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Kamps - Hoffmann

SARS Reference - 10/2003

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c Flying Publisher. All rights reserved.

All material in this book is protected by copyright. No part of this

book may be reproduced and/or distributed in any form without the

express, written permission of the author.

Third Edition, October 2003

SARS Medicine is an ever-changing field. The editors and authors of

SARSReference.com have made every effort to provide information

that is accurate and complete as of the date of publication. However,

in view of the rapid changes occurring in medical science, SARS

prevention and policy, as well as the possibility of human error, this

text may contain technical inaccuracies, typographical or other errors.

Readers are advised to check the product information currently provided

by the manufacturer of each drug to be administered to verify

the recommended dose, the method and duration of administration,

and contraindications. It is the responsibility of the treating physician

who relies on experience and knowledge about the patient to determine

dosages and the best treatment for the patient. The information

contained herein is provided "as is" and without warranty of any kind.

The contributors to this site, including AmedeoGroup and Flying

Publisher, disclaim responsibility for any errors or omissions or for

results obtained from the use of information contained herein.

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La chronique est le temoignage pour

(Albert Camus, La Peste)

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Kamps and Hoffmann (eds.)

Contents

References 25

Discovery of the SARS Virus 30

Initial Research 30

The Breakthrough 31

Coronaviridae 32

SARS Co-V 33

Genome Sequence 33

Morphology 34

Organization 34

Detection 35

Stability and Resistance 36

Natural Host 36

Antiviral Agents and Vaccines 37

Antiviral Drugs 37

Vaccines 37

Outlook 38

References 43

Routes of Transmission 49

Factors Influencing Transmission 50

Patient Factors in Transmission 51

The Unsuspected Patients 54

High-Risk Activities 54

Transmission during Quarantine 55

Transmission after Recovery 56

Animal Reservoirs 56

Conclusion 56

References 57

Introduction 61

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Modeling the Epidemic 63

Starting Point 63

Global Spread 64

Hong Kong 64

Vietnam 66

Toronto 67

Singapore, February 2003 69

China 72

Taiwan 72

Other Countries 73

Eradication 75

Outlook 75

References 76

Introduction 81

International Coordination 82

Advice to travelers 83

Management of SARS in the post-outbreak period 84

National Measures 84

Legislation 85

Infection Control in Healthcare Settings 89

General Measures 89

Protective Measures 90

Special Settings 93

Internet Sources 95

Infection Control in Households 98

Possible Transmission from Animals 101

After the Outbreak 102

Conclusion 102

References 103

WHO Case Definition 108

Suspect case 108

Probable case 109

Exclusion criteria 109

Reclassification of cases 110

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CDC Case Definition 110

Introduction 112

Laboratory tests 113

Molecular tests 114

Virus isolation 115

Antibody detection 115

Limitations 116

Biosafety considerations 117

Outlook 118

Table, Figures 120

References 122

Clinical Presentation 124

Hematological Manifestations 125

Atypical Presentation 127

Chest Radiographic Abnormalities 128

Chest Radiographs 129

CT Scans 130

Diagnosis 131

Clinical Course 132

Viral Load and Immunopathological Damage 135

Histopathology 136

Lung Biopsy 136

Postmortem Findings 136

Discharge and Follow-up 137

Psychosocial Issues 138

References 138

Appendix: Guidelines 141

Antibiotic therapy 144

Antiviral therapy 145

Ribavirin 145

Neuraminidase inhibitor 146

Protease inhibitor 146

Human interferons 146

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Human immunoglobulins 147

Alternative medicine 148

Immunomodulatory therapy 148

Corticosteroids 149

Other immunomodulators 151

Assisted ventilation 151

Non-invasive ventilation 152

Invasive mechanical ventilation 153

Clinical outcomes 153

Outlook 155

Appendix 1 156

A standardized treatment protocol for adult SARS in Hong Kong

156

Appendix 2 158

A treatment regimen for SARS in Guangzhou, China 158

References 159

Clinical Manifestation 168

Radiologic Features 169

Treatment 170

Clinical Course 171

References 171

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Contributing Authors

Virology/Molecular Diagnostics

Bernhard Nocht Inst. of Tropical Medicine

Bernhard Nocht Str. 74

20359 Hamburg

Germany

Division of Respiratory and Critical Care Medicine

Department of Medicine

Pamela Youde Nethersole Eastern Hospital

Hong Kong SAR, PR China

Institute for Medical Virology

Johann Wolfgang Goethe University

Paul Ehrlich-Str. 40

60596 Frankfurt am Main

Germany

Division of Respiratory and Critical Care Medicine

Department of Medicine

Pamela Youde Nethersole Eastern Hospital

Hong Kong SAR, PR China

Division of Respiratory and Critical Care Medicine

Department of Medicine

Pamela Youde Nethersole Eastern Hospital

Hong Kong SAR, PR China

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Kamps and Hoffmann (eds.)

Preface

First recognized in mid-March 2003, Severe Acute Respiratory Syndrome

(SARS) was successfully contained in less than four months.

On 5 July 2003, WHO reported that the last human chain of transmission

of SARS had been broken.

Much has been learned about SARS, including its causation by a new

coronavirus (SARS-CoV); however, our knowledge about the ecology

of SARS coronavirus infection remains limited. In the post-outbreak

period, all countries must remain vigilant for the recurrence of SARS

and maintain their capacity to detect and respond to the re-emergence

of SARS should it occur. Resurgence of SARS remains a distinct

possibility and we need to be prepared.

For the third edition, most chapters have remained unchanged, with

two exceptions: the Virology section has been updated and the chapter

entitled SARS Treatment has been completely rewritten by Loletta So,

Arthur Lau, and Loretta Yam from the Division of Respiratory and

Critical Care Medicine, Department of Medicine, Pamela Youde

Nethersole Eastern Hospital, Hong Kong SAR, PR China. In the event

of a new SARS outbreak, we shall have to rely on existing treatment

modalities. These have now been brilliantly overviewed by our new

colleagues.

Bernd Sebastian Kamps and Christian Hoffmann

www.HIVMedicine.com

October 17, 2003

10 Preface

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Preface to the Second Edition

Just over five months ago, SARS started to spread around the world. It

is the first major new infectious disease of this century, unusual in its

high morbidity and mortality rates, and it is taking full advantage of

the opportunities provided by a world of international travel. At the

time of this writing, more than 8,000 persons with probable SARS

have been diagnosed; 812 patients have died. Fortunately, one by one,

the outbreaks in the initial waves of infection have been brought under

control.

SARS demonstrates dramatically the global havoc that can be

wreaked by a newly emerging infectious disease. SARS was capable

of bringing the healthcare system of entire areas to a standstill, striking

nurses, doctors and other medical personnel: human resources

vital for disease control. Surgery and vital treatments for patients with

serious conditions had to be postponed; care in emergency rooms was

disrupted. A significant proportion of patients required intensive care,

thus adding to the considerable strain on hospital and healthcare systems.

Hospitals, schools, and borders were closed. The economic

impact on individuals was profound, affecting tourism, education and

employment.

The disease has several features that make it a special threat to international

public health. There is no vaccine or treatment, and health

authorities have to resort to control tools dating back to the earliest

days of empirical microbiology: isolation, infection control and contact

tracing.

The response of the scientific community to the new health threat was

immediate and breath-taking. The etiologic relationship between a

previously unknown coronavirus and SARS was established one

month after the WHO issued a global alert and called upon 11 leading

laboratories in 9 countries to join a network for multicenter research

into the etiology of SARS and to simultaneously develop a diagnostic

test. The early recognition of the etiologic agent has made the virus

available for investigation of antiviral compounds and vaccines.

Experience with SARS has shown that, with strong global leadership

by the WHO, scientific expertise from around the world can work in a

very effective, collaborative manner to identify novel pathogens.

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SARS has demonstrated how the world can come together in scientific

collaboration, and what the power of the Internet is. This outstanding

effort limited the potentially explosive spread of the outbreak.

Some hope exists that the disease might be contained, but much about

SARS remains unknown. How important are animals in its transmission?

Will SARS return with a stronger force next year? What are the

host or virus factors responsible for the "superspreader" phenomenon,

in which a single patient may infect many people through brief casual

contact or possibly environmental contamination?

At this moment, a global epidemic of the magnitude of the 1918-19

influenza pandemic appears unlikely. However, development of effective

drugs and vaccines for SARS is likely to take a long time. If

SARS is not contained, the world will face a situation in which every

case of atypical pneumonia, and every hospital-based cluster of febrile

patients with respiratory systems will have the potential to rouse suspicions

of SARS and spark widespread panic. The world will therefore

anxiously watch if new outbreaks occur.

Bernd Sebastian Kamps and Christian Hoffmann

July 10, 2003

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Preface to the First Edition

Just over three months ago, SARS started to spread around the world.

It is the first major new infectious disease of this century and it is

taking full advantage of the opportunities provided by a world of international

travel. As of this writing (May 8), more than 7,000 persons

have been infected in 29 countries. In China, the disease seems to be

difficult to control. If not contained, SARS will change the way we

live our lives.

The response of the scientific community to the new health threat has

been breath-taking. The etiologic relationship between a previously

unknown coronavirus and SARS was established just one month after

the WHO issued a global alert and called upon 11 leading laboratories

in 9 countries to join a network for multicenter research on the etiology

of SARS and to simultaneously develop a diagnostic test. The early

recognition of the etiologic agent has made the virus available for

investigation of antiviral compounds and vaccines.

The WHO, the CDC, and national health agencies have disseminated

up-to-the-minute information for clinicians, public health officials,

and healthcare workers. The network of laboratories, created by the

WHO, takes advantage of modern communication technologies (email;

secure website) so that the outcomes of investigations on clinical

samples from SARS cases can be shared in real time. On the secure

WHO website, network members share electron microscope pictures

of viruses, sequences of genetic material for virus identification and

characterization, virus isolates, and various samples from patients and

postmortem tissues. Samples from one patient can be analysed in

parallel by several laboratories and the results shared in real time.

discovery and speed of communication are hallmarks of the response

to SARS and reflect amazing achievements in science, technology,

and international collaboration. However, despite these advances, a

very sobering question remains —are we fast enough? Can we prevent

a global pandemic of SARS?"

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We don't know. It is the nature of epidemics to be unpredictable. What

we do know is that unprecedented efforts will be needed to shape a

world without SARS. SARSReference.com will accompany these

efforts with monthly updates for the duration of the epidemic.

Bernd Sebastian Kamps and Christian Hoffmann

May 8, 2003

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Summary

Severe Acute Respiratory Syndrome (SARS) is an acute respiratory

illness caused by infection with the SARS virus. Fever followed by a

rapidly progressive respiratory compromise is the key complex of

signs and symptoms, which also include chills, muscular aches, headache

and loss of appetite.

Mortality, initially believed to be around 3 %, may well be as high as

15 %. The WHO estimates that the case fatality ratio of SARS ranges

from 0% to 50% depending on the age group affected: less than 1% in

persons aged 24 years or younger; 6% in persons aged 25 to 44 years;

15% in persons aged 45 to 64 years; and greater than 50% in persons

http://www.who.int/csr/sarsarchive/2003_05_07a/en/).

The etiologic agent of SARS is a coronavirus which was identified in

March 2003. The initial clusters of cases in hotel and apartment

buildings in Hong Kong have shown that transmission of the SARS

virus can be extremely efficient. Attack rates in excess of 50% have

been reported. The virus is predominantly spread by droplets or by

direct and indirect contact. Shedding in feces and urine also occurs.

Medical personnel, physicians, nurses, and hospital workers are

among those commonly infected.

In the absence of effective drugs or a vaccine for SARS, control of

this disease relies on the rapid identification of cases and their appropriate

management, including the isolation of suspect and probable

cases and the management of their close contacts. In the great majority

of countries, these measures have prevented imported cases from

spreading the disease to others.

At present, the most efficacious treatment regimen for SARS is still

subject to debate. For patients with progressive deterioration, intensive

and supportive care is of primary importance. Immunomodulation by

steroid treatment may be important.

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Chapter 1: Timeline

The initial cases of SARS appear in the Guangdong Province, South

China.

A small notice in the Weekly Epidemiological Record reports 305

cases and 5 deaths from an unknown acute respiratory syndrome

which occurred between 16 November and 9 February 2003 in the

spread to household members and healthcare workers. The Chinese

Ministry of Health informs the WHO that the outbreak in Guangdong

is clinically consistent with atypical pneumonia. Further investigations

rule out anthrax, pulmonary plague, leptospirosis, and hemorrhagic

fever.

Two weeks later, at the end of February, the Chinese Ministry of

Health reports that the infective agent causing the outbreak of the

atypical pneumonia was probably Chlamydia pneumoniae. (WHO

A 65-year-old medical doctor from Guangdong checks into the 9th

floor of the Metropole hotel in Hong Kong. He had treated patients

with atypical pneumonia prior to departure and is symptomatic upon

arrival in Hong Kong. He infects at least 12 other guests and visitors

Dr Carlo Urbani, a WHO official based in Vietnam, is alarmed by

these cases of atypical pneumonia in the French Hospital, where he

has been asked to assist. He is concerned it might be avian influenza,

and notifies the WHO Regional Office for the Western Pacific.

New reports of outbreaks of a severe form of pneumonia come in from

Vietnam. The outbreak traces back to a middle-aged man who was

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admitted to hospital in Hanoi with a high fever, dry cough, myalgia

and mild sore throat. Following his admission, approximately 20 hospital

staff become sick with similar symptoms. In some cases, this is

followed by bilateral pneumonia and progression to acute respiratory

distress.

Eighteen healthcare workers on a medical ward in the Prince of Wales

Hospital in Hong Kong report that they are ill. Within hours, more

than 50 of the hospital's healthcare workers are identified as having

had a febrile illness over the previous few days. On March 11, 23 of

them are admitted to the hospital for observation as a precautionary

The outbreaks, both in Hanoi and Hong Kong, appear to be confined

to the hospital environment. Hospital staff seem to be at highest risk.

The new syndrome is now designated "severe acute respiratory syndrome",

or SARS.

The WHO issues a global alert about cases of severe atypical pneumonia

following mounting reports of cases among staff in the Hanoi

and Hong Kong hospitals.

The Ministry of Health in Singapore reports 3 cases of atypical pneumonia,

including a former flight attendant who had stayed at the Hong

Kong hotel. Contact tracing will subsequently link her illness to more

The WHO issues a heightened global health alert about the mysterious

pneumonia after cases are also identified in Singapore and Canada.

The alert includes a rare emergency travel advisory to international

travelers, healthcare professionals and health authorities, advising all

individuals traveling to affected areas to be watchful for the development

of symptoms for a period of 10 days after returning

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Kamps and Hoffmann (eds.)

The WHO calls upon 11 leading laboratories in 9 countries to join a

network for multicenter research into the etiology of SARS and to

simultaneously develop a diagnostic test. The network takes advantage

of modern communication technologies (e-mail; secure website)

so that the outcomes of investigations on clinical samples from SARS

cases can be shared in real time

network members share electron microscope pictures of viruses,

sequences of genetic material for virus identification and characterization,

virus isolates, various samples from patients, and postmortem

tissues. Samples from one patient can be analyzed in parallel by several

laboratories and the results shared in real time. The goal: detection

of the causative agent for SARS and the development of a diagnostic

test.

One week after the global alert, the WHO publishes an update on the

situation, saying that the failure of all previous efforts to detect the

presence of bacteria and viruses known to cause respiratory disease

strongly suggests that the causative agent might be a novel pathogen.

The Center for Disease Control (CDC) publish a preliminary clinical

description of SARS

Scientists at the CDC and in Hong Kong announce that a new coronavirus

has been isolated from patients with SARS.

Within days, sequences of the coronavirus polymerase gene are compared

with those of previously characterized strains and scientists are

able to demonstrate that this virus is distinct from all known human

pathogens. In addition, serum from patients with SARS is evaluated to

detect antibodies to the new coronavirus, and seroconversion is documented

in several patients with acute- and convalescent-phase specimens.

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The first global "grand round" on the clinical features and treatment of

SARS is held by the WHO. The electronic meeting unites 80 clinicians

from 13 countries; a summary of their discussions and conclusions

is being made available on the SARS page of the WHO website,

The CDC reports on the investigation into a cluster of 12 persons with

suspected/probable SARS in Hong Kong which could be traced back

to the medical doctor from southern China who arrived on 21 February

2003 and stayed in the Metropole hotel

In Hong Kong, a steep rise in the number of SARS cases is detected in

Amoy Garden, a large housing estate consisting of ten 35-storey

blocks, which are home to around 15,000 persons. The Hong Kong

Department of Health issues an isolation order to prevent the further

spread of SARS. The isolation order requires residents of Block E of

Amoy Gardens to remain in their flats until midnight on 9 April

to rural isolation camps for 10 days.

The New England Journal of Medicine publishes two articles about

clusters of SARS patients in Hong Kong and in Toronto on its website

The WHO recommends that persons traveling to Hong Kong and the

Guangdong Province of China consider postponing all but essential

The WHO's Weekly Epidemiological Record publishes a new case

definition, recommends measures to prevent the international spread

of SARS, and proposes the implementation of a global surveillance

Timeline 19

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includes a template of case reporting form).

The WHO recommends that airport and port health authorities in affected

areas undertake screening of passengers presenting for international

travel. In addition, the WHO issues guidance on the management

of possible cases on international flights, disinfection of aircraft

carrying suspect cases and surveillance of persons who have been in

contact with suspect cases while undertaking international travel.

Although this guidance is primarily directed at air travel, the same

procedures are recommended for international travel by road, rail or

sea from affected areas.

Three research groups publish results which suggest that a novel coronavirus

Using serological tests and a reverse-transcriptase polymerase chain

reaction (RT-PCR) specific for the new virus, one group of researchers

found that 45 out of 50 patients with SARS, but none of the controls,

examination of cultures reveals ultrastructural features

characteristic of coronaviruses. With specific diagnostic RT-PCR

primers, several identical nucleotide sequences are identified in 12

patients from several locations; a finding which is consistent with a

up to 100 million molecules per milliliter are found in sputum

Canadian researchers announce the first successful sequencing of the

coronavirus genome believed to be responsible for the global epidemic

of SARS. Scientists from the CDC confirm these reports. The

new sequence has 29,727 nucleotides which fits well with the typical

RNA boundaries of known coronaviruses. The results come just 12

days after a team of 10 scientists, supported by numerous technicians,

began working around the clock to grow cells from a throat culture,

taken from one of the SARS patients, in Vero cells (African green

monkey kidney cells) in order to reproduce the ribonucleic acid

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(RNA) of the disease-causing coronavirus (see press release

The WHO announces that a new pathogen, a member of the coronavirus

family never before seen in humans, is the cause of SARS.

To prove the causal relationship between the virus and SARS, scientists

had to meet Koch's postulates which stipulate that a pathogen

must meet four conditions: it must be found in all cases of the disease,

it must be isolated from the host and grown in pure culture, it must

reproduce the original disease when introduced into a susceptible host,

and it must be found in the experimental host that was so infected

To confirm whether the new virus was indeed the cause of the illness,

scientists at Erasmus University in Rotterdam, the Netherlands, infected

monkeys with the pathogen. They found out that the virus

caused similar symptoms – cough, fever, breathing difficulty – in the

monkeys to that seen in humans with SARS, therefore providing

strong scientific evidence that the pathogen is indeed the causative

agent.

The unprecedented speed with which the causative agent of SARS

was identified – just over a month since the WHO first became aware

of the new illness – was made possible by an unprecedented collaboration

of 13 laboratories in 10 countries.

The Chinese government discloses that the number of SARS cases is

many times higher than previously reported. Beijing now has 339

confirmed cases of SARS and an additional 402 suspected cases. Ten

days earlier, Health Minister Zhang Wenkang had admitted to only 22

confirmed SARS cases in Beijing.

The city closes down schools and imposes strict quarantine measures.

Most worrying is the evidence that the virus is spreading in the Chinese

interior, where medical resources might be inadequate.

Timeline 21

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After the identification of a cluster of illness among employees of a

crowded wholesale market in Singapore, the market is closed for 15

days and the vendors placed in home quarantine.

The WHO extends its SARS-related travel advice to Beijing and the

Shanxi Province in China and to Toronto, Canada, recommending that

persons planning to travel to these destinations consider postponing all

but essential travel.

http://www.who.int/csr/sarsarchive/2003_04_23/en/

Outbreaks in Hanoi, Hong Kong, Singapore, and Toronto show signs

of peaking.

Nearly 3,000 SARS cases have been identified in China. China closes

theaters, Internet cafes, discos and other recreational activities and

suspends the approval of marriages in an effort to prevent gatherings

where SARS can be spread.

7,000 construction workers work around-the-clock to finish a new

1,000-bed hospital for SARS patients in Beijing.

suggests that young children develop a milder form of the disease with

a less-aggressive clinical course than that seen in teenagers and adults.

The complete SARS virus genome sequence is published by two

The Xiaotangshan Hospital opens its doors for 156 SARS patients

from 15 hospitals in urban areas in Beijing. The Xiaotangshan Hospital

was built by 7,000 builders in just eight days.

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Taiwan, which has a rapidly evolving outbreak, reports a cumulative

total of 100 probable cases, with 11 new cases in 24 hours. Eight

SARS deaths have occurred in Taiwan.

Scientists in the WHO network of collaborating laboratories report

that the SARS virus can survive after drying on plastic surfaces for up

to 48 hours; that it can survive in feces for at least 2 days, and in urine

for at least 24 hours; and that the virus could survive for 4 days in

The WHO revises its initial estimates of the case fatality ratio of

SARS. It now estimates that the case fatality ratio of SARS ranges

from 0% to 50% depending on the age group affected, with an overall

estimate of case fatality of 14% to 15%. Based on new data, the case

fatality ratio is estimated to be less than 1% in persons aged 24 years

or younger, 6% in persons aged 25 to 44 years, 15% in persons aged

45 to 64 years, and greater than 50% in persons aged 65 years and

The WHO extends its SARS-related travel advice to the following

areas of China: Tianjin, Inner Mongolia, and Taipei in Taiwan province

Publication of the first prospective study on SARS (Peiris et al.,

In Taiwan, more than 150 doctors and nurses quit various hospitals in

one week, because of their fear of contracting SARS. Nine major

hospitals have been fully or partly shut down.

Health authorities in Canada inform the WHO of a cluster of five

cases of respiratory illness associated with a single hospital in Toronto.

This is the second outbreak of SARS in Toronto.

Timeline 23

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The World Health Organization removes its recommendation that

people should postpone all but essential travel to Hong Kong Special

Administrative Region and the Guangdong province, China

Research teams in Hong Kong and Shenzhen announce that they have

detected several coronaviruses closely related to the SARS coronavirus

in animal species taken from a market in southern China. Masked

palm civets, racoon-dogs, and Chinese ferret badgers are wild animals

that are traditionally considered delicacies and are sold for human

consumption in markets throughout southern China

Two studies assess the epidemic potential of SARS, and the effectiveness

of control measures. Their main message is that the SARS virus

is sufficiently transmissible to be able to cause a very large epidemic

if unchecked, but not so contagious as to be uncontrollable with good,

Singapore is removed from the list of areas with recent local transmission

of SARS because 20 days (i.e., twice the maximum incubation

period) have elapsed since the most recent case of locally acquired

SARS was isolated or a SARS patient has died, suggesting that the

chain of transmission had terminated.

Toronto is back on the WHO list of areas with local transmission after

Canada reported new clusters of 26 suspected and eight probable cases

of the disease linked to four Toronto hospitals.

82 cases are now being reported in the second outbreak of SARS in

Ontario, Canada.

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The World Health Organization removes its recommendation that

people should postpone all but essential travel to Hebei, Inner Mongolia,

Shanxi and Tianjin regions in China.

In addition, the WHO removes Guangdong, Hebei, Hubei, Inner

Mongolia, Jilin, Jiangsu, Shaanxi, Shanxi and Tianjin from the list of

areas with recent local transmission.

The WHO removes Taiwan from its list of areas to which travelers are

advised to avoid all but essential travel. The move follows vast improvements

in case detection, infection control, and the tracing and

follow-up of contacts that led to a steep drop in the daily number of

new cases.

diagnosing suspected SARS may not be sufficiently sensitive in assessing

patients before admission to hospital. Daily follow-up,

evaluation of non-respiratory, systemic symptoms, and chest radiography

would be better screening tools (see Chapter 5: Prevention).

The WHO removes Hong Kong from its list of areas with recent local

The WHO removes Beijing from its list of areas with recent local

transmission and removes its travel recommendation

The WHO removes Toronto from its list of areas with recent local

The WHO removes Taiwan from its list of areas with recent local

Timeline 25

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The WHO reports that the last human chain of transmission of SARS

has been broken.

WHO: Publication of " Alert, verification and public health management

of SARS in the post-outbreak period".

http://www.who.int/csr/sars/postoutbreak/en/

Singapore: A 27-year-old researcher is diagnosed with SARS.

The Singapore Ministry of Health releases the report of an investigation

of the recent SARS case. The investigation concludes that the patient

most likely acquired the infection in a laboratory as the result of

accidental contamination. The patient was conducting research on the

West Nile virus in a laboratory that was also conducting research

using active SARS coronavirus

full report of the review panel is available at

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http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5218a1.htm

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26 Timeline

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lished online May 7, 2003.

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http://SARSReference.com/lit.php?id=12690092

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14. Peiris J, Lai S, Poon L, Guan Y, et al. Coronavirus as a possible

cause of severe acute respiratory syndrome. Lancet 2003; 361:

15. Peiris J, Chu CM, Cheng C, et al. Clinical progression and viral

load in a community outbreak of coronavirus-associated SARS

pneumonia: a prospective study. Lancet 2003, 361:1767-72.

Published online May 9, 2003.

http://image.thelancet.com/extras/03art4432web.pdf

16. Poutanen SM, Low DE, Henry B, Finkelstein S, et al. Identification

of Severe Acute Respiratory Syndrome in Canada. N Engl

J Med 2003, 348:1995-2005.

http://SARSReference.com/lit.php?id=12671061

17. Rainer TH, Cameron PA, Smith D, et al. Evaluation of WHO

criteria for identifying patients with severe acute respiratory

syndrome out of hospital: prospective observational study. BMJ

2003; 326: 1354–8.

http://bmj.com/cgi/content/full/326/7403/1354

18. Riley S, Fraser C, Donnelly CA, et al. Transmission Dynamics

of the Etiological Agent of SARS in Hong Kong: Impact of

Public Health Interventions. Science 2003; 300:1961-6. Published

online May 23, 2003.

19. Rota PA, Oberste MS, Monroe SS, et al. Characterization of a

Novel Coronavirus Associated with Severe Acute Respiratory

Syndrome. Science 2003; 300:1394-9. Published online May 1,

2003.

http://www.sciencemag.org/cgi/content/abstract/1085952v1

20. Tsang KW, Ho PL, Ooi GC, Yee WK, et al. A Cluster of Cases

of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J

Med 2003, 348:1977-85.

http://content.nejm.org/cgi/reprint/NEJMoa030666v3.pdf

21. WHO. Severe acute respiratory syndrome (SARS): Status of the

outbreak and lessons for the immediate future. Geneva, 20 May

22. WHO, WER 7/2003. Acute respiratory syndrome, China.

Weekly Epidemiological Record 2003; 78: 41.

http://www.who.int/csr/don/2003_03_12/en/

28 Timeline

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23. WHO, WER 9/2003. Acute respiratory syndrome, China – Update.

Weekly Epidemiological Record 2003; 78: 57.

http://www.who.int/csr/don/2003_03_12/en/

24. WHO, WER 11/2003. Acute respiratory syndrome – China,

Hong Kong Special Administrative Region of China, and Viet

Nam. Weekly Epidemiological Record 2003; 78: 73-74.

http://www.who.int/wer/pdf/2003/wer7811.pdf

25. WHO, WER 15/2003. WHO Multicentre Collaborative Networks

for Severe Acute Respiratory Syndrome (SARS) diagnosis.

Weekly Epidemiological Record 2003; 78: 121-122.

http://www.who.int/wer/pdf/2003/wer7815.pdf

26. WHO Update 15: Situation in Hong Kong, activities of WHO

team in China. March 31.

http://www.who.int/csr/sarsarchive/2003_03_31/en/

27. WHO Update 42: Travel advice for Toronto, situation in China.

28. WHO Update 47: Studies of SARS virus survival, situation in

China. May 5.

http://www.who.int/csr/sarsarchive/2003_05_05/en/

29. WHO Update 49: SARS case fatality ratio, incubation period.

30. WHO Update 50: WHO extends its SARS-related travel advice

to Tianjin, Inner Mongolia and Taipei in China. May 8.

http://www.who.int/entity/csr/sars/archive/2003_05_08/en

31. WHO Update 84. Can SARS be eradicated or eliminated?

http://www.who.int/entity/csr/don/2003_06_19/en

32. WHO Update 87. World Health Organization changes last remaining

travel recommendation for Beijing, China.

http://www.who.int/entity/csr/don/2003_06_24/en

33. WHO Update 92. Chronology of travel recommendations, areas

with local transmission.

http://www.who.int/entity/csr/don/2003_07_01/en

34. WHO Update 93. Toronto removed from list of areas with recent

local transmission.

http://www.who.int/entity/csr/don/2003_07_02/en

Timeline 29

Kamps and Hoffmann (eds.)

35. WHO Update 95. Update 95 - SARS: Chronology of a serial

36. WHO Update 96. Taiwan, China: SARS transmission interrupted

in last outbreak area.

http://www.who.int/csr/don/2003_07_05/en/

30 Virology

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Chapter 2: Virology

Wolfgang Preiser, Christian Drosten

The severe acute respiratory syndrome (SARS) is due to an infection

with a novel coronavirus which was first identified by researchers in

coronavirus (SARS-CoV).

Discovery of the SARS Virus

Initial Research

The epidemic of severe atypical pneumonia which was observed in the

linked to a newly emerging influenza virus: on February 19, 2003,

researchers isolated an avian influenza A (H5N1) virus from a child in

Hong Kong. This virus was similar to the influenza virus originating

from birds that caused an outbreak in humans in Hong Kong in 1997,

and new outbreaks of similar strains were expected. However, bird

'flu', possibly of poultry origin, was soon ruled out as the cause of the

newly-termed Severe Acute Respiratory Syndrome, or SARS.

after paramyxovirus-like particles were found by electron microscopy

of respiratory samples from patients in Hong Kong and Frankfurt

am Main. Further investigations showed that human metapneumovirus

not in all, SARS patients reported at the time.

At about the same time, China reported the detection, by electron

microscopy, of Chlamydia-like organisms in patients who had died

from atypical pneumonia during the Guangdong outbreak. Again, this

finding could not be confirmed by other laboratories in SARS patients

from outside China.

Discovery of the SARS Virus 31

Kamps and Hoffmann (eds.)

On March 17, 2003, the WHO called upon eleven laboratories in nine

countries to join a network for multicenter research into the etiology

of SARS and to simultaneously develop a diagnostic test

communicated through regular telephone conferences (initially held

on a daily basis) and via a secure website and exchanged data, samples

and reagents to facilitate and speed up research into the etiology

WHO. WHO Multicentre Collaborative Networks for Severe Acute

Respiratory Syndrome (SARS) diagnosis.

The Breakthrough

The etiologic agent of SARS was identified in late March 2003, when

laboratories in Hong Kong, the United States, and Germany found

evidence of a novel coronavirus in patients with SARS. This evidence

included isolation on cell culture, demonstration by electron microscopy,

demonstration of specific genomic sequences by polymerase

chain reaction (PCR) and by microarray technology, as well as indirect

Three weeks later, on April 16, 2003, following a meeting of the collaborating

laboratories in Geneva, the WHO announced that this new

coronavirus, never before seen in humans or animals, was the cause of

then 13 participating laboratories from ten countries had demonstrated

that the novel coronavirus met all four of Koch’s postulates necessary

to prove the causation of disease:

3. It must reproduce the original disease when introduced into a

4. It must be found in the experimental host so infected.

Proof of the last two requirements was provided after inoculation of

32 Virology

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virus that had previously been isolated from a SARS case. The infection

caused interstitial pneumonia resembling SARS, and the virus

was isolated from the nose and throat of the monkeys, as shown by

polymerase chain reaction with reverse transcription (RT-PCR) and by

virus isolation. The isolated virus was identical to that inoculated

agent can be found in Drosten 2003b.

Coronaviridae

Coronavirus) are members of a family of large, enveloped, positivesense

single-stranded RNA viruses that replicate in the cytoplasm of

animal host cells (Siddell).

The genomes of coronaviruses range in length from 27 to 32 kb, the

largest of any of the RNA viruses. The virions measure between about

100 and 140 nanometers in diameter. Most but not all viral particles

show the characteristic appearance of surface projections, giving rise

to the virus' name (corona, Latin = crown). These spikes extend a

further 20 nanometers from the surface.

The Coronaviridae family has been divided up into three groups,

originally on the basis of serological cross-reactivity, but more recently

on the basis of genomic sequence homology (see online database

transmissible gastroenteritis and porcine respiratory viruses, human

coronavirus 229E) and 2 (bovine, murine hepatitis, rat sialodacryoadenitis

viruses, human coronavirus OC43) contain mammalian viruses,

while group 3 contains only avian viruses (avian infectious

bronchitis, turkey coronavirus).

In animals, coronaviruses can lead to highly virulent respiratory, enteric,

and neurological diseases, as well as hepatitis, causing epizootics

of respiratory diseases and/or gastroenteritis with short incubation

are generally highly species-specific. In immunocompetent

hosts, infection elicits neutralizing antibodies and cell-mediated immune

responses that kill infected cells.

SARS Co-V 33

Kamps and Hoffmann (eds.)

Several coronaviruses can cause fatal systemic diseases in animals,

including feline infectious peritonitis virus (FIPV), hemagglutinating

encephalomyelitis virus (HEV) of swine, and some strains of avian

infectious bronchitis virus (IBV) and mouse hepatitis virus (MHV).

These coronaviruses can replicate in liver, lung, kidney, gut, spleen,

cause economically important diseases in domestic animals.

Human coronaviruses (HCoVs) were previously only associated with

mild diseases. They are found in both group 1 (HCoV-229E) and

group 2 (HCoV-OC43) and are a major cause of normally mild respiratory

of the lower respiratory tract in children and adults and necrotizing

The known human coronaviruses are able to survive on environmental

from person-to-person by droplets, hand contamination, fomites, and

SARS-related CoV seems to be the first coronavirus that regularly

causes severe disease in humans.

SARS Co-V

Genome Sequence

In April 2003, a Canadian group of researchers from the Michael

Smith Genome Sciences Centre in Vancouver, British Columbia, and

the National Microbiology Laboratory in Winnipeg, Manitoba, were

the first to complete the genome sequencing of the new coronavirus

The genome sequence data of SARS Co-V reveal that the novel agent

does not belong to any of the known groups of coronaviruses, including

two human coronaviruses, HCoV-OC43 and HCoV-229E

The SARS-CoV genome appears to be equidistant from those of all

known coronaviruses. Its closest relatives are the murine, bovine,

porcine, and human coronaviruses in group 2 and avian coronavirus

IBV in group 1. For links to the most recent sequence data and publi

34 Virology

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cations, see the NCBI web page

It has been proposed that the new virus defines a fourth lineage of

seems to be consistent with the hypothesis that it is an animal virus for

which the normal host is still unknown and that has recently either

developed the ability to productively infect humans or has been able

is neither a mutant of a known coronavirus, nor a recombinant

between known coronaviruses.

As the virus passes through human beings, SARS-CoV is apparently

maintaining its consensus genotype and seems thus well-adapted to

between different strains of SARS-CoV, which is of great value

for epidemiological studies and may also have clinical implications

(Tsui).

Morphology

Negative-stain transmission electron microscopy of patient samples

and of cell culture supernatants reveals pleomorphic, enveloped coronavirus-

like particles with diameters of between 60 and 130 nm.

Examination of infected cells by thin-section electron microscopy

shows coronavirus-like particles within cytoplasmic membrane-bound

vacuoles and the cisternae of the rough endoplasmic reticulum. Extracellular

particles accumulate in large clusters, and are frequently seen

Organization

The SARS-CoV genome contains five major open reading frames

(ORFs) that encode the replicase polyprotein; the spike (S), envelope

(E), and membrane (M) glycoproteins; and the nucleocapsid protein

(N).

SARS Co-V 35

Kamps and Hoffmann (eds.)

The main function of the S protein is to bind to species-specific host

cell receptors and to trigger a fusion event between the viral envelope

and a cellular membrane. Much of the species specificity of the initial

infection depends upon specific receptor interactions. In addition, the

spike protein has been shown to be a virulence factor in many different

coronaviruses. Finally, the S protein is the principal viral antigen

that elicits neutralizing antibody on behalf of the host.

The M protein is the major component of the virion envelope. It is the

major determinant of virion morphogenesis, selecting S protein for

incorporation into virions during viral assembly. There is evidence

that suggests that the M protein also selects the genome for incorporation

into the virion.

One remarkable feature about coronavirus RNA synthesis is the very

high rate of RNA-RNA recombination.

Detection

SARS Co-V has been detected in multiple specimens including extracts

of lung and kidney tissue by virus isolation or PCR; bronchoalveolar

lavage specimens by virus isolation, electron microscopy and

PCR; and sputum or upper respiratory tract swab, aspirate, or wash

High concentrations of viral RNA of up to 100 million molecules per

RNA was detected in nasopharyngeal aspirates by RT-PCR in

32% at initial presentation (mean 3.2 days after onset of illness) and in

in 97% of patients two weeks after the onset of illness. 42% of

Viral RNA was also detected at extremely low concentrations in

plasma during the acute phase and in feces during the late convalescent

phase, suggesting that the virus may be shed in feces for prolonged

36 Virology

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Stability and Resistance

Work is on-going to evaluate the stability of SARS-CoV and its resistance

against various environmental factors and disinfectants.

Preliminary results, obtained by members of the WHO multicenter

collaborative network on SARS diagnosis (see:

show that the virus is stable in feces and urine at room temperature for

at least 1-2 days. The stability seems to be higher in stools from patients

with diarrhea (the pH of which is higher than that of normal

stool).

In supernatants of infected cell cultures, there is only a minimal reduction

in the concentration of the virus after 21 days at 4°C and –

80°C. After 48 hours at room temperature, the concentration of the

virus is reduced by one log only, indicating that the virus is more

stable than the other known human coronaviruses under these

conditions. However, heating to 56°C inactivates SARS-CoV

relatively quickly. Furthermore, the agent loses its infectivity after

exposure to different commonly-used disinfectants and fixatives.

Natural Host

Research teams in Hong Kong and Shenzhen detected several coronaviruses

that were closely related genetically to the SARS coronavirus

in animals taken from a southern Chinese market that was selling wild

animals for human consumption. They found the virus in masked

the civets included in the study were found to harbor SARS coronavirus,

which was isolated in cell culture or detected by a PCR molecular

technique. Serum from these animals also inhibited the growth of

SARS coronavirus isolated from humans. Vice versa, human serum

from SARS patients inhibited the growth of SARS isolates from these

animals. Sequencing of viruses isolated from these animals demonstrated

that, with the exception of a small additional sequence, the

viruses are identical to the human SARS virus (Cyranoski; Enserink

2003a).

The study provides a first indication that the SARS virus exists outside

a human host. However, at present, no evidence exists to suggest

Antiviral Agents and Vaccines 37

Kamps and Hoffmann (eds.)

that these wild animal species play a significant role in the epidemiology

of SARS outbreaks. The civets sold on Chinese markets are born

in the wild and then captured and raised on farms. They could therefore

have acquired the virus from a wild animal or from other animals

during captivity or even from humans. More research is needed before

Antiviral Agents and Vaccines

Antiviral Drugs

Efforts are underway at various institutions to assess potential anti-

Ribavirin, a "broad spectrum" agent, which is active against various

and normal human immunoglobulin, not containing specific anti-

2003b).

In the light of the widespread utilization of traditional Chinese medicine

in SARS patients in the Far East it is interesting that glycyrrhizin,

a compound found in liquorice roots, was recently reported to have a

Further research includes detailed physico-chemical analysis of

SARS-CoV proteins to allow the development of novel compounds

Vaccines

There are currently no commercial veterinary vaccines to prevent

respiratory coronavirus infections, except for infectious bronchitis

virus infections in chickens. Although an effective vaccine cannot be

expected to be available soon, the relative ease with which SARSCoV

against animal coronaviruses, such as avian infectious bronchitis virus,

transmissible gastroenteritis coronavirus of pigs, and feline infec

38 Virology

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tious peritonitis virus, are encouraging. The S protein is generally

thought to be a good target for vaccines because it will elicit neutralizing

antibodies.

The apparent genetic stability of SARS-CoV is certainly encouraging

with regard to the development of a vaccine (Brown). It should be

noted, however, that in experimental infections with human coronavirus

229E, infection did not provide long-lasting immunity. Likewise,

several animal coronaviruses can cause re-infections, so lasting immunity

may be difficult to achieve. However, re-infections seem to be

generally mild or sub-clinical. Before immunization strategies are

devised, the immune pathogenesis of feline infectious peritonitis warrants

careful investigation into whether immune enhancement also

plays a role in SARS.

Outlook

The discovery of the SARS-associated coronavirus was the result of

an unprecedented global collaborative exercise coordinated by the

rapid success of this approach results from a collaborative effort –

rather than a competitive approach – by high-level laboratory investigators

making use of all available techniques, from cell culture

techniques, in order to identify a novel agent. It demonstrates how an

extraordinarily well orchestrated effort may be able to address the

The SARS experience also sadly underlines that non-collaborative

approaches may seriously impede scientific progress and sometimes

have grave consequences (Enserink 2003b).

It may be surprising that despite the remarkable world-wide cooperative

research efforts that allowed such significant progress in such a

short time, the apparent success in ending the SARS outbreak (no new

cases have been notified since 15 June 2003, suggesting that SARSCoV

no longer circulates within the human population) is undoubtedly

due to "old-fashioned" infection control measures.

Outlook 39

Kamps and Hoffmann (eds.)

It is completely unclear at present (early September 2003) whether

SARS will reappear. Clinically "silent" infections and long-term carriage

can not be ruled out completely and may result in further outbreaks,

perhaps in a season-dependent manner. Interestingly, the annual

peak incidence of influenza virus infections is from March to

curve of the 2003 SARS outbreak. It is also likely that SARS-CoV or

a closely related coronavirus persist in an unidentified animal reservoir

from where it may again spill over into the human population.

Therefore, it is vital that vigilance for new SARS cases be maintained

(see "Alert, verification and public health management of SARS in the

Sustained control of SARS will require the development of reliable

diagnostic tests to diagnose patients in the early stages of illness and

to monitor its spread, as well as of vaccines and antiviral compounds

preventing coronavirus infections in animals, and the development of

an effective vaccine against this new coronavirus is a realistic possibility.

As is the case for the development of any vaccine, time is

needed. Suitable animal models must demonstrate efficacy, and time

is necessary in order to be able to demonstrate the safety of the new

vaccine in humans. While involvement by commercial enterprises is

clearly wanted and necessary, it is to be hoped that patent issues will

not stand in the way of scientific progress (Gold).

With the availability of different and improved laboratory methods, a

number of important questions regarding the natural history of the

SARS-associated coronavirus are now being addressed:

any? If SARS-CoV was present in an unknown animal species,

did it jump to humans because of a unique combination of random

mutations? Or can SARS-CoV now infect both its original host

and humans?

the onset of infectiousness?

What is the concentration of the virus in various body compart

40 Virology

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ments? In what way does the "viral load" relate to the severity of

the illness or the likelihood of transmission?

amounts and concentrations sufficient to cause infection?

how long? Is this epidemiologically relevant?

lower clinical manifestation index, or do they possess a (relative)

(cross-?) immunity against SARS-CoV?

and hMPV? Are they related to a clinically more severe illness or

to a higher degree of infectiousness ("super-spreaders")?

foodstuff, water, sewage?

efficient disinfection be achieved? How long can the virus "survive"

in the environment on both dry surfaces and in suspension,

including in fecal matter?

Outlook 41

Kamps and Hoffmann (eds.)

Figure 1. Electron micrograph of coronavirus-like particles in cell culture, supernatant

after ultracentrifugation and negative staining with uranyl acetate.

(Source: Department of Virology, Bernhard Nocht Institute for Tropical

Medicine; Director: H. Schmitz; full-size picture:

Figure 2. Cytopathic effect in Vero cell culture caused by SARS-associated

coronavirus 24 hours post inoculation; for comparison: uninfected cell culture.

(Source: Institute for Medical Virology, Director: H. W. Doerr; full-size picture:

42 Virology

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Figure 3. Phylogenetic tree of the SARS-associated coronavirus (Source: S.

Gunther, Department of Virology, Bernhard Nocht Institute for Tropical

Medicine; Director: H. Schmitz; full-size picture:

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