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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

www.SARSreference.com

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

www.SARSreference.com

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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R, Fouchier RA, Osterhaus AD. A newly discovered human

pneumovirus isolated from young children with respiratory tract

disease. Nat Med. 2001; 7: 719-724.

http://SARSReference.com/lit.php?id=11385510

42. WHO Update 64: Situation in Toronto, detection of SARS-like

virus in wild animals. May 23.

http://www.who.int/csr/sarsarchive/2003_05_23/en/

43. WHO. Acute respiratory syndrome – China, Hong Kong Special

Administrative Region of China, and Viet Nam. Weekly Epidemiological

Record 2003; 78(11): 73-74.

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

44. Acute respiratory syndrome in Hong Kong Special Administrative

Region of China/ Viet Nam. March 12, 2003.

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

45. WHO. Acute respiratory syndrome, China – Update. ???Weekly

Epidemiological Record 2003; 78(11): 57.

46. WHO. Alert, verification and public health management of

SARS in the post-outbreak period. August 14, 2003.

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

47. WHO. WHO Multicentre Collaborative Networks for Severe

Acute Respiratory Syndrome (SARS) diagnosis. Weekly Epidemiological

Record 2003; 78(15): 121-122.

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

48. Wong VW, Dai D, Wu AK, Sung JJ. Treatment of severe acute

respiratory syndrome with convalescent plasma.

Hong.Kong.Med.J. 2003; 9:199-201.

http://www.hkmj.org.hk/hkmj/abstracts/v9n3/199.htm

49. World Health Organization Multicentre Collaborative Network

for Severe Acute Respiratory Syndrome (SARS) Diagnosis: A

multicentre collaboration to investigate the cause of severe acute

48 Virology

www.SARSreference.com

respiratory syndrome. Lancet 2003; 36:1730-3.

http://SARSReference.com/link.php?id=11

Routes of Transmission 49

Kamps and Hoffmann (eds.)

Chapter 3: Transmission

Bernd Sebastian Kamps, Christian Hoffmann

The SARS coronavirus (SARS Co-V) is predominantly spread in

droplets that are shed from the respiratory secretions of infected persons.

Fecal or airborne transmission seem to be less frequent.

There is growing evidence that a majority of patients might not effectively

transmit the virus to other individuals: in Singapore, 162 individuals

(81%) of all probable SARS cases had no evidence of transmission

studies which indicate that SARS is moderately rather than highly

In some instances, however, so-called "superspreader" patients are

able to transmit the SARS virus to a large number of individuals.

Superspreaders and nosocomial amplification were the driving factors

behind the early 2003 outbreaks.

Routes of Transmission

The fact that the majority of new infections occurred in close contacts

of patients, such as household members, healthcare workers, or other

patients who were not protected with contact or respiratory precautions,

indicates that the virus is predominantly spread by droplets or

The presence of virus in the stool suggests the possibility of oral-fecal

an additional route of transmission. In the Amoy Gardens outbreak

(see Chapter 4: Epidemiology, Hong Kong), the SARS virus

may have been spread through the sewage systems of the buildings

50 Transmission

www.SARSreference.com

The airborne spread of SARS does not seem to be a major route of

transmission. However, the apparent ease of transmission in some

instances is of concern. In particular, the cases in the original Hong

transmission of the SARS virus, although probably a rare event,

cannot be ruled out. Clusters among healthcare workers exposed during

high-risk activities (i.e., endotracheal intubation, bronchoscopy,

sputum induction) seem to confirm airborne transmission via a contaminated

environment (i.e., re-aerosolization when removing protective

equipment, etc.)

There are currently no indications that any goods, products or animals

arriving from areas with SARS outbreaks pose a risk to public health.

The WHO does not recommend any restrictions in this regard

Factors Influencing Transmission

Whether the transmission of a viral pathogen leads to the manifestation

of the disease is determined by the intricate interplay of a multitude

of still largely undefined viral and host factors.

As in other infectious diseases, the size of the inoculum, i.e., the number

of infectious particles that are transmitted from one person to

another, is probably of major importance. The size of the inoculum is

determined by

locations, i.e., a sneeze in the elevator)

Surprisingly, in the first few days after the onset of SARS-related

symptoms, the amount of virus detected in secretion from the respiratory

tract seems to be relatively low. Findings from sequential quantitative

RT-PCR analyses of nasopharyngeal aspirates suggest that the

viral load might peak only at around day 10 after the onset of symptoms

and then decrease to the levels obtained on admission at day 15

Patient Factors in Transmission 51

Kamps and Hoffmann (eds.)

Infectivity might therefore be variable over time, even during the

symptomatic phase of the disease, and transmission more likely to

happen in the later phase of the illness.

In one study, severe disease was associated with acquisition of the

disease through household contact. People infected in this way may

have a higher dose or duration of viral exposure than people exposed

Patient Factors in Transmission

The most important factor is probably the viral load in infectious body

secretions; so far, there is no indication that strains with different

virulence are responsible for various degrees of infectivity.

Asymptomatic Patients

There are currently few data as to whether individuals can be infected

with the SARS virus but remain asymptomatic, and if so, whether

asymptomatic persons can transmit infection.

Preliminary findings suggest that some individuals that only developed

mild symptoms may have antibodies to the SARS virus, although

they did not develop SARS. Seroconversion without any disease

has also been documented.

There is no direct evidence of transmission from an asymptomatic

person. Indirect evidence that it may occur rarely includes a report that

contact tracing in Hong Kong failed to identify a known symptomatic

Symptomatic Patients

It is now generally believed that only symptomatic patients may

spread the SARS virus efficiently. However, transmission appears not

to proceed in an explosive way. As stated above, 81% of all probable

SARS cases in Singapore had no evidence of transmission of a clinically

52 Transmission

www.SARSreference.com

This is consistent with observations from the early Toronto outbreak,

when suspected cases without pneumonia were initially sent home to

spend their time in isolation. Some patients did not respect the isolation

requirements and had interaction with the community. Despite

that, apart from an outbreak in a religious group, no disease was seen

in the community.

workers, who spent a mean of 4.5 days at home after the onset of

symptoms, infected 2 out of 33 household contacts, in spite of unprotected

contact within the home environment.

Finally, a report from the Philippines describes a patient who became

symptomatic on April 6, had close contact with 254 family members

and friends, traveled extensively in the Philippines and attended a

prayer meeting and a wedding before becoming hospitalized on April

12. The contacts were placed under home quarantine for 9 days, with

twice-daily temperature monitoring by health workers. Only two individuals

(and questionably a third person) developed SARS, which

represents an infection rate of less than 1% for the non-hospital contacts

In comparison with other infectious diseases that are spread via the

respiratory route (i.e., influenza), SARS seems therefore moderately

transmissible.

Superspreaders

The term "superspreading" has been used to describe situations in

which a single individual has directly infected a large number of other

201 probable cases reported, 103 were infected by just five source

cases (Table 1).

A common feature of superspreading is nosocomial transmission, with

superspreader reported from Hong Kong spread the virus in the Metropole

Patient Factors in Transmission 53

Kamps and Hoffmann (eds.)

The most probable explanation for the phenomenon of superspreading

is extensive viral shedding by the patients. This may be due to advanced

disease or possibly co-morbidities that result in high viral

loads. However, additional data on the natural history of SARS are

needed to understand other factors that might be associated, i.e., other

transmission routes or inadequate infection control measures. In some

circumstances, transmission of the SARS virus is therefore highly

efficient.

Table 1: Superspreaders: Number of infected persons and outcome

conditions

Infected

persons**

Outcome Reference

241-8

73-4

405-11

405-11

53 Singapore n.a. Diabetes,

ischemic

heart disease

405-11

60 Singapore n.a. Chronic

kidney disease,

diabetes

405-11

64 Singapore 3 Ischemic

heart disease,

left

ventricular

failure

405-11

n.a. Toronto 6 Congestive

heart failure

44 p dead Donald

Low

43 Taiwan 6 Diabetes,

peripheral

vascular

disease

461-6

* Days between onset of illness and hospitalization

** p = probable case; s = suspected case

n.a. = not available

54 Transmission

www.SARSreference.com

The Unsuspected Patients

SARS patients with chronic illnesses occurring concurrently with

fever and/or pneumonia and who have a plausible diagnosis are the

Unrecognized cases of SARS have been implicated in recent outbreaks

these cases led to nosocomial clusters and subsequent spread to

other healthcare facilities and/or community settings. Several factors

might contribute to difficulties in recognizing cases of SARS. Early

symptoms of SARS are non-specific and are associated with other

more common illnesses. Patients with SARS who are immunocompromised

or who have chronic conditions (e.g., diabetes mellitus or

chronic renal insufficiency) might not have fever when acutely ill or

have symptoms attributable to the underlying disease, delaying the

might not reveal useful contact information (e.g., exposure to an implicated

healthcare facility) for fear of being stigmatized by the local

community or causing their friends and families to be quarantined

These experiences demonstrate that spread among health care workers

can occur despite knowledge about the epidemiology and transmission

of SARS. To reduce the number of unrecognized cases, the Singapore

Ministry of Health recommends a strategy to quickly identify febrile

or symptomatic persons with chronic illnesses or any recent healthcare

see also Chapter 5: Prevention).

High-Risk Activities

The rapid spread of SARS among healthcare workers in Hanoi, Vietnam,

and in hospitals in Hong Kong confirmed the potentially highly

contagious nature of the virus. Medical personnel, physicians, nurses,

and hospital workers are among those commonly infected. Attack

Transmission during Quarantine 55

Kamps and Hoffmann (eds.)

infection of health care workers is probably related to increased contact

with respiratory secretions, contact with patients during a more

contagious phase of critical illness, contact with particular patients at

increased likelihood of spreading SARS (i.e. superspreaders), or exposure

In particular, diagnostic and therapeutic procedures inside the hospitals,

such as diagnostic sputum induction, bronchoscopy, endotracheal

intubation, and airway suction are potent aerosol-generating procedures,

and are now being recognized as high-risk activities situations.

Other potentially aerosol-generating procedures include BiPAP, during

which air might be forced out around the facemask and thereby

aerosolize secretions, and HFOV, during which exhaust from the

ventilator tubing is more likely to escape without passing through an

In Canada, a cluster of SARS cases occurred among health care workers

despite apparent compliance with recommended infection control

precautions. The probable transmission event was an endotracheal

intubation of a patient who was in his second week of illness with

Another serious outbreak in a public hospital in Hong Kong could

have been magnified by the use of a nebulized bronchodilator (albuterol;

0.5 mg through a jet nebulizer, delivered by oxygen at a flow rate

of 6 liters per minute, four times daily for a total of seven days),

Transmission during Quarantine

There has been at least one report of SARS Co-V transmission during

became infected during hospital quarantine because strict isolation

was not observed. This illustrates the fundamental principle of not

"cohorting" suspect cases. Patients diagnosed with SARS may or may

not be infected with the SARS virus, but they are at risk of contracting

the infection if they are grouped with infected patients.

56 Transmission

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Transmission after Recovery

How long patients should remain in isolation depends on whether, and

to what extent, patients continue to shed virus from the respiratory

tract or from feces after overt clinical symptoms have stopped. Currently,

at least 14 days of home quarantine are recommended following

discharge. There have thus far been no reports of transmission

after discharge.

Animal Reservoirs

There is limited data regarding the role of animals in the origin,

transmission and reservoir of SARS CoV. Available data suggest that

at least 2 wild animal species in one market place

these species are not likely to play a role in the spread of the

SARS coronavirus

antibody prevalence among market workers in comparison to the

general population

Conclusion

The SARS virus is not easily transmissible outside of certain settings.

For a major local outbreak to occur there needs to be

populations, travel groups, religious gatherings, or funerals, with

close interactions (kissing, hugging).

References 57

Kamps and Hoffmann (eds.)

This gives some hope that SARS will not spread in a totally uncontrolled

manner in the community.

The "ideal" conditions for efficient transmission of the SARS virus

seem to be:

virus

of SARS

because of the diagnostic work-up, possibly including highrisk

procedures such as bronchoscopy, endotracheal intubation,

use of nebulizers, etc.

References

1. Avendano M, Derkach P, Swan S. Clinical course and management

of SARS in healthcare workers in Toronto: a case series.

CMAJ 2003; 168. Published online on June 24, 2003.

http://www.cmaj.ca/cgi/content/full/168/13/1649

2. CDC. Outbreak of Severe Acute Respiratory Syndrome -

Worldwide, 2003. MMWR 2003;52:226-8.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5211a5.htm

3. CDC. Update: Outbreak of Severe Acute Respiratory Syndrome

- Worldwide, 2003. MMWR 2003; 52:241-248.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5212a1.htm

4. CDC. Severe Acute Respiratory Syndrome - Singapore, 2003.

MMWR 2003; 52: 405-11.

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

5. CDC. Cluster of severe acute respiratory syndrome cases among

protected health care workers – Toronto, April 2003. MMWR

2003; 52: 433-6.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5219a1.htm

6. CDC. Severe Acute Respiratory Syndrome - Taiwan, 2003.

MMWR 2003; 52: 461-66.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5220a1.htm

58 Transmission

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7. CDC. Infection Control Precautions for Aerosol-Generating

Procedures on Patients who have Suspected Severe Acute Respiratory

Syndrome (SARS). March 20, 2003.

http://www.cdc.gov/ncidod/sars/aerosolinfectioncontrol.htm (accessed

May 3, 2003).

8. Chan-Yeung M, Yu WC. Outbreak of severe acute respiratory

syndrome in Hong Kong Special Administrative Region: case

report. BMJ 2003; 326: 850-2.

http://bmj.com/cgi/content/full/326/7394/850

9. Cho KO, Hoet AE, Loerch SC, et al. Evaluation of concurrent

shedding of bovine coronavirus via the respiratory tract and enteric

route in feedlot cattle. Am J Vet Res 2001; 62: 1436-41.

http://SARSReference.com/lit.php?id=11560274

10. Donnelly CA, Ghani AC, Leung GM, et al. Epidemiological

determinants of spread of causal agent of severe acute respiratory

syndrome in Hong Kong. Lancet 2003; 361:1761-6. Published

online May 7, 2003.

http://image.thelancet.com/extras/03art4453web.pdf

11. Drosten C, Gunther S, Preiser W, et al. Identification of a Novel

Coronavirus in Patients with Severe Acute Respiratory Syndrome.

N Engl J Med 2003, 348:1967-76. Published online Apr

12. Dwosh HA, Hong H, Austgarden D, Herman S, Schabas R.

Identification and containment of an outbreak of SARS in a

community hospital. CMAJ 2003; 168. Published online on Apr.

13. Field H. Possible Role of Animals. WHO Global Conference on

Severe Acute Respiratory Syndrome (SARS). 17-18 June 2003.

14. Government of Hong Kong Special Administrative Region,

Department of Health. Outbreak of Severe Acute Respiratory

Syndrome (SARS) at Amoy Gardens, Kowloon Bay, Hong

April 30).

15. Hon KL, Leung CW, Cheng WT, et al. Clinical presentations

and outcome of severe acute respiratory syndrome in children.

References 59

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Lancet 2003, 361:1701-3. Published online April 29, 2003.

http://image.thelancet.com/extras/03let4127web.pdf

16. Hsu LY, Lee CC, Green JA, et al. Severe acute respiratory syndrome

(SARS) in Singapore: clinical features of index patient

and initial contacts. Emerg Infect Dis 2003; 9: 713-7.

http://www.cdc.gov/ncidod/EID/vol9no6/03-0264.htm

17. Lee N, Hui D, Wu A, et al. A Major Outbreak of Severe Acute

Respiratory Syndrome in Hong Kong. N Engl J Med 2003;

18. Li T, Buckley TA, Yap F, Sung J, Joynt GM. Severe acute respiratory

syndrome (SARS): infection control. Lancet 2003; 361.

http://SARSReference.com/link.php?id=6

19. Peiris JS, Lai ST, Poon LL, et al. Coronavirus as a possible

cause of severe acute respiratory syndrome. Lancet 2003,

361:1319-25. Published online Apr 8, 2003.

http://image.thelancet.com/extras/03art3477web.pdf

20. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and

viral load in a community outbreak of coronavirus-associated

SARS pneumonia: a prospective study. Lancet 2003b; 361:1767-

72. Published online May 9, 2003.

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

21. 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

22. 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.

http://www.sciencemag.org/cgi/content/full/300/5627/1961

23. Seto WH, Tsang D, Yung R, et al. Effectiveness of precautions

against droplets and contact in prevention of nosocomial transmission

of severe acute respiratory syndrome (SARS). Lancet

24. So L, Lau A, Yam L, et al. Development of a standard treatment

protocol for severe acute respiratory syndrome. Lancet 2003;

361: 1615-6.

60 Transmission

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25. WHO. First data on stability and resistance of SARS coronavirus

compiled by members of WHO laboratory network. May 4,

4).

26. WHO. Update 53 - Situation in Singapore and Hong Kong, interpretation

of "areas with recent local transmission". May 12,

Introduction 61

Kamps and Hoffmann (eds.)

Chapter 4: Epidemiology

Bernd Sebastian Kamps, Christian Hoffmann

Introduction

Severe acute respiratory syndrome (SARS) is a new infectious disease

which was first recognized in late February 2003, when cases of an

atypical pneumonia of unknown cause began appearing among staff at

a hospital in Hanoi. Within two weeks, similar outbreaks occurred in

various hospitals in Hong Kong, Singapore and Toronto.

On March 15, the World Health Organization (WHO) issued emergency

travel recommendations to alert health authorities, physicians

and the traveling public to what was perceived to be a worldwide

threat to health. The travel recommendations marked a turning point

in the early course of the SARS outbreak. Areas with cases detected

before the recommendations were issued, namely Vietnam, Hong

Kong, Singapore and Toronto, experienced the largest and most severe

outbreaks, all characterized by chains of secondary transmission

outside the healthcare setting. After the recommendations had been

issued, all countries with imported cases, with the exception of provinces

in China, were able, through prompt detection of cases and isolation

of patients, either to prevent further transmission or to keep the

After the disease had moved out of southern China, Hanoi, Hong

Kong, Singapore, and Toronto became the initial "hot zones" of

SARS, characterized by rapid increases in the number of cases, especially

in healthcare workers and their close contacts. In these areas,

SARS first took root in hospital settings, where staff, unaware that a

new disease had surfaced, exposed themselves to the infectious agent

without barrier protection. All of these initial outbreaks were subsequently

characterized by chains of secondary transmission outside the

Now, at the beginning of July, SARS appears to be under control. It

might not be all over, though. Toronto, after having had no new cases

for more than 20 days, experienced a second outbreak with cases

62 Epidemiology

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linked to at least four hospitals, originating probably from a 96 year

old man who had a pneumonia that was misinterpreted as a postoperative

complication.

It is probably the "unsuspected SARS patients" that will be a major

medical challenge if SARS cannot be eradicated. In Singapore, early

atypical clinical presentations masking their infections, or were otherwise

not rapidly identified because of lack of an initial history of

direct contact with a known SARS case – despite efforts to implement

extensive control measures. These patients became hidden reservoirs,

and the subsequent transmission of the SARS virus resulted in substantial

morbidity and mortality and the closure of several large

healthcare facilities. Health authorities in Singapore subsequently

defined an extended case definition that picked up virtually every

person with symptoms that might possibly indicate SARS for investigation

and monitoring, regardless of whether the person has been in

contact with a SARS patient (see Chapter 5: Prevention).

The number of worldwide cases exceeded 4000 on 23 April and then

rapidly soared to 5000 on 28 April, 6000 on 2 May, and 7000 on 8

May, when cases were reported from 30 countries. During the peak of

the global outbreak, near the start of May, more than 200 new cases

were being reported each day.

As of July 3, 2003, severe acute respiratory syndrome (SARS) had

been diagnosed in more than 8,000 patients. The first SARS epidemic

can be summarized as follows (Oxford):

1. The epidemiological observation that SARS was first detected in

the Guangdong province in November 2002 and took three

months to spread even to the immediately neighboring Hong

Kong, despite easy exchange of family members between the two

areas, does suggest, fortunately, a virus with a low infectiousness.

2. Outbreaks to date have been restricted to families, often living in

high-density accommodation, and to hotels and hospitals. This

limited spread is the hallmark of a virus with low communicability.

Modeling the Epidemic 63

Kamps and Hoffmann (eds.)

3. A truly global respiratory virus like influenza rather quickly

emerged to infect millions of persons worldwide. Given the remarkable

extent of air travel today, the SARS virus is not

spreading rapidly, at least to date.

Modeling the Epidemic

Two major epidemiological studies have been published on the possible

consequences of introduction of the SARS virus into a susceptible

number" – the fundamental epidemiological quantity that

determines the potential for disease spread – is of the order of 2 to 4

for the Hong Kong epidemic. They draw the conclusion that the SARS

coronavirus, if uncontrolled, would infect the majority of people

wherever it was introduced, but that it is not so contagious as to be

uncontrollable with good, basic public health measures: improved

control measures in hospitals, quarantine of contacts of cases, and

Riley et al. estimate that in Hong Kong, 2.7 secondary infections were

generated on average per case at the start of the epidemic, with a substantial

contribution from hospital transmission. Transmission rates

fell during the epidemic, primarily due to

Starting Point

In November 2002, cases of a highly contagious and severe atypical

pneumonia were noted in the Guangdong Province of southern China.

The condition appeared to be particularly prevalent among healthcare

workers and members of their household. Many cases were rapidly

fatal. During the first week of February there was growing concern

among the public about a mysterious respiratory illness, which apparently

had a very high mortality and which caused death within hours

64 Epidemiology

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Local health officials reported 305 cases of the unknown disease to

Global Spread

SARS was carried out of the Guangdong Province on February 21,

2003, when an infected medical doctor spent a single night on the 9th

floor of a Hong Kong hotel when he visited his family (Hotel M). He

had become unwell a few days earlier and was now seriously ill. He

was admitted to a hospital on February 22 and died ten days later

Before the end of February, guests and visitors to the hotel’s ninth

floor had seeded outbreaks of cases in the hospital systems of Hong

Kong, Vietnam, and Singapore. Simultaneously, the disease began

spreading around the world along international air travel routes as

guests at the hotel flew home to Toronto and other cities around the

SARS, the first severe infectious disease to emerge in the twenty-first

century, has taken advantage of opportunities for rapid international

spread made possible by the unprecedented volume and speed of air

travel. SARS has also shown how, in a closely interconnected and

interdependent world, a new and poorly understood infectious disease

can adversely affect economic growth, trade, tourism, business and

industrial performance, and social stability as well as public health.

Hong Kong

The Hong Kong index patient (the physician from Guangdong) infected

12 other persons who had been staying at the same hotel

responsible for outbreaks in two local hospitals.

The Hong Kong health authorities immediately implemented enhanced

infection-control procedures in all hospitals in Hong Kong,

including stringent barrier and respiratory protection for healthcare

workers, daily environmental disinfection of affected wards, and cohorting

of SARS patients.

Global Spread 65

Kamps and Hoffmann (eds.)

Towards the end of March 2003, a further SARS outbreak occurred

among residents of Amoy Gardens, Hong Kong, with a total of 320

SARS cases in less than three weeks. The probable index patient was

a patient suffering from chronic renal failure; in addition to person-toperson

spread and to the use of communal facilities such as lifts and

staircases, the SARS virus may have been spread through the sewage

After the initial phase of exponential growth, the rate of confirmed

SARS cases fell to less than 20 per day by April 28. The Hong Kong

epidemic seems to have been under control even earlier, by early April

2003, in the sense that each case had, already by then, failed to replace

in the contact rate between infectious individuals and the rest of the

population.

At the beginning of June, public hospitals attempted to resume normal

service, grappling with a backlog of an estimated 16 000 postponed

operations because of the suspension of 30% of the medical services

66 Epidemiology

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By June 16, 1755 cases of SARS had been diagnosed in Hong Kong.

295 patients (16.8%) had died. 1386 patients (79.0%) had recovered.

Around 30% of cases occurred in healthcare workers. Among these,

nurses were the most exposed category, accounting for about 55% of

all infected healthcare workers. 15% were doctors, 27% support staff.

Eight medical workers had died by June 2.

On June 23, the WHO removed Hong Kong from its list of areas with

recent local transmission of SARS.

Vietnam

The outbreak in Vietnam began on February 26, when a 48-year-old

Chinese-American businessman was admitted to the French hospital

in Hanoi with a 3-day history of high fever, dry cough, myalgia and a

mild sore throat. He had previously been in Hong Kong, where he

visited an acquaintance staying on the 9th floor of the hotel where the

Guangdong physician was a guest.

By March 5, secondary probable SARS cases were identified among

health care workers in Hanoi, and subsequently 63 people were infected.

Figure 2. Epidemic curve, Hanoi (from Heymann).

Global Spread 67

Kamps and Hoffmann (eds.)

areas, making it the first country to successfully contain its SARS

outbreak. The absence of any new cases for a continuous 20-day period

(the duration of two incubation periods) was an encouraging

indicator that appropriate detection and protection measures, as recommended

by the WHO, were able to contain outbreaks and prevent

contacts;

cases;

other authorities and/or governments.

Toronto

SARS was introduced to Toronto by a woman of Hong Kong descent

who had traveled home to visit relatives from February 13 to February

23, 2003. Whilst visiting their son in Hong Kong, she and her husband

stayed at Hotel M from February 18 until February 21, at the same

time and on the same floor as the Guangdong physician from whom

the international outbreak originated. The woman and her husband

only stayed in the hotel at night, and spent the days visiting their son.

They returned to their apartment in Toronto, which they shared with

two other sons, a daughter-in-law, and a five-month-old grandson on

February 23, 2003. Two days later, the woman developed fever, anorexia,

myalgia, a sore throat, and a mild non-productive cough. She

died nine days after the onset of the illness. On March 8 and 9, five

out of the six adult family members presented with symptoms of

By mid-May, the Toronto epidemic was thought to be over after the

initial outbreak had mostly come under control. However, an undiag

68 Epidemiology

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nosed case at North York General Hospital led to a second outbreak

among other patients, family members and healthcare workers.

The new outbreak spread from the SARS ward on the eighth floor of

North York General Hospital, where a 96 year old man undergoing

surgery for a fractured pelvis on 19 April is believed to have contracted

the disease. The man developed pneumonia-like symptoms

after his surgery but was not suspected of having SARS. He died on 1

May (Spurgeon).

A woman from the hospital's orthopedic ward, who was transferred to

St John's Rehabilitation Hospital on 28 April, was later recognized as

having a mild case of SARS, and five other SARS cases then appeared

at St John's Hospital (Spurgeon).

The second Toronto outbreak (and the Taiwan outbreak, see below)

demonstrate that spread among health care workers can occur despite

knowledge about the epidemiology and transmission of SARS (see

also Chapter 3: Transmission). SARS patients with chronic illnesses

occurring concurrently with fever and/or pneumonia with a plausible

diagnosis are extremely challenging to the public health and

On July 2, the WHO removed Toronto from its list of areas with recent

To date, 251 cases of SARS have been diagnosed in Canada, most of

them in the Toronto area. 43 patients have died.

Global Spread 69

Kamps and Hoffmann (eds.)

Figure 3. Canada, number of cases

Singapore, February 2003

The index case of SARS in Singapore was a previously healthy 23-

year-old woman of Chinese ethnicity who had been staying on the 9th

70 Epidemiology

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floor of Hotel M during a vacation to Hong Kong from February 20–

and a dry cough on February 28. She was admitted to a hospital in

Singapore on March 1. At that time, SARS had not yet been recognized

as a new disease easily spread in hospitals. As a result, hospital

staff were unaware of the need to isolate patients and protect themselves.

Over a period of several days, the index patient infected at

least 20 other people. No further transmission from this patient was

observed after strict infection control measures were implemented

Figure 4. Epidemic curve, Singapore (from Yeoh).

The virus initially spread rapidly among hospital staff, patients, visitors,

and their close family contacts. Later on, spread of infection

between hospitals occurred when patients with underlying disease –

which masked the symptoms of SARS – were transferred to other

hospitals, placed in rooms with other patients, and managed without

The outbreak in Singapore was amplified by several so-called "superspreaders"

(see also chapter 3: Transmission). 144 of Singapore's 206

probable cases have been linked to contact with only 5 individuals

Global Spread 71

Kamps and Hoffmann (eds.)

Figure 5. Probable cases of severe acute respiratory syndrome, by reported

On April 20, after the identification of a cluster of illness among employees

at a crowded wholesale market, the market was closed for 15

days and more than 400 persons were placed in home quarantine. The

spread of infection was limited to only 15 other persons.

In Singapore, 76% of infections were acquired in a healthcare facility;

the remainder either had household, multiple, or unknown exposures.

Due to rigorous contact tracing and isolation procedures, 81% of

probable SARS cases had no evidence of transmission to other persons

Of the 84 (42%) healthcare workers with probable SARS, 49 were

nurses; 13, physicians; and 22, persons with other occupations (attendants,

radiographers, housekeepers, a porter, and a cleaning supervisor);

no SARS cases have been reported among laboratory workers or

238 cases of SARS were diagnosed in Singapore; 33 patients died.

On May 31, Singapore was removed from the list of areas with recent

72 Epidemiology

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China

Up until mid-April, the Chinese authorities underestimated the magnitude

of the epidemic in Beijing, with only 37 cases having been

reported by April 19. In the following two days, the Chinese authorities

to other provinces, including western Guangxi, northern Gansu, and

Inner Mongolia.

that persons planning to travel to these destinations consider

postponing all but essential travel. Four days later, the Chinese

Authorities closed theaters, Internet cafes, discos and other recreational

activities and suspended the approval of marriages in an effort

to prevent gatherings where SARS could be spread.

To date, the epidemic in China seems to be under control. 5,327 cases

of SARS have been diagnosed, 349 patients have died.

On June 24, Beijing was removed from the list of areas with recent

Taiwan

The first two suspected SARS cases were diagnosed in a couple on

March 14. The man had a history of travel in February to the Guangdong

Province and to Hong Kong. On March 26, a Taiwanese resident

of Hong Kong's Amoy Gardens flew to Taiwan and took a train to

Taichung to celebrate the traditional festival, Qing Ming. The man’s

brother became Taiwan’s first SARS fatality, and a fellow passenger

on the train was also infected.

Suddenly, in the last 10 days of April, the number of cases began to

increase steadily, which would have made Taiwan's epidemic the

third-worst in the world after China and Hong Kong. The origin of the

outbreak was a laundry worker aged 42 years with diabetes mellitus

and peripheral vascular disease who was employed at hospital A. On

April 12, 14, and 15, he had a fever and diarrhea and was evaluated in

the emergency department. The patient remained on duty and interacted

frequently with patients, staff, and visitors. The patient had

Global Spread 73

Kamps and Hoffmann (eds.)

sleeping quarters in the hospital’s basement and spent off-duty time

socializing in the emergency department. On April 16, because of

worsening symptoms, the patient was admitted to the hospital with a

patient became short of breath. A chest radiograph showed bilateral

infiltrates, and the patient was transferred to an isolation room in the

Because the index patient had been symptomatic for 6 days before

SARS was diagnosed, the number of potentially exposed persons was

estimated at 10,000 patients and visitors and 930 staff. On April 24,

hospital A was contained, and all patients, visitors, and staff were

Healthcare worker clusters at eight additional hospitals in Taiwan

have been linked to the initial outbreak at hospital A. Preliminary data

suggest that many of these clusters occurred when pre-symptomatic

patients or patients with SARS symptoms attributed to other causes

were discharged or transferred to other healthcare facilities. SARS

later extended to multiple cities and regions of Taiwan, including

several university and private hospitals. Four of these hospitals, including

a 2,300-bed facility in southern Taiwan, discontinued emergency

and routine services. Sporadic community cases also were reported

The April outbreak in Taiwan may serve as an example of the farreaching

consequences of one single unrecognized SARS case.

On July 5, Taiwan was removed from the list of areas with recent

Other Countries

The number of probable SARS cases reported from other countries

over the time period November 1, 2002 to July 2, 2003, is shown in

the following table.

74 Epidemiology

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Australia 6 0 0

Canada 251 43 17

China 5327 349 7

France 7 1 14

Germany 9 0 0

Hong Kong 1755 299 17

India 3 0 0

Indonesia 2 0 0

Italy 4 0 0

Kuwait 1 0 0

Macao 1 0 0

Malaysia 5 2 40

Mongolia 9 0 0

New Zealand 1 0 0

Philippines 14 2 14

Republic of Ireland 1 0 0

Republic of Korea 3 0 0

Romania 1 0 0

Russian Federation 1 0 0

Singapore 238 33 14

South Africa 1 1 100

Spain 1 0 0

Sweden 5 0 0

Switzerland 1 0 0

Taiwan 346 37 11

Thailand 9 2 22

United Kingdom 4 0 0

United States 29 0 9

Vietnam 63 5 8

Notes:

The cumulative number of cases includes the number of deaths. Updated

Eradication 75

Kamps and Hoffmann (eds.)

Eradication

As the number of new cases continues to dwindle, one of the most

important questions for the future is whether SARS can be eliminated

or eradicated from its new human host. Experience with many other

infectious diseases, including smallpox and poliomyelitis, has demonstrated

that complete eradication of an infectious disease is possible

1) An effective intervention capable of interrupting transmission –

ideally, a vaccine – must be available.

2) Easy-to-use diagnostic tools are needed, with sufficient sensitivity

and specificity to detect levels of infection that can lead to transmission

of the disease.

3) Finally, infection of humans must be essential to the life-cycle of

the causative agent – if the chain of human-to-human transmission

is broken, the agent cannot survive. Existence of an animal

reservoir greatly complicates eradication, but does not preclude it,

provided that interventions exist to break the chain of transmission

in the animal species as well.

To achieve eradication at the global level, the control intervention

must be safe, simple, and affordable. Current control measures for

SARS, including case detection and isolation, tracing and follow-up of

contacts, and quarantine, are effective but extremely time-intensive,

costly, and socially disruptive. Few, if any, countries can sustain such

Outlook

During the first epidemic of SARS, most countries had to deal with a

small number of imported cases. When these cases were promptly

detected, isolated, and managed according to strict procedures of infection

control, further spread to hospital staff and family members

either did not occur at all or resulted in a very small number of secondary

In countries with significant transmission of the SARS virus, the local

outbreaks of Spring 2003 have been controlled; however, second out

76 Epidemiology

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breaks, such as those in Taiwan and Toronto, teach that complacency

must be avoided.

Many lessons have been learned:

individual is sufficient to test the flexibility of modern

healthcare systems to the limit;

epidemic if unchecked, but not so contagious as to be uncontrollable

medicine if SARS cannot be eradicated

Many questions remain unsolved:

there?

located, or will it spread around the world?

introduced into populations with a high prevalence of immunocompromised

patients, i.e., people living with HIV?

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Introduction 81

Kamps and Hoffmann (eds.)

Chapter 5: Prevention

Bernd Sebastian Kamps, Christian Hoffmann

Introduction

SARS, in contrast to diseases like flu or rubella, is only moderately

transmissible. The number of secondary SARS cases per index case,

ranging in one epidemiologic study from 2.2 to 3.6, are considerably

lower than those estimated for most other diseases with respiratory

measures, including shortening the time from symptom onset to isolation

of patients, effective contact tracing and quarantine of exposed

persons, can be effective in containing SARS. Indeed, such measures

have been successful and have contributed to the prevention of major

outbreaks in other countries. On the other hand, in the absence of such

effective measures, SARS has the potential to spread widely

In the absence of a vaccine, the most effective way to control a new

viral disease such as SARS is to break the chain of transmission from

infected to healthy persons. In almost all documented cases, SARS is

spread through close face-to-face contact with infected droplets when

1. Case detection aims to identify SARS cases as soon after the

onset of illness as possible.

2. Once cases are identified, the next step is to ensure their prompt

isolation in a properly equipped facility, and management according

to strict infection control procedures.

of all close contacts of each case and assurance of their care

82 Prevention

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ful follow-up, including daily health checks and possible voluntary

home isolation.

Together, these activities limit the daily number of contacts possible

for each potentially infectious case. They also work to shorten the

amount of time that lapses between the onset of illness and isolation of

the patient, thus reducing the opportunities for the virus to spread to

International Coordination

The World Health Organization (WHO) played a vital role in the

containment of the first global outbreak of SARS.

After issuing a global alert about cases of severe atypical pneumonia

following reports of cases among staff in the Hanoi and Hong Kong

hospitals on March 12, the WHO received additional reports of more

cases. Three days later, the WHO issued emergency travel recommendations

to alert health authorities, physicians, and the traveling public

to what was now perceived to be a worldwide threat to health. The

alert included the first WHO 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

1. The causative agent, and therefore the potential for continued

spread, of this new disease were not yet known.

2. The outbreaks appeared to pose a great risk to health workers who

managed patients, and to the family members and other close

contacts of patients.

3. Many different antibiotics and antiviral therapies had been tried

empirically and did not seem to have an effect.

4. Though the numbers were initially small, a significant percentage

of patients (25 of 26 hospital staff in Hanoi, and 24 of 39 hospital

staff in Hong Kong) had rapidly progressed to respiratory failure,

International Coordination 83

Kamps and Hoffmann (eds.)

requiring intensive care and causing some deaths in previously

healthy persons.

5. The disease had moved out of its initial focus in Asia and appeared

to have spread to North America and Europe.

Within less than two weeks, a collaborative network of laboratories

set up by the WHO identified a novel coronavirus as the probable

etiologic agent of SARS (see Chapter 2: Virology).

Early in April, travel advisories became more specific. On April 2, the

WHO recommended that persons traveling to Hong Kong and the

Guangdong Province of China consider postponing all but essential

April 23, the WHO extended its travel advice to Beijing and the

Shanxi Province in China and to Toronto, Canada,

The global alert and the global effort coordinated by the WHO

achieved its purpose. All countries with imported cases, with the exception

of provinces in China, were able through

1. prompt detection of cases

2. immediate isolation, strict infection control, and

3. vigorous contact tracing

to either prevent further transmission or to keep the number of additional

cases very low. The early management of the SARS epidemic

may well serve as a model for the containment of future epidemics

and pandemics.

Advice to travelers

The most important message for international travelers concerning

SARS is to be aware of the main symptoms of SARS: high fever (>

38° C or 100.4° F), dry cough, shortness of breath or breathing difficulties.

Persons who experience these symptoms and who have been

84 Prevention

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in an area where there has been recent local transmission of SARS in

To further reduce the risk that travelers may carry the SARS virus to

new areas, international travelers departing from areas with local

transmission in the B or C categories (see "Areas with recent local

screened for possible SARS at the time of departure. Such screening

involves answering two or three questions and may include a temperature

check. Travelers with one or more symptoms of SARS and

who have a history of exposure, or who have fever, or who appear

acutely ill should be assessed by a healthcare worker and may be advised

to postpone their trip until they have recovered.

See also "Recommended procedures for prevention and management

of probable cases of SARS on International Cruise Vessels",

Management of SARS in the post-outbreak period

A detailed document published by the WHO describes a SARS alert

mechanism for the post-outbreak period. It provides guidance for

managing a SARS "alert" through to laboratory confirmation or exclusion

of persons under investigation as SARS cases and guidance to

clinicans on the clinical presentation, laboratory and radiological

findings to assist in diagnosis of SARS and in decisions to implement

National Measures

The primary focus of SARS surveillance activities in countries without

or with very few SARS cases is on the early identification and

isolation of patients who have suspected SARS.

In contrast, countries which are affected by a severe SARS outbreak

must immediately take a variety of sometimes unpopular measures to

contain the epidemic. These measures generally include

1. the creation of an emergency operating center

2. the designation of one or more SARS hospitals

National Measures 85

Kamps and Hoffmann (eds.)

3. the institution of efficient quarantine measures, possibly based on

an extended case definition (see below)

4. the rapid approval of pending legislation

In Singapore, the Tan Tock Seng Hospital, which is the second largest

hospital in town (1500 beds) and site of the initial outbreak, was

closed and designated to be the SARS hospital. Schools were closed

used its military forces to assist in contact tracing and enforcement of

home quarantine. All persons who were household, social, hospital,

and occupational contacts during the 10 days before the onset of

symptoms were traced to identify the source of infection. Persons

identified as having had contact with a SARS patient from the onset of

symptoms to the date of isolation were placed in home quarantine

the airport and seaports, imposing a no-visitors rule on all public hospitals,

and use of a dedicated private ambulance service to transport all

Military forces were deployed to assist in contact tracing and to enforce

quarantines. No visitors were allowed into any public hospital.

In Taiwan, the Department of Health efforts focused on limiting nosocomial

transmission by designating dedicated SARS hospitals

throughout the island. Approximately 100 “fever clinics” were also

established to identify potential SARS patients and to minimize the

risk of transmission in emergency departments. Patient care capacity

was expanded by the construction of 1,000 additional negative pressure

isolation rooms. Campsites and military facilities were identified

to accommodate quarantined residents, and home quarantine was to be

Legislation

On April 24, in Singapore, the Infectious Disease Act was amended

with penalties for violations 1) to require persons who might have an

infectious disease to go to a designated treatment center and to prohibit

them from going to public places; 2) to prohibit breaking home

quarantine with the possibility of electronic tagging and forced detention

for violators; and 3) to permit contaminated areas to be quarantined

and any suspected sources of infection to be destroyed. In addi

86 Prevention

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tion, persons throughout the country were requested to monitor body

temperature and to stay home or seek medical care if any signs or

This legislation allowed mandatory home quarantine for 10 days,

which was enforced by CISCO, a Singapore Security Agency. CISCO

served the quarantine order and installed an electronic picture (ePIC)

The penalty for violating quarantine was raised to as much as $5,800

and six months in prison.

Extended Case Definition

Prevention aims at identifying and isolating all people suspected of

being infected with the SARS virus. The main criteria in the current

WHO case definition for suspected SARS are fever (> 38°C) and

respiratory symptoms such as cough, shortness of breath, or breathing

difficulty, and a history of exposure (see Chapter below "Case Definition").

This definition might not be wide enough when facing an outbreak.

In one study, in the early stages of SARS, the main discriminating

symptoms were not cough and breathing difficulty but fever, chills,

malaise, myalgia, rigors, and, possibly, abdominal pain and headache

the early stages, and radiological evidence of pneumonic changes

often preceded the fever. The authors calculated that the WHO case

definition has a sensitivity of 26% and a negative predictive value of

85%. The case definition, which was initially based on patients who

were already hospitalized, might therefore define the tip of the iceberg

of an epidemic, and not be sufficiently sensitive in assessing patients

In addition, patients presenting with overt symptoms suggestive of

SARS, including fever, are unlikely to be the source of an outbreak; in

contrast, unidentified SARS cases have, to date, been responsible for

most of the sudden outbreaks. Several factors contribute to the difficulties

other more common illnesses

National Measures 87

Kamps and Hoffmann (eds.)

chronic conditions (e.g., diabetes mellitus or chronic renal insufficiency)

might not have fever when acutely ill or have symptoms

attributable to underlying disease, delaying the diagnosis of

SARS

exposure to an implicated healthcare facility) for fear of being

stigmatized by the local community or causing their friends and

families to be quarantined

These cases do not arise suspicion, are not isolated or managed according

to strict procedures of infection control, have no restrictions

on visitors, and are frequently transferred to other hospitals for further

In order to prevent transmission from asymptomatic or mildly symptomatic

and/or unrecognized patients, a "wide net" approach has been

proposed by some national authorities.

Singapore changed the threshold criteria for initial isolation, picking

up virtually every person with symptoms that might possibly indicate

SARS for investigation and monitoring, regardless of whether the

The "wide net" included all individuals with a low grade fever, chest

radiograph abnormalities, or respiratory symptoms alone, leading to

the admission to newly created "fever wards" of any patient with fever

or respiratory symptoms or a chest x-ray abnormality which could not

otherwise be explained. The rationale behind this approach is that a

patient’s likelihood of having SARS becomes clearer after 48 hours of

monitoring respiratory symptoms, temperature, white cell count (for

In one hospital in Singapore, this policy led within three weeks to the

admission to isolation wards of 275 individuals who did not meet the

WHO criteria. 72 individuals were later referred to the SARS hospital.

Quarantine

Unfortunately, tests to identify SARS patients at the earliest stages of

disease are not expected to be widely available soon. Early introduc

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tion of quarantine procedures for SARS should therefore be considered

by health authorities. Isolation and quarantine procedures will be

less effective as more cases accrue. Therefore, stringent measures

implemented early in the course of the epidemic prevent the need for

During March, health officials in Singapore, Hong Kong, and Canada

implemented quarantine and isolation measures to limit the spread of

SARS. In Singapore, all primary contacts of these individuals were

placed on home quarantine with financial penalties for violation; they

were required to appear regularly before web cameras installed in their

homes and to wear electronic bracelets if they failed to do so

On April 4, 2003, SARS was added to the list of quarantinable communicable

with the legal authority to implement isolation and quarantine measures

as part of transmissible disease-control measures, if necessary.

Quarantine does not always mean being confined to a hospital or

military camp. If patients are not sick enough to warrant admission,

the community may be best served by sending such patients home,

provided patients can restrict their activities in a responsible manner

until they are asymptomatic (Masur).

SARS Co-V may be transmitted in quarantine communities. There has

been at least one report about SARS Co-V transmission during quarantine

SARS and convalescent cases into isolation cubicles, each accommodating

diagnosed with SARS may or may not have the SARS virus, but they

are at risk of contracting the infection if they are grouped with infected

Reduce travel between districts

A recent analysis of the Hong Kong epidemic concluded that a complete

ban on travel between districts could have the potential to reduce

longer-range population movement might represent a useful control

measure in circumstances where it is not possible to substantially

Infection Control in Healthcare Settings 89

Kamps and Hoffmann (eds.)

reduce the average onset-to-hospitalization time – for example in

resource-poor countries, or if a number of super-spreading events

occur in close succession and hospital capacity is temporarily exceeded

Quarantine after Discharge

There is little reliable information about the duration of quarantine

after discharge. In Singapore, all inpatients who were discharged from

a hospital with previous SARS cases were under telephone surveillance

for 21 days; all probable SARS inpatients and selected suspect

SARS inpatients who recovered and were discharged were on home

Infection Control in Healthcare Settings

General Measures

Hospital workers remain on the front lines in the global response to

SARS. They are at considerable risk of contracting SARS when there

is an opportunity for unprotected exposure. In order to protect

healthcare workers and to prevent disease dissemination, strict infection

In the SARS hospitals, all healthcare workers should have mandatory

In non-SARS hospitals, in order to minimize patient contact and deal

with the potential increased workload from the SARS hospital, all

elective surgery is cancelled, as are most outpatient clinics. In order to

protect themselves, staff are required to wear an N95 mask, gloves

and gown when in contact with all patients. Every attempt is made to

streamline workflow to minimize the number of staff in contact with a

patient and the time spent with a patient. Because of the potential risk

of an individual healthcare worker contaminating a whole department

of colleagues, medical units have been divided into small teams who

do not have any contact with the other team. Some departments have

mandated that one team must be at home to ensure that if another team

90 Prevention

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is quarantined because of exposure, there will still be a clean team

Other measures include stopping hospital visitations, except for pediatric,

obstetric, and selected other patients. For these patients, visitors

are limited to a single person who must wear a mask and pass a temperature

check; all other visits are by video conference. An audit of

Eventually, appropriate respiratory precautions will be instituted when

assessing patients with undifferentiated respiratory conditions and

their family members, in order to prevent the introduction of SARS in

Protective Measures

Droplet infection seems to be the primary route of spread for the

five Hong Kong hospitals, with 241 non-infected and 13 infected staff

with documented exposures to 11 index patients, no infection was

observed among 69 healthcare workers who reported the use of mask,

gloves, gowns, and hand washing. N95 masks provided the best protection

for exposed healthcare workers, whereas paper masks did not

Table 1 shows a summary of precautions for droplet infection. The

implementation of aggressive infection control measures was effective

Infection Control in Healthcare Settings 91

Kamps and Hoffmann (eds.)

Administrative Region: case report.)

immediately in isolation facilities with negative pressure.

goggles, gowns, and gloves when caring for these patients.

and disinfection of the bed, handrails, bedside tables, floor, and equipment

with hypochlorite solution (1000 ppm).

avoid air leakage and enhanced disease transmission.

For detailed information, see the CDC guidelines further below.

As the SARS virus may be viable in the environment for several days,

precautionary measures, including rigorous disinfection and hygiene

procedures should provide the highest standard of protection.

Hand washing

It is essential to wash hands before touching faces or eyes.

Gloves

Health Canada advises double gloving when attending a suspected

SARS patient. Hands must be washed after de-gloving.

Face Masks

The N95 respirator/mask has a filter efficiency level of 95% or greater

against particulate aerosols free of oil when tested against a 0.3 micron

particle. It is fluid resistant, disposable and may be worn in surgery.

The "N" means "Not resistant to oil". The "95" refers to a 95%

for the healthcare worker.

92 Prevention

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recommendations. In addition, masks should be fit-checked each

time the mask is put on. To check the mask, the wearer takes a

quick, forceful inspiration to determine if the mask seals tightly to

the face.

refer to the handout provided by the manufacturer, or follow your

provincial regulations.

effective for the wearer. Health Canada recommends masks

should be changed if they become wet, interfere with breathing,

are damaged or visibly soiled.

case is considered contaminated and should be discarded.

mask. Carefully remove the mask using the straps. Discard. Wash

hands after handling the mask.

bag. Do not mark the mask with a pen or marker. The name of the

owner should be written on the outside of the paper bag to identify

the mask. Hands should be washed after handling the mask.

Even for doctors in the community, it is advisable to wear a N95 mask

Additional protection

Theatre caps may reduce the risk of staff potentially contaminating

their hands by touching their hair. The nature of the novel coronavirus

is such that mucous membrane and eye spread is likely and therefore

disposable fluid-resistant long sleeved gowns, goggles and disposable

full-face shields are recommended for frontline medical staff at risk of

exposure to SARS (Kamming).

Getting undressed

Getting undressed may seem easier than it is. The sequence that has to

Infection Control in Healthcare Settings 93

Kamps and Hoffmann (eds.)

exercise. Some healthcare workers have contracted the SARS

virus although they had been using all recommended precautions.

Special Settings

Patients who are experiencing rapid clinical progression with a severe

cough during the second week of illness should be considered particularly

infectious. Procedures that might generate aerosols (e.g.

nebulized medications, BiPAP, or HFOV) should be avoided if possible.

When intubation is necessary, measures should be taken to reduce

unnecessary exposure to health care workers, including reducing the

number of health care workers present and adequately sedating or

All high-risk procedures should be performed only by highly experienced

staff.

Intensive Care Units

A brief summary of infection control measures in intensive care units

(grouping critically ill patients with SARS in one ICU; transferring all

pre-existing patients to other uncontaminated centers; the ICU restricted

to patients with SARS; instructions to staff and visitors to put

on gowns, gloves, caps, and masks in a designated area before they

enter the unit; designation of "police nurses"; spot checks to ensure the

correct fitting of masks; goggles and visors are worn during direct

The use of nebulizer medications should be avoided in SARS patients

Intubating a SARS Patient

In some high-risk instances (i.e., endotracheal intubation, bronchoscopy,

sputum induction) airborne transmission may be possible, resulting

in exposure to a particularly high viral load.

The best summary of the measures that need to be taken to minimize

the risk to the anesthetist when intubating a suspected SARS patient,

were recently published by Kamming, Gardam and Chung from the

Toronto Western Hospital (Kamming et al.):

94 Prevention

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1. Plan ahead. It takes 5 min to fully apply all barrier precautions.

2. Apply N95 mask, goggles, disposable protective footwear, gown and gloves.

head cover. Then apply extra gown and gloves. All staff assisting to follow same

precautions. If a powered respirator is unavailable, then apply N95 mask, goggles,

disposable theatre cap, and a disposable full-face shield.

3. Most experienced anaesthetist available to perform intubation.

4. Standard monitoring, i.v. access, instruments, drugs, ventilator and suction

checked.

5. Avoid awake fibreoptic intubation unless specific indication. Atomized local

anaesthetic will aerosolize the virus.

6. Plan for rapid sequence induction (RSI) and ensure skilled assistant able to

perform cricoid pressure. RSI may need to be modified if patient has very high

to succinylcholine. If manual ventilation is anticipated, small tidal volumes

should be applied.

7. Five minutes of preoxygenation with oxygen 100% and RSI in order to avoid

manual ventilation of patient's lungs and potential aerosolization of virus from

airways. Ensure high efficiency hydrophobic filter interposed between facemask

and breathing circuit or between facemask and Laerdal bag.

8. Intubate and confirm correct position of tracheal tube.

9. Institute mechanical ventilation and stabilize patient. All airway equipment to

be sealed in double zip-locked plastic bag and removed for decontamination

and disinfection.

10. Assistant should then wipe down the Tyvek? head cover with disinfectant

(accelerated hydrogen peroxide is most effective) after exiting the negativepressure

atmosphere. The protective barrier clothing is then removed paying

close attention to avoid self-contamination. The outer gloves are used to remove

the outer gown and protective overshoes. The outer gloves are then

discarded and the inner gloves remove the disinfected head cover and the inner

gown. The inner gloves are then removed. The head cover is discarded, the

AirMate‘ tubing is pasteurized and the belt pack wiped down with disinfectant.

The N95 mask and goggles are only removed after leaving the room.

11. After removing protective equipment, avoid touching hair or face before

washing hands.

Infection Control in Healthcare Settings 95

Kamps and Hoffmann (eds.)

Anesthesia

As specialists in airway management, anesthetists are routinely exposed

to patients' respiratory secretions and are at high risk of contracting

SARS from infected patients (Kamming).

Any known or suspected SARS patient must be regarded as ultra high

risk and the attending anesthetist should wear a N95 mask, goggles,

face shield, double gown, double gloves, and protective overshoes.

Removal and disposal of these items without contaminating oneself is

critical. The use of a powered respirator by the anesthetist and assistant

is strongly advised for high-risk aerosol-generating airway procedures

in suspected SARS patients (Kamming).

Triage

Identifying persons who might be at risk of SARS on arrival at a

medical facility or office is difficult and requires changes in the way

medical evaluations are conducted. Revised interim guidelines for

triage recommend that all patients in ambulatory-care settings be

screened promptly for fever, respiratory symptoms, recent travel, and

close contact with a suspected SARS patient:

of Patients Who May Have Severe Acute Respiratory Syndrome

of patients who may have SARS in the ambulatory setting:

http://www.cdc.gov/ncidod/sars/triage_interim_guidance.htm

Internet Sources

Infection-control practitioners, clinicians providing medical care for

patients with suspected SARS, and persons who might have contact

with persons with suspected SARS should frequently consult the

(http://www.cdc.gov/ncidod/sars/ic.htm):

Healthcare and Community Setting for Patients with Suspected

the disease transmission is better understood (see details below);

http://www.cdc.gov/ncidod/sars/infectioncontrol.htm

96 Prevention

www.SARSreference.com

http://www.cdc.gov/ncidod/sars/respirators.htm

http://www.cdc.gov/ncidod/sars/aerosolinfectioncontrol.htm

Precautions for procedures such as aerosolized medication treatments

(e.g., albuterol), diagnostic sputum induction, bronchoscopy,

airway suctioning, & endotracheal intubation.

http://www.cdc.gov/ncidod/sars/sarslabguide.htm

See also the article "Infection Control Guidance for Handling of Human

Remains of Severe Acute Respiratory Syndrome (SARS) Decedents"

published by Heath Canada at

http://SARSReference.com/link.php?id=17

CDC: Updated Interim Domestic Infection Control Guidance in

the Health-Care and Community Setting for Patients with Suspected

SARS

Revised: May 1, 2003

http://www.cdc.gov/ncidod/sars/infectioncontrol.htm

For all contact with suspect SARS patients, careful hand hygiene is

urged, including hand washing with soap and water; if hands are not

visibly soiled, alcohol-based handrubs may be used as an alternative

to hand washing.

hygiene.

If a suspect SARS patient is admitted to the hospital, infection control

personnel should be notified immediately. Infection control measures

Infection Control in Healthcare Settings 97

Kamps and Hoffmann (eds.)

standard precautions, health-care personnel should wear eye protection

for all patient contact.

the patient or their environment)

relative to the surrounding area and use of an N-95 filtering

disposable respirator for persons entering the room)

If airborne precautions cannot be fully implemented, patients should

be placed in a private room, and all persons entering the room should

wear N-95 respirators. Where possible, a qualitative fit test should be

conducted for N-95 respirators; detailed information on fit testing can

respirators are not available for health-care personnel, then surgical

masks should be worn. Regardless of the availability of facilities for

airborne precautions, standard and contact precautions should be implemented

for all suspected SARS patients.

should be asked about possible exposure to someone with SARS

or recent travel to a SARS-affected area. If SARS is suspected,

provide and place a surgical mask over the patient’s nose and

mouth. If masking the patient is not feasible, the patient should be

asked to cover his/her mouth with a disposable tissue when

coughing, talking or sneezing. Separate the patient from others in

the reception area as soon as possible, preferably in a private

room with negative pressure relative to the surrounding area.

taking care of patients with suspected SARS. In addition, health

care personnel should follow standard precautions (e.g., hand hygiene),

contact precautions (e.g., use of gown and gloves for

contact with the patient or their environment) and wear eye protection

for all patient contact.

98 Prevention

www.SARSreference.com

(http://www.cdc.gov/ncidod/sars/triage_interim_guidance.htm).

Placing a surgical mask on suspect SARS patients during contact with

others at home is recommended. If the patient is unable to wear a

surgical mask, it may be prudent for household members to wear surgical

masks when in close contact with the patient. Household members

in contact with the patient should be reminded of the need for

careful hand hygiene including hand washing with soap and water; if

hands are not visibly soiled, alcohol-based handrubs may be used as

an alternative to hand washing. For more information, see the

htm.

Health-care personnel should apply appropriate infection control precautions

for any contact with patients with suspected SARS. The case

definition for suspected SARS is subject to change, particularly concerning

travel history as transmission is reported in other geographic

http://www.cdc.gov/ncidod/sars/casedefinition.htm.

Additional information

A power point file summarizing public health interventions has recently

been presented at the WHO's Kuala Lumpur meeting:

"Severe Acute Respiratory Syndrome: Response from Hong", by

Infection Control in Households

Healthcare workers should have a high index of suspicion if they or

family members develop fever and features suggestive of severe acute

respiratory syndrome. They should present themselves to hospitals

Infection Control in Households 99

Kamps and Hoffmann (eds.)

rather than treating themselves at home and putting their family members

To prevent secondary transmission, close contacts of SARS patients

should be vigilant for fever or respiratory symptoms. If such symptoms

develop, exposed persons should avoid contact with others, seek

immediate medical attention, and practice the infection control precautions

that are recommended for SARS patients. Household members

and other close contacts of SARS patients should be actively

monitored by the local health department for illness.

below), http://www.cdc.gov/ncidod/sars/ic-closecontacts.htm

http://www.cdc.gov/ncidod/sars/exposuremanagement.htm

http://www.cdc.gov/ncidod/sars/exposureguidance.htm

Contacts of proven cases should isolate themselves until the incubation

period is over. After contact with patients with respiratory symptoms,

careful hand hygiene is necessary, including washing with soap

and water.

CDC: Interim Guidance on Infection Control Precautions

for Patients with Suspected Severe Acute Respiratory

Syndrome (SARS) and Close Contacts in Households

Revised: April 29

http://www.cdc.gov/ncidod/sars/ic-closecontacts.htm

Patients with SARS pose a risk of transmission to close household

contacts and health care personnel in close contact. The duration of

100 Prevention

www.SARSreference.com

time before or after onset of symptoms during which a patient with

SARS can transmit the disease to others is unknown. The following

infection control measures are recommended for patients with suspected

SARS in households or residential settings. These recommendations

are based on the experience in the United States to date and

may be revised as more information becomes available.

1. SARS patients should limit interactions outside the home and

should not go to work, school, out-of-home child care, or other

public areas until 10 days after the resolution of fever, provided

respiratory symptoms are absent or improving. During this time,

infection control precautions should be used, as described below,

to minimize the potential for transmission.

2. All members of a household with a SARS patient should carefully

follow recommendations for hand hygiene (e.g., frequent

hand washing or use of alcohol-based hand rubs), particularly

after contact with body fluids (e.g., respiratory secretions, urine,

or feces). See the "Guideline for Hand Hygiene in Health-Care

on hand hygiene.

3. Use of disposable gloves should be considered for any direct

activities involving contact with body fluids, gloves should be

removed and discarded and hands should be cleaned. Gloves

must never be washed or reused.

4. Each patient with SARS should be advised to cover his or her

mouth and nose with a facial tissue when coughing or sneezing.

If possible, a SARS patient should wear a surgical mask during

close contact with uninfected persons to prevent spread of infectious

droplets. When a SARS patient is unable to wear a surgical

mask, household members should wear surgical masks when in

close contact with the patient.

5. Sharing of eating utensils, towels, and bedding between SARS

patients and others should be avoided, although such items can

be used by others after routine cleaning (e.g., washing with soap

and hot water). Environmental surfaces soiled by body fluids

should be cleaned with a household disinfectant according to

Possible Transmission from Animals 101

Kamps and Hoffmann (eds.)

manufacturer's instructions; gloves should be worn during this

activity.

6. Household waste soiled with body fluids of SARS patients,

including facial tissues and surgical masks, may be discarded as

normal waste.

7. Household members and other close contacts of SARS patients

should be actively monitored by the local health department for

illness.

8. Household members or other close contacts of SARS patients

should be vigilant for the development of fever or respiratory

symptoms and, if these develop, should seek healthcare evaluation.

In advance of evaluation, healthcare providers should be informed

that the individual is a close contact of a SARS patient

so arrangements can be made, as necessary, to prevent transmission

to others in the healthcare setting. Household members or

other close contacts with symptoms of SARS should follow the

same precautions recommended for SARS patients.

9. At this time, in the absence of fever or respiratory symptoms,

household members or other close contacts of SARS patients

need not limit their activities outside the home.

SARS Information for Patients and Their Close Contacts,

http://www.cdc.gov/ncidod/sars/closecontacts.htm

Possible Transmission from Animals

SARS Co-V was found in three animal species taken from a market in

Southern China (masked palm civet and racoon-dog, Chinese ferret

badger). As a precautionary measure, persons who might come into

contact with these species or their products, including body fluids and

excretions, should be aware of the possible health risks, particularly

102 Prevention

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during close contact such as handling and slaughtering and possibly

After the Outbreak

When the Toronto epidemic was already thought to be over, an undiagnosed

case at the North York General Hospital led to a second outbreak

among other patients, family members and healthcare workers.

Infection control measures may have been lifted too early. During

early and mid-May, as recommended by provincial SARS-control

directives, hospitals discontinued SARS-expanded precautions (i.e.,

routine contact precautions with use of a N95 or equivalent respirator)

for non-SARS patients without respiratory symptoms in all hospital

areas other than the emergency department and the intensive care unit

(ICU). In addition, staff were no longer required to wear masks or

respirators routinely throughout the hospital or to maintain distance

from one another while eating. In the hospital where the second outbreak

originated, changes in policy were instituted on May 8; the

number of persons allowed to visit a patient during a 4-hour period

remained restricted to one, but the number of patients who were allowed

Maintaining a high level of suspicion for SARS on the part of

healthcare providers and infection-control staff is therefore critical,

particularly after a decline in reported SARS cases. The prevention of

healthcare-associated SARS infections must involve health care workers,

Conclusion

One of the most important lessons learned to date is the decisive

power of high-level political commitment to contain an outbreak even

when sophisticated control tools are lacking. SARS has been brought

close to defeat by the diligent and unrelenting application – on a

monumental scale – of centuries-old control measures: isolation, contact

tracing and follow-up, quarantine, and travel restrictions. Other

successful measures include the designation of SARS-dedicated hospitals

to minimize the risk of spread to other hospitals, mass media

References 103

Kamps and Hoffmann (eds.)

campaigns to educate the public and encourage prompt reporting of

symptoms, and the establishment of fever clinics to relieve pressure

on emergency rooms, which have also been the setting for many new

infections. Screening at airports and other border points and, thorough

fever checks throughout selected population groups has also been

All of these measures contributed to the prompt detection and isolation

of new sources of infection – a key step on the way to breaking

the chain of transmission. Given the importance of supportive public

attitudes and actions, the single most important control “tool” in

bringing SARS under control may very well be the thermometer

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108 Case Definition

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Chapter 6: Case Definition

WHO Case Definition

As defined by the World Health Organization (WHO), a suspected

case is classified as being disease in a person with a documented fever

(temperature >38 °C), lower respiratory tract symptoms, and contact

with a person believed to have had SARS or a history of travel to a

geographic area where there has been documented transmission of the

illness.

A suspected case with 1) chest radiographic findings of pneumonia,

2) acute respiratory distress syndrome, or 3) an unexplained respiratory

illness resulting in death with autopsy findings consistent with the

pathology of ARDS without an identifiable cause is considered a

probable case.

The WHO Case Definition is available at:

Clinicians are advised that patients should not have their case definition

category downgraded while still awaiting results of laboratory

testing or on the basis of negative results. See "Use of laboratory methods

Suspect case

AND

AND one or more of the following exposures during the 10 days prior

to onset of symptoms:

SARS;

WHO Case Definition 109

Kamps and Hoffmann (eds.)

2. A person with an unexplained acute respiratory illness resulting in

performed

AND one or more of the following exposures during to 10 days prior

to onset of symptoms:

SARS;

SARS

1 The surveillance period begins on 1 November 2002 to capture cases of

atypical pneumonia in China now recognized as SARS. International transmission

of SARS was first reported in March 2003 for cases with onset in February

2003.

2 Close contact: having cared for, lived with, or had direct contact with respiratory

secretions or body fluids of a suspect or probable case of SARS.

Probable case

1. A suspect case with radiographic evidence of infiltrates consistent

with pneumonia or respiratory distress syndrome (RDS) on chest Xray

(CXR).

2. A suspect case of SARS that is positive for SARS coronavirus by

one or more assays. See "Use of laboratory methods for SARS diagnosis",

http://www.who.int/csr/sars/labmethods/

3. A suspect case with autopsy findings consistent with the pathology

of RDS without an identifiable cause.

Exclusion criteria

A case should be excluded if an alternative diagnosis can fully explain

their illness.

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Reclassification of cases

As SARS is currently a diagnosis of exclusion, the status of a reported

case may change over time. A patient should always be managed as

clinically appropriate, regardless of their case status.

alternative diagnosis can fully explain the illness, should be discarded

after carefully considering the possibility of co-infection.

definition should be reclassified as "probable".

appropriate, and monitored for 7 days. Those cases in whom recovery

is inadequate should be re-evaluated by CXR.

illness cannot be fully explained by an alternative diagnosis

should remain as "suspect".

should remain classified as "suspect". However, if this case is

identified as being part of a chain transmission of SARS, the case

should be reclassified as "probable".

is found, the case should be "discarded".

CDC Case Definition

The Centers for Disease Control and Prevention have added laboratory

criteria for evidence of infection with the SARS-associated coronavirus

(SARS-CoV) to the interim surveillance case definition.

Using the laboratory criteria, a SARS case is laboratory-confirmed if

one of the following is met:

in a serum sample, or

CDC Case Definition 111

Kamps and Hoffmann (eds.)

PCR assay, by using a second aliquot of the specimen and a

different set of PCR primers, or

Negative laboratory results for PCR, viral culture, or antibody tests

obtained within 28 days of illness do not rule out coronavirus infection.

In these cases, an antibody test of a specimen obtained more than

28 days after the onset of illness is needed to determine infection.

The "Updated Interim Surveillance Case Definition for Severe Acute

Respiratory Syndrome (SARS)", published July 18, 2003, is available

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Chapter 7: Diagnostic Tests

Wolfgang Preiser, Christian Drosten

Introduction

Despite the initial rapid progress in the discovery of the causative

agent (see Chapter 2: Virology) and the early development of diagnostic

tests, further progress in the establishment of laboratory tests

for SARS has been slower than originally expected.

While various molecular (PCR-based) assays have been developed by

different groups around the world, and although one such assay is

available commercially, results of these tests should still not be used

to rule out a suspected case of SARS, according to current WHO recommendations.

The continual lack of a rapid laboratory test to aid the diagnosis of

suspected cases of SARS makes this area a priority for further research

In many viral diseases, virus shedding is greatest during the early

symptomatic phase, i.e. around, and immediately following the onset

of symptoms. Unfortunately, virus excretion is comparatively low

during the initial phase of SARS. It peaks in respiratory specimens

and in stools at around day 10 after the onset of the clinical illness. In

order to make an early diagnosis, it is therefore necessary to use

highly sensitive tests that are able to detect the low levels of viral

genome present during the first days of illness.

Because presently available tests are not generally able to detect the

small amounts of SARS coronavirus (SARS-CoV) initially shed, they

do not yet play a role in patient management and case control, as

SARS patients may be capable of infecting others during the initial

phase and therefore need to be reliably detected and quickly isolated

The results of the first clinical studies on SARS are now available and

able to shed light on the clinical usefulness of various tests on different

patient samples at different time points. In one series, IgG seroconversion

was documented in 93% of patients at a mean of 20 days;

Laboratory tests 113

Kamps and Hoffmann (eds.)

about 50 % of patients had seroconverted at around 15 days after the

In the same study, SARS-associated coronavirus RNA was detected in

nasopharyngeal aspirates by RT-PCR in 20 patients (32%) at initial

presentation (mean 3.2 days after the onset of illness) and in 68% at

copies per ml, compared

Furthermore, viral RNA was detected in 97% of stool samples collected

later in the illness (a mean of 14.2 days after onset). Similarly,

viral RNA was detected in 42% of urine samples collected at a mean

The authors therefore conclude that although viral RNA detection in

the nasopharyngeal aspirate has a sensitivity of only 32% at presentation,

testing of multiple nasopharyngeal and fecal samples is able to

Laboratory tests

Due to the efforts of the WHO-led international multi-center collaborative

network of laboratories testing for SARS, tests for the novel

coronavirus have been developed with unprecedented speed (SARS:

Laboratory diagnostic tests – 29 April 2003;

and probable SARS cases have been tested for SARS-CoV for

some time in several countries, including Canada, France, Germany,

Hong Kong SAR, Italy, Japan, the Netherlands, Singapore, the United

Kingdom and the United States of America.

Nevertheless, until standardized reagents for virus and antibody detection

become available and methods have been adequately field

tested, the diagnosis of SARS remains based on clinical and epidemiological

findings. The revised case definition from May 1, 2003, (see:

http://www.who.int/csr/sars/casedefinition/en/) includes laboratory

results for the first time: a suspected case of SARS, that is positive for

SARS-CoV in one or more assays, should be reclassified as a probable

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case. At present there are no defined criteria for SARS-CoV test results

to confirm or reject the diagnosis of SARS.

Positive laboratory test results for other known agents that are able to

exclusion criteria: according to the case definition, a case should be

excluded if an alternative diagnosis can fully explain the illness. However,

the possibility of dual infection must not be ruled out completely.

Molecular tests

SARS-CoV-specific RNA can be detected in various clinical specimens

such as blood, stool, respiratory secretions or body tissues by the

polymerase chain reaction (PCR). A number of PCR protocols developed

by members of the WHO laboratory network are available on the

WHO website (http://www.who.int/csr/sars/primers/en/). Furthermore,

a 5’-nuclease RT-PCR test kit containing primers and positive and

negative controls, developed by the Bernhard Nocht Institute

is also available for diagnostic purposes through the European

Network for Imported Viral Infections (ENIVD;

quality assessment scheme for SARS-CoV assays.

Despite their sometimes high sensitivity, the existing PCR tests cannot

rule out, with certainty, the presence of the SARS virus in patients

in laboratories might lead to false positive results. Stringent guidelines

on laboratory quality control and confirmatory testing have therefore

been issued by the WHO

A valid positive PCR result indicates that there is genetic material

(RNA) from the SARS-CoV in the sample. It does not mean, however,

that the virus present is infectious, or that it is present in a large

enough quantity to infect another person.

Laboratory tests 115

Kamps and Hoffmann (eds.)

Negative PCR results do not exclude SARS. Besides the possibility of

obtaining incorrect, false-negative test results (e.g. through lack of

sensitivity), specimens may not have been collected at a time when the

virus or its genetic material was present.

Currently, efforts are underway to improve the sensitivity of PCR

assays to increase their clinical usefulness. One approach is to amplify

another gene of SARS-CoV than the hitherto used polymerase gene;

due to the unique transcription strategy of coronaviruses, a PCR targeting

the nucleoprotein may have a higher sensitivity (Lai). While

evaluations of such a PCR are ongoing, the protocol is already available

Virus isolation

The presence of the infectious virus can be detected by inoculating

suitable cell cultures (e.g., Vero cells) with patient specimens (such as

respiratory secretions, blood or stool) and propagating the virus in

vitro. Once isolated, the virus must be identified as SARS-CoV using

further tests. Cell culture is a very demanding test, but currently (with

the exception of animal trials) the only means to show the existence of

a live virus. It has to be performed under at least biosafety safety level

(BSL) 3 conditions (see below). Positive cell culture results indicate

the presence of live SARS-CoV in the sample tested. Negative cell

culture results do not exclude SARS (see negative PCR test result).

Antibody detection

Various methods provide a means for the detection of antibodies produced

in response to infection with SARS-CoV. Different types of

antibodies (IgM and IgG) appear and change in level during the

course of infection. They can be undetectable in the early stages of

infection. IgG usually remains detectable after resolution of the illness

(Li).

The following test formats are being developed:

– Enzyme-linked immunosorbent assay (ELISA): a test which detects

a mixture of IgM and IgG antibodies in the serum of SARS patients

and reliably yields positive results at around day 21 after the onset of

illness.

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– Immunofluorescence assay (IFA): This requires the use of SARSCoV-

infected cells fixed on a microscope slide; patient antibodies

bind to viral antigens and are in turn detected by immunofluorescentlabelled

secondary antibodies against human IgG or IgM or both,

using an immunofluorescence microscope. IFA typically yields a

positive result after about day 10 after the onset of illness. Results

may be quantified by using serial titrations of patient sera. A SARSCoV

IFA manufactured by Euroimmun AG (Seekamp 31, D-23560

for the detection of IgG and IgM antibodies against SARSCoV.

– Neutralization test (NT): This test assesses and quantifies, by means

of titration, the ability of patient sera to neutralize the infectivity of

SARS-CoV on cell culture. NT is therefore likely to be the best correlate

of immunity. However, due to the use of the infectious virus it

is limited to institutions with BSL-3 facilities.

Interpretation

Positive antibody test results indicate previous infection with SARSCoV.

Seroconversion from negative to positive or a four-fold rise in

the antibody titer from acute to convalescent serum indicates a recent

infection. A negative antibody test result later than 21 days after the

onset of illness is likely to indicate that no infection with SARS-CoV

has taken place. There seems to be no background seroprevalence

against SARS-CoV in the control populations screened so far. Antibody

testing allows the indirect diagnosis of SARS-CoV infection and

is unsuitable during the acute illness; it has the advantage of being

rather independent of the sample type and timing, in contrast to other

virus detection methods.

Limitations

All tests for SARS-CoV available so far have limitations. Extreme

caution is therefore necessary when management decisions are to be

based on virological test results. For more details, see the WHO Update

39, "Caution urged when using diagnostic tests":

false negative test results (due to low sensitivity, unsuitable sample

Biosafety considerations 117

Kamps and Hoffmann (eds.)

type, or time of sampling, etc.) may give a false sense of security; in

the worst case, they could allow persons carrying the SARS virus, and

therefore capable of infecting others, to escape detection.

To aid in the better understanding of SARS, the WHO recommends

that sequential samples be stored from patients with suspected or

probable SARS – and also close contacts who are not ill themselves –

for future use. This is particularly important for the first case(s) recognized

in countries that have not previously reported SARS. Data on

the clinical and contact history should also be collected in order to

obtain a better understanding of the shedding pattern of the virus and

the period of transmissibility. Such patient samples should be suitable

for viral culture, PCR, antigen detection, immunostaining and/or serological

antibody assays. For details, refer to "Sampling for Severe

Acute Respiratory Syndrome (SARS) diagnostic tests",

each country to designate a reference laboratory for investigation

and/or referral of specimens from possible SARS patients.

Biosafety considerations

So far, not a single case of a laboratory-associated SARS-CoV infection

has been reported. Nevertheless, the WHO has issued biosafety

guidelines for the handling of clinical specimens associated with

SARS cases and materials derived from laboratory investigations of

SARS (on April 25, 2003; see

measures must be taken to prevent the potential spread by droplets,

air, and/or contaminated surfaces and objects, with particular emphasis

on avoiding the unguarded production of aerosols.

For routine diagnostic testing of serum and blood samples, manipulations

involving known inactivated (lysed, fixed or otherwise treated)

virus particles and/or incomplete, non-infectious portions of the viral

genome, routine examination of mycotic and bacterial cultures, and

final packaging of specimens (already in a sealed, decontaminated

primary container) for transport to diagnostic laboratories for additional

testing, BSL-2 facilities with appropriate BSL-2 work practices

are deemed sufficient. Any procedure that may generate aerosols

should be performed in a biological safety cabinet, and laboratory

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workers should wear eye protection and a surgical mask in addition to

standard protective equipment such as gloves, etc.

In vitro cell culture of the etiologic agent and manipulations involving

growth or concentration of the etiologic agent require BSL-3 facilities

and BSL-3 work practices.

The current Dangerous Goods Regulations (2003) of the International

Air Transport Association (IATA) allow specimens known or suspected

of containing the SARS agent to be transported as UN 3373

“Diagnostic Specimens” when they are transported for diagnostic or

investigational purposes. Specimens transported for any other purpose,

and cultures prepared for the deliberate generation of pathogens,

must be transported as UN 2814, and marked as: "Infectious substance,

affecting humans (Severe Acute Respiratory Syndrome virus)".

All specimens that are to be transported (UN 3373 or UN 2814)

must be packaged in triple packaging consisting of three packaging

layers.

Further detailed information about containment facilities and biosafety

practices can be found in the WHO Laboratory Biosafety Manual, 2nd

revised edition, available from the WHO website

Outlook

In addition to allowing the rapid diagnosis of SARS infection, the

availability of diagnostic tests will help to address important questions

such as the period of virus shedding (and communicability) during

convalescence, the presence of virus in different body fluids and excreta,

and the presence of virus shedding during the incubation period.

Until a certain degree of standardization and quality assurance has

been achieved for the SARS-CoV laboratory tests, test results must be

used with utmost caution in clinical situations. It is strongly advisable

to closely check on updated recommendations by the WHO and relevant

national organizations regarding the availability and use of such

tests. If in doubt, advice should be sought from reference laboratories

Outlook 119

Kamps and Hoffmann (eds.)

Recent events in Canada once again demonstrated the urgent need for

for SARS-CoV require careful evaluation before valid results can be

issued. Because the previously recognized human coronaviruses received

little attention in the past, much has to be learnt about their

epidemiology and clinical relevance, and great care has to be taken in

order not to be misguided by the insufficient specificity of available

tests.

120 Diagnostic Tests

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Table, Figures

Table 1: Currently (July 2003) available diagnostic tests for the SARSassociated

coronavirus.

Detection

method

Clinical material/

specimen

Technical details Diagnostic significance

Virus isolation

on cell culture

Respiratory tract

samples: sputum,

BAL

Suitable cell

lines: Vero; biosafety

level 3

facility required

Indicates presence

of infectious virus;

negative result

does not preclude

SARS!

Polymerase

chain reaction

(PCR)

Respiratory tract

samples: sputum,

BAL, throat swab,

throat washing,

stool

Different primer

sequences and

protocols available

from the

WHO website *

Indicates presence

of viral genome, not

necessarily of

infectious virus;

negative result

does not preclude

SARS! *

Immunfluorescence

assay

(IFA)

Serum For detection of

specific IgG or

IgM antibodies or

both

IgM IFA usually

positive from day

10 after the onset

of symptoms

Enzyme-linked

immunosorbent

assay

(ELISA)

Serum May be designed

to detect specific

IgG or IgM antibodies

or both

Usually positive

from day 21 after

the onset of symptoms

Neutralization

test (NT)

Serum Requires BSL-3

facility ("live"

virus)

Under investigation;

study use only

See also: "Severe Acute Respiratory Syndrome (SARS): Laboratory diagnostic

*see "PCR primers for SARS developed by the WHO Network Laboratories"

(http://www.who.int/csr/sars/primers/en/) and "Recommendations for laboratories

testing by PCR for presence of SARS coronavirus - RNA"

Table, Figures 121

Kamps and Hoffmann (eds.)

Figure 1. Immunofluorescence assay (IFA): SARS-CoV-infected Vero cells

incubated with patient serum (1:50 dilution) obtained 11 days after the onset of

symptoms, showing cytoplasmatic fluorescence. (Source: Source: Institute for

Medical Virology, Director: W. Doerr)

http://www.sarsreference.com/archive/verocells_patientserum.jpg

Figure 2. Immunofluorescence assay (IFA): SARS-CoV-infected Vero cells

incubated with negative control serum. (Source: Source: Institute for Medical

Virology, Director: W. Doerr)

http://www.sarsreference.com/archive/verocells_controlserum.jpg

122 Diagnostic Tests

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Figure 3. Amplification plot of "TaqMan" (5'nuclease) real-time PCR for the

detection of SARS-CoV RNA in clinical specimens. This is a widely used assay,

polymerase gene of SARS-CoV (Picture source: Institute for Medical Virology,

Director: W. Doerr).

References

1. Drosten C, Gunther S, Preiser W, et al. Identification of a Novel

Coronavirus in Patients with Severe Acute Respiratory Syndrome.

N Engl J Med 2003; 348:1967-76. Published online Apr

2. Lai MM, Cavanagh D. The molecular biology of coronaviruses.

Adv.Virus Res. 1997; 48:1-100.

3. Li G, Chen X, Xu A. Profile of specific antibodies to the SARSassociated

coronavirus. N.Engl.J.Med. 2003; 349:508-509.

4. McIntosh K. The SARS coronavirus: rapid diagnostics in the

limelight. Clin Chem 2003; 49: 845-6.

http://SARSReference.com/lit.php?id=12765977

References 123

Kamps and Hoffmann (eds.)

5. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and

viral load in a community outbreak of coronavirus-associated

SARS pneumonia: a prospective study. Lancet 2003b; 361:1767-

72. Published online May 9, 2003.

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

6. Poon LL, Wong OK, Luk W, Yuen KY, Peiris JS, Guan Y.

Rapid diagnosis of a coronavirus associated with severe acute

respiratory syndrome (SARS). Clin Chem 2003; 49: 953-5. Erratum

in: Clin Chem. 2003 Jul;49(7):1234.

http://SARSReference.com/lit.php?id=12765993

7. WHO Update 71. Status of diagnostic tests, training course in

8. WHO. Outbreak in British Columbia, Canada is not SARS.

http://www.who.int/csr/don/2003_08_25a/en/

124

www.SARSreference.com

Chapter 8:

Clinical Presentation and Diagnosis

Christian Hoffmann, Bernd Sebastian Kamps

There is no single test that can be used to diagnose SARS with a reasonable

degree of accuracy. Diagnosis, therefore, continues to rely on

the clinical examination, supported by case definitions that include a

travel history. The initial symptoms of SARS are non-specific, complicating

the differential diagnosis. Some features of the history,

physical examination, radiological and laboratory findings, however,

should alert clinicians to the possible diagnosis of SARS, even when

the contact history is unreliable. These features are described below.

Clinical Presentation

The most common symptom in SARS patients is fever with a body

temperature of > 38.0°C (100.4°F). Fever is therefore a main criteria

in the current WHO case definition for suspected or probable SARS.

However, fever may be absent during the early stages of the disease

and in individuals with co-morbidities who may be impaired in their

ability to mount a fever.

Fever is mostly associated with other symptoms including chills, rigors,

within different cohorts are shown in table 1. Thus, the initial

symptoms may resemble those of other forms of "atypical pneumonia"

which are usually caused by legionella, mycoplasma and chlamydia

species.

Sputum production, sore throat, coryza, nausea, and vomiting are less

of the lung. Wheezing is generally absent. Diarrhea only seemed to be

a prominent symptom in the Amoy Gardens’ outbreak in Hong Kong

Clinical Presentation 125

Kamps and Hoffmann (eds.)

was less frequent.

Table 1 – Clinical symptoms at presentation (in %)

n=138

n=50

n > 1250

n=144

Fever 100 100 94 99

Chills or rigors 73 74 65* 28*

Cough 57 62 50 69

Myalgia 61 54 51 49

Malaise n.a. 50 64 31

Runny nose 23 24 25 2

Sore throat 23. 20 23 12

Shortness of

breath

n.a. 20 31 n.a.

Diarrhea 20 10 27 24

Headache 56 20 50 35

* chills

It is unknown to what degree asymptomatic infections can occur. A

comprehensive description of the spectrum of the clinical illness of

SARS is dependent on large serosurveys in populations to which the

SARS virus has spread.

Hematological Manifestations

During the course of illness, abnormal hematological values are common.

Early studies have shown lymphopenia and thrombocytopenia to

one study which analyzed the hematological changes during SARS in

peripheral blood of 153/157 (98 %) patients with SARS, reaching its

lowest point in the second week. Lymphopenia was also shown in

hemato-lymphoid organs at postmortem examination. The lymphocyte

count commonly recovered in the third week, but about 30% of patients

were still lymphopenic by the fifth week of SARS.

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Most patients had reduced CD4 and CD8 T cell counts during the

early phase of illness, with mean CD4 and CD8 T cell counts of 287

cells/μl (normal: 410 to 1590 cells/μl) and 242 cells/μl (normal: 62 to

559 cells/μl), respectively. Low CD4 and CD8 lymphocyte counts at

presentation were associated with an adverse outcome in this study

Transient leucopenia was found in 64% of patients during their first

week of illness. However, during the second and third week of illness,

82% of patients, possibly reflecting the wide use of corticosteroids.

In total, 55% of patients developed a self-limiting thrombocytopenia,

possibly caused by an immune mechanism. With the exception of 2%

of patients, the degree of thrombocytopenia was mild (platelet counts

Other Laboratory findings

Common electrolyte and biochemical abnormalities include elevated

levels of lactate dehydrogenase (LDH), aspartate and alanine aminotransferases

Table 2). Since high lactate dehydrogenase levels are often seen in

association with tissue damage, some authors propose that this finding

elevated levels of lactate dehydrogenase and transaminases may be, at

least partially, secondary to the hemolytic effect of ribavirin treatment

A substantial proportion of patients demonstrate low calcium, phosphorus,

These abnormalities tend to worsen during hospitalization. Again, it

remains unclear whether these changes reflect the natural course of the

infection or whether they are secondary to the effects of treatment

with ribavirin or other agents that affect renal tubular function

There is evidence that the clotting profile (prothrombin time, activated

partial-thromboplastin time, international normalized ratio, and Ddimer)

Clinical Presentation 127

Kamps and Hoffmann (eds.)

Table 2 – Laboratory findings at presentation (in %)

n=138

n=50

Leukopenia (< 3.5 x 109/l) 34 26

Lymphopenia (< 1.0 x 109/l) 70 68

Thrombocytopenia 45 40

Hyponatremia 20 n.a.

Hypokalemia 25 n.a.

Prolonged activated partialthromboplastin

time

43 n.a.

n.a. = not available.

Atypical Presentation

Not recognized or misdiagnosed SARS patients, if not discovered

within a reasonable lapse of time, may become sources for superspreading

Chapter 4: Epidemiology).

There are several reports on atypical clinical presentations of SARS.

Patients may present without fever, or with diarrhea but no pneumonia

of disease who were later diagnosed with SARS, emphasizing the

difficulties in identifying SARS without a reliable diagnostic test. On

admission, the patients did not have the SARS-typical fever (>38o

because of chronic co-morbidities (Table 3). This raises questions

about the sensitivity of temperature monitoring as a screening tool.

Only some time later, the patients became febrile with clinical and

radiological deterioration, and eventually met the SARS criteria.

However, the four patients all showed lymphopenia and raised serum

concentrations of lactate dehydrogenase. These nonspecific abnormalities

could alert doctors in affected areas to atypical presentations

(Fisher).

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Thus, atypical presentations of SARS are a threat to patients, staff, and

visitors. The WHO case definition is a useful epidemiological device;

however, it is no substitute for daily, thorough clinical, laboratory, and

radiological assessment of patients with symptoms of SARS (Fisher).

Table 3: Characteristics of four patients with atypical presentations of SARS*

Patient 1 Patient 2 Patient 3 Patient 4

Age (years) 71 43 78 63

Time to isolation

(h)

3 8 4 12

Temperature

on admission

(°C)

38.7 37.3 36.3 36.0

WBC (109/L) 4.5 19.3 11.2 9.3

Lymphocytes

(109/L)

0.78 0.94 0.69 0.63

LDH (IU/L) 747 2513 1032 1770

Initial diagnosis

Possible

congestive

cardiac failure

Pneumonia

bilateral,

possibly

bacterial

Exacerbation

of chronic

lung disease,

possible

congestive

cardiac failure

Congestive

cardiac failure

Comorbidities

Diabetes,

ischemic

heart disease

Hypertension Connective

tissue disease

on steroids,

ischemic

heart disease

Ischemic

heart disease

Outcome Survived Died Died Died

* modified from Fisher et al.

Chest Radiographic Abnormalities

Imaging plays an important role in the diagnosis of SARS and monitoring

of response to therapy. A predominant peripheral location, a

progression pattern from unilateral focal air-space opacity to unilateral

multifocal or bilateral involvement during treatment, and lack of

cavitation, lymphadenopathy, and pleural effusion are the more distinctive

Chest Radiographic Abnormalities 129

Kamps and Hoffmann (eds.)

Chest Radiographs

At the onset of fever, 70-80 % of the patients have abnormal chest

that, in a substantial proportion of cases, chest radiographs may be

normal during the febrile prodrome, as well as throughout the course

of illness. In other cases, radiological evidence of pneumonic changes

who may be impaired in their ability to mount a fever

Chest X-ray findings typically begin with a small, unilateral, patchy

shadowing, and progress over 1-2 days to become bilateral and generalized,

with interstitial or confluent infiltrates. Air-space opacities

eventually develop during the course of the disease. In patients who

deteriorate clinically, the air-space opacities may increase in size,

In the first large cohort from Hong Kong, 55 % of the patients had

unilateral focal involvement and 45 % had either unilateral multi-focal

or bilateral involvement at the onset of fever (Lee). Within a prospective

cohort, initial involvement was confined to one lung zone in 49%

The initial radiographic changes may be indistinguishable from those

associated with other causes of bronchopneumonia. The research

group from Hong Kong suggested that chest radiographs might offer

important diagnostic clues, in particular when, after approximately

one week, unilateral, predominantly peripheral areas of consolidation

progress to bilateral patchy consolidation, and when the extent of the

lung opacities is correlated with the deterioration in respiratory function

There seems to be a predominant involvement of the peripheral-zone.

Pleural effusions, cavitation, and hilar lymphadenopathy are usually

absent. Respiratory symptoms and positive auscultatory findings are

disproportionally mild compared with the chest radiographic findings

One large study focused on radiographic appearances and the pattern

patterns of radiographic progression were recognized: type 1 (initial

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radiographic deterioration to a peak level, followed by radiographic

improvement) in 70.3%, type 2 (fluctuating radiographic changes) in

17.4%, type 3 (static radiographic appearance) in 7.3%, and type 4

(progressive radiographic deterioration) in 5.1% of the patients. Findings

during deterioration are compatible with the radiological features

of acute respiratory distress syndrome.

CT Scans

The predominant abnormalities found on initial CT scans are areas of

sub-pleural focal consolidation with air bronchograms and groundglass

especially in the early stages. Patients with more advanced cases show

peripheral and smaller in the less severely affected lungs, also suggesting

an earlier stage of the disease. In patients with more advanced

cases, there is involvement of the central, perihilar regions by larger

(>3 cm) lesions. The majority of the lesions contained an area of

ground-glass opacification with or without consolidation. Other findings

include intralobular thickening, interlobular septal thickening, a

Radiographically, SARS may be indistinguishable from other severe

forms of pneumonia. It also shares CT features with other conditions

that result in subpleural air-space disease, such as the pneumonia of

Radiologists from the Prince of Wales Hospital, Hong Kong, recommend

the following protocol for diagnostic imaging of suspected

a) Patients with symptoms and signs consistent with SARS and

with abnormalities on chest radiographs are followed up with

serial radiography. CT scanning is not required for diagnosis.

b) Patients with symptoms and signs consistent with SARS and

with a normal chest radiograph undergo thin-section CT to

confirm the diagnosis. They subsequently undergo serial radiography

for follow-up.

Diagnosis 131

Kamps and Hoffmann (eds.)

Diagnosis

Identifying hospitalized patients with SARS is difficult, especially

when no epidemiological link has been recognized and the presentation

of symptoms is non-specific. Patients with SARS might develop

symptoms common to hospitalized patients (e.g., fever or prodromal

symptoms of headache, malaise, and myalgia), and diagnostic testing

tests (PCR, detection of SARS antibodies; see Chapter 7: Diagnostic

Tests) confirm the initial suspicion of SARS infection, the diagnosis

of SARS is based on the clinical findings of an atypical

pneumonia not attributed to any other cause, as well as a history of

exposure to a suspect or probable case of SARS, or to their respiratory

secretions or other body fluids.

As mentioned above, during the early stages, SARS may be difficult

to differentiate from other viral infections, especially when symptoms

SARS patients should include chest radiography, pulse oximetry,

bacterial cultures of blood, sputum, and urine, serology for mycoplasma,

chlamydia, influenza, parainfluenza, respiratory syncytial and

adenoviruses, nasopharyngeal aspirates for viral cell cultures, and

specimen for Legionella and pneumococcal urinary antigen testing

http://www.cdc.gov/ncidod/sars/diagnosis.htm).

The radiographic appearance of peripheral air-space opacities is indistinguishable

from other causes of atypical pneumonia, such as Mycoplasma,

Chlamydia, and Legionella, and overlaps with other types of

viral pneumonia. The presence of an air-space opacity on chest radiographs

Clinicians should save any available clinical specimens (respiratory,

blood, and serum) for additional testing until a specific diagnosis is

made. Acute and convalescent (greater than 21 days after the onset of

symptoms) serum samples should be collected from each patient who

meets the definition criteria for SARS. Specific instructions for collecting

specimens from suspected SARS patients are available on the

132 Clinical Presentation and Diagnosis

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Table 4: Features of SARS that may commonly help with clinical diagnosis.

Clinical history Sudden onset of

flu-like prodrome,

dry cough, nonrespiratory

symptoms

e.g. diarrhoea

common

Take a travel history, history of

hospitalisation and history of contact

with healthcare facility. The absence

of such a history should not automatically

exclude diagnosis of SARS.

Clinical examination

Does not correlate

with chest radiology

changes

Lack of respiratory signs particularly

in groups such as the elderly

Bedside monitoring

Hypoxia Temperature may not be elevated on

admission, respiratory rate should be

documented

Haematology

investigations

Low lymphocyte

count

Biochemistry

investigations

Raised LDH Check profile for electrolytes and

liver function

Radiology

investigations

CXR changes

poorly defined,

patchy, progressive

changes

May present as a lobar pneumonia,

pneumothorax and pneumomediastinum

may occur

Microbiology

investigations

Investigate for

community, and

hospital acquired

pneumonias including

atypical

pneumonias

Concurrent infections may occur

Virology investigations

Investigate for

other causes of

atypical pneumonia

Interpret SARS test results with

caution

Treatment As yet there is not

proven treatment

for SARS, supportive

measures are

recommended

Lack of response to treatment with

standard antibiotics for community

acquired pneumonia including atypical

pneumonia may be indicative of

SARS

Clinical Course

The incubation period of SARS is short. Two large studies consistently

However, the time from exposure to the onset of symptoms may vary

Clinical Course 133

Kamps and Hoffmann (eds.)

flect biases in reporting, different routes of transmission, or varying

the current best estimate of the maximum incubation period is 10 days

The clinical course of SARS is highly variable, ranging from mild

symptoms to a severe disease process with respiratory failure and

death. Clinical deterioration combined with oxygen desaturation,

requiring intensive care and ventilatory support, generally occurs 7 to

SARS is a fulminant disease, progressing from being “comfortable” to

respiratory failure requiring intubation within less than 24 hours

The first prospective study on the clinical course was published on

75 adult patients from Hong Kong. The clinical course of

SARS was remarkably uniform in this cohort, following a tri-phasic

pattern in most cases:

1. Week 1 was characterized by fever, myalgia, and other systemic

symptoms that generally improved after a few days. In terms of

disease progression, all except one patient became afebrile within

48h using the standard treatment protocol, consisting of intravenous

amoxicillin-clavulanate, oral azithromycin, intravenous ribavirin

and a tailing regimen of corticosteroids.

2. As the disease progressed into week 2, the patients frequently had

recurrence of fever, onset of diarrhea, and oxygen desaturation.

Fever recurred in 85% of the patients at a mean of 8.9 days. Radiological

worsening was noted in 80% at a mean of 7.4 days:

Nearly half the patients developed shifting of radiological lesions,

evidenced by improvement of the original lesions followed by the

appearance of new lesions. IgG seroconversion, apparently correlating

with falls in viral load, could be detected from day 10 to

15. Severe clinical worsening also occurred at this time.

3. 20% of patients progressed to the third phase, characterized by

ARDS necessitating ventilatory support. Several patients developed

nosocomial sepsis during this phase of end-organ damage

and severe lymphopenia.

134 Clinical Presentation and Diagnosis

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In total, 32% of patients required intensive care at a mean of 11.0 days

after onset of symptoms, among whom 79% had to be intubated at a

mean of 12.9 days. The mean length of stay for 75 patients was 22.1

days, whereas for the 15 patients who developed ARDS, the mean

length of stay was 26.8 days at the time of writing. In this cohort, the

total mortality was 7%.

The two retrospective cohorts from Canada and Hong Kong demonstrated

23% of the patients were admitted to the intensive care unit, and 59-

69% of these received mechanical ventilation. Mortality was lower in

first 21 days.

However, it should be mentioned that the WHO revised its initial

Canada, China, Hong Kong SAR, Singapore, and Vietnam. On the

basis of more detailed and complete data, and more reliable methods,

the WHO 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%. According to the WHO, estimates

of the case fatality ratio range from 11% to 17% in Hong Kong,

from 13% to 15% in Singapore, from 15% to 19% in Canada, and

from 5% to 13% in China.

Several studies have demonstrated a number of risk factors for a poor

outcome. In most studies, multivariate analysis revealed an older age

and co-morbid conditions as being independent predictors (Table 4).

Clinical Course 135

Kamps and Hoffmann (eds.)

Table 5 – Risk factors associated with clinical deterioration

Authors N Risk factors

aminotransferase, delayed starting of ribavirin

and steroids

(trend for older age)

There is currently no information as to whether virulent mutants of

SARS viruses are associated with fatal cases. Comparison of the genomes

of SARS isolates from fatal versus milder cases will identify

any virus mutations that may be associated with an increased virulence

In a small percentage of patients, various degrees of pulmonary fibrosis

have been reported following recovery. The pathophysiological

mechanism of this finding is unclear. It will be important to perform

follow-up evaluation of these patients to determine the long-term

repercussions of SARS.

Viral Load and Immunopathological Damage

Quantitative RT-PCR of nasopharyngeal aspirates have shown a peak

viral load at day 10 and a decrease to admission levels at day 15

The increasing viral load at the end of the first week of the disease

suggests that the symptoms and signs (recurrent fever, diarrhea, worsening

of radiographic findings) could be related to the effect of viral

However, further deterioration at the end of week 2, when some patients

had severe clinical worsening, may not be related to uncontrolled

viral replication, but may rather be caused by immunopathological

136 Clinical Presentation and Diagnosis

www.SARSreference.com

progressive decrease in rates of viral shedding from the nasopharynx,

stool, and urine from day 10 to 21 after the onset of symptoms. In

addition, nearly half the patients had shifting radiographic shadows. If

viral-induced damage was the primary pathological mechanism, such

Taken together, these findings suggest that the lung damage at this

phase is related to immunopathological damage as a result of an overexuberant

host response, rather than uncontrolled viral replication

Histopathology

Lung Biopsy

The histopathological examination of a lung biopsy specimen from a

patient with SARS showed a mild interstitial inflammation with scattered

alveolar pneumocytes showing cytomegaly, granular amphophilic

cytoplasm, and enlarged nuclei with prominent nucleoli. No

cells showed inclusions typical of herpes virus or adenovirus infection

Postmortem Findings

Postmortem histopathological evaluations of lung tissue from patients

who died from SARS showed diffuse alveolar damage at various levels

of progression and severity, consistent with the pathologic manifestations

The changes included hyaline membrane formation, interstitial mononuclear

inflammatory infiltrates, and desquamation of pneumocytes in

alveolar myxoid fibroblastic tissue, a finding consistent with the early

organizational phase of progressive pneumonia. Interalveolar septa

Bronchial epithelial denudation, loss of cilia, and squamous metaplasia

Discharge and Follow-up 137

Kamps and Hoffmann (eds.)

supports the contention that cytokine dysregulation may account, at

Examination of the liver revealed microvesicular fatty change, focal

hemorrhages, and hepatocyte necrosis with scattered acidophilic bodies.

The spleen showed large areas of probable ischemic necrosis and

In one series, autopsy of hemato-lymphoid organs from four patients

showed neither enlarged lymph nodes in the peripheral soft tissues or

other body parts, nor reactive lymphoid hyperplasia or T zone reaction.

The splenic white pulps appeared atrophic with lymphoid depletion,

and the red pulp was congested. Bone marrow appeared active

with the presence of three lineages. No features of hypoplastic marrow

Discharge and Follow-up

The duration of shedding of the SARS virus from respiratory secretions

of SARS patients appears to be variable. Some animals can shed

infectious coronavirus persistently from the enteric tract for weeks or

months without signs of disease, transmitting the infectious virus to

done to learn whether the SARS virus is shed persistently from the

respiratory and/or enteric tracts of some humans without signs of

interactions outside the home and should not go to work, school, outof-

home childcare, or other public areas until 10 to 14 days after the

fever and respiratory symptoms have resolved. During this time, the

infection control precautions for SARS patients should be followed. In

a small study of 14 patients, none reported secondary cases in their

At a follow-up visit one week after discharge, all 14 patients in one

series still felt weak and complained of dyspnea on exertion. They all

reported significant weight loss during their acute illness (mean 7 kg).

Two patients had had a low grade fever (up to 37.5°C) for 2–3 days

following discharge. Only 2 patients had persistence of a slight dry

cough. The chest radiograph was clear for 7 patients and, although

138 Clinical Presentation and Diagnosis

www.SARSreference.com

improved, abnormalities on the chest radiograph persisted for the

as weak, but still complained of easy fatiguability and dyspnea on

climbing stairs. The cough was no longer present. The chest radiograph

had cleared for an additional 2 patients. 5 patients still had an

Psychosocial Issues

Most patients express complaints consistent with depression and anxiety

regarding various aspects of their disease, hospitalization, and

and nightmares. The psychosocial aspects associated with this illness

should not be underestimated and warrant further investigation. In

addition to the effect on the patients, the psychological impact on staff

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