site and the T-cell-recognized site, both the neutralizing antibodies and T cells are ineffective, and reinfection occurs when previously infected individuals have contact with the virus. From the perspective of the current population level, COVID-19 reinfection is still an individual phenomenon, not universal. Also, it doesn’t mean that the human immune system cannot achieve

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effective protection against SARS-CoV-2. Due to the presence of reinfection, it is difficult to eliminate SARS-CoV-2 through the much-challenged “herd immunity” achieved by negative anti-epidemic strategies. In summary, COVID-19 caused by SARS-CoV-2 is a classic respiratory infectious disease, and its pathologic processes and immune response also follow typical respiratory infection processes. However, SARS-CoV-2 is a brand-new virus, only appearing for about one year. Therefore, there are still many deficiencies in internal replication, infection progress, and course of disease after SARS-CoV-2 infection. It requires further observation and research, so as to enhance people’s cognition of viruses, infectious diseases, immunology, epidemic diseases, and public health.

Chapter 3

Western Medicine Treatment 1.  Principles of Treatment 1.1  Determining the treatment site according to the condition (1) Suspected and confirmed cases should be treated in isolation in designated hospitals with effective isolation and protection protocols. Suspected cases should be treated in isolation in a single room, while multiple confirmed cases can be admitted to the same ward. (2) Critical cases should be admitted to the ICU for treatment as soon as possible.

1.2  Treatment principles of mild and moderate cases They are mainly administered with symptomatic supportive treatment and should be closely monitored in the early stage to stop the disease from worsening. Routine treatment: Bed rest, supportive treatment to ensure adequate energy intake, maintain water and electrolyte balance, maintain a

59

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stable internal environment, closely monitor vital signs, oxygen saturation, etc. Routine monitoring: Monitor blood routine, urine routine, CRP, biochemical indicators (liver enzymes, myocardial enzymes, kidney function, etc.), blood coagulation function, arterial blood gas analysis, and chest imaging according to the condition. If possible, cytokine testing is feasible. Timely oxygen treatment: Oxygen treatment includes nasal catheter oxygen inhalation, mask oxygen inhalation and high-flow nasal cannula oxygen therapy. If the condition permits, hydrogen– oxygen mixed inhalation gas (H2/O2: 66.6%/33.3%) treatment can be adopted. Antiviral treatment: Medications of α interferon, lopinavir/ritonavir, ribavirin, arbidol, and chloroquine phosphate can be selected for use. But attention should be paid to the adverse reactions and contraindications of the above medications and their interactions with other medications. The efficacy of the current medications should be further evaluated in clinical applications. Medications with potential antiviral effects are currently recommended to be used in the early course of the disease, focusing on patients with high-risk factors and a tendency to turn into severe cases. Simultaneous use of three or more antiviral drugs is not recommended, because intolerable toxic adverse reactions may appear. Also, when the antiviral medications interact with other medications, relevant medications should be suspended. The number of pregnancy weeks should be considered in the treatment of pregnant patients, and medications with less impact on the fetus should be chosen as much as possible. If there are problems that need to be treated after ending the pregnancy, the patients should be informed. Antimicrobial medication treatment: Blind or inappropriate use of antibiotics, especially the combination of wide-spectrum antibiotics, should be avoided.

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1.3  Treatment principles of severe and critical cases Treatment principles: On the basis of symptomatic treatment, actively prevent secondary infections, and provide timely organ function support. Correction of hypoxemia: Nasal catheter oxygen inhalation or mask oxygen inhalation, high-flow nasal cannula oxygen therapy or noninvasive ventilation, and invasive mechanical ventilation should be adopted for severe cases according to PaO2/FiO2 classification (200 – 300 mmHg; 150–200 mmHg; < 150 mmHg). It is necessary to evaluate in a timely manner whether the conditions of respiratory distress and/or hypoxemia are improved. If there is no obvious improvement, respiratory support measures should be replaced in time. If there is no contraindication, it is recommended for patients receiving high-flow nasal cannula oxygen therapy or non-invasive ventilation to simultaneously implement prone ventilation, namely, awake prone-position ventilation. The prone-position treatment time should be longer than 12 hours. Prone ventilation has a good effect on improving asthma symptoms, oxygen saturation, and inflammation at the base of the lungs. At the same time, it is necessary to pay attention to the respiratory tract management and strengthen the respiratory tract humidification to ensure the respiratory tract unobstructed. For patients with ARDS, recruitment maneuvers are recommended. Extracorporeal membrane oxygenation (ECMO) should be considered as soon as possible if the condition permits. Improvement of circulatory support: On the basis of adequate fluid resuscitation, microcirculation should be improved and vasoactive drugs should be used. Changes in the patient’s blood pressure, heart rate, and urine volume, as well as lactic acid and base excess in arterial blood gas analysis, should be closely monitored. Non-invasive or invasive hemodynamic monitoring should be conducted if necessary.

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Attention should be paid to fluid balance strategies to avoid excess and deficiency. Anticoagulation therapy: High blood coagulation may occur in severe or critical cases due to the release of numerous inflammation mediators, hormones, and the use of immunoglobulin. Additionally, mechanical ventilation, central venous catheter, surgery, and other operations can cause vascular endothelial injury. Due to the synthesis of the above factors, there is a higher risk of combining thromboembolism in severe or critical cases. Therefore, for those with no anticoagulant contraindications and with significantly increased D-dimer, the preventive use of anticoagulant drugs is recommended. Kidney failure and renal replacement therapy: The cause of kidney function injury should be actively investigated. The treatment of renal failure patients needs to be focused on body fluid balance, acidbase balance, and electrolyte balance. We should pay attention to nitrogen balance, calorie intake, and trace elements in terms of nutritional support treatment. Continuous renal replacement therapy may be selected for severe cases. Convalescent plasma therapy: It is suitable for patients with rapid progression, and severe and critical conditions. Blood purification treatment: The blood purification system includes plasma replacement, adsorption, irrigation, and blood/plasma filtration, which can remove inflammatory factors and block “cytokine storms”. It can be used in the treatment of early- and middle-stage “cytokine storms” in severe and critical cases. Immunotherapy: For patients with extensive double-lung lesions and severe patients, whose IL-6 levels are elevated, tocilizumab treatment may be considered. Allergic reactions should be noticed, and patients with tuberculosis and other active infections are forbidden.

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Other treatment measures: Xuebijing injection treatment may be considered. For patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and hyperactivation of body inflammatory response, glucocorticoids can be used according to the circumstances. In addition, intestinal microecologics can be used to maintain intestinal microecological balance and prevent secondary bacterial infection. Psychological intervention should be established to relieve anxiety and fear.

1.4  Treatment principles of special populations For pregnant patients, it is recommended to use the Food and Drug Administration (FDA) pregnancy safety-grade class B and C drugs for COVID-19 treatment. Patients in middle and late pregnancy can easily develop into severe cases and need to be hospitalized for close observation, quarantine, and treatment, jointly managed by relevant departments. Infants whose mothers are infected with SARS-CoV-2 should be monitored in the negative pressure ward and breast milk should be suspended. Severe or critical patients combined with pregnancy should actively terminate the pregnancy. A cesarean section is preferred. For severe and critical children, adult medication can be referred, and intravenous immunoglobulin can be considered appropriate. For the elderly, secondary prevention of the underlying diseases should be done and drug interaction should be closely monitored. The treatment principle of multisystem inflammatory syndrome in children (MIS-C) includes multidisciplinary cooperation, earlystage anti-inflammation, correction of shock and coagulation disorder, organ function support, and anti-infection treatment if necessary. Treatment for patients with typical or atypical Kawasaki disease manifestations is similar to the classic treatment regimen for Kawasaki disease. Treatment is based on intravenous human immunoglobulin, glucocorticoids, and oral aspirin.

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2.  Western Medicine Treatment 2.1  Supportive treatment 2.1.1  Respiratory support treatment 2.1.1.1  General oxygen therapy General oxygen therapy devices include a double-lumen nasal cannula, ordinary oxygen mask, oxygen storage mask, and Venturi mask. It is suitable for patients with PaO2 30 cmH2O), seven days of mechanical ventilation or longer. (4) Age: There is no age-specific contraindication, but an increased risk of death with age should be considered.

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(5) Accompanied by severe multiple organ failure. (6) If circulatory-assistant VA-ECMO support is required, moderate to severe aortic insufficiency and acute dissection of the aorta are also contraindications. (7) Immunosuppression caused by drugs (neutrophil absolute count 28 pg/mL). The observation of 187 patients with COVID-19 at another hospital found that 27.8% of the patients had different degrees of myocardial injury, elevated T cardiac troponin T (TnT), and a higher frequency of being complicated by malignant arrhythmia. Patients with elevated plasma TnT had a significantly higher mortality rate than those with normal TnT (59.6% vs. 8.9%). Another study on the clinical features and prognosis of COVID-19 patients showed that 16.7% of the 13 diagnosed patients developed an arrhythmia, and 7.2% experienced acute heart injury. It was found that severe cases were more prone to heart disease than mild cases. A German study tracking 100 patients recovering from COVID-19 examined myocardial injury markers and cardiovascular MRI. The results showed that 78% of the patients had heart injury and 60% still had myocardial inflammation. A hospital in Wuhan conducted a retrospective study of 26 patients who recovered from COVID-19

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and initially developed cardiac symptoms, among which 15 patients (58%) showed abnormal MRI results and 14 patients (54%) had myocardial edema. At present, the observation of cardiovascular sequelae in COVID-19 patients is increasing. As a virus similar to SARS-CoV in structure, SARS-CoV-2 can lead to chronic and continuous injuries to the cardiovascular system to a certain extent. The specific injuries still need to be further studied through the follow-up observation of discharged COVID-19 patients.

2.3  Pulmonary dysfunction In the study on the pulmonary function characteristics of COVID-19 patients at time of hospital discharge, scholars found that some patients had different degrees of pulmonary dysfunction, mainly including dysfunction of diffusion of the lung followed by restrictive ventilatory disorder. The extent of the injury was related to the severity of the disease during hospitalization. One of the important reasons for this is pulmonary fibrosis. The so-called pulmonary fibrosis refers to interstitial lung changes characterized by alveolar damage, excessive repair of the alveolar epithelium, fibroblast proliferation, massive extracellular matrix deposit, and damage to the lung tissue structure. In clinical practice, it often manifests dyspnea and dry cough after different degrees of activities, and different degrees of thread net opacity can be seen in chest CT. Pulmonary fibrosis caused by severe pneumonia is clinically called post-inflammatory pulmonary fibrosis (PPF). Through the analysis of CT images at admission and pre-discharge of 60 patients with COVID-19, studies found that the incidence of PPF in mild COVID-19 cases was up to 70% and 100% in severe COVID-19 cases at discharge. Around 80% of the patients still had shortness of breath after activities at discharge. Its acute imaging performance showed mostly ground-glass opacity and patchy clouding consolidation of multiple lobes and segments, with some lesions similar to organized pneumonia-like changes; diffuse ground-glass opacity was

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seen in severe patients. During convalescence, thread net opacity and traction bronchiectasis, namely pulmonary fibrosis, could be seen. Some patients showed normal interstitial pneumonia; some patients also showed patchy clouding opacity distributed along the bronchovascular bundle without pleural involvement, namely non-specific interstitial pneumonia. Pathology of small lung specimens of corpses and autopsy pathology both suggested diffuse alveolar injury, which was also found in SARS and MERS patients. It is initially presumed that the pulmonary fibrosis and consolidation of COVID-19 patients were not as serious as lesions caused by SARS, but the exudative response was more obvious. If the lesions involve more lobes and segments, they will have a great impact on pulmonary function, which will bring challenges to the self-repair of the patient’s lung and the rehabilitation treatment in the later stage. To sum up, whether the PPF of COVID-19 patients can self-heal or will continue to progress, leading to a continuous decline in pulmonary function, still needs to be clarified by further follow-up observation after discharge.

2.4  Neurosystem influence SARS-CoV-2 infection can cause persistent or even permanent injury to the nervous system, such as Alzheimer’s disease. In the UK, oneseventh of the COVID-19 patients treated in ICU may be left with long-term or permanent brain injury. Almost 70% of such patients have delirious symptoms, and 20% may have a chronic cognitive disorder. A neurologic study of 214 patients with COVID-19 showed that 78 patients (36.4%) had neurological manifestations. Specific manifestations are categorized as follows: (1) symptoms of the central nervous system such as headache, dizziness, consciousness disorder, acute cerebrovascular diseases, and epilepsy; (2) symptoms of the peripheral nervous system such as hypogeusia, hyposmia, loss of appetite, and neuralgia; (3) skeletal muscle injury. In addition, severe patients are more likely to have neurological complications, with about 15% of severe COVID-19 patients and 2.4% of mild COVID-19 patients showing altered consciousness levels.

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This may be caused by the viral invasion of the central nervous system or systemic diseases. In addition, specific neurological symptoms in COVID-19 patients include dysosmia (35.7–85.6%) and dysgeusia (33.3– 88.8%), especially in mild cases. Dysosmia is one of the important symptoms of SARS-CoV-2 infection, and “self-quarantine and testing” of such patients should be considered. The American Academy of Otolaryngology — Head and Neck Surgery also recommends incorporating dysosmia and dysgeusia in the SARS-CoV-2 screening list. All of the above suggests that the infection of SARS-CoV-2 may directly damage the mucosa of the olfactory region and olfactory cells and also lead to degenerative changes in the olfactory pathway.

2.5  Liver and kidney function injury 2.5.1  Liver injury In the previous SARS epidemic, hepatic insufficiency was found in up to 60% of the patients with SARS, and it was also found in patients with MERS-CoV infection. At present, more and more reports also indicate liver-related enzyme abnormalities in COVID-19 patients with different degrees of liver injury. It was also found that the increase of liver-related enzymes mainly occurred in male and severe patients. Hypoalbuminemia was one of the signs of severe infection and poor prognosis. Recent studies have shown that the main manifestations of liver injury were abnormal ALT/AST and elevated bilirubin. The proportion of patients developing liver injury in severe COVID-19 patients was significantly higher than that in mild patients. In the deaths of COVID-19 patients, the incidence of liver injury may be as high as 58.06% and 78%. In addition, the incidence of elevated aminotransferase and bilirubin in severe COVID-19 patients was more than twice that of other patients. Therefore, some scholars believe that SARS-CoV-2 can directly bind to ACE2 in the liver, thus causing direct injury to the liver. However, it is undeniable that some of the

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drugs for treating COVID-19, such as lopinavir and ritonavir, can also cause drug-induced liver injury. To sum up, the mechanism of liver injury in COVID-19 patients still needs further discussion. So far, there have been few case reports of COVID-19 patients complicated with acute liver failure, and liver dysfunction has been widely seen in severe COVID-19 cases. In mild COVID-19 cases, liver injury is usually transient, and it can be gradually improved to a normal level with the improvement of the disease. However, when a severe liver injury occurs, drugs with liver protection functions should be applied to such patients. Although it is not feasible to quantify the clinically obvious liver function abnormalities, we should also take the liver function as the key observation index for future follow-up. If liver function abnormalities occur, they should be treated in time to avoid more serious liver injury.

2.5.2  Renal injury Acute kidney injury (AKI) is one of the major complications of COVID-19 patients. It is more common in severe COVID-19 patients, especially those with severe infections. Moreover, it has been found that the mortality rate in COVID-19 patients is associated with the complication rate of AKI. Since SARS-CoV-2 can invade the kidneys, up to 25% of the severe patients infected with SARS-CoV-2, especially those with potential complications, had acute kidney injury. The occurrence of AKI associated with COVID-19 may be due to renal tubular injury, vascular injury, glomerulonephritis, or rhabdomyolysis caused by reduced volume, multiple organ failure, and viral infection. Autopsy reports revealed abnormalities of renal cells in patients infected with SARS-CoV-2 and found significant proximal acute renal tubular injury and the subsequent endothelial injury, glomerular and vascular changes. In addition, it has been verified that SARS-CoV-2 binds to ACE2 receptors and is highly expressed in renal foot cells and proximal renal tubular epithelial cells. ACE2 has currently be considered a binding site and plays an important role in renal injury mechanisms.

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It has been found in a study that 7-63% of COVID-19 patients were tested to have proteinuria. In another study, 26.7% of COVID-19 patients developed hematuria. The Journal of the American Society of Nephrology noted a higher incidence of proteinuria (81.2% and 85.7%, respectively) and hematuria (39.1% and 69.6%, respectively) in severe and critical COVID-19 patients. Among 333 patients with COVID-19, patients with AKI had a higher rate of proteinuria (88.6% vs. 63.1%) and hematuria (60% vs. 41.7%) compared with the non-AKI group. A retrospective study showed that COVID-19 patients complicated by AKI had a poorer prognosis than those without AKI. In addition to the potential influence of SARS-CoV-2, in severe COVID-19 patients, the potential kidney injury due to the renal toxicity of the drugs cannot be ignored. Thus, continuous monitoring of associated biomarkers may be an effective means of assessing the possible complication of AKI during the first seven days of hospitalization in severe patients. If monitoring of biomarkers suggests a high risk of AKI, early intervention is required. Overall, by the close monitoring of creatinine and urine volume of patients, optimizing the blood volume and hemodynamic state, and avoiding the use of nephrotoxic drugs (such as aminoglycosides, ACE inhibitors, nonsteroidal anti-inflammatory drugs), we can reduce the possible kidney injury in COVID-19 patients to some extent.

2.6  Reproductive system injury SARS-CoV-2 selects ACE2 as its receptor to infect various cells that express ACE2 in the body. Among them, the large amount of ACE2 expressed in testicles is mainly concentrated in testicular spermatogonium, Sertoli cells, and interstitial cells, all of which are closely related to male reproductive function. Previous studies have shown that SARS infection can cause testitis, seminiferous tubule injury, and impaired male fertility. The pathological results of 37 systematic autopsies and 54 minimally invasive autopsies showed the different degrees of decrease and injury of spermatogenic cells in the testis of

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patients with COVID-19. A clinical study of 13 patients with COVID-19 in Wuhan found that no SARS-CoV-2 was detected in semen from 12 asymptomatic or mild patients or in the testicular tissue from the one death case. Currently, no exact clinical studies have confirmed that SARS-CoV-2 infection can injure the testicles and affect male fertility. However, SARS-CoV-2 is highly similar to SARS, with the same receptor (ACE2). In theory, SARS-CoV-2 may invade the reproductive system through ACE2 and affect male reproductive function. Therefore, the reproductive health problems of men of childbearing age infected with SARS-CoV-2 should be a concern, and a fertility examination should be conducted after their rehabilitation.

2.7  Psychological disorders The COVID-19 epidemic is a sudden outbreak that is psychologically considered to be a traumatic and stressful event because it is fulminant, unpredictable, and even life-threatening. The occurrence of such events will often destroy people’s basic needs of security, sense of trust, sense of control, self-esteem, and intimate relationship, leading to a series of cognitive, emotional, and behavioral changes. Severe cases may develop into anxiety disorder, depressive disorder, and even symptoms of post-traumatic stress disorder (PTSD). An online survey of 50,000 people conducted by research teams in China found that the negative impact of the COVID-19 epidemic on national mental health was emerging. The incidence of depression, anxiety, insomnia, and acute stressful reactions in the general Chinese population was around 30%; in COVID-19 patients, it was about 70%. In addition, the incidence of mild or above anxiety symptoms, depressive symptoms, insomnia symptoms and various mental and psychological problems among medical staff was as high as 50%. The risk of anxiety, depression, and various mental and psychological problems was significantly higher among frontline medical staff. The first systematic review and meta-analysis considering the consequences of the mental diseases caused by SARS-CoV-2 were published in The Lancet Psychiatry. The review included 3,550

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patients with COVID-19, SARS, and MERS, aged 12-68, and the follow-up duration was 60 days to 12 years. System review showed that 28% of the SARS and MERS patients experienced insanity, 33% developed depression, 36% developed anxiety, 34% developed hypomnesia, and 42% developed insomnia during the acute phase. Studies of the post-recovery population (six weeks to 39 months) found that 11% of the patients experienced depression, 12% developed insomnia, 12% developed anxiety, 13% developed irritability, 19% developed dysmnesia, 19% developed fatigue, 30% developed traumatic memory, and 100% developed sleep disorders. The metaanalysis showed that in the late stage of onset, the point prevalence rate of PTSD was 32.2%, depression 14.9%, and anxiety disorder 14.8%. In the long run, clinicians should pay attention to the possibility of common mental problems such as depression, anxiety, fatigue, and PTSD after the COVID-19 epidemic. In January 2020, the National Health Commission issued the Guiding Principles of Emergency Psychological Crisis Intervention under the COVID-19 Epidemic. The guiding principles refer to the experience fighting the SARS outbreak in 2003 and recommend mental health services for patients infected with SARS-CoV-2 and their relatives and friends, medical staff, close contacts, and suspected cases under selfquarantine at home. SARS-CoV-2 not only attacks our bodies but also causes psychological distress. In the post-epidemic era, we should put much emphasis on mental health problems and pay close attention to the mental and psychological health problems of infected people, patients, close contacts, bereavement families, and medical staff. We should also provide personalized diagnosis and treatment and longterm follow-up and effectively reduce the negative impact of the COVID-19 epidemic on mental and psychological health.

2.8  Special groups 2.8.1  Pregnant women Clinical characteristics of pregnant women with COVID-19 are similar to those of non-pregnant COVID-19 adult patients, mostly

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manifesting decreased absolute lymphocyte count, increased CRP, ESR, and D-dimer, and normal leukocytes. Common symptoms include fever and cough; symptoms such as myalgia, discomfort, sore throat, diarrhea, and shortness of breath are not common. The analysis of 108 pregnant women with COVID-19 found that they usually experienced fever (68%), persistent dry cough (34%), discomfort (13%), and dyspnea (12%), only seven (6%) experienced diarrhea at admission. Of the 68 (59%) recorded cases, 40 lymphopenia cases were reported. In addition, 45 of the 64 cases showed elevated CRP (70%). The study showed that about 3% of pregnant women with COVID-19 underwent treatment for severe patients, with a pre-term birth rate of 20% and a neonatal mortality rate of 0.3%. As the total lung volume decreases in late pregnancy, lung secretions cannot be removed effectively, resulting in rapid progression of lung inflammation from focal changes in the lung parenchyma to bilateral diffuse lung parenchymal consolidation. Under the background of the above lung changes, it is more likely to lead to hypoxic respiratory failure during pregnancy. The official website of the Health and Medical Education Ministry of Iran reported two pregnant women with COVID-19 who developed ARDS and died after giving birth. A number of studies have shown that patients with concurrent pregnancy and COVID-19 may have premature birth, abortion, and fetal intrauterine growth restriction. They can also have other obstetric complications, such as pre-eclampsia, premature rupture of membranes, irregular contractions, and stillbirth. But whether these complications have a direct causal relationship with COVID-19 requires further investigation. Pregnant women with COVID-19 may face severe onset or even death due to the specific immune response during pregnancy and the potential risk of a “cytokine storm” after SARS-CoV-2 infection. In addition, adverse reactions in newborns have been reported, including fetal distress, premature birth, respiratory distress, thrombocytopenia, and abnormal liver function. However, it is not clear whether they are associated with maternal SARS-CoV-2 infection.

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2.8.2 Children The incidence of COVID-19 in children mostly has epidemiological associations with adult patients. Compared with adult patients, children’s clinical manifestations are atypical and relatively mild. Most infected children have mild clinical manifestations and good prognoses and can recover within 1–2 weeks after the onset. Children infected with SARS-CoV-2 may be asymptomatic or have a fever, dry cough, and fatigue accompanied by a handful of upper respiratory infection symptoms, including nasal obstruction and runny nose, and they can also be accompanied by gastrointestinal symptoms, such as abdominal discomfort, nausea, vomiting, abdominal pain, and diarrhea. Recent studies have shown a rare emerging inflammatory disease in children and adolescents, pediatric inflammatory multisystem syndrome (PIMS), resembling a post-infectious presentation that may be associated with COVID-19. The syndrome was reported to share common characteristics with Kawasaki disease, toxic shock syndrome, bacterial meningitis, and hemophagocytic syndrome. Common features include abdominal pain, other gastrointestinal symptoms, skin rashes, and myocardial inflammation. Among them, gastrointestinal symptoms are more prominent and appeared in 84% of children in the cohort study, and 70.5% of children developed skin rashes. In addition, abnormal cardiac manifestation is common, and a cohort study in New York showed that 10 (60%) of 16 COVID-19 children with PIMS-like symptoms had non-specific abnormal ST/T waves, and about one-third of the post-admission ECG showed moderate to severe ventricular dysfunction. Another study found that one-third of such children had a left ventricular ejection fraction of