Learning From SARS by Stacey Knobler, Et Al 2004 Edition PDF

Learning from SARS: Preparing for the Next
Disease Outbreak -- Workshop Summary

Stacey Knobler, Adel Mahmoud, Stanley Lemon, Alison
Mack, Laura Sivitz, and Katherine Oberholtzer, Editors,
Forum on Microbial Threats
ISBN: 0-309-59433-2, 376 pages, 6 x 9, (2004)
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Learning from SARS: Preparing for the Next Disease Outbreak -- Workshop Summary
Workshop Summary
Stacey Knobler, Adel Mahmoud, Stanley Lemon, Alison Mack,

Laura Sivitz, and Katherine Oberholtzer, Editors
Board on Global Health
Copyright © National Academy of Sciences. All rights reserved.

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Library of Congress Cataloging-in-Publication Data
Learning from SARS : preparing for the next disease outbreak : workshop summary / Stacey
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Includes bibliographical references.
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1. SARS (Disease)
[DNLM: 1. Severe Acute Respiratory Syndrome—prevention & control—Congresses.
2. Severe Acute Respiratory Syndrome—transmission—Congresses. 3. Disease Outbreaks—
prevention & control—Congresses. 4. SARS Virus—isolation & purification—Congresses.
5. SARS Virus—pathogenicity—Congresses. 6. Socioeconomic Factors—Congresses.
WC 505 L438 2004] I. Knobler, Stacey. II. Institute of Medicine (U.S.). Forum on Microbial
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www.national-academies.org

FORUM ON MICROBIAL THREATS

ADEL MAHMOUD (Chair), President, Merck Vaccines, Whitehouse Station,
New Jersey
STANLEY LEMON (Vice-Chair), Dean, School of Medicine, University of
Texas Medical Branch, Galveston, Texas
DAVID ACHESON, Chief Medical Officer, Center for Food Safety and
Applied Nutrition, Food and Drug Administration, Rockville, Maryland
STEVEN BRICKNER, Research Advisor, Pfizer Global Research and
Development, Pfizer Inc., Groton, Connecticut
DENNIS CARROLL, U.S. Agency for International Development,
Washington, DC
NANCY CARTER-FOSTER, Director, Program for Emerging Infections and
HIV/AIDS, U.S. Department of State, Washington, DC
GAIL CASSELL, Vice President, Scientific Affairs, Eli Lilly & Company,
Indianapolis, Indiana
JESSE GOODMAN, Director, Center for Biologics Evaluation and Research,
Food and Drug Administration, Rockville, Maryland
EDUARDO GOTUZZO, Director, Instituto de Medicina Tropical “Alexander
von Humbolt,” Universidad Peruana Cayetano Heredia, Lima, Peru
MARGARET HAMBURG, Vice President for Biological Programs, Nuclear
Threat Initiative, Washington, DC
CAROLE HEILMAN, Director, Division of Microbiology and Infectious
Diseases, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Maryland
DAVID HEYMANN, Director, Polio Eradication Program, World Health
Organization, Geneva, Switzerland
JAMES HUGHES, Assistant Surgeon General and Director, National Center
for Infectious Diseases, Centers for Disease Control and Prevention,
Atlanta, Georgia
LONNIE KING, Dean, College of Veterinary Medicine, Michigan State
University, East Lansing, Michigan
JOSHUA LEDERBERG, Raymond and Beverly Sackler Foundation Scholar,
The Rockefeller University, New York, New York
JOSEPH MALONE, Director, Department of Defense Global Emerging
Infections System, Walter Reed Army Institute of Research, Silver Spring,
Maryland
LYNN MARKS, Global Head of Infectious Diseases, GlaxoSmithKline,
Collegeville, Pennsylvania
STEPHEN MORSE, Director, Center for Public Health Preparedness,
Columbia University, New York, New York
MICHAEL OSTERHOLM, Director, Center for Infectious Disease Research
and Policy and Professor, School of Public Health, University of
Minnesota, Minneapolis, Minnesota

GEORGE POSTE, Director, Arizona BioDesign Institute, Arizona State

University, Tempe, Arizona
GARY ROSELLE, Program Director for Infectious Diseases, VA Central
Office, Veterans Health Administration, Department of Veterans Affairs,
Washington, DC
JANET SHOEMAKER, Director, Office of Public Affairs, American Society
for Microbiology, Washington, DC
P. FREDERICK SPARLING, J. Herbert Bate Professor Emeritus of
Medicine, Microbiology, and Immunology, University of North Carolina,
Chapel Hill, North Carolina
Liaisons
ENRIQUETA BOND, President, Burroughs Wellcome Fund, Research
Triangle Park, North Carolina
EDWARD McSWEEGAN, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland
Staff
STACEY KNOBLER, Director, Forum on Microbial Threats
KARL GALLE, Research Associate
KATHERINE OBERHOLTZER, Research Assistant
LAURA SIVITZ, Research Associate
vi

BOARD ON GLOBAL HEALTH

DEAN JAMISON (Chair), Senior Fellow, Fogarty International Center,
National Institutes of Health, Bethesda, Maryland
YVES BERGEVIN, Chief, Health Section, UNICEF, New York, New York
JO IVEY BOUFFORD, Professor, Robert F. Wagner Graduate School of
Public Service, New York University, New York, New York
RICHARD FEACHEM, Executive Director, Global Fund to Fight AIDS,
Tuberculosis and Malaria, Geneva, Switzerland
MARGARET HAMBURG, Vice President for Biological Programs, Nuclear
Threat Initiative, Washington, DC
GERALD KEUSCH, Director, Fogarty International Center, National
Institutes of Health, Bethesda, Maryland
JEFFREY KOPLAN, Vice President for Academic Health Affairs, Emory
University, Atlanta, Georgia
ADEL MAHMOUD, President, Merck Vaccines, Whitehouse Station, New
Jersey
MAMPHELA RAMPHELE, Managing Director, The World Bank,
Washington, DC
MARK ROSENBERG, Executive Director, Task Force for Child Survival and
Development, Emory University, Decatur, Georgia
JAIME SEPULVEDA AMOR, Director, Instituto Nacional de Salud Publica,
Cuernavaca, Mexico
DONALD BERWICK (IOM Council Liaison), Clinical Professor of Pediatrics
and Health Care Policy, Harvard Medical School, Boston, Massachusetts
DAVID CHALLONER (IOM Foreign Secretary), Vice President for Health
Affairs, University of Florida, Gainesville
Staff
PATRICK KELLEY, Director
HARRIET BANDA, Senior Project Assistant
ALLISON BERGER, Project Assistant
STACEY KNOBLER, Senior Program Officer
KATHERINE OBERHOLTZER, Research Assistant
LAURA SIVITZ, Research Associate
DIANNE STARE, Research Assistant/Administrative Assistant
vii

Reviewers
All presenters at the workshop have reviewed and approved their respective
sections of this report for accuracy. In addition, this workshop summary has been
reviewed in draft form by independent reviewers chosen for their diverse per-
spectives and technical expertise, in accordance with procedures approved by the
National Research Council’s Report Review Committee. The purpose of this
independent review is to provide candid and critical comments that will assist the
Institute of Medicine (IOM) in making the published workshop summary as
sound as possible and to ensure that the workshop summary meets institutional
standards. The review comments and draft manuscript remain confidential to
protect the integrity of the deliberative process.
The Forum and IOM thank the following individuals for their participation in
the review process:
Roy M. Anderson, Imperial College London, London, United Kingdom

Ruth L. Berkelman, Emory University, Atlanta, Georgia
David L. Heymann, World Health Organization, Geneva, Switzerland
David Naylor, University of Toronto, Toronto, Ontario
Jeffrey L. Platt, Mayo Clinic, Rochester, Minnesota
Mary Wilson, Harvard University, Boston, Massachusetts
The review of this report was overseen by Enriqueta C. Bond, President,

Burroughs Wellcome Fund, Research Triangle Park, North Carolina. Ap-
pointed by the National Research Council she was responsible for making certain
that an independent examination of this report was carried out in accordance with
institutional procedures and that all review comments were carefully considered.
Responsibility for the final content of this report rests entirely with the editors
and the institution.
viii

Preface
The Forum on Emerging Infections was created in 1996 in response to a request

from the Centers for Disease Control and Prevention and the National Institutes of
Health. The goal of the Forum is to provide structured opportunities for representatives
from academia, industry, professional and interest groups, and government1 to examine
and discuss scientific and policy issues that are of shared interest and that are specifi-
cally related to research and prevention, detection, and management of infectious dis-
eases. In accomplishing this task, the Forum provides the opportunity to foster the
exchange of information and ideas, identify areas in need of greater attention, clarify
policy issues by enhancing knowledge and identifying points of agreement, and inform
decision makers about science and policy issues. The Forum seeks to illuminate issues
rather than resolve them directly; hence, it does not provide advice or recommendations
on any specific policy initiative pending before any agency or organization. Its strengths
are the diversity of its membership and the contributions of individual members ex-
pressed throughout the activities of the Forum. In September 2003 the Forum changed
its name to the Forum on Microbial Threats.
ABOUT THE WORKSHOP

The global response to the recent severe acute respiratory syndrome (SARS)
epidemic has demonstrated strengths and weaknesses in national and interna-
1Representatives of federal agencies serve in an ex officio capacity. An ex officio member of a

group is one who is a member automatically by virtue of holding a particular office or membership in
another body.
ix

x PREFACE
tional capacities to address infectious disease challenges. The story of the emer-
gence, spread, and control of SARS illustrates the considerable economic, politi-
cal, and psychological effects—in addition to the impact on public health—of an
unanticipated epidemic in a highly connected and interdependent world. At the
same time, the rapid response to SARS reflects significant achievements in sci-
ence, technology, and international collaboration.
The future is likely to bring far greater challenges. Will SARS reemerge, and
with greater virulence? Can we contain a more widely disseminated epidemic?
Will we have preventive or therapeutic countermeasures? Can the necessary
global cooperation and resources for containment be sustained? If not SARS, are
we prepared for the next emerging infection? Are our public health and research
investments (human, technical, and financial) flexible enough to respond to the
ever-changing profile of microbial threats?
These and other questions were explored during a September 30 and October 1
workshop of the Forum on Microbial Threats. The goals of the workshop were to:
1. Discuss the origin, emergence, and spread of SARS and the ensuing glo-
bal response to the epidemic.
2. Evaluate measures employed to contain and control SARS, as well as its
clinical management.
3. Examine evidence of the economic impact of this and future epidemics.
4. Look at the political repercussions of the international effort to address
the threat posed by SARS.
5. Explore the future of research and technological development related to
SARS.
6. Consider preparations for the next infectious disease outbreak.
The issues pertaining to these goals were addressed through invited presenta-
tions and subsequent discussions, which highlighted ongoing programs and ac-
tions taken, and also identified the most vital needs in these areas.
ORGANIZATION OF WORKSHOP SUMMARY

This workshop summary was prepared for the Forum membership in the
name of the editors, with the assistance of staff and consultants, as a collection of
individually authored papers. The sections of this summary that are not specifi-
cally attributed to an individual reflect the views of the editors exclusively—they
do not reflect the views of the Institute of Medicine (IOM) or of the organizations
that sponsor the Forum on Microbial Threats. The contents of the unattributed
sections are based on the presentations and discussions that took place during the
workshop.
The SARS workshop functioned as a venue for dialogue among representa-
tives from many sectors about their beliefs on subjects that may merit further

PREFACE xi
attention. The reader should be aware that the material presented here reflects the
views and opinions of those participating in the workshop and not the delibera-
tions of a formally constituted IOM study committee. Moreover, these proceed-
ings summarize only what participants stated in the workshop and are not in-
tended to be an exhaustive exploration of the subject matter.
This summary is organized as a topic-by-topic description of the presenta-
tions and discussions from the SARS workshop. The purpose is to present lessons
from relevant experience, delineate a range of pivotal issues and their respective
problems, and put forth some potential responses as described by the workshop
participants. The Summary and Assessment chapter discusses the core messages
that emerged from the speakers’ presentations and the ensuing discussions. Chap-
ters 1 through 5 begin with overviews provided by the editors, followed by papers
that reflect the contents of invited speaker presentations. The papers in Chapter 1
describe the emergence and detection of the SARS coronavirus and the global
response to the epidemic. The papers in Chapter 2 describe the economic fall-
out—known and projected—of the SARS epidemic and analyze political and
governmental responses to it. Chapter 3 includes papers on the microbiology,
ecology, and natural history of coronaviruses, the genus of viruses to which the
SARS agent belongs. The articles in Chapter 4 describe the development of
diagnostics, therapeutics, and other technologies to control SARS. Finally, the
papers in Chapter 5 examine how SARS might reemerge and how the world
could prepare for the next major outbreak of infectious disease.
ACKNOWLEDGMENTS
The Forum on Microbial Threats and IOM wish to express their warmest
appreciation to the individuals and organizations who gave valuable time to
provide information and advice to the Forum through participation in the work-
shop (see Appendix A for the workshop agenda and Appendix F for a list of
forum, speaker, and staff biographies).
The Forum is indebted to the IOM staff who contributed during the course of
the workshop and the production of this workshop summary. On behalf of the
Forum, we gratefully acknowledge the efforts led by Stacey Knobler, director of
the Forum, and Alison Mack, technical consultant, who dedicated much effort
and time to developing this workshop’s agenda, and for their thoughtful and
insightful approach and skill in translating the workshop proceedings and discus-
sion into this workshop summary. Particular recognition is given to Katherine
Oberholtzer whose tireless research efforts and technical editing were essential to
the framing of the workshop and its report. Considerable thanks is expressed to
Laura Sivitz for her thoughtful guidance in preparing the report for review and
her editing of the report. We also express our gratitude to Karl Galle who contrib-
uted greatly to the final editing and organization of the chapter overviews and
technical papers. Initial drafts of the report benefited greatly from technical re-

xii PREFACE
views by James Hughes, Michael Osterholm, and David Relman. We would also
like to thank the following IOM staff and consultants for their valuable contribu-
tions to this activity: Patrick Kelley, Bernadette Pryde Hackley, Marcia Lewis,
Amy Giamis, Joe Esparza, Harriet Banda, Dianne Stare, Marjan Najafi, Jennifer
Bitticks, Bronwyn Schrecker, Porter Coggeshall, Jennifer Otten, and Sally
Stanfield.
Finally, the Forum also thanks sponsors that supported this activity. Finan-
cial support for this project was provided by the U.S. Department of Health and
Human Services’ National Institutes of Health, Centers for Disease Control and
Prevention, and Food and Drug Administration; U.S. Department of Defense;
U.S. Department of State; U.S. Department of Veterans Affairs; U.S. Department
of Agriculture; American Society for Microbiology; Burroughs Wellcome Fund;
Pfizer; GlaxoSmithKline; and the Merck Company Foundation. The views pre-
sented in this workshop summary are those of the editors and workshop partici-
pants and are not necessarily those of the funding organizations.
Adel Mahmoud, Chair

Stanley Lemon, Vice-Chair

Contents
SUMMARY AND ASSESSMENT 1
1 SARS: EMERGENCE, DETECTION, AND RESPONSE 41

The WHO Response to SARS and Preparations for the Future 42
J.S. MacKenzie, P. Drury, A. Ellis et al.
The Centers for Disease Control and Prevention’s Role in
International Coordination and Collaboration in Response
to the SARS Outbreak 50
James W. LeDuc and Anne Pflieger
Role of China in the Quest to Define and Control SARS 56
Robert F. Breiman, Meirion R. Evans, Wolfgang Preiser et al.
SARS: Lessons from Toronto 63
Donald E. Low
Isolation and Quarantine: Containment Strategies for SARS 2003 71
Martin Cetron, Susan Maloney, Ram Koppaka, and Patricia Simone
Impacts of SARS on Health Care Systems and Strategies for
Combating Future Outbreaks of Emerging Infectious Diseases 83
Abu Saleh M. Abdullah, Brian Tomlinson, G. Neil Thomas,
and Clive S. Cockram
2 POLITICAL INFLUENCES ON THE RESPONSE TO

SARS AND ECONOMIC IMPACTS OF THE DISEASE 91
Estimating the Global Economic Costs of SARS 92
Jong-Wha Lee and Warwick J. McKibbin
xiii

xiv CONTENTS
SARS: Political Pathology of the First Post-Westphalian Pathogen 110

David P. Fidler
The SARS Epidemic and Its Aftermath in China:
A Political Perspective 116
Yanzhong Huang
3 MICROBIOLOGY, ECOLOGY, AND NATURAL

HISTORY OF CORONAVIRUSES 137
Animal Coronaviruses: Lessons for SARS 138
Linda J. Saif
Coronavirus Research: Keys to Diagnosis, Treatment, and
Prevention of SARS 149
Mark R. Denison
Isolation and Characterization of Viruses Related to the
SARS Coronavirus from Animals in Southern China 157
Y. Guan, B.J. Zheng, Y.Q. He et al.
4 DIAGNOSTICS, THERAPEUTICS, AND OTHER

TECHNOLOGIES TO CONTROL SARS 173
Evaluation of Reverse Transcription-PCR Assays for
Rapid Diagnosis of Severe Acute Respiratory Syndrome
Associated with a Novel Coronavirus 175
W.C. Yam, K.H. Chan, L.L.M. Poon et al.
Novel Biosensor for Infectious Disease Daignostics 181
Rangarajan Sampath and David J. Ecker
In Vitro Antiviral Activity of Human Rhinovirus
3C Protease Inhibitors Against the SARS Coronavirus 186
David A. Matthews, Amy K. Patick, Robert O. Baker et al.
SARS: Clearing the Air 193
Jerome J. Schentag, Charles Akers, Pamela Campagna,
and Paul Chirayath
5 PREPARING FOR THE NEXT DISEASE OUTBREAK 206

Are We Ready for Pandemic Influenza? 208
Richard J. Webby and Robert G. Webster
Modeling a Response Strategy 218
Sam Amirfar, Mary Koshy, and Nathaniel Hupert
Reporting, Surveillance, and Information Exchange:
The SARS Imperative for Innovation 222
Ann Marie Kimball, Bill Lober, John Kobayashi et al.
Public Health Law Preparedness 230
Gene Matthews

CONTENTS xv
SARS: Lessons from a New Disease 234

David L. Heymann and Guenael Rodier
SARS: Down But Still a Threat 246
Karen J. Monaghan
APPENDIXES
A Learning from SARS: Preparing for the Next Disease Outbreak 277
B Clinical Guidance on the Identification and Evaluation of Possible
SARS-CoV Disease Among Persons Presenting with
Community-Acquired Illness 281
C In the Absence of SARS-CoV Transmission Worldwide:
Guidance for Surveillance, Clinical and Laboratory Evaluation,
and Reporting 292
D Selected Bibliography 303
E Glossary and Acronyms 324
F Forum Member, Speaker, and Staff Biographies 339


Summary and Assessment1
The emergence of a novel human coronavirus in late 2002 alarmed popula-

tions across the globe, elicited a massive public health response, gave rise to a
multinational research network, gripped the news media, wreaked political havoc
in China, and struck a blow to the tourism and travel industries of several coun-
tries. By the time this coronavirus, labeled SCoV, apparently receded from hu-
man hosts in July 2003, nearly 10 percent of more than 8,000 individuals who fit
the probable case definition had died of the disease now known as severe acute
respiratory syndrome (SARS) (World Health Organization [WHO], 2003a).
Analyses of this epidemic could lead to improvements in the global community’s
preparedness for and response to future global outbreaks of infectious disease.2
For these reasons, the Institute of Medicine’s (IOM’s) Forum on Microbial
Threats convened the workshop Learning from SARS: Preparing for the Next
1The speed with which the SARS epidemic spread last year was matched by a similar swiftness in
the rate at which the understanding of the disease and its effects evolved among scientists, public
health officials, and other members of the global health community. For this reason, individual
papers within this volume are likely to reflect different stages and perspectives from among the many
attempts that have been made to assess the course of the epidemic at different times and places. In
some cases, analyses of public health responses or variations in empirical data (such as the number of
suspected SARS cases or SARS-related deaths) may reflect the fluid nature of these circumstances.
For the most current updates on SARS and recommendations for clinicians and public health offi-
cials, readers are referred to the relevant websites of the WHO (http://www.who.int/csr/sars/en/) and
the CDC (http://www.cdc.gov/ncidod/sars/).
2This report entered final production before the January 5, 2004, confirmation of the first SARS
case since July 2003—explaining the references throughout the report to the uncertainty about the
reemergence of the disease.

2 LEARNING FROM SARS
Disease Outbreak on September 30 and October 1, 2003. Participants discussed

the emergence, detection, spread, and containment of SARS; political responses
to the epidemic; its economic consequences; basic research on coronaviruses;
preparations for a possible reemergence of SCoV; and lessons learned from the
SARS epidemic that could shape responses to future microbial threats.
This workshop summary does not contain consensus recommendations, nor
does it represent a consensus opinion of the IOM Forum on Microbial Threats.
Rather, it presents the individual perspectives and research of people who made
presentations at the IOM workshop on SARS or who participated in workshop
discussions.
While the workshop attempted to explore a range of issues that emerged
from the SARS outbreak, it is important to recognize that neither the discussions
nor this report provide an exhaustive survey of the body of knowledge about
SARS. Some important issues not addressed through workshop discussions in-
clude analyses of modes of transmission in indoor environments, especially air-
planes; consideration of major technological breakthroughs or new fields of in-
quiry that would significantly advance our ability to prevent and treat infectious
diseases; and comparative analyses of actions and outcomes related to the public
health responses of different countries.
It should also be noted that considerable effort was made to engage the
participation of more Chinese colleagues in the presentations and discussion of
the workshop. The short time during which the workshop was organized made it
very difficult for Chinese counterparts to obtain the necessary travel visas. Con-
tributions from Chinese participants were important to the workshop as were
additional phone and email consultations to the development of this report.
The following text summarizes what transpired during the workshop and
assesses how the world’s experience with SARS could potentially guide prepara-
tions by the public health community, researchers, and policy makers for future
outbreaks of infectious disease.
OVERVIEW OF THE SARS EPIDEMIC

SARS is unremarkable in certain ways among infectious diseases. For ex-
ample, the transmission rate of SCoV pales in comparison with those of other
known microbial threats, such as influenza, but appears to be similar to that of
smallpox. Despite nationwide vaccination campaigns against influenza in the
United States, an average of 36,000 U.S. residents die annually from influenza
infections—nearly 50 times more people than the number killed by SARS world-
wide (Centers for Disease Control and Prevention, 2002).
Yet the quality, speed, and effectiveness of the public health response to
SARS brilliantly outshone past responses to international outbreaks of infectious
disease, validating a decade’s worth of progress in global public health network-
ing. Thus, in several respects, the SARS epidemic reflected fundamental

improvements in how the world responds to an outbreak of infectious dis-

ease; and at the same time, highlights the continuing need for investments in
a robust response system that is prepared for the next emerging disease—
whether naturally occurring or intentionally introduced.
The World Health Organization (WHO) deserves credit for initiating and
coordinating much of this response through its Global Outbreak Alert and Re-
sponse Network (GOARN), as do the partner organizations comprising 115 na-
tional health services, academic institutions, technical institutions, and individu-
als. In the future, this public health network—originally developed to manage
outbreaks of influenza and other infectious diseases—ideally will encompass
more partners and have the capacity to handle outbreaks of greater magnitude
than SARS. Nevertheless, it is clear that multinational, collaborative, and coordi-
nated surveillance, research, and containment measures greatly limited the spread
of SCoV.
Despite the low transmission rate of SCoV and the relatively low number of
SARS deaths compared to other infectious diseases, SARS had a remarkably
powerful and negative psychological impact on many populations worldwide.
The relatively high case fatality rate, the identification of superspreaders, the
newness of the disease, the speed of its global spread, and public uncertainty
about the ability to control its spread may have contributed to the public’s alarm.
This alarm, in turn, may have led to behavior that exacerbated the economic
blows to the travel and tourism industries of the countries with the highest num-
ber of SARS cases.
In addition, the SARS epidemic starkly outlined the benefits and dangers of
the impact of globalization on infectious disease. The ease and frequency of
international travel facilitated the swift spread of SCoV infections to 5 countries
within 24 hours and to more than 30 countries on 6 continents within 6 months
(WHO, 2003a). Likewise, the increased migration of workers from rural to urban
areas within their home country or into different countries (and continents) has
increased the risk that new and previously unrecognized viruses will become
established in worldwide human populations.
Yet at the same time, worldwide telecommunications networks facilitated
collaborative research among 11 geographically distinct laboratories, helping
them to identify this new infectious agent in just 1 month. The news media,
individuals, and public health organizations disseminated information about
SARS almost in real time, influencing behavior that helped limit the spread of the
virus. It was also suggested that this information ultimately created heightened
awareness and pressure within the Chinese government and public to take action
against the SARS and to engage with the global efforts of research, prevention,
and containment.
A complex set of factors underlies the emergence and spread of microbial
threats. The extraordinary capacity of microbes to change and adapt, the disrup-
tion of human and microbial environments, and the activities that expose humans

November 2002: First case of SARS occurs in Guangdong Province, China.
November January
2002 2004
to new microbes all play a role. The convergence of these and other factors lead
to the emergence of infectious diseases, as illustrated in Figure S-1.
Emergence of SARS
Such a convergence likely occurred during late 2002 in southern China,
where merchants and farmers took small wild mammals from their native envi-
ronments to local markets and sold both slaughtered and live animals for human
consumption. Some of these mammals most likely carried a coronavirus resem-
bling SCoV (Guan et al., 2003). The likelihood of human exposure to the virus is
quite high when the crowded and relatively unsanitary conditions of these mar-
kets are considered. As a result, SARS emerged in the southern Chinese province
of Guangdong in late 2002. The index case, retrospectively identified on Novem-
ber 16, occurred in the city of Foshan; by mid-December, SARS had appeared in
two additional cities in the province.
An expert team from the provincial government and the national Ministry of
Health went to the city of Zhongshan to investigate one of these outbreaks. The
team concluded on January 21, 2003, that the infection was atypical pneumonia
probably caused by a viral agent. The team recommended measures for the pre-
vention and treatment of infection and suggested that a case reporting system be
established to monitor the disease. The investigative team’s findings were re-
ported to every hospital in the province. Unfortunately, the reporting of these
findings coincided with the Chinese New Year holiday. This compounded the
challenge for early intervention against the disease in two ways: the report did not
receive significant attention from health officials on leave; and the opportunities
for disease spread were greatly enhanced by the travel that often accompanies the
celebration of the New Year.3 Additionally, as we discuss later in this chapter,
the medical community’s understanding of the true etiology of SARS was de-
layed significantly by a February announcement from a senior scientist at the
Chinese Center for Disease Control that he suspected the infectious agent was
Chlamydia—a commonly understood bacterial agent that would not have war-
ranted heightened concern or investigation.
3Workshop presentation, Yi Guan, University of Hong Kong, September 30, 2003.

January 21, 2003: Guangdong provincial investigators report on “atypical” pneumonia.

January 31, 2003: First super-spreading SARS patient.
November January
2002 2004
PHYSICAL
ENVIRONMENTAL
FACTORS
GENETIC AND BIOLOGICAL
FACTORS
Microbe
Human
ECOLOGICAL FACTORS
SOCIAL,
POLITICAL AND
ECONOMIC FACTORS
FIGURE S-1 The Convergence Model. This diagram illustrates how four factors that
influence the interaction between humans and microbes may converge in such a way that
an infectious disease emerges (central box). The interior of the central box is black,
representing the unknown influences on emergence, and the lightening to white at the
edges of this box represents the known influences.
SOURCE: IOM (2003).

February 11, 2003: Chinese Ministry of health reports to WHO on respiratory disease in Guangdong.
November January
2002 2004
On January 31, the first hyperinfective, or superspreading, case of SARS

occurred in the city of Guangzhou. The patient was transferred among three
hospitals and infected an estimated 200 people, many of them hospital
workers.
As these events unfolded, the international public health community began
to receive news of the outbreak through e-mails, Internet chat rooms, and local
media outlets, whose reports were widely disseminated through electronic report-
ing systems such as the Global Public Health Intelligence Network (GPHIN) and
Pro-MED mail (Eysenbach, 2003). Based on this information, WHO queried the
Chinese government on February 10 and received a response the following day
describing an outbreak of an acute respiratory syndrome involving 305 cases and
five deaths in Guangdong Province (WHO, 2003b).
Some of the most severe SARS symptoms were suffered by residents of the
Amoy Gardens apartment towers in Hong Kong during an outbreak in late March
that sickened more than 300 people (WHO, 2003c). Rather than its usual route of
transmission by respiratory droplets, the virus is thought to have spread via
aerosolized fecal matter through the internal sewer system of the apartment com-
plex (WHO, 2003f). Consequently, on March 31, Hong Kong’s health authorities
issued an unprecedented quarantine order to halt the spread of SARS on the
island, which required some residents of the housing complex to remain in their
apartments until midnight of April 9 (10 days later) (WHO, 2003c).
Spread of the SARS Coronavirus Beyond China

Epidemiological investigations revealed that the spread of SCoV outside
China began on February 21, 2003, when 12 people staying in the Metropole
Hotel in Hong Kong contracted SCoV from an infected, symptomatic physician
from Zhongshan University (see Figure S-2). These 12 people subsequently car-
ried the infection with them to Singapore, Vietnam, Canada, Ireland, and the
United States—initiating chains of infection in all of these countries except for
Ireland. According to WHO estimates, most of the more than 8,000 probable
cases of SARS worldwide originated with this superspreader (WHO, 2003a).
Vietnam
Dr. Carlo Urbani, a WHO infectious disease specialist based in Vietnam,
reported concerns about a patient in the Hanoi French Hospital with a high

February 18, 2003: Senior microbiologist at Chinese Center for Disease Control announces he
suspects the disease is Chlamydia.
November January
2002 2004
fever and atypical pneumonia to WHO’s Western Pacific office on February 28

(WHO, 2003c). Responding to Dr. Urbani’s alert and other reports of atypical
pneumonia in Vietnam and Hong Kong, WHO sent GOARN teams to Hong
Kong and Hanoi to join the investigative and containment efforts already un-
derway. The early detection of SARS in Vietnam, prompt sharing of that infor-
mation with the international community, and aggressive containment efforts
by the Vietnamese government, in partnership with a GOARN team, enabled
FIGURE S-2 Portrait of a superspreader: spread of SARS from the Metropole Hotel in
Hong Kong as of March 28, 2003.

February 21, 2003: Worldwide epidemic begins at Metropole Hotel, Hong Kong.
November January
2002 2004
the Vietnamese to eradicate SARS by the end of April. This was accomplished
before SARS was contained in either Canada or Singapore, despite Vietnam’s
comparatively limited health care resources and lower education levels among
its population. (Tragically, Dr. Urbani himself died of SARS.) It was suggested
by workshop participants that containment of the disease in Vietnam was, in
fact, aided by the absence of more sophisticated medical devices and facili-
ties—such as mechanical ventilation by intubation, bronchoscopy, aerosolized
medications, and large hospital facilities that exposed large numbers of indi-
viduals to undiagnosed SARS patients awaiting care—which have been identi-
fied as factors that promoted SCoV transmission considerably in Singapore and
Toronto (Lee et al., 2003).
On March 12, WHO issued a global alert describing outbreaks of the yet-
unnamed respiratory disease in Hong Kong and Vietnam and instituted world-
wide surveillance (WHO, 2003d). A second alert on March 15 named the condi-
tion, listed its symptoms, and advised travelers to have a high level of suspicion
of SARS and report to a health worker if they had SARS symptoms and had
visited an area where SARS was known to be occurring. Two further alerts
provided recommendations for airports to screen passengers and for travelers to
avoid areas where SARS had been detected, respectively (WHO, 2003e).
Canada
Canada’s experience with SARS illustrates the importance of identifying and
isolating every infected individual in stemming the spread of the disease. There, the
index patient returned to Toronto from Hong Kong on February 23, developed a
febrile illness that was diagnosed as pneumonia, then died at home on March 5. Her
son, who cared for her, subsequently became ill and on March 7 was admitted to a
hospital, where he infected many patients and members of the staff. He died there
on March 13, one day after WHO issued its first global alert. In this, the first phase
of the Toronto epidemic, unrecognized patients who shared rooms with the son
went on to infect scores of other patients, family members, and hospital workers.
This scenario was repeated in several area hospitals, as well as others around the
globe, even after increased infection control measures were undertaken.
Realizing that SARS was not contained within a single hospital, Ontario
declared a provincial emergency on March 26 that halted the transfer of patients
among hospitals, instituted infection control measures and created SARS units
within hospitals, minimized visitor access to hospitals, and established a process

February 28, 2003: Atypical pneumonia reported in Hanoi, Vietnam.
November January
2002 2004
to screen all persons entering hospitals for symptoms of SARS. Because the
spread of SARS in Toronto was largely restricted to the hospital setting, these
precautions were effective in controlling the outbreak. When a second phase of
SARS occurred in mid-May, after emergency measures were relaxed, it was
quickly brought under control with little spread outside the affected hospital (See
D. Low in Chapter 1). A similar lapse in infection control in a Taiwan hospital
ignited an outbreak in mid-April (WHO, 2003g). Health authorities responded
quickly by increasing surveillance, redoubling infection control measures, and
launching a mass education campaign credited with reducing the time between
symptom onset and patient isolation.
Singapore
Rapid contact tracing by health authorities in Singapore, where scores of
SARS cases had been reported, linked that country’s index case to the Metropole
Hotel by April 4. Singaporean authorities imposed strict containment measures,
including contact tracing and 10-day quarantine for all contacts of known SARS
patients, as well as screening for fever among incoming and outgoing passengers
at all airports and seaports. One indication of the effectiveness of these measures
is the fact that 80 percent of Singapore’s SARS patients did not infect anyone else
(WHO, 2003h; Singapore Government, 2003).
On September 8, an isolated case of SARS was reported in Singapore, and
subsequently confirmed by the U.S. Centers for Disease Control and Prevention
(CDC) (WHO, 2003l). The patient, a 27-year-old microbiology postdoctoral stu-
dent, had no history of travel to SARS-affected areas or contact with SARS
patients. Rather, he apparently become infected through a laboratory accident
stemming from the contamination of samples containing West Nile virus, the
subject of the patient’s research, with the SCoV, which was also being studied in
the same biosafety level 3 facility.
THE IMPACT OF THE SARS EPIDEMIC

As the SARS coronavirus spread around the globe, so did its political, sociologi-
cal, and economic repercussions. Workshop participants described the official reac-
tion to the outbreak in China, examined the political and public health implications of
how China acknowledged and confronted the full dimensions of the epidemic on
national and international levels, and assessed the immediate and long-term economic

March 7, 2003: Son of Toronto index patient enters Scarborough Grace Hospital, initiating outbreak.
November January
2002 2004
impact of SARS. Central to these discussions was the recognition of the extreme
pressure SARS exerted on both international and local health care systems and the
frightening prospect of future outbreaks of greater contagion or virulence.
The multinational effort to contain SARS placed unprecedented demands on
affected and unaffected countries to accurately identify and report cases in a
timely manner, to cooperate with GOARN expert teams of scientists and medical
personnel coordinated by WHO, and to sacrifice immediate economic interests
(e.g., travel, trade, tourism). Without international legal obligation to report
SARS, most countries did so fully. Yet this extraordinary alliance would have
failed without the full cooperation of China, the epicenter of the epidemic.
Politics, Tradition, and the Chinese Response to SARS

Workshop participants asserted that China’s problems in dealing with the
SARS epidemic were fundamentally rooted in organizational obstacles. Prob-
lems cited during the workshop included impediments to the flow of information
through the governmental hierarchy, a lack of coordination among fragmented
governmental departments, and a political system in which the value of handling
problems internally overrides any recognized value of external assistance. Impor-
tantly, workshop participants noted that these systemic failings are not exclusive
to China and impede the response to public health and other social problems in a
large number of countries around the world.
Uniquely, the Chinese tradition of respect for senior scientists in positions of
authority may have substantially influenced the behavior of the Chinese Center
for Disease Control and of other Chinese scientists who were researching the
epidemic (Enserink, 2003). A highly respected Chinese scientist reportedly
claimed that Chlamydia infection caused SARS, based on an examination of only
two specimens. This may have led the Chinese Center for Disease Control and
other Chinese clinicians and scientists to maintain that Chlamydia was the SARS
agent, despite other evidence inside China indicating that the agent was viral.
Consequently, virologists in a Beijing laboratory refrained from announcing their
discovery in early March of the SARS coronavirus, a decision that set back by
weeks research on the disease and a more significant public health response in
China (Enserink, 2003).
The SARS epidemic also exposed weaknesses in China’s public health infra-
structure, including inadequate state funding, lack of effective surveillance systems,
and severe shortages in facilities and medical staff prepared for an epidemic infec-

March 10, 2003: WHO teams arrive in Hong Kong and Hanoi.
March 12, 2003: First WHO global alert issued on yet-unnamed disease.
November January
2002 2004
tious disease outbreak. As a forewarning, a workshop participant observed that these

same weaknesses are often cited by medical and public health experts when assessing
the state of preparedness for infectious disease outbreaks in the United States.4 These
statements corresponded with other participants who suggested that, in the case of
SARS, the United States was perhaps more lucky than it was prepared.
In response to the deficiencies highlighted by SARS, the Chinese govern-
ment established a case reporting structure, strengthened its emergency response
system, dismissed key officials who mismanaged the crisis during its initial
months, and provided funding for the prevention and control of SARS. Chinese
workshop participants also credited the SARS experience for increasing the rec-
ognition and understanding of government officials and the public about the
importance of infectious disease control and prevention in general.5
Economic Impact
While the most immediate and dramatic economic effects of SARS occurred
in Asia, every market in today’s global economy was at some point impacted
directly or indirectly by the epidemic. Several agencies and experts have at-
tempted to estimate the cost of SARS based on near-term expenditures and losses
in key sectors such as medical expenses, travel and related services, consumer
confidence, and investment. One model estimated that the short-term global cost
of lost economic activity due to SARS was approximately $80 billion.6 Partici-
pants agreed, however, that the true economic consequences of SARS remain to
be determined, particularly given the possibility of its return.
An economic model presented at the workshop estimated the impact of
SARS on several countries—and in aggregate, on the world. It considered two
different scenarios: a short-term shock coincident with a one-time epidemic, and
long-term effects typical of recurring outbreaks. The model was not intended to
4See IOM, 2003; General Accounting Office, 2001; National Intelligence Council, 2000.
5During the development of the this report, a Chinese author commented that the recent commit-
ment by the highest level of Chinese government officials to the prevention and treatment of AIDS,
after years of little public recognition of the disease or its victims, might in large part be credited to
the new awareness by all Chinese of the threats posed by unchecked infectious diseases.
6Workshop presentation by Warwick McKibbin, Australia National University, September 30,
2003.

March 15, 2003: Second WHO global alert names SARS; first travel advisory declared.
November January
2002 2004
calculate precise monetary effects, but rather to reveal the magnitude of the
impact on countries and regions, scaled to their individual economies (see Lee
and McKibbin in Chapter 2).
According to this model, the short-term SARS shock disproportionately af-
fected Hong Kong due to its economic dependence on services (e.g., travel,
tourism). Significant short-term losses also accrued in China as a result of a sharp
decrease in foreign investment, a trend that could be crippling if perpetuated over
several years. In the long term, the expectation of continued outbreaks of infec-
tious disease emanating from China could engulf that entire region of Asia in a
permanent “disease transmission shock.”
Paradoxically, workshop participants discussed the global cost of SARS
associated with lost economic activity—now estimated to have been around $40
billion, and possibly as high as $54 billion if investors remain cautious about the
possibility of future outbreaks—as a potential cost of neglecting to invest in
public health infrastructure. Several participants warned of a vicious spiral to be
avoided: an economic downturn resulting from SARS or another pandemic which
squeezes funding for public health, further weakening the world’s ability to pre-
vent or contain subsequent outbreaks. The message here: an ounce of prevention
is worth a pound of cure. It was suggested by several participants that further
analyses comparing the anticipated costs associated with strengthening both glo-
bal and national public health systems of surveillance and response with the
anticipated costs of another epidemic SARS (or other disease) outbreak might
reveal important results to persuade decisionmakers to make priority investments
in relevant public health and research areas.
Impact on Global and Local Public Health Systems

Like many of the emergent diseases of the last decade, the challenge of
SARS has cast a glaring spotlight on the need for greater investments in public
health infrastructure. The outbreak placed a huge burden on international health
systems that were already straining to address AIDS, tuberculosis, malaria, and a
host of other conditions. With GOARN, WHO had an established structure to
coordinate international resources and personnel and thereby muster surge capac-
ity to address such outbreaks. That network was severely tested by SARS, but the
successful containment of SARS through national actions supported by interna-
tional collaboration confirms the value of this approach in addressing future
epidemics (see Abdullah et al. in Chapter 1).

March 17, 2003: WHO establishes laboratory network to seek cause of SARS.
November January
2002 2004
A key factor underlying the influence of SARS on public health, political,

and economic systems was the infection of large numbers of health care workers.
Nowhere was the impact of SARS felt more keenly than in the local health care
systems of affected areas, where frontline caregivers all too frequently ended up
as intensive care patients in need of extended hospital stays or as fatalities. This
assault on the well-being of many health care personnel, coupled with the ex-
hausting demands put on those who remained healthy, led Toronto health offi-
cials to send out a call to infectious disease professionals in the United States and
Europe to come to Canada to bolster their capacity to fight the disease. Addition-
ally, a workshop participant alleged that in Toronto, the closing of outpatient
clinics in response to SARS may have caused greater morbidity and mortality
than the disease itself. However, other participants argued that without a vaccine
or cure for SARS, the isolation of patients and their contacts—including their
caregivers—represented the most effective method of containing the epidemic.
THE PUBLIC HEALTH RESPONSE TO SARS
The Global Response

As noted earlier, the WHO response to SARS was spearheaded by GOARN.
To extend its capacity for surveillance, reporting, and containment, WHO en-
listed the support of public health services from the United States, United King-
dom, Germany, France, and other nations. GOARN recruited more than 60 teams
of medical experts to assist with infection control in SARS-affected areas, which
included 84 personnel from the U.S. CDC. Ultimately, more than 800 CDC
employees were involved in the response to SARS.
Through GOARN, WHO also established a virtual network of 11 leading
infectious disease laboratories in 9 countries. Connected by a secure website and
daily teleconferences, the laboratories collaborated to identify the causative agent
of SARS and to develop a diagnostic test; similar groups were also created to
pool clinical knowledge and compare epidemiological data on SARS. By April
16, exactly 1 month after the laboratory network was established, its researchers
had conclusively identified SCoV as the causative agent.
When evidence revealed that persons infected with SCoV continued to
travel—placing adjacent passengers on airplanes at risk of infection—WHO
advised airlines to screen departing passengers (WHO, 2003n). Further WHO
advisories to avoid all but essential travel to certain high-risk areas were the

March 20, 2003: United States reports first cases of SARS.

March 26, 2003: Ontario declares provincial emergency.
November January
2002 2004
most restrictive in the history of the organization (WHO, 2003c). The U.S. CDC
and Health Canada also issued advisories that warned against travel to SARS-
affected countries.
Chinese Cooperation
Members of a GOARN mission to China in late March warned that country’s
health authorities that if SARS was not brought under control in China, there
would be no chance of controlling the global threat of SARS. Within days, the
GOARN team announced that Chinese authorities had agreed to join the GOARN
collaborative effort to contain the outbreak and prevent further international
spread (WHO, 2003i).
At a March 28 meeting with the Chinese Minister of Health, WHO officials
determined that the atypical pneumonia in Guangdong was SARS and that the
first cases had appeared in mid-November 2002 (WHO, 2003c). Data provided
by the Chinese Center for Disease Control suggested an association between
exotic food animals and SARS, indicating the possibility of a zoonosis. More
than a third of the earliest SARS cases—those that emerged in China before
February 2003—occurred among workers who handled, butchered, or sold wild
animals in Guangdong’s markets, or who prepared and served them as food.
Viruses closely resembling SCoV were eventually isolated from several animal
species sold in such markets; however, a natural reservoir for SCoV has yet to be
found (Guan et al., 2003).
Although Chinese officials acknowledged that SARS had emerged in their coun-
try, they continued to downplay the extent and severity of the outbreak. This led the
WHO team in Beijing to take the unusual measure of publicly expressing “strong
concern over inadequate reporting” of SARS cases on April 16 (WHO, 2003c).
On April 20, national government leaders declared a “nationwide war on
SARS” and removed the mayor of Beijing and the Minister of Health from their
posts reportedly for failing to satisfactorily address the epidemic (WHO, 2003c).
Thereafter, China increased both its disease control efforts and its cooperation
with the international community in the effort to contain SARS. Both the Chinese
government and the public took considerable action to halt the epidemic. A
workshop participant described how large numbers of government offices,
schools, and universities were shut down. Quarantines to prevent public gather-
ings and travel from cities were imposed to prevent the spread of the disease to

March 27, 2003: WHO instructs airlines to screen passengers in SARS-affected areas.
November January
2002 2004
the rural interior of the country, where it was feared that medical resources would
be unable to contain or treat the disease. In late June, after more than 5,000 cases
had been reported, the disease was contained in China. By this time, Beijing had
reported 348 deaths and Hong Kong, 298—the two greatest death tolls due to
SARS for any city or region at that time (WHO, 2003c).
When WHO declared on July 5 that all chains of SARS transmission had
been broken, the disease was thought to have spread to more than 30 countries,
only 8 of which—Canada, China, Hong Kong, the Philippines, Singapore, Tai-
wan, the United States, and Vietnam—reported more than 10 probable cases.
Assessing the Use of Public Health Tools

The experience of the SARS outbreak and the history of its control hold
clues to the origin and spread of the disease—knowledge that will help to prevent
or curtail its resurgence. In assessing the public health response to SARS at both
the global and local levels, workshop participants focused on the roles of surveil-
lance and containment in limiting the spread of SARS and anticipated the use of
these tools against future microbial threats.
Surveillance
Broad international networks of individuals and organizations within and
across disciplines were responsible in large part for the successful surveillance of
the SARS epidemic. Electronic communication networks such as the Global
Public Health Information Network (GPHIN) and ProMED mail reported the
early outbreaks. ProMED uses electronic communications to provide up-to-date
news on disease outbreaks and is open to all Internet users. GPHIN, established
by Health Canada in collaboration with WHO, is an Internet-based application
that continuously scans global electronic media (news wires, websites) for infor-
mation on global public health risks, including infectious disease outbreaks. Al-
though these systems ultimately proved to be critical tools for effective surveil-
lance, workshop participants questioned the ability of the existing system to
rapidly identify novel emerging threats, which induce symptoms and behaviors
characteristic of other infectious diseases that may not initially promote concern
or further investigation. Additionally, the sensitivity of the system was consid-
ered inadequate because of its inability to correlate disparate data from multiple

March 28, 2003: Chinese officials share details of first SARS cases.
March 30, 2003: Amoy Gardens, Hong Kong, outbreak announced.
November January
2002 2004
surveillance networks that, only when taken as a whole, might surpass a threshold
that signals an alarm to public health professionals. Retrospective analyses of the
reports on several surveillance networks revealed multiple reports of atypical
pneumonia in China between November 2002 and January 2003. However, the
lack of collaborative data analysis between multiple reporting systems and the
initial absence of clustering allowed the virus to spread unchecked. GOARN
identified and verified subsequent outbreaks with the help of the media, nongov-
ernmental organizations, agencies of the United Nations, and public health teams
from many countries in addition to those where the outbreaks occurred. GOARN
communicated new information to authorities and the public through the WHO
website, satellite broadcasts, and news conferences.
The SARS epidemic became a front-page event for the worldwide news
media. Daily updates posted on the WHO website for travelers and the public
sought to counter rumors with reliable information. The U.S. CDC, which spear-
headed the U.S. response to SARS, provided information through its website,
satellite broadcasts, and a public response hotline for clinicians and the public.
The vast Emerging Infections Network created by the Asian Pacific Eco-
nomic Community (APEC) also conducted surveillance for SARS. In addition, it
provided an arena for discussions relevant to both biomedical research and dis-
ease control, and it monitored the economic impact of SARS in its member
countries, which comprise 2.5 billion people and conduct nearly half of the
world’s trade (see Kimball et al. in Chapter 5).
Containment
While many aspects of the public health response to SARS benefited from
such technological developments as global broadband telecommunications, the
containment of the epidemic ultimately depended on the venerable strategies of
identifying and isolating persons who fit the case definition and tracing and
quarantining their contacts. In countries such as Vietnam and Singapore, where
these measures were imposed soon after the identification of index cases, the
chain of infection was broken quickly. By contrast, China’s delayed response to
the epidemic rendered contact tracing impossible and resulted in the need for
broader quarantines.
The U.S. strategy to prevent an outbreak within its borders focused on the
early detection of symptom onset and rapid implementation of infection control

March 31, 2003: Hong Kong health authorities issue quarantine order requiring some residents of the
Amoy Gardens apartment complex to remain in their homes until April 9.
November January
2002 2004
and isolation. Only in high-risk settings such as health care facilities or airline
flights carrying passengers exposed to SARS-infected individuals did CDC sug-
gest the use of quarantine (by definition, the isolation of asymptomatic individu-
als believed to have been exposed to a contagion). In the absence of an outbreak,
the agency directed its efforts toward informing the traveling public about high-
risk areas, issuing travel advisories, distributing millions of health alert notices in
seven languages at airports and U.S.–Canada border crossings, and responding to
symptomatic incoming passengers. However, several other countries quarantined
travelers arriving from SARS-affected areas.
The relative effectiveness of various strategies applied to SARS contain-
ment—the use of standardized case definitions and laboratory testing to identify
the infected, the isolation of ill persons, and the quarantine of contacts—remains
to be determined. Based on the present understanding that asymptomatic infected
individuals transmit SARS at a low rate, if at all (WHO, 2003j), and that trans-
mission occurs primarily through contact with ill individuals, workshop partici-
pants suggested that quarantine of contacts was the least effective of these strat-
egies. However, they also recognized that quarantine could facilitate the
containment of a SARS-like disease by reducing the number of contacts by
infected individuals during the delay between the onset of symptoms and diagno-
sis. This would be particularly effective when, as in the case of SARS, symptoms
are nondescript and difficult to distinguish from those of other illnesses. It was
also emphasized that quarantine should not be viewed as an impermeable cordon
sanitaire confining those at risk for illness with the known ill, but as a scalable,
self-protective measure that can be adapted to local conditions.
Less problematic than quarantine, the isolation of infected individuals clearly
played a central role in containing SARS. Although isolating SARS patients
within hospitals could be viewed as increasing the risk of infection for health care
workers and other hospital staff, evidence from Toronto indicates that hospital
personnel can be protected through strict infection-control practices, such as
washing hands, wearing masks and gloves, and requiring patients to wear masks.
The most effective type of mask remains to be determined, however.
Finally, even if it were known which of the various strategies used to
contain SARS were most effective, it is far from certain whether they would
continue to be effective should SARS return. For example, although it appears
that quarantine helped control SARS in China and Toronto, it did so largely
because of the limited contagiousness of the virus. The likelihood that SCoV

April 2, 2003: WHO declares travel advisory for Hong Kong and Guangdong Province.
April 4, 2003: Role of Metropole Hotel in global epidemic identified.
November January
2002 2004
could become more easily transmissible cannot be determined without a better

understanding of its biology, ecology, and natural history—knowledge that will
be essential to mounting a rational response should SARS recur (see Cetron et
al. in Chapter 1).
Evaluating SARS Containment Measures

To plan rationally for the containment of a future SARS outbreak, it will
be important to know the relative effectiveness of the various measures taken
to contain the recent epidemic. In the absence of such information, the strategy
for containing SARS should emphasize overall preparedness at the local level in
every community and hospital, participants agreed.
Participants discussed techniques and equipment to protect frontline
caregivers of SARS patients in the hospital and at home. Simple habits such as
frequent handwashing with soap and water are very important to prevent the
transmission of any infectious agent. Other measures include wearing a mask that
covers the nose and mouth, protective eyewear, gloves, gowns, or a containment
suit. Participants noted that masks are effective only if they fit snugly and are not
removed when the wearer coughs.
During the discussion of masks, participants debated the relative protective-
ness of standard surgical masks compared with N-95 masks (so named because
95 percent of the time, they filter out any particle equal to or greater than 0.3
microns in size). Coronaviruses are smaller than 0.3 microns, so N-95 masks
would not capture them; however, because viruses may travel in clumps, N-95
masks theoretically could capture some of the agent (University of California–
Berkeley, 2003). Participants discussed a case control study in five Hong Kong
hospitals in which wearers of surgical masks and N-95 masks did not contract the
SARS coronavirus, while a few wearers of paper masks became infected (Seto et
al., 2003). A larger study to validate this finding was proposed.
One workshop presentation described a relatively inexpensive mobile tech-
nology that potentially could be used to isolate individual patients during trans-
port to and within hospitals, to protect staff during high-risk procedures such as
intubation or bronchoscopy, to decontaminate large areas such as hospital wait-
ing rooms or airplanes, and to create air exchange systems for isolation facilities
or areas within hospitals (see Schentag et al. in Chapter 4). These mobile units
remove and destroy airborne viral particles and droplets; the latter are widely
believed to be the vector for SCoV transmission. Importantly however, it was

April 16, 2003: SARS coronavirus identified; WHO accuses Chinese government of underreporting
SARS cases.
November January
2002 2004
noted that such technologies must be thoroughly evaluated to determine their

suitability for containing SARS in a variety of clinical settings before they are
recommended for use.
CORONAVIRUS RESEARCH AND SARS

The SARS coronavirus (SCoV) appears to be zoonotic and to have origi-
nated in wild mammals in southern China. A coronavirus comprises single-
stranded RNA inside a lipid envelope. Coronaviruses cause a substantial fraction
of human colds and a number of common respiratory infections in other animals,
including livestock and poultry (Holmes, 2003). Since its emergence, several
veterinary and biomedical scientists have been called on to share their consider-
able knowledge of coronaviruses with a vast new audience and to join the re-
search response to the epidemic. This experience—and the high value evident in
available knowledge and understanding of coronavirus biology and molecular
biology, gained at a time when coronaviruses were not recognized to be the
causative agent of any severe infectious disease—attests to the value of basic
research.
Based on their genetic sequences, the 14 previously known coronaviruses
have been divided into three major groups. While SCoV has been linked with
Group II coronaviruses, whose members include human and bovine respiratory
viruses and the mouse hepatitis virus, there is still some debate over whether its
genetic features might be sufficiently distinct to warrant classification within a
separate, fourth class of coronaviruses.
Although coronaviruses generally cause disease in a single species, it has been
demonstrated that some coronaviruses can cross species barriers. Moreover, RNA
viruses are more likely to be zoonotic than DNA viruses. These findings lend
credence to the hypothesis that SCoV is a zoonosis. Viruses resembling human
SCoV reportedly have been detected in wild mammals of southern China that were
brought to marketplaces where they were sold as exotic food. Immunological and
genetic tests of these SCoV-like viruses suggest that human SCoV may be an
animal virus transmitted to humans in the recent past (Guan et al., 2003).
Understanding the Biology and Epidemiology of SARS

As one would expect of a newly characterized disease, much knowledge
about the microbiology, pathogenesis, natural history, and epidemiology of SARS

April 20, 2003: Mayor of Beijing and Chinese Minister of Health fired.
November January
2002 2004
BOX S-1
Scientific Unknowns About SARS
• What is the natural animal host of SCoV?
• How was the virus transmitted to humans, and under what circumstances might
transmission across species recur?
• What is the potential for back-and-forth transmissions between humans and
animals?
• Is there a persistent animal reservoir?
• Is the virus still present in human populations?
• Will the transmission of SCoV prove to be seasonal, as for influenza?
• What is the potential geographic range of SCoV?
• What role do cofactors play in mediating the severity of SARS symptoms?
• What explains the low rate of illness among children?
• What causes superspreading events?
• How important are routes of transmission other than infectious respiratory
droplets? Under what circumstances do alternative modes of transmission occur?
• How does pathogenesis unfold at the cellular level, and especially in nonrespi-
ratory tissues?
SOURCES: Breiman presentation; Denison presentation (see Chapters 1 and 3 respectively);
WHO, 2003j.
remains to be discovered. For example, scientists have not yet identified the
animal source of the infectious agent and have not determined whether a persis-
tent animal reservoir of the infectious agent exists. It is also unclear whether
SARS, like influenza, is a seasonal disease that would have receded on its own.
Along the same lines, it remains to be seen whether SARS will reemerge on a
seasonal basis, and if so, how virulent future manifestations of SCoV will be.
These and other unanswered scientific questions, listed in Box S-1, were a promi-
nent theme of workshop presentations and discussions. Answers to these ques-
tions would certainly advance the world’s ability to predict and prepare for a
resurgence of SARS.7
7The recent reemergence of human SARS infections in 2004 would indicate both an animal reser-
voir and a seasonality to disease emergence, but further investigation will be required for conclusive
evidence.

April 23, 2003: WHO declares travel advisory for Beijing, Shanxi Province, and Toronto.
November January
2002 2004
Considerable effort already has been applied to finding the animal source of
SCoV. For example, viral isolates from suspected animal sources were geneti-
cally characterized and compared with samples of SCoV (see Guan et al.
in Chapter 3). However, recalling previous investigations of outbreaks of
Legionnaire’s disease, Schistosomiasis, and E. coli 0157, workshop participants
noted the crucial role played by epidemiological “detective work” in developing
hypotheses that led ultimately to the source of transmission (Zhong et al., 2003).8
To this end, it was suggested at the workshop that a case control study of the
first 50 to 100 SARS patients be conducted using epidemiological data col-
lected in Guangdong Province. Such an endeavor may provide direction to
further laboratory surveys of animal viruses to reveal the source of SCoV
and, perhaps, its animal reservoir.9
SARS researchers benefit from the wealth of literature on coronaviruses in
general. Presentations by two coronavirus experts at the workshop summarized
the current understanding of coronavirus biology and pathogenesis and suggested
promising directions for research on SARS and other emerging zoonoses (see
Saif and Denison in Chapter 3).
The pathogeneses of animal coronaviruses conform to a basic model of
either intestinal (enteric) or respiratory infection. Enteric coronaviruses can cause
fatal infections in young, seronegative animals. Respiratory coronavirus infec-
tions in adult animals have shown increased severity in the presence of several
factors, including high exposure doses, respiratory coinfections, stress related to
shipping or commingling with animals from different farms, and treatment with
corticosteroids. It is unknown whether SCoV is a respiratory virus or a
pneumoenteric virus. This knowledge gap will stymie efforts to develop a
vaccine or drug against SCoV.
Studies of coronavirus replication reveal several mechanisms that account
for the repeated, persistent infections typical of coronaviral disease. High rates of
mutation and RNA-RNA recombination produce viruses that are extremely adapt-
able and capable of acquiring or regaining virulence. The relatively large corona-
virus genome tolerates deletions, mutations, and substitutions and can recover
from deleterious mutations. Molecular biological studies have also identified
8Workshop presentation by Robert Breiman, Centre for Health and Population Research, Dhaka,
Bangladesh, October 1, 2003.
9Workshop presentation by Yi Guan, University of Hong Kong, September 30, 2003.

April 28, 2003: SARS contained in Vietnam.

April 30, 2003: WHO lifts Toronto travel advisory.
November January
2002 2004
several potential targets for antiviral drug discovery, including viral binding
and uncoating, replication, protein expression and processing, assembly, and
release. Cellular functions on which the virus depends, such as cholesterol
synthesis, membrane trafficking, and autophagy, also present opportunities
for antiviral design (see Matthews et al. in Chapter 4).
The tendency of coronaviruses to undergo mutation and recombination rep-
resents a significant challenge for vaccine development. To date, no vaccine has
been produced that can provide highly effective, long-term protection against
respiratory coronavirus infections. Genetic approaches represent the best hope of
overcoming this propensity for mutability, according to workshop presenters.10
For example, it might be possible to find ways to limit RNA-RNA homologous
recombination, or to identify areas in the genome that are more or less prone to
survive mutation. Promising approaches to these challenges include the use of
reverse molecular genetics to make specific mutations in the virus genome and
test their functional effects.
Workshop presenters emphasized that appropriate animal models are needed
immediately to advance the development of a SARS vaccine. Participants also
noted that studies in existing animal models of coronavirus infection could play a
role in the development of antiviral therapies against SARS. Ultimately, a range
of natural and transspecies disease models will be critical to understanding the
pathogenesis of this and other emerging zoonoses. Coordinated, multidisci-
plinary research drawing on expertise in veterinary sciences, medicine, mo-
lecular biology, and virology will be needed to meet these goals. However,
the coronavirus experts who presented at the workshop lamented that there
is little encouragement or support for such critical cross-disciplinary re-
search at present.
BUILDING DEFENSES AGAINST A REEMERGENCE OF SARS
Anticipating the Reemergence

Considering the likelihood of a return of SARS under a variety of circum-
stances is an important first step in planning for a broad range of contingencies
10Workshop presentation by Alan Shaw, Merck Vaccine Co., October 1, 2003.

May 3, 2003: Taiwan outbreak grows to 100 cases; WHO sends team.
May 8, 2003: WHO declares travel advisory for Tianjin, Inner Mongolia, and Taipei.
November January
2002 2004
and challenges. A trio of plausible scenarios was presented at the workshop (see
Monaghan in Chapter 5). The first scenario entailed a resurgence of SARS in
China, followed by limited spread to other countries in the region. Heightened
surveillance and rapid response could quickly contain such an outbreak, but
might also cause SARS to be viewed less as a threat and more as a public
nuisance; this attitude could lead to a decline in vigilance, raising the risk of a
future epidemic.
In the second scenario, SARS spreads to poor countries in Asia and Africa,
where inadequate health systems, preexisting health problems, high population
density, and weak government leadership result in high infection rates and mor-
tality. Such an epidemic would prove difficult to contain and create a humanitar-
ian emergency that would place costly demands on international policy makers
and institutions as well as developed countries compelled to respond for reasons
that were both humane and self-protective.
The final, scenario depicts the resurgence of SARS in key trading centers of
Asia and Canada, followed by transmission to the United States, Brazil, India,
Japan, and Europe.
And even if this epidemic produced fewer cases of SARS than in 2003, it
would be likely to cause major disruptions in trade and investment flows.
In considering further preparations for the reemergence of SARS, workshop
participants discussed the development of surveillance and containment strate-
gies in case SARS reappears during the winter of 2004; ongoing efforts to de-
velop diagnostic tools for SARS and other infectious diseases; and long-term
prospects for the discovery and development of antiviral drugs and vaccines
against this newly emergent disease.
Continued Surveillance for SARS

For a number of reasons, workshop participants agreed that continued vigi-
lance in light of SARS is warranted for a number of reasons. First, it is very likely
that an animal reservoir for the virus exists in China. Second, the continued sale
of live, small wild mammals in marketplaces and the preparation of these animals
as food perpetuates a hypothesized route of SCoV transmission to humans. Third,
the possibility that SARS, like influenza, is a seasonal disease means it could
reappear during the winter of 2004. Finally, initial low-level transmission of the
virus could elude clinical recognition and reporting of the disease.

May 21, 2003: WHO declares travel advisory for all of Taiwan.
May 22, 2003: Second wave of SARS begins in Toronto.
November January
2002 2004
It was suggested that in the absence of inexpensive, accurate, and widely

available SARS diagnostics, syndromic surveillance—particularly in populations
at high risk for reemergence—might be important for spotting nascent outbreaks.
This methodological strategy, which involves monitoring groups of signs and
symptoms associated with disease activity—unusual spikes in the purchase of
commonly available health remedies, for example, or surges in particular symp-
toms reported among routinely collected information from clinical sources—has
shown some promise in the early detection of disease outbreaks in the United
States (Institute of Medicine, 2003). However, because SARS symptoms are
variable and difficult to distinguish from those of influenza and seasonal human
coronavirus infections that emerge in the same populations, it is not clear that
such methods would be capable at present of distinguishing the emergence of
novel infections such as SARS without careful consideration of the utility, quan-
tity, and specificity of the surveillance data to be collected. Until a specific
diagnostic test becomes available, there will continue to be a substantial risk of
both missed cases and false alarms, and syndromic surveillance methods should
be evaluated as possible complements to rather than replacements for maintain-
ing and strengthening traditional clinical reporting systems.
Development of SARS Diagnostics

A rapid, specific, reliable, and inexpensive clinical diagnostic test for SARS
would be a valuable tool for improving surveillance and limiting the transmission
of SCoV. First, however, scientists must determine which tissues contain the
highest concentrations of virus during the presymptomatic stage of infection. It
was also noted that in confirmed cases of SARS, the virus appears to be located
deep in the respiratory tract, making specimens difficult to collect.
Available Diagnostics
Absent a clinical diagnostic test, suspected cases of SARS must be con-
firmed in the laboratory using reverse-transcription polymerase chain reaction
(RT-PCR) or much slower methods involving serology or viral culture, isolation,
and identification by electron microscopy (Yam et al., 2003).
According to WHO, the laboratory case definition of SARS requires one of
the following:

May 23, 2003: SARS linked to masked palm civet and raccoon-dog; Hong Kong and Guangdong
travel advisories lifted.
November January
2002 2004
• A positive RT-PCR finding in two or more clinical specimens, sequential

samples, or assays using separate RNA extracts from the same sample.
• Seroconversion or a fourfold increase in titer between the acute and con-
valescent phases of infection as determined by immunoassay.
• Isolation of the virus with RT-PCR validation.
Recent incidents have highlighted the critical need for both specificity and
sensitivity of laboratory diagnostic procedures. To address these issues, WHO
and the CDC continue to work to standardize test protocols, reagents, and con-
trols and to establish procedures for evaluation and quality control throughout the
global network of diagnostic laboratories that may handle suspected SARS cases
(WHO, 2003m).
Workshop participants considered several platforms that could potentially be
adapted for the rapid, clinical diagnosis of early, asymptomatic SCoV infection.
For example, workshop participants considered the use of RT-PCR for detecting
SCoV nucleic acids. A recent evaluation of two RT-PCR protocols found them to
be highly specific for the SARS coronavirus; however, these protocols were
insufficiently sensitive to detect the virus reliably in respiratory specimens. Test-
ing two specimens from the same patient increased the probability of an accurate
diagnosis (see Yam et al. in Chapter 4).
A different platform discussed at the workshop purportedly can identify the
family, and possibly the genus, of known or novel infectious agents (see Sampath
and Ecker in Chapter 4; Hogg, 2003). Unlike many RT-PCR techniques, which
target nucleic acid sequences unique to a specific organism, this test amplifies
strategically chosen, highly conserved sequences from the broadest possible
grouping of organisms. The molecular weight of the amplimers is measured by
electrospray ionization mass spectrometry. Then the relative amounts of each
base (i.e., the percentage of adenine, cytocine, thiamine, and guanine) are de-
duced. The base-pair composition of the selected genetic sequence serves as a
signature to identify and distinguish organisms in a sample.
Originally designed for the environmental surveillance of biowarfare agents,
such technology could potentially diagnose SARS directly from a tissue sample,
obviating the need for time-consuming viral culture. According to workshop
presenters, their method can distinguish between SCoV and other coronaviruses
and perhaps even between genetic variants of SCoV. However, it is important to
note that the test’s sensitivity has yet to be evaluated using samples of human
SARS-infected tissue.

May 31, 2003: SARS contained in Singapore.
November January
2002 2004
Antiviral Drugs and Vaccines

As noted earlier, until basic research on the pathogenesis of SARS elucidates
whether the infection is respiratory or pneumoenteric, it is unclear which tissues
a therapeutic agent should target. That being said, preparing for a reemergence of
SARS might include the strategic development of a vaccine and an antiviral drug.
Theoretically, an ideal vaccine would contain an epidemic more effectively
than an ideal antiviral drug if a large segment of the population were vaccinated.
Yet mathematical models of influenza described at the workshop indicate that an
epidemic could be contained effectively by providing an antiviral prophylaxis to
close contacts of index cases. Therefore, the parallel development of both a
vaccine and a drug for SARS may be an effective course of action.
The perceived urgency of developing SARS therapeutics has led several
pharmaceutical and biotechnology companies to pursue the development of coun-
termeasures for SARS. Two advantages these companies enjoy are the panoply
of veterinary vaccines against coronaviruses and the ease with which SCoV can
be grown in culture.
Previous antiviral discovery efforts by researchers from Pfizer Inc., of New
York, focused on the human rhinovirus 3C protease, a functional, genetic, and
structural analog to a key SCoV protease named “3C-like” (3CL). This work has
proved advantageous in searching for 3CL protease inhibitors. Together with
scientists at the National Institute for Allergy and Infectious Diseases and the
U.S. Army Medical Research Institute of Infectious Diseases, who had developed
an assay to test candidate compounds for their ability to prevent death in SARS-
infected monkey kidney cells, Pfizer tested existing compounds that had shown
activity against the rhinovirus protease. An X-ray crystallographic atomic-level
resolution model of 3C protease of human rhinovirus 14 served as the basis for
structural models of the 3CL protease binding site. This structural information
enabled the scientists to identify additional compounds that demonstrated signifi-
cant antiviral activity. The group is currently evaluating the solubility, metabolic
stability, and other physicochemical properties of some of these inhibitors in
hopes of finding promising compounds for clinical development. Pfizer research-
ers are also employing structure-based design and combinatorial chemistry as an
alternative, complementary strategy to discovering 3CL protease inhibitors (see
Matthews et al. in Chapter 4).
Despite the research described earlier in this chapter and the wealth of litera-
ture on coronaviruses, it will take more time before a compound designed to

June 13, 2003: SARS contained in China, except Beijing.
November January
2002 2004
defeat SCoV reaches clinical trials. SARS vaccine development programs require
biosafety level 3 conditions, which make research efforts slower and more expen-
sive than other targets of less contagious microbes. For this reason and others,
such as the genetically unstable nature of the virus and the current lack of an
appropriate animal model, a vaccine for SARS could well postdate a return of the
disease, perhaps by several years, even if such a product were steered through a
streamlined development process. If SARS fails to reappear within the next few
years, however, it is unlikely that either antiviral or vaccine development will
continue, given the cost of these efforts.11
The Food and Drug Administration’s (FDA’s) Center for Biologics Evalua-
tion and Research (CBER) conducts research to facilitate the development of
needed biological products, including antiviral drugs and vaccines. Several func-
tions handled by CBER during the SARS epidemic would pertain to future mi-
crobial threats. These include ensuring the availability of virus isolates for vac-
cine stock, recognizing research needs and contingencies in areas such as vaccine
testing, and conducting public workshops on needed technologies, such as diag-
nostics.12
LESSONS FROM SARS FOR FUTURE OUTBREAKS

Recognizing that it would be impossible to address the vast array of potential
microbial threats individually, public health policy makers are formulating general
strategies to evaluate and respond to outbreaks of all kinds. At the international
level, revisions to the International Health Regulations—rules concerning infec-
tious disease that legally bind WHO member nations—have been underway since
1995, and are expected to be completed in 2005. Workshop participants con-
curred that efforts to address microbial threats should encompass and be
enriched by existing strategies for defense against bioterrorism. As one par-
ticipant noted, authorities do not know until well into an outbreak if it is a
naturally occurring or manmade threat—in either case a robust and prepared
system will be able to respond rapidly and effectively to contain disease spread.
11Workshop presentation by Alan Shaw, Ph.D., Merck Vaccine Co., October 1, 2003.
12Workshop presentation by Kathryn Carbone, Ph.D., CBER, Food and Drug Administration,
October 1, 2003.

June 23, 2003: SARS contained in Beijing.
November January
2002 2004
The importance of collaboration was a common theme among workshop

discussions on research. It was discussed in the context of scientists around the
globe who identified the causal agent of SARS, of veterinary and biomedical
research communities studying zoonotic pathogens, and of private sector compa-
nies working in conjunction with government agencies and academia to develop
antiviral drugs and vaccines.
Workshop participants considered what could be learned from the experi-
ence of SARS and how that knowledge could improve the public health
community’s response to future outbreaks of infectious disease. The principal
topics discussed include:
• the early detection of outbreaks,

• effective communication to the public in the event of an outbreak,
• the promotion of research and development,
• strategies for containment, and
• multinational collaboration in implementing such strategies.
Importance of Early Detection

The central response to SARS—surveillance and containment, when insti-
tuted promptly, rapidly, and effectively—applies to almost any microbial threat.
It is clear that the initial delays in not only detecting the novel SCoV, but also
alerting national and global health officials to the disease outbreak significantly
increased the spread of SARS and its impact on affected countries. However,
soon after the global outbreak alerts were issued, the timely recognition of the
emergence of SARS in other countries proved to be an important factor in break-
ing all chains of transmission. The surveillance networks such as GOARN and
GPHIN, supported by personnel and laboratories from 115 other partnerships,
made this success ultimately possible. Along with these vital resources, work-
shop participants identified additional surveillance strategies for microbial threats;
these include hospital-based surveillance systems capable of recognizing both
known and novel diseases, and occupational clustering, with particular attention
paid to illness in health care workers. Behavior-based surveillance could identify
such phenomena as drug sales, or even such phenomena as the rapid rise in
vinegar sales that occurred in response to SARS in Guangdong in January 2003

July 2, 2003: SARS contained in Toronto.
November January
2002 2004
(vinegar is commonly used to combat respiratory illness in traditional Chinese

medicine).
Drawing on the SARS experience, a recent WHO global consultation fo-
cused on strengthening national capacities for surveillance, response, and control
of communicable diseases. After SARS, it was noted, “countries increasingly
look at the integration of disease surveillance activities as an effective, efficient
and sustainable approach to improving national capacities.” Among recommen-
dations issuing from this consultation was the admonition that “member states
should review existing legal frameworks to further support strengthening of sur-
veillance including participation of the private sectors and non-governmental
organizations” (WHO, 2003k). Several workshop participants observed that more
nationally and globally coordinated systems of information-sharing and data
analyses among surveillance networks might dramatically improve the world’s
ability to contain microbial threats.
While discussing the critical role of laboratories for effective surveil-
lance, concerns about laboratory safety were raised. Accidents in a Singapore
clinical laboratory (described earlier in this chapter) and a Taiwan research
laboratory have been responsible for SARS infections in workers (Center for
Disease Control Taiwan, 2003). These incidents highlight the importance of
hospital surveillance procedures and appropriate clinical management and
infection control measures in preventing an outbreak. They should also raise
the awareness of the research community, particularly given the many labora-
tories now conducting research on SARS, to the risks inherent in handling all
communicable agents and the need for strict adherence to well established
laboratory procedures.
Overall, workshop participants observed that surveillance must be backed up
with action and reinforced by sufficient laboratory capacity, well-trained person-
nel, and a legal framework consistent with objectives of transparency, global
cooperation, and sensitivity to the balance between public protection and the
interests of individual countries and persons. Workshop discussants emphasized
that investments made toward this end should capitalize on the existing networks
and need not be prohibitively extensive or expensive.
Strategies for Containing Future Threats

An estimated 75 percent of emerging human pathogens and 61 percent of all
human pathogens are zoonotic (Taylor et al., 2001). Therefore, many predictions

July 5, 2003: SARS contained in Taiwan; WHO declares containment of worldwide epidemic.
November January
2002 2004
about the nature of future novel pathogens anticipate the emergence of zoonoses.
Thus, workshop participants considered the strategies for containing known
zoonoses—in particular, influenza—as potential models for the containment of
SARS and unidentified zoonotic diseases of the future.
Lessons Learned from Influenza

The same trends that ushered SARS into the human population have been
apparent during a century of influenza outbreaks. The exponential increase in
avian influenza virus infections among humans over the past decade has been
associated with a sharp rise in the size and density of chicken and pig farm
populations, their proximity to human settlements, and movement of animals
through market channels, which in turn parallels the world’s rapidly expanding
and mobile population. As with SARS, animal markets provide the breeding
ground for recent outbreaks of influenza; laboratory sources also appear to have
sparked at least one epidemic. Fortunately, most of the recent influenza outbreaks
did not feature the transmission of the virus to humans. However, experts agree
that it is only a matter of time until a highly virulent and contagious flu, such as
the strain that caused over 20 million and perhaps as many as 40 million deaths
during the 1918 influenza epidemic, confronts the world (see Webby and Webster
in Chapter 5).13
Vaccines and antiviral therapies play a significant role in containing epidem-
ics of influenza. It is advantageous that the timing of annual outbreaks of influ-
enza and the strain or strains of the virus can, to some extent, be anticipated.
However, strategic actions recommended against influenza that could also
inform efforts to better prepare for other viral disease outbreaks have yet to
be implemented. These strategies include:14
13Shortly before the publication of this report in January 2004, the highly pathogenic H5N1 avian
influenza virus was implicated in a human outbreak of the disease in Vietnam and Thailand. Sixteen
of the 20 individuals so far infected have died. Thousands of birds in eight countries, including
Vietnam, The Republic of Korea, Thailand, China, and Japan are suspected to be infected with the
virus. See http://www.who.int/en/disease outbreaks for more information.
14Workshop presentation, Robert Webster, St. Jude’s Children’s Research Hospital, October 1,
2003.

September 8, 2003: Isolated case of SARS occurs in Singapore due to laboratory accident.
November January
2002 2004
• stockpiling of broad-spectrum antiviral drugs,

• advanced development of pandemic strain vaccines,
• the establishment of surge capacity for rapid vaccine production, and
• the development of models to determine the most effective means of
delivering therapies during an outbreak.
It is evident from the experience of the late 2003 influenza season that our supply
and effectiveness of antiviral drugs, capabilities to accurately predict the best viral
strain for annual vaccine production, and mechanisms for surge capacity production
remain inadequate (Treanor, 2004; WHO, 2003o). Recognition of these vulnerabili-
ties lead numerous workshop participants to call for greater scientific and financial
investments to strengthen our defenses against these certain future threats.
Quarantine
Some emerging infections of the future, like SARS, may be truly novel
threats for which the world—including its pharmacopoeia—is inadequately pre-
pared. Lacking other forms of effective interventions, the implementation of
quarantine or isolation strategies may prove valuable in such instances. Work-
shop participants discussed several ways that modeling tools might be used to
improve and tailor such measures. Models based on detailed observations from
previous epidemics can be used to predict demands on hospital capacity during a
hypothetical epidemic and to guide the timing and nature of quarantine measures.
Models that can estimate the length and severity of an unfolding epidemic will
likely increase public acceptance of quarantine by permitting people to form
realistic expectations of their sacrifice and its benefit to the community (see
Amirfar et al. in Chapter 5).
Evidence indicates that a modern approach to quarantine encompassing
a range of options designed to reduce the frequency of social contact can
significantly reduce the spread of infectious disease. Such options include
short-term, voluntary home curfew; suspension or cancellation of public activi-
ties (such as events, mass transit, or access to public buildings); and “snow day”
or sheltering-in-place measures. These measures could be employed individually
or in concert. In addition to or in place of these strategies, a program of contact
surveillance—the monitoring of asymptomatic persons exposed to an infectious
disease—could be undertaken. Modern quarantine and contact surveillance pre-
serve individual liberties and require far less labor and other community re-

December 5, 2003: Taiwanese researcher contracts SARS during experiment.
November January
2002 2004
sources than would be required to enforce a mandatory quarantine. Voluntary and

other forms of scalable quarantine nevertheless reduce productivity and may
result in public perceptions that stigmatize groups of individuals and promote
irrational behavior. For example, there is evidence that consumers began to avoid
Asian restaurants in the United States and other nonaffected countries during the
SARS epidemic even though neither quarantine nor public health messages sug-
gested such action. For any quarantine to be effective, workshop participants
noted, a number of needs must be met, including:
• education to build public trust in health authorities,

• compensation and job security for quarantined workers, and
• incentives to health care workers to maintain their morale in the face
of increased risk and to pay greater attention to infection control practices.
In the more difficult case of mandatory quarantine, enforcement requires care-

ful planning and a clear understanding of public health law; this is particularly true
in the United States, where quarantine is likely to necessitate the coordination of
federal, state, and local jurisdictions and legal authorities. For example, if an infec-
tious disease has the potential to spread across state boundaries but has not yet done
so, an action by CDC to limit transmission would require the cooperation of appro-
priate state and local authorities. The presidential executive order adding SARS to
a list of other diseases subject to federal quarantine actions eliminated such jurisdic-
tional uncertainties (Executive Order 13295: Revised List of Quarantinable Com-
municable Diseases, 2003). Additional legal considerations include planning for
due process—proper notice, legal representation, court-reviewed decisions, and
remote communications to permit a quarantined person to be heard in court—and
for practical contingencies, such as the need for law enforcement officials to serve
notice of quarantine (see Matthews in Chapter 5).
Workshop participants also discussed the need to develop strategies by which
hospitals—and entire communities, in the event of quarantine—can determine
when precautions against infection can be scaled back. Some experts have argued
that containment measures should be swiftly imposed in response to a perceived
infectious disease threat (as occurred when SARS appeared in Vietnam) and
reduced only after surveillance determines the absence of a threat. Clearly, the
consequences of false alarms in this case must be weighed against the risks of

December 7-10, 2003: Infected researcher attends conference in Singapore.
November January
2002 2004
inaction in the early stages of an epidemic, as demonstrated by China’s experi-

ence with SARS.
Informing the Public

Although no presentations exclusively addressed the subject of public com-
munication, this topic was identified as important and was widely discussed by
workshop participants. Social cohesion and compliance with quarantine in
Toronto were attributed in part to a combination of clear communication and
practical guidance by public health authorities. The media’s sustained and inten-
sive focus on the epidemic, heavy traffic on informational SARS websites oper-
ated by WHO and CDC, and a great volume of calls to CDC’s SARS hotline
reflect the public’s hunger for news and information during the public health
emergency.
Official travel and health advisories, though deemed necessary, were also
linked to consumer avoidance of international travel, international events, and
even Asian restaurants. It was suggested that such adverse effects could be medi-
ated in the future by accompanying advisories with educational messages de-
signed to help the public develop a realistic perception of the risks for infection
and appropriate responses. Research designed to identify why societies re-
spond dramatically and irrationally to certain types of public health threats
might help communicators to develop messages that positively influence the
public’s behavior during medical emergencies.
The media’s powerful role in the response to SARS was characterized in
both positive and negative terms: as a cause of stigma and discrimination due to
sensationalized reporting on the epidemic; as a demystifier of quarantine and
other public health measures through exhaustive coverage; and, as a persuasive
contributor to China’s decision to cooperate with international efforts to control
SARS. The Internet, recognized as a key source of early leads to the outbreak of
SARS, was also viewed with concern for its potential to propagate false rumors.
It is important to guard against such threats in the event of public health emergen-
cies. Likewise, it will be critical to make use of the media to inform and
educate the public on how best to protect themselves and their communities
in the event of future outbreaks

December 17, 2003: Singapore authorities quarantine 70 individuals.
November January
2002 2004
Surge Capacity
Health Care Personnel

Workshop participants remarked that the strained capacity of the U.S. and
global public health infrastructure—attributed to insufficient funding, labor short-
ages, and a lack of facilities—impedes preparations for SARS and other threats to
public health. As described earlier, even some of the highly developed health care
systems of Toronto struggled to cope with inadequate numbers of health care
personnel (particularly because of the inevitable toll that moderately to highly
contagious diseases take on health care personnel) and were ultimately unable to
sustain normal levels of care for both SARS and non-SARS patients.
In moving forward, workshop participants suggested that up-to-date
information and skills needed for containing epidemic-prone diseases must
be better integrated into the training of all health care professionals, not only
those specializing in infectious diseases or infection control. In citing Toronto’s
call to health care personnel in other regions and countries, a participant recom-
mended the expansion and establishment of formal networks to rapidly iden-
tify, transport, and enlist experienced health care personnel in the event of
future outbreaks. Such contingencies would be designed for local, regional,
national, and international responses and, in particular, would facilitate the
mobilization of human and technical resources that are known to have pre-
viously tackled certain disease outbreaks. The question was asked, if SARS is
to reemerge how will we harness the skills and new knowledge of the thousands
of individuals involved with finally containing the disease? While some partici-
pants lauded the efforts of GOARN and the CDC in this regard, they questioned
if that was enough.
Health Care Facilities

The inability to effectively establish isolation areas and procedures within
hospitals and other health care facilities contributed to the spread of SARS in
several countries. Inadequate facilities not only promoted the spread of the dis-
ease, but also forced the suspension of other vital health care procedures. As
previously described, one workshop participant suspected that more patients died
during the SARS outbreak in Toronto as a result of the inability to access appro-
priate care for conditions other than SARS rather than from SARS itself.

January 5, 2004: China and WHO confirm SARS case in Guangdong Province.
November January
2002 2004
As such, participants called for preparedness planning that established

procedures for rapid identification and use of facilities designated not only
for treatment of suspected and confirmed cases of an epidemic disease, but
also facilities that could be isolated for the conduct of other critical proce-
dures such as emergency surgeries, trauma care, and organ transplantation.
In this regard, several participants credited the rapid construction of “SARS
hospitals” in China as a key element in ultimately containing the disease.
Supporting the Research Response

Years of investment in basic research on coronaviruses, largely in the veteri-
nary research fields, helped the scientific community to identify the SARS
coronavirus within months of its emergence. Consequently, numerous partici-
pants noted that the potential for future outbreaks not only justifies present-
day investments in basic research on viruses and microbes, but also argues
for greater attention to and investment in research efforts that integrate the
direct contributions of zoonotic infectious disease research with biomedical
research efforts. As noted earlier (see Box S-1), a number of basic scientific
questions about the biology and epidemiology of SARS need to be answered in
order to develop diagnostics and therapeutics for the disease, as well as to con-
struct and implement targeted surveillance strategies. Apart from research that is
specific to the SARS coronavirus, however, workshop participants discussed a
number of broader areas of basic research that might be pursued in order to
counter the threat that would arise from either a recurrence of SARS or the
emergence of other new infections.
First, now that the more urgent pace of responding to an ongoing epidemic
has subsided, researchers should be encouraged to thoroughly and methodically
take stock of data that was accumulated over the course of fighting this epidemic.
Workshop participants suggested that the public health community should not be
complacent about the eventual success that was had in containing last year’s
SARS outbreak; there remains a need to understand exactly what strategies
were most effective, what strategies were less successful or even counterpro-
ductive, and what steps would be most essential for combating the emer-
gence of a new and possibly more virulent or more infectious pathogen. As
part of this retrospective evaluation, for example, extant patient and hospital
records should be assembled, compared, and analyzed in order to provide as
exact an assessment as possible of the effectiveness of each of the many control

measures that were adopted, as well as the points of greatest weakness that
allowed the virus to spread. Some of the lessons to be learned will be specific to
the profile of SARS, but many of them will also be readily applicable to other
new infections in the crucial early stages of an epidemic when less is known
about the biology of the disease than about its manner and rate of spread. On the
next occasion when scientists and public health officials are confronted by a
novel threat, it is important that they have a battery of well-researched studies to
fall back on concerning measures that have previously been shown to be effective
and feasible in controlling even a disease entity that has not yet been well charac-
terized.
Secondly, this evaluative process should expand beyond those areas en-
compassed by clinical medicine and emergency care. The SARS epidemic il-
lustrated how rapidly the impacts of a new disease can reverberate through the
political and economic structures of successive countries and regions, and the
decisions that were made in response to the epidemic ultimately reached into
the highest levels of government and international bodies. Just as with the
measures that were taken within individual hospitals and clinical settings, the
comparative effectiveness of the broader quarantine measures, travel ad-
visories, communications with the general public, and other legal and pub-
lic health directives that were issued should be gauged relative to their
costs and difficulties. Any possible improvements in the measures that
were adopted in the case of SARS—or recommendations for flexible op-
tions or combinations of options that might be applied in the face of differ-
ent types of pathogens—may need to be examined within a broad and
multidisciplinary discussion framework.
Finally, basic research needs to be conducted into not only the measures that
were most effective in containing the last epidemic but also those steps that
would best facilitate research on understanding the next one. The uncertainty and
confusion that are likely to be present in an epidemic’s early stages may at least
be ameliorated if scientists, public health officials, and governmental bodies
understand and are well prepared to collect the types of data that have been
shown to be most crucial in assessing the nature and magnitude of a novel threat.
A number of workshop participants commented on the need to look into
better standards for data capture and coordination during the course of an
epidemic, as well as the need to have better models on hand for evaluating
the effects of possible intervention strategies as early as possible. Likewise,
while carefully controlled therapeutic trials are often impractical (or at best ex-
tremely difficult) during the first stages of a disease outbreak, some workshop
participants lamented the fact that relatively little progress was made toward
developing a standard treatment algorithm for SARS patients during last year’s
epidemic, and there remains significant controversy over the effectiveness of
certain treatments that were applied. It was suggested that in the case of any
future epidemics, better pooling of data from scattered clinical treatment

centers could at least initiate the process of assessing the efficacy of different
treatment strategies and provide groundwork for more reliable clinical ad-
visories until the time and means are available for more thorough studies.
Engaging the Private Sector

Several presentations and considerable discussion concentrated on mecha-
nisms that could potentially engage the private sector—specifically, pharmaceu-
tical and biotechnology companies—in the research and development of products
targeted at the greatest threats to public health, including infectious diseases.
For pharmaceutical researchers, streamlining the development process is
crucial to productive engagement in strategic research. Means of streamlining
this process include the clear identification of patient and physician needs, access
to detailed biological studies of the pathogen of interest, and technologies such as
computational and combinatorial chemistry that speed target selection and lead
generation. Workshop presenters described the need for technology to improve
predictions of the safety of drug candidates so unsafe compounds could be weeded
out at an early and less expensive stage of the development process.
Promotion of International Cooperation and Collaboration

If SARS never returns, the 2003 epidemic will nonetheless be remembered
as a watershed event in the history of public health because of the degree of
multinational cooperation to contain the disease. As the world becomes more
conscious of microbial threats to health, countries are increasingly compelled to
report infectious outbreaks and join international efforts to contain them. Recog-
nizing that such transparency often comes at a price to a nation’s economy,
particularly in developing countries, workshop participants attempted to identify
incentives to encourage nations and individuals to act for the common good.
Some participants offered specific ideas for incentives, including coopera-
tive grants to support disease-monitoring efforts by academic researchers in de-
veloping countries and high-profile awards from bodies such as the Institute of
Medicine or World Health Organization to countries or individuals who make
important sacrifices for the health of world.
Networking can also play a vital role in local and regional preparedness for
infectious disease threats. Tabletop exercises, in which detailed outbreak sce-
narios are presented to officials who develop a response based on the tools and
resources at their disposal, encourage preparedness and provide a forum for
building collaborations among the many individuals and sectors essential to an
effective, coordinated response. From such exercises, the real-time compilation
of epidemiological, clinical, and laboratory data that could be made available to
the international community through WHO could also stimulate cooperation and
collaboration. When implemented via the Internet or other communication net-

works, these exercises can be used to develop systems of communication, as well

as working relationships, in advance of an outbreak or other emergency.
Some countries are increasingly cognizant of the fact that the health of the
global public affects the individual security of all nations, especially those that
are most enmeshed in global networks of trade, tourism, and investment. Never-
theless, many governments continue to allocate inadequate resources to their
health care systems and lack the political will to improve the quality of their
public health systems and the integration of those systems nationally and interna-
tionally. This observation highlights an additional lesson offered by SARS, one
that echoes what we have learned from HIV/AIDS, influenza, Ebola, malaria, and
a host of other infectious diseases: the desperate state of public health infrastruc-
ture in much of the world, and especially in those countries where microbial
threats are likeliest to emerge and take hold. If such lessons are to be heeded,
global strategies to enhance the prevention and control capabilities of all nations
will be important as the world prepares for future outbreaks of infectious disease.
Adel A.F. Mahmoud, M.D., Ph.D. Stanley M. Lemon, M.D.

Chair, Forum on Microbial Threats Vice-Chair, Forum on Microbial Threats
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SARS: Emergence, Detection,

and Response
OVERVIEW
The story of the emergence, spread, and control of severe acute respiratory
syndrome (SARS) is the latest, most vivid episode of a microbial threat in our
highly connected world. The SARS epidemic of 2002–2003 not only demon-
strated the ease with which a local outbreak can rapidly transform into a world-
wide epidemic, but also how news of such a threat can travel faster than a mi-
crobe. Notably, the experience demonstrated how effectively the global public
health community can collaborate to contain a novel microbial threat.
SARS emerged in November 2002 in the southern Chinese province of
Guangdong and has been linked with the handling and preparing of exotic mam-
mals for human consumption. The virus ultimately spread to 30 countries and
administrative regions within 6 months. Key points in the chronology of the epi-
demic are included in the Summary and Assessment.
This chapter begins with a description of the World Health Organization’s
(WHO) coordination of a massive and multinational public health response to
SARS. While the authors emphasize that the actions of individual nations ulti-
mately contained the epidemic, they describe the many ways that WHO sup-
ported governments through its Global Outbreak Alert and Response Network
(GOARN) and its country offices. These efforts served to highlight the important
brokering role that can be played by the WHO in catalyzing and galvanizing the
capacity of its member states in response to global public health challenges. This
is followed by a discussion of the contributions made by the U.S. Centers for
Disease Control and Prevention (CDC) in responding to and helping contain the
SARS outbreak in the U.S. and overseas. In both of these papers, the authors
describe not just the actions taken by the WHO and the CDC during the recent
41

epidemic but also the lessons that were learned and the preparations being made
to handle any future challenges that may arise from SARS or other emerging
diseases.
The chapter continues with a broad overview of what is known and hypoth-
esized about the emergence of SCoV, the natural history of the epidemic, the
evolution of the virus, and the clinical profile of SARS. The authors suggest
studies to answer some of the many remaining questions about this new disease.
Given the likelihood of an animal reservoir for the virus in China that could
reinfect the human population, continued vigilance for SARS is warranted. This
chapter explores the value of modern quarantine in curtailing the spread of infec-
tious disease in general and SARS in particular. Risks for the reintroduction of
SARS include the possibility of initial low-level transmission that eludes surveil-
lance and a laboratory-acquired infection, as occurred in Singapore in September
2003 and in Taiwan in December 2003.
During the epidemic, hospitals in Hong Kong, Singapore, Vietnam, and
Canada struggled to contain SARS within their walls. For example, in the first
phase of the Toronto epidemic, which began on February 23, unrecognized SARS
patients infected scores of other patients, family members, and hospital workers.
Even after increased infection control measures were undertaken, this scenario
was replayed in several area hospitals, as well as others around the globe. A
sobering analysis of mistakes made in the communication and practice of hospital
and community hygiene during the epidemic concludes the chapter.
THE WHO RESPONSE TO SARS AND

PREPARATIONS FOR THE FUTURE
J.S. Mackenzie, P. Drury, A. Ellis,1 T. Grein, K.C. Leitmeyer,
S. Mardel, A. Merianos, B. Olowokure, C. Roth, R. Slattery, G. Thomson,
D. Werker, and M. Ryan
Global Alert and Response, Department of Communicable Disease
Surveillance and Response
Severe acute respiratory syndrome (SARS) is the first severe and readily
transmissible new disease to emerge in the 21st century. Initially recognized as a
global threat in mid-March 2003, SARS was successfully contained in less than 4
months, largely because of an unprecedented level of international collaboration
and cooperation. The international response to SARS was coordinated by the
World Health Organization (WHO) with the assistance of the Global Outbreak
1Strategy for Development and Monitoring Zoonoses, Foodborne Diseases and Kinetoplastidae,
Department of Communicable Diseases Control, Prevention and Eradication, World Health Organi-
zation, Geneva, Switzerland.

EMERGENCE, DETECTION, AND RESPONSE 43
Alert and Response Network (GOARN) and its constituent partners made up of
115 national health services, academic institutions, technical institutions, and in-
dividuals. The SARS outbreak has also shown how, in a closely interconnected
and interdependent world, a new and poorly understood infectious disease can
have an adverse affect not only on public health, but also on economic growth,
trade, tourism, business and industrial performance, and political and social sta-
bility.
The chronology of the outbreak has been published on the WHO website
(WHO, 2003a). The first recorded case occurred in mid-November in the city of
Foshan, Guangdong Province, China. The Chinese Ministry of Health officially
reported to WHO in mid-February that there had been 300 cases and 5 deaths in
an outbreak of “acute respiratory syndrome” in which symptoms were clinically
consistent with atypical pneumonia, and that the outbreak was coming under con-
trol. To complicate the issue, however, there were also cases of avian influenza,
influenza A (H5N1), with three deaths among members of a Hong Kong family
who had traveled to Fujian Province. WHO activated its global influenza labora-
tory network and called for heightened global surveillance on February 19, 2003;
GOARN partners were alerted on February 20.
The SARS virus was carried out of southern China on February 21, when a
64-year-old medical doctor who had treated patients in Guangzhou and was him-
self suffering from respiratory symptoms checked into a room on the ninth floor
of the Metropole Hotel in Hong Kong. Through mechanisms that are not yet fully
understood, he transmitted the SARS virus to at least 16 other guests, all linked to
the ninth floor. Those guests carried the disease to Toronto, Singapore, and Hanoi,
or they entered hospitals in Hong Kong. The medical doctor fell severely ill the
following day, was hospitalized immediately, and died on March 4. A global
outbreak was thus seeded from a single person on a single day on a single floor of
a Hong Kong hotel.
A businessman, infected in the Metropole Hotel, traveled to Hanoi, fell ill,
and was hospitalized on February 26. He was attended by a WHO official, Dr.
Carlo Urbani, following concerns raised by hospital staff. Alarmed at the unusual
disease and concerned that it could be an avian influenza, Dr. Urbani contacted
the WHO Western Pacific Regional Office (WPRO) on February 28.
On March 10, the Ministry of Health in China asked WHO to provide techni-
cal and laboratory support to clarify the cause of the Guangdong outbreak of
atypical pneumonia. On March 12, WHO alerted the world to the appearance of a
severe respiratory illness of undetermined cause that was rapidly spreading among
hospital staff in Vietnam and Hong Kong. Three days later, on March 15, it be-
came clear that the new disease was carried along major airline routes to reach
new areas, and WHO issued a further global alert, giving the new disease its
name: severe acute respiratory syndrome, or SARS.

The WHO Response

As the outbreak of SARS moved into the spotlight of intense global concern,
an unprecedented multifaceted, multilateral, and multidisciplinary response was
coordinated jointly by WHO Headquarters, Switzerland, and by WHO WPRO,
the Philippines. The management of the global SARS response involved intense
daily coordination in the areas of etiology and laboratory diagnosis, surveillance
and epidemiology, clinical issues, animal sources, and field operations.
WHO Regional Offices, working through a worldwide network of Country
Offices and intercountry networks, were the main channels for support to affected
countries. While the six WHO Regional Offices were fully engaged in the global
coordination of the SARS response, the Western Pacific Regional Office—cover-
ing the area where the vast majority of cases were occurring—bore the brunt of the
response, deploying a total of 116 additional experts as short-term consultants dur-
ing the outbreak. At WHO Headquarters, 75 people worked on the SARS outbreak
response, with additional surge capacity provided by partners in the GOARN.
The GOARN is a global technical partnership, coordinated by WHO, to pro-
vide rapid multidisciplinary support for outbreak response to affected popula-
tions (WHO, 2000; 2001). The GOARN provided critical operational capacity for
the initial response to SARS. Responding to requests for assistance from several
countries, WHO and its GOARN partners mobilized field teams to support out-
break response in China, Hong Kong, Singapore, Taiwan, and Vietnam. Through-
out the outbreak, WHO continued to work with GOARN partners to ensure ongo-
ing support to health authorities, and GOARN teams continued in the field until
the chains of transmission were conclusively broken.
Through GOARN, WHO coordinated development of a number of networks
that proved pivotal in developing tools and standards for containment of the epi-
demic. The networks met regularly by teleconference, usually on a daily basis, to
share information and data in real time. They were also assisted by dedicated,
secure websites on which network participants were able to share preliminary
information. The networks brought frontline workers and international experts
together, and demonstrated the international collaboration and cooperation that
was characteristic of the response to the SARS outbreak. A virtual network of
clinicians was set up to exchange experiences, thoughts, and findings about SARS
in an attempt to better understand and treat the disease effectively. The clinical
network linked infection control issues closely with every aspect of case manage-
ment, from clinical diagnosis and investigation to therapy. The discussions also
allowed the rapid evaluation of the infection control risks of a number of inter-
ventions and helped to indicate potential alternative approaches.
A virtual network of epidemiologists brought together public health institu-
tions, ministries of health, and WHO Country Offices to analyze the spread of
SARS and to define appropriate public health measures. Activities of the epide-
miology network have included the preparation of a consensus document on the

epidemiology of SARS (WHO, 2003b). The laboratory network was established

to assist with identifying the etiologic agent of SARS and to develop specific and
robust laboratory diagnostic tests for the agent responsible. The network com-
prised members of the international influenza laboratory network in those coun-
tries in which cases of SARS had been reported. Thus a total of 11 expert labora-
tories in nine countries were included in the network. The success of the laboratory
network was quickly demonstrated by the discovery and characterization of the
etiological agent, the SARS coronavirus (SCoV), and the rapid development of
the first generation of diagnostic tests.
WHO Country Offices: A Critical In-Country Presence

WHO Country Offices work as direct partners with Member States on all
issues related to health, including those related to health and poverty, health and
macroeconomic reforms, and the Millennium Development Goals. SARS dra-
matically illustrated the effects of a new disease on the broader health and devel-
opment agenda.
Traditionally, the Ministry of Health is the primary working partner at the
national level; however, in many countries WHO is encouraging a more inclusive
definition of the nature of the health sector, leading to greater collaboration with
other government institutions, United Nations agencies, nongovernmental orga-
nizations (NGOs), and the international donor community—this was particularly
important in the SARS outbreak response.
During the SARS outbreak, WHO was widely recognized as a key organiza-
tion to assist health authorities with national policy formulation and multisectoral
coordination of preparedness activities and the SARS outbreak response. WHO
provided objective and neutral policy and technical advice to strengthen the ca-
pacity of national health administrations to better manage preparedness activities
and the SARS outbreak response and to build local capacity. WHO Country Of-
fices—particularly in China and Vietnam—provided extensive technical input on
policy development, guidelines and strategies, dissemination of information on
key issues, and technical advice for preparedness and response activities. The
WHO Country Offices in Beijing and Hanoi, supported considerably by experts
from partners in GOARN and WPRO, worked with national authorities to ad-
dress rapidly developing needs: strengthening disease surveillance and reporting
systems; improving the classification and reporting of cases; and advising on
field epidemiology, contact tracing, infection control in health care settings, ru-
mor management, and risk communications.
Ultimately, controlling the course of SARS in China and elsewhere was the
result of concerted multisectoral preparedness and outbreak response activities
by national authorities. WHO’s activities and advice played an important role in
catalyzing and coordinating this reponse. These activities are increasingly the
routine work of a WHO Country Office anywhere in the world; however, the

scale of the SARS outbreak and the attendant political and media interest ensured
that the scale of operations was enormous.
In addition to providing direct support through WHO to affected areas, many
GOARN partners were also involved in other SARS activities, including provid-
ing bilateral assistance to affected areas and supporting other countries in the
Western Pacific and Southeast Asia regions. The International Federation of Red
Cross and Red Crescent Societies helped to ensure that marginalized sections of
society were reached by social mobilization activities. International NGOs and
United Nations organizations were also involved in addressing humanitarian
aspects of the response and preparedness activities. National surveillance and
response institutions provided experts for field teams and, participating in the
virtual networks, were also working at their own national levels to enhance pre-
paredness and reporting on SARS cases to WHO. Regional disease surveillance
networks provided information on measures and activities to be undertaken to
prevent and control outbreaks of SARS.
The initial call for global surveillance was followed by a more detailed de-
scription of the surveillance system, which had as its objectives describing the
epidemiology of SARS and monitoring the magnitude and spread of the disease
in order to provide advice on prevention and control. This description, including
revised case definitions and reporting requirements to WHO, was distributed with
tools for its implementation through the WHO network to national public health
authorities. It was also published on April 4, 2003, in the Weekly Epidemiological
Record (Anonymous, 2003). With some minor changes, this global surveillance
system remained in place until July 11, 2003, a week after the last chain of human
transmission was broken.
Global SARS surveillance was primarily based on the reporting mechanism
established through the Daily Country Summary of Cases of SARS. This form
requested national public health authorities to report to WHO Geneva (with a
copy to the WHO country and regional office) the number of new cases and
deaths since the previous report, the cumulative number of probable cases and
their geographic distribution, and the areas where local chains of transmission
had occurred. Case numbers and information on areas with local transmission
were updated daily on the WHO website in accordance with the information re-
ceived by the national public health authorities. Local transmission was defined
as one or more reported probable case(s) of SARS having most likely acquired
the infection locally, regardless of the setting in which this may have occurred.
An area was removed from the list 20 days after the last reported locally acquired
probable case died or was appropriately isolated.
By July 11, 2003, 29 countries had reported a total of 8,437 probable cases,
including 813 deaths (crude case fatality ratio 8.6 percent) from November 1,
2002. Ninety-two percent (n = 7,754) of the reports were received from China
(including Hong Kong, Macao, and Taiwan). In the final compilation of reports
received from public health authorities, there were 18 areas in 6 countries that

experienced local transmission of SARS, with the first reported chain transmis-
sion starting on November 16, 2002, in Guangdong Province, China (WHO,
2003c).
The Origin of the Etiological Agent

As the SARS outbreak spread, and before the etiological agent was identi-
fied, questions were being raised as to where this new infection had originated.
Early discussions between members of the first WHO Mission in China and col-
leagues from the Chinese Centers for Disease Control (CDC and Guangdong
CDC implicated food preparers possibly connected with preparation of animals
for food as being a particular risk group. As a result, on April 10 WHO formed an
internal working group to address the potential that SARS could be a zoonotic
disease. With the collaboration of the Food and Agriculture Organization (FAO)
and the Office of International des Epizooties (OIE), an international working
group on the animal reservoir of SARS was established. Animal susceptibility
studies were carried out in various laboratories around the world. Subsequently,
findings from Guan et al. (2003) from the University of Hong Kong indicated that
masked palm civets and raccoon dogs sampled in a Shenzen market carried a
virus very similar to SCoV.
In mid-July, WHO received permission to organize a mission to China to
review animal studies conducted by Chinese scientists and recommend further
research on the role of animals in the transmission of SCoV. The mission was
carried out as a joint endeavor among the government of China, FAO, and WHO
from August 10 to 22, 2003. A comprehensive report of the mission and recom-
mendations were provided to the government of China for review. Important col-
laborations were established between members of the mission and Chinese scien-
tists. Collaborative projects are ongoing and focus on developing a screening test
for animals, animal susceptibility studies, and further testing of animals from
markets. As part of enhanced SARS surveillance in China, wild animal handlers
are considered a high-risk group. Protocols have been developed to prompt an
appropriate epidemiological investigation should this group begin presenting at
hospitals with symptoms of SARS.
Preparations for the Future

Reemergence
Will SARS return? This is difficult to answer without recourse to a crystal
ball. If SARS is to return, it has to reemerge from one of three sources: (1) from
undetected transmission cycles in areas with little or no health care facilities; (2)
from an animal source; or (3) from a laboratory accident. With respect to the first
possible source, it is difficult to believe that there have been continued, undetec-
ted transmission cycles. However, as SCoV is believed to have spread into the

human population from a wild animal source, this has to remain a possibility, but
whether it will occur this year or sometime in the future remains unknown. Pre-
liminary results would indicate that SCoV, or a related virus, occurs in a number
of wildlife species. However, the ability of the virus to cross the species barrier to
cause disease in humans, and then to become adapted to transmit between hu-
mans, may be a relatively rare event. Of greater immediate concern is the threat
posed by stocks of SCoV and clinical specimens potentially containing SCoV,
which are kept in many laboratories globally, as well as the paucity of safer
biosafety level 3 (BSL3) facilities in many parts of south and eastern Asia.
Surveillance and Laboratory Safety

WHO has been very active in preparing for the possible return of SARS. Of
particular importance has been the preparation of an epidemiological and surveil-
lance document, Alert, Verification and Public Health Management of SARS in
the Post-Outbreak Period, which was posted on the WHO website on August 14
(WHO, 2003d); a workshop concerned with laboratory preparedness and plan-
ning to ensure rapid, sensitive, and specific early diagnosis of SCoV infections,
and aspects of biosafety in the laboratory (WHO, 2003e); clinical trial prepared-
ness; a meeting to determine SARS research priorities; training courses on SARS
diagnosis and epidemiology; a meeting to discuss the development of SCoV vac-
cines (WHO, 2003f); and a series of capacity-building developments and assis-
tance to countries within the Western Pacific Region as well as a continuing
dialogue with and assistance to China.
Health authorities in nodal areas, where cases had occurred previously, and
in areas of potential re-emergence (WHO, 2003d) have maintained heightened
SARS surveillance established during the outbreak period, and continue doing so
for the foreseeable future. WHO will also continue to identify and verify rumors
about SARS through its usual, well-established mechanisms.
Laboratory preparedness has been a major concern as the northern hemi-
sphere has approached the winter season with the prospects of increased influ-
enza activity and other respiratory diseases, potentially leading to a significant
increase in requests for diagnostic tests for SCoV. This could lead to an unsus-
tainable surge in the work of clinical diagnostic laboratories, and the strong possi-
bility of false-positive test results. Thus a number of recommendations were made
at a SARS laboratory workshop held in Geneva in October 2003, all of which
have been introduced or are in the process of being introduced (WHO, 2003e).
The major outcomes have been the establishment of an International SARS Ref-
erence and Verification Laboratory Network to provide a diagnostic service to
those countries and areas that do not have the necessary diagnostic facilities and
to verify any laboratory-diagnosed case of SCoV infection reported in the inter-
epidemic period; the development of a panel of positive control sera; and the
formulation of strong recommendations about laboratory safety. Indeed, biosafety

has become a major issue since the occurrence of the laboratory-acquired cases in
Singapore and Taiwan (WHO, 2003f), and a major biosafety document is nearing
completion with respect to the containment level and conditions under which
work is undertaken with live SCoV. This document will support and extend the
earlier document posted on the WHO website (WHO, 2003g). Finally, the work-
shop attendees considered the algorithms under which laboratory diagnosis should
be undertaken, and these have been incorporated into the algorithms developed in
the epidemiological document Alert, Verification and Public Health Manage-
ment of SARS in the Post-Outbreak Period.
Diagnostics and Therapeutic Countermeasures

Insufficient evidence is available to evaluate the effectiveness of specific
treatment measures, including antivirals, steroids, traditional Chinese medicine,
and the appropriate type of mechanical ventilation. Therefore, generic protocols
urgently need to be developed for SARS and other future disease outbreaks. The
WHO SARS Clinical team hosted a workshop to plan future clinical trials for
SARS with the following objectives: (1) to review treatment experiences in dif-
ferent countries during the last outbreak; (2) to share existing plans for future
clinical trials and identify candidate therapies; (3) to agree on basic trial design,
including a hierarchy of outcome parameters and agreed standards of care; and
(4) to assist in preparedness for clinical trials at relatively short notice.
A SARS Research Advisory Committee was established to determine the
major gaps in our knowledge of the origin, ecology, epidemiology, clinical diag-
nosis and treatment, and social and economic impacts of SARS, and to discuss
research needs required to fill these gaps for effective public health management
of SARS, including preparedness and response to future outbreaks. The commit-
tee was asked to prioritize the research issues with the aim that the prioritized list
of issues could be widely circulated to international and national funding bodies
as a consensus blueprint of international research objectives aimed at achieving a
better understanding of the virus, its origins, and pathogenesis, so that public
health management could be improved if SCoV returns. A report on the meeting
is available on the WHO website (WHO, 2003h), and the full recommendations
will be placed on the website in early 2004.
Training courses on laboratory diagnosis of SCoV were held in the fall in
collaboration with WHO Regional Offices in Europe and Africa, and a further
“train-the-trainer” course is being planned in association with the WHO Regional
Office for the Americas (AMRO/PAHO) in 2004.
WHO has also held a meeting to discuss possible SCoV vaccines, and a
number of recommendations were made to facilitate and accelerate SARS vac-
cine development and evaluation (WHO, 2003i).
In the Western Pacific Region, a number of activities have been started that
are aimed at improving preparedness for the possible reemergence of SCoV, in-

cluding updating existing guidelines for surveillance and response activities in

the interoutbreak period, updating an assessment protocol for national prepared-
ness, and developing a WPRO SARS risk assessment and preparedness frame-
work (WHO Western Pacific Regional Office, 2003). Other priorities have been
to strengthen infection control and establish a regional laboratory network. The
objectives of the latter are to ensure proper laboratory diagnosis by providing
coordination, technical support, and communication among country and regional
reference laboratories.
Concluding Comments
WHO’s vision for global health security is a world on alert and ready to
respond rapidly—both locally and globally—to epidemic-prone and emerging
disease threats, whether they are natural or intentional in origin, minimizing their
impact on the health and economy of the world’s populations.
Defense against the threat posed by epidemics such as SARS requires a col-
laborative, multifaceted response. National and international public health sys-
tems represent a major pillar of action for rapid and effective containment.
Through unprecedented collaboration the world community has demonstrated
that it is possible to contain a serious infectious threat to the world population.
Pivotal to addressing future threats is the need for a global coordinating mecha-
nism that allows the worldwide community to be alerted and to respond to health
events of international concern as rapidly, appropriately, and effectively as pos-
sible. The World Health Assembly recognized the role played by WHO, its staff,
and GOARN partners during the 56th Assembly in passing a resolution,
WHA56.29, in which it strongly supported the GOARN partnership and WHO’s
global role in surveillance and response to infectious disease threats.
Harnessing the undoubted global capacities for detection, characterization,
and containment of epidemic threats will require sustained strategic investment
in initiatives like GOARN. However, at the end of the day these threats can only
truly be faced with the courage and personal sacrifice as made by the thousands
of individuals who came together to put a genie back in the bottle.
THE CENTERS FOR DISEASE CONTROL AND PREVENTION’S

ROLE IN INTERNATIONAL COORDINATION AND
COLLABORATION IN RESPONSE TO THE SARS OUTBREAK
James W. LeDuc and Anne Pflieger
National Center for Infectious Diseases, Centers for Disease Control and
Prevention, Atlanta, Georgia
The global outbreak of an acute respiratory illness that became known as

severe acute respiratory syndrome (SARS) was the first major international out-

break of the 21st century and clearly had a dramatic, worldwide effect far exceed-
ing the morbidity and mortality that directly resulted from infection with the novel
coronavirus that causes SARS. In addition to the infection and hospitalization of
several thousand individuals and the nearly 900 deaths that occurred in the coun-
tries with SARS cases, the entire global economy was affected by SARS, leading
to serious losses of revenue, collapse of regional tourist and travel industries, and
significant decreases in the gross national product among the nations affected
(Lee and McKibbin, 2003). Despite several introductions of the virus from re-
turning infected travelers, the United States was spared from the worst of SARS,
given that there was no significant secondary spread, no large hospital-based out-
breaks as seen in several countries, and no fatalities.
The fact that the United States had relatively few cases belies the enormous
effort put forth by public health officials in responding to the outbreak. The Cen-
ters for Disease Control and Prevention (CDC) worked closely with state and
local governments, the health care delivery industry, and other federal agencies to
actively alert the traveling public about the risks of SARS, to prepare the health
care delivery system to recognize and treat suspected SARS patients, and to as-
sure the public that appropriate interventions to protect them from infection were
being taken. These efforts were undertaken in close collaboration with interna-
tional partners in the World Health Organization (WHO) and in the countries
most affected by SARS. The collaborative international response can be consid-
ered in five parts: coordination of response, collaborations in science, communi-
cations at home and abroad, capacity building and response preparedness, and
challenges and lessons learned.
Coordination of Response
More than 800 CDC staff members were organized into 13 domestic teams,
with core members serving throughout most of the 7-month response period.
Domestic teams each focused on one critical aspect of the response, including
clinical care and infection control, epidemiology of the outbreak, diagnostics and
laboratory studies, quarantine issues, information management, occupational
health issues (included staff from the National Institute for Occupational Safety
and Health), communications, environmental issues, and community outreach
programs focused on the challenges of providing accurate information to special
groups such as immigrants and the Asian community. In addition, two teams
were organized to review and offer constructive criticism of the response as it
unfolded and to plan for possible pandemic transmission of SARS, and two other
teams engaged in international efforts to respond to the outbreak and conduct
subsequent scientific studies. Each group worked closely with experts from
throughout the CDC Centers and often included members from other federal agen-
cies (e.g., Department of Defense, Department of State, and National Institutes of
Health, Food and Drug Administration [FDA], and others from the Department

of Health and Human Services [DHHS]) or affected countries (specifically

Canada). Many of the groups held frequent telephone conference calls with their
constituents and academic experts to brainstorm and discuss next steps. For ex-
ample, weekly telephone conference calls with virologists from several academic
centers were held to coordinate laboratory studies, share results, and design col-
laborative studies, which often were undertaken by these same scientists at their
own facilities.
CDC staff were deployed either directly to affected countries, as was the
case with Taiwan, or as part of the WHO-coordinated Global Outbreak Alert and
Response Network deployments. A total of 84 staff members were dispatched on
92 deployments to 11 countries affected by the SARS outbreak (CDC, unpub-
lished) (see Tables 1-1 and 1-2). The largest group of personnel, 30 individuals,
was sent to Taiwan, where a total of 696 person-days of assistance were provided.
In all, staff were deployed for a total of 1,959 days, or 7.8 work-years, as deter-
mined on the basis of the standard U.S. federal work schedule. Deployed staff
contributed diverse skills and expertise to these deployments (Table 1-2). Medi-
cal officers and epidemiologists were dispatched most often, with these personnel
going to Taiwan (17), China (12), Vietnam (8), Singapore (2), the Philippines (3),
Hong Kong (4), Canada (4), Switzerland and Thailand (2 shared), and Cambodia
and Laos (1 shared). Other critical staff included pathologists and laboratory sci-
entists, infection control officers, industrial hygienists, information management
specialists, public health administrators, and communications experts. As the out-
break continued and staff rotations were required, it soon became apparent that
CDC staff alone would be insufficient to meet a sustained demand for deploy-
ment of skilled personnel. As a result, the search to identify appropriate and avail-
able personnel was expanded to include public health professionals at state and
local health departments, hospitals, other public health agencies, and academic
centers.
TABLE 1-1 CDC’s 2003 International SARS Response by Center, Institute,

Office (CIO)
CIO Number (%) of Staff Deployed Number (%) of Days Deployed
EPO 7 (8.3) 197 (10)
NCCDPHP 3 (3.6) 68 (3.5)
NCEH 1 (1.2) 29 (1.5)
NCHSTP 4 (4.8) 115 (5.9)
NCID 59 (70.2) 1,345 (68.7)
NIOSH 6 (7.1) 83 (4.2)
NIP 4 (4.8) 122 (6.2)
Total number 84 1,959
NOTE: EPO = Epidemiology Program Office; NCCDPHP = National Center for Chronic Disease
Prevention and Health Promotion; NCEH = National Center for Environmental Health; NCID = Na-
tional Center for Infectious Diseases; NIOSH = National Institute for Occupational Safety and Health;
NIP = National Immunization Program.

TABLE 1-2 CDC International SARS Response: Staff Deployed by Country

and Area of Technical Expertise
Number (%) No. (%)
of Staff De- of Days Med/ Path/ Inf Ind Data/
Country ployed Deployed Epi Lab Cont Hyg IT PHA Consult Media
Taiwan 30 (32.6) 696 (35.5) 17 1 5 4 3
China 17 (18.5) 498 (25.4) 12 5
Vietnam 10 (10.9) 226 (11.5) 8 1 1
Singapore 5 (5.4) 137 (7) 2 2 1
Philippines 4 (4.3) 98 (5) 3 1
Hong Kong 6 (6.5) 88 (4.5) 4 1 1
Thailand 4 (4.3) 60 (3.1) 2 2
Canada/ 5 (5.4) 57 (2.9) 3 2
Ottawa
Canada/ 4 (4.3) 46 (2.5) 1 3
Toronto
Switzerland 4 (4.3) 33 (1.7) 2
Cambodia 1 (1.1) 15 (0.8)
Laos 2 (2.2) 5 (0.3) 1 1
Total:
By deployment 92 53 9 8 7 2 6 2 2
and by staff 84 1,959 52 8 7 7 2 4 2 2
NOTES: Areas of technical expertise: Consult = scientific consultant; Data/IT = data manager/analyst
or information technology specialist; Ind Hyg = industrial hygienist or environmental engineer; Inf
Cont = nurse or infection control specialist; Med/Epi = physician or epidemiologist; Media = commu-
nications or media relations specialist; Path/Lab = pathologist or laboratorian; PHA = public health
advisor. The difference in the total number of personnel deployed (84) versus the total number of
deployments (92) reflects the redeployment of 8 staff members, whose areas of expertise are shown
by the differences in the totals for 4 public health specialties.
Fortunately, the outbreak peaked before serious personnel shortages were

encountered; however, it is clear that CDC must both enhance retention of the
uniquely skilled staff needed to assist with such outbreak responses and iden-
tify external partners who can be recruited when needed to help meet such
challenges. The outbreak also highlighted the benefit of having well-estab-
lished laboratory Infections Program, which was established in 2001 in part-
nership with the Thailand Ministry of Health, repeatedly proved its value as
skilled staff were deployed rapidly to assist affected countries within the re-
gion and to work with Thai health officials responding to the importation of
SARS cases. The CDC staff assisted Thai officials with caring for Dr. Carlo
Urbani, the WHO physician who acquired SARS and died early in the course of
the outbreak.

Collaborations in Science
Early in the course of the outbreak, WHO facilitated the exchange of laboratory
information being generated in response to the SARS outbreak by establishing daily
conference calls with representatives of the 11 leading laboratories participating in
the response (WHO, 2003j). They also created a secure website where laboratory
findings could be posted and shared with others, and they assisted with the acquisition
and distribution of clinical material for laboratory testing (Stohr, 2003). These critical
steps led to the rapid and virtually simultaneous recognition by several international
laboratories of a new coronavirus (SCoV) as the likely cause of the outbreak (Ksiazek
et al., 2003; Peiris et al., 2003a), and soon thereafter, the determination of the com-
plete genomic sequence of the virus (Rota et al., 2003). The rapidity with which these
results were obtained was truly historic and clearly emphasized the benefits of global
data sharing and scientific collaboration. Despite widespread application of molecu-
lar techniques to determine the cause of the outbreak, it was the traditional virologic
procedure of inoculation of acutely acquired patient specimens into cell cultures and
laboratory animals that ultimately proved successful in isolating SCoV.
Communications at Home and Abroad

One of the most daunting challenges faced by public health officials in re-
sponding to the SARS outbreak was meeting the need for timely, accurate, and
consistent information regarding the evolving outbreak and response activities.
WHO did an exceptional job in providing information through nearly daily press
briefings and updates on its website, by hosting global conference calls with inter-
national partners to discuss specific issues, and by effectively using a secure website
to post sensitive information, such as results of ongoing laboratory investigations.
Video conferences were arranged between the Director General of WHO, the Sec-
retary of DHHS, and the Director of CDC to provide an opportunity for direct
dialogue between agency leaders and their key staff. All of these activities served to
calm a nervous world by rapidly providing accurate information on the evolution of
the outbreak and interventions under way and on the evolving discovery of the
cause of the outbreak and development of treatment and prevention strategies.
The communications burden faced by CDC was enormous and as intense as
any previous public health emergency experienced by the agency. More than
10,000 news media calls were handled, 12 SARS news releases were issued, and
21 live telebriefings and news conferences were broadcast. Thirty specialized
conference calls were made to the health care provider community, and nearly
35,000 public inquires were answered by telephone. A special clinical hotline
was established for physicians inquiring about SARS, and more than 2,000 such
calls were answered. Over 1.9 million global participants are estimated to have
seen one or more of the three SARS satellite broadcasts directed to health care
workers, and more than 17 million hits were recorded on the CDC SARS websites,
with 3.8 million hits occurring during the week of April 20–26 alone (Personal

TABLE 1-3 CDC Shipments of Diagnostic Materials During the 2003 SARS
Outbreak, by Recipient
Recipient RNA Virus Antigen Total, All Materials
Academic centers 32 13 1 46
Commercial companies 26 15 1 42
Government agencies 21 18 4 43
Total, all recipients 79 46 6 131
communications, Dan Rutz and Bill Pollard, CDC, September 26, 2003). Provid-
ing accurate, real-time information to meet these demands was one of the most
challenging aspects of the entire outbreak response effort.
Capacity Building and Response Preparedness

With recognition that SCoV was responsible for the outbreak, laboratory
efforts quickly turned to establishment of diagnostic tests to identify infected
patients. Several laboratories rapidly developed prototype assays to measure
SCoV—specific nucleic acid sequences, viral antigen in tissues, and the sero-
logic response to infection. CDC distributed assays to measure both SCoV ge-
nomic material by polymerase chain reaction and specific immunoglobulin re-
sponse by enzyme immunoassay; recipients of these assays included state health
departments, members of the Laboratory Response Network established to re-
spond to bioterrorism threats, and several countries following their requests for
assistance. CDC also reisolated SCoV under formal Good Laboratory Practices
conditions, using FDA-approved certified cells provided by Aventis Pasteur and
clinical material obtained from an acutely ill American traveler who had returned
recently from Hong Kong. This isolate was made available to vaccine manufac-
turers free of charge and has now been used in the development of candidate new
vaccines by several companies (WHO, 2003i). In all, CDC provided purified
RNA, virus, or antigen to more than 130 academic centers, commercial firms,
and government agencies (Personal communication, Betty Robertson, CDC, Sep-
tember 26, 2003) (see Table 1-3).
Challenges and Lessons Learned

The SARS outbreak of 2003 gave the world a clear example of future chal-
lenges in addressing emerging infectious diseases. As demonstrated by SARS, an
outbreak of infection even in seemingly remote areas of the world can pose a
threat to the health and economies of countries worldwide. All nations need to
have access to accurate and timely information and must be prepared to respond
appropriately. The benefit of having well-established partnerships with countries
was demonstrated repeatedly, especially as it became apparent that there is a
serious shortage of available United States–based skilled personnel. Similarly,

because specialized skill sets, such as infection control expertise, were in criti-
cally short supply, future preparedness planning should include establishing con-
tingency plans whereby partners from outside the government can assist with
outbreak response efforts as needed. The benefit of global collaboration in ad-
dressing scientific challenges was well documented; nevertheless, serious chal-
lenges were encountered in the acquisition and transport of clinical material criti-
cal to establishing the cause of the outbreak, clearly indicating the need to further
facilitate technology transfer and enhance preparedness. Once the cause of the
outbreak was determined, an enormous demand for validated diagnostics, train-
ing, and technical assistance emerged. Meeting this demand proved to be a major
undertaking as well. Last, the long-standing political obstacle in regard to WHO’s
interactions with Taiwan was highlighted as the SARS outbreak exploded across
the island. Initially, only CDC experts responded to Taiwan’s call for assistance;
however, a decision by the director general of WHO soon led to formal WHO
participation in the outbreak response. Once again, we learned that infectious
diseases respect neither geographic nor political boundaries.
ROLE OF CHINA IN THE QUEST TO DEFINE AND CONTROL SARS

Robert F. Breiman,1 Meirion R. Evans,2 Wolfgang Preiser,3 James
Maguire,4 Alan Schnur,5 Ailan Li,5 Henk Bekedam,5 and John S. MacKenzie6
*Reprinted with permission from the Centers for
Disease Control and Prevention
© Copyright Centers for Disease Control and Prevention, 2003
China holds the key to solving many questions crucial to global control of
severe acute respiratory syndrome (SARS). The disease appears to have origi-
nated in Guangdong Province, and the causative agent, SARS coronavirus, is
likely to have originated from an animal host, perhaps sold in public markets.
Epidemiologic findings, integral to defining an animal-human linkage, may be
confirmed by laboratory studies; once animal host(s) are confirmed, interven-
tions may be needed to prevent further animal-to-human transmission. Commu-
nity seroprevalence studies may help determine the basis for the decline in dis-
ease incidence in Guangdong Province after February 2002. China will also be
1International Centre for Diarrheal Disease Research, Bangladesh–Centre for Health and Popula-
tion Research, Dhaka, Bangladesh.

2National Public Health Service for Wales, Cardiff, United Kingdom.
3Institute for Medical Virology, Frankfurt, Germany.
4Centers for Disease Control and Prevention, Atlanta, Georgia.
5World Health Organization, Beijing, China.
6University of Queensland, Brisbane, Australia.

able to contribute key data about how the causative agent is transmitted and how
it is evolving, as well as identifying pivotal factors influencing disease outcome.
SARS is a newly emerged disease, caused by a previously unknown
coronavirus. The first known cases occurred in Guangdong Province in southern
China in November and December 2002. During late February 2003, a physician
who was incubating SARS traveled from Guangzhou, the provincial capital, to
Hong Kong, Special Administrative Region of China, and stayed at a hotel. There,
the virus was transmitted from him to local residents and to travelers, who be-
came ill and transmitted disease to others when they returned to Vietnam,
Singapore, Canada, and Taiwan, Province of China (Tsang et al., 2003). SARS
has now occurred in >8,450 people with >800 deaths worldwide.
The tally of SARS climbed rapidly in China through May 2003, then deceler-
ated markedly during June. The disease has now been reported in 24 of China’s
31 provinces. By June 26, 2003, a total of 5,327 SARS cases and 348 deaths had
been reported from mainland China, including 2,521 cases in Beijing and 1,512
in Guangdong Province.
Since February 2003, teams of technical consultants for the World Health
Organization have been working in China to provide assistance to the Ministry of
Health and provincial governments on public health responses to the SARS out-
break. A team that began working in China in March reviewed considerable clini-
cal, epidemiologic, and laboratory data with scientists and officials from a variety
of settings in Guangdong Province and Beijing. The team worked closely with
colleagues from the National and Guangdong Provincial Centers for Disease Con-
trol, and together were able to establish that cases occurring in Guangdong begin-
ning in November were clinically and epidemiologically similar to subsequent
cases of SARS documented elsewhere.
The team observed detailed, comprehensive data collection forms, which are
completed for activities and behaviors and clinical manifestations of patients with
SARS. The team was informed that serum and respiratory secretion specimens
collected from many patients from Guangdong were being held under appropriate
storage conditions, awaiting further laboratory testing.
While a dedicated, collaborative international effort has resulted in substan-
tial understanding of this disease with remarkable speed, critical information is
still lacking. We detail a variety of knowledge gaps that should be addressed
through a set of activities to optimize prevention and control of SARS.
Emergence of SARS-Associated Coronavirus in Humans

Available evidence suggests that SARS emerged in Guangdong Province, in
southern China. How and when did it emerge? Did the causative agent evolve in
an animal species and jump to humans (or perhaps first to other animal species),
or did the virus evolve within humans? The genetic sequence of the virus has
been obtained in several laboratories, and phylogenetic analyses have shown that

it is unlike other coronaviruses of animal and human origin. Indeed, the virus has
been tentatively placed in a new fourth genetic group (Marra et al., 2003; Rota et
al., 2003).
Why is it so important to answer the question of how SARS emerged? Most
recently recognized novel emergent viruses have been zoonotic, usually with a
reservoir in wildlife (Ludwig et al., 2003; Williams et al., 2002). Thus, SARS
coronavirus, if zoonotic, may provide the basis for modeling and predicting the
appearance of other potential zoonotic human pathogens. More importantly, the
information may be crucial for control of SARS. If this disease is to be curtailed
or eliminated by strict public health measures, blocking further animal-to-human
transmission is indicated. Only about half of the cases in Guangdong are attrib-
uted to contact with a SARS patient. Transmission from an unknown, but persist-
ing animal reservoir might explain this finding; however, a nonspecific case defi-
nition (i.e., many “cases” might not actually be SARS) and limitations in
contact-tracing capacity are other potential explanations.
Finding a potential animal source is, however, a daunting task. The province
is famous for its “wet markets,” where a bewildering variety of live fauna are
offered for sale (sometimes illegally) for their medicinal properties or culinary
potential. The opportunity for contact, not only with farmed animals but also with
a variety of otherwise rare or uncommon wild animals, is enormous. More than
one third of early cases, with dates of onset before February 1, 2003, were in food
handlers (persons who handle, kill, and sell food animals, or those who prepare
and serve food) (Guangdong Province Center for Disease Control and Preven-
tion, unpub. data,).
Hypothesis-generating epidemiologic studies are indicated to focus on early
cases of SARS and cases in persons without known contact with infected persons.
These studies should also collect information from appropriately selected con-
trols (i.e., matched by categories such as community and age), regarding expo-
sures to animals of any kind in any setting (including food preparation, dietary
habits, pets, and a variety of other activities and behaviors in the community).
Plausible hypotheses generated by epidemiologic studies should be briskly
followed by intensive, focused, laboratory studies where relevant, including sur-
veys of specific animal populations to identify SARS-associated coronaviruses
(by culture and polymerase chain reaction [PCR]) or to measure specific antibod-
ies. Some virologic surveys have already been conducted among prevalent ani-
mal populations, including those known to harbor other coronaviruses or other
viruses transmissible to humans or wild animals, handled and sold in the markets;
a variety of animals, most notably masked palm civets, have been reported to
harbor SARS-associated coronavirus. However, whether these animals are trans-
mitting virus or are recipients of virus transmission is not yet clear. Solutions will
lie with identifying epidemiologic links, which should guide targeted animal stud-
ies. Molecular epidemiologic and genetic studies can then be helpful in evaluat-
ing viruses isolated from animals and from humans.

Natural History of the Epidemic

Since the earliest known cases were in Guangdong Province, China has had
more time than any other location to observe disease incidence over time. Evi-
dence from Guangdong Provincial Centers for Disease Control suggests that the
disease incidence peaked in mid-February, and declined weekly through May.
What were the reasons for the decline? Introduction of stringent infection-control
measures in hospital settings undoubtedly resulted in reduced incidence in
healthcare settings but would not likely have accounted for reductions in commu-
nity transmission. Efforts have been made to reduce the interval between onset of
illness and hospitalization (minimizing the potential for community transmission).
This effort likely had substantial impact in reducing disease incidence, as shown
elsewhere (Riley et al., 2003).
The initial hypothesis was that the virus attenuated after multiple generations
of transmission; this hypothesis now seems unlikely. We note several other con-
siderations. Were there a limited number of susceptible people within the popula-
tion to begin with? Such a concept is possible if there had been earlier spread of a
less virulent coronavirus, providing some immunity to a proportion of the popu-
lation. If so, whether this occurrence was unique to Guangdong will be important
to determine.
Alternatively, did the population develop widespread immunity to the caus-
ative agent itself? This scenario would require a good deal of asymptomatic or
mildly symptomatic disease. At this stage, no reason exists to exclude the possi-
bility of a much wider spectrum of disease than is currently appreciated, since the
spectrum of illness has not been fully evaluated.
Another possibility is that a second agent might be required, in addition to
coronavirus, to produce severe illness; if this is the case, the epidemiology (like
seasonality) of the second agent (perhaps a less recently emerged pathogen for
which there is already fairly widespread immunity), rather than coronavirus, may
actually be responsible for the decline of the incidence of SARS in Guangdong.
Extensive seroprevalence studies will be helpful for sorting through these
possibilities. Analyzing stored serum samples, collected before the onset of this
outbreak, could be of immense value in evaluating the possibility of preexisting
immunity. Some researchers have found human metapneumoviruses (Poutanen
et al., 2003) and species of Chlamydia in patients with SARS, but the importance
of these findings is unclear. Systematic evaluation of specimens available from
all cases, severe cases, and healthy controls in China regarding the presence of
antibodies to coronavirus, as well as hypothesized co-infecting agents, should be
done. Important clues may come from seroprevalence and other epidemiologic
studies in children. As in other affected countries, children were disproportion-
ately less affected by SARS than adults. Carefully working through the bases for
reduced incidence and severity may uncover cross-protecting infectious or im-
munizing agents or crucial host factors for protection.

Superspreading Events
When documenting the source of person-to-person transmission of SARS
has been possible, a substantial proportion of cases have emanated from single
persons, so-called superspreaders (Tsang et al., 2003). While contact tracing is
undoubtedly incomplete, most infected patients have transmitted illness to few
other people. Understanding the differentiating characteristics of persons who
transmit, especially patients who are able to transmit to several other people,
often after minimal contact, may provide important clues for public health strate-
gies focused on preventing transmission. In addition, better defining environmen-
tal settings or circumstances that facilitate high transmission rates would be help-
ful. China is not unique in documenting superspreaders. The country could
participate in multinational studies to define the characteristics of superspreaders
and their role in the epidemiology of SARS. Of particular interest is the virus load
of superspreaders, compared with those of other infected persons.
Little is known about the importance of fecal-oral transmission or about the
length of time that infectious virus shedding occurs in the gastrointestinal tract.
Virus shedding in feces has major implications for control strategies and for the
possibility of continued carriage and shedding by clinically recovered patients.
China has the opportunity to explore the role of fecal spread in the transmission
of SARS.
Evolution of the Virus

The causative agent is a coronavirus, and the entire genome of several strains
has been fully sequenced by many laboratories globally (Marra et al., 2003; Rota
et al., 2003; Ruan et al., 2003). Tests have been developed to detect coronavirus
genetic sequences by PCR. In addition, tests to detect SARS-associated
coronavirus antibodies have been developed, but the sensitivity and specificity of
these tests are low, especially early in the illness when public health and clinical
needs are greatest. A good test for SARS would be important not only for diagno-
sis and management but also for investigating the origin of the disease and for
defining its epidemiology.
If the causative agent can be isolated from stored specimens from the earliest
group of patients (from November 2002 to January 2003), how their genetic se-
quences compare with those from viruses isolated later from various parts of
China and elsewhere, and from animals from Guangdong and Guanxi Provinces,
would be useful to know. Mutations may be important for a number of reasons.
They may affect transmissibility and virulence; they may provide (or frustrate)
therapeutic targets for new drugs; and they may pose challenges for development
of diagnostic tests and vaccines. Specimens from Chinese patients provide the
longest observation window with which mutational tendencies can be evaluated.
An analysis of 14 full-length sequences suggests that two genetic lineages
might have arisen from Guangdong. One lineage is represented by the chain of

transmission associated with the physician from Guangzhou who traveled to Hong
Kong, Special Administrative Region, in February. The other lineage is associated
with isolates from Hong Kong, Guangzhou, and Beijing (Ruan et al., 2003). If two
genetic lineages arose in Guangdong, were there two separate transmission events
from an animal host to humans, or did the lineage diverge within humans? Speci-
mens from early cases in Guangdong may be helpful in addressing this question.
Outcomes of Infection
Epidemiologic, immunologic, and microbiologic factors associated with se-
vere outcome are not fully defined. Clearly, though, a principal determinant for
poor outcome is advancing age. As with other respiratory diseases, age-related
coexisting conditions reduce the capacity to compensate to conditions associated
with severe disease. Understanding other specific factors that result in poor out-
come will have value for optimizing therapeutic approaches.
Clinicians disagree about the value of early treatment with ribavirin and high-
dose corticosteroids,7 and some are reticent to ventilate patients because of high
risk for transmission to health-care workers associated with intubation. More data
are needed to help define the most effective treatment strategy, particularly for
areas with limited resources.
Extraordinary clinical expertise exists among health professionals in
Guangdong Province. They have substantial experience with a variety of anti-
virals, antibiotics, alternative (herbal) medicines, and corticosteroids, and with
using assisted ventilation in the treatment of patients with SARS (Zhong and
Zeng, 2003). While randomized clinical trials have not been conducted, careful
compilations of existing case series data would be helpful in evaluating the po-
tential effectiveness of various management regimens.
The store of clinical data, accumulated from treating hundreds of SARS cases,
needs to be put to good use. One priority is to investigate clinical, epidemiologic,
and laboratory predictors of poor outcome. Such experience will supplement other
recently published data from Hong Kong, Special Administrative Region
(Donnelly et al., 2003; Lee et al., 2003; Peiris et al., 2003b; Tsang et al., 2003),
and Singapore (Hsu et al., 2003).
Several questions remain unanswered. Do patients exposed to high viral doses
(for which a short incubation period may be a surrogate) or to a co-infecting patho-
gen have poorer outcomes? What is the impact of multiple exposures to SARS-
associated coronavirus, like that which occurred among health-care workers early
in the epidemic? Do patients infected early in the transmission cycle perform more
poorly than those infected during subsequent cycles of transmission?
7[IOM editor’s note: For more on the controversy over ribavirin use, see Zhaori, G., 2003, Antiviral
treatment of SARS: Can we draw any conclusions? Canadian Medical Association Journal 169(11):
1165-6.]

Learning from the SARS Epidemic

Seldom have intersections between politics, economic development, and pub-
lic health been more graphically demonstrated. While awaiting the development
of effective prophylactic and therapeutic options, many countries have had to
muster substantial political will for quick and transparent steps to declare the
presence of a lethal pathogen within their borders; conduct surveillance and re-
port the results; use contact tracing, quarantine, and border control measures when
needed; and apply stringent infection control measures in health-care settings.
Providing the general public with timely and candid information about the mag-
nitude of the problem, the known risks, and how persons can protect themselves
has also been necessary. These actions were necessary even when they appeared
contrary to economic interests in the short run. Delaying implementation can
result in major public health consequences, in addition to damage to the economy
and national image.
The work outlined here involves descriptive and epidemiologic inquiry, fun-
damental to establishing an understanding of this new pathogen and disease.
While refined and esoteric research will likely also be conducted, support must
first be established for systematically addressing these basic questions and rap-
idly disseminating results through publication in international journals, presenta-
tions at international meetings, and public communications. In China, in contrast
with many other settings globally, scientific inquiry and dissemination of results
to the international community are subject to institutional interference. The SARS
pandemic has shown that virulent pathogens are beholden to no political philoso-
phy or edict. Only careful and rapid application of knowledge and reason through
a variety of public health measures has been effective in minimizing the spread
and severity of the SARS epidemic. More information and data generated from
studies of the epidemic in China are needed immediately to save lives and to
prevent fear and disease, both in China itself and elsewhere in the world.
SARS became a public health emergency for China, where investment in
health services has been given low priority for many years. Maintaining control
in a country so large and diverse will be a major challenge for the months, and
perhaps years, to come. Each of China’s mainland provinces (including munici-
palities with equivalent status, autonomous regions, and special administrative
regions) is like a country within a country. Many are larger than most countries in
Europe. Some, such as Shanghai, are wealthy and highly developed, while others
such as Guangxi (bordering Guangdong and Vietnam) are poor and typical of
developing countries. Given the potential for reemergence of SARS in the future,
if sustained control measures are not in place in China, the possibility of control-
ling the global threat posed by the disease until new technology (i.e., an effective
vaccine) is available may be slight. Key strategies include effective disease sur-
veillance and reporting with early detection and isolation; hospital infection con-

trol during triage and treatment of cases; and transparent, open public communi-
cation about risk and disease magnitude.
China has recently begun to vigorously address the need for better surveil-
lance, accurate reporting, and forthright public communication. Substantial epi-
demiologic, clinical, virologic, and immunologic expertise and interest are avail-
able within China to address the fundamental questions. International expertise is
also available to provide guidance, feedback, and assistance when requested. Iden-
tifying the modest resources needed to implement the work should not be a bar-
rier. Support from the government will be needed to carry out valid, transparent
studies, and for permission to report the findings, regardless of the conclusions.
SARS provides a jarring reminder of the preparedness that is needed to respond
to emerging and existing disease threats; it highlights the need to reinvest in health
in China, and strengthen public health programs, including surveillance systems
and response capacity.
While disease incidence has abated in China and in other locations globally,
the disease may still represent an important threat in the future. Many of the
solutions to solve the multifaceted puzzle of SARS and to prevent future epidem-
ics must come from China. Without solutions from that country, the degree of
difficulty for sustained control of the problem globally is raised still higher.
SARS: LESSONS FROM TORONTO

Donald E. Low, M.D., FRCPC
Toronto Medical Laboratories, Mt. Sinai Hospital, Toronto
Toronto’s experience with severe acute respiratory syndrome (SARS) illus-

trated how quickly the disease can spread in hospitals and highlighted the danger-
ous phenomenon of SARS superspreaders (see Figure 1-1). Unrecognized cases
in Toronto caused significant morbidity and mortality (see Tables 1-4 and 1-5).
The absence of rapid tests to distinguish this new disease from pneumonia, influ-
enza, or other common diseases bodes ill for future outbreaks. In the meantime,
however, it is clear that a number of simple precautionary measures can signifi-
cantly reduce hospital-based transmission of the SARS coronavirus, SCoV, dur-
ing an outbreak.
During the first phase of the outbreak in Toronto, SARS chiefly affected
health care workers (HCW), patients, and their visitors at four hospitals (see Table
1-6). The second phase of the outbreak occurred primarily in the workers and
visitors of a single hospital ward. The following text chronicles the two phases of
the SARS outbreak in Ontario and describes the preventive measures taken by
hospitals and individual HCWs once the outbreak became apparent.

20
18
16
14
12
Number of Cases
10
0
23-Feb 5-Mar 15-Mar 25-Mar 4-Apr 14-Apr 24-Apr 4-May 14-May 24-May 3-Jun 13-Jun 23-Jun
Date of Onset
FIGURE 1-1 SARS Toronto: Phases I and II. The two SARS outbreaks that occurred in
Toronto and the age distribution of cases. The majority of cases, which occurred between
the ages of 18 and 64, were among health care workers, patients, and visitors to patients in
hospitals.
TABLE 1-4 Case Distribution by Age Group

Phase I Phase II
Age Group No. % No. %
<18 18 7 2 2
18-35 71 28 20 17
36-64 132 51 70 59
>64 36 14 26 22
Total 257 100 118 100
TABLE 1-5 Case Fatality by Age Group

Phase I Phase II
Age Group No. % No. %
<18 0 0 0 0
18-35 0 0 0 0
36-64 10 38 6 31
>64 16 62 11 69
Phase I of the Toronto SARS Outbreak

The index case and her husband had vacationed in Hong Kong and had
stayed at a hotel in Kowloon from February 18 to 21, 2003. The index case
began to experience symptoms after her return on February 23 and died at home

TABLE 1-6 SARS Toronto: Phases I and II

Phase
I II
Exposure No. (%) No. (%)
2002 91 (33%) 52 (42%)
Hospital -worker 49 (18%) 64 (51%)
patient/visitor
Other health care 8 (2.9%) 2 (1.6%)
(clinic, EMS)
Household contact 76 (28%) 9 (7.2%)
“Community” 16 (5.9%) —
Travel 12 (4.4%) —
Under investigation 21 (7.7%) —
on March 5. During her illness, family members, including her son (case A),
provided care at home. Case A became ill on February 27 and presented to the
index hospital on March 7 (Varia et al., 2003).
Nosocomial transmission in the hospital began when case A presented to the
emergency department on March 7 with severe respiratory symptoms. He was
placed in a general observation area of the emergency department and received
nebulized salbutamol. During this time, SARS was transmitted to two other pa-
tients in the emergency department (cases B and C). Case B, who had presented
with rapid atrial fibrillation, was in the bed adjacent to case A, about 1.5 meters
away and separated by a curtain, and was discharged home after 9 hours in the
emergency department. Case C, who had presented with shortness of breath sec-
ondary to a pleural effusion, was three beds (about 5 meters) away from case A
and was transferred to a hospital ward and later discharged home on March 10.
The three patients were cared for by the same nurse.
Case A was transferred briefly to a medical unit, then to the intensive care
unit (ICU) 18 hours after his presentation to the emergency department. Three
hours later, he was placed in airborne isolation because tuberculosis was included
in his differential diagnosis. Contact and droplet precautions were implemented
on March 10 by ICU staff caring for case A, and the patient remained in isolation
until his death, on March 13. Case A’s family visited him in the ICU on March 8,
9, and 10. During this time, some family members were febrile, and two were
experiencing respiratory symptoms. Chest radiographs were taken of the family
members on March 9 and again on March 11. Four members had abnormal radio-
graphs and were instructed to wear masks at all times, wash their hands upon
entering and leaving the ICU, and limit their visits to the ICU.
On March 12, the WHO alerted the global community to a severe respiratory
syndrome that was spreading among HCWs in Hanoi, Vietnam, and Hong Kong.
The alert was forwarded to infectious disease and emergency department physi-
cians in Toronto. The following day, case A died and it became clear that several

other family members had worsening illness. The clinicians involved and the lo-
cal public health unit suspected the family’s illnesses might be linked to cases of
atypical pneumonia reported in Hong Kong. Four family members were admitted
to three different hospitals on March 13, and another family member was admit-
ted to hospital on March 14. All were managed using airborne, droplet, and con-
tact precautions. No further transmission from these cases occurred after admis-
sion to hospital.
Case B became febrile on March 10, 3 days after exposure to case A in the
emergency department and discharge home. Respiratory symptoms evolved over
the next 5 days. He was brought to the index hospital on March 16 by two Emer-
gency Medical Services paramedics, who did not immediately use contact and drop-
let precautions. After 9 hours in the emergency department, where airborne, contact
and droplet precautions were used, case B was transferred to an isolation room in
the ICU. His wife became ill on March 16. She was in the emergency department
with case B on March 16 (no precautions used) and visited him in the ICU on March
21 (precautions used); he died later that day. The infection also spread to three other
members of case B’s family. SARS developed in a number of people who were in
contact with case B and his wife on March 16, including the 2 paramedics who
brought him to the hospital, a firefighter, 5 emergency department staff, 1 other
hospital staff, 2 patients in the emergency department, 1 housekeeper who worked
in the emergency department while case B was there, and 7 visitors who were also
in the emergency department at the same time as case B (symptom onset March 19
to 26). The 16 hospital staff, visitors, and patients transmitted the infection to 8
household members and 8 other family contacts. In the ICU, intubation for me-
chanical ventilation of case B was performed by a physician wearing a surgical
mask, gown and gloves. He subsequently acquired SARS and transmitted the infec-
tion to a member of his family. Three ICU nurses who were present at the intubation
and who used droplet and contact precautions had onset of early symptoms between
March 18 and 20. One transmitted the infection to a household member.
Case C became ill on March 13 with symptoms of a myocardial infarction and
was brought to the index hospital by paramedics. It was unknown that he had been in
contact with case A on March 7, and thus it was not recognized that he had SARS. As
a result, he was not isolated, and other precautions were not used. He was admitted to
the coronary care unit (CCU) for 3 days and then transferred to another hospital for
renal dialysis. He remained in the other hospital until his death, on March 29. Subse-
quent transmission of SARS occurred within that hospital (Dwosh et al., 2003). Case
C’s wife became ill on March 26. At the index hospital, case C transmitted SARS to 1
patient in the emergency department, 3 emergency department staff, 1 housekeeper
who worked in the emergency department while case C was there, 1 physician, 2
hospital technologists, 2 CCU, patients, and 7 CCU staff. One of the paramedics who
transported case C to the index hospital also became ill. Further transmission then
occurred from ill staff at the index hospital to 6 of their family members, 1 patient, 1
medical clinic staff, and 1 other nurse in the emergency department.

On March 23, 2003, officials recognized that the number of available nega-
tive pressure rooms in Toronto was being exhausted. In a 4-hour period on the
afternoon of March 23, staff at West Park Hospital, a chronic care facility in the
city, recommissioned 25 beds in an unused building formerly used to house pa-
tients with tuberculosis. Despite the efforts of West Park physicians and nurses,
and assistance from staff at the Scarborough Grace and Mount Sinai Hospitals,
qualified staff could be found to care for only 14 patients.
Faced with increasing transmission, the Ontario government designated
SARS as a reportable, communicable, and virulent disease under the Health Pro-
tection and Promotion Act on March 25, 2003. This move gave public health
officials the authority to track infected people, and issue orders preventing them
from engaging in activities that might transmit the new disease. Provincial public
health activated its emergency operations center.
By the evening of March 26, 2003, the West Park unit and all available nega-
tive pressure rooms in Toronto hospitals were full; however, 10 ill Scarborough
Hospital staff needing admissions were waiting in the emergency department,
and others who were ill were waiting at home to be seen. Overnight, with the
declaration of a provincial emergency, the Ontario government required all hos-
pitals to create units to care for SARS patients.
By March 25, 2003, Health Canada was reporting 19 cases of SARS in
Canada—18 in Ontario and the single case in Vancouver. But 48 patients with a
presumptive diagnosis of SARS had in fact been admitted to hospital by the end
of that day. Many more individuals were starting to feel symptoms, and would
subsequently be identified as SARS patients. Epidemic curves later showed that
this period was the peak of the outbreak. On March 19, nine Canadians developed
“probable” SARS, the highest single-day total. Taking “suspect” and “probable”
cases together, the peak was March 26, and the 3 days, March 25 to 27 are the
highest 3-day period in the outbreak.
The Ontario government declared SARS a provincial emergency on March
26, 2003. Under the Emergency Management Act, the government has the power
to direct and control local governments and facilities to ensure that necessary
services are provided.
All hospitals in the Greater Toronto Area (GTA) and Simcoe County were
ordered to activate their “Code Orange” emergency plans by the government.
“Code Orange” meant that the involved hospitals suspended nonessential ser-
vices. They were also required to limit visitors, create isolation units for potential
SARS patients, and implement protective clothing for exposed staff (i.e., gowns,
masks, and goggles). Four days later, provincial officials extended access restric-
tions to all Ontario hospitals.
On May 14, 2003, WHO removed Toronto from the list of areas with recent
local transmission. This was widely understood to mean that the outbreak had
come to an end. Consistent with the notion that the disease was contained, the
government of Ontario lifted the emergency on May 17. Directives continued to

reinforce the need for enhanced infection control practices in health care settings.
Code Orange status for hospitals was revoked.
It appeared that the total number of cases had reached a plateau—140 prob-
able and 178 suspect infections. Twenty-four Canadians had died, all in Ontario.
Phase II of the Toronto SARS Outbreak

During early and mid-May, as recommended by provincial SARS-control
directives, all hospitals discontinued SARS expanded precautions (i.e., routine
contact precautions with use of an N95 or equivalent respirator) for non-SARS
patients without respiratory symptoms in all hospital areas other than the emer-
gency department and the ICUs. In addition, staff no longer were required to wear
masks or respirators routinely throughout the hospital or to maintain distance
from one another while eating.
On May 20, five patients in a rehabilitation hospital in Toronto were reported
with febrile illness. One of these five patients was determined to have been hospi-
talized in the orthopedic ward of North York General (NYG) Hospital during
April 22 to 28, and a second was found on May 22 to have SARS-associated
SCoV by nucleic acid amplification test. On investigation, a second patient was
determined to have been hospitalized in the orthopedic ward of NYG hospital
during April 22 to 28. After the identification of these cases, an investigation of
pneumonia cases at NYG hospital identified eight cases of previously unrecog-
nized SARS among patients.
The first patient linked to the second phase of the Ontario outbreak was a
man aged 96 years who was admitted to NYG hospital on March 22 with a frac-
tured pelvis. On April 2, he was transferred to the orthopedic ward, where he had
fever and an infiltrate on chest radiograph. Although he appeared initially to re-
spond to antimicrobial therapy, on April 19, he again had respiratory symptoms,
fever, and diarrhea. He had no apparent contact with a patient or an HCW with
SARS, and aspiration pneumonia and Clostridium difficile—associated diarrhea
appeared to be probable explanations for his symptoms. In the subsequent out-
break investigation, other patients in close proximity to this patient and several
visitors and HCWs linked to these patients were determined to have SARS. At
least one visitor became ill before the onset of illness of a hospitalized family
member, and another visitor was determined to have SARS although his hospital-
ized wife did not.
On May 23, NYG hospital was closed to all new admissions other than pa-
tients with newly identified SARS. Soon after, new provincial directives were
issued, requiring an increased level of infection-control precautions in hospitals
located in several greater Toronto regions. HCWs at NYG hospital were placed
under a 10-day work quarantine and instructed to avoid public places outside
work, avoid close contact with friends and family, and wear a mask whenever
public contact was unavoidable. As of June 9, of 79 new cases of SARS that

resulted from exposure at NYH hospital, 78 appear to have resulted from expo-
sures that occurred before May 23.
Transmission
The SCoV has been isolated in sputum, nasal secretions, serum, feces, and
bronchial washings (Drosten et al., 2003; Peiris et al., 2003b). Evidence suggests
that SCoV is transmitted via contact and/or droplets (Peiris et al., 2003a; Poutanen
et al., 2003) and that the use of any mask (surgical or N95) significantly decreases
the risk of infection (Seto et al., 2003). However, there are cases that defy expla-
nation based on these modes of transmission suggesting that alternative modes of
transmission may also occur (Varia et al., 2003). SCoV remains viable in feces
for days and the outbreak at the Amoy Gardens apartments highlights the possi-
bility of an oral-fecal or fecal-droplet mode of transmission (WHO, 2003m,n).
A number of cases occurred in HCWs wearing protective equipment follow-
ing exposure to high risk aerosol- and droplet-generating procedures such as air-
way manipulation, administration of aerosolized medications, noninvasive posi-
tive pressure ventilation, and bronchoscopy or intubation (Lee et al., 2003; Ofner
et al., 2003). 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 paralyzing the patient to
reduce cough. Updated interim infection control precautions for patients who
have SARS are under development and will be available from CDC at http://
www.cdc.gov/ncidod/sars/index.htm.
Currently, epidemiological evidence suggests that transmission does not oc-
cur prior to the onset of symptoms or after symptom resolution. Despite this,
shedding of SCoV in stool has been documented by reverse-transcription poly-
merase chain reaction (RT-PCR) for up to 64 days following the resolution of
symptoms (Ren et al., 2003). A small group of patients appear to be highly infec-
tious and have been referred to as superspreaders (CDC, 2003a). Such
superspreaders appear to have played an important role early in the epidemic but
the reason for their enhanced infectivity remains unclear. Possible explanations
for their enhanced infectivity include the lack of early implementation of infec-
tion control precautions, higher load of SCoV, or larger amounts of respiratory
secretions.
Clinical Disease
Case Definition
The Centers for Diseases Control and Prevention in Atlanta (CDC) has clas-
sified SARS into suspect and probable with further classification based on labo-
ratory findings (CDC, 2003b). The World Health Organization has a similar case

classification (WHO, 2003d). Although these classifications have proven epide-

miologically useful, they have a low sensitivity for diagnosis in patients early in
disease (sensitivity, 26 percent; specificity, 96 percent) (Rainer et al., 2003), un-
derscoring the importance of a rapid, accurate diagnostic test.
Presentation
The typical incubation period of SARS ranges from 2 to 10 days but may
rarely be as long as 16 days (Booth et al., 2003; Lee et al., 2003). The prodrome
includes influenza-like symptoms such as fever, myalgias, headache, and diarrhea
(Booth et al., 2003; Lee et al., 2003). Fever can vary from low to high grade, and
can occasionally be absent on presentation, particularly in older patients. The
respiratory phase, consisting of an early and late stage, starts 2-7 days after the
prodrome and can be associated with watery diarrhea (Booth et al., 2003; Lee et
al., 2003; Peiris et al., 2003b). The early stage includes a dry nonproductive cough
and mild dyspnea. Patients may only have prodromal or early respiratory symp-
toms at the time of presentation making the diagnosis of SARS difficult. Chest
radiographic and laboratory findings may help in making an early diagnosis. Early
chest radiographs often show subtle peripheral pulmonary infiltrates, that can be
more readily detected as consolidation or ground-glass appearance using high-
resolution computed tomographic (CT) lung scans (Wong et al., 2003a, b). Atypi-
cal presentations of the disease have been described also complicating the diag-
nosis (Fisher et al., 2003; Wu and Sung, 2003). Interestingly, the disease has been
rare in children and if present appears to be milder (Hon et al., 2003; Li et al.,
2003).
Natural History
SARS is characterized by a spectrum of disease. Asymptomatic cases have
been described but only in small number (Gold et al., 2003). Another infrequent
subset of cases includes those who have a febrile illness without a respiratory
component. More frequent is a mild variant of the disease that includes mild
respiratory symptoms with fever. Within this category is a cough variant with
persistent intractable cough. The classic moderate-severe variant is characterized
by a more serious later respiratory phase with dyspnea on exertion or at rest, and
hypoxia. This later respiratory phase often occurs 8 to 12 days after the onset of
symptoms (Booth et al., 2003; Lee et al., 2003; Peiris et al., 2003b). In 10-20
percent of hospitalized patients, persistent or progressive hypoxia results in intu-
bation and mechanical ventilation (Booth et al., 2003; Fowler et al., 2003; Lew et
al., 2003). Among patients developing respiratory failure, intubation was required
at a median of 8 days following symptom onset. Subtle but progressive declines
in oxygen saturation are often indicative of impeding respiratory failure and
should trigger more intensive monitoring and preparation for intubation under

controlled circumstances. In total, the respiratory phase lasts approximately 1

week. The recovery phase begins approximately 14 to 18 days from the onset of
symptoms with resolution of the lymphopenia and thrombocytosis.
Clinical Outcome
The case fatality rate during recent outbreaks was 9.6 percent ranging from 0
to 40 percent (WHO, 2003o). Advanced age is the most important risk factor for
death with patients older than 60 years having a case fatality rate of 45 percent
(Booth et al., 2003; Peiris et al., 2003b). Other risk factors for death include
diabetes mellitus and hepatitis B virus infection (Booth et al., 2003; Fowler et al.,
2003; Lee et al., 2003; Lew et al., 2003; Peiris et al., 2003b). Little data exist
regarding the long-term morbidity of SARS although preliminary studies suggest
that the psychological impact of the disease is considerable (Maunder et al., 2003;
Styra et al., 2003).
Conclusion
The experience with SARS in Toronto indicates that this disease is entirely
driven by exposure to infected individuals. Transmission occurred primarily
within health care settings or in circumstances where close contacts occurred.
The infectious agent was spread by respiratory droplets in the great majority of
cases, and some patients were more infectious than others. Ultimately, the strict
adherence to precautions—and practice implementing them—was critical to the
containment of SARS in Toronto and the restoration of safe conditions for hospi-
tal staff and patients.
ISOLATION AND QUARANTINE: CONTAINMENT STRATEGIES

FOR SARS 2003
Martin Cetron, M.D., Susan Maloney, M.D., M.H.Sc., Ram Koppaka, M.D.,
and Patricia Simone, M.D.
National Center for Infectious Diseases, Centers for
Disease Control and Prevention
Quarantine is an ancient tool used to prevent the spread of disease. The Bible
describes the sequestering of persons with leprosy, and the practice was used
widely in 14th-century Europe to control the spread of bubonic and pneumonic
plague. To prevent disease transmission, ships were required to stay in harbor for
40 days before disembarkation (thus the term quarantine, which derives from the
Latin quadragina or the Italian quaranta, meaning 40).
Quarantine has been used for centuries, but because it was often implemented
in a way that equated disease with crime, the practice has negative connotations.

Persons under quarantine were often detained without regard to their essen-
tial needs. Those who were exposed but not yet ill were not always separated
from the ill, allowing disease to spread within the detained group. Populations
targeted for quarantine, such as foreigners, were stigmatized. In some cases, the
power of quarantine was abused; for example, at the end of the 19th century, the
steerage passengers on arriving ships were frequently quarantined while the first-
and second-class passengers were allowed to disembark without being examined
for illness.
Despite its history, quarantine—when properly applied and practiced accord-
ing to modern public health principles—can be a highly effective tool in prevent-
ing the spread of contagious disease. It may play an especially important role
when vaccination or prophylactic treatment is not possible, as was the case with
severe acute respiratory syndrome (SARS). Even when direct medical counter-
measures are available (e.g., smallpox and pneumonic plague), reducing mobility
in the at-risk population may enable the most rapid and efficient delivery of
postexposure vaccination and chemoprophylaxis.
Isolation and Quarantine

Before discussing the role of quarantine as a component of community re-
sponse and containment for SARS, it is necessary to distinguish, from a public
health perspective, between the related practices of isolation and quarantine. Both
are usually imposed by health officials on a voluntary basis; however, federal,
state, and local officials have the authority to impose mandatory quarantine and
isolation when necessary to protect the public’s health.
Isolation refers to the separation and restricted movement of ill persons who
have a contagious disease in order to prevent its transmission to others. It typi-
cally occurs in a hospital setting, but can be done at home or in a special facility.
Usually individuals are isolated, but the practice may be applied in larger groups.
Quarantine refers to the restriction of movement or separation of well per-
sons who have been exposed to a contagious disease, before it is known whether
they will become ill. Quarantine usually takes place in the home and may be
applied at the individual level or to a group or community of exposed persons.
Contact surveillance, in the context of quarantine, is the process of monitor-
ing persons who have been exposed to a contagious disease for signs and symp-
toms of that disease. Surveillance may be done passively, for example, by inform-
ing contacts to seek medical attention if signs or symptoms occur. Contact
surveillance can also be performed actively, for example, by having health work-
ers telephone contacts daily to inquire about signs and symptoms or even having
health workers directly assess contacts for fever or other symptoms. All quaran-
tined persons should be monitored for development of signs and symptoms of
disease to ensure appropriate isolation, management, and/or treatment. For per-
sons without a known contact but believed to be at increased risk for disease or

exposure, enhanced surveillance and education can be used for risk assessment
monitoring. During the SARS epidemic, this approach was used effectively with
airline passengers arriving in the United States from areas of high transmission
during the SARS epidemic.
Principles of Modern Quarantine

Quarantine as it is now practiced is a public health tool and a collective
action for the common good. Today’s quarantines are more likely to involve a
few people exposed to contagion in a small area, such as on an airplane or at a
public gathering, and only rarely are applied to entire cities or communities. The
main goal of modern quarantine is to reduce transmission by increasing the “so-
cial distance” between persons; that is, reducing the number of people with whom
each person comes into contact (see Figure 1-2).
If quarantine is to be used, the basic needs of those infected and exposed
must be met. The following key principles of modern quarantine ensure that it
strikes the appropriate balance between individual liberties and the public good:
• Quarantine is used when persons are exposed to a disease that is highly

dangerous and contagious.
• Exposed well persons are separated from those who are ill.
• Care and essential services are provided to all people under quarantine.
• The “due process” rights of those restricted to quarantine are protected.
Exponentiation Suppression
Ro = 2.0, RoRo = 0.67,

= 0.67,
Progression = 1:2:4:8:16 Progression = 1:2:4: 3:2
FIGURE 1-2 Effectiveness of vaccination and quarantine to contain a smallpox outbreak
after the release of bioengineered, aerosolized smallpox in an airplane carrying 500 people.

• Quarantine lasts no longer than is necessary to ensure that quarantined

persons do not become ill. Its maximum duration would be one incubation period
from the last known exposure, but it could be shortened if an effective vaccina-
tion or prophylactic treatment is available and can be delivered in a timely fash-
ion.
• Quarantine is used in conjunction with other interventions, including—
• Disease surveillance and monitoring for symptoms in persons quaran-
tined.
• Rapid diagnosis and timely referral to care for those who become ill.
• The provision of preventive interventions, including vaccination or
prophylactic antibiotics.
Quarantine encompasses a range of strategies that can be used to detain,

isolate, or conditionally release individuals or populations infected or exposed
to contagious diseases, and should be tailored to particular circumstances. Quar-
antine activities can range from only passive or active symptom monitoring or
short-term voluntary home curfew, all the way to cancellation of public gather-
ings, closing public transportation, or, under extreme circumstances, to a cor-
don sanitaire: a barrier erected around a geographic area, with strict enforce-
ment prohibiting movement in or out. In a “snow day” or “sheltering in place”
scenario, schools may be closed, work sites may be closed or access to them
restricted, large public gatherings may be cancelled, and public transportation
may be halted or restricted. People who become ill under these conditions would
need specific instructions for seeking evaluation and care; they would only ex-
pose others in their households—or perhaps no one at all, if precautions are
taken as soon as symptoms develop. The fact that most people understand the
concept of sheltering at home during inclement weather, regarding home in
these circumstances as the safest and most sensible place to be, increases the
likelihood that similar conditions of quarantine will be accepted. “Snow day”
measures can be implemented instantaneously, and most essential services can
be met without inordinate additional resources, especially if the quarantine lasts
only a few days.
Another important feature of quarantine is that it need not be absolute to
be effective. Even a partial or “leaky” quarantine, such as occurs with volun-
tary compliance, can reduce the transmission of disease. Voluntary measures,
which rely on the public’s cooperation, reduce or remove the need for legal
enforcement and leverage the public’s instinct to remain safely sheltered. In
contrast, compulsory confinement may precipitate the instinct to “escape.” If
an effective vaccine is available, partial quarantine can be an effective supple-
ment to vaccination, further reducing transmission of disease. For example,
Figure 1-3 shows a model illustrating various outcomes of a hypothetical sce-
nario of 500 people, all of whom are vaccinated against smallpox, exposed to
an intentional aerosol release of that contagion on an airplane. In the model,

2,500
2,000
Total Smallpox Cases
1,500
1,000
500
0
V100%, V100%, V100%, V100%, V100%, V100%,
Q0% Q50% Q90% Q95% Q99% Q100%
Ro=3 Ro=5 Ro=10
FIGURE 1-3 Impact of varying Ro and percent quarantined on total smallpox cases. Even
with 100 percent vaccination against smallpox, quarantine effectively reduces the spread
of disease in the community. This effect remains significant even at lower reproductive
rates, and differs little between 90 and 100 percent quarantine.
all 500 people are offered postexposure smallpox vaccine; the model assumes
that the vaccine is 95 percent effective. Even under these unlikely and theo-
retical circumstances, the addition of even partial (50 percent to 90 percent)
quarantine to vaccination can have a profound effect on reducing the number
of eventual cases in the community. This trend remains significant even at
low rates of transmission (“reproductive rates”).
In order to implement modern quarantine effectively, there must be a clear
understanding of the roles of public health staff at federal, state, and local levels,
and each group should know their legal authorities. Effective implementation
also requires identifying appropriate partners, including transportation authorities
and law enforcement officials, and engaging them in coordinated planning. Fi-
nally, quarantine can be most successful if the public has advance knowledge of
the disease threat and understands the role of quarantine in containing an epi-
demic. People who are actually quarantined need to believe that their sacrifice is
justified and that they will be supported during the period of quarantine.
Quarantine and the Response to SARS

Containment strategies employed during the recent SARS epidemic included
case and contact management, infection control in hospitals and other facilities,
community-wide temperature screening, mask use, isolation and quarantine, and

FIGURE 1-4 Reported cases of SARS, United States, May 19, 2003.
the monitoring of travelers and response at national borders. Various combina-

tions of these strategies were applied in different places, depending on factors
such as the magnitude and scope of the local outbreak, the availability of re-
sources to support containment, and the level of public cooperation and trust. In
the United States, where only eight laboratory-confirmed cases of SARS and no
community transmission occurred (see Figure 1-4), the principal strategies of
containment were education of high-risk populations (e.g., international travelers
and health-care workers); early detection of suspected and probable cases; and
rapid implementation of isolation and other infection control tools. Additional
measures such as quarantine were used in other countries where SARS presented
a greater threat.
Case and Contact Management

In the United States, most people with suspected or probable SARS were
isolated at home; hospital isolation was reserved for those who required such care
or had no suitable home environment. (e.g., homeless, out-of-town visitors). Iso-
lation was continued while symptoms persisted and for 10 days thereafter. In
some other countries, most persons with suspected or probable SARS were iso-
lated in the hospital. For contact management, the U.S. Centers for Disease Con-
trol and Prevention (CDC) recommended quarantine only for health-care workers
who had a high-risk exposure to a SARS patient. In several states, however, local

health officials “furloughed” health-care workers who were exposed to high-risk

probable cases. In general, CDC recommended only passive surveillance. Per-
sons who were exposed to suspected or probable SARS, as well as travelers re-
turning from areas with SARS transmission, were asked to monitor their health
for 10 days and seek medical attention immediately if fever or respiratory symp-
toms developed. Active surveillance was reserved for probably and lab-confirmed
cases and their high risk close contacts; this was usually conducted by members
of the local or state health departments.
In some countries other than the United States (e.g., China, Taiwan [ROC],8
Singapore, and Canada), home quarantine was used for most close contacts of
people with suspected or probable SARS. Designated quarantine facilities were
used in some situations for homeless persons, travelers, and people who did not
wish to be quarantined at home. In some situations, as a result of staffing short-
ages and relatively high exposure rates in hospitals, exposed health-care workers
and ambulance personnel were placed on “work quarantine,” which entailed
working during their regular shifts, using comprehensive infection control pre-
cautions and personal protective equipment, and staying either at home or in a
building near the hospital when off duty. Most persons in home quarantine were
asked to monitor their temperature regularly, once or twice a day; health workers
called them twice a day to get a report on temperature and symptoms. Other
health-care workers had their temperature checked twice a day or more at work.
In Singapore, video cameras linked to telephones were occasionally used to moni-
tor patients.
Authorities used a variety of methods to enforce quarantine during the SARS
epidemic. In select places, quarantine orders were given to all persons placed in
quarantine, while in the majority, only those who demonstrated noncompliance
were given orders. Under some orders, noncompliant individuals were isolated in
guarded rooms; others were confined at home wearing security ankle bracelets;
yet others received fines or even jail sentences. However, these instances of com-
pulsory enforced quarantine orders were clearly the exception rather than the
norm during the SARS epidemic.
Community Containment
In the United States, community containment strategies consisted mainly of
coordinating the SARS response activities through emergency operations centers
and providing information and education to the public, health workers, and oth-
ers. This strategy included publishing guidelines and fact sheets on websites,
holding press conferences, making presentations to a variety of audiences, and
meeting with groups and communities who were experiencing stigmatization.
8ROC stands for Republic of China.

On some occasions, such as occurred in mainland China, Hong Kong (SAR),

Taiwan (ROC), and Singapore, large-scale quarantine was imposed on travelers
arriving from other SARS areas, work and school contacts of suspected cases,
and, in a few instances, entire apartment complexes where high attack rates of
SARS were occurring.
In addition to imposing large-scale quarantine in some cases, many areas
with high transmission (e.g., Hong Kong, Singapore, Taiwan, Toronto, and main-
land China) used strategies such as mandated fever screening before entry to
schools, work, and other public buildings; requiring masks in certain settings; and
implementing populationwide temperature monitoring and disinfection cam-
paigns. Community mobilization programs were also developed to educate the
public about SARS and what to do to prevent and control it; for example, a
populationwide body temperature monitoring campaign and a SARS hotline to
promote early detection of fever as a warning sign for SARS. Taiwan and main-
land China also undertook a series of community disinfection campaigns in which
streets, buildings, and vehicles were sprayed with bleach and bleach was distrib-
uted free throughout the community.
Several important lessons can be gained from the experience of countries
where large-scale quarantine measures were imposed in response to SARS. First,
when the public was given clear messages about the need for quarantine, it was
well accepted—far better, in fact, than many public health officials would have
anticipated. Indeed, voluntary quarantine was effective in the overwhelming ma-
jority of cases. Yet, despite the widespread acceptance of and cooperation with
quarantine, it represented a great sacrifice for many people through consequences
such as loss of income, concerns for the health of their families, feelings of isola-
tion, and stigma. Finally, large-scale quarantine was found to be complicated and
resource intensive to implement, creating enormous logistic, economic, ethical,
and psychological challenges for public health authorities. Recent data evaluat-
ing the efficacy of quarantine in Taiwan and Beijing, China, during the SARS
epidemic suggest that efficiency could be improved by focusing quarantine ac-
tivities on persons with known or suspected contact with SARS cases. In order to
prepare for future epidemics, enhanced systems and personnel will need to be
established to deliver essential services to persons in quarantine, to monitor their
health and refer them to necessary medical care, and to offer mental health and
other support services.
Border and Travel Response

Several strategies for border and travel response were used in the United
States, including issuing travel advisories and alerts, distributing health alert no-
tices at ports of entry, and meeting planes and responding to reports of ill passen-
gers. Additional strategies used in other countries (e.g., Canada, China, and
Singapore) included predeparture screening of temperature, SARS symptoms,

TABLE 1-7 Travel Alerts and Advisories for SARS, March–July 2003
Region Advisory Started Advisory Stopped Alert Started Alert Stopped
Mainland China 3/13/03 6/17/03 6/17/03 7/3/03
Beijing, China 6/17/03 6/25/03 6/25/03 7/11/03
Taiwan 6/25/03 6/25/03 6/25/03 7/15/03
Hong Kong 5/1/03 6/25/03 6/25/03 7/1/03
Hanoi, Vietnam 3/13/03 4/29/03 4/29/03 5/15/03
Toronto Never had an Never had an 4/23/03 5/20/03
advisory advisory restarted: 5/23/03 restopped: 7/8/03
Singapore 3/13/03 5/4/03 5/4/03 6/4/03
and recent exposures to SARS patients; postarrival disembarkation screening with

questions about travel and exposure to SARS, maintaining “stop lists” of people
with suspected SARS and their contacts at airports to prevent such individuals
from traveling, isolation of ill travelers with suspected or probable SARS, and
quarantine of healthy travelers returning from other areas with high SARS trans-
mission.
In the United States, CDC issued a series of travel alerts and advisories re-
lated to SARS (see Table 1-7). A travel alert describes a health situation in a
particular area and gives recommendations about appropriate precautions, while
a travel advisory goes a step further and recommends postponement of nonessen-
tial travel to an affected area. During the SARS epidemic, CDC staff met nearly
12,000 flights and distributed more than 2.7 million health alert notices to passen-
gers arriving directly and indirectly from affected areas. The notices instructed
travelers to monitor their health for fever and respiratory symptoms for 10 days
and immediately seek medical attention (with advance notice to the health-care
facility) if the symptoms occurred. Health alert notices (HANs) were also distrib-
uted at 13 U.S.–Canada land crossings, as well as in the predeparture area at the
Toronto airport. If an ill passenger was reported on a flight arriving in the United
States, it was met by members of the CDC quarantine staff. They evaluated the
affected passenger for possible SARS, provided referral to a health-care provider,
collected locating information from other passengers, and coordinated with fed-
eral, state, and local public health authorities.
Preparedness Planning
Preparations for a resurgence of SARS (or indeed an outbreak of any conta-
gious disease) should be made at all levels of government. Plans must encompass
general logistics and planning for case and contact management, including quar-
antine. A framework for the community containment of SARS (see Figure 1-5)
lists several criteria for establishing movement restrictions and a range of options
for containment that could be applied in response. In deciding whether and how

Public Health Criteria for No restrictions

Community Response
• Number of cases/exposed Targeted restrictions

•Population -specific
• Exposure category (i.e., congregate settings or
•Known group gatherings)
•Travel
•Close contact
•Health care-related
•Voluntary general movement restrictions
•Household •“Shelter in Place” or “Snow Day”
•Unknown (unlinked) •Closing of public places
•Type of transmission •Suspension of public gatherings
•Restriction of mass transit schedules
• Generations of transmission
• Morbidity and mortality
• Ease/rapidity of spread
•Compulsory movement/activity restrictions
• Movement in/out of community •Curfews on activities
• Resources •Closing of mass transit
•Closing access routes
• Need urgent public health action
•Roads, airports,seaports
• Risk of public panic •Closing borders
•Border surveillance/monitoring
•“SARS checkpoints”
•Travel permits
FIGURE 1-5 Range of available responses to SARS at the national, state, and community
levels.
to restrict movement during an epidemic, community officials would consider

factors such as:
• the number of suspected, probable, and confirmed cases;

• whether cases have well-defined exposure risks;
• how many potential new exposures each case has been in contact with;
• what type of transmission is predominant (e.g., airborne, droplet,
fomite);
• how many generations of transmission have occurred; and
• the morbidity and case-fatality rate of the epidemic.
Decision makers would also need to consider the baseline amount of move-
ment in the community, the impact of curtailing movement on critical infrastruc-
ture, the resources available to support containment, and the public’s reaction to
the epidemic.
Planning for Community Containment

In some circumstances, containment of SARS or other microbial threats at
the community level could be accomplished without restricting movement, with
the focus instead on educating the public through such means as press releases

and travel alerts and advisories (as was done in the United States in 2003). In
other situations, targeted restrictions, including quarantine of close contacts and
restriction of some group gatherings, would be appropriate. A more restrictive
option would include general voluntary movement restrictions, including mea-
sures such as fever screening at entrances of public places, “snow-day” or “shel-
ter-in-place” quarantines, closing public places, canceling public gatherings, and
restricting mass transit. Rarely, in the most extreme circumstances, compulsory
movement restrictions, including the closing of airports and borders, would be
warranted.
Advance planning is necessary to enable officials to assess risk, make deci-
sions, and implement necessary measures as effectively as possible in the event
of a disease outbreak. Jurisdictions should establish an emergency operations
center structure and a legal preparedness plan, and forge connections among es-
sential partners such as law enforcement officials, first responders, health-care
facilities, educators, the media, and the legal community. Provisions must be
made to monitor and assess factors such as those above to determine response
level for both implementing and scaling back interventions and movement re-
strictions. Educational message strategies should be developed to disseminate
information to government decision makers, health-care providers and first re-
sponders, and the public; it will be especially important to address the possibility
that some people may experience stigmatization as a result of containment. A
draft of the CDC SARS Preparedness Plan entitled, “Public Health Guidance for
Community-Level Preparedness and Response to Severe Acute Respiratory Syn-
drome (SARS) is posted at http://www.cdc.gov/ncidod/sars/updatedguidance.htm.
Appendices D and E specifically address Community Containment and Border
Strategies, respectively. A SARS preparedness checklist (available at http://
www.astho.org) also provides guidance for public health officials in developing
such plans.
To plan for case and contact management, jurisdictions should secure neces-
sary protocols for clinical evaluation and monitoring, contact tracing and moni-
toring, and reporting of disease. Standards, tools, and supplies must be estab-
lished for home and nonhospital isolation facilities. A telecommunications plan
should be developed to provide for case and contact monitoring and fever triage,
as well as to provide information to decision makers, health-care workers, and the
public. Provisions must be made to ensure that all isolated and quarantined indi-
viduals receive food, medicine, and mental health and other supporting services,
including transportation to medical facilities. Jurisdictions should also identify
and develop assessment procedures for appropriate nonhospital residential facili-
ties. These sites could be used for quarantining contacts or persons for whom
“home isolation” is indicated, but who do not have an appropriate “home” envi-
ronment.
To prepare for the implementation of community containment measures, ju-
risdictions must establish legal authorities and procedures to implement all levels

• Travel alerts, advisories, press releases

• Meet all SARS-affected arriving flights
• Visual inspection
• Disembarkation notices
Public Health Criteria for Border Response • HAN distribution
• Triage ill passengers
• Contact follow-up and surveillance
• Number of global cases/exposed
• Adequacy of global surveillance/control
• Volume of travel
• Morbidity and mortality • Intensified arrival screening
• Ease/rapidity of spread • Questionnaire
• Characteristics of local outbreaks • Temperature monitoring
• Active registration with local
• Community response levels health department
• Border and local resources • Health certification
• Need urgent public health action • Pre-departure screening
• Risk for public panic
• Restrict departures and flights

• Suspend travel and other visa issuance
• Quarantine any arrivals from affected areas
• Close borders?
FIGURE 1-6 Range of available responses to SARS at borders.
of movement restrictions. Essential personnel for the implementation of quaran-

tine and other movement restrictions will include law enforcement officials, first
responders and other deployable government services workers, and key person-
nel from the transportation, business, and education sectors. Training programs
and deployment drills should be developed for these partners, as well as for pub-
lic health personnel.
Preparing to Respond and Secure National Borders

Similar criteria to those used to determine community-level containment policy
must be considered when determining appropriate responses to SARS at national
borders (see Figure 1-6). In addition to considering circumstances in their area,
officials contemplating movement across national borders must also monitor events
in adjacent areas and, given the frequency of global travel, throughout the world. A
limited border response could resemble that mounted by the United States in 2003
(i.e., issuing travel advisories and alerts; meeting flights from SARS areas to triage
arriving ill passengers; and monitoring contacts for symptoms of illness). More
intensive arrival screening could include questionnaires on symptoms and exposure
to SARS, temperature screening, or even requiring health certification or registra-
tion with the local health department. In some circumstances, predeparture screen-
ing also would be appropriate. A further step would be to quarantine arriving pas-
sengers from affected areas, and under the most extreme circumstances, restriction
of inbound and outbound travel may be necessary.

Conclusion
Modern quarantine represents a wide range of scalable interventions to sepa-
rate or restrict movement (e.g. detain, isolate, or conditionally release) of indi-
viduals or populations infected by or exposed to highly dangerous contagions.
These strategies can be an important part of the public health toolbox for sup-
pressing transmission and stopping epidemics such as SARS. However, the ethi-
cal implementation of modern quarantine can be resource and labor intensive.
Quarantine is most effective when it is tailored to specific circumstances and
used in conjunction with other containment measures; people affected by quaran-
tine must be ensured appropriate support services. The effectiveness of quaran-
tine is further improved by comprehensive preparedness planning. Effective com-
munication and public trust are quintessential components; consequently, the
public must receive clear messages about the role and importance of quarantine
as a means of containing certain infectious disease in advance of, as well as dur-
ing, the epidemic.
If a future epidemic affects the United States as SARS did other countries in
2003, it may be necessary to recommend quarantine, among other containment
measures, in this country. Thus, it is essential that planning for the effective imple-
mentation of quarantine and other containment measures be undertaken at every
level of government, and well in advance of the need. Strategic and operative
plans should be exercised at all levels to expose and rectify gaps and pitfalls in
nonurgent settings to ensure our readiness in an emergency.
Acknowledgments
The authors thank Alison Mack, Katherine Oberholtzer, Alexandra Levitt,
and Ava Navin for technical assistance in the preparation and review of the manu-
script.
IMPACTS OF SARS ON HEALTH CARE SYSTEMS AND

STRATEGIES FOR COMBATING FUTURE OUTBREAKS OF
EMERGING INFECTIOUS DISEASES
Abu Saleh M. Abdullah,9 Brian Tomlinson,10
G. Neil Thomas,9 and Clive S. Cockram10
Severe acute respiratory syndrome (SARS), resulting from a novel corona-

virus, originated in November 2002 in, Guangdong Province, China. By Febru-
ary 2003 it had spread to Hong Kong and subsequently to 32 countries or regions
on most continents, infecting about 8,098 patients and resulting in 774 deaths
9Department of Community Medicine, The University of Hong Kong.

10Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong.

(WHO, 2003k). The overall case fatality ratio is approximately 15 percent (WHO,
2003b). The nonspecific disease presentation, coupled with a long incubation
period and the initial absence of a reliable diagnostic test, limited the understand-
ing of the magnitude of the outbreak. The outbreak has identified a number of
deficiencies in hospital and community infection control systems in Hong Kong.
The lessons learned should be applied on a worldwide basis to help prevent the
spread of other new infections that may emerge (Abdullah et al., 2003). In this
chapter we outline our experience with medical and public health issues that have
arisen in dealing with the outbreak of SARS in Hong Kong and suggest appropri-
ate strategies for combating future infections.
The SARS Epidemic in Hong Kong

The first case of SARS to be identified in Hong Kong was a physician, who
had been treating patients in Guangzhou. He traveled to Hong Kong on February
21, 2003. He rapidly became ill and was hospitalized, and he died soon after. This
doctor apparently was able to warn his medical attendants of the highly infectious
nature of his illness based on his own experience. Precautions were taken to pre-
vent the spread of infection, so there were few cases of transmission within the
hospital from this case (Tsang et al., 2003).
In contrast, the index case at the Prince of Wales Hospital who was the source
of the first large hospital-based outbreak was not known to be highly infectious
(Lee et al., 2003; Tomlinson and Cockram, 2003). This patient was admitted
before the discovery of the SARS coronavirus and any international recognition
of the disease. The clinical picture was that of “typical” community-acquired
pneumonia with no suspicious circumstances. This patient was thus treated using
standard protocols established for previous cases in Hong Kong—in an eight-bed
cubicle of an open general medical ward. Heightened infection control precau-
tions were not instituted.
During the epidemic, cases who were admitted to hospitals who did not show
symptoms suggestive of SARS may not have been treated with strict isolation
precautions, and this resulted in larger hospital outbreaks in areas such as Hong
Kong and Toronto (Simmerman et al., 2003). In Hong Kong, this first received
attention when 11 health care workers from the same ward of a hospital went on
sick leave simultaneously in early March 2003. At that point different hypotheses
were tested and different control measures were instituted to combat the disease.
However, the prolonged epidemic affected a total of 1,755 individuals over a
period of 3 months in Hong Kong. The last case was confirmed on June 11, 2003.
Learning from the Experience

A few important lessons were learned over the course of the SARS outbreak.
Cardiopulmonary resuscitation and endotracheal intubation were identified as

procedures causing very high risk to medical personnel. During some resuscita-
tion procedures and difficult intubations, cases were reported of health care work-
ers becoming infected despite the use of what was believed to be appropriate
protective equipment. The use of nebulizers received particular attention in rela-
tion to the index patient at the Prince of Wales Hospital in Hong Kong (Lee et al.,
2003). Other procedures such as nasopharyngeal aspiration, bronchoscopy, air-
way suction, and noninvasive ventilation procedures such as Bi-level Positive
Airway Procedure (BiPAP) were also suspected to increase the dissemination of
infection. It soon became apparent that respiratory secretions were not the only
source of transmission of infection. Feces and urine were recognized to be major
hazards. Cleaning the patient and the bedding after fecal incontinence, often per-
formed by health care workers less trained in infection control procedures, proved
to be a high-risk duty.
Another problem found with the hospital management of SARS patients was
that even after implementation of usual infection precautions for staff with gloves,
gowns, and face masks, new infections in health care workers continued to occur
(Lee and Sung, 2003). These may have been partly related to lapses in following
standard procedures and partly because of initial lack of awareness of the mode of
spread of the virus. Although it was concluded at an early stage that the infection
was spread by droplets, it was not immediately recognized that the virus was so
tenacious that it could survive outside the body on surfaces for long periods of
time. The estimates of the time that the virus could survive on various surfaces
grew longer and longer—from hours to days over the period of the outbreak—as
understanding of the virus increased.
Another contributing factor to the spread of infection within hospitals in Hong
Kong was probably the relative inexperience of most hospital staff with respira-
tory pathogens with such a degree of infectivity. In recent years the only common
infective respiratory conditions encountered in Hong Kong hospitals have been
tuberculosis and influenza, and these generally have been contained quite easily
within hospitals without specialized isolation facilities. Lack of experience in
dealing with such a novel agent as the SARS coronavirus must have contributed
to the high rate of infection within hospitals. This must be addressed by appropri-
ate training, with repeated reinforcement and checking of infection control tech-
niques so that hospital staff are ready for the next emerging infection.
It is also likely that over the years a degree of complacency has developed,
and that procedures that should be considered routine, such as washing hands
between examining different patients, are no longer strictly implemented. Fur-
thermore, the use of face masks in Hong Kong hospitals was previously a rarity
except in operating rooms and designated high-risk areas.
Guidelines need to be developed that are based on the best available evi-
dence. In hospital settings in Hong Kong, such guidelines were established at a
relatively early stage of the outbreak (Ho, 2003), but in the general community, it
was more difficult to provide clear guidelines apart from applying the principles

of common hygiene. The use of face masks outside of the hospital environment
was adopted by a large percentage of the population, but guidelines for the use of
this and other preventive measures were often vague and inconsistent.
In the community setting, contact tracing and quarantining of people who
had been in close contact with cases who developed SARS was rapidly intro-
duced and was of vital importance in curtailing the spread of the disease and
bringing the epidemic to an end (Riley et al., 2003). Again much experience was
gained during the course of the outbreak, particularly regarding communication
between different sectors of the health services, and mechanisms have been intro-
duced to improve such communications. The initial case of the Guangzhou doc-
tor was reported to the Hong Kong Department of Health, but contact tracing was
not initially conducted at the Metropole Hotel where he stayed because there
were no other reports of atypical pneumonia related to that hotel and little was
understood about the nature of the condition. In retrospect such contact tracing
clearly should have been attempted, although it is unlikely that it could have
prevented the spread of disease to other countries. The other people who were
infected at the hotel would have left Hong Kong soon afterward, at a time when
they were still asymptomatic.
International travel provides a means to disseminate an infection like SARS
throughout the world. Fortunately few cases seem to have actually acquired the
infection during air travel. Although measures were instituted to stop people with
fever from traveling by air, those who were incubating the disease and were still
asymptomatic would not be identified, so perhaps stricter measures are needed to
effectively reduce the risk of spread of such diseases to other countries. The ease
and frequency of international travel demand effective channels be established for
rapid international communication of information about infectious diseases. Rapid
alerting to potential threats will help ensure that appropriate measures can be insti-
tuted and official public information can be disseminated to mitigate public alarm.
Conclusion
Based on our current understanding about its pathogenicity and transmissi-
bility, SARS needs to be regarded as a serious disease. Health care workers and
service providers should use SARS as an example to prepare themselves with
potential measures to combat any future outbreak of infectious disease. The SARS
outbreak provides a timely reminder of the importance of the reorganization of
health care systems with an international focus to ensure adequate surveillance
mechanisms, rapid response to epidemics, effective prevention and control strat-
egies, and maintenance of optimal infrastructure nationally and internationally
(Lee and Abdullah, 2003). In advance of future disease outbreaks, countries where
no SARS cases have been reported should be prepared with clear national and
provincial contingency plans and mechanisms for integrating such plans into an
international response (Lee and Abdullah, 2003).

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Political Influences on the Response to

SARS and Economic Impacts of the Disease
OVERVIEW
As the severe acute respiratory syndrome (SARS) coronavirus spread around
the globe, so too did its political, economic, and sociological repercussions. The
ensuing multinational effort launched in response to SARS placed unprecedented
demands on affected countries for timely, accurate case reporting; cooperation with
expert teams coordinated by the World Health Organization (WHO); and the sacri-
fice of immediate economic interests, such as trade, tourism, and investment.
The first paper in this chapter presents an economic model of the past and pro-
jected costs of the SARS epidemic (see Lee and McKibbin). As one would expect, the
model indicates that significant short-term economic losses in China resulted from a
sharp decrease in foreign investment. Although the most immediate and dramatic
economic effects of SARS occurred in Asia, nearly every major market was impacted
directly or indirectly by the epidemic. Several agencies and experts have attempted to
estimate the cost of SARS based on expenditures and near-term losses in key areas
such as medical expenses, travel and related services, consumer confidence, and in-
vestment. The extent of the long-term economic consequences resulting from SARS
will depend on whether—and how—the disease returns.
The chapter continues with two political analyses that reflect upon issues of
both national and global governance impacted by the SARS epidemic. The first
political analysis frames the issue in terms of the new rules of international en-
gagement during the age of globalization, described by the author as the post-
Westphalian era (see Fidler) in which nonstate actors such as multinational cor-
porations and multilateral organizations have increasing influence on global
governance.
91

The second article hypothesizes that the structure and operation of China’s
central government account for most of that country’s initial resistance to interna-
tional collaboration at the onset of the SARS epidemic (see Huang). The author
describes considerable internal and external pressures that ultimately influenced
the Chinese government to declare its “war on SARS.” He identifies both im-
provements in the Chinese public health infrastructure and challenges the country
may face if SARS reemerges.
ESTIMATING THE GLOBAL ECONOMIC COSTS OF SARS*

Jong-Wha Lee and Warwick J. McKibbin
Korea University and The Australian National University, The Australian
National University and The Brookings Institution
While the number of patients affected by the SARS coronavirus and its
broader impact on the global public health community have been surveyed in
considerable detail, the consequences of the disease in other areas are less well
calibrated. The purpose of this paper is to provide an assessment of the global
economic costs of SARS. Our empirical estimates of the economic effects of the
SARS epidemic are based on a global model called the G-Cubed (Asia-Pacific)
model. Most previous studies on the economic effects of epidemics focus on the
economic costs deriving from disease-associated medical costs or forgone in-
comes as a result of the disease-related morbidity and mortality. However, the
direct consequences of the SARS epidemic in terms of medical expenditures or
demographic effects seem to be rather small, particularly when compared to other
major epidemics such as HIV/AIDS or malaria. A few recent studies—including
Chou et al. (2003), Siu and Wong (2003), and Wen (2003)—provide some esti-
mates on the economic effects of SARS on individual Asian regions such as
mainland China, Hong Kong (SAR), and Taiwan. But these studies focus mostly
*This paper is adapted from an article that will appear later this year in Asian Economic Papers
(MIT Press). An earlier version of the paper was originally presented to the Asian Economic Panel
meeting held in Tokyo, May 11–12, 2003, and the Pacific Economic Cooperation Council (PECC)
finance forum, Hua Hin, Thailand, July 8–9, 2003. We have updated that original paper to include the
last known case of SARS as well as adjusting the scale of some shocks given the knowledge that the
SARS epidemic lasted approximately 6 months rather than the full year originally assumed. The
authors particularly thank Andrew Stoeckel for interesting discussions and many participants at the
conferences, particularly Ifzal Ali, Richard Dorbnick, George Von Furstenberg, Yung Chul Park,
Jeffrey Sachs, Wing Thye Woo, and Zhang Wei for helpful comments. Alison Stegman provided
excellent research assistance and Kang Tan provided helpful data. See also the preliminary results and
links to the model documentation at http://www.economicscenarios.com. The views expressed in the
paper are those of the authors and should not be interpreted as reflecting the views of the institutions
with which the authors are affiliated, including the trustees, officers, or other staff of the Brookings
Institution.

POLITICAL INFLUENCES AND ECONOMIC IMPACTS 93
on assessing the damages by SARS in affected industries such as tourism and the
retail service sector.
However, just calculating the number of canceled tourist trips, declines in
retail trade, and similar factors is not sufficient to get a full picture of the impact
of SARS because there are linkages within economies, across sectors, and across
economies in both international trade and international capital flows. The eco-
nomic costs from a global disease such as SARS go beyond the direct damages
incurred in the affected sectors of disease-inflicted countries. This is not just be-
cause the disease spreads quickly across countries through networks related to
global travel, but also because any economic shock to one country is quickly
spread to other countries through the increased trade and financial linkages asso-
ciated with globalization. As the world becomes more integrated, the global cost
of a communicable disease like SARS can be expected to rise. Our global model
is able to capture many of the important linkages across sectors as well as coun-
tries through capital flows and the trade of goods and services, thereby providing
a broader assessment of disease-associated costs.
The G-Cubed model also incorporates rational expectations and forward-
looking intertemporal behavior on the part of individual agents. This feature
is particularly important when we are interested in distinguishing the effects
of a temporary shock from those of a persistent shock. For example, when
foreign investors expect that SARS or other epidemics of unknown etiology
can break out in some Asian countries not just this year but persistently for
the next few years, they would demand a greater risk premium from investing
in affected economies. Their forward-looking behavior would have immedi-
ate global impacts.
Needless to say, our empirical assessment is preliminary and relies on our
limited knowledge about the disease and constrained methodology. For instance,
there is speculation that SARS could reemerge in an even deadlier form in the
next influenza season. There is also no consensus yet on the likely developments
of any future epidemic and the precise mechanism by which SARS affects eco-
nomic activities. Although a global model is better than simple back-of-the-enve-
lope calculations, it is a coarse representation of a complex world. Nonetheless,
even simple calculations are important inputs into the model. We saw this with
the Asian Crisis of 1997, when the transmission of shocks in Asia to the rest of
the world and the adjustment within economies in Asia were poorly predicted
when only trade flows were considered.1 Thus it is important to go beyond the
rough estimates that currently permeate commentary on the economic conse-
quences of SARS. Because we take into account the interdependencies among
economies and the role of confidence, our costs are larger than many of the esti-
mates that currently appear in the media.
1See McKibbin (1998) for a study of the Asia crisis that included the critical role of capital flow
adjustment.

Economic Impacts of SARS

Despite the catastrophic consequences of infectious diseases such as malaria
and HIV/AIDS, the impact of epidemics has been considerably under-researched
in economics.2 Traditionally, studies have attempted to estimate the economic
burden of an epidemic based on the private and nonprivate medical costs associ-
ated with the disease, such as expenditures on diagnosing and treating the dis-
ease. The costs are magnified by the need to maintain sterile environments, imple-
ment prevention measures, and conduct basic research. Such economic costs can
be substantial for major epidemics such as HIV/AIDS. According to UNAIDS
(the Joint United Nations Programme on HIV/AIDS), 42 million people globally
are living with HIV/AIDS. The medical costs of various treatments of HIV pa-
tients, including highly active antiretroviral therapies (HAARTs), are estimated
to be more than $2,000 per patient per year. In the Southern African regions, the
total HIV-related health service costs, based on an assumed coverage rate of 10
percent, ranges from 0.3 to 4.3 percent of gross domestic product (GDP) (Haacker,
2002).
The costs of disease also include income forgone as a result of disease-re-
lated morbidity and mortality. Forgone income is normally estimated by the value
of workdays lost due to the illness. In the case of mortality, forgone income is
estimated by the capitalized value of future lifetime earnings lost to the disease-
related death, based on projected incomes for different age groups and age-spe-
cific survival rates. This cost can be substantial for some epidemics. Malaria kills
more than 1 million people a year, and HIV/AIDS is estimated to have claimed
3.1 million lives in 2002.
Previous researchers have also focused on long-term effects from the demo-
graphic consequences of epidemics. The first and foremost impact of epidemics
is a negative shock to population and labor force. However, economic theory
provides conflicting predictions regarding the economic effects of negative popu-
lation shocks. A disease that kills mostly children and the elderly without affect-
ing the economically active population aged 15 to 54 can lead to an initial in-
crease in GDP per head. Even when the disease mostly attacks prime earners, its
long-term economic consequences are not unambiguous. Standard neoclassical
growth models predict that a negative shock to population growth can lead to a
faster accumulation of capital and subsequently faster output growth (see Barro
and Sala-I-Martin, 1995). Conversely, an exogenous, one-time reduction in labor
force raises the capital-labor ratio and lowers the rate of return to capital, which
subsequently leads to slower capital accumulation and thereby lower output
growth.
Empirical studies also present conflicting results. Brainerd and Siegler (2002)
show that the Spanish flu epidemic of 1918–1919, which killed at least 40 million
2Exceptions can be found in the Commission on Macroeconomics and Health (2002).

people worldwide and 675,000 in the United States, had a positive effect on per
capita income growth across states in the United States in the 1920s. In contrast,
Bloom and Mahal (1997) show no significant impact of that epidemic on acreage
sown per capita in India across 13 Indian provinces.
Epidemics can have further effects on demographic structures by influencing
fertility decisions of households. According to the “child-survivor hypothesis,”
parents desire to have a certain number of surviving children. Under this theory,
risk-averse households raise fertility by even more than expected child mortality.
Evidence shows that high infant and child mortality rates in African regions of
intense malaria transmission are associated with a disproportionately high fertil-
ity rate and high population growth (Sachs and Malaney, 2002). Thus, the in-
crease in fertility has a further negative impact on long-term growth.
Aside from the direct demographic consequences of an epidemic, another
important mechanism by which a disease has an adverse impact on the economy’s
long-term growth is the destruction of human capital. Human capital, the stock of
knowledge embodied in the population, is considered an important determinant
of long-term growth (Barro and Sala-I-Martin, 1995). Furthermore, the decline in
“health capital,” as measured in general by life expectancy, has negative effects
on economic growth (Bloom et al., 2001). Epidemics also adversely affect labor
productivity by inhibiting the movement of labor across regions within a country
as well as across countries. Restricted mobility thus inhibits labor from moving to
the places where it is most productive. Researchers simulating the effect of AIDS
on growth in Southern African countries find that AIDS has had significant nega-
tive effects on per capita income growth mainly through the decline in human
capital (Haacker, 2002).
While previous studies have emphasized the economic cost of disease asso-
ciated with private and nonprivate medical costs, this doesn’t seem to be the
principal issue in the case of SARS. The number of probable SARS cases is still
small in comparison to other major historical epidemics. Furthermore, unlike
AIDS, the duration of hospitalization of the infected patients is short, with more
than 90 percent of the patients recovering in a relatively short period, thereby
rendering the medical costs comparatively very low. The SARS-related demo-
graphic or human capital consequences are also currently estimated to be insig-
nificant. The fatality rate of the SARS coronavirus is high, but, with current esti-
mates indicating fewer than 800 deaths from SARS worldwide, the death toll is
tiny compared with the 3 million who died of AIDS last year or at least 40 million
people worldwide who died in the Spanish flu epidemic of 1918–1919. There-
fore, forgone incomes associated with morbidity and mortality as a result of SARS
appear to be insignificant. If SARS became endemic in the future, it would sub-
stantially increase private and public expenditures on health care and would have
more significant impacts on demographic structure and human capital in the in-
fected economies. However, based on information to date, this is unlikely to hap-
pen with the SARS epidemic.

Although the medical expenditures and demographic consequences associ-

ated with SARS are insignificant, SARS apparently has already caused substan-
tial economic effects by other important channels. We summarize three mecha-
nisms by which SARS influences the global economy.
First, fear of SARS infection leads to a substantial decline in consumer demand,
especially for travel and retail sales service. The fast speed of contagion makes people
avoid social interactions in affected regions. The adverse demand shock becomes
more substantial in regions that have much larger service-related activities and higher
population densities, such as Hong Kong or Beijing, China. The psychological shock
also ripples around the world, not just to the countries of local transmission of SARS,
because the world is so closely linked by international travel.
Second, the uncertain features of the disease reduce confidence in the future of
the affected economies. This effect seems to be potentially very important, particu-
larly as the shock reverberates through China, which has been a key center of for-
eign investment. The response by the Chinese government to the epidemic was
fragmented and nontransparent. The greater exposure to an unknown disease and
the less effective government responses to the disease outbreaks must have elevated
concerns about China’s institutional quality and future growth potential. Although
it is difficult to measure directly the effects of diseases on decision making by
foreign investors, the loss of foreign investors’ confidence would have potentially
tremendous impacts on foreign investment flows, which would in turn have signifi-
cant impacts on China’s economic growth. This effect is also transmitted to other
countries competing with China for foreign direct investment (FDI).
Third, SARS undoubtedly increases the costs of disease prevention, espe-
cially in the most affected industries such as the travel and retail sales service
industries. This cost may not be substantial, at least in global terms, as long as the
disease is transmitted only by close human contact. However, the global cost
could become enormous if the disease is found to be transmitted by other chan-
nels such as through international cargo.
Simulations Using the G-Cubed (Asia Pacific) Model

Given the important linkages among affected countries in the region through
capital flows and the trade of goods and services, any analysis of the implications
of SARS on the global economy needs to be undertaken with a model that ad-
equately captures these interrelationships. The G-Cubed (Asia Pacific) model,
based on the theoretical structure of the G-Cubed model outlined in McKibbin
and Wilcoxen (1998), is ideal for such analysis, having both a detailed country
coverage of the region and rich links between countries through goods and asset
markets.3 A number of studies—summarized in McKibbin and Vines (2000)—
3Full details of the model, including a list of equations and parameters, can be found online at http:
//www.gcubed.com.

show that the G-Cubed model has been useful in assessing a range of issues
across a number of countries since the mid-1980s.4 A summary of the principal
characteristics of the G-Cubed model is presented as an annex at the end of this
paper.
We make two alternative assumptions in generating a range of possible sce-
narios under this model. In an earlier analysis, we assumed in the first scenario
that the shock lasted for a year. To capture the fact that the shock lasted 6 months,
in reality we now scale down the shocks by 50 percent to capture the shorter
duration. This is called a temporary shock. The second assumption is that the
shocks are the same magnitude in the first year as the temporary shock, but are
more persistent in that they fade out equiproportionately over a 10-year period.
This illustrates the impact of expectations of the future evolution of the disease
on the estimated costs in 2003. It also gives some insight into what might happen
to the region if the SARS virus is considered the beginning of a series of annual
epidemics emerging from China.
Initial Shock to China and Hong Kong

We first calculate the shocks to the economies of mainland China and Hong
Kong (SAR), which were hit most heavily by the disease, and then work out some
indexes summarizing how these shocks are likely to occur in other economies.
There are three main shocks, based on observations of financial market analysts
about the existing data emerging from China and Hong Kong:5
• A 200 basis-point increase in country risk premium.6

• A sector-specific demand shock to the retail sales sector, amounting to a
15 percent drop in demand for the exposed industries in the service sector.
• An increase in costs in the exposed activities in the service sector of 5
percent.
These shocks are then scaled to last only 6 months rather than 1 year.
We could also consider several other shocks, such as the impact on health
expenditures and fiscal deficits. It is not clear how large this shock should be for
the persistent shock, nor even whether the schock should have a positive or nega-
tive sign. Because SARS kills a higher proportion of vulnerable people in a very
short period, it may be that the large expenditure for these people will be reduced
4These issues include Reaganomics in the 1980s, German unification in the early 1990s, fiscal
consolidation in Europe in the mid-1990s, the formation of NAFTA, the Asian crisis, and the produc-
tivity boom in the United States.
5These are also consistent with other papers on particular countries presented at the Asian Eco-
nomic Panel in May 2003.

6In the May version of this paper we assumed a 300 basis-point shock. We follow the updated
research of Australian Treasury (2003) in adjusting this shock to 200 basis points.

as a result of SARS. There might also be a reaction by medical authorities to

substantially increase investments in public health. Given the current state of
information, we would be forced to speculate concerning all of these potential
effects on health expenditures. We therefore explicitly ignore such fiscal impacts
of SARS in this version of the paper.
Shocks to Other Countries

The transmission of SARS, as distinct from the transmission of economic
impacts through global markets, depends on a number of factors. We refer to this
as the global exposure to SARS. The speed of spread is likely to depend on (i)
tourist flows, (ii) geographical distance to China, (iii) health expenditures and
sanitary conditions, (iv) government response, (v) climate, (vi) per capita income,
(vii) population density, and so on. Table 2-1 presents indicators on health expen-
ditures, tourist arrivals, and sanitary conditions for selected countries. There are
more than 33 million annual visitors to mainland China. Hong Kong (SAR) has
annual tourist arrivals that are more than 200 percent of the local population.
Overall health expenditure as a ratio to GDP is not small in Asian countries, but
health expenditure per capita is only $45 in China.
With more data we could do some econometric estimation to capture these
influences. Lacking that data, for the purposes of this paper we construct a rough
TABLE 2-1 Health Expenditures, Tourist Arrivals, and Sanitation Indicators

for Selected Countries
Improved
Health Health Tourist Sanitation
Expenditure, Expenditure Tourist Arrivals Facilities
Total per Capita Arrivals Arrivals/ (% of
(% of GDP) (current US$) (million) Population (%) population
China 5.3 45 33.2 3 29
Hong Kong 4.4 950 13.7 203 100
India 4.9 23 2.5 0 16
Indonesia 2.7 19 5.2 2 47
North Korea 2.1 18 n.a. n.a. 99
South Korea 6.0 584 5.1 14 63
Malaysia 2.5 101 12.8 53 n.a.
Philippines 3.4 33 1.8 4 74
Singapore 3.5 814 6.7 163 100
Thailand 3.7 71 10.1 16 79
Vietnam 5.2 21 1.4 2 29
United States 13.0 4,499 n.a. n.a. 100
Japan n.a. n.a. 4.8 4 n.a.
High-income OECD 10.2 2,771 377.6 n.a. n.a.
World 9.3 482 696.5 n.a. 55
SOURCE: CEIC, World Development Indicators. Recited from Hanna and Huang (2003).

measure of the intensity of exposures to SARS, based on the above information

and the cumulative number of cases of SARS for each country. This index of
“global exposure to SARS” is contained in Figure 2-1. This will be used to scale
down the country risk shocks calculated for all other countries. For example, if a
country has an index of 0.5, the country risk premium shock will be the Chinese
shock of 2 percent adjusted by the “global exposure to SARS” index, which gives
a shock of 1 percent.
For the shocks to the service industries, before applying the global exposure
index to each country, we need to adjust the sector-specific shocks. Because we
only have an aggregate service sector in the model, we need to take account for
structural differences within the service sectors of each country. We do this by
creating an “index of sectoral exposure to SARS.” This index is assumed to be
proportional to the share of industries affected by SARS within the service sector.
Industries such as tourism, retail trade, and airline travel have been impacted
severely. We use the GTAP5 database to calculate the share of exposed sectors to
total services for each country.7 We define the exposed sectors based on GTAP
definitions as wholesale and retail trade (TRD, including hotels and restaurants),
land transport (OTP), and air transport (ATP). The “index of sectoral exposure to
SARS” is shown in Figure 2-2. This index is applied to the sector-specific shocks
we developed for the Chinese economy. We then apply the “global exposure to
SARS” to the resulting shocks.
The direct impact on any economy will be a function of a number of factors.
An important aspect of the impact will be the size of the service sector in the
economy as well as the relative indexes of exposure. Figure 2-3 shows the size of
the service sector relative to total output in each economy in the model.
Simulation Results
We apply the shocks outlined in the previous section to the global economy.
We begin the simulation in 2003, assuming in 2003 that the SARS outbreak was
completely unanticipated. Both the temporary and persistent shocks are assumed to
be understood by the forward-looking agents in the model. Clearly this is problem-
atic when it comes to a new disease like SARS, when there is likely to be a period
of learning about the nature of the shock. In this case, rational expectations might
not be a good way to model expectations. Yet an alternative approach is not clear.
In our defense, it is worth pointing out that only 30 percent of agents have rational
expectations and 70 percent of agents are using a rule of thumb in adjusting to
contemporaneous information about the economy. Table 2-2 contains results for
the percentage change in GDP in 2003 as a result of the temporary and permanent
7For more information on this database, see the website of the Global Trade Analysis Project at
http://www.gtap.agecon.purdue.edu/.

Index
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FIGURE 2-2 Sectoral exposure to SARS: share of retail sale and travel industry in ser-
vice sector.
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FIGURE 2-3 Share of service sector in total output.
SARS shocks as well as the contribution of each component (i.e., demand decline
for services, cost increase for services, and country risk premium).
The full dynamics of adjustment will be outlined shortly. Focusing on the
GDP results, it is clear that there are interesting differences among the various
components of the overall shock as well as between the temporary and permanent
shocks. The temporary shock has its largest impact on China and Hong Kong

102
TABLE 2–2 Percentage Change in GDP in 2003 Due to SARS

Temporary Shock Persistent Shock over 10 years
Total Effects Demand Shift Cost Rise Country Risk Total Effects Demand Shift Cost Rise Country Risk
United States –0.07 –0.01 –0.06 0.00 –0.07 –0.01 –0.06 0.00
Japan –0.07 –0.01 –0.06 0.00 –0.06 –0.01 –0.06 0.01
Australia –0.07 0.00 –0.06 0.00 –0.06 0.00 –0.06 0.01
New Zealand –0.08 0.01 –0.08 0.00 –0.08 0.00 –0.08 0.00
Indonesia –0.08 0.01 –0.09 0.00 –0.07 0.01 –0.08 0.00
Malaysia –0.15 0.01 –0.16 0.00 –0.17 0.01 –0.15 –0.02
Philippines –0.10 0.04 –0.14 0.00 –0.11 0.03 –0.13 –0.02
Singapore –0.47 –0.02 –0.45 0.00 –0.51 –0.01 –0.44 –0.05
Thailand –0.15 0.00 –0.15 0.00 –0.15 0.00 –0.15 0.00
China –1.05 –0.37 –0.34 –0.33 –2.34 –0.53 –0.33 –1.48
India –0.04 0.00 –0.04 0.00 –0.04 0.00 –0.04 0.00
Taiwan –0.49 –0.07 –0.41 –0.01 –0.53 –0.07 –0.39 –0.07
Korea –0.10 –0.02 –0.08 0.00 –0.08 –0.01 –0.08 0.00
Hong Kong –2.63 –0.06 –2.37 –0.20 –3.21 –0.12 –2.37 –0.71
ROECD –0.05 0.00 –0.05 0.00 –0.05 0.00 –0.05 0.00
Non-oil developing countries –0.05 –0.01 –0.04 0.00 –0.05 0.00 –0.04 0.00
Eastern Europe and Russia –0.06 –0.01 –0.05 0.00 –0.05 –0.01 –0.05 0.00
OPEC –0.07 –0.01 –0.05 0.00 –0.09 –0.01 –0.06 –0.02

SOURCE: G–Cubed (Asia Pacific) Model version 50n.
(SAR), as expected. The loss to Hong Kong of 2.63 percent of GDP, however, is
much larger than that of 1.05 percent for the remainder of mainland China. This
primarily reflects the larger role of the service sector in Hong Kong, the larger
share of impacted industries within the service sector in Hong Kong, and the
greater reliance on trade within the Hong Kong region. Taiwan is the next most
affected area, losing 0.49 percent of GDP in 2003, followed closely by Singapore,
with a loss of 0.47 percent of GDP.
For Hong Kong, the increase in costs in the service sector is by far the largest
contributing factor to the loss of GDP. In the rest of mainland China it is evenly
spread across the three factors. The temporary increase in the country risk pre-
mium of 200 basis points is estimated to lower GDP by 0.33 percent for China
and by 0.20 percent for Hong Kong. Interestingly, the risk premium shock has
very negligible impacts, of less than 0.01 percent of GDP, on Taiwan and
Singapore, which adopt floating exchange rate regimes, although they are also
subject to a substantial rise in the country risk premium by 150 and 100 basis
points, respectively. The difference comes from the fact that exchange rate depre-
ciation helps Taiwan and Singapore to avoid a rise in real interest rate and subse-
quent output decline.
The calculations when expressed as a percent of each country’s GDP may
appear to be small. However, when translated into an absolute dollar amount,
these figures imply that the global economic loss from SARS was close to $US
40 billion in 2003. This is a figure much greater than any calculation of the medi-
cal costs of treating SARS patients.
The persistent SARS shock is also much more serious for China and Hong
Kong. The primary impact is from the persistence in the rise of the country risk
premium. Although the same in 2003 as for the temporary shock, the persistence
of the country risk premium causes much larger capital outflow from China and
Hong Kong. This impacts on short-run aggregate demand through a sharp con-
traction in investment, as well as a persistent loss in production capacity through
a resulting decline in the growth of the capital stock, which reduces the desirabil-
ity of investment. The extent of capital outflow will be discussed below.
Interestingly, the difference in GDP loss in 2003 when SARS is expected
to be more persistent distinguishes between two regions. China, Hong Kong
(SAR), Malaysia, the Philippines, Singapore, and Taiwan experience a larger
loss in 2003, whereas the OECD economies and others experience a lower GDP
loss. This reflects the greater capital outflow from the most affected countries
into the least affected countries, which tends to lower the GDP of those coun-
tries losing capital and raise the GDP of those countries receiving capital. The
countries in the first group that are less affected by SARS are nonetheless worse
off with a more persistent disease because of their trade links with China, Hong
Kong, and Singapore. The expectation of a more persistent problem with SARS
leads to a total GDP loss of roughly $US 54 billion in 2003 alone (this ignores
any future years’ losses).

The results for GDP illustrate how the costs of SARS can be very different in
2003, depending on expectations of how the disease will unfold. It is also inter-
esting to examine the change in economic impacts over time.
We present two sets of figures containing six charts within each figure. These
results are all expressed as deviation from the underlying baseline of the model
projections (which is described in more detail in the annex at the end of this
paper). They show how key variables change relative to what would have been
the case without SARS. Figures 2-4 and 2-5 describe simulation outcomes for the
temporary SARS shock in the three panels on the left and simulation outcomes
for the more persistent SARS shock in the three panels on the right. This enables
a comparison between the two for the impacts on the real economy and trade
flows.
Figure 2-4 contains results for real GDP, investment, and exports for both the
temporary and persistent SARS shock. The loss in GDP from the temporary shock
is largely confined to 2003. The persistent shock not only has a larger impact on
GDP in 2003—because of expectations about future developments—but has a
persistent impact on real GDP for a number of years afterward. Investment falls
more sharply in 2003, which is the source of the larger GDP loss.
The results for exports are also interesting. In the case of the temporary shock,
exports from Hong Kong fall sharply. Yet, in the more persistent case, exports
from Hong Kong rise in 2003. The reason for this difference is that the more
persistent the shock, the larger the capital outflow from affected economies. A
capital outflow will be reflected in a current account surplus and a trade balance
surplus. For this to occur, either exports must rise or imports must fall or both.
This can be seen clearly in Figure 2-5.
In the case of the temporary SARS shock, the net capital outflow from China
and Hong Kong (relative to base) is around 0.3 percent of GDP. However, when
the shock is more persistent, this capital outflow rises sharply (top right panel of
Figure 2-5), to 1.4 percent of GDP for Hong Kong and 0.8 percent of GDP for
China. This capital outflow is reflected in the trade balance surplus in both. This
shift in the trade balance is achieved by the capital outflow depreciating the real
exchange rate of both China and Hong Kong substantially.
All of these linkages have many dimensions, but a global model is able to
help untangle some of the more important factors. Under this model, the SARS
outbreak is predicted to have widespread economic impacts beyond the regions
immediately infected with the disease and beyond the decline in the most affected
service industries.
Conclusion
The impact of SARS is estimated to be large on the affected economies of
China and Hong Kong (SAR). This impact is due not to the consequence of the
disease itself for the affected people, but to the impact of the disease on the be-

Real GDP - Temporary SARS Real GDP - Persistent SARS

(% deviation) (% deviation)
1 1
0 0
-1 -1
-2 -2
-3 -3
-4 -4
2002 2005 2008 2011 2014 2017 2020 2002 2005 2008 2011 2014 2017 2020
Hong Kong China Hong Kong China

Japan Singapore Japan Singapore
Investment - Temporary SARS Investment - Persistent SARS

(%GDP deviation) (%GDP deviation)
1 1
0.5 0.5
0 0
-0.5 -0.5
-1 -1
-1.5 -1.5
-2 -2
2002 2005 2008 2011 2014 2017 2020 2002 2005 2008 2011 2014 2017 2020

Exports - Temporary SARS Exports - Persistent SARS

(% GDP deviation) (% GDP deviation)
0.6 0.6
0.4 0.4
0.2
0.2
0
0
-0.2
-0.2
-0.4
-0.4 2002 2005 2008 2011 2014 2017 2020
2002 2005 2008 2011 2014 2017 2020
Hong Kong China
Hong Kong China Japan Singapore Japan Singapore
FIGURE 2-4 Real impacts of temporary versus persistent SARS shock.

Net Capital Outflow-Temporary Net Capital Outflow-Persistent SARS

SARS (%GDP deviation) (%GDP deviation)
1.5 1.5
1 1
0.5 0.5
0 0
-0.5 -0.5
2002 2005 2008 2011 2014 2017 2020 2002 2005 2008 2011 2014 2017 2020

Trade Balance - Temporary SARS Trade Balance - Persistent SARS

(% GDP deviation) (% GDP deviation)
1.4 1.4
0.9 0.9
0.4 0.4
-0.1 -0.1
-0.6 -0.6
2002 2005 2008 2011 2014 2017 2020 2002 2005 2008 2011 2014 2017 2020

Real Effective Exchange Rates - Real Effective Exchange Rates -

Temporary SARS Persistent SARS
(% deviation) (% deviation)
1.5 1.5
0.5 0.5
-0.5 -0.5
-1.5 -1.5
-2.5 -2.5
-3.5 -3.5
2002 2005 2008 2011 2014 2017 2020 2002 2005 2008 2011 2014 2017 2020

FIGURE 2-5 Trade and captial flow impacts of temporary versus persistent SARS shock.

havior of many people within these economies. It also depends on the disease-
associated adjustment of expectations reflected in integrated real and financial
markets. The more persistent SARS is expected to be, the larger the negative
economic impacts in 2003 in affected economies, but the smaller the impact in
countries outside the core countries. The calculations above suggest that the cost
in 2003 of SARS for the world economy as a whole are close to $US 40 billion in
the case where SARS is expected to be a single event, versus costs of close to
$US 54 billion in 2003 if SARS is expected to recur (this does not include the
actual costs of later years if in fact SARS did recur). The higher costs from a
persistent shock relate to the loss of investment and the impact on confidence and
therefore spending in 2003.
These results illustrate that the true cost of disease is far greater than the cost
to a health budget of treatment of the cases involved. The more persistent shock
in this paper can be thought of as SARS lasting longer than anyone hopes, but it
can also be interpreted as a recurring series of annual epidemics emerging from
China and infecting the world through increased globalization. This is not a new
phenomenon, since influenza viruses have been emanating from China since at
least the 1918–1919 Spanish flu. Fortunately, most have been less devastating
than the well-known major outbreaks. A key point of this paper is an attempt to
evaluate the true underlying global cost of these diseases. If the threat of recur-
ring SARS or SARS-like diseases from China is real, then the estimated risk to
economic activity in this region and the world, as calculated in this paper, might
be very large. The estimates in this paper suggest that there is a strong economic
case for direct intervention in improving public health in China and other devel-
oping countries where there are inadequate expenditures on public health and
insufficient investments in research into disease prevention.
As we observed from the Asian financial flu in 1997 and SARS in 2003,
there is an important role for global monitoring and coordination mechanisms in
containing both economic and microbial epidemics.
Annex 2-1—Characteristics of the G-Cubed (Asia Pacific) Model

Some of the principal features of the G-Cubed (Asia Pacific) model are as
follows:
• The model is based on explicit intertemporal optimization by the agents

(consumers and firms) in each economy.8 In contrast to static computable gen-
eral equilibrium (CGE) models, time and dynamics are of fundamental impor-
tance in the G-Cubed model.
• In order to track the macro time series, however, the behavior of agents is
modified to allow for short-run deviations from optimal behavior either due to
8See Blanchard and Fischer (1989) and Obstfeld and Rogoff (1996).

myopia or to restrictions on the ability of households and firms to borrow at the

risk-free bond rate on government debt. For both households and firms, devia-
tions from intertemporal optimizing behavior take the form of rules of thumb,
which are consistent with an optimizing agent that does not update predictions
based on new information about future events. These rules of thumb are chosen to
generate the same steady-state behavior as optimizing agents, so that in the long
run there is only a single intertemporal optimizing equilibrium of the model. In
the short run, actual behavior is assumed to be a weighted average of the optimiz-
ing and the rule-of-thumb assumptions. Thus aggregate consumption is a weighted
average of consumption based on wealth (current asset valuation and expected
future after-tax labor income) and consumption based on current disposable in-
come. Similarly, aggregate investment is a weighted average of investment based
on Tobin’s q (a market valuation of the expected future change in the marginal
product of capital relative to the cost) and investment based on a backward-look-
ing version of Q.
• There is an explicit treatment of the holding of financial assets, including

money. Money is introduced into the model through a restriction that households
require money to purchase goods.
• The model also allows for short-run nominal wage rigidity (by different
degrees in different countries) and therefore allows for significant periods of
unemployment depending on the labor market institutions in each country. This
assumption, when taken together with the explicit role for money, is what gives
the model its “macroeconomic” characteristics. (Here again, the model’s as-
sumptions differ from the standard market-clearing assumption in most CGE
models.)
• The model distinguishes between the stickiness of physical capital within
sectors and within countries and the flexibility of financial capital, which imme-
diately flows to where expected returns are highest. This important distinction
leads to a critical difference between the quantity of physical capital that is avail-
able at any time to produce goods and services, and the valuation of that capital
as a result of decisions about the allocation of financial capital.
As a result of this structure, the G-Cubed model contains rich dynamic be-
havior, driven on the one hand by asset accumulation, and on the other by wage
adjustment to a neoclassical steady state. It embodies a wide range of assump-
tions about individual behavior and empirical regularities in a general equilib-
rium framework. The interdependencies are solved out using a computer algo-
rithm that solves for the rational expectations equilibrium of the global economy.
It is important to stress that the term “general equilibrium” is used to signify that
as many interactions as possible are captured, not that all economies are in a full
market-clearing equilibrium at each point in time. Although it is assumed that
market forces eventually drive the world economy to a neoclassical steady state

growth equilibrium, unemployment does emerge for long periods due to wage
stickiness, to an extent that differs between countries on account of differences in
labor market institutions.
Baseline Business-as-Usual Projections for G-Cubed Model Simulations

To solve the model, we first normalize all quantity variables by each
economy’s endowment of effective labor units. This means that in the steady
state, all real variables are constant in these units, although the actual levels of the
variables will be growing at the underlying rate of growth of population plus
productivity. Next, we must make base-case assumptions about the future path of
the model’s exogenous variables in each region. In all regions we assume that the
long-run real interest rate is 5 percent, tax rates are held at their 1999 levels, and
fiscal spending is allocated according to 1999 shares. Population growth rates
vary across regions as per the 2000 World Bank population projections.
A crucial group of exogenous variables are productivity growth rates by sec-
tor and country. The baseline assumption in G-Cubed (Asia Pacific) is that the
pattern of technical change at the sector level is similar to the historical record for
the United States (where data are available). In regions other than the United
States, however, the sector-level rates of technical change are scaled up or down
in order to match the region’s observed average rate of aggregate productivity
growth over the past 5 years. This approach attempts to capture the fact that the
rate of technical change varies considerably across industries while reconciling it
with regional differences in overall growth. This is clearly a rough approxima-
tion; if appropriate data were available, it would be better to estimate productivity
growth for each sector in each region.
Given these assumptions, we solve for the model’s perfect-foresight equi-
librium growth path over the period 2002–2081. This a formidable task: the
endogenous variables in each of the 80 periods number over 7,000 and in-
clude, among other things: the equilibrium prices and quantities of each good
in each region, intermediate demands for each commodity by each industry in
each region, asset prices by region and sector, regional interest rates, bilateral
exchange rates, incomes, investment rates and capital stocks by industry and
region, international flows of goods and assets, labor demanded in each indus-
try in each region, wage rates, current and capital account balances, final de-
mands by consumers in all regions, and government deficits.9 At the solution,
the budget constraints for all agents are satisfied, including both intra-tempo-
ral and intertemporal constraints.
9Because the model is solved for a perfect-foresight equilibrium over an 80-year period, the nu-
merical complexity of the problem is on the order of 80 times what the single-period set of variables
would suggest. We use software summarized in McKibbin and Sachs (1991), Appendix C, for solving
large models with rational expectations on a personal computer.

SARS: POLITICAL PATHOLOGY OF THE FIRST POST-

WESTPHALIAN PATHOGEN10
David P. Fidler
Professor of Law and Ira C. Batman Faculty Fellow
Indiana University School of Law—Bloomington
The World Health Organization (WHO) has asserted that severe acute respi-
ratory syndrome (SARS) was “the first severe infectious disease to emerge in the
twenty-first century” and posed “a serious threat to global health security, the
livelihood of populations, the functioning of health systems, and the stability and
growth of economies” (WHO, 2003a). This paper argues that SARS was also the
first post-Westphalian pathogen, and it constructs a political pathology of the
outbreak to advance this claim.
In some respects, the SARS outbreak was nothing new. The great cliché of
international infectious disease control—germs do not recognize borders—ap-
plies to SARS as it applied to earlier outbreaks. SARS joins a long list of infec-
tious diseases that have not recognized borders. For my purposes, what makes
SARS interesting is not its germ (SCoV); rather, SARS is important because of
the political context in which the germ did not recognize borders. Put another
way, I am interested in the borders SARS did not recognize. SARS is the first
post-Westphalian pathogen because its nonrecognition of borders transpired in a
public health governance environment radically different from what previous
border-hopping bugs encountered.
Westphalian and Post-Westphalian Public Health
Of Germs and Borders

Principles for public health governance between countries traditionally de-
rived from the structure for international relations known as the “Westphalian
system”: a system composed of principles guided by national sovereignty and
nonintervention (Harding and Lim, 1999). “Westphalian public health” refers to
public health governance structured by Westphalian principles. “Post-
Westphalian public health” describes public health governance that departs from
the Westphalian template and responds to increasing forces of globalization that
include the interests of both multinational corporations and multilateral organiza-
tions. SARS is the first post-Westphalian pathogen because it highlights public
health’s transition from a Westphalian to a post-Westphalian governance context.
10This document summarizes Fidler DP. 2003. SARS: Political pathology of the first post-
Westphalian pathogen, Journal of Law, Medicine & Ethics. This article served as the basis for Fidler
DP. 2004. SARS, Governance, and the Globalization of Disease, London: Palgrave Macmillan.

The concepts that characterize post-Westphalian public health began to ap-

pear before SARS, but SARS still represents the first post-Westphalian pathogen
for two reasons. First, the SARS outbreak was the first epidemic since HIV/AIDS
to pose a truly global threat. Other new and not previously recognized microbes
that emerged in the past 20 years had more limited capacity to threaten interna-
tional public health because of inefficient human-to-human transmission or de-
pendence on food or insects as vectors or on specific geographical conditions
(WHO, 2003b). SARS posed a greater threat because of its more efficient person-
to-person transmission and its fatality rate—comparable to some of history’s
greatest infectious disease foes, smallpox and influenza.
Second, because of the nature of the SARS threat, the epidemic seriously
challenged the emerging post-Westphalian governance system. SARS was a glo-
bal public health emergency (WHO, 2003c), and the sternest measure of gover-
nance systems is their performance in times of crisis. The SARS outbreak pro-
vided the first opportunity to evaluate how the new governance approach for
infectious diseases would fare under serious microbial attack on a global basis.
Westphalian Public Health

The Westphalian system is a system dominated by states (Scholte, 2001).
The key principle of the Westphalian structure is sovereignty (Brownlie, 1998;
Scholte, 2001). The sovereignty principle spins off corollary principles: (i) the
principle of nonintervention (Jackson, 2001); and (ii) rules governing interac-
tions among states arose from the states themselves and were not binding unless
states consented to be bound (i.e., international law) (Brownlie, 1998; The SS
Lotus, 1927). The combination of sovereignty, nonintervention, and consent-
based international law meant that Westphalian governance was horizontal in
nature, so that governance (i) involved only states; (ii) primarily addressed the
mechanics of state interaction; and (iii) did not penetrate sovereignty to address
how a government treated its people or ruled over its territory. The Westphalian
system exhibited another characteristic—the great powers dominated Westphalian
politics (Bull, 1977).
Infectious disease control became a diplomatic issue in the mid-19th century
(Fidler, 1999). The regime that developed for international infectious disease con-
trol bore the imprint of all the characteristics of the Westphalian system. The
International Health Regulations (IHR) (WHO, 1983), promulgated by WHO,
illustrate the essence of Westphalian public health. The regulations are the only
set of international legal rules binding on WHO members concerning infectious
diseases (WHO, 2002), and they are are classically Westphalian in structure and
content.
The IHR’s objective is to ensure maximum security against the international
spread of disease with minimal interference with world traffic (WHO, 1983). The
regulations seek to achieve maximum security against the international spread of

disease by requiring governments to (i) notify WHO of outbreaks of diseases

subject to the Regulations; and (ii) maintain certain public health capabilities at
ports and airports (WHO, 1983). The regulations seek to achieve minimum inter-
ference with world traffic by regulating the trade and travel restrictions WHO
members can impose against countries suffering outbreaks of diseases subject to
the Regulations (WHO, 1983).
In keeping with Westphalian principles, the regulations are consent-based
rules of international law binding on states. The IHR’s disease notification rules
mandate that only information from governments can be used in surveillance
(WHO, 1983). The regulations respect the principle of nonintervention by ad-
dressing only aspects of infectious diseases that relate to the intercourse among
states. They do not address aspects of public health that touch on how a govern-
ment prevents and controls infectious diseases within its sovereign territory. The
IHR’s limited governance scope is also clear from the small number of diseases
subject to IHR rules—currently only cholera, plague, and yellow fever (WHO,
1983).
As a regime on international infectious disease control, the IHR proved to be
a failure. WHO members routinely violated the IHR (e.g., not reporting disease
outbreaks and applying excessive trade- and travel-restricting measures to other
countries suffering disease outbreaks) (Fidler, 1999), and the IHR was irrelevant
as a matter of international law to the emergence of the worst infectious disease
epidemic in the 20th century, HIV/AIDS, because HIV/AIDS was not a disease
subject to the IHR (Fidler, 1999).
The IHR’s failure combined with other developments in international health
policy to suggest that Westphalian public health governance was fundamentally
bankrupt. After its creation, WHO began to concentrate less on horizontal public
health strategies (such as those in the IHR) in order to focus more on vertical
public health strategies that addressed infectious diseases at their sources inside
states (e.g., disease eradication campaigns) (Arhin-Tenkorang and Conceico,
2003). Another way to sense this change in policy is to compare the IHR’s hori-
zontal approach and WHO’s Health for All strategy announced at the end of the
1970s, which stressed universal access to primary health care (WHO, 1978). Or,
compare the IHR’s state-centric focus and lack of rules regulating domestic pub-
lic health systems with the emphasis on the right to health proclaimed in the
WHO Constitution (WHO, 1994) and implemented through the Health for All
strategy.
Post-Westphalian Public Health

The considerable challenges presented by emerging and re-emerging infec-
tious diseases in the 1990s and early 2000s stimulated thinking on strategies dif-
ferent from the IHR’s Westphalian approach. Two key post-Westphalian con-
cepts were “global health governance” (a new kind of political process) (Dodgson

et al., 2002) and “global public goods for health” (a new kind of substantive
policy goal) (Smith et al., 2003). Global health governance (GHG) includes
nonstate actors in the governance process. One of the best examples can be found
in the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund, 2003).
Its board of directors includes nongovernmental organization representatives as
voting members.
Global public goods for health (GPGH) are goods or services, the consump-
tion of which is nonexcludable and nonrival across national boundaries and in-
volving countries and peoples that are in different regional groupings (e.g., North
America and sub-Saharan Africa) (Smith et al., 2003). Under the GPGH concept,
public health governance should not serve the interests of the great powers, but
should produce globally accessible health goods and services. The explosion of
so-called public–private partnerships in global public health provide the best il-
lustration of attempts to produce GPGH (e.g., ventures to develop new antimi-
crobial drugs for malaria and tuberculosis) (Reich, 2002).
The post-Westphalian strategies of GHG and GPGH can be seen in WHO’s
attempts to revise the IHR in the latter half of the 1990s and early 2000s. WHO
proposed changes to the IHR that would create GHG and produce GPGH and that
were, from the perspective of the Westphalian approach, radical. Two critical
proposed changes sought to improve global infectious disease surveillance: (i)
moving away from disease-specific reporting to notifications of “public health
emergencies of international concern”; and (ii) allowing WHO to incorporate
nongovernmental sources of information into its surveillance activities (WHO,
2002). Revising the IHR in these ways would: (i) produce GHG by including
nonstate actors in the process of global infectious disease surveillance; and (ii)
produce the GPGH of better infectious disease surveillance information for use
by states and nonstate actors.
The development of GHG and GPGH strategies indicate that post-
Westphalian public health governance had started to form in the late 1990s and
early 2000s, before SARS emerged. But, prior to SARS, the post-Westphalian
strategies, particularly in the context of the Global Fund and HIV/AIDS, were
showing signs of severe stress, generating skepticism about the new governance
approaches. The IHR revision process was not progressing well and was obscure
and ignored in much of the ferment happening in global public health circles in
the latter half of the 1990s and early 2000s (Fidler, 2003). If post-Westphalian
public health could not handle the strain that existing diseases created, what would
happen when the next infectious disease crisis broke in the world?
China, SARS, and Post-Westphalian Public Health

SARS proved to be the next crisis. Instead of failure, the global campaign
against SARS achieved a victory that will go down in the annals of public health
and international relations history. In SARS, the world confronted a virus never

before found in humans that was transmitted from person to person, that had a
relatively high fatality rate, and against which public health practitioners had
neither adequate diagnostic technologies nor effective treatments or vaccines.
The last time the world confronted a virus with this disturbing profile was when
HIV emerged in the early 1980s, and HIV triggered one of the worst disease
epidemics in human history that is still raging globally. SARS was a crisis of the
first order for global public health. Yet, unlike with HIV/AIDS, victory was
achieved. How?
China Confronts Public Health’s “New World Order”

We answer this question by focusing on what happened with China’s
response to the SARS outbreak. China was the epicenter of the SARS out-
break; thus, it was the governance epicenter. What happened to China during
its response to SARS illustrated the power of the GHG and GPGH strategies
of post-Westphalian public health. China’s initial responses to SARS followed
the Westphalian template because China was under no international legal ob-
ligation to report SARS cases to any state or international organization, nor
did it have an express duty to cooperate with WHO on the outbreak. China
made the mistake, however, of acting Westphalian in a post-Westphalian
world. In its confrontation with public health’s “new world order,” China
miscalculated and lost.
GHG mechanisms—especially WHO’s access to nongovernmental sources
of information for surveillance purposes—trumped Chinese attempts to exercise
its sovereignty through control of epidemiological information about SARS.
China’s initial handling of SARS demonstrated that it had not grasped the new
context for public health governance—epidemiological information about dis-
ease does not recognize borders. At the outset of the SARS epidemic, China
played the sovereignty card, only to retreat when its sovereignty was seen as a
deliberate attempt to hide an outbreak—one that was already indicating serious
consequences for the rest of the world.
The need for producing GPGH for the SARS battle—especially accurate sur-
veillance data on the outbreak in China—swept aside China’s narrow construc-
tion of its national interest vis-à-vis the outbreak. China behaved as if its national
interest in preserving flows of trade and investment into China and the image of
the Communist Party could simply ignore the legitimate concerns of other states
and nonstate actors, such as multinational corporations. China’s conception of its
national interest broke apart in the post-Westphalian public health atmosphere of
SARS.
In the SARS outbreak, the world did not witness China enjoying the
Westphalian privileges normally accorded powerful countries, but rather saw
post-Westphalian public health governance humble a rising great power in the
international system for disease control.

Beyond China: SARS and Post-Westphalian Public Health

The SARS outbreak contains other interesting features that support the emer-
gence of post-Westphalian public health governance. The most amazing involved
WHO’s issuance of geographically specific travel advisories that recommended
that people not travel to locations experiencing local chains of SARS transmis-
sion (e.g., Guangdong Province, Beijing, Toronto). These travel advisories were
revolutionary developments in international policy on infectious diseases because,
in issuing the alerts, WHO exercised independent power over its member states
without express authority in international law to do so. The approval by WHO
member states at the May 2003 World Health Assembly meeting of these radical
acts (WHO, 2003a,d) confirms the existence of an entirely new governance con-
text for infectious disease control.
Other aspects of the outbreak’s handling also illustrated the power and prom-
ise of GPGH, including the unprecedented nature of the global collaborative ef-
forts to create, analyze, and disseminate information on (1) the SARS virus; (2)
clinical management of SARS cases; and (3) public health strategies for breaking
the chain of transmission. The SARS outbreak was also post-Westphalian in how
it elevated public health as a matter of national political priority in many coun-
tries (National Intelligence Council, 2003) and reinforced the linkage between
infectious disease control and international human rights through the widespread
use of quarantine and isolation (McNeil, 2003).
SARS and the Vulnerabilities of Post-Westphalian Public Health

The political pathology of SARS also reveals vulnerabilities that post-
Westphalian public health governance faces in light of the SARS outbreak. SARS
was a victory for post-Westphalian public health, but serious problems continue
to exist, including the presence of public health infrastructures in China and many
other countries that remain inadequately prepared for severe infectious disease
threats. Repeated warnings that SARS may return in the winter months of 2003–
2004 stress the necessity of sustaining the kind of national and international com-
mitment witnessed during the SARS outbreak, but whether sufficient political,
financial, and public health commitment will be forthcoming remains unclear.
Conclusion
The political pathology of SARS constructed in the paper suggests that gov-
ernance innovations used to move public health into a post-Westphalian context
contributed to the successful global response to a severe infectious disease threat.
The global containment of SARS represents a historic triumph that will enter the
annals of history as one of the most significant achievements in global infectious
disease control since the eradication of smallpox.

Commenting on SARS, WHO’s executive director for communicable dis-

eases, Dr. David Heymann, argued that “[i]n the 21st century there is a new way
of working”(Heymann, 2003). Against the global health emergency of SARS, the
“new way of working” proved effective, which constitutes a victory for the emerg-
ing framework of post-Westphalian public health.
Although victory should be savored, everyone should remember that germs
do not recognize victories or defeats. The challenge for post-Westphalian public
health is to create the conditions necessary for the governance innovations suc-
cessfully deployed in the SARS outbreak to be refined, improved, expanded, and
sustained to meet the ongoing threat that pathogenic microbes present. The germs
will keep coming. The great task for the global community that answered the
initial challenge from SARS is to ensure that the “new way of working” continues
to work far into the 21st century.
THE SARS EPIDEMIC AND ITS AFTERMATH IN CHINA:

A POLITICAL PERSPECTIVE
Yanzhong Huang*
John C. Whitehead School of Diplomacy and International Relations,
Seton Hall University
In November 2002, a form of atypical pneumonia called severe acute respi-

ratory syndrome (SARS) began spreading rapidly around the world, prompting
the World Health Organization (WHO) to declare the ailment “a worldwide health
threat.” At the epicenter of the outbreak was China, where the outbreak of SARS
infected more than 5,300 people and killed 349 nationwide (Ministry of Health,
2003). History is full of ironies: the epidemic caught China, at first, unprepared to
defeat the disease 45 years after Mao Zedong bade “Farewell to the God of
Plagues.”
The SARS epidemic was not simply a public health problem. Indeed, it
caused the most severe socio-political crisis for the Chinese leadership since the
1989 Tiananmen crackdown. Outbreak of the disease fueled fears among econo-
mists that China’s economy was headed for a serious downturn. A fatal period of
hesitation regarding information-sharing and action spawned anxiety, panic, and
rumor-mongering across the country and undermined the government’s efforts to
create a milder image of itself in the international arena. As Premier Wen Jiabao
pointed out in a cabinet meeting on the epidemic, “the health and security of the
people, overall state of reform, development, and stability, and China’s national
*This paper is adapted from The Politics of China’s SARS Crisis. Harvard Asia Quarterly (Au-
tumn 2003). An earlier version of the article appeared in “Dangerous Secrets: SARS and China’s
Healthcare System,” Roundtable before the Congressional-Executive Commission on China, May 12,
2003, www.cecc.gov.

interest and international image are at stake (Zhongguo xinwen wang, 2003a).” In
the weeks that followed, the Chinese government launched a crusade against
SARS, effectively bringing the disease under control in late June and eliminating
all known cases by mid-August.
While clearly a test for the public health infrastructure of China, the course
of the epidemic also raised crucial questions about the capacity and dynamics of
the Chinese political structure and its ability to address future outbreaks. What
accounted for the initial government decisions to withhold information from the
public and take little action against the disease, and then the subsequent dramatic
shift in government policy toward SARS? Why was the government able to con-
tain the spread of SARS in a relatively short period? What lessons has the govern-
ment drawn from the crisis? A political analysis of the crisis not only demon-
strates crucial linkages between China’s political system and its pattern of crisis
management but also sheds light on the government’s ability to handle the next
disease outbreak. While problems in the formal institutional structure and bu-
reaucratic capacity accounted for the initial official denial and inaction, the insti-
tutional forces unleashed from the terrain of state-society relations led to dra-
matic changes in the form and content of government policy toward SARS.
Through mass mobilization, the government successfully brought the disease
under control. While these developments are encouraging, China’s capacity to
effectively prevent and contain future infectious disease outbreaks remains un-
certain. Prevention and control programs are still troubled by problems in agenda-
setting, policy making, and implementation which, in turn, can be attributed to its
political system. A healthier China therefore demands some fundamental changes
in the political system.
The Making of a Crisis

With hindsight, China’s health system seemed initially to respond relatively
well to the emergence of the illness. The earliest case of SARS is thought to have
occurred in Foshan, a city southwest of Guangzhou in Guangdong province, in
mid-November 2002. It was later also found in Heyuan and Zhongshan in
Guangdong. This “strange disease” alerted Chinese health personnel as early as
mid-December. On January 2, a team of health experts was sent to Heyuan and
diagnosed the disease as an infection caused by a certain virus (Hai and Hua,
2003). A Chinese physician, who was in charge of treating a patient from Heyuan
in a hospital in Guangzhou, quickly reported the disease to a local anti-epidemic
station (Renmin ribao, 2003a). We have reason to believe that the local anti-
epidemic station alerted the provincial health bureau about the disease, with the
bureau in turn reporting to the provincial government and the Ministry of Health
shortly afterwards, since the first team of experts sent by the Ministry arrived at
Guangzhou on January 20, and the new provincial government (who took over on
January 20) ordered an investigation of the disease almost at the same time

(Renmin wang, 2003a). A combined team of health experts from the Ministry and
the province was dispatched to Zhongshan and completed an investigation report
on the unknown disease. On January 27, the report was sent to the provincial
health bureau and, presumably, to the Ministry of Health in Beijing. The report
was marked “top secret,” which meant that only top provincial health officials
could open it.
Further government reaction to the emerging disease, however, was delayed
by the problems of information flow within the Chinese hierarchy. For 3 days,
there were no authorized provincial health officials available to open the docu-
ment. After the document was finally read, the provincial bureau distributed a
bulletin to hospitals across the province. However, few health workers were
alerted by the bulletin because most were on vacation for the Chinese New Year
(Pomfret, 2003a). In the meantime, the public was kept uninformed about the
disease. According to the Implementing Regulations on the State Secrets Law
regarding the handling of public health–related information, any occurrence of
infectious diseases should be classified as a state secret before they are “an-
nounced by the Ministry of Health or organs authorized by the Ministry.” In other
words, until such time as the Ministry chose to make information about the dis-
ease public, any physician or journalist who reported on the disease would risk
being persecuted for leaking state secrets (Li et al., 1999). A virtual news black-
out about SARS thus continued well into February.
The initial failure to inform the public heightened anxieties, fear, and wide-
spread speculation. On February 8, reports about a “deadly flu” began to be sent
via short messages on mobile phones in Guangzhou. In the evening, words like
bird flu and anthrax started to appear on some local Internet sites (South China
Morning Post, 2003). On February 10, a circular appeared in the local media that
acknowledged the presence of the disease and listed some preventive measures,
including improving ventilation, using vinegar fumes to disinfect the air, and
washing hands frequently. Responding to the advice, residents in Guangzhou and
other cities cleared pharmacy shelves of antibiotics and flu medication. In some
cities, even the vinegar was sold out. The panic spread quickly in Guangdong,
and was felt even in other provinces.
On February 11, Guangdong health officials finally broke the silence by hold-
ing press conferences about the disease. The provincial health officials reported a
total of 305 atypical pneumonia cases in the province. The officials also admitted
that there were no effective drugs to treat the disease and that the outbreak was
only tentatively contained (Nanfang zhoumu, 2003). From then on, information
about the disease was reported to the public through the news media. Yet in the
meantime, the government played down the risk of the illness. Guangzhou city
government on February 11 went so far as to announce the illness was “compre-
hensively” under effective control (Renmin wang, 2003b). As a result, while the
panic was temporarily allayed, the public also lost vigilance about the disease.
When some reports began to question the government’s handling of the outbreak,

the provincial propaganda bureau again halted reporting on the disease on Febru-
ary 23. This news blackout continued during the run-up to the National People’s
Congress in March, and government authorities shared little information with the
World Health Organization until early April.
The continuing news blackout not only restricted the flow of information to
the public but contributed to the government’s failure to take further actions to
address the looming catastrophe. Here it is worth noting that the Law on Preven-
tion and Treatment of Infectious Diseases (enacted in September 1989) contains a
number of significant loopholes. First, provincial governments are obliged to pub-
licize epidemics in a timely and accurate manner only after being authorized by
the Ministry of Health (Article 23). Second, atypical pneumonia was not listed in
the law as an infectious disease under surveillance, and thus local government
officials legally were not accountable for reporting the disease. While the law
allows for the addition of new items to the list, it does not specify the procedures
through which new diseases can be added. Both of these factors provided disin-
centives for the government to effectively respond to the crisis. In fact, the Chi-
nese Center for Disease Control and Prevention did not issue a nationwide bulle-
tin to hospitals on how to prevent the ailment from spreading until April 3, and it
was not until mid-April that the government formally listed SARS as a disease to
be closely monitored and reported on a daily basis under the Law of Prevention
and Treatment of Infectious Diseases.
Evidence also indicates that the provincial government, in deciding whether
to publicize the event, considered not only the public health implications of the
outbreak, but also the effect such information might have on local economic de-
velopment (Garrett, 2003; Pomfret, 2003a). In part, this correlates with a signifi-
cant shift in China’s national agenda, which makes economic growth the key to
solving the nation’s problems and makes social stability the prerequisite to devel-
opment (Development, 2000). In the words of the late paramount leader Deng
Xiaoping, “the overwhelmingly important issue for China is stability, without
which nothing can be achieved (Renmin Rabao, 2001).” Such concerns were only
complicated by the fact that during some of the most crucial period of the disease
outbreak, party elites were busy preparing for the National People’s Congress
(NPC) in March, which would mark the beginning of a new government (follow-
ing the selection of new leaders to the Politburo Standing Committee in Novem-
ber). To publicly acknowledge the outbreak at this critical juncture might have
risked not only causing socioeconomic instability but sullying the party’s image
among the people.
In fairness here, it should be noted that officials in any nation or region of the
world would likely face a similar dilemma in attempting to consider its obliga-
tions to protect the public’s health while at the same time considering how to
maintain equally important aspects of social stability and economic development.
In addition, the media blackout and the government’s slow response were not the
sole factors leading to the crisis. With little knowledge about the true cause of the

disease and its rate and modes of transmission, the top-secret document submit-
ted to the provincial health bureau did not even mention that the disease showed
signs of being considerably contagious. Neither did it call for rigorous preventive
measures, which may explain why by the end of February, nearly half of
Guangzhou’s 900 cases were health care workers (Pomfret, 2003a). Indeed, even
countries like Canada were having difficulty controlling SARS. In this sense,
SARS is a natural disaster, not a humanmade one.
Nevertheless, there is no doubt that government inaction paralleled by the
absence of an effective response to the initial outbreak resulted in a crisis. To
begin with, the security designation for the top-secret document meant that
Guangdong health authorities could not discuss the situation with other provin-
cial health departments in China. Consequently, hospitals and medical personnel
in most localities were completely unprepared for the outbreak. When the first
SARS case in northern China was admitted to the PLA 301 Hospital in Beijing on
March 2, doctors in charge of the treatment had little information about the dis-
ease (Zhongguo qingnian bao, 2003). Even as the traffic through emergency
rooms began to escalate, major hospitals in Beijing took few measures to reduce
the chances of cross-infection. Likewise, Inner Mongolia’s first SARS patient,
who sought treatment in the Hohhot Hospital around March 20, was not correctly
diagnosed until early April (Kahn and Rosenthal, 2003). The security designation
of the Guangdong report also prevented health authorities in neighboring Hong
Kong from receiving information about the disease, and consequently they were
denied the knowledge they needed to prepare (Pomfret, 2003a). Soon after, the
illness developed into an epidemic in Hong Kong, which proved to be a major
international transit route for SARS.
Beyond Guangdong: The Ministry of Health and Beijing

The Ministry of Health learned about SARS in January and informed WHO
and provincial health bureaus about the outbreak in Guangdong around February
7, and yet no further action was taken. It is safe to assume that Zhang Wenkang,
the health minister, brought the disease to the attention of Wang Zhongyu (secre-
tary general of the State Council) and Li Lanqing (the vice premier in charge of
public health and education). We do not know what happened during this period
of time, but it is likely that the leaders were so preoccupied preparing for the
National People’s Congress that no explicit directive was issued from the top
until April 2. By March 1, the epidemic was raging in Beijing. For fear of distur-
bance during the NPC meeting, however, city authorities kept information about
its scope not only from the public but also from the Party Center. According to
Dr. Jiang Yanyong, medical staff in Beijing’s military hospitals were briefed
about the dangers of SARS in early March, but were told not to publicize what
they had learned lest it interfere with the NPC meeting (Jakes, 2003). Similar
communication obstacles hampered cooperation between China and the World

Health Organization. WHO experts were invited to China by the Ministry of

Health but were not allowed to have access to Guangdong until April 2, 8 days
after their arrival. It was not until April 9 that they were allowed to inspect mili-
tary hospitals in Beijing.
Such obstructions to information flow and the lack of interdepartmental co-
operation during the crisis provide a reference point for the “fragmented
authoritarianism” model of the Chinese political system, which posits that au-
thority below the very peak of the Chinese system is fragmented and disjointed,
leading to a bogged-down policy process which is characterized by extensive
bargaining (Lampton, 1987; Lieberthal and Lampton, 1992). While this model
offers only a static description of how the core state apparatus works (Oksenberg,
2001), it correctly points out the coordination problems in China’s policy pro-
cess. Medical personnel in the city of Guangzhou blamed poor communication
between the province’s health bureau and the city’s health authorities for the
failure to control the spread of the disease (Pomfret, 2003a). In addition to the
tensions among different levels of health authorities, coordination problems ex-
isted between functional departments and territorial governments, as well as be-
tween civilian and military institutions. As one senior health official admitted,
before anything could be done, the Ministry of Health had to negotiate with other
ministries and government departments (Pomfret, 2003b). In the public health
domain, territorial governments like Beijing and Guangdong maintain primary
leadership over the provincial health bureau, with the former determining the
size, personnel, and funding of the latter. This constitutes a major problem for the
Ministry of Health, which is bureaucratically weak, not to mention that its minis-
ter is just an ordinary member of the Chinese Communist Party (CCP) Central
Committee and not represented in the powerful Politburo. A major policy initia-
tive from the Ministry of Health, even issued in the form of a central document, is
mainly a guidance document (zhidao xin wenjian) that has less binding power
than one that is issued by territorial governments. Whether it will be honored
hinges on the “acquiescence” (liangjie) of the territorial governments. This helps
explain the continuous lack of effective response by Beijing city authorities until
April 17 (when an anti-SARS joint team was established).
At one level, Beijing’s municipal government apparently believed that it
could handle the situation by itself and thus refused assistance from the Ministry
of Health. At another, the Ministry did not have control over all available health
facilities. Of Beijing’s 175 hospitals, 16 are under the control of the army, which
maintains a relatively independent health system. Having admitted a large num-
ber of SARS patients, military hospitals in Beijing withheld SARS statistics from
the Ministry until mid-April. Organizational barriers also delayed the process of
correctly identifying the cause of the disease. According to government regula-
tions, only the Chinese CDC is the legal holder of virus samples. As a result,
researchers affiliated with other government organizations had been to
Guangdong many times in search of virus samples and returned empty handed

(Chinese Scientists, 2003). In addition, even the Chinese CDC in Beijing had to
negotiate with local disease-control centers to obtain the samples (Garrett, 2003).
After an examination of just two available samples, its chief virologist rushed to
announce chlamydia as the etiological agent of SARS on February 18 (Huailing,
2003).
The presence of such a fragmented and disjointed bureaucracy within an
authoritarian political structure means that policy immobility can only be over-
come with the intervention of an upper-level government that has the authority to
aggregate conflicting interests. However, this tends to encourage lower-level gov-
ernments to shift their policy overload to the upper levels in order to avoid assum-
ing responsibilities. As a consequence, a large number of agenda items compete
for the upper level government’s attention. In addition, the drive toward eco-
nomic growth in the post-Mao era has marginalized public health issues (Ruan,
1992). Compared to economic issues, a public health problem often needs an
attention-focusing event (e.g., a large-scale outbreak of a contagious disease) to
be finally recognized, defined, and formally addressed (Kingdon, 1995). Not sur-
prisingly, SARS did not raise the eyebrows of top decision makers until it had
developed into a nationwide epidemic.
By early April, it was evident that SARS was being taken very seriously at
the top level. Yet the government’s ability to formulate a sound policy against
SARS was hampered as lower-level government officials intercepted and dis-
torted the upward information flow. For fear that any mishap reported in their
jurisdiction might be used as an excuse to pass them over for promotion, govern-
ment officials at all levels tended to distort the information they pass up to their
political masters in order to place themselves in a good light. While this is not
unique to China, the problem is alleviated in democracies through “decentralized
oversight,” which enables citizen interest groups to check up on administrative
actions. Because the general public in China is not enfranchised to oversee the
activities of government agencies, however, lower-level officials can fool higher
authorities more easily than their counterparts in liberal democracies (Shirk,
1993). This exacerbates the information asymmetry problems inherent in a hier-
archical structure. Beijing municipal authorities, for example, kept hiding the
actual SARS situation in the city from the Party Center until April. Initial decep-
tion by lower-level officials in turn led the central leaders to misjudge the situa-
tion. On April 2, Premier Wen Jiabao chaired an executive meeting of the State
Council to discuss SARS prevention and control. Based on the briefing given by
the Ministry of Health, the meeting declared that SARS had “already been brought
under effective control.”
The growing dispersal of political power at the highest level in the post-Mao
era further reduced the autonomy of the top leaders in responding to the crisis in
a timely manner. Instead of having a personalized leadership unconstrained by
laws and procedures, the post-Mao regime features collective leadership, with the
Party general secretary acting as the first among equals. Political power at the

national level has been further diluted since the 16th Party Congress, which ex-
panded the membership of the Politburo Standing Committee and allowed former
president Jiang Zemin (who is not a member of the CCP Central Committee) to
retain the position of Chairman of the Central Military Commission. Because
China’s decision making emphasizes consensus, the involvement of more actors
with equal status in decision making only increases the time and effort needed for
policy coordination and compromise.
The Government Crusade Against SARS

As the virus continued to spread, China’s political leadership came under
growing domestic and international pressures (Pomfret, 2003d). Despite the pro-
hibition against public discussion of the epidemic, 40.9 percent of the urban resi-
dents had already heard about the disease through unofficial means (Haiyan,
2003). As mentioned above, news of the disease reached residents in Guangzhou
through mobile-phone text messages in early February, forcing the provincial
government to hold a news conference admitting to the outbreak. Starting on
February 11, the Western news media began to aggressively report on SARS in
China and the government’s cover-up of the outbreak. On March 15, the WHO
issued its first global warning about SARS. While China’s government-controlled
media was prohibited from reporting on the warning, the news circulated via
mobile phones, e-mail, and the Internet. On March 25, 3 days after the arrival of
a team of WHO experts, the government for the first time acknowledged the
spread of SARS outside of Guangdong. The State Council held its first meeting to
discuss the SARS problem 2 days after the Wall Street Journal published an
editorial calling for other countries to suspend all travel links with China until it
implemented a transparent public health campaign. The same day, the WHO is-
sued the first travel advisory in its 55-year history advising people not to visit
Hong Kong and Guangdong, prompting Beijing to hold a news conference in
which the health minister promised that China was safe and SARS was under
control. Enraged by the minister’s false account, Dr. Jiang Yanyong, a retired
surgeon at Beijing’s 301 military hospital, sent an e-mail to two TV stations,
accusing the minister of lying. While neither station followed up on the e-mail,
Time magazine picked up the story and posted it on its website on April 9, which
triggered a political earthquake in Beijing.
The aforementioned events are revealing examples of how evolving state-
society relations can significantly influence the trajectory of public policy devel-
opment in post-Mao China. Economic reform and globalization provide more
Chinese with the information, connections, resources and incentives to act on
their own for their personal security and personal fulfillment. In the words of
Thomas Friedman, these empowered, even superpowered individuals become
more demanding of the government and will get angry when their leaders fail to
meet their aspirations (Friedman, 2000). The torrent of messages sent through

cell phones or the Internet and Dr. Jiang Yanyong’s exposure of the cover-up thus
challenged the state’s monopoly on information. Furthermore, while party lead-
ers are not formally accountable to their people, they may have to take into ac-
count mass reactions of the population when they make policies, or otherwise risk
a lack of cooperation with their programs from below. As a result of the strategic
interaction between the state with increasing legitimacy concerns and social forces
with more political and economic resources, the state may have more incentives
to take seriously the people’s interests and demands (Huang, forthcoming).
The growing epidemic, combined with pressures from inside and outside the
country, ultimately engendered a strong and effective action by the government to
contain the disease and end the crisis. On April 2, the State Council held a meeting
to discuss the SARS problem, the first of three meetings held within the space of a
month. This was followed by an urgent meeting of the Standing Committee of the
CCP Politburo on April 17. Meanwhile, the government also showed a new level of
candor. Premier Wen Jiabao on April 13 said that although progress had been made,
“the overall situation remains grave” (Business Week, 2003). In hindsight, one of
the strengths of party-state dualism in China is the Party’s ability to push the gov-
ernment by signaling its priorities loudly and clearly. This helps explain why the
April 2 meeting held by the State Council did not generate any serious response
from the lower level, whereas the system was fully mobilized after April 17, when
the Politburo’s Standing Committee explicitly warned against covering up SARS
cases and demanded accurate and timely reporting of the disease. After the April 17
meeting, government media began to publicize the number of SARS cases in each
province, updating on a daily basis. An order from the Ministry of Health formally
listed SARS as a disease to be monitored under the Law of Prevention and Treat-
ment of Infectious Diseases and made it clear that every provincial unit should
report the number of SARS cases on a given day by 12 noon on the following date.
The party and government leaders around the country were now to be held account-
able for the overall SARS situation in their jurisdictions.
On April 20, Health Minister Zhang Wenkang and Beijing mayor Meng
Xuenong were ousted for their mismanagement of the crisis. While they were not
the first ministerial-level officials since 1949 to be dismissed mid-crisis on a policy
matter, the case was a signal of political innovation from China’s new leadership.
As an article in The Economist remarked, the unfolding of the event—minister
presides over policy bungle; bungle is exposed and there is public outcry; minister
resigns to take the rap— “almost looks like the way that politics works in a demo-
cratic, accountable country” (China’s Chernobyl, 2003). The crisis also led the gov-
ernment to take measures to strengthen fundamental authority links within the sys-
tem. As part of a nationwide mobilization campaign, the State Council sent out
inspection teams to 26 provinces to scour government records for unreported cases
and to fire officials for lax prevention efforts. According to the official media, by
May 8 China had fired or penalized more than 120 officials for their “slack” re-
sponse to the SARS epidemic (Tak-ho, 2003). It was estimated that by the end of

May, nearly 1,000 government officials had been disciplined for the same reason
(Lianhe zaobao, 2003). These actions shook the complacency of local government
officials, who then abandoned their initial hesitation and jumped onto the anti-
SARS bandwagon. Driven by political zeal, they sealed off villages, apartment
complexes, and university campuses, quarantined tens of thousands of people, and
set up checkpoints to take temperatures. By May 7, 18,000 people had been quaran-
tined in Beijing. The Maoist “Patriotic Hygiene Campaign” was revitalized. In
Guangdong, 80 million people were mobilized to clean houses and streets (Renmin
ribao, 2003b). In the countryside, virtually every village was on SARS alert, with
roadside booths installed to examine all those who entered or left.
The crisis also improved interdepartmental and interagency coordination and
speeded up the process of institutionalizing China’s emergency response system
to be able to handle public health contingencies. On April 17, an anti-SARS joint
team was created for the city of Beijing, which included leading members from
the Ministry of Health and the military (Xinhua News, 2003a). On April 23, a
task force known as the SARS Control and Prevention Headquarters of the State
Council was established to coordinate national efforts to combat the disease. Vice
Premier Wu Yi was appointed as commander-in-chief of the task force, and simi-
lar arrangements were made at the provincial, city, and county levels. On May 12,
China issued a set of Regulations on Public Health Emergencies. According to
these regulations, the State Council shall set up an emergency headquarters to
deal with any public health emergencies, which are referred to as serious epidem-
ics, widespread unidentified diseases, mass food and industrial poisoning, and
other serious public health threats (Xinhua News, 2003b).
Direct involvement of the political leadership also increased program re-
sources and mobilized resources from other systems. On April 23, a national fund
of 2 billion yuan ($US 250 million) was created for SARS prevention and con-
trol. The fund was to be used to upgrade county-level hospitals, to finance the
treatment of farmers and poor urban residents infected with SARS, and to pur-
chase SARS-related medical facilities in central and western China. This central
government funding was complemented by an additional 7 billion yuan ($US 875
million) from local governments (Renmin wang, 2003c). Free treatment was of-
fered to SARS sufferers anywhere in the country.
These momentous measures appeared to have worked. The epidemic started
to lose its momentum in late May, and on June 24, the World Health Organization
lifted its advisory against travel to Beijing. On August 16, with the last two SARS
patients discharged from the Beijing Ditan Hospital, China for the time being was
free from SARS.
Improvements Resulting from the SARS Crisis

The weaknesses and strengths demonstrated by the government during the
crisis raised questions regarding its capacity to respond to other disease outbreaks.

With the SARS outbreak wreaking havoc and shaving an estimated seven-tenths
of a percentage point off China’s gross domestic product for 2003, the govern-
ment appears to have drawn some important lessons from the crisis, including the
need for coordinated development. When interviewed by the executive editor of
the Washington Post, Premier Wen Jiabao said that “one important inspirational
lesson” the new Chinese leadership learned from the SARS crisis was that “un-
even development between the urban and rural areas, and imbalance between
economic development and social progress” were “bound to stumble and fall
(Renmin ribao, 2003d).” On various occasions since the crisis, central leaders
have emphasized the importance of public health, especially rural health care
(Renmin ribao, 2003e,f,g; Ministry of Health, 2003). The government has also
provided more funding to public health. It earmarked billions of dollars to SARS
prevention and control, and recently it invested 6.8 billion yuan ($US 850 mil-
lion) for the construction of a three-tiered network of disease control and preven-
tion (Guangming ribao, 2003). While a nationwide SARS training program is
underway, the government has initiated an Internet-based disease reporting sys-
tem which allows local hospitals to directly report suspected SARS cases to the
Chinese CDC and the Ministry of Health (Zhongguo xinwen wang, 2003b).
Moreover, as China emerges from the shadow of SARS, Chinese leaders appear
to be showing a new, more proactive attitude toward AIDS. Since summer 2003, the
government has started offering free treatment for poor people with HIV/AIDS, and it
plans to expand the program next year until free treatment is available for all poor
HIV carriers and AIDS patients (Chang, 2003; Yardley, 2003). The government has
also allocated 11.4 billion yuan ($US 1.42 billion) for strengthening the AIDS medi-
cal assistance system and training more health personnel for AIDS prevention and
treatment (Jiankang bao, 2003). On December 1, Premier Wen Jiabao appeared on
state television shaking hands with AIDS patients and called on the nation to treat
them with “care and love.” This event was significant because until then, no senior
Chinese leader had even discussed the disease in public.
These measures reflected the increased efforts of the Party to cultivate a new
image for its leadership. It wants citizens to see the leaders as being in touch with
the people and committed to their best interests. More attention has thus been
paid to the basic needs of China’s farmers and workers. On August 17, the gov-
ernment promulgated Regulations on the Management of Village Doctors, prom-
ising more professional training for rural health personnel (Xinhua news, 2003c).
In September, Premier Wen indicated that a majority of the increased health fund-
ing will be used to support rural public health. He also reaffirmed his commit-
ment to a new medical insurance scheme in the countryside (Renmin ribao,
2003h). Given that rural areas were viewed as the weakest link in containing the
spread of SARS, such measures are expected to strengthen the ability of the pub-
lic health system to respond to a future disease outbreak.
Equally important, the government seems to have learned that in an era of the
Internet and cell phones, a complete information blackout is not only impossible

but also counterproductive. There are signs suggesting that the crisis is forcing
the government to take steps to establish an image of a more open and transparent
government. For example, an April 28 Politburo meeting obviously made the
decision to publicize a submarine accident that same month that cost 70 lives.
News of the tragedy was reported by the official Xinhua news agency on May 2.
This marks a significant departure from the traditionally secretive approach taken
to the nation’s military disasters. If this new openness continues in the post-SARS
era, it will not only create conditions for a government that is more accountable to
its people but might also provide considerable incentives for sharing knowledge
of an outbreak with the international community as early as possible.
As evidenced by the government campaign against SARS, an infectious dis-
ease can potentially trigger the party-state to organize a political campaign to reach
deep into the hinterlands and snap people into action. This government capacity to
mobilize against a disease outbreak is enhanced by a more institutionalized crisis
management system. The Regulations on Public Health Emergencies issued by the
State Council in mid-May, for example, require setting up an emergency headquar-
ters right after a public health emergency is identified. It has also been reported that
the government plans to set up an Emergency Response Bureau, which would draw
on the example of the U.S. Federal Emergency Management Administration to
tackle future health crises and natural disasters (Wiest, 2003).
Problems and Concerns

These changes are worth applauding, but will they suffice to effectively con-
tain future epidemics? Here, one of the major problems is a public health system
in China that has been compromised by a lack of sufficient state funding. The
portion of total health spending financed by the government has fallen from 34
percent in 1978 to less than 20 percent now (Huang, 2003), and a lack of adequate
facilities and medical staff shortages compromised early government efforts to
contain SARS. For example, hospitals in Guangdong reportedly faced shortages
in hospital beds and ambulances, and even among the 66,000 health care workers
in Beijing, less than 3,000 (or 4.3 percent) were familiar with respiratory diseases
(Renmin ribao, 2003c). Apart from imposing severe constraints on the
government’s ability to respond to a public health crisis, the shortage of afford-
able health care also impacted the ability and willingness of patients to seek out
treatment. The Washington Post reported a SARS patient who fled quarantine in
Beijing because he did not believe that the government would treat his disease
free of charge, and some hospitals are reported to have refused to accept patients
who had affordability problems (Washington Post, 2003). More broadly, accord-
ing to a recent report by the Chinese Consumer’s Association, about 50 percent of
people who are sick do not see a doctor because of the extremely high out-of-
pocket payments (Zhongguo jingji shibao, 2003). All of these factors sow the
seeds for a larger and more catastrophic disease attack.

We should also keep in mind that SARS is not the sole microbial threat
confronting China. The country faces challenges from other major infectious dis-
eases such as the plague, cholera, HIV/AIDS, other sexually transmitted diseases,
tuberculosis, viral hepatitis, and endemic schistosomiasis (Renmin ribao, 2003i).
These multiple public health challenges require China to build on the anti-SARS
momentum and integrate a comprehensive epidemic control plan into the na-
tional socioeconomic development agenda. While the health sector is now receiv-
ing increased attention at high levels, the government so far has placed top prior-
ity only on preventing the return of SARS. The top leaders have been generally
silent on other major infectious diseases. Despite official recognition of the seri-
ousness of HIV/AIDS, China does not have a comprehensive national program
for disease prevention and control to help stop the epidemic. In rural areas hard-
hit by AIDS, local governments continue to harass public health activists, devote
few resources to educating people about the disease, and sometimes even meet
the demands of the villagers with violence (Pan, 2003). Furthermore, there has
been no fundamental change in the government’s development agenda. The cen-
tral government still equates development with economic growth and uses that as
a yardstick in measuring local government performance.
In addition, it is worth noting that the apparent policy transparency has not
been accompanied by significant state relaxation of media control. On May 12,
the very same day that Premier Wen Jiabao released the new regulations to pro-
mote openness, the Beijing Morning News carried an article on how people who
spread “rumors” about SARS could be jailed for up to 5 years. While the newly
promulgated Regulations on Public Health Emergencies stipulate that govern-
ment officials make timely and truthful reports about any such emergencies, they
do not enshrine the public’s right to be informed in the same manner. Indeed, a
recent speech by Vice Premier Wu Yi reiterated state control over the media in
order to “strictly prohibit the spread of rumors and other harmful information
(Wu Yi, 2003).”
While feedback from the public may matter more for the government than it
used to, government officials ultimately remain responsible not to the public but
to the higher authorities. Hence, the government will always be more sensitive to
pressure that comes top down, rather than bottom up. Ironically, the likelihood of
deception has increased as a result of the spread of some government measures in
fighting SARS, such as the practice of holding bureaucratic officials personally
accountable for local SARS cases through a “responsibility pledge” (junling
zhuang) without giving due consideration of actual local conditions (e.g., the
public health infrastructure). If indeed an outbreak is imminent, a local govern-
ment official concerned about his post may well choose to lie. Manipulation of
SARS-related data remained a serious problem even after April 17—among other
things, a pattern could be easily identified in the government war against SARS
in which when upper-level leaders demanded a reduction of SARS cases, their
orders would be reflected in statistics afterwards (Wong, 2003).

To the extent that upward accountability and performance-based legitimacy

will cause problems in agenda setting and policy making, the lack of effective
civil society participation reduces government effectiveness in policy enforce-
ment. In initiating many anti-SARS projects during the crisis, the government did
nothing to consult or inform the local people. Chinese non-governmental organi-
zations (NGOs), if anything, were absent in the war against SARS (21st Century
Economic Herald, 2003). Instead, the government relied on the extensive array of
mobilization vehicles installed in the Mao era—village party branches, street sub-
district offices, former barefoot doctors—to take temperatures, quarantine people,
trace infections and round up laggards. To be sure, party leaders undertaking the
anti-SARS measures differed from their predecessors by emphasizing “science”
and “rule by law.” Yet the absence of genuinely engaged civil society groups as a
source of oversight and information, coupled with the increasing pressure from
higher authorities, easily created a results-oriented implementation structure that
made nonscientific, heavy-handed measures more appealing to local government
officials. They found it safer to be overzealous than to be seen as “soft.” Until
June 2, for example, Shanghai was quarantining people from the regions hard hit
by SARS (such as Beijing) for 10 days even if they had no symptoms (Pomfret,
2003c).
The government’s heavy reliance on quarantine during the epidemic also
raises a question about the impact of future disease control measures and the
worsening of the human rights situation in China. This question, of course, is not
unique to China—even countries like the United States are debating whether it is
necessary to apply mandatory approaches to confront health risks more effec-
tively. The Model Emergency Health Powers pushed by the Bush administration
would permit state governors in a health crisis to impose quarantines, limit
people’s movements and ration medicine, and seize anything from dead bodies to
private hospitals (Kristof, 2003). While China’s Law on Prevention and Treat-
ment of Infectious Disease did not until recently explicate that quarantines apply
to the SARS epidemic, Articles 24 and 25 authorize local governments to take
emergency measures that may compromise personal freedom. The problem is
that unlike democracies, China in applying these measures excludes the input of
civil associations. Official reports suggested that innocent people were dubbed
rumor spreaders and arrested simply because they relayed some SARS-related
information to their friends or colleagues (Xinhua News, 2003d). According to
the Ministry of Public Security, public security departments have investigated
107 cases in which people used Internet and cell phones to spread SARS-related
“rumors (Renmin wang, 2003d).” Some Chinese legal scholars have already ex-
pressed concerns that the government, in order to block information about epi-
demics, may turn to more human rights violations (ChineseNewsNet, 2003).
The lack of engagement by civil society in the policy process could deplete
the social capital that would be so important for future government outbreak con-
trol efforts. In the case of SARS, the government’s failure to publicize the out-

break in a timely and accurate manner and the ensuing rapid policy turnaround
eroded the public’s trust and contributed to the spread of rumors even after the
government adopted a more open stance toward information on the epidemic. In
late April, thousands of residents of a rural town of Tianjin ransacked a building,
believing it would be used to house ill patients with confirmed or suspected SARS,
even though officials insisted that it would be used only as a medical observation
facility to accommodate people who had close contacts with SARS patients and
for travelers returning from SARS hot spots. Opposition to official efforts to con-
tain SARS was also found in a coastal Zhejiang province, where several thousand
people took part in a violent protest against six people being quarantined after
returning from Beijing (Kuhn, 2003). Here again, the lack of active civilian par-
ticipation exacerbated existing problems of trust. In initiating the project in
Tianjin, the government had done nothing to consult or inform the local people
(Eckholm, 2003).
Finally, the mobilization model for confronting public health crises also suf-
fers from a problem of sustainability in the post-Mao era. By placing great politi-
cal pressure on local cadres in policy implementation, mobilization is a conve-
nient bureaucratic tool for overriding fiscal constraints and bureaucratic inertia
while promoting grassroots cadres to behave in ways that reflect the priorities of
their superiors. Direct involvement of the local political leadership increases pro-
gram resources, helps ensure they are used for program purposes, and mobilizes
resources from other systems, including free manpower transferred to program
tasks. Yet in doing so, a bias against routine administration is built into its imple-
mentation structure. While personal rewards of private life (e.g., medals, higher
pay, extra credits for medical workers’ children attending the college entrance
exam) were provided for activism in the anti-SARS campaign, decades of re-
forms have eroded state control and increased the opportunity cost of participa-
tion. While the government demonstrated in this case a continued ability to spur
people to action in even the most remote villages, in a post-totalitarian context it
is generally difficult to sustain a state of high alert across the country for an
extended period.
Conclusions
The pattern of the Chinese government’s response to SARS was shaped by
the institutional dynamics of the country’s political system. A deeply ingrained
authoritarian impulse to maintain secrecy, in conjunction with a performance-
based legitimacy and an obsession with development and stability during politi-
cal succession, contributed to China’s initial failure to publicize the outbreak.
Meanwhile, an upwardly directed system of accountability, a fragmented bureau-
cracy, and an oligarchic political structure hampered any effective government
response to the outbreak. In spite of these problems, interactions between the
state and society unleashed dynamics that prompted the central party-state to

intervene on society’s behalf. The direct involvement of the Party strengthened

authority links, increased program resources, and maximized the potential for
interdepartmental and intergovernmental cooperation. In this manner, the party-
state remains capable of implementing its will throughout the system without
serious institutional constraints. The government’s capacity for crisis manage-
ment has been further enhanced by a series of measures taken in the post-SARS
era. However, this does not mean that the government is ready for the next dis-
ease outbreak. In the absence of fundamental changes in the political system and
a comprehensive epidemic control plan, not only is the same pattern of cover-up
and inaction likely to be repeated, but the government will find it increasingly
difficult to control the multiple public health challenges it is now facing.
The above analysis clearly points to a need for the Chinese government to
significantly enhance its capacity to combat future outbreaks of SARS and other
infectious diseases. Given that a public health crisis reduces state capacity just
when ever-increasing capacity is needed to tackle the challenges, purely endog-
enous solutions to build capacity are unlikely to be successful, and capacity will
have to be imported from exogenous sources such as massive foreign aid (Price-
Smith, 2002). In this sense, building state capability also means building more
effective partnerships and institutions internationally. International actors can play
an important role in creating a more responsible and responsive government in
China (Huang, 2003). First, aid from international organizations opens an alter-
native source of financing for health care, increasing the government’s financial
capacity in the health sector. Second, international aid can strengthen bureau-
cratic capacity through technical assistance, policy counseling, and personnel
training. Third, while international organizations and foreign governments pro-
vide additional health resources in policy implementation, the government in-
creasingly has to subject its agenda-setting regime to the donors’ organizational
goals, which can make the government more responsive to its people. The agenda
shift for SARS to a large extent was caused by strong international pressures
exerted by the international media, international organizations, and foreign gov-
ernments. There are also indications that the Internet is increasingly used by the
new leadership to solicit policy feedback, collect public opinions, and mobilize
political support. Starting February 11, Western news media were aggressively
reporting about SARS and about government cover-ups of the number of cases in
China. It is very likely that Hu Jintao and Wen Jiabao, both Internet users, made
use of international information in making decisions concerning the epidemic. In
other words, external pressures can be very influential because Chinese govern-
mental leaders are aware of weaknesses in the existing system for effectively
responding to a crisis and therefore have incentives to seek political resources
exogenous to the system.
From the perspective of international actors, helping China to fight future
epidemics also helps themselves. Against the background of a global economy,
diseases originating in China can be spread and transported globally through trade,

travel, and population movements. Moreover, an unsustainable economy or state

collapse spawned by poor health will deal a serious blow to the global economy.
As foreign companies shift manufacturing to China, the country is becoming a
workshop to the world. A world economy that is so dependent on China as an
industrial lifeline can become increasingly vulnerable to a major supply disrup-
tion caused by disease epidemics. Perhaps equally important, if future epidemics
in China result in truly global health crises, the unwanted social and political
changes will be felt by even the most powerful nations. As every immigrant or
visitor from China or Asia is viewed as a potential Typhoid Mary, minorities and
immigration could become a sensitive domestic political issue in countries such
as the United States and Canada. An incident in New Jersey during the SARS
outbreak, in which artists of Chinese background were denied access to a middle
school, suggests that when SARS becomes part of a national lexicon, fear, rumor,
suspicion, and misinformation can jeopardize racial harmony in any country
(Newman and Zhao, 2003).
Given the international implications of China’s public health, it is in the
interest of the United States and other industrialized nations to expand coopera-
tion with China in the areas of information exchange, research, personnel train-
ing, and improvement of public health facilities. Meanwhile, these countries could
send clear signals to the Chinese leadership that reform-minded leaders in the
forefront of fighting epidemic diseases and supporting public health will be sup-
ported. The world’s interests will be well served by continuing to support a Chi-
nese government that is increasingly more open and interested in international
engagement. It should also not miss this unique opportunity to help create a
healthier China.
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Microbiology, Ecology, and Natural History

of Coronaviruses
OVERVIEW
Coronaviruses cause a substantial fraction of human colds and a host of com-
mon respiratory infections in many other animals, including economically impor-
tant diseases of livestock, poultry, and laboratory rodents. Moreover, although
these viruses were not known for producing more than mild infections in humans
prior to the SARS epidemic, veterinary coronavirologists have long been aware
of their potential for producing lethal infections in animals, as Linda Saif de-
scribes in this chapter’s first paper. For this reason, there is already an extensive
amount of research on animal coronaviruses that can be drawn from for under-
standing the life cycle and pathogenicity of the SARS virus, and veterinary scien-
tists are now being called on to join the research response to the epidemic and
share their knowledge of coronaviruses with a broader audience. Mark Denison’s
paper describes the current state of research on animal coronaviruses and dis-
cusses how results from these animal models suggest promising directions for
future research on SARS and other emerging zoonoses.
Animal coronaviruses tend to follow one of two basic pathogenic models,
producing either enteric or respiratory infections. Both models show parallels to
the clinical features of SARS patients, the majority of whom presented with res-
piratory infections but in some cases also suffered from enteric complications. In
adult animals, coronavirus infections of a respiratory nature have shown increased
severity in the presence of several factors, including high exposure doses, respira-
tory coinfections, stress related to shipping or commingling with animals from
different farms, and treatment with corticosteroids. In young, seronegative ani-
mals, enteric coronaviruses can cause fatal infections. Although coronaviruses
137

generally cause disease in a single animal species, some have been demonstrated
to cross species barriers.
Considerable effort has already been applied toward uncovering an animal
source of the SARS virus. This has been sought primarily through the genetic
characterization of viral isolates from suspected animal sources and comparison
with human SARS coronavirus samples. In the past, however, epidemiological
detective work has identified the source of many outbreaks of infectious disease,
and one workshop participant suggested that a case control study of the first 50 to
100 SARS patients from China’s Guangdong Province, where the earliest cases
of the disease were detected, might prove similarly fruitful. While a natural reser-
voir for the SARS virus has not yet been identified, the combination of such
genomic and epidemiological techniques is already yielding suggestive results.
For example, the last paper in this chapter by Yi Guan et al. describes the pres-
ence of coronaviruses closely related to SARS among live animals sold in
Guangdong markets. Similar epidemiological principles may yet provide valu-
able direction for further laboratory surveys of animal viruses aimed at finding
the original source and reservoir of the SARS coronavirus.
Coronaviruses have been classified into three major categories based on their
genetic characteristics. While the SARS virus has been linked with Group II
coronaviruses, whose members include human and bovine respiratory viruses and
the mouse hepatitis virus, there is still some debate over whether its genetic fea-
tures might be sufficiently distinct to warrant classification within a separate,
fourth class of coronaviruses. Studies of coronavirus replication at the molecular
level reveal several mechanisms that account for the repeated, persistent infec-
tions typical of coronaviral disease. High rates of mutation and RNA-RNA re-
combination produce viruses that are able to adapt to acquire and regain viru-
lence. Although researchers have identified several potential targets for antiviral
therapies, the ability of the virus to mutate and recombine represents a major
challenge to vaccine development. A vaccine that can provide highly effective,
long-term protection against respiratory coronavirus infections has not yet been
developed, nor have appropriate animal models been developed to test potential
vaccines against SARS. It was noted by several workshop participants that a co-
ordinated, multidisciplinary research effort, drawing on expertise in both the vet-
erinary and biomedical sciences, will likely be needed to meet these goals.
ANIMAL CORONAVIRUSES: LESSONS FOR SARS

Linda J. Saif
Department of Food Animal Health Research Program, Ohio Agricultural
Research and Development Center
The emergence of severe acute respiratory syndrome (SARS) illustrates that

coronaviruses (CoVs) may quiescently emerge from possible animal reservoirs and

CORONAVIRUSES 139
can cause potentially fatal disease in humans, as previously recognized for animals.
Consequently the focus of this review will be on the emergence of new CoV strains
and the comparative pathogenesis of SARS CoV with those CoVs that cause enteric
and respiratory infections of various animal hosts. A review of animal CoV vaccines
recently has been compiled (Saif, in press), so this topic will not be addressed.
Emergence of New Coronaviruses

The medical community was amazed by the emergence of a new coronavirus
associated with SARS in healthy adults in 2003 (Drosten et al., 2003; Ksiazek et
al., 2003; Peiris et al., 2003b; Poutanen et al., 2003). Historically human CoV
infections (229E and OC43 CoV strains) were mild and associated with only
common cold symptoms although reinfections, even with the same strain, occur
(Callow et al, 1990; Holmes, 2001). However, veterinary coronavirologists had
previously recognized the potential for coronaviruses to cause fatal enteric or
respiratory infections in animals and for new CoV strains to emerge from un-
known reservoirs, often evoking fatal disease in naïve populations. For example,
the porcine epidemic diarrhea CoV (PEDV) first appeared from an unknown
source in Europe and Asia in the 1970s and 1980s, causing severe diarrhea and
widespread deaths in baby pigs before becoming endemic in swine (Pensaert,
1999). The PEDV is absent in U.S. swine. Interestingly, PEDV is genetically
more closely related to human CoV 229E than to the other animal group I CoV
(Duarte et al., 1994), and unlike the other group I CoV, it grows in Vero cells like
SARS CoV (Hoffman and Wyler, 1988). These observations raise intriguing, but
unanswered, questions about its origin.
Alternatively new CoV strains differing in tissue tropism and virulence may
arise from existing strains. The less virulent porcine respiratory coronavirus
(PRCV) evolved as a spike (S) gene deletion mutant of the highly virulent enteric
CoV, transmissible gastroenteritis virus (TGEV) ( reviewed in Laude et al., 1993;
Saif and Wesley, 1999). Curiously, differences in the sizes of the 5′ end S gene
deletion region (621–681 nucleotides) between European and U.S. PRCV strains
provided evidence for their independent origin on two continents within a similar
time frame (1980s). Deletion of this region (or in combination with deletions in
ORF 3a) presumably accounted for altered tissue tropism from enteric to respira-
tory and reduced virulence of the PRCV strains (Ballesteros et al., 1997; Sanchez
et al., 1999). The ability of certain CoVs to persist in their host also provides a
longer opportunity for new mutants to be selected with altered tissue tropisms
and virulence from among the viral RNA quasispecies (or swarm of viruses). An
example is the virulent systemic variant, the feline infectious peritonitis virus
(FIPV), which likely arises from persistent infection of cats with the less virulent
feline enteric CoV (Herrewegh et al., 1997; Vennema et al., 1995).
Furthermore, animal CoVs may acquire new genes via recombination, as
exemplified by the acquisition of an influenza C-like hemagglutinin by bovine

CoV or its ancestor CoV (Brian et al., 1995). Recombination events among CoVs
may also generate new strains with altered tissue or host tropisms. For example,
targeted recombination between feline and mouse S proteins enables feline CoV
to infect mice (Haijema et al., 2003). Recent phylogenetic analysis suggests that
SARS CoV may have evolved from a past recombination event between mamma-
lian-like and avian-like parent strains with the S gene representing a mammalian
(group 1)–avian origin mosaic (Stavrinides and Guttman, 2004). This recognition
that CoVs can further evolve in a host population to acquire new tissue tropisms
or virulence via mutations or recombination suggests that similar events may
occur if SARS CoV persists in humans.
Interspecies Transmission of Coronaviruses

The genus coronavirus is composed of at least three genetically and
autigenically distinct groups of CoV that cause mild to severe enteric, respiratory,
or systemic disease in domestic and wild animals, poultry, rodents, and carni-
vores and mild colds in humans (Table 3-1) The SARS CoV is genetically dis-
tantly related to known CoVs and comprises a provisional new group (IV)
(Drosten et al., 2003; Marra et al., 2003; Rota et al., 2003) or alternatively, using
rooted tree phylogenetic analysis, belongs to a subgroup of group II (Snijder et
al., 2003). Coronaviruses from two wild animal species (civet cats and raccoon
dogs) recently have been characterized genetically as members of the SARS CoV
group (Guan et al., 2003). Coronaviruses within each group share various levels
of genetic and antigenic relatedness and several show cross-species transmission.
Thus the likelihood that SARS CoV is a zoonotic infection potentially transmit-
ted from wild animals to humans is not unprecedented based on previous research
on interspecies transmission of animal CoV and wildlife reservoirs for CoV. As
examples, the porcine CoV, TGEV, and canine and feline CoVs can cross-infect
pigs, dogs, and cats with variable disease expression and levels of cross-protec-
tion in the heterologous host (Saif and Wesley, 1999; Saif and Heckert, 1990).
These three related CoVs appear to be host range mutants of an ancestral CoV.
Wildlife reservoirs for CoVs were recognized prior to SARS. Captive wild rumi-
nants harbor CoVs antigenically closely related to bovine CoV and CoV isolates
from the wild ruminants experimentally infected domestic calves (Tsunemitsu et
al., 1995; Majhdi et al., 1997). The promiscuousness of bovine CoV is evident by
infection of dogs and also humans by genetically similar (>97 percent identity)
CoV strains (Erles et al., 2003; Zhang et al., 1994). Even more dramatic than
infection of mammalian hosts by bovine CoV is the finding that bovine CoV can
experimentally infect and cause disease (diarrhea) in phylogenetically diverse
species such as avian hosts, including baby turkeys, but not baby chicks (Ismail et
al., 2001b). It is notable that in the latter study, the bovine CoV-infected baby
turkeys also transmitted the viruses to unexposed contact control birds. The rea-
sons for the broad host range of bovine CoV are unknown, but may relate to the

TABLE 3-1 Coronavirus Groups, Target Tissues, and Diseases
Disease/Infection Site
Genetic
Group Virus Host Respiratory Enterica Otherb
I HCoV-229E Human X upper
TGEV Pig X upper X S1
PRCV Pig X upper/lung Vitremia
PEDV Pig X SL, colon

F1PV Cat X upper X Systemic
FCoV Cat X S1
CCOV Dog X S1
RaCoV Rabbit Systemic
11 HCoV-OC43 Human X upper ?? (BCoV?)
NUN Mouse X Hepatitis, CNS,
RcoV Rat X systemic
(sialodocry- Eye, salivary glands
adenitis) Pig X CNS
BEV Cattle X upper/lung X S1, colon
BCoV
III IBV Chicken X upper X Kidney,
oviduct
TCoV (TECoV) Turkey X S1
IV?? SARS Human X lung X (?) Viremia, kidney?
IIA? Civet cat CoV Himalayan X X Subclinical?

palm civet

Raccoon dog
Raccoon dog CoV ? X Subclinical?
aSl= small intestine; ?? = BCoV-Iike CoV from a child, Zhang et al. (1994); ? = unknown.
bCNS = central nervous system.
141
presence of a hemagglutinin on bovine CoV and its possible role in binding to

diverse cell types.
Recent data suggest that SARS CoV may also have a broad host range be-
sides humans. Genetically similar CoVs were isolated from civet cats and rac-
coon dogs (Guan et al., 2003). In experimental studies, the SARS CoV infected
and caused disease in macaques and ferrets and infected cats subclinically
(Fouchier et al., 2003; Martina et al., 2003). In the latter two species, the SARS
CoV was further transmitted to exposed contacts, documenting transmission
within the new host species. Consequently, although previous data document the
emergence of new animal CoV strains and the broad host range of several CoVs,
the determinants for host range specificity among CoVs are undefined. In addi-
tion, we understand little about CoVs circulating in wildlife and relatively few
animal CoV strains have been fully sequenced for comparative phylogenetic
analysis to trace their evolutionary origins.
Pathogenesis of Animal Enteric and Respiratory Coronaviruses
Pathogenesis of Group I TGEV and PRCV CoV: Models of Enteric and

Respiratory Infections
Because both pneumonia and diarrhea occur in SARS patients, an understand-
ing of the tissue tropisms and pathogenesis of respiratory and enteric animal CoVs
should contribute to our understanding of similar parameters for SARS. The TGEV
targets the small intestinal epithelial cells leading to severe villous atrophy,
malabsorptive diarrhea, and a potentially fatal gastroenteritis (Table 3-1). The virus
also infects the upper respiratory tract with transient nasal shedding (Van Cott et al.,
1993), but infection or lesions in the lung are less common. In adults, TGEV is mild
with transient diarrhea or inappetence, but pregnant or lactating animals develop
more severe clinical signs and agalactia (Saif and Wesley, 1999).
The PRCV, an S gene deletion mutant of TGEV, has an altered tissue tro-
pism (respiratory) and reduced virulence (Laude et al., 1993; Saif and Wesley,
1999). Like SARS, PRCV spreads by droplets and has a pronounced tropism for
the lung, replicating to titers of 107-108 TCID50 and producing interstitial pneu-
monia affecting 5 to 60 percent of the lung (Cox et al., 1990; Halbur et al., 1993;
Laude et al., 1993; Saif and Wesley, 1999). Although many uncomplicated PRCV
infections are mild or subclinical, lung lesions are invariably present. Like SARS,
clinical signs of PRCV include fever with variable degrees of dyspnea, polypnea,
anorexia, and lethargy, and less coughing and rhinitis (Cox et al., 1990; Halbur et
al., 1993; Hayes, 2000; Laude et al., 1993; Saif and Wesley, 1999). Further re-
sembling SARS, PRCV replicates in lung epithelial cells, although viral antigen
is also detected in type I and II pneumocytes and alveolar macrophages. In lungs,
bronchiolar infiltration of mononuclear cells, lymphohistiocytic exudates, and
epithelial cell necrosis leads to interstitial pneumonia. PRCV induces transient

CORONAVIRUSES 143
viremia with virus also detected from nasal swabs and in tonsils and trachea,
similar to SARS (Drosten et al., 2003; Ksiazek et al., 2003; Peiris et al., 2003b).
The PRCV further replicates in undefined cells in the gut lamina propria, but
without inducing villous atrophy or diarrhea and with limited fecal shedding (Cox
et al., 1990; Saif and Wesley, 1999). Recently, however, fecal isolates of PRCV
were detected with consistent, minor point mutations in the S gene compared to
the nasal isolates from the same pig (Costantini et al., in press). Such observa-
tions suggest the presence of CoV quasispecies in the host with some strains more
adapted to the intestine, a potential corollary for the fecal shedding of SARS CoV
(Drosten et al., 2003; Ksiazek et al., 2003; Peiris et al., 2003a). Of further rel-
evance to SARS was the displacement of the virulent TGEV infections by the
widespread dissemination of PRCV in Europe and the disappearance of PRCV
from swine herds in summer with its reemergence in older pigs in winter (Laude
et al., 1993; Saif and Wesley, 1999).
Group II Bovine CoV (BCoV): Models of Pneumoenteric Infections

The shedding of SARS in feces of many patients and the occurrence of diar-
rhea in 10 to 27 percent of patients (Peiris et al., 2003a), but with a higher per-
centage (73 percent) in the Amoy Gardens, Hong Kong, outbreak (Chim et al.,
2003) suggests that SARS may be pneumoenteric like BCoV. BCoV causes three
distinct clinical syndromes in cattle: calf diarrhea; winter dysentery with hemor-
rhagic diarrhea in adults; and respiratory infections in cattle of various ages, in-
cluding cattle with shipping fever (Table 3-1) (Clark, 1993; Lathrop et al., 2000a;
Lathrop et al., 2000b; Saif and Heckert, 1990; Storz et al., 1996, 2000a,
Tsunemitsu et al., 1995). Based on BCoV antibody seroprevalence, the virus is
ubiquitous in cattle worldwide. All BCoV isolates from both enteric and respira-
tory infections are antigenically similar in virus neutralization (VN) tests, com-
prising a single serotype, but with two to three subtypes identified by VN or using
monoclonal antibodies (MAbs) (Clark, 1993; Hasoksuz et al., 1999a; Hasoksuz
et al., 1999b; Saif and Heckert, 1990; Tsunemitsu and Saif, 1995). In addition,
genetic differences (point mutations but not deletions) have been detected in the
S gene between enteric and respiratory isolates, including ones from the same
animal (Chouljenko et al., 2001; Hasoksuz et al., 2002b). Nevertheless, inocula-
tion of gnotobiotic or colostrum-deprived calves with calf diarrhea, winter dysen-
tery, or respiratory BCoV strains led to both nasal and fecal CoV shedding and
cross-protection against diarrhea after challenge with a calf diarrhea strain (Cho
et al., 2001b; El-Kanawati et al., 1996). However, subclinical nasal and fecal
virus shedding detected in calves challenged with the heterologous BCoV strains
(Cho et al., 2001b; El-Kanawati et al., 1996) confirmed field studies showing that
subclinically infected animals may be a reservoir for BCoV (Heckert et al., 1990,
1991). Cross-protection against BcoV-induced respiratory disease has not been
evaluated.

Calf Diarrhea and Calf Respiratory BCoV Infections

Calf diarrhea BCoV strains infect the epithelial cells of the distal small and
large intestine and superficial and crypt enterocytes of the colon, leading to vil-
lous atrophy and crypt hyperplasia (Saif and Heckert, 1990; Van Kruiningen et
al., 1987). One- to 4-week-old calves develop a severe, malabsorptive diarrhea,
resulting in dehydration and often death. Concurrent fecal and nasal shedding
often occur. BCoV are also implicated as a cause of mild respiratory disease
(coughing, rhinitis) or pneumonia in 2- to 24-month-old calves and are detected
in nasal secretions, lungs, and often the intestines (Clark, 1993; Heckert et al.,
1990; Heckert et al., 1991; Saif and Heckert, 1990). In studies of calves from
birth to 20 weeks of age, Heckert and colleagues (1990, 1991) documented both
fecal and nasal shedding of BCoV, with repeated respiratory shedding episodes
in the same animal with or without respiratory disease, and subsequent increases
in their serum antibody titers consistent with these reinfections. These findings
suggest a lack of long-term mucosal immunity in the upper respiratory tract after
natural CoV infection, confirming similar observations for human respiratory
CoV (Callow et al., 1990; Holmes, 2001).
Winter Dysentery BCoV Infections

Winter dysentery (WD) occurs in adult cattle during the winter months and
is characterized by hemorrhagic diarrhea, frequent respiratory signs, and a
marked reduction in milk production in dairy cattle (Saif, 1990; Saif and
Heckert, 1990; Van Kruiningen et al., 1987). Intestinal lesions and BCoV-in-
fected cells in the colonic crypts resemble those described for calf diarrhea. The
BCoV isolates from WD outbreaks at least partially reproduced the disease in
BCoV seropositive nonlactating cows (Tsunemitsu et al., 1999) and in BCoV
seronegative lactating cows (Traven et al., 2001). Interestingly, in the later
study, the older cattle were more severely affected than similarly exposed
calves, mimicking the milder SARS cases seen in children versus adults (Kamps
and Hoffmann, 2003a).
Shipping Fever BCoV Infections

More recent studies done in 1995 have implicated BCoV in association with
respiratory disease (shipping fever) in feedlot cattle (Lathrop et al., 2000a, Storz
et al., 1996). BCoV was isolated from nasal secretions and lungs of cattle with
pneumonia and from feces (Hasoksuz et al., 1999a, 2002a; Storz et al., 2000a, b).
In a subsequent study, a high percentage of feedlot cattle (45 percent) shed BCoV
both nasally and in feces by ELISA (Cho et al., 2001a). Application of nested
RT-PCR detected higher BCoV nasal and fecal shedding rates of 84 percent and
96 percent, respectively (Hasoksuz et al., 2002a).

CORONAVIRUSES 145
Cofactors That Exacerbate CoV Infections, Disease, or Shedding

Underlying disease or respiratory coinfections, dose and route of infection,
and immunosuppression (corticosteroids) are all potential cofactors related to the
severity of SARS. These cofactors can also exacerbate the severity of BCoV,
TGEV, or PRCV infections. In addition, these cofactors may play a role in the
superspreader cases seen in the SARS epidemic (Kamps and Hoffmann, 2003b)
by enhancing virus transmission.
Impact of Respiratory Co-Infections on CoV Infections, Disease, and Shedding

Shipping fever is recognized as a multifactorial, polymicrobial respiratory
disease complex in young adult feedlot cattle with several factors exacerbating
respiratory disease, including BCoV infections (Lathrop et al., 2000a,b; Storz et
al., 1996; Storz et al., 2000a; Storz et al., 2000b). Shipping fever can be precipi-
tated by several viruses, alone or in combination, including viruses similar to
common human respiratory viruses (BCoV, bovine resiratory syncytial virus,
parainfluenza-3 virus), bovine herpesvirus, and viruses capable of mediating im-
munosuppression (bovine viral diarrhea virus, etc.). The shipping of cattle long
distances to feedlots and the commingling of cattle from multiple farms creates
physical stresses that overwhelm the animal’s defense mechanisms and provides
close contact for exposure to new pathogens or strains not previously encoun-
tered. Such factors are analogous to the physical stress of long airplane trips with
close contact among individuals from diverse regions of the world, both of which
may play a role in enhancing an individual’s susceptibility to SARS. For shipping
fever, various predisposing factors (viruses, stress) allow commensal bacteria of
the nasal cavity (Mannheimia haemolytica, Pasteurella spp., Mycoplasma spp.,
etc.) to infect the lungs, leading to fatal fibrinous pneumonia (Lathrop et al.,
2000a,b; Storz et al., 1996, 2000a,b). Like PRCV or SARS infections, it is pos-
sible that antibiotic treatment of such individuals with massive release of bacte-
rial lipopolysaccharides (LPS) could precipitate induction of proinflammatory
cytokines, which may further enhance lung damage. For example, Van Reeth et
al. (2000) showed that pigs infected with PRCV followed by a subclinical dose of
E. coli LPS within 24 hours developed enhanced fever and more severe respira-
tory disease compared to each agent alone. They concluded that the effects were
likely mediated by the significantly enhanced levels of proinflammatory cytokines
induced by the bacterial LPS. Thus there is a need to examine both LPS and lung
cytokine levels in SARS patients as possible mediators of the severity of SARS.
Bacteria (Chlamydia spp.) have been isolated from SARS patients, but their role
in enhancing the severity of SARS is undefined (Poutanen et al., 2003).
Interactions between PRCV and other respiratory viruses may also parallel
the potential for concurrent or preexisting respiratory viral infections to interact
with SARS CoV (such as metapneumoviruses, influenza, reoviruses, respiratory

syncytial virus [RSV], OC43 or 229E CoV). Hayes (2000) showed that sequen-
tial dual infections of pigs with the arterivirus (order Nidovirales, like CoV)
PRRSV followed in 10 days by PRCV significantly enhanced lung lesions and
reduced weight gains compared to each virus alone. The dual infections also led
to more pigs shedding PRCV nasally for a prolonged period and surprisingly, to
fecal shedding of PRCV. The lung lesions observed resembled those in SARS
victims (Nicholls et al., 2003).
In another study, Van Reeth and Pensaert (1994) inoculated pigs with PRCV
followed in 2 to 3 days by swine influenza A virus (SIV). They found that SIV
lung titers were reduced in the dually compared to the singly infected pigs, but
paradoxically the lung lesions were more severe in the dually infected pigs. They
postulated that the high levels of IFN-alpha induced by PRCV may mediate inter-
ference with SIV replication but may also contribute to the enhanced lung le-
sions. Such studies are highly relevant to potential dual infections with SARS
CoV and influenza virus and potential treatments of SARS patients with IFN
alpha.
Impact of Route (Aerosols) and Dose on CoV Infections

Experimental inoculation of pigs with PRCV strains showed that administra-
tion of PRCV by aerosol compared to the oronasal route, or in higher doses,
resulted in higher virus titers shed and longer shedding (Van Cott et al., 1993). In
other studies, high PRCV doses induced more severe respiratory disease. Pigs
given 108.5 TCID50 of PRCV had more severe pneumonia and deaths than pigs
exposed by contact (Jabrane et al., 1994), and higher intranasal doses of another
PRCV strain (AR310) induced moderate respiratory disease whereas lower doses
produced subclinical infections (Halbur et al., 1993). By analogy, hospital proce-
dures that could potentially generate aerosols or exposure to higher initial doses
of SARS CoV may enhance SARS transmission or lead to enhanced respiratory
disease (Kamps and Hoffman, 2003a,b).
Impact of Treatment with Corticosteroids on CoV Infections of Animals

Corticosteroids are known to induce immunosuppression and reduce the
numbers of CD4 and CD8 T cells and certain cytokine levels (Giomarelli et al.,
2003). Many hospitalized SARS patients were treated with steroids to reduce
lung inflammation, but there are no data to assess the outcome of this treatment
on virus shedding or respiratory disease. A recrudescence of BCoV fecal shed-
ding was observed in one of four winter dysentery BCoV infected cows treated
with dexamethasone (Tsunemitsu et al., 1999). Similarly, treatment of older pigs
with dexamethasone prior to TGEV challenge led to profuse diarrhea and re-
duced lymphoproliferative responses in the treated pigs (Shimizu and Shimizu,
1979). These data raise issues for corticosteroid treatment of SARS patients re-

CORONAVIRUSES 147
lated to possible transient immunosuppression leading to enhanced respiratory

disease or increased and prolonged CoV shedding (superspreaders). Alternatively,
corticosteroid treatment may be beneficial in reducing proinflammatory cytokines
if found to play a major role in lung immunopathology (Giomarelli et al., 2003).
Group I Feline CoV (FCoV): Model for Systemic and Persistent CoV Infection
The spectrum of disease evident for FCoV (feline infectious peritonitis vi-
rus) exemplifies the impact of viral persistence and macrophage tropism on CoV
disease progression and severity. Historically, two types of FCoVs have been
recognized: feline enteric CoV (FECoV) and FIPV. Current information suggests
that the FECoV that causes acute enteric infections in cats establishes persistent
infections in some cats, evolving into the systemic virulent FIPV in 5 to 10 per-
cent of cats (deGroot and Horzinek, 1995; Herrewegh et al., 1997; Vennema et
al., 1995). The relevance of this model to SARS is whether similar persistent
CoV infections might occur in some patients, leading to the emergence of mac-
rophage-tropic mutants of enhanced virulence and precipitating systemic or im-
mune-mediated disease. The initial site of FCoV replication is in the pharyngeal,
respiratory, or intestinal epithelial cells (deGroot and Horzinek, 1995; Olsen,
1993), and clinical signs include anorexia, lethargy, and mild diarrhea. The pro-
longed incubation period for FIPV and its reactivation upon exposure to immuno-
suppressive viruses or corticosteroids suggested that FCoVs could cause chronic
enteric infections in cats (deGroot and Horzinek, 1995; Olsen, 1993). Recent
reports of chronic fecal shedding and persistence of FCoV mRNA or antigen in
infected cats confirm this scenario (Herrewegh et al., 1997).
A key pathogenetic event for development of FIPV is productive infection of
macrophages followed by cell-associated viremia and systemic dissemination of
virus (deGroot and Horzinek, 1995; Olsen, 1993). Stress (immunosuppressive
infections, transport to new environments, cat density) leading to immune sup-
pression may trigger FIP in chronically infected cats, similar to its role in ship-
ping fever CoV infections of cattle. Two major forms of FIP occur: (1) effusive,
with a fulminant course and death within weeks to months, and (2) noneffusive,
progressing more slowly (deGroot and Horzinek, 1995; Olsen, 1993). The effu-
sive form is characterized by fibrin-rich fluid accumulation in peritoneal, pleural,
pericardial, or renal spaces, with fever, anorexia, and weight loss. Noneffusive
FIP involves pyogranulomatous lesions with thrombosis, central nervous system,
or ocular involvement. Fulminant FIP with accelerated early deaths appears to be
immune mediated in FCoV seropositive cats. At least two mechanisms implicat-
ing IgG antibodies to FCoV S protein in FIP immunopathogenesis have been
described. In the first, circulating immune complexes (IC) with C’ depletion in
sera and IC in lesions are evident in cats with terminal FIP (deGroot and Horzinek,
1995). In the second, antibody dependent enhancement (ADE) of FCoV infection
of macrophages in vitro is mediated by neutralizing IgG MAbs to the S protein of

FIPV, or of interest, to the antigenically-related CoV, TGEV (Olsen et al., 1993).

Similar accelerated disease was seen in vivo in cats inoculated with recombinant
vaccinia virus expressing the S protein (but not the M or N proteins) of FIPV
(deGroot and Horzinek, 1995; Olsen et al., 1993). Thus the FIPV model provides
a frightening glimpse of the severity and potential complications associated with
a persistent, systemic CoV infection.
Group III CoVs: Infectious Bronchitis Virus (IBV): Model for Respiratory CoV
Infection with Other Target Tissues
The IBV is a highly contagious respiratory disease of chickens, like SARS,
spread by aerosol or possibly fecal-oral transmission, and distributed worldwide
(Cavanagh and Naqi, 2003; Cook and Mockett, 1995). Genetically and antigeni-
cally closely related CoV have been isolated from pheasants and turkeys (Guy et
al., 1997; Ismail et al., 2001a), but in young turkeys, they cause mainly enteritis.
Respiratory infections of chickens are characterized by tracheal rales, coughing,
and sneezing, with the disease most severe in chicks (Cavanagh and Naqi, 2003;
Cook and Mockett, 1995). The IBV also replicates in the oviduct, causing de-
creased egg production. Nephropathogenic strains can cause mortality in young
birds. In broilers, severe disease or death ensues from systemic E. coli co-infec-
tions after IBV damage to the respiratory tract or Mycoplasma sp. co-infections
with IBV. The IBV is recovered intermittently from the respiratory tract for about
28 days after infection and from the feces after clinical recovery, with the cecal
tonsil being a possible reservoir for IBV persistence, similar to the persistence of
FCoV in the intestine of cats (Herrewegh et al., 1997). The IBV was recovered
from both tracheal and cloacal swabs in chickens at onset of egg production,
suggesting re-excretion of IBV from chronically infected birds, as also demon-
strated for fecal shedding of FCoV or BCoV after induction of immunosuppres-
sion (Olsen, 1993; Tsunemitsu et al., 1999).
The IBV replicates in epithelial cells of the trachea and bronchi, intestinal
tract, oviduct, and kidney, causing necrosis and edema with small areas of pneu-
monia near large bronchi in the respiratory tract and interstitial nephritis in the
kidney (Cavanagh and Naqi, 2003; Cook and Mockett, 1995). Of interest for
SARS is the persistence of IBV in the kidney and its prolonged fecal shedding
because SARS CoV is detected in urine and shed longer term in feces. However,
it is unclear if SARS CoV shedding in urine is a consequence of viremia or a
kidney infection like IBV. Both diagnosis and control of IBV are complicated by
the existence of multiple serotypes and the occurrence of IBV recombinants
(Cavanagh and Naqi, 2003; Cook and Mockett, 1995). This is unlike the scenario
for most group 1 or 2 respiratory CoVs in which only one or two (FCoV) sero-
types are known. Also relevant to SARS CoV is the finding that IBV strains also
replicate in Vero cells, but only after passage in chicken embryo kidney cells
(Cavanagh and Nagi, 2003).

CORONAVIRUSES 149
In summary, studies of animal CoV infections in the natural host provide

enteric and respiratory disease models that enhance our understanding of both the
similarities and divergence of CoV disease pathogenesis and targets for control.
Unanswered questions for SARS pathogenesis, but highly relevant to the design
of strategies for prevention and control, include the following: What is the initial
site of viral replication? Is SARS CoV pneumoenteric like BCoV, with variable
degrees of infection of the intestinal and respiratory tracts and disease precipi-
tated by the co-factors discussed or unknown variables? Alternatively, is SARS
primarily targeted to the lung like PRCV, with fecal shedding of swallowed virus
and with undefined sequelae contributing to the diarrhea cases? Does SARS CoV
infect the lung directly or via viremia after initial replication in another site (oral
cavity, tonsils, upper respiratory tract) and does it productively infect secondary
target organs (intestine, kidney) via viremia after replication in the lung?
Finally, the persistent, macrophage tropic, systemic FIPV CoV infection of
cats presents yet another CoV disease model and a dilemma for attempted control
strategies. In this disease scenario, induction of neutralizing IgG antibodies to the
FIPV S protein not only fails to prevent FIPV infections, but actually potentiates
the immunopathogenesis of FIPV (Olsen, 1993).
The suspected zoonotic origin of SARS CoV (Guan et al., 2003) and the
recognized propensity of several CoV to cross species barriers illustrate the need
for additional animal studies of the mechanisms of interspecies transmission of
CoVs and adaptation to new hosts. The possible animal reservoir for SARS re-
mains undefined. At present we understand very little about CoVs or other vi-
ruses circulating in wildlife or their potential to emerge or recombine with exist-
ing CoVs (Stavrinides and Guttman, 2004) as public or animal health threats.
Hopefully the SARS epidemic will generate new interest and funding for these
fundamental research questions applicable not only to SARS CoV, but also to the
estimated 75 percent of newly emerging human diseases arising as zoonoses (Tay-
lor, 2001).
CORONAVIRUS RESEARCH: KEYS TO DIAGNOSIS, TREATMENT,

AND PREVENTION OF SARS
Mark R. Denison, M.D.
Department of Pediatrics, Department of Microbiology & Immunology,
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University
Medical Center, Nashville, TN
For coronavirus investigators, the recognition of a new coronavirus as the

cause of severe acute respiratory syndrome (SARS) was certainly remarkable, yet
perhaps not surprising (Baric et al., 1995). The cadre of investigators who have
worked with this intriguing family of viruses over the past 30 years are familiar
with many of the features of coronavirus biology, pathogenesis, and disease that

manifested so dramatically in the worldwide SARS epidemic. Advances in the

biology of coronaviruses have resulted in greater understanding of their capacity
for adaptation to new environments, transspecies infection, and emergence of
new diseases. New tools of cell and molecular biology have led to increased
understanding of intracellular replication and viral cell biology, and the advent in
the past five years of reverse genetic approaches to study coronaviruses has made
it possible to begin to define the determinants of viral replication, transpecies
adaptation, and human disease. This summary will discuss the basic life cycle
and replication of the well-studied coronavirus, mouse hepatitis virus (MHV),
identifying the unique characteristics of coronavirus biology and highlighting
critical points where research has made significant advances, and which might
represent targets for antivirals or vaccines. Areas where rapid progress has been
made in SCoV research will be described. Finally, areas of need for research in
coronavirus replication, genetics, and pathogenesis will be summarized.
Coronavirus Life Cycle

The best studied model for coronavirus replication and pathogenesis has been
the group 2 murine coronavirus, mouse hepatitis virus, and much of what is known
of the stages of the coronavirus life cycle has been determined in animals and in
culture using this virus. Thus this discussion will focus on MHV with compari-
sons to SCoV and other coronaviruses. This is appropriate because bioinformatics
analyses suggest that SCoV, while a distinct virus, has significant similarities in
organization, putative protein functions, and replication to the group II
coronaviruses, particularly within the replicase gene (Snijder et al., 2003). Excel-
lent, detailed reviews of MHV and coronavirus replication are available else-
where (Holmes and Lai, 1996; Lai and Cavanagh, 1997).
The coronavirus virion is an enveloped particle containing the spike (S),
membrane (M), and envelope (E) proteins. In addition, some strains of
coronaviruses, but not SCoV, express a hemagglutinin protein (HE) that is also
incorporated in the virion. The genome of coronaviruses is a linear, single-
stranded RNA molecule of positive (mRNA) polarity, and from 28 to 32 kb in
length (Bonilla et al., 1994; Drosten et al., 2003; Lee et al., 1991). Within the
virion, the genome is encapsidated by multiple copies of the nucleocapsid protein
(N), and has the conformation of a helical RNA/nucleocapsid structure. The S
protein has been a focus of pathogenesis studies in mice because it appears to be
the critical determinant of cell tropism, species specificity, host selection, cell
tropism, and disease (Navas and Weiss, 2003; Navas et al., 2001; Rao and
Gallagher, 1998).
Virus replication is initiated by binding of the S protein to specific receptors
on the host cell surface. For MHV, the primary receptor has been shown to be the
carcino-embryonic antigen–cell adhesion molecule (CEACAM) (Dveksler et al.,
1991; 1996; Holmes and Lai, 1996; Yokomuri and Lai, 1992), and for the human

CORONAVIRUSES 151
coronavirus, HCoV-229E, and other group 1 coronaviruses, the receptor is ami-

nopeptidase N (Yeager et al., 1992). The precise mechanisms of entry and
uncoating have yet to be defined, but likely occur by either fusion from without
or viroplexis through endocytic vesicles. For wildtype MHV, entry and uncoating
constitute a pH independent process that is probably direct fusion mediated by a
fusion peptide in the S protein (Gallagher et al., 1991). The understanding of the
region of the S1 component of coronavirus that binds to receptors was the basis
for studies leading to the very recent and very rapid identification of angiotensin
converting enzyme 2 (ACE 2) as a receptor for SCoV (Li et al., 2003).
The next discrete stage in the life cycle is translation and proteolytic process-
ing of viral replicase proteins from the input genome RNA, followed by forma-
tion of cytoplasmic replication complexes in association with cellular membranes
(Denison et al., 1999; Gosert et al., 2002; Shi et al., 1999; van der Meer et al.,
1999). Replication complexes are thought to be sites of all stages of viral RNA
transcription and replication, and possibly assembly of nascent viral nucleo-
capsids. Viral assembly occurs both temporally and physically distinct from viral
replication complexes in the endoplasmic-reticulum-Golgi-intermediate compart-
ment (ERGIC), a transitional zone between late ER and Golgi (deVries et al.,
1997; Klumperman et al., 1994; Krijnse-Locker et al., 1994; Rottier and Rose,
1987). Although the mechanisms by which replication products are delivered to
sites of assembly remain to be determined, it has been shown that subpopulations
of replicase proteins and the structural nucleocapsid (N) translocate from replica-
tion complexes to sites of assembly and may mediate the process in association
with cellular membrane/protein trafficking pathways (Bost et al., 2000). Virus
assembly in the ERGIC involves interactions of genome RNA, N, the membrane
protein (M), and the small membrane protein (E), resulting in budding of virions
into the lumen of ER/Golgi virosomes (Opstetten et al., 1995). Further matura-
tion of virus particles occurs during movement through the Golgi, resulting in
virosomes filled with mature particles (Salamuera et al., 1999). Trafficking of the
virosomes to the cell surface has not been well characterized, but is presumed to
occur via normal vesicle maturation and exocytic processes. The outcome is the
nonlytic release of the vast majority of mature virions into the extracellular space.
For MHV and several other coronaviruses that can directly fuse with cells, there
is a characteristic and rapidly detectable cytopathic effect of cell-cell fusion into
multinucleated syncytia. Production of infectious virus continues even after the
majority of cells are fused. Syncytia were recently reported as a readout of SCoV
receptor expression and cell infection (Li et al., 2003).
Viral Replication Complex Formation and Function

Following entry and uncoating, the 5′ most replicase gene of the input posi-
tive strand RNA genome is translated into two co-amino terminal replicase
polyproteins that are co- and post-translationally processed by viral proteinases

to yield 15 to 16 mature replicase proteins, as well as intermediate precursors.

The nascent replicase polyproteins and intermediate precursors likely mediate the
formation of viral replication complexes in the host cell cytoplasm. Interestingly,
coronavirus replication requires continuous replicase gene translation and pro-
cessing throughout the life cycle to maintain productive infection (Kim et al.,
1995; Perlman et al., 1987; Sawicki and Sawicki, 1986). Replication complexes
of MHV are associated with double-membrane vesicles (Gosert et al., 2002), and
all tested MHV replicase proteins have been shown to colocalize to replication
complexes at the earliest time of detection, likely both by membrane integration
and by protein-protein and protein-RNA interactions (Bost et al., 2000; Denison
et al., 1999; Prentice and Denison, in press; Shi et al., 1999; Sims et al., 2000; van
der Meer et al., 1999). Further, replicase proteins likely mediate the process of
double-membrane vesicle formation, likely by induction of cellular autophagy
pathways (E. Prentice, unpublished results).
Coronavirus replication complexes are sites for replicase gene translation and
replicase polyprotein processing, and also for viral RNA synthesis. Replicase gene
proteins likely mediate positive-strand, negative-strand, subgenomic, and genomic
RNA synthesis, as well as processes of capping, polyadenylation, RNA unwinding,
template switching during viral RNA synthesis, and discontinuous transcription
and transcription attenuation. The coronavirus replicase polyproteins and mature
replicase proteins represent the largest and most diverse repertoire of known and
predicted distinct enzymatic functions of any positive-strand RNA virus family.
Until recently, of the 15 or more mature replicase proteins, only the proteinase,
RNA helicase, and RNA-dependent RNA polymerase activities had been predicted
or experimentally confirmed (Brockway et al., 2003; Heusipp et al., 1997; Lee et
al., 1991; Ziebuhr et al., 2000). With the advent of SARS, more extensive
bioinformatics analyses have resulted in predictions of several additional functions
involved in RNA processing, including methyltransferase and exonuclease activi-
ties (Snijder et al., 2003; Thiel et al., 2003). Even with inclusion of distant predicted
relationships, up to eight of the replicase proteins remain without predicted or con-
firmed functions. In summary, it is likely that coronaviruses have exploited their
genetic capacity to encode proteins in the replicase gene with distinct functions in
RNA synthesis and processing, as well as proteins with specific roles in induction
or modification in host cellular membrane biogenesis and trafficking, delivery of
replication products to sites of assembly, and possibly virus assembly. Thus repli-
case translation, replicase polyprotein processing, and mature replicase proteins
constitute important targets for interference with coronavirus replication, virus-cell
interactions, or viral pathology.
Coronavirus Replicase Protein Expression and Processing

The proteinase activities for all coronaviruses include both papain-like pro-
teinase (PLP) and picornavirus 3C-like proteinase activities that are encoded

CORONAVIRUSES 153
within the replicase polyproteins and mediate both cis and trans cleavage events
(Ziebuhr et al., 2000). Because of the parallel evolution of the proteinases, their
cleavage sites, and the hierarchical cleavage processes, the proteolytic processing
of the coronavirus replicase proteins may serve as distinct regulatory and genetic
elements (Ziebuhr et al., 2001). Specifically, there are both conserved and diver-
gent regions of the replicase polyproteins by amino acid identity and similarity,
with the sequences and predicted mature proteins beginning with the 3C-like pro-
teinases through the carboxy terminus of the replicase polyprotein retaining higher
identity and similarity across the predicted proteins. In contrast, the amino-termi-
nal third of the replicase demonstrates the most variation in proteins, cleavage
site locations, and the number of proteinases that mediate maturation processing.
SCoV appears to have the general organization of, and similar protein sizes to,
the group 2 coronaviruses such as MHV in this part of the genome (Snijder et al.,
2003). However, SCoV likely uses only one PLP to mediate the cleavages, simi-
lar to the group 3 coronavirus infectious bronchitis virus (IBV). Thus this region
of the replicase may experience the most variability, suggesting either the encod-
ing of accessory functions that are flexible and tolerant of changes, or conversely
group or host-specific roles that are subject to pressure for more rapid change.
Expression of Structural and Accessory Genes

Only the 5' most replicase gene is translated from the input positive-strand
genome RNA. The genome contains multiple other genes for the known struc-
tural proteins S, E, M, and N, as well as other genes for expression of proteins that
have been labeled as “nonstructural” or “accessory” because they have been pre-
sumed to not be required for replication, and are not thought to be incorporated
into virions. MHV encodes six of these genes, while SCoV encodes possibly up
to 11 structural and accessory genes, which are expressed from subgenomic
mRNAs (Snijder et al., 2003). Subgenomic RNA transcription occurs during mi-
nus-strand RNA synthesis by acquisition of the antileader RNA sequences from
the 5′ end of the genome via homology to a transcriptional regulatory sequence
(TRS, also known as an intergenic sequence), and requiring a discontinuous ac-
tivity of the nascent minus-strand template and polymerase complex to acquire
the leader (Sawicki and Sawicki, 1998). The outcome of transcription is the gen-
eration of a “nested set” of subgenomic negative-strand RNAs that all contain the
antileader sequences that serve as templates for similar size subgenomic mRNAs.
This transcriptional strategy exposes different genes as the 5′ ORF in different
mRNAs, all of which also contain the 3′ sequence downstream of the gene, in-
cluding the 3′ nontranslated region of the genome.
For MHV, genes 3, 5b, 6, and 7 encode S, E, M, and N, respectively. Genes
2, 4, and 5a are not required for replication in culture, and have been mutated to
block expression, deleted, or substituted with noncoronavirus genes such as GFP
(de Haan et al., 2002; Ortego et al., 2003; Sarma et al., 2002). Because all

coronaviruses retain these genes in various combinations in the face of presumed

pressure for genetic economy and apparent lack of functions in RNA synthesis, it
is presumed that these genes serve roles in modification of host cells, pathogen-
esis, or interactions with the immune system. SCoV encodes a larger and more
complex array of these genes than MHV or other coronaviruses, which may re-
flect its evolution in its original animal host (Ksiazek et al., 2003; Marra et al.,
2003; Snijder et al., 2003; Thiel et al., 2003). In addition, the report of a deletion
within one of the accessory genes in human isolates of SCoV suggests that this
may be a gene involved in host range or adaptation for replication and transmis-
sion in humans (Guan et al., 2003).
Coronavirus Genetics
Until recently, the genetics of coronavirus replication and pathogenesis have
largely been studied using natural variants, host range mutants, passaged virus,
and mutagenized viruses selected for temperature sensitivity and specific pheno-
types. Classical complementation of functions made it possible to define at least
eight genetic groups for MHV, with most of the complementation groups local-
ized to the replicase gene (Stalcup et al., 1998). Taking advantage of naturally
high rates of homologous RNA-RNA recombination and of host range determi-
nants in the S protein, the development of targeted recombination has allowed
more defined and detailed studies of the accessory and structural genes of MHV,
transmissible gastroenteritis virus (TGEV), and feline infectious peritonitis virus
(FIPV) (Haijema et al., 2003; Kuo et al., 2000; Masters et al., 1994). Studies with
natural variants and targeted recombination genetic studies have demonstrated
that the S protein is the major determinant of host range, tropism, and pathogen-
esis; other genetic elements, possibly in the replicase, may influence these char-
acteristics of different coronaviruses (Navas and Weiss, 2003). The capacity of
coronaviruses to change host range, transmission, pathogenesis, and disease has
been established in the laboratory using cell adaptation and virus passage (Baric
et al., 1997, 1999; Chen and Baric, 1995, 1996), and has been demonstrated in
nature by natural variants of MHV, TGEV, and bovine coronavirus (BCoV), as
well as by studies using heterologous viruses such as canine coronavirus (CcoV)
to immunize cats against FIPV (Enjuanes et al., 1995; Tresnan et al., 1996). Fur-
ther, targeted recombination studies have confirmed the genetic flexibility of the
coronavirus genome and the ability of coronaviruses to recover wild-type replica-
tion following deletions, mutations, substitutions, and gene order rearrangements
in the structural and accessory genes (de Haan et al., 2002).
Challenges for genetic studies using natural variants and mutants, particu-
larly in defining the precise changes responsible for altered phenotypes, has lim-
ited progress in genetic studies. Targeted recombination, while a robust system
with powerful selection, has been limited to studies of the 3′ 10 kb of the MHV
genome, and is limited to selection of viable recombinants. Recently, the estab-

CORONAVIRUSES 155
lishment of “infectious clone” reverse genetic strategies for the coronaviruses

TGEV (Transmissible Gastroenteritis Coronavirus), HCoV-229E, IBV, and MHV
has made it theoretically possible to study the genetics of the entire genome and
all of the structural, accessory, and replicase genes. Approaches to “infectious
cloning” have included full-length cDNA clones of TGEV genome in bacterial
artificial chromosomes (Gonzalez et al., 2001), recombinant vaccinia viruses con-
taining full-length cDNA clones of HCoV-229E and IBV genomes (Casais et al.,
2001; Thiel et al., 2001), and in vitro assembly strategies for TGEV, MHV, and
most recently, SCoV (Yount, 2000; Yount et al., 2002, 2003).
The in vitro assembly approach was developed to overcome the challenge of
full-length cDNA cloning of the TGEV and MHV genomes, which contained
“toxic” regions in the replicase gene, resulting in unstable or toxic clones in E.
coli (Yount, 2000; Yount et al., 2002). Subcloning of the regions required split-
ting the toxic domains into separate clones. The result of this strategy was the
cloning of the MHV genome into seven fragments (A through G). To recover
viable virus, the following strategy is pursued: (1) cloned cDNA fragments are
excised from plasmid using class 2 restriction enzymes that remove the recogni-
tion site and leave overhanging genomic sequence; (2) excised fragments are
ligated (assembled) in vitro; (3) transcription of full-length genomic RNA is
driven in vitro using a T7 promoter on the 5′ fragment A; (4) full-length genome
RNA is electroporated into competent cells that are then plated on a monolayer of
naturally permissive cells; and (5) cells are monitored for cytopathic effect or
plaques, and virus is recovered from plaques or media supernatant.
In vitro assembly has many advantages for genetic studies of such a large
and complex genome RNA. First, genetic changes can be introduced and con-
firmed in stable small fragments without the need for a ~30kb genomic clone.
Second, the cloned fragments make it possible to develop libraries of mutations
that can rapidly be tested in different combinations. Furthermore, identification
of putative second-site reversion mutations for deleterious introduced changes
can be introduced with the original mutation to confirm their reversion poten-
tial. In combination with biochemical and cell imaging approaches, it also is
possible to study highly defective or lethal mutations in electroporated cells, in
order to define critical determinants of replication. The in vitro assembly ap-
proach has been used to introduce marker mutations that are silent for replica-
tion in culture (Yount et al., 2003). In addition, we have engineered mutations
in the MHV replicase gene to define the requirements for polyprotein process-
ing and to determine the role of specific replicase proteins in replication in
culture and in pathogenesis in animals. Using this approach we have recovered
viruses with mutations at polyprotein cleavage sites and proteinase catalytic
residues, all of which have distinct phenotypes in protein processing, viral
growth, and viral RNA synthesis (unpublished results). Thus, direct reverse
genetic studies of the critical replicase gene functions can be performed using
in vitro assembly of infectious clones.

Advances in SCoV Research

The rapid progress in the identification and characterization of SCoV as the
etiologic agent of SARS was made possible by the fact that the virus grows well
in culture, and by the foundational research in coronaviruses that has been sup-
ported by the National Institutes of Health, the Multiple Sclerosis Foundation, the
U.S. Department of Agriculture, and other organizations over the past two de-
cades. The application of knowledge concerning virus structure, genetics, recep-
tor binding, virus entry, and viral pathogenesis has made it possible to target the
spike protein for studies of SCoV replication, pathogenesis, and immune response
(Xiao et al., 2003). The remarkably rapid identification of ACE 2 as a receptor for
SARS has demonstrated the foundational importance of studies of other
coronaviruses (Li et al., 2003). Similarly, understanding of replicase gene expres-
sion, processing, and predicted functions has identified possible targets for struc-
ture/function studies and possible therapeutic intervention. The studies of
coronavirus proteinase activities, cleavage site, and structures were the basis for
studies leading to the rapid determination of SCoV replicase polyprotein cleav-
age sites and 3CLpro crystal structure (Anand et al., 2003; Campanacci et al.,
2003; Snijder et al., 2003; Thiel et al., 2003).
Application of Reverse Genetics to Studies of SCoV

Because of the potential for reemergence of SARS, it is important to move
forward with research in diagnostics, vaccines, and therapeutics for SCoV. Expe-
rience with the development and use of reverse genetics to study other
coronaviruses resulted in establishment of reverse genetics for SCoV within
months of the onset of the worldwide epidemic (Yount et al., 2003). How should
the understanding of other coronaviruses, the rapid advances in research with
SCoV, and the development of reverse genetics for SCoV be harnesssed to
achieve these goals and attack these critical questions in SCoV replication, patho-
genesis, and disease? Certainly, the use of SCoV reverse genetics, along with
robust tissue culture systems and emerging animal models, creates the potential
to rapidly answer questions concerning: (1) determinants of virus growth in cul-
ture; (2) potential mechanisms of transpecies adaptation; (3) sensitivity to and
escape from biochemical and immune interference with replication; (4) determi-
nants of virulence and pathogenesis; (5) mechanisms of genome recombination
and mutation; (6) functions of and requirements for replicase, structural, and ac-
cessory proteins; and (7) development of stably attenuated viruses for use as seed
stocks for inactivated vaccine or testing as live-attenuated vaccines.
How then should these critical issues be investigated while recognizing the
potential of SCoV to cause severe disease, as well as the potential for rapid
spread? First, there is significant experience with other coronaviruses in attenua-
tion of virus replication and pathogenesis, both using virus passage and by direct
engineering of changes. Although coronavirus genome organization, proteins, and
replication appear more tolerant of changes then previously thought, all changes

CORONAVIRUSES 157
of gene order, gene deletion, insertion, or mutagenesis so far reported have led to
viruses impaired in replication, pathogenesis, or both. Many of the attenuating
changes in MHV and other coronaviruses are conserved in SCoV and thus could
be tested for likely attenuation in SCoV culture and animal models. Second, where
there is clear conservation of sequences, motifs, proteins, or putative functions
between SCoV and model viruses such as MHV, new or untested changes might
be most rapidly analyzed under BSL2 conditions in those model viruses, and then
directly applied to SARS once their phenotypes are determined. Third, all work
with SCoV will be performed only under BSL3 conditions. This would also apply
to chimeric viruses, whether engineered by introduction into the SCoV back-
ground, or by introducing SCoV proteins or sequences with known or predicted
pathogenic consequences into other coronavirus backgrounds. Finally, it is im-
portant to develop strains of SCoV that are attenuated and stabilized against re-
version and recombination, to be used as the basis for studies of other replication
and pathogenesis determinants and construction of virus chimeras. Such attenu-
ated variants would provide additional safeguards while allowing application of
powerful genetic tools to the study of SCoV emergence, biology, disease, treat-
ment, and prevention. Overall, newly invigorated programs in other human and
animal coronaviruses, combined with the new research in SCoV, will shed im-
portant new light on this important virus family and perhaps lead to better under-
standing of the potential for resurgence of SCoV or the emergence of other
coronaviruses into human populations.
ISOLATION AND CHARACTERIZATION OF VIRUSES RELATED TO

THE SARS CORONAVIRUS FROM ANIMALS IN SOUTHERN CHINA
Y. Guan,1 B. J. Zheng,1 Y. Q. He,2 X. L. Liu,2 Z. X. Zhuang,2 C. L. Cheung,1
S. W. Luo,1 P. H. Li,1 L. J. Zhang,1 Y. J. Guan,1 K. M. Butt,1 K. L. Wong,1 K. W.
Chan,3 W. Lim,4 K. F. Shortridge,1 K. Y. Yuen,1 J. S. M. Peiris,1 and L. L. M. Poon1,5
Reprinted with permission from Guan et al., 2003. Copyright 2003 AAAS.
A novel coronavirus (SCoV) is the etiological agent of severe acute respiratory

syndrome (SARS). SCoV-like viruses were isolated from Himalayan palm civets
1Department of Microbiology, The University of Hong Kong, University Pathology Building, Queen
Mary Hospital, Hong Kong Special Administrative Region (S.A.R.), of the People’s Republic of
China (China).
2Center for Disease Control and Prevention, Shenzhen, Guangdong Province, China.
3Department of Pathology, The University of Hong Kong, University Pathology Building, Queen
Mary Hospital, Hong Kong S.A.R., China.

4Government Virus Unit, Department of Health, Hong Kong S.A.R., China.
5We thank the Department of Health and Department of Agriculture of Shenzhen Government for
facilitating the study. We gratefully acknowledge the encouragement and support of L.C. Tsui, Vice-
Chancellor, The University of Hong Kong. We thank X.Y. Zhao from the Department of Microbiol-

found in a live-animal market in Guangdong, China. Evidence of virus infection

was also detected in other animals (including a raccoon dog, Nyctereutes
procyonoides) and in humans working at the same market. All the animal isolates
retain a 29-nucleotide sequence that is not found in most human isolates. The detec-
tion of SCoV-like viruses in small, live wild mammals in a retail market indicates a
route of interspecies transmission, although the natural reservoir is not known.
Severe acute respiratory syndrome (SARS) recently emerged as a human disease
associated with pneumonia (WHO, 2003c). This disease was first recognized in
Guangdong Province, China, in November 2002. Subsequent to its introduction to
Hong Kong in mid-February 2003, the virus spread to more than 30 countries and
caused disease in more than 7900 patients across five continents (WHO, 2003d). A
novel coronavirus (SCoV) was identified as the etiological agent of SARS (Ksiazek et
al., 2003; Peiris et al., 2003a), and the virus causes a similar disease in cynomolgous
macaques (Fouchier et al., 2003). Human SCoV appears to be an animal virus that
crossed to humans relatively recently. Thus, identifying animals carrying the virus is
of major scientific interest and public health importance. This prompted us to exam-
ine a range of domestic and wild mammals in Guangdong Province.
Because the early cases of SARS in Guangdong reportedly occurred in res-
taurant workers handling wild mammals as exotic food (Zhong et al., 2003), our
attention focused on wild animals recently captured and marketed for culinary
purposes. We investigated a live-animal retail market in Shenzhen. Animals were
held, one per cage, in small wire cages. The animals sampled included seven
wild, and one domestic, animal species (see Table 3-2). They originated from
different regions of southern China and had been kept in separate storehouses
before arrival to the market. The animals remained in the markets for a variable
period of time, and each stall holder had only a few animals of a given species.
Animals from different stalls within the market were sampled. Nasal and fecal
samples were collected with swabs and stored in medium 199 with bovine serum
albumin and antibiotics. Where possible, blood samples were collected for serol-
ogy. Before sampling, all animals were examined by a veterinary surgeon and
confirmed to be free of overt disease. Serum samples were also obtained, after
informed consent, from traders in animals (n = 35) and vegetables (n = 20) within
the market. Sera (n = 60) submitted for routine laboratory tests from patients
ogy, The University of Hong Kong, for the excellent technical assistance. We also thank C.C. Hon
and F.C. Leung from the Department of Zoology, The University of Hong Kong, and Richard Webby
from St. Jude Children’s Research Hospital (Memphis, TN) for assistance in the phylogenetic analy-
sis. We thank K.V. Holmes’ laboratory from the Department of Microbiology, University of Colorado
Health Sciences Center (Denver, CO) for validating the animal viral sequences. Supported by re-
search funding from Public Health Research (Grant A195357), the U.S. National Institute of Allergy
and Infectious Diseases, the Wellcome Trust (067072/D/02/Z), and SARS research funds from The
University of Hong Kong.

CORONAVIRUSES 159
TABLE 3-2 Animal Species Tested for Coronavirus Detection

Virus detection
RT-PCR Isolation
Sample number Animal N F N F Titer to SZ16
SZ1 HPC +* + ND
SZ2 HPC + + 40
SZ3 HPC + + +* 40
SZ4 HB <20
SZ5 B <20
SZ6 DC ND
SZ7 DC <20
SZ8 CH ND
SZ9 CH <20
SZ10 CM <20
SZ11 CFB 160
SZ12 CFB <20
SZ13 RD + +* 640
SZ14 CM <20
SZ15 B <20
SZ16 HPC + + +* + <20
SZ17 HPC + 640
SZ18 B <20
SZ19 CH <20
SZ20 CH <20
SZ21 DC <20
SZ22 DC <20
SZ23 HB ND
SZ24 HB ND
SZ25 HPC + ND
NOTE: Abbreviations of animal species: B = beaver (Castor fiber); CFB = Chinese ferret-badger
(Melogale moschata); CH = Chinese hare (Lepus sinensis); CM = Chinese muntjac (Muntiacus reevesi);
DC = domestic cat (Felis catus); HB = hog-badger (Arctonyx collaris); HPC = Himalayan palm civet (P.
larvata); RD = raccoon dog (N. procyonoides) (China species information system, 2003); N = nasal
sample; F = fecal sample; titer to SZ16, neutralizing antibody titer to SZ16; + denotes positive by RT-
PCR or virus isolation; *denotes the PCR product or virus isolates sequenced in the study; ND = not
done.
hospitalized for nonrespiratory disease in Guangdong were made anonymous and

used for comparison.
Nasal and fecal swabs from 25 animals were tested for SCoV viral nucleic
acid by using reverse transcription–polymerase chain reaction (RT-PCR) for the
N gene of the human SCoV. Swabs from four of six Himalayan palm civets were
positive in the RT-PCR assay (see Table 3-2). All specimens were inoculated into
FRhK-4 cells as previously described for virus isolation (Peiris et al., 2003a). A
cytopathic effect was observed in cells inoculated with specimens from four Hi-
malayan palm civets (Paguma larvata), two of which also positive for coronavirus
in the original specimen by RT-PCR. A virus was also detected by virus isolation

and direct RT-PCR from the fecal swab of a raccoon dog (Nyctereutes
procyonoides). No virus was detectable in six other species sampled. Electron
microscopy of one infected cell supernatant (SZ16) showed viral particles with a
morphology compatible with coronavirus (see Figure S-1)6. Sera from five animals
had neutralizing antibody to the animal coronavirus; these were from three palm
civets, a raccoon dog, and a Chinese ferret badger, respectively (see Table 3-2).
To further validate the results from the neutralization test, a Western blot
assay was used to detect SCoV-specific antibodies from these animal serum
samples (see Figure 3-1). Indications of positive antibodies were observed from
samples SZ2, SZ3, SZ11, and SZ17 (which were also positive in the neutraliza-
tion assay) and from the positive control human serum. No positive signal was
observed from those serum samples that were negative in the neutralization test.
There was insufficient serum left over from the raccoon dog (SZ13) to be ana-
lyzed by this assay.
Sera from humans working in the market were tested for antibody to SZ16
virus by neutralization and indirect immunofluorescence assays. Although 8 out
of 20 (40 percent) of the wild-animal traders and 3 of 15 (20 percent) of those
who slaughter these animals had evidence of antibody, only 1 (5 percent) of 20
vegetable traders was seropositive. None of these workers reported SARS-like
symptoms in the past 6 months. In comparison, none of 60 control sera from
patients admitted to a Guangdong hospital for nonrespiratory diseases was serop-
ositive (see Table 3-3).
Two of the virus isolates (SZ3 and SZ16) isolated from the nasal swabs of
palm civets were completely sequenced, and the amino acid sequence was de-
duced. Two other viruses were partially sequenced, from the S gene to the 3' end
of the virus (GenBank accession numbers AY304486 to AY304489). Viral RNA
sequences from these original swab samples from animal were confirmed in an
independent laboratory (Holmes K., unpublished observations). The full-length
genome sequences had 99.8 percent homology to the human SCoV, which indi-
cates that the human and animal SCoV-like viruses were closely related. Phylo-
genetic analysis of the S gene of both human and animal SCoV-like viruses indi-
cated that the animal viruses are separate from the human virus cluster (see Figure
3-2 and Figure S-2)7 . However, the viruses SZ1, SZ3, and SZ16 from palm civets
were phylogenetically distinct. The viruses SZ3 and SZ16 had 18 nucleotide dif-
ferences between them over the 29,709–base pair (bp) genome, whereas the hu-
man SCoV isolated from five geographically separate sites (GZ50, CUHK-W1,
6Supporting online material, www.sciencemag.org/cgi/content/full/1087139/DC1, Materials and
Methods, Figures S1 and S2, and References and Notes.

7Supporting online material, www.sciencemag.org/cgi/content/full/1087139/DC1, Materials and
Methods, Figures S1 and S2, and References and Notes.

CORONAVIRUSES 161
FIGURE 3-1 Detection of antibodies against recombinant nucleocapsid protein of SCoV

in animal sera by Western blot assay. Recombinant nuleocapsid protein (NP, 49.6 kD) was
used as an antigen to detect anti-ScoV antibodies in animal sera. Protein A-HRP was used
as a secondary antibody, and reactive bands were visualized by the enhanced
chemiluminesence Western blotting system. A serum sample from a convalescent SARS
patient was used as a positive control. Blots reacted with animal (SZ2, SZ3, SZ11, SZ17,
SZ7, SZ16, or SZ19) or human sera are indicated. Results from the neutralization test for
ScoV-specific antibodies in these serum samples are also shown.
TABLE 3-3 Prevalence of Antibody to Animal SCoV SZ16 in Humans.

Controls Are Serum Specimens from Patients Hospitalized for Nonrespiratory
Diseases in Guangdong Made Anonymous
Occupation Sample numbers Antibody positive (%)
Wild-animal trader 20 8 (40)
Slaughterer of animals 15 3 (20)
Vegetable trader 20 1 (5)
Control 60 0 (0)

FIGURE 3-2 Phylogenetic analysis of the nucleotide acid sequence of the spike gene of
SCoV-like viruses. Nucleotide sequences of representative SCoV Sgenes (Sgene coding
region 21477 to 25244, 3768 bp) were analyzed. The phylogenetic tree was constructed by
the neighbor-joining method with bootstrap analysis (1000 replicates) using MEGA 2 (Kumar
et al., 2001). Number at the nodes indicates bootstrap values in percentage. The scale bar
shows genetic distance estimated using Kimura’s two-parameter substitution model (Kimura,
1980). In addition to viruses sequenced in the present study, the other sequences used in the
analysis could be found in GenBank with accession number: from AY304490 to AY304495,
AY278741, AY278554 , AY278491, AY274119, and AY278489.
Tor-2, HKU-39848, and Urbani) differed by only 14 nucleotides (nt). Neverthe-

less, animal virus SZ13 (raccoon dog) and SZ16 (palm civet) were genetically
almost identical, and transmission or contamination from one host to the other
within the market cannot be excluded.
When the full genome of the animal (n = 2) and human (n = 5, see above)
virus groups were compared, the most striking difference was that these human
viruses have a 29-nt deletion (5'-CCTACTGGTTACCAACCTGAATG-
GAATAT-3', residue 27869 to 27897) that is 246 nt upstream of the start codon
of the N gene (see Figure 3-3). Of human SCoV sequences currently available in
GenBank, there was only one (GZ01) with this additional 29-nt sequence. In ad-
dition to that, there were 43 to 57 nucleotide differences observed over the rest of
the genome. Most of these differences were found in the S gene coding region.
The existence of the additional 29-nt sequence in the animal viruses results in
demolishing the open reading frames (ORFs) 10 and 11 (Marra et al., 2003) and
merging these two ORFs into a new ORF encoding a putative protein of 122

CORONAVIRUSES 163
amino acids (see Figure 3-3). This putative peptide has a high homology to the
putative proteins encoded by ORF10 and ORF11. Because ORF11 does not have
a typical transcription regulatory sequence for SCoV (Marra et al., 2003), the
putative ORF11 reported by others may just be the direct result of the deletion of
the 29-nt sequence. BLAST search of this peptide yields no significant match to
any other known peptide. Further investigation is required to elucidate the bio-
logical significance of this finding.
When the S-gene sequences of the four animal viruses were compared with
11 human SCoV viruses, 38 nucleotide polymorphisms were noted, and 26 of
them were nonsynonymous changes (see Table 3-4). The S genes among the four
FIGURE 3-3 A 29-nt deletion in the human SCoV genome. (A) Genetic organization of
SCoV-like viruses found in humans and animals. ORFs 1a and 1b, encoding the
nonstructural polyproteins, and those encoding the S, E, M, and N structural proteins are
indicated (green boxes). (B) Expanded view of the SCoV genomic sequence (27700 nt to
28200 nt, based on AY278554 numbering). ORFs for putative proteins and for N in human
isolates are indicated as brown and green boxes, respectively (Marra et al., 2003). An extra
29-nt sequence is present downstream of the nucleotide of 27868 of the animal SCoV
(based on AY278554 numbering). The presence of this 29-nt sequence in animals isolates
results in fusing the ORFs 10 and 11 (top) into a new ORF (bottom; ORF10', light blue
box). (C) Protein sequence alignment of ORF10 and 11 from human isolates and ORF 10'
from animal isolates.

164
TABLE 3-4 Nucleotide Sequence Variation of the S Gene of Animal and Human SCoV
Nucleotide residue
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 5
6 6 6 6 7 7 1 1 1 2 2 2 4 5 5 5 6 9 9 9 0 1 2 2 4 5 6 7 7 8 8 1 1 3 5 8 9 0
2 9 9 9 0 0 3 5 9 0 0 5 0 0 0 5 4 1 3 7 0 4 0 9 7 7 1 0 3 0 5 5 9 6 5 5 6 1
Virus 2 0 1 2 0 6 0 7 2 5 7 8 7 2 7 5 6 3 6 8 3 8 5 5 0 8 7 3 7 8 6 6 7 8 1 7 3 2
SZ3 C A T T C A T A T T C A G G G C A A G T G T T C C T C G T G C G C G C T G T
SZ16 C A T T C A T A T C C A G G G C G A G T G A T C C T C G T G C G C T C T G T
SZ1 C A T T C A T A T T C A G G G C G A G T T A T C C T T G T G C G T T T T G T
SZ13 C A T T C A T A T T C A G G G C G A G T G A T C C T C G T G C G C T C T G T
GZ01 C A T T C A C C T C C C A G G T G T C A G T T T T C C A C G T A C G C T A T
GZ43 C – – – G A T C T C C C A G G T G T C T G T T T C C C A C G C A C G C T A C
GZ60 C – – – G A T C T C C C A G G T G T C T G T T T C C C A C G C A C G C T A C
GZ50 T A T T C A T C C C C C G A A T G T C T G T T T T C C A C G C A C G T T A T
CUHK-W1 C A T T C A T C C C C C G A A T G T C T G T T T T C C A C T C A C G T T A T
HKU-36871 C A T T C A T C C C C C G A A T G T C T G T T T T C C A C T C A C G T T A T
HKU-39848 C A T T C G T C C C T C G A A T G T C T G T T T T C C A C T C A C G T T A T
Urbani C A T T C G T C C C T C G A A T G T C T G T T T T C C A C T C A C G T C A T

Tor2 C A T T C G T C C C T C G A A T G T C T G T G T T C C A C T C A C G T T A T
NOTE: The nucleotide residues are based on AY278554 numbering. Nonsilent mutations are highlighted in bold. Dash indicates a nucleotide deletion.
CORONAVIRUSES 165
animal viruses had eight nucleotide differences, whereas there were 20 nucleotide
differences among 11 human viruses. Thus, the animal viruses, although isolated
from one market, are no less divergent than the human viruses isolated from Hong
Kong, Guangdong, Canada, and Vietnam. However, whereas 14 (70 percent) of
the 20 polymorphisms among the human viruses were nonsynonymous muta-
tions, only two (25 percent) of the eight nucleotide substitutions within the animal
viruses were. An amino acid deletion (nucleotide positions 21690 to 21692) was
observed in two of the human viruses (GZ43 and GZ60). Of the 38 polymor-
phisms, there were 11 consistent nucleotide signatures that appeared to distin-
guish animal and human viruses. The observation that the human and animal
viruses are phylogenetically distinct (see Figure 3-2) makes it highly unlikely that
the SCoV-like viruses isolated in these wild animals is due to the transmission of
SCoV from human to animals.
Our findings suggest that the markets provide a venue for the animal SCoV-
like viruses to amplify and to be transmitted to new hosts, including humans, and
this is critically important from the point of view of public health. However, it is
not clear whether any one or more of these animals are the natural reservoir in the
wild. It is conceivable that civets, raccoon dog, and ferret badgers were all in-
fected from another, as yet unknown, animal source, which is in fact the true
reservoir in nature. However, because of the culinary practices of southern China,
these market animals may be intermediate hosts that increase the opportunity for
transmission of infection to humans. Further extensive surveillance on animals
will help to better understand the animal reservoir in nature and the interspecies
transmission events that led to the origin of the SARS outbreak.
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Diagnostics, Therapeutics, and Other

Technologies to Control SARS
OVERVIEW
The strong possibility that SARS will return is being addressed by multiple
sectors, including public health planners preparing for a broad range of chal-
lenges and contingencies (see also Chapter 1); researchers developing clinical
diagnostics and technologies for infection control, as well as antiviral drugs and
vaccines; and epidemiologists searching for clues from the recent SARS epidemic
that could prevent a future outbreak or reduce its impact. Each of these perspec-
tives is discussed in this chapter.
The development of a diagnostic test to rapidly detect SARS in its early
stages is a top research priority. Because researchers do not know which tissues
contain the highest concentrations of virus in the presymptomatic stages of in-
fection, this task is particularly challenging. Reverse-transcription polymerase
chain reaction (RT-PCR), a method to detect viral nucleic acids, is considered
to be a likely platform for early SARS testing due to its high analytical sensitiv-
ity and speed. An evaluation of two RT-PCR protocols presented in this chapter
found them to be highly specific for the SARS coronavirus; however, the tests
were determined to be insufficiently sensitive to reliably detect the virus in
respiratory specimens. Without a clinical diagnostic test, suspected cases of
SARS must be confirmed in the laboratory, using RT-PCR or slower methods
of detection—involving serology or viral culture, isolation, and identification
by electron microscopy—thereby causing a significant increase in the time re-
quired for an accurate diagnosis.
173

This chapter also includes a description of an alternative diagnostic plat-

form—the mass spectroscopic identification of microbial nucleic acid signa-
tures—that can be adapted to detect the SARS coronavirus. Using technology
originally designed for the environmental surveillance of biowarfare agents,
this platform could potentially identify the SARS virus directly from a patient
sample, obviating the need for time-consuming viral culture. This method is
designed to distinguish between SARS and other coronaviruses, and perhaps
even between genetic variants of the SARS virus; however, direct comparisons
of sensitivity between this and other SARS detection systems using patient
samples have yet to be conducted.
Several workshop participants expressed concern about the limited ca-
pacity in health care systems—particularly related to workforce and facili-
ties shortages—that present a significant barrier to preparations for SARS
and other threats to public health. It was suggested at the workshop by
Jerome Schentag that this situation might be mitigated in some degree
through the use of flexible approaches to isolating SARS patients. One
such approach, discussed in this chapter, is a mobile technology that de-
stroys viral particles and droplets in the air. These mobile units, by isolating
individual patients being transported to and within hospitals, potentially
could be used to protect staff during high-risk procedures such as intubation
or bronchoscopy, to decontaminate larger areas such as hospital waiting
rooms or airplanes, and to create air exchange systems for isolation facili-
ties or areas within hospitals. Importantly however, it was noted during the
workshop that the technologies described here must be thoroughly evalu-
ated to determine their suitability for containing SARS in a variety of clini-
cal settings before they are recommended for use.
Research has proceeded rapidly to develop antiviral drugs and vaccines to
combat SARS. Previous antiviral discovery efforts by researchers at Pfizer on the
human rhinovirus protease 3C—a functional, genetic, and structural analog to a
key SARS coronavirus protease that has therefore been named “3C-like” (3CL)—
are recounted in this chapter. This knowledge has aided in a search for 3CL
protease inhibitors, a project undertaken by Pfizer in collaboration with scientists
at the National Institute of Allergy and Infectious Diseases and the U.S. Army
Medical Research Institute of Infectious Diseases (USAMRIID). Several candi-
date inhibitors have been selected by bioassay and are currently being evaluated
for clinical development, while others are being sought through alternative strat-
egies such as structure-based design and combinatorial chemistry. A vaccine for
SARS—even if steered along a highly streamlined route to development—might
still postdate a return of SARS, perhaps by several years. Nevertheless, because
the medical need for developing such a vaccine and/or effective antiviral drugs is
perceived to be acute, several pharmaceutical and biotechnology companies have
taken up this challenge.

DIAGNOSTICS, THERAPEUTICS, AND OTHER TECHNOLOGIES 175
EVALUATION OF REVERSE TRANSCRIPTION-PCR ASSAYS FOR

RAPID DIAGNOSIS OF SEVERE ACUTE RESPIRATORY
SYNDROME ASSOCIATED WITH A NOVEL CORONAVIRUS
W.C. Yam, K.H. Chan, L.L.M. Poon, Y. Guan, K.Y. Yuen,

W.H. Seto, and J.S.M. Peiris
Department of Microbiology, Queen Mary Hospital, The University of
Hong Kong, Hong Kong, People’s Republic of China
Reprinted with permission, American Society for Microbiology.
Copyright 2003, American Society for Microbiology. All Rights Reserved.
The reverse transcription (RT)-PCR protocols of two World Health Organi-

zation (WHO) severe acute respiratory syndrome (SARS) network laboratories
(WHO SARS network laboratories at The University of Hong Kong [WHO-HKU]
and at the Bernhard-Nocht Institute in Hamburg, Germany [WHO-Hamburg])
were evaluated for rapid diagnosis of a novel coronavirus (CoV) associated with
SARS in Hong Kong. A total of 303 clinical specimens were collected from 163
patients suspected to have SARS. The end point of both WHO-HKU and WHO-
Hamburg RT-PCR assays was determined to be 0.1 50 percent tissue culture
infective dose. Using seroconversion to CoV as the “gold standard” for SARS
CoV diagnosis, WHO-HKU and WHO-Hamburg RT-PCR assays exhibited diag-
nostic sensitivities of 61 and 68 percent (nasopharyngeal aspirate specimens), 65
and 72 percent (throat swab specimens), 50 and 54 percent (urine specimens),
and 58 and 63 percent (stool specimens), respectively, with an overall specificity
of 100 percent. For patients confirmed to have SARS CoV and from whom two or
more respiratory specimens were collected, testing the second specimen increased
the sensitivity from 64 and 71 percent to 75 and 79 percent for the WHO-HKU
and WHO-Hamburg RT-PCR assays, respectively. Testing more than one respi-
ratory specimen will maximize the sensitivity of PCR assays for SARS CoV.
A global outbreak of a new emerging illness, severe acute respiratory syn-
drome (SARS), was associated with a novel coronavirus, SARS CoV (Lee et al.,
2003; Peiris et al., 2003a; Tsang et al., 2003). By the end of April 2003, more than
1,500 patients were diagnosed with SARS in Hong Kong. Transmission within
hospitals was a major contributor to disease amplification. Rapid laboratory con-
firmation of SARS CoV infection was important for managing patient care and
for preventing nosocomial transmission. While serological testing was reliable as
a retrospective diagnostic method, diagnosis of the infection in the early phase of
the illness was important for patient care. The identification of the etiological
agent and its partial gene sequence data made it possible to develop molecular
diagnostic methods for SARS CoV (Drosten et al., 2003; Peiris et al., 2003b). The
protocols were made available through the WHO website (http://www.who.int/
csr/sars/primers/en). This study evaluates two of the first-generation reverse tran-
scription (RT)-PCR assays that were used during this outbreak.

Materials and Methods
Patients and Specimen Collection

Specimens were available for 163 patients who presented with clinically sus-
pected SARS according to the WHO definition (WHO, 2003) and who were ad-
mitted to three acute regional hospitals in Hong Kong between 26 February and
17 April 2003. For each patient, paired acute- and convalescent-phase serum
samples and at least one respiratory specimen were collected for study. A total of
303 specimens (124 nasopharyngeal aspirate specimens, 65 throat swab speci-
mens, 95 urine specimens, and 19 stool specimens) were available for study.
Respiratory specimens were collected between days 1 and 5 after admission,
whereas urine and stool specimens were collected between days 5 and 10. The
acute-phase sera were collected in the first week of illness, and the convalescent-
phase sera were collected 21 days after the onset of clinical symptoms. Nasopha-
ryngeal aspirate specimens were assessed by rapid direct immunofluorescent an-
tigen detection for influenza virus A and B, para-influenza virus types 1, 2, and 3,
respiratory syncytial virus (RSV), and adenovirus as described previously (Chan
et al., 2002). Paired serum samples were assayed for increasing titer against CoV.
Nasopharyngeal aspirate and stool specimens from patients suffering from unre-
lated diseases were collected as controls.
Extraction of CoV RNA

Nasopharyngeal aspirate and throat swab specimens were suspended in viral
transport medium. Urine specimens were transported in sterile containers. Stool
specimens were mixed in viral transport medium (diluted 1:10) and
microcentrifuged at 10,000 × g for 1 min, and supernatant was collected. Viral
RNA was extracted from 140 µl samples using a Qiagen viral RNA mini kit
(Qiagen, Hilden, Germany). The initial processing of specimens was performed
under biohazard level 2 containment conditions. After lysis of the sample by the
lysing buffer, the mixture was applied to a spin column as described by the manu-
facturer. The extracted RNA was eluted in a total volume of 50 µl of RNase-free
water before RT-PCR amplification.
RT-PCR Amplification
The RT-PCR protocols of two WHO SARS network laboratories (Table 4-1)
were evaluated in this study. The WHO SARS network laboratory at the Univer-
sity of Hong Kong (WHO-HKU) used a single RT step to synthesize cDNA,
followed by subsequent PCR amplification with specific primers in another reac-
tion tube (Peiris et al., 2003a). The WHO SARS network laboratory at the
Bernhard-Nocht Institute in Hamburg, Germany (WHO-Hamburg) used a single

TABLE 4-1 RT-PCR Protocols for Rapid Diagnosis of CoV Associated with SARSa
Characterisitic
or component WHO-HKU
of protocol RT PCR RT-PVR Second PCR
Primer TACACACCIFCAGCGTTG ATGAATTACCAAGTCAATGGTTAC GAAGCTATfCGTCACG

sequences CACGAACGTIGACGAAT CATAACCAGTCGGTACAGCTAC CTGTAGAAAATCCTAGCTGGAG
Sense
Antisense
Reagent Superscript II RTA ( Invitrogen) AmpliTaq Gold (Roche) Superscript II RT-PCR (Invitrogen) AmpliTaq Gold (Roche)
formulation (i) 4 µl of 5x first-strand buffer (i) 5 µl of 10x reaction buffer (i) 10µl of 2x reaction buffer (i) 5 µl of 10x reaction buffer
(ii) 10 mM DTT (ii) 200 µM dlU (ii) 2.45 mM MgSO4 (ii) 200 µM dNTP
(iii) 500 µMdNTP (iii) 2.5 µM MgSO4 (iii) 500 µM (each) primer (iii) 2.5 µM MgSo4
(iv) 0.15 µg of random primer (iv) 250 nM (each) primer (iv) 0.4 µl of RTA-Taq mixture (iv) 200 nM (each) primer
(v) 200 U of Superscript II (v) 2 U of AmpliTaq Gold (v) 2 µl of RNA extract (v) 2 U of AmpliTaq Gold
(vi) 12 µl of RNA extract (vi) 2 µl of RT product (vi) Make up total volume of 20 µl (vi) 1 µl of RT-PCR product
(vii) Make up total volume of (vii) Make up total volume of (vii) Make up total volume of
20 µl 50 µl 50 µl
Thermal (i) 25°C, 10 min (i) 94°C, 10 min (i) 45°C, 30 min (i) 95°C, 5 min
cycling (ii) 42°C, 50 min (ii) 40 cycles (ii) 95°C, 3 min (ii) 10 cycles
profile (iii) 94°C, 3 min (a) 94°C, 30 s (iii) 10 cycles (a) 95°C, 10 s
(b) 50°C, 40 s (a) 95°C, 10 s (b) 60°C, 10 s (decrease by 1°C/cycle)
(c) 72°C, 15 s (b) 60°C, 10 s (decrease by 1°C/cycle) (c) 72°C, 20 s
(iii) 72°C, 10 min (c) 72°C, 30 s (iii) 20 cycles
(iv) 40 cycles (a) 95°C, 10 s
(a) 95°C, 10 s (b) 56°C, 10 s
(b) 56°C, 10 s (decrease by 1°C/cycle) (c) 72°C, 20 s
(c) 72°C, 30

Expected 182 189 108
PCR product
size (bp)
aThe RT-PCR protocols of two WHO SARS network laboratories. WHO-HKU (Peiris et al., 2003a) and WHO-Hamburg (Drosten et al., 2003) are also available online (http://www/
who.int/esr/sars/primers/en). Abbreviations: RTA, reverse transcriptase; DDT, dithiotheritol; dNTP, deoxynucleoside triphosphate.
177
RT-PCR step, followed by transfer of the initial PCR products to the nested PCR
amplification mixture (Drosten et al., 2003). Positive and negative controls were
included in each run, and all precautions to prevent cross-contamination were
observed. For nested PCR, RT-PCR amplicon tubes were spun (in pulses) before
the tubes were opened using separate Eppendorf tube openers for transferring
RT-PCR products to the nested PCR mix. Negative control was incorporated for
every five nested PCRs to monitor cross-contamination. Amplified products were
electrophoresed through a 2 percent agarose gel in Tris-borate buffer. Target
bands were visualized by staining with ethidium bromide.
CoV Immunoglobulin G Serology

Smears of CoV-infected Vero cells were prepared, fixed in acetone for 10
min, and stored at –80°C before use (Peiris et al., 2003a). Each batch of SARS
CoV-infected cell smears with 60 to 70 percent infected cells was prepared and
tested with a high-titer, positive-control serum sample from a confirmed SARS
patient as a standard to assess sensitivity and batch-to-batch variations. Serial
twofold dilutions starting with a 1:10 dilution of each patient serum sample were
added to the smears and incubated for 30 min at 37°C. After two 5-min washes in
phosphate-buffered saline, fluorescein isothiocyanate-conjugated goat anti-human
immunoglobulin G (INOVA Diagnostics, Inc., San Diego, California) was added
to the smears, and the smears were incubated for 30 min at 37°C. Acute- and
convalescent-phase serum samples from each patient were assayed for SARS
CoV antibodies in the same experiment to minimize experimental variations. The
titer was determined as the highest dilution of serum exhibiting fluorescence of
the infected cells. A weakly positive patient serum sample was included as a
control in each run. A sample was scored as a positive result if the fluorescent
intensity was equal to or higher than that of the positive control.
Determination of the End Points of the RT-PCR Assays

A 96-well microtiter plate containing 0.1 ml of confluent Vero cells was
used to determine the 50 percent tissue culture infective dose (TCID50) of SARS
CoV under biohazard level 3 containment conditions. Tenfold serial dilutions of
a cell-adapted SARS CoV strain from 10–1 to 10–8 were prepared. One hundred
microliters of each dilution were added to each well of four replicate wells and
incubated at 37°C for 2 to 3 days to observe cytopathic effect. TCID50s were
determined by the Kärber method (Ballew, 1992). For the same serial dilutions of
virus, 100-µl samples were subjected to RNA extraction, and the end points of the
two RT-PCR assays were determined.

Results
Of 303 specimens from clinically suspected SARS cases (see Table 4-2), 145
were positive by one or both PCR assays and more than 87 percent of PCR-
positive samples were identified by both PCR assays. Common respiratory viral
pathogens, including influenza virus A and B, parainfluenza virus types 1, 2, and
3, RSV, and adenovirus, were not detected in the 124 nasopharyngeal aspirate
specimens. The end point for both WHO-HKU and WHO-Hamburg RT-PCR
methods was determined to be 0.1 TCID50. The acute-phase serum samples from
all patients were seronegative for SARS CoV. Eighty-six patients were confirmed
to have SARS CoV infections on the basis of seroconversion. Using sero-
conversion as the gold standard for SARS diagnosis, the sensitivities of the
WHO-HKU and WHO-Hamburg RT-PCR assays were found to be 61 and 68
percent (nasopharyngeal aspirate specimens), 65 and 72 percent (throat swab
specimens), 50 and 54 percent (urine specimens), and 58 and 63 percent (stool
specimens). A specificity of 100 percent was exhibited by both RT-PCR assays,
as none of the seronegative patient samples and control samples gave a positive
PCR result. Among the 163 patients, two or more respiratory specimens (na-
sopharyngeal aspirate or throat swab specimens) were available from 41 patients.
Of the 41 patients, 28 were subsequently confirmed to have SARS CoV on the
basis of seroconversion. In these 28 patients, the numbers of first specimens posi-
tive for WHO-HKU and WHO-Hamburg RT-PCR were 18 and 20, respectively,
but testing a second specimen increased the overall sensitivity from 64 and 71
percent to 75 and 79 percent, respectively.
Discussion
In Hong Kong, SARS is a serious respiratory illness that led to significant
morbidity and mortality (Donnelly et al., 2003). The diagnosis depends mainly
on the clinical findings of an atypical pneumonia not attributed to another cause
and a history of exposure to a suspect or probable case of SARS or to the respira-
tory secretions and other bodily fluids of individuals with SARS. Definitive diag-
nosis of this novel CoV relies on classic tissue culture isolation, followed by
electron microscopy studies to identify the virus on cell culture, which is techni-
cally very demanding. Serological testing for increasing titer against SARS-asso-
ciated CoV was shown to be highly sensitive and specific (Peiris et al., 2003a) but
was not suitable for rapid laboratory diagnosis. The rapid isolation and character-
ization of the novel CoV associated with SARS allowed for the timely develop-
ment of diagnostic tests (Marra et al., 2003; Rota et al., 2003). RT-PCR protocols
of two WHO SARS network laboratories were evaluated for rapid diagnosis of
SARS-associated CoV in Hong Kong. The end point for the novel CoV by both
RT-PCR assays was similar to the previous finding for human CoV (Vabret et al.,
2001), yet sufficient diagnostic sensitivity was not achieved, despite attaining a

180
TABLE 4-2 Performance of RT-PCR Assays for Rapid Detection of CoV Associated with SARS
No. of specimens positive by RT-PCR assay
No. of
specimens Both WHO-HKU and

Specimens (no.) tested Seroconversiona WHO-HKU WHO-Hamburg WHO-Hamburg
Clinically suspected SARS
Nasopharygneal aspirate 72 + 44 49 43
specimens (124)
52 – 0 0 0
Throat swab specimens (65) 54 + 35 39 33
Urine specimens (19) 78 + 39 42 39
Stool specimens 19 + 11 12 11
Controls
Nasopharygneal aspirate specimens 22b ND 0 0 0
Stool specimen 21c ND 0 0 0
aA fourfold rise of more in antibody titer against CoV was considered seroconversion (+). ND, not done.
bSamples positive for other viral pathogens included nine samples positive for influenza virus A, one sample positive for influenxa virus B, six samples positive
for adenovirus, and six samples positive for RSV by immunoflourescence (Chan et al., 2002).
cNo intestinal pathogens detected.

specificity of 100 percent. A recent study using real-time RT-PCR revealed that
the viral load in nasopharyngeal aspirate specimens peaked in the second week of
the illness (Peiris et al., 2003b). Results indicated a more sensitive RT-PCR assay
is essential for rapid diagnosis of SARS CoV during the early stage of disease.
Due to the nature of respiratory specimens with inconsistent pathogen loads at
various sample times, testing of multiple specimens has been shown to increase
the sensitivity of laboratory diagnosis for Mycobacterium tuberculosis (Nelson et
al., 1998). Testing a second respiratory specimen by RT-PCR increased the sensi-
tivity of diagnosis for SARS CoV.
The examination of more than one respiratory specimen is necessary to maxi-
mize the sensitivity of RT-PCR assays for SARS CoV. As molecular character-
ization of this novel CoV is ongoing, targeting genomic segments of the virus for
diagnostic application is still unclear. Amplification of a second genome region
may further increase test specificity. In this study, the high specificity and con-
cordance of both RT-PCR assays verified that the amplified genomic segments
for both protocols are suitable for diagnostic application. Incorporation of inter-
nal probe hybridization will probably increase the sensitivity of the WHO-HKU
RT-PCR assay. In this global outbreak of SARS, prompt communication and
exchange of information among the WHO collaborating laboratories facilitate
development of rapid diagnostic assays with shortened turnaround time. The
availability of the protocols on the WHO website was helpful to diagnostic labo-
ratories. The collaborative approach can be invaluable in our efforts to under-
stand and control emerging pathogens in the future.
Acknowledgments
We thank Christian Drosten of the Bernhard-Nocht Institute (Hamburg, Ger-
many) and TIB-MOLBIOL (Hamburg, Germany) for providing DNA primers
used in the WHO-Hamburg RT-PCR protocol. We also thank the staff of the
Department of Microbiology, Queen Mary Hospital, The University of Hong
Kong for their technical assistance.
NOVEL BIOSENSOR FOR INFECTIOUS DISEASE DIAGNOSTICS

Rangarajan Sampath and David J. Ecker
Ibis Therapeutics, a division of Isis Pharmaceuticals
We describe a novel approach for surveillance of emerging infectious dis-

eases that can be used for rapid and broad identification of infectious disease
causative agents. The premise of our technology is that we can provide rapid,
sensitive, and cost-effective detection of a broad range of “normal” pathogenic
organisms and simultaneously also diagnose disease caused by a biological
weapon or an unexpected emerging infectious organism. This broad-function

technology may be the only practical way to rapidly diagnose diseases caused by
a bioterrorist attack or emerging infectious diseases that otherwise might be
missed or mistaken for a more common infection.
According to a recent review (Taylor et al., 2001), more than 1,400 organ-
isms are infectious to humans. These numbers do not include numerous strain
variants of each organism, bioengineered versions, or pathogens that infect
plants or animals. Paradoxically, most of the new technology being developed
for detection of infectious agents incorporates a version of quantitative PCR,
which is based on the use of highly specific primers and probes designed to
selectively detect specific pathogenic organisms. This approach requires as-
sumptions about the type and strain of bacteria or virus. Experience has shown
that it is very difficult to anticipate where the next emerging infectious agent
might come from, as was the case with the outbreak of SARS early in 2003. An
alternative to single-agent tests is to do broad-range consensus priming of a
gene target conserved across groups of organisms (Kroes et al., 1999; Oberste
et al., 2000, 2001, 2003). The drawback of this approach for unknown agent
detection and epidemiology is that analysis of the PCR products requires the
cloning and sequencing of hundreds to thousands of colonies per sample, which
is impractical to perform rapidly or on a large number of samples. New ap-
proaches to the parallel detection of multiple infectious agents include multi-
plexed PCR methods (Brito et al., 2003; Fout et al., 2003) and microarray strat-
egies (Wang et al., 2002, 2003; Wilson et al., 2002). Microarray strategies are
promising because undiscovered organisms might be detected by hybridization
to probes on the array that were designed to bind conserved regions of previ-
ously known families of bacteria and viruses.
Here we present an alternative, a universal pathogen-sensing approach for
high-throughput detection of infectious organisms that is capable of identifying
previously undiscovered organisms (see Figure 4-1).
Our strategy is based on the principle that, despite the enormous diversity of
microbes, all forms of life on earth share sets of essential common features in the
biomolecules encoded in their genomes. Bacteria, for example, have highly con-
served sequences in a variety of locations on their genomes. Most notable is the
universally conserved region of the ribosome, but there are also conserved ele-
ments in other noncoding RNAs, including RNAse P and the signal recognition
particle, among others. There are also conserved motifs in essential protein-en-
coding genes, in bacteria as well as viruses. Use of such broad-range priming
targets across the broadest possible grouping of organisms for PCR, followed by
electrospray ionization mass spectrometry for accurate mass measurement, en-
ables us to determine the base composition (numbers of A, G, C, and T nucle-
otides) of the PCR amplicons. The measured base compositions from strategi-
cally selected locations of the genome are used as a signature to identify and
distinguish the organisms present in the original sample. An important feature of
the primer design strategy used in our approach is the positioning of propynylated

FIGURE 4-1 Overview of the universal pathogen sensor for the detection of a diverse mixture of microbial organisms present in a sample.
Genomic DNA, or cDNA obtained by batch reverse-transcription of RNA, from each sample are amplified using broad range PCR primers to

generate a complex mixture of PCR products. This mixture of DNA is directly sprayed into a mass spectrometer that essentially weighs each intact
nucleic acid strand in the mixture at the same time, This measurement is done at high mass accuracy, which enables us to calculate the exact number
of A’s, C’s, G’s, and T’s that make up the DNA in our sample. This count serves as a base-composition fingerprint that can be mapped back to
specific organisms. Examination of multiple base-count fingerprints for each organism generated by multiple pairs of broad-range primers to
183
conserved sites distributed across the microbial genome (not shown) allows discrimination of microbial species and subspecies with great accuracy.
nucleotides (5-propynyl deoxy-cytidine and deoxy-thymidine) at highly con-

served sequence positions that enables priming of short consensus regions and
significantly increases the extent to which broad groups of organisms can be
amplified (Barnes and Turner, 2001a,b; Wagner et al., 1993). Furthermore, we
use multiple target sites spread across different parts of the genome to add further
resolution and lower the risk of missed detections.
A key to the development of a practical broad priming technology is the
ability to characterize signals produced by infectious organisms in the milieu of
the background that might have an excess of harmless organisms. While cloning
and exhaustively sequencing many colonies can solve this, this cannot be done in
a rapid diagnostic device. Our strategic breakthrough was the use of mass spec-
trometry to analyze the products of broad-range PCR. Mass spectrometry is re-
markably sensitive and can measure the weight and determine the base composi-
tion from small quantities of nucleic acids in a complex mixture with a throughput
of about a sample per minute. The ability to detect and determine the base com-
position of a large number of PCR amplicons in a mixed sample enables analysis
and identification of broad-range PCR products essentially instantaneously. In
contrast to cloning and sequencing, the information product of the mass spec-
trometer is base composition. While the base composition of a gene fragment is
not as information rich as the sequence, a base-composition signature can be
thought of as a unique index of a specific gene in a specific organism. Our detec-
tion algorithm searches a database to link each sequence for a particular organism
to a composition signature so that the presence of the organism can be inferred
from the presence of the signature.
During the SARS epidemic outbreak in early 2003, we demonstrated that the
above-described paradigm of identification of microbial nucleic acid signatures by
mass spectrometry could be adapted to identify the SARS virus. In the absence of a
SARS genome sequence at the onset of the epidemic, pairs of broad primers that
were designed to broadly target all other known coronaviruses were used to test
clinical isolates obtained from the Centers for Disease Control and Prevention
(CDC). We showed that the SARS virus potentially could be identified directly
from a patient sample, obviating the need for time-consuming viral culture. We
further showed that this method could distinguish between SARS and other known
coronaviruses, including the human coronaviruses 229E and OC43. While direct
comparisons of sensitivity, using actual patient samples, have yet to be conducted
between this and other methods employed to detect SARS, we did show, using
titred SARS virus spiked into human serum, that we could obtain PCR sensitivities
of <1 PFU, which is consistent with our previous experience. The details of the
above study will be published elsewhere (Sampath et al., under preparation).
One of the limitations of our approach is that base compositions, like
sequences, vary slightly from isolate to isolate within species. We have shown
that it is possible to manage this diversity by building probability “clouds”

around the composition constraints for each species. This permits identifica-
tion of organisms in a fashion similar to sequence analysis, albeit with some-
what lower resolution. It is counterintuitive that base composition has suffi-
cient resolving power to distinguish organisms (one might suspect that
sequences from different organisms will degenerate to similar overlapping
compositions). A rigorous mathematical analysis has shown, however, that
base composition retains more than sufficient information to solve the prob-
lem, provided the target sequences are strategically selected. It is important to
note that, in contrast to probe-based techniques, mass spectrometry determi-
nation of base composition does not require prior knowledge of the composi-
tion in order to make the measurement, only to interpret the results. In this
regard, our strategy is like DNA sequencing and phylogenetic analysis, but at
lower resolution. However, the resolution provided by this analysis is more
than sufficient for most rapid diagnostic applications such as identification of
any organism, or to classify organisms into known phylogenetic groupings
(Sampath et al., under preparation).
We envision developing applications where human clinical samples can be
analyzed for diagnostically relevant levels of disease-causing agents and biologi-
cal weapons simultaneously. We envision that the technology will be used in
reference labs, hospitals, and the laboratory response network (LRN) laboratories
of the public health system in a coordinated fashion with the ability to report the
results via a computer network to a common data-monitoring center in real time.
Clonal propagation of specific infectious agents, as occurs in the epidemic out-
break of infectious disease, can be tracked with base composition signatures,
analogous to the pulse field gel electrophoresis fingerprinting patterns used in
tracking the spread of specific food pathogens in the CDC Pulse Net system
(Swaminathan et al., 2001). Effectively, our technology provides a digital barcode
in the form of a series of base composition signatures, the combination of which
is unique for each organism. This capability enables real-time infectious disease
monitoring across broad geographic locations, which may be essential in a simul-
taneous outbreak or attack in different cities.
Acknowledgments
This methodology described is being developed jointly by Ibis and Sci-
ence Applications International Corporation (SAIC) under a Defense Ad-
vanced Research Projects Agency (DARPA) sponsored program known as
TIGER. A detailed description of the technology will be published sepa-
rately. More than 25 key participants who contributed significantly to the
development and implementation of various aspects of the technology are not
listed individually by name.

IN VITRO ANTIVIRAL ACTIVITY OF HUMAN RHINOVIRUS 3C

PROTEASE INHIBITORS AGAINST THE SARS CORONAVIRUS
David A. Matthews,1 Amy K. Patick,1 Robert O. Baker,2 Mary A. Brothers,1
Peter S. Dragovich,1 Chris J. Hartmann,2 Theodore O. Johnson,1 Eric M.
Mucker,2 Siegfried H. Reich,1 Paul A. Rejto,1 Peter W. Rose,1 Susan H. Zwiers,2
and John W. Huggins2,3
The construction of a homology model of the 3C-like (3CL) protease derived

from the SARS coronavirus (SCoV) is described. This model is used to qualita-
tively evaluate the potential for several Michael acceptor-containing human rhi-
novirus 3C protease inhibitors to also disrupt the function of the SCoV 3CL en-
zyme. The antiviral activity of three such compounds (AG7088, AG7404, and
AG7122) determined against SCoV in cell culture is reported (see Figure 4-2).
The former two molecules fail to inhibit in vitro replication of SCoV up to the
highest concentrations tested (100 µg/mL) while AG7122 exhibits measurable
antiviral activity against SCoV that is distinguishable from cytotoxicity (EC50 =
14.1 µg/mL, CC50 >100 µg/mL).
Severe acute respiratory syndrome (SARS) is a potentially serious global
health concern and the disease has been responsible for considerable negative
economic impact in affected regions (Poutanen et al., 2003; Tsang et al., 2003).
A newly discovered coronavirus (SCoV) has been strongly implicated as the caus-
ative agent of SARS by independent research conducted at several laboratories
around the world (Drosten et al., 2003; Fouchier et al., 2003; Ksiazek et al., 2003;
Lee et al., 2003; Peiris et al., 2003a). Recently, sequencing and analysis of the
SARS virus genome has led to the identification of gene products that may be
critical for viral replication (Marra et al., 2003; Rota et al., 2003). In particular,
such analysis suggests that the SARS pathogen, like other known coronaviruses
(Ziebuhr et al., 2000), encodes a critical enzyme that is required for C-proximal
processing of two overlapping polyproteins produced by cellular translation of
the viral RNA. This coronavirus enzyme has been termed a “3C-like” (3CL)
protease due to numerous similarities with the well-known picornavirus 3C pro-
teases including substrate preferences, particularly the requirement of a P1
glutamine residue, and the use of cysteine as an active site nucleophile during
catalysis (Hegyi and Ziebuhr, 2002; Ziebuhr et al., 2000). In addition, the
coronavirus 3CL and picornavirus 3C proteins share a similar polypeptide fold,
as evidenced by comparison of the crystal structure of the 3CL protease derived
from porcine transmissible gastroenteritis coronavirus (Anand et al., 2002) with
1Pfizer Global Research and Development.

2Viral Therapeutics Branch, Virology Division, USAMRIID.
3We thank Drs. Catherine Laughlin, Christopher Tseng, and Jack Secrist (NIAID/NIH) for facilitat-
ing the in vitro evaluation of Pfizer compounds against SCoV.

P4 P3 P2 P1
O
NH
O O
H3C N N
H H
O N O
CO2Et
F
AG7088
O
NH
O O
N
H3C N N
H H
O N O
CO2Et
AG7404
O
NH
N
H
CO2Et
AG7122
FIGURE 4-2 Compounds tested in cell culture for antiviral activity against SCoV.

those of corresponding picornaviral 3C enzymes (e.g., human rhinovirus 3C pro-

tease [HRV 3CP]) (Matthews et al., 1999).
The structural and functional homologies noted above between the
coronavirus 3CL and picornavirus 3C enzymes were apparent (Anand et al., 2002)
before the relationship between SARS and its causative agent was disclosed.
Coincident with the announcement that a new coronavirus causes SARS and prior
to publication of the SARS virus genome, we initiated a computational study to
explore whether Michael acceptor-containing HRV 3CP inhibitors (discovered
during our previous efforts to identify antirhinoviral therapeutic agents [Matthews
et al., 1999]) might also bind to coronavirus 3CL proteases. The availability of
the SCoV genetic sequence (Fouchier et al., 2003; Marra et al., 2003; Rota et al.,
2003) enabled us to further extend these studies using a proprietary homology
model of the SARS 3CL enzyme. Recently, Anand et al. (2002) disclosed an
independent computational evaluation of several known picornaviral 3C protease
inhibitors against SARS 3CL and reported that, although such molecules were
not necessarily optimized, they could serve as starting points for the design of
new SARS antiviral agents. In this communication, we report an alternate com-
putational assessment of the potential for several Pfizer compounds to inhibit
SARS 3CL along with their experimentally determined antiviral activities against
SCoV in cell culture.
Our homology model for SARS 3CL protease was created using the atomic
coordinates of TGEV 3CL protease (PDB accession code 1LVO) as a template.
BLAST was employed to identify the 3CL protease from the genomic RNA se-
quence of SARS (AY274119). Minor adjustment to the BLAST output resulted
in an alignment with high percent identity and few gaps (see Figure 4-3), and this
alignment was used to create a homology model with the MODELLER package
in Insight2000 (Sali and Blundell, 1993). Twelve residues with high structural
conservation (see Table 4-3) were identified by visual inspection of the human
rhinovirus 3C (1CQQ) and TGEV 3CL protease (1LVO) structures, as well as the
SARS 3CL protease homology model. The structures were superimposed in a
common reference frame by minimizing the root mean square distance (r.m.s.d.)
between the backbone atoms of these residues, with r.m.s.d. < 0.6 Å (Drosten et
al., 2003; Fouchier et al., 2003; Ksiazek et al., 2003; Peiris et al., 2003a).
Putative Michael acceptor-containing SARS 3CL protease inhibitors from
the Pfizer chemical archive were computationally evaluated by first creating three-
dimensional structures of the compounds using CORINA version 2.6 (Sadowski
and Gasteiger, 1993), then employing a constrained docking approach using
AGDOCK (Gehlhaar et al., 1999) to determine their binding mode to the model.
The geometry of the reaction product as observed in the co-crystal structure of
one such Pfizer compound (AG7088) with human rhinovirus 3C protease
(Matthews et al., 1999) (PDB accession code 1CQQ) was used as a template to
model the covalent binding of Michael acceptors with the active site cysteine of
SARS 3CL protease (see Figure 4-4). The Michael acceptor portions of the in-

1LVO (1) SGLRKMAQPSGLVEPCIVRVSYGNNVLNGLWLGDEVICPRHVIAS-DTTRVI

SARS (1) SGFRKMAFPSGKVEGCMVQVTCGTTTLNGLWLDDTVYCPRHVICTAEDMLNP
1LVO (52) NYENEMSSVRLHNFSVSKNNVFLGVVSARYKGVNLVLKVNQVNPNTPEHKFK

SARS (53) NYEDLLIRKSNHSFLVQAGNVQLRVIGHSMQNCLLRLKVDTSNPKTPKYKFV
1LVO (104) SIKAGESFNILACYEGCPGSVYGVNMRSQGTIKGSFIAGTCGSVGYVLENGI

SARS (105) RIQPGQTFSVLACYNGSPSGVYQCAMRPNHTIKGSFLNGSCGSVGFNIDYDC
1LVO (156) LYFVYMHHLELGNGSHVGSNFEGEMYGGYEDQPSMQLEGTNVMSSDNVVAFL

SARS (157) VSFCYMHHMELPTGVHAGTDLEGKFYGPFVDRQTAQAAGTDTTITLNVLAWL
1LVO (208) YAALINGERWFVTNTSMSLESYNTWAKTNSFTELSS--TDAFSMLAAKTGQS

SARS (209) YAAVINGDRWFLNRFTTTLNDFNLVAMKYNYEPLTQDHVDILGPLSAQTGIA
1LVO (258) VEKLLDSIVR-LNKGFGGRTILSYGSLCDEFTPTEVIRQMYGV---

SARS (261) VLDMCAALKELLQNGMNGRTILGSTILEDEFTPFDVVRQCSGVTFQ
FIGURE 4-3 Sequence alignment between the TGEV 3CL protease (PDB accession code
1LVO) and SARS 3CL protease used to create the homology model.
hibitors were forced onto the template structure and then constrained during dock-
ing. The resulting protein-ligand interactions were qualitatively evaluated by
visual inspection. The outcome of computationally docking AG7088 into the
SARS 3CL homology model is also depicted (see Figure 4-4).
Of the Michael acceptor-containing HRV 3CP inhibitors examined, only two
have been the subject of human clinical trials: AG7088 (rupintrivir) (Matthews et
al., 1999; Patick et al., 1999) as an intranasally administered agent and AG7404
(Dragovich et al., 2003) as an orally delivered compound. Unfortunately, our
computational evaluation detected relatively poor complementarity between the
compounds’ P3 and P4 substituents and SARS 3CL that resulted in numerous
TABLE 4-3 Residues Employed for the Superposition of Human Rhinovirus

(HRV) 3C Protease and TGEV 3CL Protease Structures Along with
Corresponding SARS 3CL Amino Acids
HRV (1CQQ) TGEV (1LVO) SARS
PRO-38 PRO-39 PRO-39
THR-39 ARG-40 ARG-40
HIS-40 HIS-41 HIS-41
LYS-143 ILE-140 LEU-141
SER-144 ALA-141 ASN-142
GLY-145 GLY-142 GLY-143
TYR-146 THR-143 SER-144
CYS-147 CYS-144 CYS-145
ILE-160 MET-161 MET-162
HIS-161 HIS-162 HIS-163
VAL-162 HIS-163 HIS-164
GLY-163 LEU-164 MET-165

FIGURE 4-4 Top: Co-crystal structure of AG7088 with HRV 3C protease (Connolly
surface shown). Bottom: AG7088 docked into the SCoV 3CL protease homology model
(Connolly surface shown).

structural clashes and several unsatisfied hydrogen bonds.4 These findings are in
partial contrast with those reported by Anand et al. which suggest “easy accom-
modation” of the AG7088 P4 substituent by SARS 3CL (Anand et al., 2003). Our
evaluation also indicated that a truncated compound related to AG7088 which
lacks both P3 and P4 substituents (AG7122) interacted more favorably with the
SARS 3CL protein (Johnson et al., 2002). In order to help define the accuracy of
our modeling efforts, the potential for all three molecules (AG7088, AG7404,
and AG7122) to inhibit the SARS virus in cell culture was evaluated.
Stocks of tested compounds were made by dissolving them in DMSO to a
concentration of 20 mg/mL. Compounds were then diluted to 400 mg/mL in cell
culture medium [high glucose Dulbeco’s Modified Eagle Medium (DMEM)
supplemented with 1% fetal calf serum, 10 U/mL penicillin-streptomycin, and
12.5 ng/mL fungizone], serially diluted threefold in medium, and 50 µL added to
96-well microtiter plates of confluent Vero 76 cells already containing 100 µL
medium. At each compound concentration, three wells were infected with 2×102
pfu/well (MOI = 0.001) of SCoV (strain 200300592) in 50 µL medium, while
three were left uninfected for cytotoxicity determination (50 µl medium added to
each well). The plates were incubated at 37°C in a 5 percent CO2 atmosphere,
examined daily, and were stained once virus-infected, untreated cells showed
maximum cytopathic effect (about 3 days). Neutral red was added to the medium
to give a final concentration of 0.22 mg/mL, and cells were returned to the incu-
bator for 90 minutes. The medium containing neutral red was removed, the wells
were rinsed twice with buffered saline solution, and plates were decontaminated
by soaking in 10 percent buffered formalin followed by a water wash. Retained
stain was solubilized by adding 100 µL of a 50 percent ethanol, 50% 0.01 M
ammonium phosphate (NH4H2PO4) (pH 3.5) solution. The plates were incubated
for 15 minutes at room temperature and the optical density (OD) of the wells at a
wavelength of 450 nm was measured on a plate reader. The data were graphed
and analyzed using the four parameter-logit curve fit option of the computer pro-
gram SoftMax Pro (Molecular Devices, Menlo Park, CA) to determine the 50
percent inhibitory (EC50) and cytotoxic (CC50) compound concentrations.
As shown in Table 4-4, both AG7088 and AG7404 failed to inhibit in vitro
replication of SCoV up to the highest concentrations tested (100 mg/mL). In
contrast, AG7122 exhibited moderate but measurable inhibition of SCoV that
was distinguishable from cytotoxicity (see Figure 4-5, Table 4-4). Although these
antiviral data parallel our qualitative computational evaluation of the three mol-
ecules against the SARS 3CL protease, other factors such as differing cell perme-
ability properties may also influence the results. We are therefore uncertain
whether the poor complementarity noted in silico is responsible for the lack of
4The nomenclature used for describing the individual amino acid residues of a peptide substrate (P ,
2
P1, P1’, P2’, etc.) and the corresponding enzyme subsites (S2, S1, S1’, S2’, etc.) is described in Schechter I,
Berger A. 1967. Biochem. Biophys. Res. Commun. 27:157.

TABLE 4-4 In Vitro Antiviral Activity (EC50) and Cytotoxicity (CC50) of

Pfizer Compounds Determined Against SCoV in Cell Culture
Compound Antiviral Activity (µg/ml) Cytotoxicity (µg/ml)
AG7088 >100 >100
AG7404 >100 >100
AG7122 14.1 >100
observed activity of AG7088 and AG7404 against SCoV in cell culture. While
this inactivity is disappointing, the antiviral effects displayed by AG7122 encour-
agingly suggest that proper optimization of such Michael acceptor-containing
protease inhibitors may lead to agents with improved anti-SCoV properties.5
Since the majority of the Michael acceptors contained in the Pfizer chemical
archive are optimized against HRV 3CP, we do not anticipate that their exhaus-
tive screening against SCoV will afford ideal therapeutic agents. However, we
110
100
90
Cell viability (%)
80
70
60
50
40
30
0.01 0.1 1 10 100
AG7122 Concentration (µg/ml)
FIGURE 4-5 Antiviral activity of AG7122 against SCoV in Vero 76 cells. Cells were
treated with the indicated compound concentrations and infected with virus (circles) or left
uninfected (squares). Cell viability was measured by neutral red uptake, and is expressed
as a percentage of the value in uninfected, untreated wells. Data shown are the mean of
three replicate wells. Bars indicate the standard error of the mean.
5The mechanism of action by which AG7122 exerts its anti-SCoV effects has not yet been rigor-
ously determined.

are still continuing such in vitro evaluation and have identified several additional
Pfizer compounds that display improved antiviral activity (EC50 = 1-2 µg/mL,
CC50 >100 µg/mL) relative to that exhibited by AG7122. We are currently using
these molecules to help refine our SARS 3CL computational model and will re-
port the progress of our endeavors in due course.6
SARS: CLEARING THE AIR

Jerome J. Schentag, Pharm. D.,7,8,9 Charles Akers, Ph.D.,8
Pamela Campagna,8 and Paul Chirayath8
The integrated technologies incorporated into the FailSafe Mobile Contain-

ment Systems have a wide range of applications, including homeland security,
bioterrorism, disaster management, airborne infection control, sick-building syn-
drome, and facility environmental service applications. The specific objective of
this overview is to focus on the use of FailSafe Mobile Containment Systems for
isolation precautions in a medical environment. FailSafe has not used these de-
vices directly in an outbreak of severe acute respiratory syndrome (SARS), and
thus actual clinical experience will not be reported here. Given that a major
component of the spread of SARS occurs via aerosolized droplets, the systems
described for clearing the air may be applicable to the containment of this new
viral pathogen in hospitals and health care systems.
The guidelines for isolation precautions for hospitals and health care facili-
ties are outlined by the Centers for Disease Control and Prevention (2004) and
American Institute of Architechts (2001). These guidelines outline the precau-
tions that infection control personnel should take to mitigate the spread of infec-
tion within facilities and protect the health care worker. Precautions must be
taken to prevent the spread of infection from direct contact with contaminated
surfaces (contact contamination), from large droplets of infectious material that
fall out of the air, or from small droplets that can be carried by the air stream
throughout the hospital (airborne contamination).
The guidelines for the creation of an isolation room are based on the prin-
ciple that the isolation room is maintained under negative pressure to minimize
the ability of any airborne contamination from entering the hospital. To validate
the design recommendations, the precautions listed in Box 4-1 must be taken.
6The in vitro anti-SARS activity of glycyrrhizin (EC = 300 µg/mL) was recently disclosed: Cinatl
50
J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. 2003. Lancet 361:2045. The precise
mechanism responsible for this molecule’s antiviral activity remains to be determined.
7University at Buffalo School of Pharmacy, Department of Pharmaceutical Sciences and Pharmacy.
8FailSafe Air Safety Systems Corporation.
9It should be noted that the author serves as a paid consultant to the FailSafe Air Safety Systems
Corporation and has been involved in the development of these technologies.

BOX 4-1
Considerations for Effective Isolation Rooms
Air flow: Air from the hospital is to flow into the isolation
room.
Air changes per There shall be greater than 12 ACH within the
hour (ACH) isolation room. It is preferred to pump the air from
the isolation room to the outdoors. The air pump
output vent must be further than 50 feet from any
building air inlet vent. To augment the ACH
guideline, or if outdoor venting is not possible,
room air may be recirculated if the airborne par-
ticulates are filtered using an approved HEPA filter.
Air pressure To ensure a negative room pressure, there
(differential) should be greater than 0.01 inches of water col-
umn. It is recommended that a continuous moni-
tor of differential air pressure be used in conjunction
with an audiovisual alarm.
Failsafe Air Safety Systems Approach

FailSafe Air Safety Systems (FASS) manufactures two medical isolation
units the Model 77 and the Model 07 (see Figure 4-6)—that provide personalized
isolation and infection control. These medical units employ a patented air safety
process that was developed in response to the lack of market availability of por-
table containment systems. Both the Transport Isolation Unit and the Portable
Isolation Unit are equivalent in technology to an isolation room, but have the
ability to bring isolation to an infected patient.
The Model 77 can be moved to an area and set up in minutes. The main
components are a prefilter; an industrial, high-capacity, micro-fiberglass HEPA
filter; ultraviolet lamp(s); and a high-volume blower.
The Model 07 provides isolation on wheels. At 27 inches wide, a single
attendant can handle and move the unit throughout hallways and corridors. The
main components are a prefilter; an industrial, high-capacity, micro-fiberglass
HEPA filter; ultraviolet lamp(s); and a high-volume blower. These units are also
battery powered to provide for isolation during transport.
Both of the Medical Isolation Units can be rolled to the location of a sus-
pected infected patient, where aerosols containing SARS viruses are drawn into
the system while clean air is filtered and recirculated into the air. The flexibility
of the FASS Medical Isolation Units allows for a wide variety of applications:
• Immediate isolation of patients with SARS, tuberculosis, or unknown res-

piratory infection.

FIGURE 4-6 The Model 07.
• Coverage during bronchoscopy or other aerosol-generating procedures.

• Removal of toxic smoke or fumes.
The FASS Medical Isolation Units offer the following benefits:
• Minimal set-up time to respond immediately to an emergency situation.

• Dual-use flexibility to provide isolation containment (negative pressure

enclosure) at any place at any time.
• A system that does not alter the infrastructure within the enclosed protec-
tive area.
• A cost-effective solution to emergency isolation.
• Clean air for extended use.
FASS Applications
The FASS Medical Isolation Units are fume hoods on wheels that combine
the proven HEPA filter capacity of 99.97 percent capture at 0.1 microns with
ultraviolet light. This toxic microbial capture and containment system builds on
years of proven studies specifically involving Bacillus anthracis (anthrax) and
smallpox, and can readily be applied to infection control of SARS-related inci-
dents. These units are approved by the Food and Drug Administration (FDA) and
satisfy CDC guidelines for isolation. They are the only FDA-approved portable
isolation units currently on the market.
SARS Response: Deployment Considerations

FailSafe Medical Isolation Units can be deployed in several ways as a re-
sponse to a suspected SARS incident:
1. Immediate isolation and evacuation of a suspected SARS patient.

2. Transport of infected patients through crowded population (e.g., airports,
train stations).
3. Transport to hospital or triage area.
4. Transport within hospital (from emergency room to SARS isolation floor).
Emergency workers can provide isolation and unrelated medical treatment to

suspected SARS patients within the confines of the Medical Isolation Units while
protecting caregivers and the healthy population. Bedridden patients showing
symptoms of SARS can be quarantined immediately without having to be moved
to another room or facility.
System Description
Both of these FASS Isolation Units combine HEPA filtration with UVGI
irradiation. The units consist of a mobile platform that allows the patient to sit in
a mobile chair or a bed that is surrounded by a plastic curtain. The outside air is
drawn under the curtain, across the patient, and then up into the air-purifying
system that consists of a HEPA filter and a UVGI lamp, thereby reducing infec-
tious aerosols such as tuberculosis and SARS.

The FailSafe Mobile Containment System is a patented process (U.S. Patent

No. 6,162,118 [18 December 2000] entitled “Portable Isolation Device and
Method”) that integrates the technologies of filtration, ultraviolet germicidal irra-
diation, and ozone oxidation. The FailSafe process primary technology is based
on high-efficiency filtration using a glass fiber HEPA filtration media that col-
lects and traps particles greater than 0.1 micron with an efficiency greater than
99.97 percent. The filtration will collect most biological pathogens, including
fungi, bacteria, and encapsulated viruses. To ensure that the pathogens collected
and trapped on the HEPA filter are neutralized, the HEPA filter media surface
face is illuminated with ultraviolet germicidal irradiation. Another advantage of
illuminating both faces of the HEPA filter is that viruses smaller than 0.1 micron
will be neutralized by irradiation.
FailSafe Mobile Containment Systems (NOT the medical Model 77 or 07
units) also incorporate ozone generation capability as a third technology. Ozone
is generated with the use of ultraviolet (UV) lamps that will convert atmospheric
oxygen into ozone. At concentrations below NIOSH limits, the ozone will chemi-
cally react with volatile organic compounds or odor. The FailSafe Mobile Con-
tainment Systems also have the capability of generating very high ozone levels
that can be used for neutralizing pathogens on surfaces such as walls, ceilings,
and floors.
Setup and Operation

The Medical Isolation Units for health care are designed with operational
simplicity to make it a “turnkey” operation and to allow health providers to
focus on the individual patient and the biological contamination itself. The units
are designed for easy use with three switches, and the controls are simple, as
follows:
1. Power up the system. Check to see that the system is working properly
and that the operation light is on. Turn the FASS system ON and select the appro-
priate fan speed to begin air scrubbing, treatment, and capture.
2. Identify suspected infected patient.
3. Place patient in Model 07 chair, or encompass sickbed under Model 77
unit. Place plastic curtains around patient.
Preliminary Efficacy Testing

Laboratory testing: FDA 510k application. The HEPA filtration and UVGI
irradiation components used in the FASS units are incorporated in Model 07 and
Model 77 to protect medical personnel transporting TB and other infectious pa-
tients. Preliminary laboratory testing was performed on these units by an inde-
pendent laboratory for FDA Class II certification.

Discussion of Biological Efficacy
Filtration
HEPA filters. The safety and health protection offered by HEPA (High-
Efficiency Particulate Air) filtered fume hoods has long been established by the
FDA, CDC, Environmental Protection Agency (EPA), NIOSH, ASTM, and
JCAHO. HEPA Filtration is the “Best Available Control Technology” at 99.99
percent at 0.3-micron efficiency level and is “Generally Accepted Control Tech-
nology” at 99.97 percent at 0.1-micron efficiency level. The added feature of the
new 0.1-micron advanced filters is the “gel” seal and micro fiberglass construc-
tion that allows combining these filters with UV light disinfection. HEPA filters
combined with charcoal and prefilters are the highest approved filters available
for NIOSH-certified respirators. There are no adverse safety, health, or environ-
mental aspects to HEPA filters. HEPA filters are now the primary filtration
media for electronic clean room assembly, hospital surgery rooms, bioengineer-
ing, pharmaceutical processes, and any applications where maximum reduction
or removal of submicron particulates is required. Air from HEPA filters is free of
99.99 percent of all particles larger than 0.3 microns (including bacterial, fungal,
and other opportunistic microbiological organisms) according to the size exclu-
sion as described in Table 4-5.
Generally, HEPA filters belong to the “interception” family of filters and are
variously referred to as “absolute” or “super interception.” Such filters have a
deep bed of randomly positioned fibers in which the total bed depth is very large
in comparison to the average fiber diameter and effective pore or free-path cross-
sectional area. Even though the media may be only 1/16 thick, this is an enor-
mous distance compared to the 0.3- to 1.0-micron fiber diameter. The passage
through which air must flow is not straight, but full of twists and turns. As
particulates impact on the fibers, they adhere. Thus the pore size becomes in-
creasingly smaller, resulting in the filter efficacy increasing. New HEPA filters,
used by FailSafe in Models 77 and 07, provide efficiency down to 0.1-micron
particles at a removal efficiency of 99.97 percent.
HEPA filter bed media manufactured from glass fibers are reflective to ultra-
violet irradiation, allowing the UVGI irradiation to partially penetrate the filter
bed. The result of the combination of UVGI with ozone generation and the HEPA
TABLE 4-5 Relative Size of Fungus, Bacteria, and Viruses

Microbe Size Range (diameter–micron)
Fungus 0.2–80
Bacteria 0.2–2.0
Viruses 0.02–0.3
CDC guideline cutoff 0.3
FASS unit cutoff 0.1

filter is that the bacteria, fungi, and viruses that are trapped in the filter media will
be exposed to sufficient irradiation and ozone concentration to disinfect the filter.
The advantage of this antimicrobial treatment combination is that the air stream is
inhibited from becoming recontaminated from any growth on the filter media
resulting in particle breakthrough.
Ultraviolet
UV irradiation can cause eye damage and surface burns on unshielded hu-
man skin, eyes, and other organs. Therefore the UV lights used in the FASS units
are sealed inside and not visible to the operator or other personnel.
Ultraviolet radiation, in the wavelength range of 2,250 to 3,020 angstroms as
used for air/surface disinfection and sterilization, is referred to as ultraviolet germi-
cidal irradiation or UVGI. Ultraviolet germicidal radiation was first applied to disin-
fect water systems in 1909. Its use in air purification was first evaluated in the labora-
tory in the 1920s, in an operating room in the 1930s to sterilize the air in an operating
room (Sharp, 1939), and in a school ventilation system to reduce measles infection
(Riley, 1972). It is also common practice to use to disinfect medical equipment.
UVGI is currently being employed to control bacteria, fungus, and algae growth
on surfaces. European breweries have been using UVGI to control microbial growth
on cooling coils since 1975. The use of UVGI can control microbial growth on
filter surfaces that are subject to moisture or high humidity that will allow for natu-
ral fungal growth. Figure 4-7 illustrates a filter with natural fungal growth and a
filter that was irradiated with UVGI at a rated intensity of 100 micro/cm at a dis-
tance of 1m from the midpoint of the filter (Kowalski and Bahnfleth, 2000). This
surface disinfection protects the air stream from being recontaminated due to bacte-
rial, fungus, or viruses that are collected by the filter media.
FIGURE 4-7 (left) Microbial growth on nonirradiated filters. (right) Microbe-free UV

irradiated filters (Kowalski and Bahnfleth, 2000).

Microbial Response to Ultraviolet Radiation

The FASS system is an integration of room recirculation to rid the air of
biological threats and surface disinfection to kill the biothreat that is collected on
the HEPA filters. The primary target of UV radiation is the microorganism DNA
molecule with the predominant injury of strand breakage and the formation of
photo-induced byproducts such as thymine diamers. This damaged DNA cannot
be used for cell reproduction or for proper mRNA templates that is required for
the formation of all cellular toxic products. Viruses are especially susceptible to
UVGI, more so than bacteria, and are also difficult to filter because of their size.
However, viruses are more susceptible to ultraviolet radiation at wavelengths
slightly above the normal UVGI broadband wavelength of 253.7 nm.
Microorganisms, when exposed to UVGI irradiation, will be killed or de-
creased in population at a rate according to a first order equation:
S(t) = e–kIt
where k = standard decay-rate constant, cm2/microW-s
I = Intensity of UVGI irradiation, microW/cm2
t = time of exposure (sec)
The rate constant [k] is unique to each microorganism and defines its sensi-
tivity of each microorganism to UVGI intensity.
The dose of ultraviolet radiation that an airborne microbe receives depends on
the amount of time the microbe is being irradiated and the UV intensity. The upper
limit of kill rate is obtained by mixing the air within the UVGI exposure chamber.
This mixed airflow will have an average velocity that will determine the exposure
time required for all microbes in the air stream. If the air is not mixed, then the flow
will be partial laminar resulting in the microbes receiving different dosages of UV
radiation. Microbes nearest the UV lamp will get the highest dosages and those
near the wall of the chamber will have significantly less exposure to the UV radia-
tion. Laboratory experiments can be used to determine the upper limit of Kill Rate
Constant (mixed air) and lower limit of Kill Rate Constant (unmixed air).
Ozone
Ozone, an allotropic form of oxygen, possesses unique properties when it
oxidizes or interacts with chemical and biological systems. Ozone, best known
for its protective role in the earth’s ecological environment and its interaction
with industrial pollutants, has bactericidal, virucidal, and fungicidal actions that
have been used in water treatment, odor control, and medicinal applications.
Ozone [O3], a powerful oxidant reacting with organic molecules containing
double or triple bonds, yields many complex byproducts. It is this property of
ozone that has been applied as a disinfectant and sterilant against bacteria, viruses,
and fungi.

Although the inhibitory and lethal effects of ozone on pathogenic organisms

have been observed since the latter part of the 19th century, the mechanisms for
these actions have not yet been satisfactorily highlighted. The most often cited
explanation for ozone’s bactericidal effects centers on disruption of envelope in-
tegrity through peroxidation of phospholipids. There is also evidence for interac-
tion with proteins (Mudd et al., 1969). In one study (Ishizaki et al., 1987) explor-
ing the effect of ozone on E. coli, investigators found cell membrane penetration
with ozone, subsequent reaction with cytoplasmic substances, and conversion of
the closed circular plasmid DNA to open circular DNA. It is notable that higher
organisms have enzymatic mechanisms to stabilize disrupted DNA and RNA,
which could provide a partial explanation for why, in clinical treatment, ozone
appears to be toxic to infecting organisms and not to the patient (Cech, 1986).
Ozone possesses fungicidal effects, although the mechanism is poorly under-
stood. In one study, Candida utilis cell growth inhibition with ozone was greatly
dependent on phases of their growth, budding cells exhibiting the most sensitivity
to its presence (Matus et al., 1981). Interestingly, low doses of ozone stimulated
the growth and development of Monilia fructagen and Phytophtora infestans,
while higher doses were inhibitory (Matus et al., 1982). Thus, high concentra-
tions of ozone are required for effective antimicrobial activity.
Viruses have been studied during their interaction with ozone (Roy et al., 1981).
After 30 seconds of exposure to ozone, 99 percent of the viruses were inactivated
and demonstrated damage to their envelope proteins, which could result in failure
of attachment to normal cells and breakage of the single-stranded RNA.
The Occupational Safety and Health Administration (OSHA) has set Public
Health Air Standards of 0.1 ppm for 8 hours or 0.3 ppm for 15 minutes as the
limit of the amount of ozone to which people can be safely exposed. Air cleaners
based on ozone must not generate ozone levels above the Public Health Stan-
dards, which are far below any antimicrobial activity or effective odor control.
Low ozone concentrations, below the EPA-acceptable indoor limit, have been
used as air cleaners, but their effectiveness has been questioned by many studies
(Dyas et al., 1983; Foard et al., 1997). At high ozone concentration, ozone has
been used to decontaminate unoccupied spaces of some chemical and biological
contaminants and odors such as smoke.
Air Flow
The Center for Disease Control and Prevention’s guidelines for air flow into
an isolation room state that there shall be greater than 12 air changes per hour
(ACH). However, a higher ACH means more efficiency in removing any air-
borne infectious materials. There are two settings on the air flow volumes. The
number of ACH obtained is a function of room volume, as illustrated in Table 4-
6, which is color coded based on obtaining 12 ACH as the minimal level required
for meeting CDC guidelines for isolation precautions.

TABLE 4-6 ACH as a Function of Isolation Room Volume and FASS

Capabilities (calculated on a 10 percent reduction in air flow capability)
Room Size Room Volume FASS 700 FASS 1000 FASS 2000
L×W×H (cu ft) (ACH) (ACH) (ACH)
9' × 12' × 8' 864 43.8 62.5 125.0
12' × 12' × 8' 1,152 32.8 46.9 93.8
15' × 12' × 8' 1,440 26.3 37.5 75.0
15' × 20' × 8' 2,400 15.8 22.5 45.0
20' × 20' × 8' 3,200 11.8 16.9 33.8
20' × 30' × 8' 4,800 7.9 11.3 22.5
30' × 30' × 8' 7,200 5.3 7.5 15.0
Summary
The described FASS Medical Isolation Units are available in the United
States, Canada, and Asia from FailSafe Air Safety Systems Corporation of
Tonawanda, NY. They may offer the best opportunity to increase the numbers of
isolation rooms in hospitals and especially in emergency rooms. By doing this,
they provide a cost-effective solution to the challenge of new viral pathogen out-
breaks. It must be emphasized that these units will only control respiratory trans-
missions, and are not a substitute for contact precautions or for treatment of the
infection itself. Traditional measures still must be instituted to deal with surface
contamination. For cleanup of biological contamination, the FASS Mobile Con-
tainment Systems also generate ozone to eradicate pathogens from surfaces.
These units should be used in conjunction with the Models 77 and 07 for addi-
tional remediation of the hospital or emergency room environment.
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Preparing for the Next Disease Outbreak
OVERVIEW
Although it is possible that the future will bring a more contagious, deadly
form of SARS, it is certain to bring influenza and other infectious diseases, some
of which may be introduced intentionally. Recognizing that it would be impos-
sible to address the vast array of potential microbial threats individually, public
health policy makers are formulating strategies to evaluate and respond to out-
breaks of all kinds. Lessons learned from the recent SARS epidemic regarding
surveillance and containment were described in earlier chapters; this chapter will
discuss additional strategic issues, including anticipating the confluent threats of
SARS and influenza, understanding the epidemiological factors that are likely to
shape future epidemics, and ensuring that public health institutions and legal
frameworks are appropriately designed for responding to any new outbreaks.
Like SARS and influenza, many of the microbial pathogens to come are
likely to be viral zoonoses. The paper by Richard Webby and Robert Webster in
this chapter argues that the trends that ushered SARS into the human population
are in fact similar to those seen over a century of influenza outbreaks. As with
SARS, livestock and poultry markets provide a breeding ground for influenza
outbreaks, and laboratory sources appear to have sparked at least one epidemic.
Although recent severe outbreaks of avian influenza have not featured viral trans-
mission between humans, it may be only a matter of time until a highly conta-
gious flu, such as the strain that is estimated to have caused over 20 million and
perhaps as many as 40 million deaths in 1918–1919, confronts the world.
In the case of influenza, in which the virus can be anticipated to some extent,
vaccines and antiviral therapies can play a significant role in containing an epi-
206

PREPARING FOR THE NEXT DISEASE OUTBREAK 207
demic. However, strategic actions recommended against influenza that could

also inform efforts to better prepare for other viral disease outbreaks have
yet to be implemented. These strategies include:1
• stockpiling of broad-spectrum antiviral drugs,

• advanced development of pandemic strain vaccines,
• the establishment of surge capacity for rapid vaccine production, and
• the development of models to determine the most effective means of
delivering therapies during an outbreak.
It is evident from the experience of the late 2003 influenza season that our
supply and effectiveness of antiviral drugs, capabilities to accurately predict the
best viral strain for annual vaccine production, and mechanisms for surge capac-
ity production remain inadequate (Treanor, 2004). Recognition of these vulner-
abilities led numerous workshop participants to call for greater scientific and
financial investments to strengthen our defenses against these certain future
threats.
However, most emerging infections other than influenza will represent a truly
novel threat for which the world is inadequately prepared. In these cases, models
based on detailed observations from previous epidemics can be used to predict
demands on hospital capacity during a hypothetical epidemic and to guide the
timing and nature of quarantine measures. Two papers in this chapter (Amirfar et
al. and Kimball et al.) examine the modeling strategies that have been used for
analyzing public health responses to epidemics as well as the particular chal-
lenges that SARS presented for international disease surveillance and alert net-
works. As with other public health measures, these strategies are potentially ap-
plicable not just to SARS but to any future outbreaks in which appropriate actions
to protect the public’s health must be taken swiftly (and possibly even before the
complete clinical profile of the new disease and the etiological agent behind it are
fully understood).
When containment measures such as quarantines must be put in place, estab-
lishing the trust of the public is crucial to their effectiveness. Social cohesion and
compliance with SARS quarantine in Toronto, for example, have been attributed
in part to a combination of clear communication and practical guidance by public
health authorities. In the extreme case of mandatory quarantine, enforcement re-
quires careful planning and a clear understanding of public health law. This is
particularly true in the United States, where quarantine is likely to necessitate the
coordination of federal, state, and local jurisdictions and legal authorities. As
Gene Matthews’ paper elaborates, additional legal considerations include: due
process, which requires proper notice; legal representation; court-reviewed deci-
sions; and remote communications to permit a quarantined person to be heard in
1Workshop presentation, Robert Webster, St. Jude Children’s Research Hospital, October 1, 2003.

court, as well as practical contingencies such as the need for law enforcement
officials to serve notice of quarantine.
As the world becomes more conscious of microbial threats to health, coun-
tries are increasingly recognizing the necessity of reporting outbreaks promptly
and cooperating fully in international efforts to contain them. Indeed, if there is
one piece of good news to be noted from last year’s epidemic, it is the fact that—
as David Heymann and Guenael Rodier observe in this chapter—an array of di-
agnostic and surveillance tools, coordinated strategies of containment, and inter-
national collaboration among scientists and public health authorities were in this
case able to control the outbreak of SARS, even in the absence of curative drugs
or vaccines. Nevertheless, last year’s experiences further reinforce the lessons
that HIV/AIDS, influenza, Ebola, malaria, and a host of other persistent and
emerging infectious diseases have already made clear—that the health of any one
nation cannot be isolated from the health of its neighbors, and that public health
challenges in any locality have the potential to reverberate swiftly around the
globe. Karen Monaghan’s paper for the National Intelligence Council, which con-
cludes this chapter, summarizes the continuing threat that SARS may still pose,
as well as the challenges that lie ahead for attempting to contain any further deadly
outbreaks of SARS or other infectious diseases in the future.
ARE WE READY FOR PANDEMIC INFLUENZA?

Richard J. Webby and Robert G. Webster2
Division of Virology, Department of Infectious Diseases,
St. Jude Children’s Research Hospital
Reprinted with permission from Webby and Webster, 2003. Copyright 2003 AAAS.
During the past year, the public has become keenly aware of the threat of
emerging infectious diseases with the global spread of severe acute respiratory
syndrome (SARS), the continuing threat of bioterrorism, the proliferation of West
Nile virus, and the discovery of human cases of monkeypox in the United States.
At the same time, an old foe has again raised its head, reminding us that our worst
nightmare may not be a new one. In 2003, highly pathogenic strains of avian
influenza virus, including the H5N1 and H7N7 subtypes, again crossed from birds
to humans and caused fatal disease. Direct avian-to-human influenza transmis-
sion was unknown before 1997. Have we responded to these threats by better
preparing for emerging disease agents, or are we continuing to act only as crises
arise? Here we consider progress to date in preparedness for an influenza pan-
2We thank W. Shea for helpful advice, S. Naron for editorial assistance, and A. Blevins for illustra-
tions. Influenza research at St. Jude Children’s Research Hospital is supported by Public Health Ser-
vice grant AI95357 and Cancer Center Support (CORE) grant CA–21765 from the National Institutes
of Health and by the American Lebanese Syrian Associated Charities (ALSAC).

demic and review what remains to be done. We conclude by prioritizing the re-
maining needs and exploring the reasons for our current lack of preparedness for
an influenza pandemic.
In February 2003, during a family visit to mainland China, a young girl from
Hong Kong died of an unidentified respiratory illness. After returning to Hong
Kong, both her father and brother were hospitalized with severe respiratory dis-
ease, which proved fatal to the father. When H5N1 (avian) influenza virus was
isolated from both patients, the World Health Organization (WHO) went to pan-
demic alert status (WHO, 2003a). At about the same time, there were rumors of
rampant influenza-like disease in China. Influenza experts feared that H5N1 in-
fluenza virus had acquired the ominous capacity to pass from human to human.
That outbreak is now known to have been SARS, caused by a novel coronavirus.
In March 2003, another alarming situation arose on the other side of the
world. A highly pathogenic H7N7 avian influenza outbreak had recently erupted
in the poultry industry of the Netherlands (Koopmans et al., 2003), and workers
involved in the slaughter of infected flocks contracted viral conjunctivitis. The
H7N7 virus isolated from these patients had several disquieting features: Not only
could it replicate in the human conjunctiva, but there was also evidence of hu-
man-to-human spread. Nearby herds of swine (which are often implicated in the
adaptation of influenza viruses to humans) also showed serologic evidence of
exposure (Koopmans et al., 2003). When a veterinarian died of respiratory infec-
tion (Abbott, 2003; Koopmans et al., 2003; Sheldon, 2003; van Kolfschooten,
2003), WHO again acknowledged the presence of a severe threat (WHO, 2003b).
Luckily, the worst-case scenarios did not come about in either of the 2003
avian influenza virus scares. However, the year’s events eliminated any remain-
ing doubts that global advance planning for pandemic influenza is necessary. They
also highlighted how far, as a scientific community, we have come since the 1997
event: We are now much better equipped with technologies and reagents to rap-
idly identify and respond to pandemic influenza threats. On the other hand, the
legislative and infrastructure changes needed to translate these advances into real
public health benefits are alarmingly slow.
The Role of WHO in Influenza Surveillance and Control

In 2001, WHO initiated the development of a Global Agenda for Influenza
Surveillance and Control. Its four main objectives are to strengthen influenza
surveillance, improve knowledge of the disease burden, increase vaccine use, and
accelerate pandemic preparedness (Stohr, 2003). In May 2002, this document
was adopted after proposals and public comment were invited. The document
advocates the development of methods and reagents that can be used to rapidly
identify all influenza virus subtypes, thereby allowing integrated influenza sur-
veillance in humans and in other animals. WHO, with its global influenza net-
work of more than 100 laboratories and its distinguished record of planning for

yearly interpandemic influenza, is ideally situated to play a broader role in facili-

tating international cooperation for the rapid exchange of viruses, reagents, and
information. Influenza continually evolves at the human–lower animal interface
and thus can be unpredictable. As an example, within a brief period, the H7N7
virus events occurred in European poultry and humans, H5N1 viruses infected
Asian poultry and humans, and novel, rapidly spreading reassortant viruses were
isolated in swine in the United States (Olsen, 2002; Zhou et al., 1999). Therefore,
the capacity to simultaneously manage multiple potential pandemic situations is
important. The WHO global agenda document will help to prioritize areas of
influenza research and facilitate national pandemic preparedness plans.
Prioritization of Viral Subtypes for Surveillance and Control

Influenza experts agree that another influenza pandemic is inevitable and
may be imminent (Figure 5-1). A major challenge in controlling influenza is the
sheer magnitude of the animal reservoirs. It is not logistically possible to prepare
reagents and vaccines against all strains of influenza encountered in animal reser-
voirs, and therefore, virus subtypes must be prioritized for pandemic vaccine and
reagent preparation. Preliminary findings have identified the H2, H5, H6, H7, and
H9 subtypes of influenza A as those most likely to be transmitted to humans.
(Influenza viruses are typed according to their hemagglutinin [H] and neuramini-
dase [N] surface glycoproteins.) The influenza A subtypes currently circulating in
humans, H1 and H3, continue to experience antigenic drift. That is, their anti-
genic surface glycoproteins are continually modified, allowing them to escape the
population’s immunity to the previous strain and thus to continue causing annual
outbreaks. Although these continual modifications may lead to an increase in viru-
lence, the mildness of the past three influenza seasons suggests that the domi-
nance of the H1N1 and H3N2 viruses is waning as their ability to cause serious
disease becomes increasingly attenuated. H2 influenza viruses are included in the
high-risk category because they were the causative agent of the 1957 “Asian flu”
pandemic and were the only influenza A subtype circulating in humans between
1957 and 1968. Counterparts of the 1957 H2N2 pandemic virus continue to circu-
late in wild and domestic duck reservoirs. Under the right conditions (which are
still not completely understood), H2N2 viruses could again be transmitted to and
spread among humans, none of whom under the age of 30 years now has immu-
nity to this virus. Seroarchaeology data from the late 19th and early 20th centuries
indicate that only the H1, H2, and H3 influenza virus subtypes have been success-
fully transmitted among humans. It is possible, but unlikely, that they are the only
subtypes able to do so.
Not only are the H1, H2, and H3 influenza viruses of concern, but the H5
subtype has threatened to emerge as a human pandemic pathogen since 1997,
when it killed 6 of 18 infected humans. Before that event, the receptor specificity
of avian influenza viruses was thought to prevent their direct transmission to hu-


FIGURE 5-1 Timeline of human influenza over the past 100 years. The black triangles represent documented human
influenza A infections characterized by multiple cases. In each instance the species of animals implicated in the emergence
of disease is highlighted. Since 1997 there has been a disproportionate increase in the number of reports of novel subtypes
in humans and in the number of animal and bird species involved, suggesting that the next influenza pandemic is imminent.
211
mans. Transmission from aquatic birds to humans was hypothesized to require

infection of an intermediate host, such as the pig, that has both human-specific
(␣-6 sialic acid) and avian-specific 2-3 sialic acid) receptors on its respiratory
epithelium. The 1997 H5N1 event demonstrated that domestic poultry species
may also act as intermediate hosts. H5N1 viruses continue to emerge and evolve
despite heroic measures taken to break their evolutionary cycle in the live poultry
markets of Hong Kong: the elimination of live ducks and geese (the original
source), the elimination of quail (the source of the internal genes of H5N1/97),
and the institution of monthly “clean days,” when all 1,000-plus retail markets are
emptied and cleaned.
Two things have become clear. Live poultry markets are potential breeding
grounds for influenza and other emerging disease agents, and there is an Asian
source of H5N1 influenza viruses outside of Hong Kong SAR. Between 1997 and
2003, H5N1 virus was isolated from duck meat imported from China into Korea
(Tumpey et al., 2002) and Japan (ProMED-mail, 2003). These observations sug-
gest that ducks and possibly other avian species in mainland China are a reservoir
of H5N1, although there have been no official reports of H5N1 virus in China.
At the beginning of the SARS outbreak, China missed an opportunity to show
the world its considerable intellectual and scientific potential (Enserink, 2003a).
In the case of H5N1 influenza, a pandemic in waiting, it remains to be seen
whether China will show leadership in proactively addressing the problem. Con-
certed national and international efforts are required to deal effectively with the
threat.
The third virus subtype on the most wanted list is H7. The H7 and H5 viruses
have a unique ability to evolve into a form highly virulent to chickens and turkeys
by acquiring additional amino acids at the hemagglutinin (HA) cleavage site (HA
cleavage is required for viral infectivity) (Steinhauer, 1999). The highly patho-
genic H7N7 influenza viruses that were lethal to poultry infected the eyes of more
than 80 humans and killed one person (Enserink, 2003b). In the case of this out-
break, the Netherlands’ policy of openness was important in reducing the poten-
tial threat and should serve as a model. When the virus was first detected at the
end of February 2003, the European Community and international community,
via the Office International des Epizooties, were notified so that surrounding coun-
tries, including Belgium and Germany, could immediately respond if the disease
was detected. Culling of all poultry on infected farms and quarantine of surround-
ing farms succeeded in eradicating the virus once the etiologic agent was identi-
fied. After human infection was observed, an anti-influenza drug was given as
prophylaxis, and vaccination with the current human influenza vaccine was done
to reduce the likelihood that the avian virus would reassort with human H1N1 and
H3N2 strains.
The remaining two viral subtypes on the priority list, H6 and H9, do not
share the virulent phenotypes of the H5 and H7 viruses, but still pose a consid-
erable threat. Both of these influenza viruses have spread from a wild aquatic

bird reservoir to domestic poultry over the past 10 years. H9N2 viruses have
also been detected in humans and in pigs (Peiris et al., 1999, 2001) and have
acquired human-like receptor specificity (Matrosovich et al., 2001). Neither of
these viruses was able to infect chickens before the mid-1980s. Now, for un-
known reasons, H9 viruses are endemic in chickens in Eurasia and H6 viruses
are becoming endemic in both Eurasia and the Americas. These facts highlight
the continuing adaptation of influenza viruses in the aquatic bird reservoirs to
domestic chickens.
The Challenge of Developing Candidate Vaccines

If the next influenza pandemic were to begin tomorrow, inactivated vac-
cines would offer the only immediate means of mass prophylaxis, yet their sup-
ply is limited by inadequate production capabilities and suboptimal utilization
of adjuvants (Fedson, 2003; IOM, 2003). The stocks of antiviral drugs are too
low to cope with an epidemic and would be quickly depleted (IOM, 2003).
Tissue culture–based and live attenuated vaccines are now licensed in some
countries, and could supplement the supply of inactivated vaccine. Further de-
velopment of these options is urgently needed to provide alternative substrates
in the face of a pandemic.
Since the 1970s, influenza vaccines have been made by exploiting the ten-
dency of the segmented influenza genome to reassort (Wood and Williams, 1998).
This natural process has been used to produce vaccine strains that simultaneously
contain gene segments that allow them to grow well in eggs and gene segments
that produce the desired antigenicity. Natural reassortment is allowed to occur in
embryonated chicken eggs, and reassortants with the desired characteristics are
selected. These recombinant vaccine strains contain the hemagglutinin and
neuraminidase genes of the target virus (encoding glycoproteins that induce neu-
tralizing antibodies); their remaining six gene segments come from A/Puerto Rico/
8/34 (H1N1), which replicates well in eggs and is safe for use in humans
(Kilbourne, 1969). These “6+2” reassortants are then grown in large quantities in
embryonated chicken eggs, inactivated, disrupted into subunits, and formulated
for use as vaccines. Although this process creates an effective and safe influenza
vaccine, it is too time-consuming and too dependent on a steady supply of eggs to
be reliable in the face of a pandemic emergency. Even during interpandemic peri-
ods, 6 months is required to organize sufficient fertile chicken eggs for annual
vaccine manufacture (Gerdil, 2003), and the preparation of the desired “6+2”
recombinant vaccine strain can be a time-consuming process. Influenza vaccine
preparation is seasonal and is a remarkable achievement, in that an essentially
new vaccine is made every year. However, two of the viruses of greatest concern,
those of the highly pathogenic H5 and H7 subtypes, cannot be successfully grown
in eggs. Their unique ability to accumulate multiple basic amino acids at the site
of hemagglutinin cleavage increases their ability to spread systemically in an in-

fected host and cause significant disease (Steinhauer, 1999). This feature also
renders H5 and H7 viruses rapidly lethal to chicken embryos.
The most promising means of expediting the response to pandemic influenza
is the use of plasmid-based reverse genetic systems to construct influenza virions
and vaccines. These systems also offer a successful alternative means of produc-
ing H5 and H7 vaccine seed strains. Because viable viruses can be generated from
individually cloned cDNA copies of each of the eight viral RNA segments,
reassortment can be prospectively defined and directed, and the extra amino acids
at the HA cleavage site (which are associated with high virulence) can be re-
moved to allow rapid generation of a vaccine seed strain in eggs. Plasmids encod-
ing the internal genes of the base vaccine are already available. A vaccine seed
strain can be created by cloning the appropriate hemagglutinin and neuraminidase
genes from the target virus, altering its HA connecting peptide if necessary, and
transfecting an appropriate cell line (see Figure 5-2). This technology has been
shown to be effective for the production of reassortants carrying several different
surface glycoprotein combinations, including those considered to have a high pan-
demic potential (Hoffman et al., 2002; Liu et al., 2003; Schickli et al., 2003;
Subbarao et al., 2003). The next step is to take these plasmid-derived influenza
vaccines through clinical trials to address crucial questions such as number and
quantity of doses and the role of adjuvants. Most of the vaccines derived after the
1997 H5N1 episode by various alternative strategies induced a disappointing im-
mune response (Wood, 2001). The optimal pandemic vaccination regimens can
be anticipated only by collecting the necessary data and experience through clini-
cal trials of vaccines against different subtypes of influenza virus.
Although they are well suited to the manufacture of inactivated influenza vac-
cines, reverse genetic systems introduce new variables. One of the most limiting of
these is the need to use cell lines. There are surprisingly few suitable accredited cell
lines and cell banks available, and many of those are the property of pharmaceutical
companies. The practical options are very few, in view of the technical and regula-
tory restrictions. Perhaps the only cell line that meets all criteria for international
use at this time is the African green monkey kidney cell line, Vero. However, al-
though Vero cell lines are in widespread laboratory use, only those that are derived
from WHO-approved sources and have a detailed history are acceptable for manu-
facture of human pharmaceuticals. A second new variable is the use of a genetically
modified virus seed strain. Because the traditional vaccine strains are made by natu-
ral reassortment, they have escaped being labeled “genetically modified.” This dif-
ference, although largely semantic, may affect the acceptance of the new vaccines.
Before many of these traits can be tested, the virus must be amplified, inactivated,
purified, and formulated for vaccine use (Gerdil, 2003).
In preparing for a pandemic threat, collaboration between government, in-
dustry, and academia is needed to overcome the obstacles and guarantee the most
rapid production of a vaccine candidate. The recent SARS episode has shown that
international collaboration in the face of a truly global threat is indeed possible.

FIGURE 5-2 Proposed method of influenza vaccine seed virus production using the eight-
plasmid reverse genetics system (Hoffman et al., 2002). The hemagglutinin (HA) and
neuraminidase (NA) genes from the target strain are cloned into the bacterial plasmid
vector pHW2000 in a process that allows for the alteration of the HA cleavage site when
necessary (see text for explanation). These two plasmids, along with six others containing
the remaining influenza A gene segments derived from the master vaccine strain A/Puerto
Rico/8/34 (H1N1), are then introduced into a suitable cell line (e.g., Vero). After expres-
sion of positive- and negative-sense RNA and viral proteins from these plasmids, a pro-
ductive replication cycle is initiated and viable virus particles are produced.
The Safety Testing of Candidate Pandemic Vaccines and Liability Issues

Unfortunately, there are only a few facilities available to carry out safety
testing under the high-level biocontainment conditions required for handling
highly pathogenic influenza viruses. Overcoming the technical hurdles to effi-
cient vaccine production is only the start of a long, expensive process. Manufac-
turing scale-up presents its own problems, not least because plant workers will
have no immunity to the pathogens they will be handling. Of prime importance
is vaccine safety testing, but the need for safety testing will have to be balanced
against the need for rapid mass production of a vaccine. In response to the 2003
H5N1 scare in Hong Kong, WHO has created an Interim Biosafety Risk Assess-
ment (WHO Global Influenza Programme, in press) guideline for the safety test-
ing of pandemic vaccines, particularly the H5 and H7 subtypes, signifying a sub-
stantial advance in preparedness for the production of a pandemic influenza
vaccine.

A major risk for all vaccine manufacturers is the occurrence of adverse reac-
tions in a percentage of recipients. These reactions may be attributable to the
vaccine, to the host, or (most likely) to a unique combination of the vaccine and
the host genetic factors. Guillain-Barré syndrome in human beings first became
apparent during the U.S. swine influenza vaccination program (Roscelli et al.,
1991; Safranek et al., 1991). The inevitability of adverse reactions underscores
the product liability dilemma inherent in any vaccine program. The risk of devas-
tating financial liability, and the unavailability or high cost of liability insurance,
are increasingly discouraging vaccine manufacture, especially for universal use.
Legislative measures can be taken to reduce the impact of liability exposure.
For example, the U.S. Congress passed the National Childhood Injury Compen-
sation Act of 1986 (the “Vaccine Act”), which created a no-fault compensation
program funded by an excise tax on vaccines. Plaintiffs need only establish that
their injuries were caused by the vaccine. Claimants who are not satisfied with the
administrative decision may still elect to sue the manufacturer, but the legal argu-
ments available to the claimant are limited. Although the Vaccine Act represents
progress in achieving a balance between consumer and manufacturer concerns, it
would not apply to vaccines given to the general population, such as those for
influenza or smallpox. Congress again attempted to address these concerns in a
provision of the Homeland Security Act of 2002, and an Institute of Medicine
panel is currently wrestling with the problem as well; however, drug manufactur-
ers remain hesitant. The bottom line is that unless the government authorities of
every country implement mechanisms that equitably limit vaccine liability, no
prospective vaccine for H5N1, H7N7, or any other threatening influenza virus is
likely to be produced for universal human use. It is hoped that governments will
rise to the occasion after a crisis emerges, but logic suggests that the issue should
be addressed now.
Antiviral Drugs
A global influenza strategy would call for the stockpiling of influenza antivi-
ral drugs for use in the event of a pandemic until vaccines can be prepared. “But,”
as noted by Albert Osterhaus (Abbott, 2003b), “no country has yet started to
stockpile antiviral drugs.” The potential value of antivirals was demonstrated in
the recent H7N7 outbreak in poultry and humans. Further, because epidemiologi-
cal modeling has suggested that it is more infectious than SARS (Ferguson et al.,
2003; Lipstitch et al., 2003; Riley et al., 2003), influenza is unlikely to be control-
lable by SARS-like quarantine measures. The estimated US$ 10 billion cost of
SARS and the societal disruption it caused in China and Toronto make a compel-
ling case for stockpiling of antiviral drugs.
Pandemic influenza has already threatened twice in 2003. The events associ-
ated with these outbreaks show that we are in a much better position to rapidly
respond to an influenza threat than we were in 1997; however, much remains to
be accomplished. Overall, our state of preparedness is far from optimal.

Priorities to Ensure Pandemic Preparedness

To conclude, let us revisit our concern that the next influenza pandemic alert
may involve a virus that has acquired the capacity to spread from human to hu-
man. What are our most urgent needs?
1. A sufficiently large supply of anti-influenza drugs to reduce the severity

and spread of infection. Specific efficacious drugs are available, but no country
has yet invested in stockpiling.
2. A vaccine matching the subtype of the emerging pandemic influenza strain
that has been tested in clinical trials and for which manufacturers are prepared to
“scale up” production. Such a vaccine would probably not match the emerging
strain antigenically and would not prevent infection, but it could reduce the sever-
ity of illness until a matching vaccine is produced. Such vaccines have been dis-
cussed for 20 years. None is available, but specific plans to produce such a vac-
cine are currently being formulated.
3. The preparation, testing (safety and clinical trials), and availability of a
vaccine derived by reverse genetics. The scientific technology is in place to
achieve this goal, but manufacturing, intellectual property, and liability issues
remain unresolved. In the event of a pandemic, reverse genetics would be the
most rapid means by which to produce an antigenically matched vaccine. To be
truly prepared, such a vaccine needs to be produced and tested now to identify and
resolve the issues, rather than doing so in direct response to an emergency.
4. An improvement in the global influenza vaccine manufacturing capacity.
Without the use of adjuvants, the current capacity is inadequate and could not be
quickly augmented. The country best prepared to meet this need is Canada; in Ontario,
influenza vaccination is recommended and available at no charge to people of all ages
during the influenza season (Schabas, 2001). This progressive strategy during
interpandemic years will ensure the vaccine-manufacturing capacity of that region.
The conclusion of this analysis is inescapable: The world will be in deep
trouble if the impending influenza pandemic strikes this week, this month, or
even this year. It is now time to progress from talking about pandemic vaccines to
taking action. Our hope is that the “Ontario experiment” will inspire other regions
of the world to similarly promote the expansion of manufacturing capacity for
influenza vaccines.
Although reverse genetics offers great advantages for the rapid preparation
of influenza vaccine strains and for understanding pathogenesis (Hatta et al.,
2001), the reverse side of this benefit is its potential for the development of
bioterrorism agents (Krug, 2003). Regardless of human endeavors, nature’s on-
going experiments with H5N1 influenza in Asia and H7N7 in Europe may be the
greatest bioterror threat of all. The time for talking is truly over. We must be
prepared.

MODELING A RESPONSE STRATEGY

Sam Amirfar, M.D., Mary Koshy, M.P.A., and Nathaniel Hupert, M.D., M.P.H.
Department of Public Health, Weill Medical College of Cornell University
Containment of the 2002–2003 severe acute respiratory syndrome (SARS)

epidemic posed unprecedented challenges to health care delivery and public health
systems worldwide. In addition to the human costs of infection in medical work-
ers, efforts to contain the spread of the virus led to widespread disruptions in the
provision of routine medical care. Response strategies for potential recurrences
of SARS will need to address treatment of infected individuals, quarantine of
potential victims, and health system action plans that lead to containment of the
outbreak without undue impact on the delivery of care for the wider populace.
Since the outbreak of SARS, several computational models have been developed
to investigate the transmission dynamics of the SARS coronavirus. Although these
studies have identified certain parameters (e.g., maximum allowable delay in
quarantining new cases) that may lead to more efficient management of new
outbreaks, further research is needed to better define the practical steps required
for such optimized response strategies. This chapter summarizes the current state
of theoretical modeling for SARS and proposes a research agenda to improve
forecasting of resource requirements at the hospital, health system, and regional
levels for containment of future outbreaks.
Eight models of SARS transmission and control were published in the En-
glish and Chinese scientific literature in 2003 (Chen, 2003; Chowell et al., 2003;
Lin et al., 2003; Lipsitch et al., 2003; Lloyd-Smith et al., 2003; Riley et al., 2003;
Shi, 2003; Wang and Zhao, 2003). Seven of these utilize the standard SEIR (sus-
ceptible, exposed, infectious, recovered) dynamic mathematical model of disease
transmission or variations on that model accounting for the use of quarantine
(Table 5-1) (Chen, 2003; Chowell et al., 2003; Lipsitch et al., 2003; Lloyd-Smith
et al., 2003; Riley et al., 2003; Shi, 2003; Wang and Zhao, 2003). SEIR models
can provide estimates of critical parameters for a disease outbreak, such as the
basic reproductive number R0 (that is, the number of new cases for every existing
case) or maximal lag time for isolation of new cases (Dye and Gay, 2003).
Five of these studies consider outbreak response variables that reflect both
public health activity (e.g., time to isolation of each new case) and hospital-based
measures (e.g., efficacy of isolation and reduction in transmission rate of virus)
(Chowell et al., 2003; Lipsitch et al., 2003; Lloyd-Smith et al., 2003; Riley et al.,
2003; Shi, 2003). For example, Chowell and colleagues predicted that contain-
ment of the Canadian outbreak would require a time-to-isolation of 3 to 6 days
and a 50 to 90 percent reduction in person-to-person transmission from identified
cases (Chowell et al., 2003). In a similar fashion, most of these papers provide
model-derived threshold values, but do not focus on the practical steps needed to
attain them. Only one paper, by Lloyd-Smith and colleagues (2003), went into

TABLE 5-1 SARS Dynamic Transmission Models
Authors Disease Model Typea Data Sources Key Parameter Threshold Values
Chen et al. SIR, deterministic Hong Kong, In-hospital transmission N/A
Beijing
Wang and Zhao SIR, deterministic Hong Kong, N/A N/A
Beijing
Chowell et al. SEIJR, deterministic Toronto, Hong a. 3-6 days to diagnosis

R0=1.2
Kong, a. Time to diagnosis b. 50-90% effectiveness of
Singapore b. Isolation effectiveness quarantine in stopping
population-based spread
Riley et al. SEIR, stochastic/deterministic Hong Kong R0=2.7 a. 50% reduction in
a. Time to isolation hospital infection and
b. Infection control population contact rate
c. Population contact rate b. Complete cessation of
pop ulation movement
between r egions
Lipsitch et al. SEI(Q)R, Singapore R0=1.2 Variable based on other
stochastic/deterministic a. “Public health interventions” modeled factors
b. Population contact rate
Lloyd-Smith et al. SEIR, deterministic with Monte Hong Kong, a. Time to isolation If R0~3, then need:
Carlo simulation and Singapore b. Isolation effectiveness a. < 3 days to isolation of
heterogeneous stochastic effects (hospital-based contact new cases
precaution and case b. 80% reduction in
management measures) transmission

c. HCW-community contact

Shi SIR, stochastic Monte Carlo Vietnam R0=1.8 ≤ 7 days to strict is olation
Days to strict isolation of new cases
aS = susceptible, E = exposed, I = infective, J = diagnosed, Q = quarantined, R = recovered.
219
sufficient detail about methods of disease containment to provide practical guid-

ance for public health and hospital managers in attaining these goals. For ex-
ample, these authors found that efforts to interrupt health care worker-to-patient
transmission would yield greater improvements in epidemic containment than
reductions in population-based transmission. This finding provided the basis for a
practical recommendation to initiate hospital-wide campaigns to increase contact
precautions and strict case management of infected individuals. Additionally, this
report alone—among the eight model-based papers—acknowledges that contain-
ment efforts would be carried out in an environment of limited hospital resources,
where scarcity of items such as gowns, gloves, and masks would require
prioritization of population-wide and hospital-based strategies.
These eight reports provide the beginnings of an evidence base on which to
design effective response strategies for future SARS outbreaks. In parallel with
these efforts, a number of researchers have developed prediction models for medi-
cal outcomes of SARS patients (Table 5-2) (Booth et al., 2003; Chan et al., 2003;
Donnelly et al., 2003; Han et al., 2003; He et al., 2003). The current challenge is
to use these findings from both theoretical modeling and patient care to assist
health planners in practical ways. For example, hospital administrators may ben-
efit from guidance on determining when in the course of an epidemic it is better
to cease all admissions, isolate a specific ward, or simply isolate a number of
patients in individual rooms. More complex response models may begin to weigh
the relative benefits of drastic steps such as shuttering entire hospitals in order to
contain the spread of SARS in light of the potential harms that may accrue to
affected communities through the loss of routine medical care capacity. Such
cost-benefit studies will highlight the difficult choices faced by health planners
and hospital administrators in the real-world setting of financial and resource
constraints. Finally, with the prospect of a SARS vaccine on the horizon, new
models will be needed to quantify optimal pre- and post-detection vaccination
rates for disease containment given the significant resource requirements of any
mass vaccination campaign. Recent efforts to model mass antibiotic prophylaxis
strategies for bioterrorism response may provide insight into the methods and
data requirements for this type of logistical modeling as well as techniques (e.g.,
Internet-based platforms) for wide dissemination of modeling tools (Hupert and
Cuomo, 2003; Hupert et al., 2002).
Publication of data on resources consumed in isolating and treating SARS
patients as well as quarantine of potentially infected individuals will assist mod-
elers in developing realistic forecasting models capable of leading public health
and hospital planners through “what if” scenarios that may require difficult trade-
offs of personnel, materials, and patient care arrangements. The more accurate
the data underlying these models, the better they can serve planners and their
communities. The goal of such efforts should be to give every decision maker the
ability to understand, in relevant terms and for their particular institution or com-
munity, not just the knowledge that containment of SARS would require isolation

TABLE 5–2 Prediction Models for Medical Outcomes of SARS Patients

Authors Model Type Predictor Variable(s) Outcomes of Interest
Booth et al. Multivariable regression Diabetes, comorbidity Death, intensive care admission
Chan et al. Multivariable regression Age, diabetes, heart disease Death
Han et al. Correlation Radiology information technology systems use Infection rate
He et al. Multivariable regression Age, hypoxia, thrombocytopenia, hypernatremia, renal failure Death
Donnelly et al. Gamma distribution Age, infection to onset, onset to admission Death

221
of new cases within a certain number of days, but also an estimate of how to go
about achieving that containment goal (i.e., how many staff, rooms, media cam-
paigns, and other factors). Planning models that focus on critical resources in this
manner can provide guidance for live exercises and may influence future invest-
ments in both infrastructure (e.g., installation of negative pressure isolation
rooms) and disposable medical equipment (e.g., gowns and masks).
REPORTING, SURVEILLANCE, AND INFORMATION EXCHANGE:

THE SARS IMPERATIVE FOR INNOVATION
Ann Marie Kimball,3 Bill Lober,4 John Kobayashi,5 Yuzo Arima,6 Louis Fox,7
Jacqueline Brown,8 and Nedra Floyd Pautler9
Asia Pacific Economic Cooperation, Emerging Infections Network (EINET)
The emergence and widespread transmission of severe acute respiratory syn-

drome (SARS) in the winter of 2003 severely tested national, regional, and global
reporting and surveillance systems for emergent infectious diseases. It presented
a three-pronged challenge: (1) alerting responsible authorities; (2) rapidly de-
scribing the geographically diverse outbreaks in a consistent and useful fashion;
and (3) providing guidance for prevention and control strategies based on experi-
ence in varied locations. Given the persistent emergence of new infections in
recent years in the Asia Pacific—accompanied by the continued increase in popu-
lation size and the greater range and volume of trade and travel in the region—
this scenario must be considered a harbinger for the future. The gaps brought to
light in this experience should be used to guide the rapid deployment of labora-
tory and communications systems in the region. In this article, the informatics
components of the response to SARS are described and characterized. Prospec-
tive areas for applications of new technologies are discussed.
Hypothesis
The SARS experience represents a precursor to future scenario planning for
the Asia Pacific. Descriptive data suggest both successes and gaps in timeliness,
3Director, APEC/EINET, Professor, Departments of Epidemiology and Health Services, School of
Public Health, University of Washington.

4Research Associate Professor, Department of Biomedical and Health Informatics, School of Medi-
cine, University of Washington.

5Clinical Associate Professor, School of Public Health, University of Washington, Consultant, Ja-
pan Field Epidemiology Training Program, Government of Japan.

6Research Associate, Epidemiology, School of Public Health, University of Washington.
7Vice Provost, Educational Partnerships and Learning Technologies, University of Washington.
8Director, Technology Outreach Computing and Communications, University of Washington.
9Information Manager, APEC Emerging Infections Network.

laboratory diagnostic tools, and useful, practical transparent communications

among sectors within nations, and between nations partnered in trade and travel.
This report will focus on gaps in the latter two areas: practical transparent com-
munications among sectors and between nations.
Methods
We conducted a focused and systematic review of the 2003 SARS epidemic
based on (1) our EINET experience operating an electronic, multisectoral com-
munications network in the region, in collaboration with (2) a literature review
for the identification of potential applications of informatics technology based on
the 2003 experience (including response management, collaboration, capacity
development, tabletops/training, and other factors).
Findings/Conclusions
SARS presented the confluence of three urgent requirements of the global
public health informatics response: (1) expansion of knowledge about the disease
in a rapid, systematic manner, particularly in microbiology and epidemiology
through collaborative discovery; (2) communication of appropriate aspects of that
knowledge base to guide implementation of isolation, quarantine, and prevention
measures by public health workers and other policy makers; and (3) mitigation of
adverse societal response through broader social communication. However, with
concurrent outbreaks in numerous locations, each of these requirements rapidly
increased in complexity. Working relationships in the Asia Pacific public health
community have been formed in the course of the outbreak response that can be
reinforced in the present “inter SARS” period. Specific computing and telecom-
munications tools can be expanded to assist more fully in the public health re-
sponse. We propose the use of a virtual tabletop (scenario) tool to proactively
implement improved communications and collaboration strategies in the region.
Background
The SARS outbreaks of 2003 have been described in numerous scientific
reports (CDC, 2003a). In fact, the unprecedented volume and speed of scientific
discovery and the dissemination of that knowledge has been the subject of a re-
port (Drazen and Campion, 2003). This report focuses on (1) how informatics
and telecommunications strategies assisted in the timeliness of this effort; and (2)
what technologies or strategies could be tested and applied in the current “inter
SARS” period to assure public health readiness for the future.
The factors related to the emergence of new infectious diseases have been
described for more than a decade (IOM, 1992, 2003). The role of anthropogenic
factors of emergence related to microbial pathogens in humans, while generally

understood to be important, has become the object of systematic biomedical and

interdisciplinary research. The overlay of globalization in manufacturing, com-
merce, travel, and trade on an uneven public health and sanitary infrastructure has
put some populations at risk of new infections. These risks become reality in
epidemics that increasingly challenge our ability to respond effectively.
The Asia Pacific has witnessed the emergence of numerous new human
pathogens, including Nipah virus, enterovirus 71, E. coli 0157H:7, and
Cyclospora Cayetanensis. The reemergence of “old” pathogens such as cholera
and multidrug-resistant tuberculosis has also affected the region. This may reflect
the pace of change that countries bordering the Pacific Ocean have experienced
in their demographics, migration, and rapid shifts in economic activity. In addi-
tion, these nations are among the most trade dependent in the world. The Asia
Pacific dwarfs other regions of the globe in the volume and dollar value of trade
and travel revenues.
Asia has had sustained growth of Internet connectivity over the past decade,
despite economic crises in the region (Kimball et al., 1999). In a recent report, the
International Telecommunications Union (ITU, 2003) noted that the number of
broadband subscribers rose 72 percent in 2002, with Korea (21 subscribers per
100 inhabitants), Hong Kong (15 per 100), and Canada (11 per 100) showing the
highest rates of broadband use. In Korea, “Disweb,” an electronic surveillance
system, has been in place since 1999 using web-based reporting over the Internet.
Many other economies are increasingly integrating Internet-based reporting into
their disease alert and surveillance systems.
While numerous electronic disease surveillance and alert networks are oper-
ating in the region, the Asia Pacific Emerging Infections Network (APEC-EINET)
is unique in that it includes membership from trade and commerce (see Figure
5-3) as well as health. Now in its eighth year of operation, the network spans the
entire Asia Pacific community. The network consists of a user group of more than
500 in 19 of the 21 APEC economies. Providing a biweekly bulletin and enriched
website, the APEC-EINET is supported by APEC, the U.S. government, and the
University of Washington.
Methods
Of the 1,150 articles entered into the Medline index with “SARS” in their
text, 60 include the word “information” and 2 include “information technology”
(Eysenbach, 2003). The 60 information-related articles were scanned for discus-
sion on informatics or information technology employed during the outbreak by
scientists or public health workers. In addition, informal discussions were held in
person and through electronic communications with World Health Organization/
Geneva (WHO/Geneva) and regional academic institutions and public health or-
ganizations to augment the information available for review in this report. Be-
cause the SARS experience is still being understood, the data obtained through
personal communications may be incomplete.

225
FIGURE 5-3 Integrated process for public health disease response.

Figure 2

After compiling this information, we segregated our conclusions into the

informatics domains of (1) generation of new biomedical knowledge about the
SARS agent; and (2) generation of new knowledge about the epidemiology of
SARS disease prevention for purposes of predicting and monitoring success in
control. We provide our assessment based on this analysis of the need for specific
new communications and collaboration strategies.
Results
If the basic systems model of an outbreak alert, investigation, and response
resembles the work model in Figure 5-4, then numerous frontiers for information
technology application and evaluation exist. This diagram integrates business pro-
cesses and the information flow that supports these processes in the course of
work done to investigate and respond to an outbreak (Kitch and Yashoff, 2002).
The focus of international information technology application during SARS cen-
tered on three aspects, which are shown in the figure: alert, diagnosis (biomedical
discovery), and epidemiologic investigation.
Alert
According to WHO, the earliest alerts about an unknown pneumonia in
Guandong were discovered by Global Public Health Information Network
FIGURE 5-4 Percentage of APEC EINet users from trade and commerce by economy.

(GPHIN) (Heymann et al., 2001). Essentially a webcrawler, text-mining tool,

this application was developed with Canadian government funding and imple-
mented through an agreement with WHO in 2000. The “hits” generated daily
are reviewed manually in Canada, and about 200 reports are forwarded to
WHO per day. However, despite such alerts, all reports from GPHIN require
independent verification from reliable sources on site (Grein et al., 2000;
Hsueh et al., 2003).. In the absence of such confirmation, an international
alert cannot be issued.
Biomedical Discovery
Response depends on diagnosis of what an outbreak is or is not. In the case
of SARS, new scientific discovery was probably the largest beneficiary of new
information technology, and this was in line with its priority in enabling effective
public health response. Bioinformatics software tools were used extensively to
identify the genome of SARS (Li et al., 2003), calculate the likelihood of fre-
quencies in the annotation process (Ruan et al., 2003), and model the virus for
prospective drug design among other uses. These tools, employed by teams of
scientists across international boundaries, allowed bench scientists to rapidly gen-
erate new information about the SARS agent.
Interlaboratory communication was a second area in which the Internet and
communications technologies added value. Stohr and colleagues report on the
multicenter collaboration convened by WHO to “identify the causal agent and to
develop a diagnostic test” (WHO Multicentre Collaborative Network, 2003). The
11 laboratories were located in nine countries. Countries both affected and not
affected by SARS figured among the nine.
The electronic tools implemented included: (1) a secure, password-pro-
tected website where primer sequences and other information were posted for
researchers; (2) electronic mail communications using the Internet; and (3) the
telephone for daily teleconferences. Probably as important, the ethical frame-
work for collaboration was established through an agreed protocol for sharing
results and information. This protocol protected the work of scientists involved
and fostered information sharing for advancement of the mutual collaboration.
This networked activity of distributive efforts was efficient, resulting in the
discovery and initial description of the coronavirus of SARS over the period of
one month.
Epidemiologic Knowledge
Disease investigation was carried out in earnest at each of the outbreak sites.
Case counts and mortality counts were reported through PROMED, WHO,
EINET, and the media. However, in our experience with EINET, the need for
practical guidance for the Asia Pacific outstripped the available information in

the first weeks of the epidemic. We received numerous queries about hospital
isolation procedures, quarantine, airport measures, treatment, and other issues.
While recommendations addressing these eventually were posted by international
authorities, practitioners in closely linked but unaffected economies desired more
specific and detailed information in a more timely manner.
WHO has convened the Global Outbreak Alert and Response Network part-
ners over the past 8 years to begin to address exactly the kind of crisis presented
by SARS. This activity proved to be a major asset to WHO in coping with SARS.
However, the secure network and website approach that was implemented was
less able to cope with the volume and diversity of information required. Specifi-
cally, the need for detailed information by public health authorities in unaffected
areas was not optimally met (Kimball and Pautler, 2003).
The ability to monitor the impact of interventions is important to modulating
the public health response. The key epidemiologic parameter to be followed is the
reproductive rate of the epidemic in progress. If this rate is above 1.0, the epi-
demic will continue to expand as it infects new susceptibles at a greater rate than
infected individuals recover (Lipsitch et al., 2003). This rate relies on modeling,
and parameters that are difficult to collect through field investigation. In retro-
spect, only some of the affected localities were able to collect quality data in
adequate amounts to enable such modeling to be reliably applied (Donnelly et al.,
2003). As noted by one group, “Limited data and inconclusive epidemiologic
information place severe restrictions on efforts to model the global spread of the
SARS etiological agent” (Chowell et al., 2003).
Because our own user group includes trade and commerce officials from a
number of APEC economies (Figure 5-4), our network was one of the few that
provided updates on the epidemic situation in the region systematically to indi-
viduals not employed in the health sector. Although we have no quantitative in-
formation to document this, anecdotally we have been told this was useful in
decision-making during the epidemic period.
Discussion: “Inter-SARS” Preparedness

SARS presented a challenge on both the research and response fronts. How-
ever, a similar challenge would be faced with any acute, severe viral respiratory
infection for which diagnostic, treatment, and containment recommendations had
not been well established. Influenza is an agent that could produce a similar pic-
ture and create similar chaos in the region. Thus, the overall concept of “pre-
paredness” for such a natural disaster can serve to inform our actions in preparing
for the “next wave.” In fact, in the midst of SARS, this genre of concept surfaced
in the literature (Augustine, 2003).
The processes to address two major domain needs of the SARS re-
sponse—laboratory research and epidemic investigation—were not truly ad
hoc during the outbreak period. The basic structures of the two collaborative

groups—the linked laboratories and the outbreak alert and response partners
(including the implementation of GPHIN)—had been created over the years
prior to the outbreak. However, the implementation of emergency response
was ad hoc, as was the area of epidemiologic investigation. Response encoun-
tered obstacles in communications, which can be partially addressed through
preparedness exercises.
Tabletop or scenario exercises have been a centerpiece in preparation for
emergency response in the United States. In Japan and Korea, exercises of alert
and syndromic surveillance systems have been conducted to prepare for events
such as the World Cup (Suzuki et al., 2003). The scenario “Dark Winter” con-
vened high-level policy makers to discuss smallpox preparedness planning in the
United States, and the more recent “Global Mercury” exercise carried out by the
Global Health Security Action Group demonstrated the utility of this approach
internationally (U.S. Department of State, 2003).
The tabletop as envisioned will: (1) bring together research universities
and their public health counterparts in a collaborative process to tailor a sce-
nario for their location in response to the threat of a travel-related, highly infec-
tious disease; (2) create automated access to pertinent information sources at
multiple sites that will add value to actual response efforts should these be
needed; (3) promote international communications and collaboration using
newer communications strategies among partners, thus ensuring the availabil-
ity of these new tools to the public health community; and (4) create a flexible
scenario for use in preparedness domestically and potentially by multiple APEC
economies in training efforts. We believe the use of access node communica-
tions (see Box 5-1) for collaborative conferencing will demonstrate added value
in the collaborative design process and in the debriefing on generic lessons
learned in the exercises.
Beyond the virtual tabletop exercise, systematic analysis of the integrated
workflow diagram suggests many other potential application sites for new infor-
mation technologies. One apparent area would be the development of a software
tool that could allow individual outbreak sites to assess their own data and calcu-
late their own rate of reproduction for the outbreak they are experiencing (Chowell
et al., 2003; Donnelly et al., 2003; Lipsitch et al., 2003). Such a tool could enable
local public health officials to step up or step down response as success is or is not
achieved. However, such a tool would rely heavily on the generation of reliable
field investigation data in a timely way. The generation, compilation, and analy-
sis of these data during the course of an outbreak remain the cornerstone of suc-
cessful outbreak curtailment. Innovations in information technology need to be
evaluated for their ability to support the key function of effective public health
outbreak response.
Electronic networking and promoting intersectoral collaboration figure
among the five strategies adopted by APEC to respond to emergent infections
(Asia-Pacific Economic Corporation, 2001). The virtual tabletop will begin

BOX 5-1
The Access Grid
“The Access Grid™ is one example of advanced communica-
tions resources now accessible within the Asia Pacific. An ensemble
of resources including multimedia large-format displays, presentation
and interactive environments, and interfaces to Grid middleware and
to visualization environments, access grid nodes are used to support
group-to-group interactions across the Grid. The Access Grid (AG) is
used for large-scale distributed meetings, collaborative work ses-
sions, seminars, lectures, tutorials, and training. The Access Grid thus
differs from desktop-to-desktop tools that focus on individual commu-
nication.
The Access Grid is now used at over 150 institutions worldwide
(including institutions in Japan, Taiwan, Korea, Singapore, Canada, US,
China, Hong Kong, Thailand). Each institution has one or more AG
nodes, or “designed spaces,” that contain the high-end audio and visual
technology needed to provide a high-quality compelling user experience.
The nodes are also used as a research environment for the develop-
ment of distributed data and visualization corridors and for the study of
issues relating to collaborative work in distributed environments”
(www.accessgrid.org).
to leverage the sophistication already in place in communications and com-

puting in the Asia Pacific in the service of the public good. Specifically, (1)
communications technologies and middleware capacities of Asia Pacific re-
search and education telecommunication networks are in place to be tested
and adapted within the EINET community to support reporting, surveillance,
and information exchange, particularly through the use of the Access Grid;
and (2) a network of Pacific Rim research universities are being brought into
the effort to serve as primary points of access for these advanced networks
and technologies and as hubs of a broader communications network with the
capacity to engage public health as well as other professionals throughout the
APEC community.
PUBLIC HEALTH LAW PREPAREDNESS

Gene Matthews, J.D.
Legal Advisor, Centers for Disease Control and Prevention
The Central Intelligence Agency’s (CIA’s) unclassified report on severe acute

respiratory syndrome (SARS) sets the tone for our current status on legal pre-

paredness for the next outbreak. “The effective application and efficacy of quar-
antine and isolation [during the SARS epidemic] proved a pleasant surprise to the
public health community,” the CIA reports. “Equally unexpected was the wide-
spread acceptance of the need for these measures by the general public.”
Another perspective on legal preparedness for an outbreak of infectious dis-
ease in the United States can be gained by considering a pair of paradoxes. The
first paradox is that, in the same year (1954), the need for community-wide public
health control measures was greatly reduced through the development of the Salk
polio vaccine, and the U.S. Supreme Court initiated a trend toward increased
procedural protections of individual liberties with its ruling that in Brown vs.
Board of Education. Prior to 1954, the United States had regularly used commu-
nity-wide quarantine in our legal system as a public health control measure. Dur-
ing the past 50 years, however, the judicial, legislative, and executive branches
have each established ways to increase the protection of individual rights from
government infringement. So, the public reaction to SARS was indeed surprising,
as the CIA report says, because it marked the first true meeting in the United
States of historical public health quarantine and modern civil liberties.
The second paradox could be referred to as “the paradox of the silos.” As the
U.S. government has evolved during the past 50 years, we have developed more
governance, but we have partitioned various responsibilities and authorities into
different jurisdictional silos. We now have a public health silo stratified at the
federal, state, and local levels, and it is separated from the silos of law enforce-
ment, emergency management, agriculture, animal control, medical services,
courts, transportation, and others. Reports of the SARS outbreak in China de-
scribed silos of health care in that country as well. Health care in military hospi-
tals, for example, was totally separate from health care in hospitals run by the
railway system. When this silo effect occurs in complex governments, the legal
structure is limited in its ability to arch over and effectively connect all the juris-
dictions that need to respond to the problem. This is the challenge we face in the
“paradox of the silos.”
Quarantine and Public Health Law

The quarantine issue during the SARS outbreaks illustrates the sort of bridg-
ing of silos that has to occur in public health law. Most emergency public health
measures imposed within a state are subject to state law and regulations, which
can vary. Some state laws concerning quarantine are procedurally outdated, and
some local laws may be very useful. The federal government also has authority
concerning quarantine. The U.S. Department of Health and Human Services
(HHS) has concurrent federal power to apprehend, detain, and conditionally re-
lease individuals to prevent interstate spread or international importation of cer-
tain diseases.
These federally quarantinable diseases are specified by executive order of

the President. On April 4, 2003, President Bush signed an executive order adding
SARS to the list of conditions that warrant quarantines; other conditions include
cholera, diphtheria, infectious tuberculosis, plague, smallpox, yellow fever, and
suspected viral hemorrhagic fevers (e.g., Lassa, Marburg, Ebola, Congo-Crimean,
and others not yet isolated or named). Violation of quarantine authority in these
cases is a criminal misdemeanor under federal law.
How would federal, state, and local laws interact to address an infectious
outbreak? State and local governments have primary responsibility for isolation,
quarantine and most of the emergency public health powers. The federal govern-
ment has the authority to prevent interstate spread and international importation,
but it can accept state and local assistance in enforcing the federal quarantine
regulations. Conversely, HHS can assist state and local officials in their control
of communicable diseases.
Because SARS has the potential to spread rapidly into different states, the
federal quarantine authority could be applied to a single SARS case inside a state
or local jurisdiction as necessary. In other words, it would not be necessary to
wait for an interstate spread of SARS actually to take place before the Centers for
Disease Control and Prevention (CDC), part of HHS, used this federal authority.
However, any CDC action on SARS using this authority would be carefully coor-
dinated with the appropriate state or local officials. The CDC did not use this
authority during the 2003 SARS outbreak.
However, a situation may arise in which all three concurrent jurisdictions
come into play. For example, if a disease outbreak occurred in a New York air-
port, federal, state, and local authority—all with overlapping police power—could
be used. Since such activities would require coordination with the “law enforce-
ment silo,” the CDC is intensively pursuing joint training between law enforce-
ment and public health officials.
Lessons from Toronto

Toronto exemplifies the surprising level of public acceptance of quarantine
described in the aforementioned CIA report. Dr. Barbara Yaffee and attorney
Jane Speakman report that of the 13,000 persons “voluntarily” quarantined in
Toronto, only 27 needed to be served with a formal quarantine order, and only
one person sought to appeal (and this person later withdrew the appeal after he
was told how he was exposed to SARS and could potentially transmit the dis-
ease). Few legal or public health professionals would have expected that level of
public cooperation. One possible explanation is that the intense media coverage
rapidly demystified the concept of quarantine. Additional analysis of this social
phenomenon is urgently needed.
Toronto also exemplified social cohesion in a public health emergency; resi-
dents showed responsibility and cooperation, rather than the divisiveness and
panic that some public health, media, or legal experts might have predicted. The

experience seems to indicate that when the public is presented with clear commu-
nication and practical guidance in a public health emergency, they can behave
quite responsibly. Interestingly, there are abundant examples in the literature of
such temporary, cohesive community behavior in an emergency. Of course, it is
difficult to speculate how much the Toronto (or Canadian) experience would re-
semble that of the United States in a similar situation. Yet despite the differences
between the U.S. and Canadian legal systems, it does seem that the recent history
of quarantine in Toronto will influence how the United States would handle a
similar situation.
Another key lesson from Toronto, as well as from several Asian countries, is
the broad range of situations encompassed under quarantine. These included
“work quarantine,” a concept discussed by Martin Cetron (see Chapter 1).
Through “work quarantine,” needed public service employees can go to work and
be isolated there or at home, and continue to maintain essential services. This is
an important new tool to have available to compliment “snow day” and “shelter-
in-place” community emergency strategies
Finally, as CDC director Julie Gerberding said in a press conference during
the SARS epidemic, the public health community must be prepared to act boldly
and swiftly, yet treat individuals with dignity and fairness. That is a good descrip-
tion of what happened during the SARS outbreak in Toronto: People were treated
fairly, they received clear messages about their situation, and quarantine pro-
ceeded smoothly.
Practical Steps for Legal Preparedness

Some practical steps to prepare for a possible resurgence of SARS or an
outbreak of another infectious disease. A more detailed treatment is available at
www.cdc.gov.
• Know the relevant legislation. All states, and most cities and munici-
palities, have quarantine laws. Some of these laws have not been used on a com-
munity-wide basis in 50 or 80 years. All such laws need to be examined on a
case-by-case basis to determine whether they could be applied appropriately if
SARS returned.
• Plan due process. Be able to take the necessary steps, even if the laws are
old, to give a quarantined person notice, a way to be heard, legal representation,
and a final decision that a court can review. On the other hand, recognize that due
process should not interfere with isolation if lives are threatened.
• Draft documents in advance. Examples of quarantine orders that were
used in Texas, as well as orders that have been drafted in North Carolina and
other areas, are available on the CDC Public Health Law website at
www.phppo.cdc.gov/od/phlp. These documents are accompanied by affidavits,
descriptions of due process mechanisms, and other contingent material.

• Contact other jurisdictions. Put law enforcement, emergency manage-

ment, and health care in touch with each other. Create legal mechanisms to bridge
these “silos” horizontally and vertically, and to connect federal, state, and local
jurisdictions as well as geographical clusters. Personal networking is vital before
an event takes place.
• Engage the courts in advance. Toronto judges were somewhat surprised
when health agency lawyers introduced quarantine orders. If the judiciary is en-
gaged in advance of an outbreak, it can manage due process or habeas corpus
proceedings efficiently.
• Anticipate practical problems. In Toronto, for example, contract civil
process servers refused to serve quarantine orders during the SARS epidemic.
Law enforcement agents were therefore required to serve these quarantine orders.
• Plan electronic communications for quarantined persons. They should
be able to participate in hearings via video feed, cell phone, or other mechanism,
rather than risk transmitting disease in the courtroom.
• Emphasize communication, communication, communication. Two key
reasons explain why quarantine worked so smoothly in Toronto: it was perceived
as being fair and everyone was generally aware of what was happening. Commu-
nication among the “silos” is critical to success or failure of governance in a
public health emergency.
SARS: LESSONS FROM A NEW DISEASE

David L. Heymann and Guenael Rodier
World Health Organization
Reprinted with permission from WHO, 2003.
© Copyright World Health Organization, 2004. All Rights Reserved.
New diseases have been emerging at the unprecedented rate of one a year for
the last two decades, and this trend is certain to continue. The sudden and deadly
arrival of SARS on the global health stage early in 2003 was in some ways per-
haps the most dramatic of all. Its rapid containment is one of the biggest success
stories in public health in recent years. But how much of that success was a result
of good fortune as well as good science? How narrow was the escape from an
international health disaster? What tipped the scales? The international response
to SARS will shape future strategies against infectious epidemics.
The day-by-day struggle to control the outbreak of severe acute respiratory
syndrome (SARS) represents a major victory for public health collaboration. Key
lessons emerge that will be invaluable in shaping the future of infectious disease
control—and being ready for the day when the next new disease arrives without
warning. First and most important is the need to report, promptly and openly,
cases of any disease with the potential for international spread in a closely inter-
connected and highly mobile world. Second, timely global alerts can prevent im-

ported cases from igniting big outbreaks in new areas. Third, travel recommenda-
tions, including screening measures at airports, help to contain the international
spread of an emerging infection. Fourth, the world’s best scientists, clinicians and
public health experts, aided by electronic communications, can collaborate to
generate rapidly the scientific basis for control measures. Fifth, weaknesses in
health systems play a key role in permitting emerging infections to spread. Sixth,
an outbreak can be contained even without a curative drug or a vaccine if existing
interventions are tailored to the circumstances and backed by political commit-
ment. Finally, risk communication about new and emerging infections is a great
challenge, and it is vital to ensure that the most accurate information is success-
fully and unambiguously communicated to the public. WHO is applying these
lessons across the Organization as it scales up its response to the HIV/AIDS
emergency.
The First Cases

On March 12, 2003, WHO alerted the world to the appearance of a severe
respiratory illness of undetermined cause that was rapidly spreading among hos-
pital staff in Hong Kong Special Administrative Region (China) and Viet Nam.
Within two days, it was clear that the illness was also spreading internationally
along major airline routes when hospitals in Singapore and Toronto, Canada,
reported seeing patients with similar signs and symptoms. The potential for fur-
ther international spread by air travel was vividly illustrated on March 15. In the
early hours of the morning, the head of WHO’s outbreak alert and response op-
erations was woken by a call from health authorities in Singapore. A doctor who
had treated the first cases of atypical pneumonia there had reported having simi-
lar symptoms shortly before boarding an international flight returning to
Singapore from New York. Asked to intervene, WHO alerted the airline and
health authorities in Germany, where the flight was scheduled for a stopover. The
doctor and his wife disembarked in Frankfurt and were immediately hospitalized
in isolation, becoming the first two cases in Europe. Because of these events,
WHO issued a second, stronger alert later in the day. It set out a case definition,
provided advice to international travellers should they develop similar symptoms,
and gave the new disease its name: severe acute respiratory syndrome (SARS).
The global outbreak of SARS became the focus of intense international concern,
and it remained so for almost four months.
Origins and International Spread

SARS is a newly identified human infection caused by a coronavirus unlike
any other known human or animal virus in its family. Analysis of epidemiologi-
cal information from the various outbreak sites is still under way, but the overall
case fatality ratio, with the fate of most cases now known, approaches 11 percent,

but with much higher rates among elderly people. Transmission occurs mainly
from person to person during face-to-face exposure to infected respiratory drop-
lets expelled during coughing or sneezing, or following contact with body fluids
during certain medical interventions. Contamination of the environment, arising
from fecal shedding of the virus, is thought to play a small role in disease trans-
mission, illustrated by the almost simultaneous infection in late March of more
than 300 residents of a housing estate in Hong Kong where faulty sewage dis-
posal was identified. At present, the disease has no vaccine, no curative treat-
ment, and no reliable point-of-care diagnostic test, though antibody tests have
been developed that can reliably confirm previous infection using acute and con-
valescent sera. Management of SARS is supportive, and control strategies rely on
standard epidemiological interventions: identification of those fitting the case
definition, isolation, infection control, contact tracing, active surveillance of con-
tacts, and evidence-based recommendations for international travellers. Though
demanding and socially disruptive, particularly when large numbers of people
were placed in quarantine, these standard interventions, supported by high-level
political commitment, proved sufficiently powerful to contain the global outbreak
less than four months after the initial alert.
The earliest cases of SARS are now thought to have emerged in mid-Novem-
ber 2002 in the southern Chinese province of Guangdong. Retrospective analysis
of patient records, to date incomplete, has identified small clusters of cases, each
traced to a different initial case, that occurred independently in at least seven
municipalities, with the first case recorded on November 16, 2002, in Foshan
City and the largest number of cases concentrated in Guangzhou City. Analysis
has uncovered no links among the various initial cases in the clusters. Some cases
with no previous known history of exposure also occurred (WHO, 2003c;
Breiman et al., 2003). Early collaborative studies conducted in Guangdong have
detected a virus almost identical to the SARS coronavirus in domesticated game
animals — the masked palm civet cat and the raccoon dog—sold in Guangdong
live markets, suggesting that these animals might play a role in transmission of
the virus to humans.
The initial phase of the Guangdong outbreak, characterized by small, inde-
pendent clusters and sporadic cases, was subsequently followed by a sharp rise in
cases during the first week of February 2003, thought to result from amplification
during care in hospitals. Cases gradually declined thereafter. Altogether, some
1,512 clinically confirmed cases occurred in the Guangdong outbreak, with health
care workers in urban hospitals accounting for up to 27 percent of cases (WHO,
2003c; Chinese Center for Disease Control and Prevention, 2003). This pattern—
occurrence in urban areas, with most cases concentrated in hospitals, and ampli-
fication during care—was repeated as the disease began to spread outside
Guangdong Province to other areas in China and then internationally.
The first recorded case of SARS outside China occurred on February 21,
2003, when a medical doctor who had treated patients in Guangzhou City and

was himself suffering from respiratory symptoms spent a single night in a hotel
in Hong Kong. Through presumed contact, the mechanism of which is not fully
understood, he transmitted SARS to at least 16 other guests and visitors, all
linked to the same hotel floor. They carried the virus with them as they entered
local hospitals or traveled on to Singapore, Toronto, and Viet Nam. An interna-
tional outbreak that eventually spread to 30 countries had thus been seeded.
Figure 5-5 maps the distribution of 8422 cases and 916 deaths that had occurred
by August 7, 2003.
Detection and Response

On March 15, 2003, when the second alert was made, the cause of SARS had
not yet been identified. Cases were concentrated in hospital workers and did not
respond to medicines known to be effective against a number of different lung
infections. Many patients were rapidly progressing to severe pneumonia. The
situation was alarming: no patients, including young and previously healthy health
workers, had recovered. Many of the patients were in a critical condition, several
required mechanical ventilatory support, and two had died. The spread to major
cities around the world meant that any city with an international airport was at
potential risk of imported cases. From the outset, WHO’s objective was clear: to
halt further international spread and interrupt human-to-human transmission
through a global containment effort, and by so doing to minimize opportunities
for the disease to establish endemicity (see Box 5-2).
The global response to SARS was in reality the roll out of a way of detecting
and responding to outbreaks that had been developed over the preceding seven
years by WHO and its partners, partly as a result of major weaknesses that came
to light during the 1995 Ebola outbreak in the Democratic Republic of the Congo
and during previous outbreaks of plague in India and cholera in Latin America.
The SARS response depended on collaboration of the world’s top public health
and laboratory experts, and took advantage of up-to-date communication tech-
nologies, including the Internet and video and telephone conferencing.
Two principal partners of the WHO Global Outbreak Alert and Response
Network (GOARN), an electronically interconnected network of experts and in-
stitutes formally set up in early 2000, contributed to the detection of the SARS
outbreak. One was the Canadian Global Public Health Intelligence Network
(GPHIN), a worldwide web-crawling computer application, used by WHO since
1997, that systematically searches for keywords in seven different languages to
identify reports of what could be disease outbreaks. Throughout the outbreak,
GPHIN provided the raw intelligence that helped WHO maintain up-to-date and
high-quality information on indications that the disease might be spreading to
new areas. The second partner was the WHO Influenza Laboratory Network of
110 laboratories in 84 countries that constantly keeps the world in general and

238
FIGURE 5-5 Probable cases of SARS worldwide, August 7, 2003.

BOX 5-2
The Response to SARS in the Western Pacific Region
More than 95 percent of SARS cases occurred in the Western Pa-
cific Region. As an immediate response, a SARS outbreak response and
preparedness team—including international experts—was established in
the Regional Office. The main objectives were to:
• contain and control the outbreaks,

• support the health care infrastructure in affected countries,
• provide guidance and assistance to enable vulnerable countries to
prepare for the possible arrival of the virus, and
• provide the most up-to-date information to health officials and re-
spond to public concerns.
Teams of epidemiologists and infection control experts were imme-
diately sent to China, including Hong Kong Special Administrative Re-
gion, as well as to the Philippines, Singapore and Viet Nam and across
the southern Pacific, training health care workers in infection control pro-
cedures and preparing them for the possible arrival of the disease. Prac-
tical infection control and preparedness guidelines and training tools were
developed, and the first version of preparedness guidelines was issued
at the beginning of April. Logistic support and supplies (personal protec-
tive equipment, including masks, collection materials for blood and respi-
ratory samples, and internationally approved containers for shipment of
samples) were sent to both affected and unaffected countries, supported
by a US$ 3 million grant from the Government of Japan.
Countries were classified according to three levels of risk and three
levels of capability to respond to SARS cases, in order for WHO to priori-
tize its support to countries. WHO worked closely with countries to ensure
that enhanced surveillance was put in place to enable early detection of
cases and contact tracing. Guidelines were drawn up on enhanced sur-
veillance, hospital and community infection control, international travel,
laboratory procedures and public awareness. To improve public aware-
ness, close contact was established with national media focal points, and
the web site of the Western Pacific Regional Office was regularly updated.
A regional laboratory network was established to ensure that neces-
sary testing for SARS could be done for countries with limited laboratory
capacities. National and regional reference laboratories were identified
and shipping of specimens was arranged between the laboratories.
WHO’s efforts were paralleled by the contribution of Member States.
Viet Nam was the first to interrupt local transmission of the virus. Other
countries introduced a wide range of measures, including isolation, home
quarantine and comprehensive contact tracing. The willingness of gov-
ernments in the Western Pacific Region to put public health consider-
ations ahead of economic concerns about the impact of SARS was cru-
cial to the success of the collaborative effort.

vaccine manufacturers in particular informed of which strains of influenza are

circulating, so that an effective influenza vaccine can be produced each year.
On February 10, 2003, GPHIN and other partners of GOARN identified re-
ports of an outbreak associated with health worker mortality and the closing of
hospitals in Guangdong. One day later the Chinese government officially reported
to WHO an outbreak of respiratory illness, beginning in mid-November, involv-
ing 300 cases and five deaths in Guangdong Province. Just over a week later, on
19 February, an outbreak of avian influenza was reported to the WHO Influenza
Laboratory Network by the collaborating laboratory in Hong Kong. This out-
break first came to light when a 33-year-old man died of an unknown cause after
returning from a family trip to Fujian Province, China. His 8-year-old daughter
had died of a similar disease while in Fujian Province and his 9-year-old son was
hospitalized in Hong Kong with the same symptoms. It was from this son that
avian influenza virus was isolated and reported to the Influenza Laboratory Net-
work. The same influenza virus had been identified in Hong Kong in 1997. Con-
trol efforts at that time required the slaughter and incineration of all chickens in
the many live markets there; human-to-human transmission was never established.
This heightened level of alert led to the identification of an early SARS case
in Viet Nam on February 28, 2003. At the same time as GOARN collected infor-
mation about this outbreak in real time, it sent an international team of partners to
work with the Viet Nam authorities to better understand the disease, and by March
12 GOARN had accumulated the initial information necessary to issue the first
global alert. It was through the continued instant sharing of information by gov-
ernments, public health experts, clinicians and laboratory scientists that evidence-
based decisions could progressively be made, culminating in the successful con-
tainment of SARS.
Under GOARN, a virtual collaborative network of 11 leading laboratories, linked
by a secure website and daily teleconferences, identified the SARS causative agent
and developed early diagnostic tests. The network, in turn, served as a model for
similar electronically linked groups of clinical and epidemiological experts who
pooled clinical knowledge and compiled the epidemiological data needed to chart the
outbreak’s evolution and assess the effectiveness of control interventions.
WHO issued daily updates about the outbreaks on its website to keep the
general public—especially travellers—informed and, as far as possible, to counter
rumours with reliable information. Equally important, the website was used to
issue a range of evidence-based technical and practical guidelines for control as
knowledge and information about the disease progressed and became available
through the virtual groups of experts.
As more and more evidence accumulated through real time collaboration of
public health experts, a range of additional evidence-based control measures be-
came possible. It was soon evident, for example, that people with SARS continued
to travel internationally by air after March 15, and that some of them had infected
passengers sitting nearby. At the same time it was also apparent that contacts of

SARS patients likewise continued to travel, becoming ill once they arrived at their
destination. Recommendations were therefore made that countries with major out-
breaks should screen departing passengers to make sure that they did not have fever
and other signs of SARS, or known contact with SARS patients.
As the outbreak continued in Hong Kong, contact tracing there further dem-
onstrated that transmission of SARS was occurring outside the confined environ-
ment of the health care setting, and later suggested that it was also occurring
following exposure to some factor in the environment, thus creating further op-
portunities for exposure in the general population. Additional evidence-based
guidance was therefore made for sites where contact tracing could not link all
cases to a chain of transmission, on the understanding that if the disease were
spreading in the wider community it would greatly increase the risk to travellers
and the likelihood that cases would be exported to other countries. This guidance
was aimed at international travelers, and recommended that they postpone all but
essential travel to designated areas in order to minimize their risk of becoming
infected. Such guidance was also needed in view of the confusion created by
several different national recommendations, many of which were based on crite-
ria other than epidemiological data.
Authorities in areas where outbreaks were occurring responded to SARS with
mass public education campaigns and encouraged populations to conduct daily
fever checks. Hotlines and websites answered questions. Screening measures were
set up at international airports and border crossings, and procedures of infection
control were reinforced in hospitals. Singapore drew on its military forces to
conduct contact tracing, while Hong Kong adapted a tracing system that had been
developed for use in criminal investigations and electronically mapped the loca-
tion of all residences of cases. Chinese authorities opened hundreds of fever clin-
ics throughout the country where suspected SARS cases were triaged. Heads of
state and ministers of health of of countries of the Association of Southeast Asian
Nations (ASEAN) and the Asia–Pacific Economic Cooperation (APEC) met and
resolved to establish closer collaborative mechanisms for disease surveillance
and response. Health staff everywhere worked with dedication, and many, in-
cluding WHO staff member Dr. Carlo Urbani, lost their lives.
On July 5, 2003, WHO announced that Taiwan, China, where the last known
probable case of SARS had been isolated 20 days earlier, had broken the chains
of human-to-human transmission. A recurrence of SARS cannot, however, be
ruled out. Further research on many unresolved questions is needed. In the mean-
time, systems are now in place to detect a re-emergence should it occur (WHO,
2003d).
The Impact of SARS

The economic impact of the SARS outbreak has been considerable and illus-
trates the importance that a severe new disease can assume in a closely interde-

pendent and highly mobile world. Apart from the direct costs of intensive medi-
cal care and control interventions, SARS caused widespread social disruption and
economic losses. Schools, hospitals, and some borders were closed and thou-
sands of people were placed in quarantine. International travel to affected areas
fell sharply by 50 to 70 percent. Hotel occupancy dropped by more than 60 per-
cent. Businesses, particularly in tourism-related areas, failed, while some large
production facilities were forced to suspend operations when cases appeared
among workers.
A second impact is more positive: SARS stimulated an emergency re-
sponse—and a level of media attention—on a scale that has very likely changed
public and political perceptions of the risks associated with emerging and epi-
demic-prone diseases. It also raised the profile of public health to new heights by
demonstrating the severity of adverse effects that a health problem can also have
on economies and social stability. The resulting high level of political commit-
ment was decisive in the containment of SARS and has much to say about the
ability of nations to achieve public health results even when drugs and vaccines
are not available to cure or prevent the infection.
Lessons Learnt
Although much about SARS—including its potential to reoccur—remains to be
learnt through systematic analysis of existing data, and focused research activities in
China, several important lessons are already apparent. WHO is applying these lessons
across the entire Organization as it responds to the HIV/AIDS emergency.
The first and most compelling lesson concerns the need to report, promptly
and openly, cases of any disease with the potential for international spread. At-
tempts to conceal cases of an infectious disease, for fear of social and economic
consequences, must be recognized as a short-term stop-gap measure that carries a
very high price: the potential for high levels of human suffering and death, loss of
credibility in the eyes of the international community, escalating negative domes-
tic economic impact, damage to the health and economies of neighboring coun-
tries, and a very real risk that outbreaks within the country’s own territory will
spiral out of control. Following the adoption during the World Health Assembly
in May 2003 of a resolution on the International Health Regulations, WHO has
been confirmed in its responsibility to take on a strong coordinating role in lead-
ing the fight against any infectious disease that threatens international public
health (WHO, 2003e). In a second resolution specific to SARS, all countries are
urged to report cases promptly and transparently, and to provide information re-
quested by WHO that could help prevent international spread. It was explicitly
acknowledged that across-the-board strengthening of systems for outbreak alert
and response was the only rational way to defend public health security against
not only SARS but also against all future infectious disease threats, including
those that might be deliberately caused (WHO, 2003f).

The second lesson is closely related: timely global alerts, especially when
widely supported by a responsible press and amplified by electronic communica-
tions, worked well to raise awareness and vigilance to levels that can prevent
imported cases of an emerging and transmissible infection from causing signifi-
cant outbreaks. The global alerts issued by WHO on March 12 and 15 provide a
clear line of demarcation between areas with severe SARS outbreaks and those
with none or only a few secondary cases. Following the SARS alerts, all areas
experiencing imported cases, with the exception of Taiwan, China, either pre-
vented any further transmission or kept the number of locally transmitted cases
very low. Figure 5-6 shows the weekly onset of 5,910 cases. A climate of in-
creased awareness also helps to explain the speed with which developing coun-
tries readied their health services with preparedness plans and launched SARS
campaigns, often with WHO support, to guard against imported cases.
The third lesson is that travel recommendations, including screening mea-
sures at airports, appear to be effective in helping to contain the international
spread of an emerging infection. Initial analysis of data on in-flight transmission
of SARS has implicated four flights in the exposure of 27 probable cases, of
which 22 occurred on a single flight from Hong Kong to Beijing, China, on March
15. Some of these cases may also have been exposed elsewhere because of being
in the same tour group. Following the recommendation of airport screening mea-
sures on March 27, no cases associated with in-flight exposure were reported; and
initial information reveals that two probable SARS cases were identified by air-
port screening procedures in Hong Kong and immediately hospitalized. Travel
recommendations based on the epidemiological evidence also gave areas where
outbreaks were occurring a benchmark for quickly containing SARS, and then
regaining world confidence that the area was safe from the risk of SARS trans-
mission. In fact, passenger movement figures provided by Hong Kong Interna-
tional Airport show a rapid rebound from the lowest number of passengers, 14,670
(recorded just before May 23 when the travel recommendations were removed) to
54,195 on July 12, a little over a month later.
The fourth lesson concerns international collaboration: the world’s scien-
tists, clinicians and public health experts are willing to set aside academic compe-
tition and work together for the public health good when the situation so requires.
International collaboration greatly advanced understanding of the science of
SARS. One month after the laboratory network was established, participating
scientists collectively announced conclusive identification of the SARS virus;
complete sequencing of its RNA followed shortly afterwards. The network of
clinical experts provided a platform for comparison of patient management strat-
egies to indicate to the world which treatments and strategies were effective. In
addition, the epidemiology network confirmed the modes of transmission of
SARS and began the long-term collaboration needed to understand clearly the
clinical spectrum of disease, including its case fatality ratio, while also providing
the information needed to regularly reassess and adjust the case definition.

244
FIGURE 5-6 Probable cases of SARS worldwide, November 1, 2002, to July 11, 2003.

Lesson five is that weaknesses in health systems can permit emerging infections
to amplify and spread, and can compromise patient care. The strengthening of health
systems thus deserves high priority. The people at greatest risk for SARS were health
workers who either became infected by close face-to-face contact with patients or by
procedures that brought them into contact with respiratory secretions. Women pre-
dominate among the lower ranks of health personnel in many countries; available
data reveal that infected health care workers were 2.7 times more likely to be women
than men, while infection was roughly equal between the sexes in the general popula-
tion. The surge of SARS patients placed an enormous burden on health services,
requiring facilities for isolation, long periods of intensive and expensive care, and the
use of demanding and socially disruptive measures such as mass screening, contact
tracing, active surveillance of contacts and—at some outbreak sites—enforced quar-
antine. Even in areas with highly developed social services, the burden of coping with
SARS, including the large number of hospitals with patients and the high number of
health workers who became infected, often required closing some hospitals and sec-
tions of others. As a result of SARS outbreaks, many long-standing and seemingly
intractable problems that have traditionally weakened health systems are being cor-
rected in fundamental and often permanent ways. New surveillance and reporting
systems, methods of data management, mechanisms for collaborative research, hos-
pital policies, procedures for infection control, and channels for informing and edu-
cating the public are part of the initial positive legacy of SARS that will shape the
capacity to respond to future outbreaks of new or re-emerging infections.
Lesson six is that in the absence of a curative drug and a preventive vaccine,
existing interventions, tailored to the epidemiological data and supported by po-
litical commitment and public concern, can be effectively used to contain an out-
break. The virtual laboratory, and clinical and epidemiological collaborating net-
works regularly provided information that was used by WHO and its partners to
update guidance for containment. Initial guidance was provided for containing
outbreaks nationally—as additional evidence was obtained, guidance to limit in-
ternational spread was also provided. Areas where outbreaks were occurring, and
countries which considered themselves at risk of imported cases from these areas,
adapted WHO guidance for their use. Some countries introduced active surveil-
lance of suspected contacts using surveillance cameras or military personnel. Oth-
ers relied on self-surveillance by contacts who voluntarily isolated themselves in
their homes and regularly checked for fever. Measures introduced at airports
ranged from passive screening of passengers, involving optional completion of
questionnaires, to the use of interviews conducted by health workers and sophis-
ticated infrared equipment to screen all passengers for fever and indications of
possible exposure. In addition to maximizing the impact of surveillance and
screening, these measures were also considered by governments to be reassuring
for national citizens as well as international travelers.
The seventh lesson highlights one of the major difficulties faced during the con-
tainment activities for SARS: risk communication about new and emerging infec-

tious diseases is a great challenge. Work along these lines is currently under way in
conjunction with the risk that a biological agent might be used in an act of terrorism.
SARS will not be the last new disease to take advantage of modern global
conditions. In the last two decades of the 20th century, new diseases emerged at
the rate of one per year, and this trend is certain to continue (Woolhouse and Dye,
2001). Not all of these emerging infections will transmit easily from person to
person as does SARS. Some will emerge, cause illness in humans and then disap-
pear, perhaps to recur at some time in the future. Others will emerge, cause hu-
man illness and transmit for a few generations, become attenuated, and likewise
disappear. And still others will emerge, become endemic, and remain important
parts of our human infectious disease ecology.
The rapid containment of SARS is a success in public health, but also a warning.
It is proof of the power of international collaboration supported at the highest political
level. It is also proof of the effectiveness of GOARN in detecting and responding to
emerging infections of international public health importance. At the same time, con-
tainment of SARS was aided by good fortune. The most severely affected areas in the
SARS outbreak had well-developed health care systems. Had SARS established a
foothold in countries where health systems are less well developed cases might still
be occurring, with global containment much more difficult, if not impossible.
Although control measures were effective, they were extremely disruptive and
consumed enormous resources resources that might not have been sustainable over
time. If SARS reoccurs during an influenza season, health systems worldwide will
be put under extreme pressure as they seek to isolate all those who fit the clinical
case definition until diagnosis can be ascertained. Continued vigilance is vital.
SARS: DOWN BUT STILL A THREAT

Karen J. Monaghan
National Intelligence Council10
Reprinted with permission from National Intelligence Council, 2003.
Copyright 2003 National Intelligence Council.
Scope Note
This Intelligence Community Assessment (ICA) was requested by Secretary
of Health and Human Services Tommy Thompson and Ambassador Jack Chow,
Deputy Assistant Secretary of State for International Health Affairs. It highlights
the evolution of severe acute respiratory syndrome (SARS) and the potential im-
10Prepared under the auspices of Karen Monaghan, Acting National Intelligence Officer for Eco-
nomics and Global Issues. Additional copies of this assessment can be downloaded from the NIC
public website at www.odci.gov/nic or obtained from Karen Monaghan, Acting National Intelligence
Officer for Economics and Global Issues, at (703) 482-4128.

plications of the disease for the United States under several scenarios; this paper
does not attempt to provide a scientific assessment of the epidemiology of SARS.
Even though SARS has infected and killed far fewer people than other common
infectious diseases such as influenza, malaria, tuberculosis, and HIV/AIDS, it has
had a disproportionately large economic and political impact because it spread in
areas with broad international commercial links and received intense media atten-
tion as a mysterious new illness that seemed able to go anywhere and hit anyone.
As the first infectious disease to emerge as a new cause of human illness in
the 21st century, SARS underscores the growing importance of health issues in a
globalized world. The December 1999 unclassified National Intelligence Esti-
mate, The Global Infectious Disease Threat and Its Implications for the United
States, warned that new and reemerging diseases would pose increasing chal-
lenges to the United States and the rest of the world. The 1999 estimate high-
lighted several key health trends that track with the emergence of SARS:
• The forces of globalization, which are speeding the spread of infectious diseases
and amplifying the impact, also are giving us better tools to protect human health.
• Major infectious disease threats to the United States and the world, like
HIV/AIDS, will continue to emerge, challenging our ability to diagnose, treat,
and control them.
• Infectious diseases will loom larger in global interstate relations as related
embargoes and boycotts to prevent their spread create trade frictions and contro-
versy over culpability.
In addition to coordinating the draft within the intelligence community, the Na-
tional Intelligence Council asked several health experts to review the paper as part of
its effort to capitalize on expertise inside and outside the government. The experts
included Dr. Anthony Fauci, director of the National Institute of Allergy and Infec-
tious Diseases at the National Institutes of Health; Dr. Steve Ostroff, deputy director,
National Center for Infectious Diseases, Centers for Disease Control and Prevention
(CDC); and Dr. Joshua Lederberg, professor emeritus at Rockefeller University and
Nobel laureate. The NIC also shared the draft with counterparts in Canada at the
Privy Council Office, Intelligence Assessment Secretariat.
DISCUSSION
The Global Health Challenge

The emergence of SARS illustrates the challenge of battling infectious dis-
eases in an increasingly globalized world. SARS is the latest of more than 35 new
or reemerged infectious diseases over the last 30 years. Infectious diseases have
long raged through human communities, but forces of globalization—including
rapid growth in international trade and travel and increasing urbanization—have

amplified their spread and impact. These same forces of globalization, however,
also have led to significant advances in communication, travel, and technology,
which have aided in the fight against infectious diseases.
• On balance, infectious disease pathogens have the upper hand because

they constantly evolve new mechanisms that can exploit weak links in human
defenses.
• SARS has subsided for now, but many health experts warn that it is likely
to come back when cooler weather returns to temperate areas, bringing a resur-
gence of respiratory infections.
Downsides of Globalization
Population growth and development are bringing more people into contact
with non-domesticated animals, introducing new diseases more frequently into
the human population. The transmission of pathogens from animals to humans
is a process called zoonosis. Some researchers believe that SARS may have
originated in China in animals such as wildcat species that were trapped and
sold as food in exotic markets. In mid-August 2003, China lifted the ban on the
sale and consumption of exotic animals imposed during the SARS epidemic.
• HIV/AIDS, monkeypox, and hantavirus are other infectious diseases be-

lieved to have originated in animals.
Modern travel and labor migration patterns played a key role in spreading
SARS after it emerged in November 2002 in Guangdong Province, China (see
Figure 5-7). From Guangdong, the disease made its way to Hong Kong and then
to Vietnam, Singapore, and Taiwan as well as Europe and North America.
• Within China, as many as 180 million people are considered migrant la-
bor, moving between rural areas, cities, and manufacturing centers in search of
employment.
• Asia has become a major hub for business and tourist travel, putting mil-
lions of passengers within 24 hours of almost every major city in the world,
providing little time to identify and isolate people infected with diseases that may
take several days to show symptoms.
• More people also are migrating overseas to find jobs, and travel by work-
ers and their families can spread diseases. For example, a Filipino nurse working
in Toronto contracted SARS and transmitted it to family members on a visit to the
Philippines.
In addition to spreading the disease geographically, global links also have
amplified the economic and political impact of the disease. Even though SARS
has killed far fewer people up to now—around 815—than those who die each

FIGURE 5-7 Portrait of a superspreader: spread of SARS from the Metropole Hotel in
Hong Kong as of March 28, 2003.
year from more common maladies such as pneumonia, influenza, malaria, and
tuberculosis, as a new disease it was more disruptive and generated more atten-
tion (see Figure 5-8). The disease exhibited some characteristics of a potentially
explosive epidemic in the early stages, and SARS hit countries that have exten-
sive commercial links with other parts of the world, generating widespread eco-
nomic disruptions and media attention.
• The outbreak of SARS in Asia and Canada disrupted a wide-ranging glo-

bal network of businesses increasingly dependent on international trade and travel.
Airlines were the highest profile economic victims, but service industries like
tourism and supply chains in industries as diverse as seafood and microchips also
were affected.
• Intense media attention and uncertainty about the disease fueled wide-
spread fear, even in some areas without any cases, exacerbating economic
disruptions.

FIGURE 5-8 Comparative worldwide mortality of infectious diseases.a

aWHO estimates of worldwide deaths in 2001 from major infectious diseases. SARS deaths
occurred from November 2002 to July 2003.
• The suspicion of Asians as carriers of the disease reduced patronage of

Asian businesses and communities in the United States and sparked travel bans
against Asian tourist groups and conference participants worldwide.
Benefits of Globalization
Intense international media coverage facilitated by global communication
networks increased pressure on governments to respond effectively to SARS and

prompted many citizens and healthcare workers to be vigilant in taking precau-

tions, monitoring symptoms, and seeking early treatment.
• China initially tried to cover up SARS as it did with other diseases in the
past, but international media scrutiny and leaks to the press led Beijing to pub-
licly acknowledge and respond to the disease.
• The public has been able to track the evolution of the disease more closely
with everything from text messaging on cell phones to publicly and privately run
websites; Singaporeans could even watch a special public service television chan-
nel devoted to SARS.
Modern communications and medical technologies provided key tools to

combat SARS.
• Health workers utilized the World Health Organization’s (WHO) global

network of research facilities to share data and speed the identification of the
virus causing SARS.
• International medical journals took the rare step of promptly publishing
research on SARS on the Internet prior to hard copy publication.
• Thermal imaging equipment was acquired in numerous countries in an
effort to screen large numbers of people for high fevers. Hong Kong employed
software to track the spread of the disease in urban areas, and some countries
employed cameras and electronic bracelets to help security officials enforce home
quarantines.
Economic and Political Fallout of SARS

Government and private sector economists have had difficulty calculating
the costs of the SARS epidemic. Early on, forecasters estimated that the macro-
economic impact would be negligible but hastily cut growth estimates for several
economies, including China, as the disease spread, cases mounted, and the situa-
tion appeared to be out of control (see Table 5-3). Service industries, particularly
airlines and tourism, were affected immediately. SARS began to threaten the re-
tail and manufacturing sectors, particularly in China, when business trips and
trade fairs were canceled, new orders were placed on hold, and investors delayed
new expansion and constructions plans.
• In late April, the World Bank cut its growth forecast for East Asia to 5.0
percent—from 5.8 percent in 2002—due in part to SARS.
• In early May, the Asian Development Bank warned that East Asia could
lose $US 28 billion in income and output if the disease continued until September.
• Several investment banks shaved up to one percentage point off China’s
growth forecasts and cautioned that a more serious slowdown could occur if
SARS were not brought under control by July.

TABLE 5-3 Economic Impact of SARS
252
Gross Employment Sectoral Impact Stimulus Pack- Cumulative

Domestic ages SARS cases
Economy Product (deaths)*
Early predictions Major impact on Retail sales and No comprehen
China of severe impact jobless rate, es- restaurant sector sive package,
revised, fore- pecially among stall, particularly but some ad hoc
casts suggest migrant in urban areas. measures for 5,327(348)
strong growth of workforce; un- Export and service sector,

7 to 8 percent for employment manufacturing including tempo
2003. nearly doubles to have proven rary tax cuts.
over 8 million. more resilient.
Hong Kong Official growth Unemployment Tourism and A US $1.8 billion
estimate cut to hits record high retail sector rav- relief package,
1.5 percent from 8.3 percent over aged, but few including rent 1755 (298)
March-to-May period, could signs SARS has reductions and
earlier forecasts swell to 10 per- hurt trade. Air tax rebates,
of 3 percent. cent by year end. traffic fell 80 especially for
percent in May. hardest hit
businesses.
Taiwan Official growth Minimal impact Tourism and Emergency re-
estimate cut to as employers cut retail sectors lief and economic
2.7 percent from pay and grant hardest hit. stimulus packages 671 (84)
earlier forecasts unpaid leave but worth $3.7 billion,
of 3.7 percent. miss target of and a 3-year

reducing unem- $8.6 billion

ployment to 4.5 public works
percent in 2003. program.
Singapore Private sector Unemployment Hospitality and $US 130 million
growth forecasts expected to rise travel industries relief package
cut to I percent to record high most affected; targeted at
from earlier es- 5.5 percent; also hit retail SARS-affected 206 (32)
timates of more wage freezes and stores and res- sectors.
than 2 percent. cuts imple- taurants.
mented.
Thailand Private sector First quarter Tourist arrivals None
forecasts put employment were down 10 implemented.
growth as low as data show no percent in the

4.2 percent, impact. first 5 months 9(2)
down one per- this year; exports
centage point also suffered.
from 2002.
Growth expected Unemployment Lost tourism and In July, the Bank
Canada to slow to 2.2 increased in May airport revenues of Canada cut
percent, down to 7.8 percent; amounted to interest rate one- 250 (38)
one percentage thousands of $950 million, quarter to 3 percent.
point from ear- jobs lost in the $570 million in
lier forecasts due hospitality sector Toronto alone.
to SARS, mad- nationwide.
cow, other
problems.
*Information from VMO as of July 8, 2003.
NOTE: The chart below reflects estimates for 2003 based on second quarter data, but the delayed impact and potential for recurrence in the fall suggest that it may
be premature to measure the full impact on growth.

253
• North Korea imposed tight border restrictions and quarantines, slowing

trade flows and temporarily closing a lucrative new tourist resort.
Recent data suggest that growth in most countries plummeted in April and
May but started to recover as the disease was brought under control, reports of
new cases dwindled, and the WHO removed countries from its travel advisory
list. Most notably, no major disruptions in trade and investment flows occurred.
Moreover, most factories in China, including those in Guangdong where the dis-
ease originated, continued to operate even during the height of the epidemic. In
some countries, monetary and fiscal stimulus packages also helped to cushion the
blow.
Certain locales, notably Hong Kong, Beijing, and Toronto, were hurt more
than others. Moreover, additional indirect costs—the so-called SARS tax—prob-
ably will be incurred by businesses consumers, governments, and nongovern-
ment agencies.
• Collectively, the ASEAN countries—Brunei, Cambodia, Indonesia, Laos,

Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Vietnam—are es-
timated to have lost $US 25 billion to $US 30 billion, mostly in the tourism,
service, aviation, and restaurant sectors.
• Although China is forecast to achieve growth of 7 to 8 percent this year,
the economies of China and Hong Kong will take longer to recover because the
tourism, transport, communication, food, and entertainment industries suffered
substantial losses.
• Most analysts forecast that SARS would shave a minimal amount off
Canada’s 2003 growth but cut 1 percent off Toronto’s $200 billion economy.
SARS dealt a body blow to the travel and tourism industries, already facing a
slowdown from post-9/11 terrorism concerns. They will be slow to recover. Busi-
ness travel has resumed more rapidly as firms catch up on a backlog of deals, but
tourist travel is far below last year’s levels. Hotels in Asia are cutting room rates
in a bid to attract customers.
An industry trade group estimates the tourist sector in China, Hong Kong,
Singapore, and Vietnam will lose up to $US 10 billion and 3 million jobs this year
because of SARS.
Airlines have restored most canceled flights, but carriers will have difficulty
recouping lost revenues, and some may be forced into bankruptcy. The airline
industry’s slow recovery will be a further drag on the aviation industry. Asian
airlines were to account for one-quarter of Airbus deliveries and 30 percent of
Boeing’s deliveries in 2003. Several Asia-Pacific carriers asked Airbus and
Boeing to postpone deliveries of new aircraft. Both manufacturers have been
counting on robust growth in the Asian travel market to boost revenues.
Anecdotal evidence suggests that some export-oriented industries, particu-

larly clothing manufacturers, temporarily shifted some orders to Bangladesh,

Turkey, India, and Pakistan. Foreign electronics manufacturers, including a large
Japanese electronics firm, shifted some production to plants in Philippines and
Malaysia with highly specialized sectors and relatively low costs. There is no
evidence to suggest that foreign manufacturers pulled out investments or perma-
nently shifted production outside China or East Asian production plants. Some
multinationals probably have begun to rethink the costs and benefits of concen-
trating investment in one country or region, however.
• Over the last decade, China has attracted massive amounts of foreign di-
rect investment (FDI)—$53 billion in 2002—thanks to its reputation as a low-
cost and relatively low-risk manufacturing locale with a rapidly growing domes-
tic market.
SARS has had minimal impact on global semiconductor production, even

though nearly 80 percent of production in this $US 8 billion industry is located in
Asia, largely in Taiwan and China.
None of the semiconductor operations was forced to curtail production, al-
though SARS disrupted some visits by foreign equipment suppliers and prompted
the temporary closing of some Hong Kong sales and marketing offices.
Political Impact
SARS seriously tested the leadership skills of politicians and civil servants in
every country affected. The public was quick to criticize leaders in China, Canada,
Hong Kong, and Taiwan for failing to grasp the seriousness of the situation, to act
quickly to contain the spread, and to accept responsibility for missteps. In some
countries, public confidence in the ability of government leaders and state institu-
tions to protect them may be permanently damaged.
• In China, SARS intensified behind-the-scenes jockeying between Presi-

dent Hu Jintao and his predecessor, Jiang Zemin, who initially downplayed the
disease. Hu publicly acknowledged the threat of SARS, allowed greater media
coverage of the crisis, and sacked one of Jiang’s loyalists as Minister of Health.
• In Canada the Prime Minister, Premier of Ontario, and Mayor of Toronto
drew fire from media and opposition party critics accusing them of failing to
respond effectively and address public fears.
In contrast, the WHO and CDC lauded the Vietnamese government’s swift
action and willingness to accept outside assistance, noting these factors were key
to its success in containing the spread of SARS. In Singapore, the public ex-
pressed confidence and support for the government’s rigorous efforts to identify

and isolate suspected SARS patients. An early April poll showed three out of four
Singaporeans were confident that the government could stop SARS.
Tracking the Downturn in SARS

Since WHO first issued a global alert about SARS in March 2003, almost
8,500 probable cases have been reported from 29 countries around the world,
with most cases (over 7,000) occurring in China. At one point in May, over 180
new infections were being reported daily, mostly in China.
The number of SARS cases peaked in May and steadily declined worldwide with
the WHO declaring on July 5 that all transmission chains of the disease had been
broken. The decline may reflect a seasonal retreat of the disease in warmer months,
which is common for respiratory illnesses in temperate climates. Nonetheless, the
downturn clearly illustrates that, even in a globalized world, the old-fashioned work
of identifying and isolating suspected cases, tracing and quarantining others who might
be exposed, and issuing travel advisories can control an emerging disease.
• Most countries hit by SARS had not used traditional public health tools
such as quarantine and isolation on such a large scale for decades, which slowed
the containment.
• Governments also had to mobilize enormous resources to implement
large-scale quarantine operations.
Surveillance
The first line of defense in arresting the spread of SARS has been the success
in identifying possible cases—despite the lack of a proven screening test and
symptoms common to many respiratory ailments. Taking people’s temperature
generally has been the simplest, most cost-effective means of initial screening for
possible SARS cases, followed by clinical examination for respiratory symptoms
in those with fevers.11
• Singapore issued over a million SARS toolkits with thermometers and

facemasks to every residence in the country. Residents were regularly stopped at
office buildings, schools, and other public places for temperature checks.
• China mobilized local party and government officials, including 85 mil-
lion family planning workers, to try to monitor citizens for symptoms. China also
mobilized its large militia to provide the rural public with instructions on SARS
prevention. The government distributed tens of thousands of thermometers to the
provinces.
11Anecdotal evidence suggests that some people with SARS may not have classic respiratory symp-
toms, which makes detection more difficult.

BOX 5-3
SARS Basics
Origins. The SARS epidemic spread rapidly because people had
little immunity to the newly emerged coronavirus that causes the dis-
ease. Close contact with sick individuals appears to be the primary
means of virus transmission, although research indicates that SARS
does not transmit as easily from person-to-person as more common dis-
eases like the cold or flu. The disease spread most rapidly among
healthcare workers and family members of infected individuals. Evidence
indicates that the virus also is spread through contact with inanimate
objects contaminated with virus-containing secretions. Recent detection
of a related coronavirus in wildcat species in China raises concerns that
SARS may continue to have an animal reservoir, which would compli-
cate control efforts.
Symptoms. SARS can progress rapidly from fever and cough to
serious pneumonia after an average four-to-six-day incubation period,
with up to 20 percent of patients needing mechanical ventilation to sur-
vive. In some patients, progression to pneumonia may be delayed. Death
may occur several weeks to months after initial symptoms.
Diagnosis. Accurate, rapid screening diagnostic tests for SARS are
being developed but are not yet licensed in the United States. During the
epidemic healthcare workers generally relied on clinical symptoms for
detection. WHO defines a suspected SARS case as someone with a
temperature over 38° Celsius, a cough or difficulty breathing, and one or
more of the following exposures: close contact with a person who is a
suspect or probable SARS case, or someone who has lived in or visited
a region with SARS transmissions. A “probable case” is a suspected
case with radiographic evidence of pneumonia or positive laboratory
tests that may take days to weeks to complete.
Treatment. No proven therapy is available for severe SARS pneu-
monia cases. Most clinicians employ respiratory support, antibiotics, fe-
ver reduction, and hydration. Some Chinese doctors have used steroids
and the antiviral drug ribavirin with varying degrees of success.
Fatalities. Although the overall lethality of SARS is higher than ini-
tially believed, most deaths continue to be among older patients and those
with underlying health problems, such as diabetes or hepatitis B. The WHO
reported in May 2003 that death rates vary substantially by age:
• Less than 1 percent in persons 24 years or younger.

• Up to 6 percent in persons 25 to 44 years old.
• Up to 15 percent in persons 44 to 64 years old.
• Greater than 55 percent in persons aged 65 or older.
Continued

BOX 5-3 Continued
Preliminary reports on nonfatal cases showed SARS patients required

longer hospital stays—an average of three weeks for those under 60 years
of age—than patients with other typical respiratory viruses, raising the
economic costs of the SARS outbreak. Moreover, preliminary evidence
suggests that some people who survive SARS could suffer long-term res-
piratory damage that increases health complications and costs.
• After WHO confirmed that SARS could be transmitted on airline flights,

including 22 infections traced to a single flight in March, airlines have become
more stringent at keeping people who might be infected off airplanes.
Even though checks of passengers at airports were relatively effective at

keeping infected people off airplanes, some lapses did occur.
• Japan installed infrared thermometers to monitor passengers at Tokyo’s

international airport after voluntary testing proved ineffective, but press reports
indicate that the machines cannot keep up with all travelers at peak times.
• An Asian man suspected of having SARS boarded a flight to the United
States in May because his flight left before lab results were received and he had
no other symptoms.
Quarantines and Isolation12

As SARS spread and political and economic stakes rose, countries took
tougher measures to contain it. Some countries resorted to strong steps, such as
closing schools despite the low number of cases among children, probably to
compensate for weaknesses in their health-care infrastructure. Open societies
seemed to have trouble enforcing quarantine orders.
• Some Chinese citizens fled cities and industrial hubs in response to early
government efforts to isolate suspected cases and quarantine their contacts. Sub-
sequently, Beijing forcibly locked both patients and healthcare workers in hospi-
tals during the peak of infections, and the government instituted fines for people
violating isolation orders and employed citizens to keep outsiders out of various
villages. Shanghai officials announced in late May they had quarantined nearly
29,000 people in the previous 2 months.
12Quarantine is the sequestering of those possibly exposed to an infection, while isolation is the
sequestering of those individuals with known or suspected infection.

BOX 5-4
The World Health Organization:
Playing Fairly Well with a Weak Hand
The World Health Organization (WHO) issued an international health
warning on SARS in March 2003 and travel advisories regarding particu-
lar regions hit by the disease. The WHO, in collaboration with the U.S.
Centers for Disease Control and Prevention (CDC) and other organiza-
tions, worked to identify the cause of the disease, assisted local investi-
gators, and provided guidance on control measures.
The SARS experience highlights the bureaucratic and technical limi-
tations WHO faces in trying to identify and control the international spread
of infectious diseases. Under existing international health regulations,
countries are only required to report to WHO outbreaks of yellow fever,
cholera, and plague. With these diseases, WHO, the United Nations, and
domestic officials have the authority to intervene and prevent the move-
ment of people and goods to avert cross-border transmission. With other
diseases, WHO plays an advisory role, including issuing travel advisories
and offering advice to member governments on screening procedures.
Unless a country invites in WHO investigators, WHO has a limited ability
to respond to outbreaks. Moreover, WHO has limited capability to investi-
gate suspicious outbreaks before a country officially reports them.
• The World Health Assembly, the body that oversees the WHO,
recommended expanding the list of reportable diseases by 2005 to in-
clude notification for public health emergencies of international concern.
• In 2000, WHO, with assistance from the Canadian Government,
set up the Global Outbreak Alert and Response Network to enhance
global surveillance, detection, and response to emerging infectious dis-
eases. It uses an electronic collection system to scan worldwide news
reports, websites, discussion groups, and other open source information
networks for rumors or reports of disease outbreaks. These notifications
trigger WHO staff to notify country representatives, who query national
authorities for more information about possible disease outbreaks, by-
passing official government notification channels.
• Despite these advances, the system may not have picked up early
clues to the SARS outbreak. The electronic monitoring system currently
only searches in English and French, although WHO plans to add search
capabilities in Arabic, Chinese, Russian, and Spanish. In addition, once
WHO receives notification, country cooperation is essential to validate
the outbreak, something Chinese officials avoided until late in the out-
break.

BOX 5-5
The World’s Quick Response to SARS
Several factors appeared to facilitate a faster international reaction
to SARS in comparison to other diseases in recent decades.
Fear and Uncertainty. The rapid geographic spread of the mysteri-
ous illness created a sense of urgency to respond to a disease that
seemed able to “go anywhere and hit anyone.”
Stronger Leadership. The World Health Organization took a more
public, activist stance in sounding the alarm and mobilizing the global
response.
Scientific Advances. New tools and techniques allowed research-
ers better and faster ways to study everything from patterns of lung dam-
age to the genetic sequence of the coronavirus.
Heightened Awareness of BW Threat. Concerns about the threat
posed by biological weapons enhanced the ability and speed of many
countries to identify new infectious diseases.
Concern About Missing “Another” AIDS. Some health officials
acknowledge they reacted more quickly to SARS partly due to fears that
the world’s slow response in the 1980s to the emergence of HIV/AIDS
allowed the disease to build up devastating momentum.
• Canada threatened those who violated quarantines with fines or court-ordered

isolation after some people defied voluntary measures, but news reports indicate that
some people violated quarantines when the SARS threat appeared to be fading.
• Singapore’s strict quarantines proved particularly effective in bringing
the disease under control.
Sometimes the most effective isolation and quarantine policies raised con-
cerns about political freedom and human rights. For example, India and Thailand
at one point isolated foreign visitors from countries that had SARS outbreaks,
even though they did not have symptoms or known exposures.
• North Korea, which has quarantined entire areas to deal with epidemics in
the past, imposed such tight restrictions for SARS that it constrained some inter-
national aid flows.
Political Leadership
A key variable in managing the SARS epidemic was the willingness of po-
litical leaders to raise public awareness of the disease, focus resources, and speed
the government response. As noted above, Vietnamese leaders promptly acknowl-

edged the SARS threat at an early stage in the outbreak and sought international
help. In contrast, China’s political leaders clearly exacerbated the situation by
initially suppressing news of the disease.
Reasons to Stay on Guard

Despite the downturn in cases, SARS has not been eradicated and remains a
significant potential threat. Senior WHO officials and many other noted medical
experts believe it highly likely that SARS will return. SARS, like other respira-
tory diseases such as influenza, may have subsided in the northern hemisphere as
summer temperatures rise, only to come back in the fall.
• Most infectious diseases follow a similar epidemiological curve, emerg-

ing, peaking, and declining over time to a steady state, but the number of infec-
tions, the lethality, and length of time can vary enormously.
• Even as WHO officials removed the last of its travel advisories for SARS
early this summer, officers repeatedly emphasized the risk that the disease would
be back.
• Some experts caution that SARS might even lay low for several years
before reappearing, as diseases such as Ebola and Marburg have done.
• The apparent reservoir of the coronavirus in animals, Beijing’s decision
to lift the ban on sales of exotic animals, and lack of a reliable diagnostic kit,
vaccine, or antiviral drug are factors that preclude eradication.
No Reliable Screening Tests

Diagnosis remains almost as much an art as a science as long as no proven
screening test has been developed. Diagnostic kits currently under development
can catch only about 70 percent of SARS cases, and their utility for widespread
deployment is not yet known. SARS is difficult to detect, particularly in the early
stages, even for countries with the most modern medical capabilities, raising the
risk that healthcare workers will miss mild cases. Moreover, there is little pros-
pect of a vaccine in the short-term.
Various countries have different definitions of suspected and probable cases
and have changed the definitions over time.
SARS Could Mutate

Natural mutations in the coronavirus which causes SARS could alter basic
characteristics of the disease, but whether a mutation would make SARS more or
less dangerous is impossible to predict. A significant increase in the transmissi-
bility or lethality of SARS obviously would pose greater health risks and raise
fears around the globe.

• Mutations could be particularly problematic if they alter the symptoms

associated with SARS, making it harder to identify suspected cases.
• Researchers are studying a group of Canadians who tested positive for the
SARS virus last spring but never got sick in order to see if they still might have
infected others.
• Mutations also would complicate the development of a treatment or vac-
cine, which already probably is several years away.
Difficult to Maintain Vigilance

The willingness of healthcare workers to serve in the face of significant in-
fection risks has been a key variable in the battle against SARS and other emerg-
ing diseases. Most healthcare workers in countries hit by SARS toiled long hours
under dangerous conditions. The rate of infection among hospital workers was
much higher than among the general public, underscoring the difficulty even pro-
fessionals had in maintaining stringent infection control procedures.
• At one point 20 percent of those infected in Hong Kong were nurses, and
over 300 healthcare workers were infected within a 17-day period in China dur-
ing April.
Some health workers refused to work in SARS wards. This problem is likely
to grow in both rich and poor countries if the disease resurges.
• In Taiwan, where over 90 percent of SARS infections occurred in hospi-
tals, over 160 health workers quit or refused to work on SARS wards. The gov-
ernment threatened to revoke their professional licenses.
• The Chinese government fired at least six doctors who refused to treat
SARS patients and barred them from practicing for life. China also tried to en-
courage healthcare workers by launching public relations campaigns hailing the
work of the Angels in White, and Beijing offered bonus pay and staffed SARS
hospitals with Army medical staff.
• Press reports in Canada indicate that some nurses refused to work in SARS
wards in Toronto despite a doubling of their wages and lobbied for an official
government inquiry on the handling of the epidemic.
Shortages in trained healthcare personnel were exacerbated when many
healthcare workers fell ill to SARS and were replaced by workers with less training.
• Taiwan appeared so eager to declare victory over SARS that it relaxed its
standards before the disease was brought under control. Press reports suggest that
some health-care workers were so fatigued from the crisis that they cut corners.
• Canadian officials acknowledge that the second outbreak in Toronto re-
sulted from hospitals relaxing infection control regimes too quickly.

SARS Scenarios
Faced with these uncertainties, we have constructed three scenarios to con-
sider potential trajectories for the disease and the implications for the United
States. We have not attempted to identify a most likely scenario because the fu-
ture course of SARS will depend on a host of complex variables, including the
scope of present infections, mutations in the virus, the vulnerability of host popu-
lations, how individuals and governments respond, and chance.
Scenario One: SARS Simmers

SARS could resurface this fall but be limited to random outbreaks in a few
countries. Rapid activation of local and international surveillance systems and
isolation procedures would be key to identifying suspect cases and containing the
spread. Initially, some cases might elude detection by hospital workers and air-
port personnel, who have relaxed screening procedures since the disease ebbed.
Smaller, poorly funded transit facilities would remain vulnerable because they
lacked trained staff and equipment to effectively monitor all passengers.
• In most affected countries, the small number of cases and transmission

would render SARS more of a public health nuisance than a crisis.
Some countries would be tempted to hide a resurgence. China’s experience

demonstrated that hiding an outbreak is increasingly difficult and costly in a glo-
balized world, but some governments still probably calculate that transparency
also has drawbacks. Indeed, the economic repercussions of WHO travel adviso-
ries for SARS probably reinforce the incentives countries have to hide or under-
report cases.
• The WHO had to lean on Beijing throughout the crisis to share data.
• Some countries over the past decade have not acknowledged HIV/AIDS
cases in the military for security reasons, suggesting they would withhold infor-
mation on other diseases that might affect readiness.
Even if new SARS outbreaks were sporadic and small-scale, economic, po-
litical, and psychological ripples would occur. China faces the biggest risks. Al-
though foreign investors are unlikely to withdraw substantial amounts of FDI,
firms with considerable exposure to China might redirect a percentage of new
investment to other locations to diversify their manufacturing operations. Com-
panies that already have temporarily shifted some production outside China prob-
ably would establish more permanent arrangements.

• Companies and governments outside China probably would attempt to

exploit these concerns by more aggressively trying to turn temporary production
into longer-term investments.
Multinationals also are likely to become more concerned about the “SARS
tax” on their businesses, including increased healthcare expenditures for expatri-
ate employees and expanded insurance to cover the risk to operations and person-
nel from infectious diseases. Some firms probably would calculate that the risks
of frequent business travel outweighed the costs and switch to teleconferencing,
telecommuting, and e-commerce.
• SARS has alerted companies to the potential operational disruptions

caused by a contagious disease, risks that are rarely priced into business costs or
considered in contingency planning.
• Whereas previous business continuity plans focused on data protection
and recovery, businesses probably will begin to consider plans that involve pro-
tection of human resources, backup teams, and alternate locations for operation.
Paradoxically, keeping SARS out of the United States might become more
difficult as fewer cases are seen, because health, transportation, and security work-
ers are more likely to drop their guard in monitoring for infected people if only a
few cases pop up now and then.
• The U.S. status as a major hub for international travel increases the statis-
tical risk that lapses in surveillance abroad could facilitate the spread of SARS to
American cities.
• It is difficult for many visitors to acquire visas for travel to the United
States; thus they probably would be inclined to withhold information that could
complicate their visit.
Scenario Two: SARS Spreads to Poor Countries, Regions

SARS could gain a foothold in one or more poor countries, potentially gener-
ating more infections and deaths than before but with relatively little international
economic impact. Few poor countries have had SARS appear on their doorstep
up to now because most have relatively few links to the affected regions, but the
longer the disease persists the more likely it is that SARS will spread more widely.
• Impoverished areas of Africa, Asia, and Latin America remain at poten-

tial risk for SARS because of weak healthcare systems and vulnerable popula-
tions. Even a small number of cases in large, underdeveloped cities such as Dhaka,
Kinshasa, or Lagos could generate a large number of victims in a short period.
• No evidence thus far suggests that people with malaria or HIV/AIDS are

more susceptible to becoming infected by SARS, but experience indicates that

diseases are more lethal among sick and malnourished populations. Sub-Saharan
Africa has the highest concentration of HIV-infected people in the world, and
those with full-blown AIDS have severely deficient immune response.
Most poor countries would have trouble organizing control measures against
SARS, especially if the disease gained momentum before it was identified by
healthcare workers. Most countries have inadequate hospital facilities to effec-
tively isolate large numbers of patients, and most hospitals even lack the resources
to provide food and care to patients.
• Voluntary home quarantine might not be viable in crowded urban slums,

where large families might share small dwellings and people might have to go out
each day for food or work.
• Identifying and tracking down people who might have been exposed prob-
ably would be substantially more difficult in countries with poor infrastructure
and underfunded local security services.
• Repressive countries, fearful that the disease could spark political up-
heaval, probably would quarantine entire towns or villages with military force or
incarcerate quarantine violators. Outside countries and international organizations
providing assistance are likely to split over how much to condemn or withhold
aid over apparent human rights violations.
The spread of SARS into various poor countries is likely to significantly

disrupt local economies while having relatively little impact on broader interna-
tional markets.
• The local impact could be worse than in places like Taiwan and Canada,
because people in poor countries are living closer to the margin and governments
have less resources for emergencies. In countries with a much smaller pool of
skilled workers, the loss of key personnel can have a relatively large effect on
society—as HIV/AIDS has illustrated in Africa.
• Even poor countries like Bangladesh have at least some global trade
and business links that could be disrupted if they were hit by SARS, but the
more isolated the country, the smaller the global economic impact probably
would be.
The spread of SARS to poor countries also would complicate international

efforts to control the disease.
• Diagnosing SARS is likely to be more difficult among populations with

many preexisting health problems.
• Even if SARS claimed hundreds of victims in poor countries, their gov-

ernments probably would not be inclined to devote substantial resources to the

fight when other diseases—such as malaria, tuberculosis, and HIV/AIDS—were
claiming many more lives.
The spread of SARS to countries with weak healthcare systems and vulner-
able populations also is likely to make the disease appear more transmissible and
lethal, heightening public fears in other parts of the world:
• Poor, isolated regions of Russia and China would have trouble containing
an outbreak, although their governments probably could mobilize more resources
to respond once infections began to climb.
• Even if SARS outbreaks were limited to poor countries, the persistence of
the disease probably would fuel some unease around the world about a broader
resurgence. The impact probably would marginally decrease demand for travel
and increase demand for medical products.
An outbreak of SARS in poor countries would pose particular challenges for

the United States and other governments and multilateral organizations providing
assistance. WHO and CDC probably would come under pressure to provide
money and technical assistance to compensate for weak healthcare systems. The
higher the number of infected people, the more the international community
would be called on to do something.
• Neighboring countries are likely to press for help with disease monitoring
to prevent SARS from spreading into their countries, especially if panic began
generating refugee flows.
• Repressive regimes like North Korea might accept material assistance but
block outside experts from visiting, even at the risk of putting more of their own
citizens at risk. North Korea in previous years has been accused of diverting NGO
assistance to the military and not allowing outsiders to monitor how it is used.
Scenario Three: SARS Resurges in Major Trade Centers

SARS could stage a comeback this fall in the main places it hit before—such
as China, Hong Kong, Taiwan, and Canada—or gain a foothold in other places
with extensive international travel and trade links like the United States, Japan,
Europe, India, or Brazil.
• An outbreak almost certainly would spark another wave of WHO health
warnings and travel advisories; Japan already has canceled an international con-
ference on HIV/AIDS planned for this winter due to fears it would coincide with
a resurgence of SARS.

Even if the number of infected persons were not greater in a second wave, an
outbreak of SARS in major trade centers again would be likely to have significant
economic and political implications. The resurgence of SARS in Asia probably
would cause less disruption as citizens, companies, and governments learn to live
with it, as they do with other diseases, unless the transmissibility or lethality rose
substantially. Nonetheless, a second wave of SARS in Asia probably would
prompt some multinationals to modestly reduce their exposure to the region if
they concluded that SARS posed a long-term health challenge.
• Given the size of the Asian market and low wage-rates, few companies
are likely to yank existing production out of China unless SARS debilitates or
kills large numbers of workers. Firms probably would divert some future invest-
ments to other regions to diversify their supply chains.
• Disruptions due to SARS are likely to persuade some companies to loosen
just-in-time production chains by creating some cushion in key inventories, in-
creasing costs but not productivity.
• Global trade and investment flows could seize up if quarantines shut down
factories and shipments.
A substantial decline in China’s manu-facturing sector would reverberate in

Southeast Asian economies that provide critical manufactured inputs, raw materi-
als, and energy and disrupts production chains throughout East Asia.
Bigger outbreaks in places such as Europe and the United States would affect
new sets of business and government players. The level of public fear almost
certainly would be higher in places that had not been affected by the first wave of
SARS, driving up social disruption and economic costs.
• The economic cost of SARS probably would skyrocket if fears grew about
the transmission of the disease in planes or on objects.
• Some buyers this spring demanded that Asian manufacturers irradiate their
export goods after research indicated that SARS could survive for several days on
inanimate objects.
Even the health systems of rich countries could be overwhelmed if the resur-
gence of SARS cases coincided with the annual influenza epidemic this winter.
As long as no quick and reliable test to diagnose SARS exists, people with fevers
and a cough could overwhelm hospitals and clinics as healthcare workers
struggled to distinguish patients with SARS and isolate them from others.
• A pneumonia-like illness erupted in western Canada in mid-August, raising
questions among health experts about whether a milder version of SARS had returned.
• Surges of people seeking medical care almost certainly would increase
the odds of healthcare workers missing some cases.

• Some SARS patients have not displayed classic respiratory symptoms,

suggesting some “silent” spreaders may not even know they have the disease, and
some travelers with mild symptoms might lie about contact with infected persons
to avoid quarantine.
Given the high economic and political stakes already seen in the SARS epi-
demic, some jurisdictions probably would try to fudge health data in an effort to
avoid official health warnings or get them lifted more quickly.
• Some governments might narrow the definition of “probable” SARS cases
to reduce crowding in hospitals, yet such moves could spark tensions with WHO
and other countries over the accuracy of data.
Building Better Defenses Against Disease

The emergence of SARS has sparked widespread calls for greater interna-
tional surveillance and cooperation against such diseases. SARS has demonstrated
to even skeptical government leaders that health matters in profound social, eco-
nomic, and political ways.
BOX 5-6
Influenza: Lurking Killer
Influenza is an ideal virus for worldwide spread (a pandemic) and
many epidemilogists argue that the world is “overdue” for a major influ-
enza pandemic. When a new type of flu virus emerges from a
reassortment of animal and human viruses to which humans have no
prior immunity, a pandemic may ensue. Scientists believe the past two
influenza pandemics originated in China where people live in close con-
tact with birds and swine, the major sources of animal flu viruses. Influ-
enza spreads even more quickly than SARS because flu can be trans-
mitted efficiently through the air. As a result, close contact is not required
for people to become infected, making it almost impossible to trace and
isolate ill people who are spreading the disease.
Three major flu epidemics stand out in modern U.S. history:
• 1918-19: “Spanish Flu” caused 20-50 million deaths worldwide,

including 500,000 in the United States.
• 1957-58: “Asian Flu” originated in China and spread globally, kill-
ing around 70,000 Americans.
• 1968-69: “Hong Kong Flu,” a global pandemic, began in Hong
Kong and ultimately claimed 34,000 U.S. lives.

• The experience with SARS probably will help countries prepare for future
disease outbreaks.
This intense focus on SARS has opened a window of opportunity to pursue

bilateral and international cooperation against infectious diseases. The United
States and WHO may be able to develop new institutional channels to foster long-
term cooperation on health issues.
• Momentum is likely to flag if SARS continues to subside and political

leaders lose interest.
• Budget constraints and turf battles almost certainly will retard progress
and agreements may fail to be implemented at the provincial, state and local
levels if added responsibilities are not accompanied by additional funding.
Areas of Need
Several countries already are seeking assistance from the WHO and the U.S.
CDC in an effort to strengthen their health systems. Some even are moving to
commit more resources.
• Both China and Taiwan have held technical discussions with US officials
exploring ways to improve their health system, and Beijing publicly has commit-
ted $1.3 billion in new funds.
Surveillance
Despite substantial progress in recent decades in building networks to moni-
tor disease, the surveillance systems in most countries remain weak. Many sur-
veillance systems have been built over the years to detect specific diseases, such
as polio and guinea worm. The WHO also has created a global network of over
100 centers in 83 countries to track influenza. The longer-term challenge is to
build networks throughout countries and regions and the means to issue warnings
to national and international authorities.
• Systems focusing on specific diseases generally have been more cost ef-
fective than trying to increase surveillance for all diseases, but either approach
leaves holes.
• International surveillance networks also must work out differences be-
tween countries over what health patterns are “normal” and which should set off
alarm bells. The death of working-age pneumonia patients in the United States
would be so unusual it would trigger closer examination, but this phenomenon
probably was not considered abnormal in China in the early stage of SARS.

BOX 5-7
Health Surveillance and Biological Weapons
The SARS outbreak illustrates the difficulty in distinguishing the
emergence of new infectious disease from the release of a BW agent.
Ongoing efforts to improve global health surveillance, however, probably
will aid international monitoring for detecting the possible release of bio-
logical warfare agents, especially traditional types. As baselines for natu-
ral diseases are established in the coming years, a deliberate release of
traditional BW agents could be more readily recognized. Unfortunately,
many developing countries probably will not acquire domestic detection
capabilities, such as tools to identify genetic sequences in disease or-
ganisms. Moreover, history suggests that some countries will not sup-
port internal disease surveillance efforts for political or economic rea-
sons, leaving significant gaps in a global surveillance system.
• Even if local health workers identify worrisome developments, many

medical facilities in developing countries lack communications equipment and
vehicles to alert national officials and transport samples or patients.
• Although rapid online journal publication aided in sharing information on
the new SARS virus, outbreak responders need to share data even earlier.
Epidemiological Expertise
Many countries lacked trained experts to map the trajectory of SARS. Such
expertise was critical to understanding the transmissibility, lethality, and scope of
the disease.
• Press reports indicate that Chinese officials have had trouble processing
and sharing research information within China and with outsiders, such as WHO.
Laboratory Facilities
Few countries have the sophisticated laboratories or trained personnel to do
the hard science of cracking mysterious new illnesses. As a result, regional or
mobile labs may be the most viable prospect for speeding up diagnoses and re-
search.
• WHO reports that staff in over 90 percent of developing country laborato-

ries are not familiar with quality assurance principles, and 60 percent of the lab
equipment is inoperable or outdated.

Equipment
The cost of basic diagnostic and protective equipment is relatively modest
yet still unaffordable for many countries. SARS highlighted a widespread short-
age of ventilators to support patients with pneumonia. The lack of adequate ster-
ilization equipment raises the risk of spreading disease when medical instruments
are reused.
• The highest priority for many countries is likely to be diagnostic tests to

determine which patients need to be isolated; the need for such tests would be all
the more pressing if research indicates SARS can be transmitted through the blood
supply.
BOX 5-8
SARS and HIV/AIDS
SARS has focused greater international attention on the importance
of health, but the new disease probably will not lead to a significant boost
in the fight against HIV/AIDS in the coming years. Indeed, many coun-
tries are likely to view spending on diseases like SARS and HIV/AIDS as
a zero-sum game in the short term.
• SARS is generating international interest in improving health sur-

veillance systems that could broaden screening for HIV/AIDS as well,
but the interests will not always coincide on allocating limited resources.
The small number of HIV/AIDS surveillance sites already in most coun-
tries is designed to gather health data on specific groups, such as young
women, drug users, or prostitutes, rather than samples of the population
at large.
• Some countries may be willing to devote more resources to im-
proving general health and fighting HIV/AIDS within their security ser-
vices. With HIV/AIDS prevalence rates running as high as 50 percent in
some African militaries, a growing number of governments are working
with the US on control programs. Political leaders may see it as critical
and cost effective to work with outsiders for better healthcare for soldiers
as well.
China’s new health minister has said she plans to focus on HIV/
AIDS now that SARS has subsided, according to press reports. Some
AIDS activists and NGOs within China also have expressed hope that
the government response to SARS will translate into more action on
HIV/AIDS.
A resurgence of SARS this winter could delay activity on AIDS, and
some AIDS activists in China fear the government might believe the strin-
gent controls used to fight SARS should be used against HIV/AIDS as well.

• Many countries need more ventilators to support patients with pneumo-

nia. In addition, negative pressure rooms to isolate infected patients are in shorter
supply; even many hospitals in affluent countries are not likely to have enough
rooms to handle a serious outbreak.
Developing Countermeasures
Progress in developing diagnostic tests, treatments, and vaccines would fun-
damentally improve prospects for combating SARS. This will take time, how-
ever, and first-generation products often are not completely effective without fur-
ther research and improvement.
• Tracking down infected and exposed persons on airline flights also could
be improved significantly if airlines retained electronic records of passenger lists.
Political Hurdles
Almost all countries will express support for improving international
healthcare capabilities, but negotiations are likely to be contentious, and many
players will see this as an opportunity to win concessions or score points with
Washington. Some areas of possible contention are:
• Money. Many developing countries will say they cannot improve their
surveillance systems and healthcare infrastructure without significant outside as-
sistance, in the form of training, equipment, or grants.
• “Rich” vs. “poor” Diseases. Some developing countries may argue that
they will work to improve surveillance for diseases like SARS if the United States
and the international community do more to help them fight diseases which claim
more lives in their countries, such as malaria and tuberculosis.
• Multilateral Channels. European countries are likely to use the focus on
health issues to renew pressure on the United States to work through multilateral
organizations such as the Global Fund for AIDS, Tuberculosis, and Malaria.
• Pharmaceutical Access. Any forum to discuss international health coop-
eration almost certainly will include some criticism of U.S. positions in the WTO
on pharmaceutical sales. Research to develop tests, treatments, and vaccines is
underway, but drug companies will have little incentive to bring such products to
market without public sector support if SARS appears to fade away.
• WHO Authority. Some countries probably will argue for strengthening the
authority of the WHO to sanction states that do not share health data or bar out-
side health experts from visiting. Other countries, such as China and Malaysia,
are likely to resist any moves they see as infringing on sovereignty. Taiwan al-
most certainly will continue trying to use health issues to win recognition from
WHO and other multilateral organizations.

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Appendix A
Learning from SARS:

Preparing for the Next Disease Outbreak
September 30-October 1, 2003

SMITHSONIAN S. DILLON RIPLEY CENTER
WASHINGTON, DC
AGENDA
TUESDAY, SEPTEMBER 30, 2003
8:30 Continental Breakfast

9:00 Welcome and Opening Remarks
Adel Mahmoud, M.D., Ph.D.
Chair, Forum on Emerging Infections
President, Merck Vaccines
RECAPPING THE EVENTS: EXPERIENCES FROM THE FIELD
Session I: The Evolution of the Outbreak

Moderator: Harvey Fineberg, President, Institute of Medicine
9:15-9:40 CHINA: The Epicenter

Yi Guan, M.D., Ph.D., The University of Hong Kong,
Queen Mary Hospital
9:40-10:00 Discussion
10:00-10:25 SARS: Lessons from Toronto

Don Low, M.D., FRCPC., Toronto Medical Laboratories,
Mt. Sinai Hospital, Toronto
277

10:45-11:10 WHO: The Global Response

David Heymann, M.D., World Health Organization, Geneva
11:30 BREAK
Session II: Discussion Panel

Moderator: Stanley Lemon, M.D., Vice Chair, Forum on Emerging Infec-
tions/ Dean of Medicine, The University of Texas Branch at Galveston
11:45 Discussants: Reporting Tools and Surveillance Networks:

Ann-Marie Kimball, M.D., M.P.H.,
School of Public Health and Community Medicine,
University of Washington
International Coordination and Collaboration:
Ray Arthur, Ph.D., National Center for Infectious
Diseases, Global Health, CDC (Invited)
Animal Coronaviruses—Lessons from SARS:
Linda Saif, Ph.D., Ohio Agricultural Research
Center, Ohio State University
12:30 Open Discussion
1:00 Lunch
Session III: The Spectrum of Consequences and Responses

Moderator: James Hughes, M.D., NCID, CDC
2:00-2:25 Economic Impacts

Warwick McKibbin, Ph.D., Australian National University
2:45-3:10 The Implications of SARS Epidemic for China’s Public

Health Infrastructure and Political System
Yanzhong Huang, Ph.D., Seton Hall University, Whitehead
School of Diplomacy and International Relations,
Center for Global Health Studies

APPENDIX A 279
3:30-3:55 Quarantine and Containment Strategies

Marty Cetron, M.D., National Center for
Infectious Diseases, CDC
4:15-4:40 Impacts on Health Care Systems

G. Neil Thomas, M.D., Department of Community Medicine,
University of Hong Kong (Invited)
Session IV: Open Discussion

5:00 Moderator: Joshua Lederberg, Ph.D., Nobel Laureate,
Sackler Foundation Scholar, Rockefeller University
Open Discussion
6:00 Adjournment of the first day
WEDNESDAY, OCTOBER 1, 2003

8:30 Continental Breakfast
9:00 Opening Remarks/Summary of Day 1
Stanley Lemon, M.D.
Vice Chair, Forum on Emerging Infections
LEARNING FROM OUR LESSONS: THE AGENDA AHEAD
Session V: The Research Agenda and Emerging Technologies

Moderator: Carole Heilman Ph.D., Director, Division of Microbiology and
Infectious Diseases, NIAID, NIH
9:15-9:40 Coronavirus Research

Mark Denison, M.D., Vanderbilt University
10:00-10:25 TIGER Technology for Emerging Infectious

Disease Surveillance
Ranga Sampath, Ph.D., Ibis Therapeutics, A Division of
Isis Pharmaceuticals

10:45-11:20 Pharmaceutical Approaches to Antiviral Drug

Development
Amy Patick, Ph.D. and Peter Dragovich, Ph.D., Pfizer Inc.
11:30 BREAK
11:45-12:10 Vaccines: Can We Prevent the Unexpected?

Alan Shaw, Ph.D., Merck Research Laboratories
12:30-12:50 SARS: Clearing the Air

Jerome Schentag, Pharm.D., State University of
New York-Buffalo
1:00 LUNCH
Session VI: Panel Discussion—Preparing for the Next Disease Outbreak

Moderator: Frederick Sparling, M.D., Professor of Medicine, Microbiology,
and Immunology, University of North Carolina
2:00 Discussants: The Quest to Define and Control SARS:

Robert Breiman, M.D.,
Centre for Health and Population Research,
Dhaka, Bangladesh
Regulatory Laboratory Planning/Preparedness:
Kathryn Carbone, M.D., Center for Biologics,
Food and Drug Administration
Future Threats Assessment: Karen Monaghan,
NIC, National Intelligence Council Report
Public Health Law: Gene Matthews, J.D.,
Legal Advisor to CDC
Modeling a Response Strategy: Nathaniel Hupert,
M.D., M.P.H., Weill Cornell Medical College
Face to Face w/ Influenza: Robert Webster, Ph.D.,
St. Jude Children’s Research Hospital
3:30 Open Discussion
5:00 Closing Remarks/Adjourn

Appendix B
Clinical Guidance on the Identification and

Evaluation of Possible SARS-CoV Disease
Among Persons Presenting with
Community-Acquired Illness1,2
Version 2. Reprinted with Permission from the Centers for
Disease Control and Prevention, 2003.
INTRODUCTION
Severe acute respiratory syndrome (SARS) is a recently recognized febrile se-
vere lower respiratory illness that is caused by infection with a novel coronavirus,
SARS-associated coronavirus (SARS-CoV). During the winter of 2002 through the
spring of 2003, WHO received reports of >8,000 SARS cases and nearly 800 deaths.
No one knows if SARS-CoV transmission will recur, but it is important to be pre-
pared for that possibility. Early recognition of cases and application of appropriate
infection control measures will be critical in controlling future outbreaks.
Many studies have been undertaken or are underway to evaluate whether
there are specific laboratory and/or clinical parameters that can distinguish
1This document provides guidance on the clinical evaluation and management of patients who
present from the community with fever and/or respiratory illnesses. The material in this document
supplements the information provided in Public Health Guidance for Community-Level Preparedness
and Response to Severe Acute Respiratory Syndrome (SARS). Available: http://www.cdc.gov/ncidod/
sars/guidance/index.htm.
2Summary of Changes in Version 2: This updated version of the clinical guidance clarifies that, in a
setting of ongoing SARS-CoV transmission in a facility or community, the presence of either fever or
lower respiratory symptoms should prompt further evaluation for SARS-CoV disease. In addition, in
accordance with the new SARS case definition, when persons have a high risk of exposure to SARS-
CoV (e.g., persons previously identified through contact tracing or self-identified as close contacts of
a laboratory-confirmed case of SARS-CoV disease; persons who are epidemiologically linked to a
laboratory-confirmed case of SARS-CoV disease), the clinical screening criteria should be expanded
to include, in addition to fever or lower respiratory symptoms, the presence of other early symptoms
of SARS-CoV disease.
281

BOX B-1
Key Concepts
• The vast majority of patients with SARS-CoV disease 1) have a
clear history of exposure either to a SARS patient(s) or to a setting in
which SARS-CoV transmission is occurring, and 2) develop pneumonia.
• Laboratory tests are helpful but do not reliably detect infection early
in the illness.
SARS-CoV disease from other febrile respiratory illnesses. Researchers are

also working on the development of laboratory tests to improve diagnostic
capabilities for SARS-CoV and other respiratory pathogens. To date, how-
ever, no specific clinical or laboratory findings can distinguish with certainty
SARS-CoV disease from other respiratory illnesses rapidly enough to inform
management decisions that must be made soon after the patient presents to
the healthcare system. Therefore, early clinical recognition of SARS-CoV
disease still relies on a combination of clinical and epidemiologic features.
IDENTIFICATION OF POTENTIAL CASES OF SARS-COV DISEASE

The diagnosis of SARS-CoV disease and the implementation of control mea-
sures should be based on the risk of exposure. In the absence of any person-to-
person transmission of SARS-CoV worldwide, the overall likelihood that a patient
being evaluated for fever or respiratory illness has SARS-CoV disease will be ex-
ceedingly low unless there are both typical clinical findings and some accompany-
ing epidemiologic evidence that raises the suspicion of exposure to SARS-CoV.
Therefore, one approach in this setting would be to consider the diagnosis only for
patients who require hospitalization for unexplained pneumonia and who have an
epidemiologic history that raises the suspicion of exposure, such as recent travel to
a previously SARS-affected area (or close contact with an ill person with such a
travel history), employment as a healthcare worker with direct patient contact or as
a worker in a laboratory that contains live SARS-CoV, or an epidemiologic link to
a cluster of cases of unexplained pneumonia. Once person-to-person SARS-CoV
transmission has been documented anywhere in the world, the positive predictive
value of even early clinical symptoms (e.g., fever or lower respiratory symptoms in
the absence of pneumonia), while still low, may be sufficiently high—when com-
bined with an epidemiologic link to settings in which SARS-CoV has been docu-
mented— to lead clinicians to consider a diagnosis of SARS-CoV disease.
In that context, the guidance that follows should be considered in the evaluation and
management of patients who present from the community with fever or lower respiratory
illnesses. For more detailed guidance on infection control, see Supplement I in Public
Health Guidance for Community-Level Preparedness and Response to Severe Acute Res-
piratory Syndrome (SARS): http://www.cdc.gov/ncidod/sars/guidance/index.htm.

APPENDIX B 283
GUIDELINES FOR EVALUATION OF SARS-COV DISEASE AMONG

PERSONS PRESENTING WITH COMMUNITY-ACQUIRED ILLNESS
(SEE FIGURES B-1 AND B-2)
The following is an approach for the evaluation of possible SARS-CoV dis-
ease among persons presenting with community-acquired illness. As part of the
evaluation, in addition to identification of suggestive clinical features, clinicians
should routinely incorporate into the medical history questions that may provide
epidemiologic clues to identify patients with SARS-CoV disease.
ADDITIONAL CONSIDERATIONS
In some settings, early recognition of SARS-CoV disease may require additional
measures. The following guidance is provided to assist in the evaluation of patients in
settings or with characteristics not detailed/outlined in Figures B-1 and B-2. These include
SARS outbreaks in the surrounding community, management of patients who become ill
while already in the hospital, workers from laboratories that contain live SARS-CoV,
pediatric patients, the elderly, and persons with chronic underlying diseases.
Additional Epidemiologic Risk Factors to Consider in

Community Outbreak Settings
The risk factors that should trigger suspicion for SARS-CoV disease may
vary depending on the level of SARS-CoV transmission occurring in the commu-
nity. Specifically, as outbreaks become more widespread, the types of epidemio-
logic characteristics that are considered as risk factors for SARS-CoV disease
should be broadened appropriately. Two examples are given below.
1. Evaluating patients in the midst of a community outbreak in which more extensive

secondary transmission of SARS-CoV is occurring in well-defined settings with
all cases linked to other cases (e.g., an outbreak in a local hospital)
• Continue the activities for evaluation of persons with ‘fever and/or

lower respiratory illness’ outlined in Figure B-2, but in addition:
• Consider the diagnosis of SARS-CoV disease among all persons with radio-
graphic evidence of pneumonia (even if not requiring hospitalization) if they:
• Have had exposure to hospitals in the 10 days before onset of symptoms

(e.g., patient, visitor, or staff), or
• Are employed in an occupation at particular risk for SARS-CoV expo-
sure, including a healthcare worker with or without direct patient con-
tact or a worker in a clinical or research virology laboratory, or
• Have close contact with a patient with documented pneumonia.

BOX B-2
Diagnosis of SARS-CoV Disease
In the absence of person-to-person transmission of SARS-CoV
anywhere in the world, the diagnosis of SARS-CoV disease should
be considered only in patients who require hospitalization for radio-
graphically confirmed pneumonia and who have an epidemiologic history
that raises the suspicion of SARS-CoV disease. The suspicion for SARS-
CoV disease is raised if, within 10 days of symptom onset, the patient:
• Has a history of recent travel to mainland China, Hong Kong, or

Taiwan (see Figure B-1, footnote 3) or close contacta with ill persons with
a history of recent travel to such areas, OR
• Is employed in an occupation at particular risk for SARS-CoV ex-
posure, including a healthcare worker with direct patient contact or a
worker in a laboratory that contains live SARS-CoV, OR
• Is part of a cluster of cases of atypical pneumonia without an alter-
native diagnosis
Persons with such a clinical and exposure history should be evalu-
ated according to the algorithm in Figure B-1.
Once person-to-person transmission of SARS-CoV has been
documented in the world, the diagnosis should still be considered
in patients who require hospitalization for pneumonia and who have the
epidemiologic history described above. In addition, all patients with fever
or lower respiratory symptoms (e.g., cough, shortness of breath, difficulty
breathing) should be questioned about whether within 10 days of symp-
tom onset they have had:
• Close contact with someone suspected of having SARS-CoV dis-
ease, OR
• A history of foreign travel (or close contact with an ill person with a
history of travel) to a location with documented or suspected SARS-CoV,
OR
• Exposure to a domestic location with documented or suspected
SARS-CoV (including a laboratory that contains live SARS-CoV), or close
contact with an ill person with such an exposure history.
Persons with such an exposure history should be evaluated for
SARS-CoV disease according to the algorithm in Figure B-2.
aClose contact: A person who has cared for or lived with a person with SARS-
CoV disease or had a high likelihood of direct contact with respiratory secretions
and/or body fluids of a person with SARS-CoV disease. Examples of close contact
include kissing or hugging, sharing eating or drinking utensils, talking within 3 feet,
and direct touching. Close contact does not include activities such as walking by a
person or briefly sitting across a waiting room or office.

APPENDIX B 285
2. Evaluating patients in the midst of a community outbreak in which transmis-

sion is widespread and epidemiologic linkages between cases are not well
defined
• Since epidemiologic links to persons with SARS-CoV disease may not be

identifiable at this point, SARS-CoV disease should be considered in any
patient presenting with fever or lower respiratory illness, even in the ab-
sence of known epidemiologic risk factors.
Persons with a High Risk of Exposure

For persons with a high risk of exposure to SARS-CoV (e.g., persons previ-
ously identified through contact tracing as close contacts of a laboratory-con-
firmed case of SARS-CoV disease; persons who are epidemiologically linked to
a laboratory-confirmed case of SARS-CoV disease), symptoms that should trig-
ger the clinical algorithm should be expanded to include the presence of any of
the following: sore throat, rhinorrhea, chills, rigors, myalgia, headache, diarrhea.
For more details on the clinical features of SARS-CoV disease, see Figure B-2,
footnote 1.
Management of Patients Who Acquire Illness While in the Hospital

This document focuses on the evaluation and management of patients who
present from the community, although many of the same principles apply to hos-
pitalized patients who develop nosocomial fever or lower respiratory symptoms.
The diagnosis of nosocomial SARS-CoV disease may be particularly challeng-
ing, however, since many inpatients may have other reasons for developing noso-
comial fever, lower respiratory symptoms, and pneumonia. Therefore, in hospi-
tals known to have or suspected of having patients with SARS-CoV disease,
clinicians and public health officials must be particularly vigilant about evaluat-
ing fever and respiratory illnesses among inpatients. Additional guidance on when
to apply Figure B-2 in the evaluation of patients who develop fever and/or respi-
ratory illness while hospitalized is provided in Supplement C, Public Health Guid-
ance for Community-Level Preparedness and Response to Severe Acute Respira-
tory Syndrome (SARS): http://www.cdc.gov/ncidod/sars/guidance/index.htm.
Laboratory Workers
Breaks in technique in laboratories that contain live SARS-CoV can result in
laboratory-acquired cases of SARS-CoV disease. Personnel working in laborato-
ries that contain live SARS-CoV should report any febrile and/or lower respira-
tory illnesses to the supervisor, be evaluated for possible exposures, and be closely
monitored for clinical features and course of illness. If laboratory workers with

FIGURE B-1 Algorithm for evaluation and management of patients requiring hospital-
ization for radiographically confirmed pneumonia, in the absence of person-to-person
transmission of SARS-CoV in the world.
1Or Acute Respiratory Distress Syndrome (ARDS) of unknown etiology.

2Guidance for the management of community-acquired pneumonia is available from the Infectious
Diseases Society of America (IDSA) and can be found at www.journals.uchicago.edu/IDSA/guide-
lines/.
3The 2003 SARS-CoV outbreak likely originated in mainland China, and neighboring areas such as
Taiwan and Hong Kong are thought to be at higher risk due to the high volume of travelers from
mainland China. Although less likely, SARS-CoV may also reappear from other previously affected
areas. Therefore, clinicians should obtain a complete travel history. If clinicians have concerns about
the possibility of SARS-CoV disease in a patient with a history of travel to other previously affected
areas (e.g., while traveling abroad, had close contact with another person with pneumonia of unknown
etiology or spent time in a hospital in which patients with acute respiratory disease were treated), they
should contact the health department.

287
FIGURE B-2

FIGURE B-2 Algorithm for management of patients with fever or lower respiratory
symptoms when person-to-person transmission of SARS-CoV is occurring in the world.
1Clinical description of SARS-CoV disease and approach to treatment:
Clinical judgment should be used to determine when symptoms trigger initiation of the algorithm
in Figure B-2. The early symptoms of SARS-CoV disease usually include fever, chills, rigors,
myalgia, and headache. In some patients, myalgia and headache may precede the onset of fever by
12-24 hours. Respiratory symptoms often do not appear until 2-7 days after the onset of illness and
most often include shortness of breath and/or dry cough. Diarrhea, sore throat, and rhinorrhea may
also be early symptoms of SARS-CoV disease. In the absence of fever, when screening patients for
potential SARS-CoV disease, respiratory symptoms that would trigger the clinical algorithm are
generally defined as lower respiratory tract symptoms (e.g., cough, shortness of breath, difficulty
breathing). However, when screening patients who have a high risk of exposure to SARS-CoV
(e.g., persons previously identified through contact tracing or self-identified as close contacts of a
laboratory-confirmed case of SARS-CoV disease; persons who are epidemiologically linked to a
laboratory-confirmed case of SARS-CoV disease), symptoms that should trigger the clinical
algorithm should be expanded to include any of the following: sore throat, rhinorrhea, chills, rig-
ors, myalgia, headache, diarrhea.
Although not diagnostic, the following laboratory abnormalities have been seen in some patients
with laboratory-confirmed SARS-CoV disease:
• Lymphopenia with normal or low white blood cell count
• Elevated hepatic transaminases
• Elevated creatine phosphokinase
• Elevated lactate dehydrogenase
• Elevated C-reactive protein
• Prolonged activated partial thromboplastin time
As of December 1, 2003, no specific treatment recommendations can be made for management of
SARS-CoV disease. Empiric therapy for community-acquired pneumonia should include treatment
for organisms associated with any community-acquired pneumonia of unclear etiology, including
agents with activity against both typical and atypical respiratory pathogens. Treatment choices may
be influenced by both the severity of and the circumstances surrounding the illness. Infectious disease
consultation is recommended. The Infectious Diseases Society of America has guidelines for the
management of community-acquired pneumonia at www.journals.uchicago.edu/IDSA/guidelines/.
2Exposure history for SARS-CoV, once SARS-CoV transmission is documented in the world:
In settings of no or limited local secondary transmission of SARS-CoV, patients are considered

exposed to SARS-CoV if, within 10 days of symptom onset, the patient has:
• Close contact with someone suspected of having SARS-CoV disease, OR
• A history of foreign travel (or close contact with an ill person with a history of travel) to a
location with documented or suspected SARS-CoV, OR
• Exposure to a domestic location with documented or suspected SARS-CoV (including a labora-
tory that contains live SARS-CoV), or close contact with an ill person with such an exposure history.
In settings with more extensive transmission, all patients with fever or lower respiratory symptoms
should be evaluated for possible SARS-CoV disease, since the ability to determine epidemiologic
links will be lost.
For up-to-date information on where recent SARS-CoV transmission is suspected or documented,
see the CDC and WHO websites: www.cdc.gov/sars and www.who.int.
3Clinical work-up: Clinicians should work up patients as clinically indicated. Depending on symp-
toms and exposure history, initial diagnostic testing for patients with suspected SARS-CoV disease
may include:
• Complete blood count (CBC) with differential
• Chest radiograph
• Pulse oximetry

APPENDIX B 289
• Blood cultures
• Sputum Gram’s stain and culture
• Testing for viral respiratory pathogens, notably influenza A and B and respiratory syncytial
virus
• Legionella and pneumococcal urinary antigen testing if radiographic evidence of pneumonia
(adults only)
An acute serum sample and other available clinical specimens (respiratory, blood, and stool) should
be saved for additional testing until a specific diagnosis is made.
SARS-CoV testing may be considered as part of the initial work-up if there is a high level of
suspicion for SARS-CoV disease based on exposure history. For additional details on specialized
laboratory testing options available through the health department and the Laboratory Response Net-
work (LRN), see CDC’s SARS website: www.cdc.gov/sars/.
4Alternative diagnosis:
An alternative diagnosis should be based only on laboratory tests with high positive-predictive
value (e.g., blood culture, viral culture, Legionella urinary antigen, pleural fluid culture, transthoracic
aspirate). In some settings, PCR testing for bacterial and viral pathogens can also be used to help
establish alternative diagnoses. The presence of an alternative diagnosis does not necessarily rule out
co-infection with SARS-CoV.
5Radiographic testing:
Chest CT may show evidence of an infiltrate before a chest radiograph (CXR). Therefore, a chest
CT should be considered in patients with a strong epidemiologic link to a known case of SARS-CoV
disease and a negative CXR 6 days after onset of symptoms. Alternatively, the patient should remain
in SARS isolation, and the CXR should be repeated on day 9 after symptom onset.
6Discontinuation of SARS isolation precautions:
SARS isolation precautions should be discontinued only after consultation with the local public
health authorities and the evaluating clinician. Factors that might be considered include the strength
of the epidemiologic exposure to SARS-CoV, nature of contact with others in the residential or work
setting, strength of evidence for an alternative diagnosis, and evidence for clustering of pneumonia
among close contacts. Isolation precautions should be discontinued on the basis of an alternative
diagnosis only when the following criteria are met:
• Absence of strong epidemiologic link to known cases of SARS-CoV disease
• Alternative diagnosis confirmed using a test with a high positive-predictive value
• Clinical manifestations entirely explained by the alternative diagnosis
• No evidence of clustering of pneumonia cases among close contacts (unless >1 case in the
cluster is confirmed to have the same alternative diagnosis)
• All cases of presumed SARS-CoV disease identified in the surrounding community can
be epidemiologically linked to known cases or locations in which transmission is known to have
occurred.

fever and/or lower respiratory illness are found to have an exposure to SARS-
CoV, they should be managed according to the guidance in Figure B-2. In addi-
tion, in an exposed laboratory worker, symptoms that should trigger the clinical
algorithm in Figure B-2 should be expanded to include the presence of any of the
following: sore throat, rhinorrhea, chills, rigors, myalgia, headache, diarrhea (see
Figure B-2, footnote 1, for more information). Detailed information for persons
who work in laboratories that contain live SARS-CoV is provided in Supplement
F, Public Health Guidance for Community-Level Preparedness and Response to
Severe Acute Respiratory Syndrome (SARS), http://www.cdc.gov/ncidod/sars/
guidance/index.htm.
Considerations for the Pediatric Population

The document does not specifically address the evaluation and management
of infants and children. Much less is known about SARS-CoV disease in pediat-
ric patients than in adults. During the 2003 outbreaks, infants and children ac-
counted for only a small percentage of patients and had much milder disease with
better outcome. Their role in transmission is not well described but is likely much
less significant than the role of adults. Taking these factors into account, the
following guidance may change as more information becomes available on
SARS-CoV disease in the pediatric population:
• In the absence of person-to-person SARS-CoV transmission in the world,

evaluation and management for possible SARS-CoV disease should be
considered only for adults, unless special circumstances make the clini-
cian and health department consider a child to be of potentially high risk
for having SARS-CoV disease.
• In the presence of person-to-person SARS-CoV transmission in the world,
the evaluation algorithm established for adults can be used in children
with the following caveats:
• Both the rate of development of radiographically confirmed pneumo-
nia and the timing of development of such radiographic changes in
children are unknown.
• The positive predictive value of rapid virus antigen detection tests (e.g.,
RSV) “in season” will be higher in a pediatric population.
• Pneumococcal and legionella urinary antigen testing are not recom-
mended for routine diagnostic use in children.
Elderly Persons and Patients with Underlying Chronic Illnesses

Typical symptoms of SARS-CoV disease may not always be present in eld-
erly patients and those with underlying chronic illnesses, such as renal failure.
Therefore, the diagnosis should be considered for almost any change in health

APPENDIX B 291
status, even in the absence of typical clinical features of SARS-CoV disease,

when such patients have epidemiologic risk factors for SARS-CoV disease (e.g.,
close contact with someone suspected to have SARS-CoV disease or exposure to
a location [domestic or international] with documented or suspected recent trans-
mission of SARS-CoV).

Appendix C
In the Absence of SARS-CoV Transmission

Worldwide: Guidance for Surveillance,
Clinical and Laboratory Evaluation,
and Reporting1,2
BACKGROUND
Severe acute respiratory syndrome (SARS) came to global attention in Feb-
ruary 2003, when officials in China informed the World Health Organization
(WHO) about 305 cases of atypical pneumonia that had occurred in Guangdong
Province. By the time the new infectious disease was declared contained in July
2003, more than 8,000 cases and 780 deaths had been reported from 29 countries
worldwide. Since then, active global surveillance for SARS-associated
coronavirus (SARS-CoV) disease in humans has detected no laboratory-con-
firmed person-to-person transmission of SARS-CoV.
No one knows if, when, or where person-to-person transmission of SARS-
CoV will recur. However, the rapidity of spread of infection and the high levels
1This is an updated version of a document first issued by CDC in December 2003. The document
provides guidance for surveillance, clinical and laboratory evaluation, and reporting in the setting of
no known person-to-person transmission of SARS-CoV worldwide. Recommendations are derived
from Public Health Guidance for Community-Level Preparedness and Response to Severe Acute
Respiratory Syndrome (SARS): www.cdc.gov/ncidod/sars/guidance/index.htm.
2Summary of Changes in Version 2: This version of the guidance document clarifies that the
recommendations apply to situations in which no known person-to-person transmission of SARS-

CoV is occurring in the world. Some wording has also been revised for consistency with the
companion documents, Public Health Guidance for Community-Level Preparedness and Re-
sponse to Severe Acute Respiratory Syndrome (SARS), and Clinical Guidance on the Identifica-
tion and Evaluation of Possible SARS-CoV Disease among Persons Presenting with Community-
Acquired Illness.
292

APPENDIX C 293
of morbidity and mortality associated with SARS-CoV call for careful monitor-
ing for the recurrence of transmission and preparations for the rapid implemen-
tation of control measures. The 2003 global outbreaks demonstrated the ease
with which SARS-CoV can seed and spread in human populations when cases
remain undetected or when infected persons are not cared for in controlled en-
vironments that reduce the risk of transmission to others. The two laboratory-
acquired infections and the recent cases in Southern China show that SARS-
CoV continues to be a threat. Early detection of SARS cases and contacts, plus
swift and decisive implementation of containment measures, are therefore es-
sential to prevent transmission. Although the United States had only a limited
SARS-CoV outbreak during the 2003 epidemic—with only eight laboratory-
confirmed cases and no significant local spread—the U.S. population is clearly
vulnerable to the more widespread, disruptive outbreaks experienced in other
countries. During this period of no known person-to-person transmission of
SARS-CoV in the world, healthcare and public health officials must therefore
do what they can to prepare for the possibility that SARS-CoV transmission
may recur.
This document provides guidance for surveillance, clinical and laboratory
evaluation, and reporting in the setting of no known person-to-person transmis-
sion of SARS-CoV worldwide. Recommendations are derived from Public Health
Guidance for Community-Level Preparedness and Response to Severe Acute Res-
piratory Syndrome (SARS) www.cdc.gov/ncidod/sars/guidance/index.htm. If such
transmission recurs anywhere in the world, CDC will promptly review all avail-
able information and provide additional guidance via the Health Alert Network
(HAN), Epi-X, and partner organizations. Current information will also be posted
on CDC’s SARS website: www.cdc.gov/sars.
CLINICAL FEATURES OF SARS-COV DISEASE

The median incubation period for SARS-CoV appears to be approxi-
mately 4 to 6 days; most patients become ill within 2 to 10 days after expo-
sure. Early clinical features of SARS-CoV disease can be similar to other
viral illnesses and are not sufficiently distinct to enable diagnosis by signs
and symptoms alone. The illness usually begins with systemic symptoms such
as fever, headache, and myalgias. Respiratory complaints often develop 2 to 7
days after illness onset and usually include a non-productive cough and dysp-
nea. Upper respiratory symptoms such as rhinorrhea and sore throat may oc-
cur but are uncommon. Almost all patients with laboratory evidence of SARS-
CoV disease evaluated to date developed radiographic evidence of pneumonia
by day 7-10 of illness, and most (70 percent-90 percent) developed lymphope-
nia. The overall case-fatality rate of approximately 10 percent can increase to
>50 percent in persons older than age 60.

BOX C-1
Key Clinical Features of SARS-CoV Disease
• Incubation period of 2-10 days
• Early systemic symptoms followed within 2-7 days by dry cough
and/or shortness of breath, often without upper respiratory tract symp-
toms
• Development of radiographically confirmed pneumonia by day 7-
10 of illness
• Lymphopenia in most cases
SURVEILLANCE: EARLY CASE DETECTION

Potential sources of virus for a recurrence of person-to-person spread of
SARS-CoV include reintroduction to humans from an animal reservoir, persis-
tent infection in previously ill persons, or the laboratory. Since SARS-CoV cur-
rently exists in the animals in southern China—the apparent source of the 2003
outbreak—this area remains under scrutiny for SARS-CoV disease activity. Po-
tential sources of recurrence also include other areas where SARS-CoV transmis-
sion occurred and large cities that are international travel hubs connecting to
locales that might harbor persistent infections in humans. Laboratory personnel
working with SARS-CoV might also become infected as a result of compromised
laboratory techniques.3 Because persons with SARS-CoV disease tended to ap-
pear in clusters (e.g., in healthcare facilities, households, and a few special set-
tings) during the 2003 outbreaks, early signals of the reappearance of the illness
in U.S. communities could include unusual clusters of unexplained pneumonia.
In the absence of person-to-person transmission of SARS-CoV world-
wide, the goal of domestic surveillance is to maximize early detection of cases
of SARS-CoV disease while minimizing unnecessary laboratory testing, con-
cerns about SARS-CoV, implementation of control measures, and social dis-
3Persons who work in laboratories that contain live SARS-CoV should report any febrile and/or
respiratory illnesses to the supervisor. They should be evaluated for possible exposures, and their
clinical features and course of illness should be closely monitored, as described in Appendix F6,
Supplement F, in Public Health Guidance for Community-Level Preparedness and Response to Se-
vere Acute Respiratory Syndrome (SARS): www.cdc.gov/ncidod/sars/guidance/F/pdf/app6.pdf.
If laboratory workers with fever and/or lower respiratory illness are found to have an exposure to
SARS-CoV, they should be managed according to the algorithm in Figure 2, Clinical Guidance on the
Identification and Evaluation of Possible SARS-CoV Disease among Persons Presenting with Com-
munity-Acquired Illness (www.cdc.gov/ncidod/sars/clinicalguidance.htm). In an exposed laboratory
worker, symptoms that should trigger the clinical algorithm in Figure 2 should be expanded to in-
clude the presence of any of the following: sore throat, rhinorrhea, chills, rigors, myalgia, headache,
diarrhea (see Figure 2, footnote 1, for more details).

APPENDIX C 295
ruption. Early and efficient detection of SARS cases is not, however, a straight-
forward task. In the absence of known transmission worldwide, the overall likeli-
hood that a person in the United States with fever and respiratory symptoms will
have SARS-CoV disease is exceedingly low. Moreover, the nonspecific clinical
features of early SARS-CoV disease and the current lack of diagnostic tests that
can reliably detect the virus during the first few days of illness pose challenges to
finding SARS-CoV-infected persons during the predictable seasonal upsurge in
respiratory infections.
Nonetheless, lessons learned from the 2003 outbreaks have identified three fea-
tures of SARS-CoV disease that can be used to focus surveillance activities during the
period of no transmission worldwide: (1) most patients infected with SARS-CoV
develop radiographic evidence of pneumonia; (2) most SARS-CoV transmission oc-
curs when patients are seriously ill and require hospitalization; and (3) most infected
patients have an identifiable exposure to a known SARS-CoV case or a suggestive
cluster of SARS-like illness or a location with known SARS transmission.
Given these features, the potential sources of recurrence of SARS-CoV, and
the predilection for SARS-CoV transmission to occur in healthcare settings or to
be associated with geographically focused pneumonia clusters, surveillance ef-
forts in the absence of person-to-person SARS-CoV transmission should aim to
identify patients who require hospitalization for radiographically confirmed
pneumonia or acute respiratory distress syndrome without identifiable etiol-
ogy AND who have one of the following risk factors in the 10 days before the
onset of illness:
• Travel to mainland China, Hong Kong, or Taiwan, or close contact4 with

an ill person with a history of recent travel to one of these areas, OR
• Employment in an occupation associated with a risk for SARS-CoV ex-
posure (e.g., healthcare worker5 with direct patient contact; worker in a labora-
tory that contains live SARS-CoV), OR
• Part of a cluster of cases of atypical pneumonia without an alternative
diagnosis
Infection control practitioners and other healthcare personnel should also be

alert for clusters of pneumonia among two or more healthcare workers who work
in the same facility.
4Close contact: A person who has cared for or lived with a person with SARS-CoV disease or had
a high likelihood of direct contact with respiratory secretions and/or body fluids of a person with
SARS-CoV disease. Examples of close contact include kissing or hugging, sharing eating or drinking
utensils, talking within 3 feet, and direct touching. Close contact does not include activities such as
walking by a person or briefly sitting across a waiting room or office.
5Healthcare worker: Any employee in a healthcare facility who has close contact with patients,
patient-care areas, or patient-care items.

The 2003 SARS-CoV outbreak likely originated in mainland China, and

neighboring areas such as Taiwan and Hong Kong are thought to be at higher risk
due to the large volume of travelers from mainland China. Although less likely,
SARS-CoV may also reappear from other previously affected areas. Therefore,
clinicians should obtain a complete travel history. If clinicians have concerns
about the possibility of SARS-CoV disease in a patient with a history of travel to
other previously affected areas (e.g., while traveling abroad, had close contact
with another person with pneumonia of unknown etiology or spent time in a
hospital in which patients with acute respiratory disease were treated), they should
contact the health department.
In the absence of person-to-person transmission of SARS-CoV in the world,
the screening of persons requiring hospitalization for radiographically confirmed
pneumonia for risk factors suggesting SARS-CoV exposure should be limited to
adults, unless there are special circumstances that make the clinician and public
health personnel consider a child to be of potentially high risk for having SARS-
CoV disease. During the 2003 global outbreaks, infants and children accounted
for only a small percentage of SARS cases and had a much milder disease and
better outcome than adults. Although information on SARS-CoV disease in pedi-
atric patients is limited, the role of children in transmission is likely much less
significant than the role of adults.
BOX C-2
Case Detection
Severe respiratory illness in the context of a documented exposure
risk is the key to diagnosing SARS-CoV disease. Providers should there-
fore consider SARS-CoV disease in patients requiring hospitalization for:
• Radiographically confirmed pneumonia or acute respiratory dis-

tress syndrome of unknown etiology, AND
• One of the following risk factors in the 10 days before illness onset:
• Travel to mainland China, Hong Kong, or Taiwan, or close con-
tact with an ill person with a history of recent travel to one of these areas;
OR
• Employment in an occupation associated with a risk for SARS-
CoV exposure (e.g., healthcare worker with direct patient contact; worker
in a laboratory that contains live SARS-CoV); OR
• Part of a cluster of cases of atypical pneumonia without an al-
ternative diagnosis.
Infection control practitioners and other healthcare personnel should

be alert for clusters of pneumonia among two or more healthcare work-
ers who work in the same facility.

APPENDIX C 297
INFECTION CONTROL AND CLINICAL EVALUATION

SARS-CoV disease provides a reminder of the risks of nosocomial transmission
of respiratory pathogens and an opportunity to improve overall infection control in
healthcare facilities. All healthcare facilities need to re-emphasize the importance of
basic infection control measures for the control of SARS-CoV disease and other res-
piratory illnesses. Facilities should also consider adopting a “respiratory hygiene/
cough etiquette” strategy to help limit nosocomial transmission of respiratory patho-
gens. To contain respiratory secretions, all persons with signs and symptoms of a
respiratory infection, regardless of presumed cause, should be instructed to:
• Cover the nose and mouth when coughing or sneezing.

• Use tissues to contain respiratory secretions.
• Dispose of tissues in the nearest waste receptacle after use.
• Perform hand hygiene after contact with respiratory secretions and con-
taminated objects and materials.
Healthcare facilities should ensure the availability of materials for adhering

to respiratory hygiene/cough etiquette in waiting areas for patients and visitors:
• Provide tissues and no-touch receptacles for used tissue disposal.

• Provide conveniently located dispensers for alcohol-based hand rub.
• Provide soap and disposable towels for hand washing where sinks are
available.
During periods of increased respiratory infection in the community,

healthcare facilities should offer procedure or surgical masks to persons who are
coughing and encourage coughing persons to sit at least 3 feet away from others
in waiting areas. Healthcare workers should practice Droplet Precautions, in ad-
dition to Standard Precautions, when examining a patient with symptoms of a
respiratory infection. Droplet precautions should be maintained until it is deter-
mined that they are no longer needed (see www.cdc.gov/ncidod/hip/ISOLAT/
Isolat.htm). An algorithm for patient evaluation is provided in Appendix 1.
If the clinician and health department have a high index of suspicion for
SARS-CoV disease or if laboratory evidence of SARS-CoV disease is found,
then the patient should be placed immediately on SARS isolation precautions,
and contacts should be immediately identified, evaluated, and monitored for evi-
dence of respiratory disease. Prompt SARS-CoV laboratory diagnostics should
be arranged through the health department. Initial diagnostic evaluation to look
for an alternative diagnosis in suspected SARS-CoV patients should be performed
as clinically indicated, and may include:
• Chest radiograph
• Pulse oximetry

BOX C-3
Infection Control and Clinical Evaluation
• Healthcare facilities should re-emphasize the importance of basic
infection control measures for respiratory infections and consider adopt-
ing a “respiratory hygiene/cough etiquette” strategy.
• All patients admitted to the hospital with radiographically confirmed
pneumonia should be:
• Placed on Droplet Precautions
• Screened for risk factors for possible exposure to SARS-CoV
• Evaluated with a chest radiograph, pulse oximetry, complete
blood count, and etiologic workup as indicated.
• If there is a high index of suspicion for SARS-CoV disease (by
clinicians and health department), the patient should immediately be
placed on SARS isolation precautions, and all contacts of the ill patient
should be identified, evaluated, and monitored. Prompt SARS-CoV labo-
ratory diagnostics should be arranged through the health department.
• Complete blood count with differential

• Blood cultures
• Sputum Gram’s stain and culture
• Testing for viral respiratory pathogens, notably influenza A and B and
respiratory syncytial virus
• Specimens for Legionella and pneumococcal urinary antigen testing
LABORATORY TESTING FOR SARS-COV

Laboratory testing for SARS-CoV is now available at many state public
health laboratories. Available tests include antibody testing using an enzyme im-
munoassay (EIA) and reverse transcription polymerase chain reaction (RT-PCR)
tests for respiratory, blood, and stool specimens. In the absence of person-to-
person transmission of SARS-CoV, the positive predictive value of a diagnostic
test is extremely low. False-positive test results may generate tremendous anxiety
and concern and expend valuable public health resources. Therefore, SARS-CoV
testing should be performed judiciously, and preferably only in consultation
with the local or state health department. SARS-CoV testing should be con-
sidered if no alternative diagnosis is identified 72 hours after initiation of the
clinical evaluation and the patient is thought to be at high risk for SARS-CoV
disease (e.g., is part of a cluster of unexplained pneumonia cases).
Providers should immediately report all positive SARS-CoV test results to
the local or state health department. Confirmatory SARS-CoV testing at an ap-

APPENDIX C 299
BOX C-4
Laboratory testing for SARS-CoV
• Perform laboratory testing judiciously and in consultation with the
local or state health department.
• Providers should report all positive test results immediately to the
local or state health department.
• Arrange for confirmatory testing at an appropriate test site through
the local or state health department.
propriate confirmatory test site should be arranged through the local or state health
department as outlined in Supplement F, Public Health Guidance for Commu-
nity-Level Preparedness and Response to Severe Acute Respiratory Syndrome
(SARS) www.cdc.gov/ncidod/sars/guidance/index.htm.
Guidelines for the collection and transport of specimens for SARS-CoV test-
ing are provided in Appendix F4, Supplement F, in Public Health Guidance for
Community-Level Preparedness and Response to Severe Acute Respiratory Syn-
drome (SARS) www.cdc.gov/ncidod/sars/guidance/F/pdf/app4.pdf.
CDC is working with the Association of Public Health Laboratories (APHL)
and the Laboratory Response Network (LRN) to ensure that SARS RT-PCR and
EIA tests meet quality control guidelines. CDC will also be distributing profi-
ciency testing materials to participating laboratories.
REPORTING OF POTENTIAL SARS-COV CASES

Healthcare providers should report to the state or local health department:
• All persons requiring hospitalization for radiographically confirmed pneu-

monia who report at least one of the three risk factors for exposure to SARS-CoV
outlined in Section III above.
• Any clusters (two or more persons) of unexplained pneumonia, especially
among healthcare workers
• Any positive SARS-CoV test result
Note: In the absence of known person-to-person transmission of SARS-CoV

in the world, any SARS-CoV-positive test result should be phoned in to the state
or local health department immediately for confirmation and implementation of
urgent and appropriate isolation precautions, contact tracing, and follow-up.
Health departments should immediately report any SARS-CoV positive
test result to CDC. Health departments should also inform CDC of other cases or
clusters of pneumonia that are of particular concern by calling 770-488-7100.

BOX C-5
Report to state or local health department:
• All persons requiring hospitalization for radiographically confirmed
pneumonia who report at least one of the three risk factors for exposure
to SARS-CoV
• Any clusters of unexplained pneumonia, especially among
healthcare workers
• Any positive SARS-CoV test result
APPENDIX C-1
IN THE ABSENCE OF PERSON-TO-PERSON TRANSMISSION OF
SARS-COV WORLDWIDE: GUIDANCE FOR EVALUATION AND
MANAGEMENT OF PATIENTS REQUIRING HOSPITALIZATION
FOR RADIOGRAPHICALLY CONFIRMED PNEUMONIA
In the absence of SARS-CoV transmission in the world, a diagnosis of SARS-
CoV disease should be considered only in patients who require hospitalization for
radiographically confirmed pneumonia and who have an epidemiologic history
that raises the suspicion for SARS-CoV disease (see Figure C-1, page 296). The
suspicion for SARS-CoV disease is increased if, within 10 days of the onset of
SARS-like symptoms, the patient: 1) traveled to mainland China, Hong Kong, or
Taiwan, or had close contact with an ill person with a history of recent travel to
one of these areas; 2) is employed in an occupation associated with a risk for
SARS-CoV exposure (e.g., healthcare worker with direct patient contact; worker
in a laboratory that contains live SARS-CoV); or 3) is part of a cluster of cases of
atypical pneumonia without an alternative diagnosis. Persons with such a clinical
and exposure history should be evaluated according to the following algorithm.
In some settings, early recognition of SARS-CoV disease may require addi-
tional measures:
• Laboratory workers—Breaks in technique in laboratories that contain live

SARS-CoV could result in laboratory–acquired cases of SARS. Persons work-
ing in laboratories that contain live SARS-CoV should report any fever and/or
lower respiratory illness to the supervisor. They should be evaluated for possible
exposures, and their clinical features and course of illness should be closely
monitored as described in Appendix F6 in Supplement F, Public Health Guid-
ance for Community-Level Preparedness and Response to Severe Acute Respi-
ratory Syndrome (SARS) www.cdc.gov/ncidod/sars/guidance/index.htm. If labo-
ratory workers with fever and/or lower respiratory illness are found to have an
exposure to SARS-CoV, they should be managed according to the algorithm in

APPENDIX C 301
Figure 2, Clinical Guidance on the Identification and Evaluation of Possible

SARS-CoV Disease among Persons Presenting with Community-Acquired Ill-
ness (www.cdc.gov/ncidod/sars/clinicalguidance.htm). In an exposed laboratory
worker, symptoms that should trigger the clinical algorithm in Figure 2 should
be expanded to include the presence of any of the following: sore throat, rhinor-
rhea, chills, rigors, myalgia, headache, diarrhea (see Figure 2, footnote 1, for
more details).
• Pediatric populations—Information on SARS-CoV disease in pediatric
patients is limited. During the global outbreaks of 2003, infants and children
accounted for only a small percentage of cases and had a much milder disease and
better outcome than adults. Their role in transmission is not well described but is
likely much less significant than the role of adults. Therefore, in the setting of no
person-to-person SARS-CoV transmission in the world, the evaluation and man-
agement algorithm applies only to adults, unless there are special circumstances
that make the clinical and health department consider a child to be of potentially
high risk for having SARS-CoV disease.

FIGURE C-1 Evaluation and management of patients requiring hospitalization for radio-
graphically confirmed pneumonia, in the absence of person-to-person transmission of
SARS-CoV in the world
1Or acute respiratory distress syndrome (ARDS) of unknown etiology

2Guidance for the management of community-acquired pneumonia is available from the Infectious
Diseases Society of America (IDSA) at: www.journals.uchicago.edu/IDSA/guidelines/.
3The 2003 SARS-CoV outbreak likely originated in mainland China, and neighboring areas such as
Taiwan and Hong Kong are thought to be at higher risk due to the high volume of travelers from
mainland China. Although less likely, SARS-CoV may also reappear from other previously affected
areas. Therefore, clinicians should obtain a complete travel history. If clinicians have concerns about
the possibility of SARS-CoV disease in a patient with a history of travel to other previously affected
areas (e.g., while traveling abroad, had close contact with another person with pneumonia of unknown
etiology or spent time in a hospital in which patients with acute respiratory disease were treated), they
should contact the health department.

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WHO. WHO post-outbreak biosafety guidelines for handling of SARS-CoV
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Wilder-Smith A, Paton NI, Goh KT. 2003. Experience of severe acute respiratory
syndrome in Singapore: importation of cases, and defense strategies at the
airport. Journal of Travel Medicine. 10(5):259-62.
LAW, GOVERNMENT, AND ETHICS

Bernstein M. 2003. SARS and ethics. Hospital Quarterly. 7(1):38-40.
CDC. 2004. SARS: Community containment, including quarantine. Web Page.
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CDC. 2004. SARS: Legal authorities for isolation and quarantine. Web Page.
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Fidler DP. 2003. Emerging trends in international law concerning global
infectious disease control. Emerging Infectious Diseases [serial online]
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Gostin LO, Bayer R, Fairchild AL. 2003. Ethical and legal challenges posed by
severe acute respiratory syndrome: implications for the control of severe in-
fectious disease threats. JAMA. 290(24):3229-37.
Hopkins RS, Misegades L, Ransom J, Lipson L, Brink EW. 2004. SARS pre-
paredness checklist for state and local health officials. Emerging Infectious
Diseases [serial online]. 10(2). Available at: http://www.cdc.gov/ncidod/
EID/vol10no2/03-0729.htm.

Misrahi JJ, Foster JA, Shaw FE, Cetron MS. 2004. HHS/CDC legal response to
SARS outbreak. Emerging Infectious Diseases [serial online]. 10(2). Avail-
Parashar UD, Anderson LJ. 2004. SARS preparedness and response. Emerging
Richards EP, Rathburn KC. 2004. Making state public health laws work for SARS
outbreaks. Emerging Infectious Diseases [serial online]. 10(2). Available at:
Rothstein, MA, Alcalde, MG, Elster, NR, Majumder, MA, Palmer, LI, Stone,
TH, and Hoffman, RE. 2003. Quarantine and isolation: Lessons learned from
SARS. A report to the Centers for Disease Control and Prevention. Web
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Singer PA, Benatar SR, Bernstein M, Daar AS, Dickens BM, MacRae SK, Upshur
RE, Wright L, Shaul RZ. 2003. Ethics and SARS: lessons from Toronto.
BMJ. 327( 7427):1342-4.
COMMUNICATION WITH THE PUBLIC

Arguin PM, Navin AW, Steele SF, Weld LH, Kozarsky PE. 2004. SARS travel
alerts and advice. Emerging Infectious Diseases [serial online] 10(2). Avail-
Lau JT, Yang X, Tsui H, Kim JH. 2003. Monitoring community responses to the
SARS epidemic in Hong Kong: from day 10 to day 62. Journal of Epidemi-
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Leung GM, Lam TH, Ho LM, Ho SY, Chan BH, Wong IO, Hedley AJ. 2003. The
impact of community psychological responses on outbreak control for severe
acute respiratory syndrome in Hong Kong. Journal of Epidemiology & Com-
munity Health. 57(11):857-63.
Person B, Sy F, Holton K, Govert B, Liang A, NCID/SARS Emergency Outreach
Team. 2004. Fear and stigma: the epidemic within the SARS outbreak.
Quah SR, Lee H-P. 2004. Crisis prevention and management during SARS out-
break, Singapore. Emerging Infectious Diseases [serial online]. 10(2). Avail-
CLINICAL FEATURES AND PATHOLOGY

Antonio GE, Wong KT, Chu WC, Hui DS, Cheng FW, Yuen EH, Chung SS, Fok
TF, Sung JJ, Ahuja AT. 2003. Imaging in severe acute respiratory syndrome
(SARS). Clinical Radiology. 58(11):825-32.

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Avendano M, Derkach P, Swan S. 2003. Clinical course and management of

SARS in health care workers in Toronto: a case series. Canadian Medical
Association Journal. 168(13):1649-60.
Babyn PS, Chu WC, Tsou IY, Wansaicheong GK, Allen U, Bitnun A, Chee TS,
Cheng FW, Chiu MC, Fok TF, Hon EK, Gahunia HK, Kaw GJ, Khong PL,
Leung CW, Li AM, Manson D, Metreweli C, Ng PC, Read S, Stringer DA.
2004. Severe acute respiratory syndrome (SARS): chest radiographic fea-
tures in children. Pediatric Radiology. 34(1):47-58.
Beijing Group of National Research Project for SARS. 2003. Dynamic changes
in blood cytokine levels as clinical indicators in severe acute respiratory syn-
drome. Chinese Medical Journal. 116(9):1283-7.
Chan MS, Chan IY, Fung KH, Poon E, Yam LY, Lau KY. 2004. High-resolution
ct findings in patients with severe acute respiratory syndrome: a pattern-
based approach. American Journal of Roentgenology. 182(1):49-56.
Chao CC, Tsai LK, Chiou YH, Tseng MT, Hsieh ST, Chang SC, Chang YC.
2003. Peripheral nerve disease in SARS: report of a case. Neurology. 61(12):
1820-1.
Chen SY, Chiang WC, Ma MH, Su CP, Hsu CY, Chow-In Ko P, Tsai KC, Yen
ZS, Shih FY, Chen SC, Lin SJ, Wang JL, Chang SC, Chen WJ. 2004. Se-
quential symptomatic analysis in probable severe acute respiratory syndrome
cases. Annals of Emergency Medicine. 43(1):27-33.
Choi KW, Chau TN, Tsang O, Tso E, Chiu MC, Tong WL, Lee PO, Ng TK, Ng
WF, Lee KC, Lam W, Yu WC, Lai JY, Lai ST, Princess Margaret Hospital
SARS Study Group. 2003. Outcomes and prognostic factors in 267 patients
with severe acute respiratory syndrome in Hong Kong. Annals of Internal
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Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, Lu
Y, Wu D, He L, Yao K . 2003. The clinical pathology of severe acute respi-
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282-9.
Fowler RA, Lapinsky SE, Hallett D, Detsky AS, Sibbald WJ, Slutsky AS, Stewart
TE, Toronto SARS Critical Care Group. 2003. Critically ill patients with
severe acute respiratory syndrome. JAMA. 290(3):367-73.
Franks TJ, Chong PY, Chui P, Galvin JR, Lourens RM, Reid AH, Selbs E,
McEvoy CP, Hayden CD, Fukuoka J, Taubenberger JK, Travis WD. 2003.
Lung pathology of severe acute respiratory syndrome (SARS): a study of 8
autopsy cases from Singapore. Human Pathology. 34(8):743-8.
Grinblat L, Shulman H, Glickman A, Matukas L, Paul N. 2003. Severe acute
respiratory syndrome: radiographic review of 40 probable cases in Toronto,
Canada. Radiology. 228(3):802-9.
Jang TN, Yeh DY, Shen SH, Huang CH, Jiang JS, Kao SJ. 2004. Severe acute
respiratory syndrome in Taiwan: analysis of epidemiological characteristics
in 29 cases. Journal of Infection. 48(1):23-31.

Lang ZW, Zhang LJ, Zhang SJ, Meng X, Li JQ, Song CZ, Sun L, Zhou YS,
Dwyer D. 2003. A clinicopathological study of three cases of severe acute
respiratory syndrome (SARS). Pathology. 35(6):526-31.
Lau K-K, Yu W-C, Chu C-M, Lau S-T, Sheng B, Yuen K-Y. 2004. Possible
central nervous system infection by SARS coronavirus. Emerging Infectious
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Leung TF, Wong GW, Hon KL, Fok TF. 2003. Severe acute respiratory syn-
drome (SARS) in children: epidemiology, presentation and management.
Paediatric Respiratory Reviews. 4(4):334-9.
Leung WK, To KF, Chan PK, Chan HL, Wu AK, Lee N, Yuen KY, Sung JJ.
2003. Enteric involvement of severe acute respiratory syndrome-associated
coronavirus infection. Gastroenterology. 125(4):1011-7.
Lew TW, Kwek TK, Tai D, Earnest A, Loo S, Singh K, Kwan KM, Chan Y, Yim
CF, Bek SL, Kor AC, Yap WS, Chelliah YR, Lai YC, Goh SK. 2003. Acute
respiratory distress syndrome in critically ill patients with severe acute respi-
ratory syndrome. JAMA. 290(3):374-80.
Li SS, Cheng CW, Fu CL, Chan YH, Lee MP, Chan JW, Yiu SF. 2003. Left
ventricular performance in patients with severe acute respiratory syndrome:
a 30-day echocardiographic follow-up study. Circulation. 108(15):1798-803.
Li T, Qiu Z, Han Y, Wang Z, Fan H, Lu W, Xie J, Ma X, Wang A. 2003. Rapid
loss of both CD4+ and CD8+ T lymphocyte subsets during the acute phase of
severe acute respiratory syndrome. Chinese Medical Journal. 116(7):985-7.
Li Z, Guo X, Hao W, Wu Y, Ji Y, Zhao Y, Liu F, Xie X. 2003. The relationship
between serum interleukins and T-lymphocyte subsets in patients with se-
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Manocha S, Walley KR, Russell JA. 2003. Severe acute respiratory distress syn-
drome (SARS): a critical care perspective. Critical Care Medicine. 31(11):
2684-92.
Ooi CG, Khong PL, Lam B, Ho JC, Yiu WC, Wong WM, Wang T, Ho PL, Wong
PC, Chan RH, Lam WK, Lai KN, Tsang KW. 2003. Severe acute respiratory
syndrome: relationship between radiologic and clinical parameters. Radiol-
ogy. 229(2):492-9.
Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS,
Hon TY, Chan CS, Chan KH, Ng JS, Zheng BJ, Ng WL, Lai RW, Guan Y,
Yuen KY, HKU/UCH SARS Study Group. 2003. Clinical progression and
viral load in a community outbreak of coronavirus-associated SARS pneu-
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Robertson CA, Lowther SA, Birch T, Tan C, Sorhage F, Stockman L, et al. 2004.
SARS and pregnancy: a case report. Emerging Infectious Diseases [serial
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Tan T, Tan B, Kurup A, Oon L, Heng D, Se Thoe S, et al. 2004. SARS and
Escherichia coli bacteremia. Emerging Infectious Diseases [serial online].
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Tee AKH, Oh HML, Hui KP, Lien CTC, Narendran K, Heng BH, et al. 2004.
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Tiwari A, Chan S, Wong A, Tai J, Cheng K, Chan J, Tsang K, Nursing Task
Force on Anti-SARS of Queen Mary Hospital. 2003. Severe acute respira-
tory syndrome (SARS) in Hong Kong: patients’ experiences. Nursing Out-
look. 51(5):212-9.
Tsang O, Chau T, Choi K, Tso E, Lim W, Chiu M, Tong W, Lee P, Lam B, Ng T,
Lai J, Yu W, Lai S. 2003. Coronavirus-positive nasopharyngeal aspirate as
predictor for severe acute respiratory syndrome mortality. Emerging Infec-
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Tsui PT, Kwok ML, Yuen H, Lai ST. 2003. Severe acute respiratory syndrome:
clinical outcome and prognostic correlates. Emerging Infectious Diseases
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Vu HT, Leitmeyer KC, Le DH, Miller MJ, Nguyen QH, Uyeki TM, et al. 2004.
Clinical description of a completed outbreak of severe acute respiratory syn-
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Wong KT, Antonio GE, Hui DS, Lee N, Yuen EH, Wu A, Leung CB, Rainer TH,
Cameron P, Chung SS , Sung JJ, Ahuja AT. 2003. Severe acute respiratory
syndrome: radiographic appearances and pattern of progression in 138 pa-
tients. Radiology. 228(2):401-6.
Wong KT, Antonio GE, Hui DS, Lee N, Yuen EH, Wu A, Leung CB, Rainer TH,
Cameron P, Chung SS , Sung JJ, Ahuja AT. 2003. Thin-section CT of severe
acute respiratory syndrome: evaluation of 73 patients exposed to or with the
disease. Radiology. 228(2):395-400.
Wong PN, Mak SK, Lo KY, Tong GM, Wong Y, Watt CL, Wong AK. 2003.
Clinical presentation and outcome of severe acute respiratory syndrome in
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Wong RS, Wu A, To KF, Lee N, Lam CW, Wong CK, Chan PK, Ng MH, Yu
LM, Hui DS, Tam JS, Cheng G, Sung JJ. 2003. Haematological manifesta-
tions in patients with severe acute respiratory syndrome: retrospective analy-
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Yang G-G, Lin S-Z, Liao K-W, Lee J-J, Wang L-S. 2004. SARS-associated
coronavirus infection in teenagers. Emerging Infectious Diseases [serial
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DIAGNOSIS AND DETECTION OF THE SARS CORONAVIRUS

CDC. SARS: Evaluation and diagnosis. 2004. Web Page. Available at: http://
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Chan KH, Poon LLLM, Cheng VCC, Guan Y, Hung IFN, Kong J, et al. 2004.
Detection of SARS coronavirus in patients with suspected SARS. Emerging
Chong PY, Chui P, Ling AE, Franks TJ, Tai DY, Leo YS, Kaw GJ, Wansaicheong
G, Chan KP, Ean Oon LL, Teo ES, Tan KB, Nakajima N, Sata T, Travis
WD. 2004. Analysis of deaths during the severe acute respiratory syndrome
(SARS) epidemic in Singapore: challenges in determining a SARS diagno-
sis. Archives of Pathology & Laboratory Medicine. 128 (2):195-204.
Emery SL, Erdman DD, Bowen MD, Newton BR, Winchell JM, Meyer RF, et al.
2004. Real-time reverse transcription–polymerase chain reaction assay for
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Hui JY, Hon TY, Yang MK, Cho DH, Luk WH, Chan RY, Chan KS, Loke TK,
Chan JC. 2004. High-resolution computed tomography is useful for early
diagnosis of severe acute respiratory syndrome-associated coronavirus pneu-
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sisted Tomography. 28(1):1-9.
Jiang SS, Chen TC, Yang JY, Hsiung CA, Su IJ, Liu YL, Chen PC, Juang JL.
2004. Sensitive and quantitative detection of severe acute respiratory syn-
drome coronavirus infection by real-time nested polymerase chain reaction.
Clinical Infectious Diseases. 38(2):293-6.
Lau LT, Fung YW, Wong FP, Lin SS, Wang CR, Li HL, Dillon N, Collins RA,
Tam JS, Chan PK, Wang CG, Yu AC. 2003. A real-time PCR for SARS-
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Mazzulli T, Farcas GA, Poutanen SM, Willey BM, Low DE, Butany J, Asa SL,
Kain KC. 2004. Severe acute respiratory syndrome-associated coronavirus
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Ng EK, Hui DS, Chan KC, Hung EC, Chiu RW, Lee N, Wu A, Chim SS, Tong YK,
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vere acute respiratory syndrome. Clinical Chemistry. 49(12):1976-80.

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Poon LL, Chan KH, Wong OK, Cheung TK, Ng I, Zheng B, Seto WH, Yuen KY,
Guan Y, Peiris JS. 2004. Detection of SARS coronavirus in patients with
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Shi Y, Yi Y, Li P, Kuang T, Li L, Dong M, Ma Q, Cao C. 2003. Diagnosis of
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Tang P, Louie M, Richardson SE, Smieja M, Simor AE, Jamieson F, Fearon M,
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Dick D, Grolla A, Fernando L, Booth TF, Henry B, Rachlis AR, Matukas
LM, Rose DB, Lovinsky R , Walmsley S, Gold WL, Krajden S, The Ontario
Laboratory Working Group for the Rapid Diagnosis of Emerging Infections.
2004. Interpretation of diagnostic laboratory tests for severe acute respira-
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Wu HS, Chiu SC, Tseng TC, Lin SF, Lin JH, Hsu YF, et al. 2004. Serologic and
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Wu HS, Hsieh YC, Su IJ, Lin TH, Chiu SC, Hsu YF, Lin JH, Wang MC, Chen
JY, Hsiao PW, Chang GD, Wang AH, Ting HW, Chou CM, Huang CJ. 2004.
Early detection of antibodies against various structural proteins of the SARS-
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Zhai J, Briese T, Dai E, Wang X, Pang X, Du Z. 2004. Real-time polymerase
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Zhang J, Meng B, Liao D, Zhou L, Zhang X, Chen L, Guo Z, Peng C, Zhu B, Lee
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THERAPEUTICS
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. 2003.
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De Groot AS. 2003. How the SARS vaccine effort can learn from HIV: speeding
towards the future, learning from the past. Vaccine. 21(27-30):4095-104.
Ho JC, Ooi GC, Mok TY, Chan JW, Hung I, Lam B, Wong PC, Li PC, Ho PL,
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Knowles SR, Phillips EJ, Dresser L, Matukas L. 2003. Common adverse events
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MOLECULAR AND CELLULAR BIOLOGY

Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. 2003. Coronavirus
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Chou KC, Wei DQ, Zhong WZ. 2003. Binding mechanism of coronavirus main
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Fan K, Wei P, Feng Q, Chen S, Huang C, Ma L, Lai B , Pei J, Liu Y, Chen J, Lai
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Tanner JA, Watt RM, Chai YB, Lu LY, Lin MC, Peiris JS, Poon LL, Kung HF,
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Zhang R, Guo Z, Lu J, Meng J, Zhou C, Zhan X, Huang B, Yu X, Huang M, Pan
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GENOMICS
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Appendix E
Glossary and Acronyms
GLOSSARY
Adenovirus any of a family (Adenoviridae) of DNA viruses shaped like a 20-
sided polyhedron, originally identified in human adenoid tissue, causing respira-
tory diseases (as catarrh), and including some capable of inducing malignant tu-
mors in experimental animals.
Aerosolize to disperse (as a medicine, bactericide, or insecticide) as an aerosol.
Agalactia the failure of the secretion of milk from any cause other than the nor-
mal ending of the lactation period.
Agent any power, principle, or substance capable of producing an effect, whether

chemical, physical, or biological.
AIDS acquired immunodeficiency syndrome, the end stage of HIV disease.
Airborne the dissemination of microbial agents through a suitable portal of en-

try, usually the respiratory tract. Microbial aerosols are suspensions of particles
in the air consisting partially or wholly of microorganisms.
Algae a plant or plantlike organism of any of several phyla, divisions, or classes

of chiefly aquatic usually chlorophyll-containing nonvascular organisms of poly-
phyletic origin that usually include the green, yellow-green, brown, and red algae
in the eukaryotes and the blue-green algae in the prokaryotes.
324

APPENDIX E 325
Aminopeptidase an enzyme (as one found in the duodenum) that hydrolyzes

peptides by acting on the peptide bond next to a terminal amino acid containing a
free amino group.
Angiotensin either of two forms of a kinin of which one has marked physiologi-
cal activity and the other is its physiologically inactive precursor; a synthetic
amide derivative of angiotensin II used to treat some forms of hypotension.
Antibiotic chemical substance produced by a microorganism which has the ca-

pacity to inhibit the growth of or to kill other microorganisms; antibiotics that are
nontoxic to the host are used as chemotherapeutic agents in the treatment of in-
fectious diseases.
Antibody a protein produced by the immune system in response to the introduction

of a substance (an antigen) recognized as foreign by the body’s immune system.
Antibody interacts with the other components of the immune system and can render
the antigen harmless, although for various reasons this may not always occur.
Antigen a usually protein or carbohydrate substance (as a toxin or enzyme) ca-

pable of stimulating an immune response.
Antimicrobial a drug for killing microorganisms or suppressing their multiplica-

tion or growth. For the purposes of this report, antimicrobials include antibiotics
and antivirals.
Antiretroviral substance that stops or suppresses the activity of a retrovirus such

as HIV.
Antiviral drugs, including interferon, which stimulate cellular defenses against

viruses, reducing cell DNA synthesis and making cells more resistant to viral
genes, enhancing cellular immune responses or suppressing their replication.
Asymptomatic presenting no symptoms of disease.
Atypical pneumonia any of a group of pneumonias (as Q fever and psittacosis)

caused especially by a virus, mycoplasma, rickettsia, or Chlamydia.
Autophagy digestion of cellular constituents by enzymes of the same cell.
Avian influenza any of several highly variable diseases of domestic and wild
birds that are caused by orthomyxoviruses and characterized usually by respira-
tory symptoms but sometimes by gastrointestinal, integumentary, and urogenital
symptoms.

Bioinformatics the collection, classification, storage, and analysis of biochemi-

cal and biological information using computers especially as applied in molecu-
lar genetics and genomics.
Biomedical of, relating to, or involving biological, medical, and physical

science.
Biomolecule an organic molecule and especially a macromolecule (as a protein

or nucleic acid) in living organisms.
Biosafety safety with respect to the effects of biological research on humans and
the environment.
Biotechnology applied biological science (as bioengineering or recombinant

DNA technology).
Bioterrorism terrorism involving use of biological warfare agents (as disease-

causing viruses or herbicides).
Bronchodilator relating to or causing expansion of the bronchial air passages.
Bronchoscopy the use of a bronchoscope in the examination or treatment of the

bronchi.
Cholera any of several diseases of humans and domestic animals usually marked
by severe gastrointestinal symptoms: as a: an acute diarrheal disease caused by
an enterotoxin produced by a comma-shaped gram-negative bacillus of the genus
Vibrio (V. cholerae syn. V. comma) when it is present in large numbers in the
proximal part of the human small intestine.
Cloaca the common chamber into which the intestinal, urinary, and generative
canals discharge especially in monotreme mammals, birds, reptiles, amphibians,
and elasmobranch fishes b: the terminal part of the embryonic hindgut of a mam-
mal before it divides into rectum, bladder, and genital precursors; a passage in a
bone leading to a cavity containing a sequestrum.
Colostrum milk secreted for a few days after parturition and characterized by
high protein and antibody content.
Combinatorial chemistry a branch of applied chemistry concerned with the rapid

synthesis and screening of large numbers of different but related chemical com-
pounds generated from a mixture of known building blocks in order to recover
new substances optimally suited for a specific function.

APPENDIX E 327
Communicable disease an infectious disease transmissible (as from person to

person) by direct contact with an affected individual or the individual’s discharges
or by indirect means (as by a vector).
Computational chemistry Computer-based modeling and prediction of the struc-

ture of chemical compounds most likely to bind a protein drug target. Known
properties are used to calculate properties of new molecules and energy minimi-
zation is used to adjust the structure.
Coronavirus any of a family (Coronaviridae) of single-stranded RNA viruses

that have a lipid envelope with club-shaped projections and include some causing
respiratory symptoms in humans.
Corticosteroid any of various adrenal-cortex steroids (as corticosterone, corti-

sone, and aldosterone) that are divided on the basis of their major biological
activity into glucocorticoids and mineralocorticoids.
Cysteine a sulfur-containing amino acid C3H7NO2S occurring in many proteins

and glutathione and readily oxidizable to cystine.
Cytokine any of a class of immunoregulatory proteins (as interleukin, tumor ne-

crosis factor, and interferon) that are secreted by cells especially of the immune
system.
Cytopathic of, relating to, characterized by, or producing pathological changes

in cells.
Cytotoxic toxic to cells.
Dexamethasone a synthetic glucocorticoid C22H29FO5 used especially as an anti-

inflammatory and antiallergic agent.
Diphtheria an acute febrile contagious disease marked by the formation of a

false membrane especially in the throat and caused by a bacterium of the genus
Corynebacterium (C. diphtheriae) which produces a toxin causing inflammation
of the heart and nervous system.
Dyspnea difficult or labored respiration.
Ebola the hemorrhagic fever caused by the Ebola virus.
E. Coli a straight rod-shaped gram-negative bacterium (Escherichia coli of the

family Enterobacteriaceae) that is used in public health as an indicator of fecal

pollution (as of water or food) and in medicine and genetics as a research organ-
ism and that occurs in various strains that may live as harmless inhabitants of the
human lower intestine or may produce a toxin causing intestinal illness.
Enteric of, relating to, or affecting the intestines.
Enterovirus any of a genus (Enterovirus) of picornaviruses (as the causative

agent of poliomyelitis) that typically occur in the gastrointestinal tract but may be
involved in respiratory ailments, meningitis, and neurological disorders.
Epidemic the occurrence in a community or region of cases of an illness (or

outbreak) with a frequency clearly in excess of normal expectancy.
Epidemiology branch of science that deals with the incidence, distribution, and
control of disease in a population; the sum of the factors controlling the presence
or abundance of a disease or pathogen.
Epithelial of or relating to a membranous cellular tissue that covers a free surface

or lines a tube or cavity of an animal body and serves especially to enclose and
protect the other parts of the body, to produce secretions and excretions, and to
function in assimilation.
Etiology a branch of medical science dealing with the causes and origin of diseases.
Exonuclease an enzyme that breaks down a nucleic acid by removing nucle-

otides one by one from the end of a chain.
Fomite an inanimate object (as a dish, toy, book, doorknob, or clothing) that may
be contaminated with infectious organisms and serve in their transmission.
Fungus any of the major group Fungi of saprophytic and parasitic spore-produc-
ing organisms that lack chlorophyll, are often considered to be plants, and include
the ascomyetes, basidiomycetes, phycomycetes, imperfect fungi, and slime molds.
Gastroenteritis inflammation of the lining membrane of the stomach and the intestines.
Glycoprotein a conjugated protein in which the nonprotein group is a carbohy-

drate.
Gnotobiotic of, relating to, living in, or being a controlled environment contain-
ing one or a few kinds of organisms ; free from other living organisms.
Gross Domestic Product measures the output produced by factors of production

located in the domestic country regardless of who owns these factors.

APPENDIX E 329
Guillain-Barré syndrome French neurologists. Guillain published several sig-

nificant neurological studies concerning the brain and the spinal column. An au-
thority on the spinal column in particular, he made studies of the cerebrospinal
fluid and the marrow of the spinal cord. Guillain and Barré published their de-
scription of the Guillain-Barré syndrome in 1916.
Hantavirus any of a genus (Hantavirus) of bunyaviruses (as the Hantaan virus)

that are transmitted by rodent feces and urine and cause hantavirus pulmonary
syndrome and hemorrhagic fevers marked by renal necrosis.
Hemagglutinin a molecule, such as an antibody or lectin, that agglutinates red

blood cells.
Hemorrhagic fever an acute destructive disease of warm regions marked by

sudden onset, prostration, fever, albuminuria, jaundice, and often hemorrhage
and caused by a flavivirus (genus Flavivirus) transmitted especially by a mos-
quito of the genus Aedes (A. aegypti).
Heterologous derived from a different species; characterized by cross-reactivity.
HIV disease the broad spectrum of opportunistic infections and diseases that
occur in an individual infected with the human immunodeficiency virus.
Human metapneumovirus a respiratory viral pathogen that causes a spectrum

of illnesses, ranging from asymptomatic infection to severe bronchiolitis.
Hyperplasia an abnormal or unusual increase in the elements composing a part

(as cells composing a tissue).
Immunoassay a technique or test (as the enzyme-linked immunosorbent assay)

used to detect the presence or quantity of a substance (as a protein) based on its
capacity to act as an antigen or antibody.
Immunocompromised a condition (caused, for example, by the administration

of immunosuppressive drugs or irradiation, malnutrition, aging, or a condition
such as cancer or HIV disease) in which an individual’s immune system is unable
to respond adequately to a foreign substance.
Immunofluorescence the labeling of antibodies or antigens with fluorescent dyes

especially for the purpose of demonstrating the presence of a particular antigen or
antibody in a tissue preparation or smear.
Immunology a science that deals with the immune system and the cell-mediated
and humoral aspects of immunity and immune responses.

Immunopathology a branch of medicine that deals with immune responses asso-

ciated with disease; the pathology of an organism, organ system, or disease with
respect to the immune system, immunity, and immune responses.
Immunosuppression the retardation or cessation of an immune response as a

result of, for example, anticancer drugs.
Index case an instance of a disease or a genetically determined condition that is

discovered first and leads to the discovery of others in a family or population.
Infectious capable of causing infection; communicable by invasion of the body

of a susceptible organism.
Infectious agent an organism (virus, rickettsia, bacteria, fungus, protozoan, or

helminth) that is capable of producing infection or infectious disease.
Influenza an acute highly contagious virus disease that is caused by various

strains of orthomyxoviruses belonging to three major types now considered as
three separate genera and that is characterized by sudden onset, fever, prostration,
severe aches and pains, and progressive inflammation of the respiratory mucous
membrane—often used with the letter A, B, or C to denote disease caused by a
virus of a specific one of the three genera; any human respiratory infection of
undetermined cause—not used technically; any of numerous febrile usually virus
diseases of domestic animals (as shipping fever of horses and swine influenza)
marked by respiratory symptoms, inflammation of mucous membranes, and often
systemic involvement.
Interstitial pneumonia any of several chronic lung diseases of unknown etiol-

ogy that affect interstitial tissues of the lung without filling of the alveolae and
that may follow damage to the alveolar walls or involve interstitial histological
changes.
Intubation the introduction of a tube into a hollow organ (as the trachea or intes-
tine) to keep it open or restore its patency if obstructed.
Irradiate to affect or treat by radiant energy (as heat); specifically to treat by

exposure to radiation (as ultraviolet light or gamma rays).
Lassa a disease especially of Africa that is caused by the Lassa virus and is
characterized by a high fever, headaches, mouth ulcers, muscle aches, small hem-
orrhages under the skin, heart and kidney failure, and a high mortality rate.
Lethal of, relating to, or causing death; capable of causing death.

APPENDIX E 331
Lymphoproliferative of or relating to the proliferation of lymphoid tissue.
Malaria an acute or chronic disease caused by the presence of sporozoan para-

sites of the genus Plasmodium in the red blood cells, transmitted from an infected
to an uninfected individual by the bite of anopheline mosquitoes, and character-
ized by periodic attacks of chills and fever that coincide with mass destruction of
blood cells and the release of toxic substances by the parasite at the end of each
reproductive cycle.
Mass spectrometry an instrumental method for identifying the chemical consti-

tution of a substance by means of the separation of gaseous ions according to
their differing mass and charge—called also mass spectroscopy.
Methyltransferase any of several transferases that promote transfer of a methyl

group from one compound to another.
Microbe any microorganism or biologic agent that can replicate in humans (in-
cluding bacteria, viruses, protozoa, fungi, and prions); in other usage, any multi-
cellular organism.
Microbiology a branch of biology dealing especially with microscopic forms of life.
Morbidity a diseased state or symptom; the incidence of disease : the rate of

sickness.
Mortality the quality or state of being mortal; the number of deaths in a given
time or place; the proportion of deaths to population.
Mutation a transmissible change in the genetic material of an organism, usually

in a single gene.
Nasopharyngeal of, relating to, or affecting the nose and pharynx or the na-
sopharynx.
Nebulise to reduce to a fine spray.
Neuraminidase a substance used (as in detecting or measuring a component, in

preparing a product, or in developing photographs) because of its chemical or
biological activity.
Nucleocapsid the nucleic acid and surrounding protein coat of a virus.
Nucleophile a nucleophilic substance (as an electron-donating reagent).

Oronasal of or relating to the mouth and nose; especially : connecting the mouth
and the nasal cavity.
Outbreak a sudden rise in the incidence of a disease.
Pandemic an epidemic that occurs worldwide.
Parainfluenza any of several paramyxoviruses (genus Paramyxovirus) that are

associated with or responsible for some respiratory infections especially in chil-
dren—called also parainfluenza.
Pathogen a specific causative agent (as a bacterium or virus) of disease.
Pathogenesis the origination and development of a disease.
Pathogenic capable of causing disease.
PCR see polymerase chain reaction.
Pericardium of, relating to, or affecting the conical sac of serous membrane that
encloses the heart and the roots of the great blood vessels of vertebrates and
consists of an outer fibrous coat that loosely invests the heart and is prolonged on
the outer surface of the great vessels except the inferior vena cava and a double
inner serous coat of which one layer is closely adherent to the heart while the
other lines the inner surface of the outer coat with the intervening space being
filled with pericardial fluid.
Peritoneal of, relating to, or affecting the smooth transparent serous mem-
brane that lines the cavity of the abdomen of a mammal, is folded inward over
the abdominal and pelvic viscera, and consists of an outer layer closely adher-
ent to the walls of the abdomen and an inner layer that folds to invest the
viscera.
Peroxidation the process of converting (a compound) into a peroxide for a chemi-

cal compound.
Pharmacopoeia a book describing drugs, chemicals, and medicinal preparations;

especially : one issued by an officially recognized authority and serving as a
standard; a collection or stock of drugs.
Pharyngeal relating to or located in the region of the pharynx; innervating the

pharynx especially by contributing to the formation of the pharyngeal plexus;
supplying or draining the pharynx.

APPENDIX E 333
Phenotype the visible properties of an organism that are produced by the interac-
tion of the genotype and the environment.
Phospholipid any of numerous lipids (as lecithins and sphingomyelin) in which

phosphoric acid as well as a fatty acid is esterified to glycerol and which are
found in all living cells and in the bilayers of plasma membranes.
Phylogenetic of or relating to the evolutionary development of organisms.
Physiochemical of or relating to physiological chemistry.
Picornavirus any of a family (Picornaviridae) of small single-stranded RNA vi-

ruses that have an icosahedral virion with no envelope and that include the en-
teroviruses, rhinoviruses, and the causative agents of hepatitis A, foot-and-mouth
disease, hand-foot-and-mouth disease, and encephalomyocarditis.
Plague an epidemic disease causing a high rate of mortality; a virulent conta-

gious febrile disease that is caused by a bacterium of the genus Yersinia (Y. pestis
syn. Pasteurella pestis), that occurs in bubonic, pneumonic, and septicemic forms,
and that is usually transmitted from rats to humans by the bite of infected fleas (as
in bubonic plague) or directly from person to person (as in pneumonic plague).
Pleural of or relating to the pleura or the sides of the thorax.
Pneumonia a disease of the lungs characterized by inflammation and consolida-

tion followed by resolution and caused by infection or irritants.
Polymerase chain reaction a laboratory method of amplifying low levels of spe-

cific microbial DNA or RNA sequences.
Polymicrobial of, relating to, or caused by several types of microorganisms.
Polypnea rapid or panting respiration.
Prophylactic guarding from or preventing the spread or occurrence of disease or

infection; tending to prevent or ward off.
Proteolytic of, relating to, or producing the hydrolysis of proteins or peptides

with formation of simpler and soluble products (as in digestion).
Public health the art and science of dealing with the protection and improvement
of community health by organized community effort and including preventive
medicine and sanitary and social health.

Quarantine the enforced isolation or restriction of free movement imposed to

prevent the spread a contagious disease.
Reagent a substance used (as in detecting or measuring a component, in prepar-

ing a product, or in developing photographs) because of its chemical or biological
activity.
Reovirus any of a family (Reoviridae) of double-stranded RNA viruses that have

an icosahedral structure, are 60 to 80 nanometers in diameter, have an inner core
surrounded by several layers of protein, and include many plant or animal patho-
gens (as the orbiviruses and the rotaviruses).
Respirator a device (as a gas mask) worn over the mouth or nose for protecting
the respiratory system; a device for maintaining artificial respiration.
Respiratory syncytial virus a paramyxovirus (genus Pneumovirus) that has nu-

merous strains, forms syncytia in tissue culture, and is responsible for severe
respiratory diseases (as bronchopneumonia and bronchiolitis) in children and es-
pecially in infants.
Retrovirus any of large family of RNA viruses that includes lentiviruses and
oncoviruses, so called because they carry reverse transcriptase.
Rhinitis inflammation of the mucous membrane of the nose.
Ribosome any of the RNA- and protein-rich cytoplasmic organelles that are sites
of protein synthesis.
Serological the use of immune serum in any number of tests (agglutination, pre-
cipitation, enzyme-linked immunosorbent assay, etc.) used to measure the re-
sponse (antibody titer) to infectious disease; the use of serological reactions to
detect antigen.
Serology a science dealing with serums and especially their reactions and proper-
ties.
Seronegative negative result in a serological test; that is, the inability to detect
the antibodies or antigens being tested for.
Seropositive positive results in a serological test.
Seroprevalence the frequency of individuals in a population that have a particu-

lar element (as antibodies to HIV) in their blood serum.

APPENDIX E 335
Serotype the characterization of a microorganism based on the kinds and combi-

nations of constituent antigens present in that organism; a taxonomic subdivision
of bacteria based on the above.
Smallpox an acute contagious febrile disease characterized by skin eruption with

pustules, sloughing, and scar formation and caused by a poxvirus (genus
Orthopoxvirus) that is believed to exist now only in lab cultures.
Superspreader highly infective patient.
Syncytial of, relating to, or constituting a multinucleate mass of protoplasm (as

in the plasmodium of a slime mold) resulting from fusion of cells.
Thrombosis the formation or presence of a blood clot within a blood vessel during life.
Transmissible capable of being transmitted (as from one person to another).
Tropism involuntary orientation by an organism or one of its parts that involves

turning or curving by movement or by differential growth and is a positive or
negative response to a source of stimulation.
Tuberculosis a usually chronic highly variable disease that is caused by the tu-
bercle bacillus and rarely in the U.S. by a related mycobacterium (Mycobacte-
rium bovis), is usually communicated by inhalation of the airborne causative
agent, affects especially the lungs but may spread to other areas (as the kidney or
spinal column) from local lesions or by way of the lymph or blood vessels, and is
characterized by fever, cough, difficulty in breathing, inflammatory infiltrations,
formation of tubercles, caseation, pleural effusion, and fibrosis.
Vaccine a preparation of purified polypeptide, protein or polysaccharide, or DNA

or of killed microorganisms, living attenuated organisms, or living virulent or
crude or purified organisms that is administered to produce or artificially in crease
immunity to a particular disease.
Viremia the presence of virus in the blood of a host.
Virology a branch of science that deals with viruses.
Virulence the degree of pathogenicity of an organism as evidenced by the sever-

ity of resulting disease and the organisms’s ability to invade the host tissues.
West Nile virus a flavivirus (genus Flavivirus) that causes an illness marked by
fever, headache, muscle ache, skin rash, and sometimes encephalitis or meningi-

tis, that is spread chiefly by mosquitoes, and that is closely related to the viruses
causing Japanese B encephalitis and Saint Louis encephalitis.
Westphalian system “westphalian public health” refers to public health gover-

nance structured by Westphalian principles. “Post-Westphalian public health”
describes public health governance that departs from the Westphalian template
Yellow fever an acute destructive disease of warm regions marked by sudden

onset, prostration, fever, albuminuria, jaundice, and often hemorrhage and caused
by a flavivirus (genus Flavivirus) transmitted especially by a mosquito of the
genus Aedes (A. aegypti).
Zoonotic a disease communicable from animals to humans under natural conditions.
ACRONYMS
3CL 3C-like
ACH air changes per hour

AG access grid
AIDS acquired immunodeficiency syndrome
AMRO/PAHO WHO Regional Office for the Americas
APEC Asian Pacific Economic Community
ASEAN Association of Southeast Asian Nations
ASTM American Society for Testing and Materials
ATP air transport
BCoV bovine coronavirus

BiPAP bi-level positive airway pressure
BSL biosafety laboratory
CBER Center for Biologics Evaluation and Research

CDC Centers for Disease Control and Prevention
cDNA complementary DNA
CEACAM carcino-embryonic antigen-cell adhesion molecule
CIA Central Intelligence Agency
CNS central nervous system
CoV coronavirus
CSR Department of Communicable Disease
Surveillance and Response
DARPA Defense Advanced Research Projects Agency

DHHS Department of Health and Human Services

APPENDIX E 337
DMEM Dulbeco’s Modified Eagle Medium

DNA deoxyribonucleic acid
EINET Emerging Infections Network

EPA Environmental Protection Agency
ERGIC endoplasmic-reticulum-golgi-intermediate compartment
FAO Food and Agriculture Organization

FASS FailSafe Air Safety Systems
FDA Food and Drug Administration
FCoV Group I Feline CoV
FDI foreign direct investment
FECoV feline enteric peritonitis virus
FIPV feline infectious peritonitis virus
GDP gross domestic product

GHG global health governance
GOARN Global Alert and Response Network
GPGH global public goods for health
GPHIN Global Public Health Information Network
HAART Highly Active Antiretroviral Therapy

HEPA high efficiency particulate air
HIV human immunodeficiency virus
IBV infectious bronchitis virus
ICA intelligence community assessment

IHR International Health Regulations
IOM Institute of Medicine
ITU International Telecommunications Union
JCAHO Joint Commission on Accreditation of Health Care

Organizations
LPS lipopolysaccharides
MAbs monoclonal antibodies

MHV mouse hepatitis virus
MoH Ministry of Health
NGO nongovernmental organization

NIAID National Institute for Allergy and Infectious Diseases
NIC National Intelligence Council

NIH National Institutes of Health

NIOSH National Institute for Occupational Safety and Health
OECD Organization for Economic Cooperation and Development

OIE Office International des Epizooties
OSHA Occupational Safety and Health Administration
OTP land transport
PCR polymerase chain reaction

PRCV porcine respiratory coronavirus
PEDV porcine epidemic diarrhea CoV
PHE public health emergency
PRCV porcine respiratory coronavirus
PROMED Program for Monitoring Emerging Diseases
RNA ribonucleic acid

RSV respiratory syncytial virus
RT-PCR reverse-transcription polymerase chain reaction
SAIC Science Applications International Corporation

SARS severe acute respiratory syndrome
SCoV severe acute respiratory syndrome coronavirus
SIV swine influenza virus
SRP signal recognition particle
TCID tissue culture infective dose

TGEV transmissible gastroenteritis virus
TIGER triangulation identification for genetic evaluation of risks
TRD hotels and restaurants
TRS transcriptional regulatory sequence
UNAIDS Joint United National Program on HIV/AIDS

USAMRIID United States Army Medical Research Institute for
Infectious Diseases
USDA United States Department of Agriculture
UV ultraviolet
UVGI ultraviolet germicidal irradiation
VN virus neutralization
WD winter dysentery
WHO World Health Organization
WPRO Western Pacific Regional Office of the World
Health Organization

Appendix F
Forum Member, Speaker, and

Staff Biographies
FORUM MEMBERS
ADEL A.F. MAHMOUD, M.D., Ph.D., (Chair), is President of Merck Vac-
cines at Merck & Co., Inc. He formerly served Case Western Reserve University
and University Hospitals of Cleveland as Chairman of Medicine and Physician-
in-Chief from 1987 to 1998. Prior to that, Dr. Mahmoud held several positions,
spanning 25 years, at the same institutions. Dr. Mahmoud and his colleagues
conducted pioneering investigations on the biology and function of eosinophils.
He prepared the first specific anti-eosinophil serum, which was used to define the
role of these cells in host resistance to helminthic infections. Dr. Mahmoud also
established clinical and laboratory investigations in several developing countries,
including Kenya, Egypt, and The Philippines, to examine the determinants of
infection and disease in schistosomiasis and other infectious agents. This work
led to the development of innovative strategies to control those infections, which
have been adopted by the World Health Organization (WHO) as selective popu-
lation chemotherapy. In recent years, Dr. Mahmoud turned his attention to devel-
oping a comprehensive set of responses to the problems associated with emerging
infections in the developing world. He was elected to membership of the Ameri-
can Society for Clinical Investigation in 1978, the Association of American Phy-
sicians in 1980, and the Institute of Medicine of the National Academy of Sci-
ences in 1987. He received the Bailey K. Ashford Award of the American Society
of Tropical Medicine and Hygiene in 1983, and the Squibb Award of the Infec-
tious Diseases Society of America in 1984. Dr. Mahmoud currently serves as
Chair of the Forum on Emerging Infections and is a member of the Board on
339

Global Health, both of the Institute of Medicine. He also chairs the U.S. Delega-
tion to the U.S.-Japan Cooperative Medical Science Program.
STANLEY M. LEMON, M.D., (Vice-Chair), is Dean of the School of Medicine

at the University of Texas Medical Branch at Galveston. He received his under-
graduate degree in biochemical sciences from Princeton University summa cum
laude, and his M.D. with honors from the University of Rochester. He completed
postgraduate training in internal medicine and infectious diseases at the Univer-
sity of North Carolina at Chapel Hill, and is board-certified in both. From 1977 to
1983, he served with the U.S. Army Medical Research and Development Com-
mand, directing the Hepatitis Laboratory at the Walter Reed Army Institute of
Research. He joined the faculty of the University of North Carolina School of
Medicine in 1983, serving first as Chief of the Division of Infectious Diseases,
and then Vice Chair for Research of the Department of Medicine. In 1997, Dr.
Lemon moved to the University of Texas Medical Branch as Professor and Chair
of the Department of Microbiology & Immunology. He was subsequently ap-
pointed Dean pro tem of the School of Medicine in 1999, and permanent Dean of
Medicine in 2000. Dr. Lemon’s research interests relate to the molecular virology
and pathogenesis of the positive-stranded RNA viruses responsible for hepatitis
C and hepatitis A. He is particularly interested in the molecular mechanisms con-
trolling replication of these RNA genomes and related mechanisms of disease
pathogenesis. He has published over 180 papers, and numerous textbook chapters
related to hepatitis and other viral infections, and has a longstanding interest in
vaccine development. He has served previously as chair of the Anti-Infective
Drugs Advisory Committee and the Vaccines and Related Biologics Advisory
Committee of the U.S. Food and Drug Administration, and is past chair of the
Steering Committee on Hepatitis and Poliomyelitis of WHO’s Programme on
Vaccine Development. He presently serves as Chairman of the U.S. Hepatitis
Panel of the U.S.-Japan Cooperative Medical Sciences Program, and recently
chaired an Institute of Medicine study committee related to vaccines for the pro-
tection of the military against naturally occurring infectious disease threats.
DAVID ACHESON, M.D., is Chief Medical Officer at the Center for Food
Safety and Applied Nutrition, U.S. Food and Drug Administration. He received
his medical degree at the University of London. After completing internships in
general surgery and medicine, he continued his postdoctoral training in Manches-
ter, England, as a Wellcome Trust Research Fellow. He subsequently was a
Wellcome Trust Training Fellow in Infectious Diseases at the New England Medi-
cal Center and at the Wellcome Research Unit in Vellore, India. Dr. Acheson was
Associate Professor of Medicine, Division of Geographic Medicine and Infec-
tious Diseases, New England Medical Center until 2001. He then joined the fac-
ulties of the Department of Epidemiology and Preventive Medicine and Depart-
ment of Microbiology and Immunology at the University of Maryland Medical

APPENDIX F 341
School. Currently at the FDA, his research concentration is on foodborne patho-

gens and encompasses a mixture of molecular pathogenesis, cell biology, and
epidemiology. Specifically, his research focuses on Shiga toxin-producing E. coli
and understanding toxin interaction with intestinal epithelial cells using tissue
culture models. His laboratory has also undertaken a study to examine Shiga
toxin-producing E. coli in food animals in relation to virulence factors and anti-
microbial resistance patterns. More recently, Dr. Acheson initiated a project to
understand the molecular pathogenesis of Campylobacter jejuni. Other studies
have undertaken surveillance of diarrheal disease in the community to determine
causes, outcomes, and risk factors of unexplained diarrhea. Dr. Acheson has
authored/coauthored over 72 journal articles, and 42 book chapters and reviews,
and is coauthor of the book Safe Eating (Dell Health, 1998). He is reviewer of
more than 10 journals and is on the editorial board of Infection and Immunity and
Clinical Infectious Diseases. Dr. Acheson is a Fellow of the Royal College of
Physicians, a Fellow of the Infectious Disease Society of America, and holds
several patents.
STEVEN J. BRICKNER, Ph.D., is Research Advisor, Antibacterials Chemis-

try, at Pfizer Global Research and Development. He received his Ph.D. in organic
chemistry from Cornell University and was a NIH Postdoctoral Research Fellow
at the University of Wisconsin–Madison. Dr. Brickner is a medicinal chemist
with nearly 20 years of research experience in the pharmaceutical industry, all
focused on the discovery and development of novel antibacterial agents. He is an
inventor/co-inventor on 21 U.S. patents, and has published numerous scientific
papers, primarily within the area of the oxazolidinones. Prior to joining Pfizer in
1996, he led a team at Pharmacia and Upjohn that discovered and developed
linezolid, the first member of a new class of antibiotics to be approved in the last
35 years.
NANCY CARTER-FOSTER, M.S.T.M., is Senior Advisor for Health Affairs

for the U.S. Department of State, Assistant Secretary for Science and Health and
the Secretary’s Representative on HIV/AIDS. She is responsible for identifying
emerging health issues and making policy recommendations for USG foreign
policy concerns regarding international health, and coordinates the Department’s
interactions with the non-governmental community. She is a member of the Na-
tional Academy of Sciences Institute of Medicine’s Forum on Infectious Dis-
eases, and a member of the Infectious Diseases Society of America (IDSA), and
the American Association of the Advancement of Science (AAAS). She has
helped bring focus to global health issues in U.S. foreign policy and brought a
national security focus to global health. In prior positions as Director for Con-
gressional and Legislative Affairs for the Economic and Business Affairs Bureau
of the U.S. Department of State, and Foreign Policy Advisory to the Majority
WHIP U.S. House of Representatives, Trade Specialist Advisor to the House of

Representatives Ways and Means Trade Subcommittee, and consultant to the

World Bank, Asia Technical Environment Division, Ms. Carter-Foster has worked
on a wide variety of health, trade and environmental issues amassing in-depth
knowledge and experience in policy development and program implementation.
GAIL H. CASSELL, Ph.D., is Vice President, Scientific Affairs, Distinguished

Lilly Research Scholar for Infectious Diseases, Eli Lilly & Company. Previously,
she was the Charles H. McCauley Professor and (since 1987) Chair, Department
of Microbiology, University of Alabama Schools of Medicine and Dentistry at
Birmingham, a department which, under her leadership, has ranked first in re-
search funding from the National Institutes of Health since 1989. She is a mem-
ber of the Director’s Advisory Committee of the Centers for Disease Control and
Prevention. Dr. Cassell is past president of the American Society for Microbiol-
ogy (ASM) and is serving her third 3-year term as chairman of the Public and
Scientific Affairs Board of ASM. She is a former member of the National Insti-
tutes of Health Director’s Advisory Committee and a former member of the Ad-
visory Council of the National Institute of Allergy and Infectious Diseases. She
has also served as an advisor on infectious diseases and indirect costs of research
to the White House Office on Science and Technology and was previously chair
of the Board of Scientific Counselors of the National Center for Infectious Dis-
eases, Centers for Disease Control and Prevention. Dr. Cassell served eight years
on the Bacteriology-Mycology-II Study Section and served as its chair for three
years. She serves on the editorial boards of several prestigious scientific journals
and has authored over 275 articles and book chapters. She has been intimately
involved in the establishment of science policy and legislation related to biomedi-
cal research and public health. Dr. Cassell has received several national and inter-
national awards and an honorary degree for her research on infectious diseases.
JESSE L. GOODMAN, M.D., M.P.H., was professor of medicine and Chief of

Infectious Diseases at the University of Minnesota, and is now serving as Deputy
Director for the U.S. Food and Drug Administration’s (FDA) Center for Biologics
Evaluation and Research, where he is active in a broad range of scientific, public
health, and policy issues. After joining the FDA commissioner’s office, he has
worked closely with several centers and helped coordinate FDA’s response to the
antimicrobial resistance problem. He was co-chair of a recently formed federal
interagency task force which developed the national Public Health Action Plan
on antimicrobial resistance. He graduated from Harvard College and attended the
Albert Einstein College of Medicine followed by internal medicine, hematology,
oncology, and infectious diseases training at the University of Pennsylvania and
University of California Los Angeles, where he was also chief medical resident.
He received his master’s of public health from the University of Minnesota. He
has been active in community public health activities, including creating an envi-
ronmental health partnership in St. Paul, Minnesota. In recent years, his

APPENDIX F 343
laboratory’s research has focused on the molecular pathogenesis of tickborne dis-

eases. His laboratory isolated the etiological intracellular agent of the emerging
tickborne infection, human granulocytic ehrlichiosis, and identified its leukocyte
receptor. He has also been an active clinician and teacher and has directed or
participated in major multicenter clinical studies. He is a Fellow of the Infectious
Diseases Society of America and, among several honors, has been elected to the
American Society for Clinical Investigation.
EDUARDO GOTUZZO, M.D., is Principal Professor and Director at the

Instituto de Medicina Tropical “Alexander von Humbolt,” Universidad Peruana
Cayetan Heredia (UPCH), in Lima, Peru. As well as Chief of the Department of
Infectious and Tropical Diseases at the Cayetano Heredia Hospital. As well as an
Adjunct Professor of Medicine at the University of Alabama-Birmingham School
of Medicine. Dr. Gotuzzo has proven to be an active member in numerous inter-
national societies such as President of the Latin America Society of Tropical
Disease (2000-2003), Member of the Scientific Program of Infectious Diseases
Society of America (2000-2003), Member of the International Organizing Com-
mittee of the International Congress of Infectious Diseases (1994-Present), Presi-
dent Elect of the International Society for Infectious Diseases (1996-1998), and
President of the Peruvian Society of Internal Medicine (1991-1992). He has pub-
lished over 230 articles and chapters as well as six manuals and one book. Recent
honors and awards include being named an Honorary member of American Soci-
ety of Tropical Medicine and Hygiene (since 2002), Associated Member of Na-
tional Academy of Medicine (since 2002), Honorary Member of Society of Inter-
nal Medicine (since 2000), Distinguished Visitor, Faculty of Medical Sciences,
University of Cordoba, Argentina (since 1999), and the Golden Medal for “Out-
standing Contribution in the field of Infectious Diseases,” awarded by the Trnava
University, Slovakia (1998), among many others.
MARGARET A. HAMBURG, M.D., is Vice President for Biological Programs

at Nuclear Threat Initiative (NTI), a charitable organization working to reduce
the global threat from nuclear, biological, and chemical weapons. Dr. Hamburg is
in charge of the biological program area. Before taking on her current position,
Dr. Hamburg was the Assistant Secretary for Planning and Evaluation, U.S. De-
partment of Health and Human Services, serving as a principal policy advisor to
the Secretary of Health and Human Services with responsibilities including policy
formulation and analysis, the development and review of regulations and/or leg-
islation, budget analysis, strategic planning, and the conduct and coordination of
policy research and program evaluation. Prior to this, she served for almost six
years as the Commissioner of Health for the City of New York. As chief health
officer in the nation’s largest city, Dr. Hamburg’s many accomplishments in-
cluded the design and implementation of an internationally recognized tuberculo-
sis control program that produced dramatic declines in tuberculosis cases; the

development of initiatives that raised childhood immunization rates to record lev-

els; and the creation of the first public health bioterrorism preparedness program
in the nation. She completed her internship and residency in Internal Medicine at
the New York Hospital/Cornell University Medical Center and is certified by the
American Board of Internal Medicine. Dr. Hamburg is a graduate of Harvard
College and Harvard Medical School. She currently serves on the Harvard Uni-
versity Board of Overseers. She has been elected to membership in the Institute
of Medicine, the New York Academy of Medicine, and the Council on Foreign
Relations, and is a Fellow of the American Association for the Advancement of
Science and the American College of Physicians.
CAROLE A. HEILMAN, Ph.D., is Director of the Division of Microbiology

and Infectious Diseases (DMID) of the National Institute of Allergy and Infec-
tious Diseases (NIAID). Dr. Heilman received her bachelor’s degree in biology
from Boston University in 1972, and earned her master’s degree and doctorate in
microbiology from Rutgers University in 1976 and 1979, respectively. Dr.
Heilman began her career at the National Institutes of Health as a postdoctoral
research associate with the National Cancer Institute where she carried out re-
search on the regulation of gene expression during cancer development. In 1986,
she came to NIAID as the influenza and viral respiratory diseases program officer
in DMID and, in 1988, she was appointed chief of the respiratory diseases branch
where she coordinated the development of acellular pertussis vaccines. She joined
the Division of AIDS as deputy director in 1997 and was responsible for develop-
ing the Innovation Grant Program for Approaches in HIV Vaccine Research. She
is the recipient of several notable awards for outstanding achievement. Through-
out her extramural career, Dr. Heilman has contributed articles on vaccine design
and development to many scientific journals and has served as a consultant to the
World Bank and WHO in this area. She is also a member of several professional
societies, including the Infectious Diseases Society of America, the American
Society for Microbiology, and the American Society of Virology.
DAVID L. HEYMANN, M.D., is currently the Executive Director of the World

Health Organization (WHO) Communicable Diseases Cluster. From October
1995 to July 1998 he was Director of the WHO Programme on Emerging and
Other Communicable Diseases Surveillance and Control. Prior to becoming di-
rector of this program, he was the chief of research activities in the Global
Programme on AIDS. From 1976 to 1989, prior to joining WHO, Dr Heymann
spent 13 years working as a medical epidemiologist in sub-Saharan Africa
(Cameroon, Ivory Coast, the former Zaire, and Malawi) on assignment from the
Centers for Disease Control and Prevention (CDC) in CDC-supported activities
aimed at strengthening capacity in surveillance of infectious diseases and their
control, with special emphasis on the childhood immunizable diseases, African
hemorrhagic fevers, pox viruses, and malaria. While based in Africa, Dr.

APPENDIX F 345
Heymann participated in the investigation of the first outbreak of Ebola in

Yambuku (former Zaire) in 1976, then again investigated the second outbreak of
Ebola in 1977 in Tandala, and in 1995 directed the international response to the
Ebola outbreak in Kikwit. Prior to 1976, Dr. Heymann spent two years in India as
a medical officer in the WHO Smallpox Eradication Programme. Dr. Heymann
holds a B.A. from the Pennsylvania State University, an M.D. from Wake Forest
University, and a Diploma in Tropical Medicine and Hygiene from the London
School of Hygiene and Tropical Medicine, and completed practical epidemiology
training in the Epidemic Intelligence Service (EIS) training program of the CDC.
He has published 131 scientific articles on infectious diseases in peer-reviewed
medical and scientific journals.
JAMES M. HUGHES, M.D., received his B.A. in 1966 and M.D. in 1971 from
Stanford University. He completed a residency in internal medicine at the Uni-
versity of Washington and a fellowship in infectious diseases at the University of
Virginia. He is board-certified in internal medicine, infectious diseases, and pre-
ventive medicine. He first joined CDC as an Epidemic Intelligence Service of-
ficer in 1973. During his CDC career, he has worked primarily in the areas of
foodborne disease and infection control in health care settings. He became Direc-
tor of the National Center for Infectious Diseases in 1992. The center is currently
working to address domestic and global challenges posed by emerging infectious
diseases and the threat of bioterrorism. He is a member of the Institute of Medi-
cine and a fellow of the American College of Physicians, the Infectious Diseases
Society of America, and the American Association for the Advancement of Sci-
ence. He is an Assistant Surgeon General in the Public Health Service.
LONNIE KING, D.V.M., is Dean of the College of Veterinary Medicine, Michi-

gan State University. Dr. King’s previous positions include both Associate Ad-
ministrator and Administrator of the USDA Animal and Plant Health Inspection
Service (APHIS) and Deputy Administrator for USDA/APHIS/Veterinary Ser-
vices. Before his government career, Dr. King was in private practice. He also has
experience as a field veterinary medical officer, station epidemiologist, and staff
member on assignments involving Emergency Programs and Animal Health In-
formation. Dr. King has also directed the American Veterinary Medical Associa-
tion’s Office of Governmental Relations, and is certified in the American College
of Veterinary Preventive Medicine. He has served as President of the Association
of American Veterinary Medicine Colleges, and currently serves as Co-Chair of
the National Commission on Veterinary Economic Issues, Lead Dean at Michigan
State University for food safety with responsibility for the National Food Safety
and Toxicology Center, the Institute for Environmental Toxicology, and the
Center for Emerging Infectious Diseases. He is also co-developer and course
leader for Science, Politics, and Animal Health Policy. Dr. King received his B.S.
and D.V.M. degrees from The Ohio State University, and his M.S. degree in

epidemiology from the University of Minnesota. He has also completed the Senior
Executive Program at Harvard University, and received a M.P.A. from American
University. Dr. King previously served on the Committee for Opportunities in
Agriculture, the Steering Committee for a Workshop on the Control and Preven-
tion of Animal Diseases, and the Committee to Ensure Safe Food from Production
to Consumption.
JOSHUA LEDERBERG, Ph.D., is Professor emeritus of Molecular Genetics

and Informatics and Sackler Foundation Scholar at The Rockefeller University,
New York, New York. His lifelong research, for which he received the Nobel
Prize in 1958, has been in genetic structure and function in microorganisms. He
has a keen interest in international health and was co-chair of a previous Institute
of Medicine Committee on Emerging Microbial Threats to Health (1990–1992)
and currently is co-chair of the Committee on Emerging Microbial Threats to
Health in the 21st Century. He has been a member of the National Academy of
Sciences since 1957 and is a charter member of the Institute of Medicine.
JOSEPH MALONE, M.D., the director of the Department of Defense Global

Emerging Infection System (DoD-GEIS), completed the Centers for Disease Con-
trol and Prevention’s Epidemic Intelligence Service (EIS) program in June, 2003.
He graduated from Boston University School of Medicine in 1980, and trained in
internal medicine and infectious diseases at Naval Hospitals in San Diego, and
Bethesda, MD leading to board certification. He was a staff physician at the Na-
val Hospitals in San Diego, CA and Bethesda, MD. He deployed to Guantanamo
Bay, Cuba, in support of Operation Safe Harbor and was attached to Surgical
Team 1 during Operation Desert Shield. He later directed the Infectious Disease
Division and HIV unit at the Naval Medical Center at Portsmouth, VA, from
1996-1996. In 1999 he worked for the Disease Surveillance Program (in affilia-
tion with DoD-GEIS) at the U.S. Naval Medical Research Unit No. 3 in Cairo,
Egypt. While at CDC’s EIS program he was deployed to New York City to assist
in the emergency public health response after the September 11th 2001attacks,
assisted in the public health response to documented anthrax contamination in
Kansas City and was the acting state epidemiologist for the State of Missouri
from February-June 2003. Capt. Malone has several military awards, including
the HHS/USPHS Crisis Response Service Award. He is an Associate Professor at
the Uniformed Services University of Health Sciences and holds the Certificate
of Knowledge in Travelers’ Health and Tropical Medicine from the American
Society of Tropical Medicine and Hygiene. He has over 20 publications.
LYNN MARKS, M.D., is board-certified in internal medicine and infectious

diseases. He was on faculty at the University of South Alabama College of Medi-
cine in the Infectious Diseases department focusing on patient care, teaching, and
research. His academic research interest was on the molecular genetics of bacte-

APPENDIX F 347
rial pathogenicity. He subsequently joined SmithKline Beecham’s (now

GlaxoSmithKline) anti-infectives clinical group and later progressed to global
head of the Consumer Healthcare Division Medical and Regulatory Group. He
then returned to pharmaceutical research and development as global head of the
Infectious Diseases Therapeutic Area Strategy Team for GlaxoSmithKline.
STEPHEN S. MORSE, Ph.D., is Director of the Center for Public Health Pre-
paredness at the Mailman School of Public Health of Columbia University, and
a faculty member in the Epidemiology Department. Dr. Morse recently returned
to Columbia from 4 years in government service as Program Manager at the
Defense Advanced Research Projects Agency (DARPA), where he co-directed
the Pathogen Countermeasures program and subsequently directed the Advanced
Diagnostics program. Before coming to Columbia, he was Assistant Professor
(Virology) at The Rockefeller University in New York, where he remains an
adjunct faculty member. Dr. Morse is the editor of two books, Emerging Viruses
(Oxford University Press, 1993; paperback, 1996) (selected by American Scien-
tist for its list of “100 Top Science Books of the 20th Century”), and The Evolu-
tionary Biology of Viruses (Raven Press, 1994). He currently serves as a Section
Editor of the CDC journal Emerging Infectious Diseases and was formerly an
Editor-in-Chief of the Pasteur Institute’s journal Research in Virology. Dr. Morse
was Chair and principal organizer of the 1989 NIAID/NIH Conference on
Emerging Viruses (for which he originated the term and concept of emerging
viruses/infections); served as a member of the Institute of Medicine-National
Academy of Sciences’ Committee on Emerging Microbial Threats to Health (and
chaired its Task Force on Viruses), and was a contributor to its report, Emerging
Infections (1992); was a member of the IOM’s Committee on Xenograft Trans-
plantation; currently serves on the Steering Committee of the Institute of
Medicine’s Forum on Emerging Infections, and has served as an adviser to
WHO, PAHO (Pan-American Health Organization), FDA, the Defense Threat
Reduction Agency (DTRA), and other agencies. He is a Fellow of the New York
Academy of Sciences and a past Chair of its Microbiology Section. He was the
founding Chair of ProMED (the nonprofit international Program to Monitor
Emerging Diseases) and was one of the originators of ProMED-mail, an interna-
tional network inaugurated by ProMED in 1994 for outbreak reporting and dis-
ease monitoring using the Internet. Dr. Morse received his Ph.D. from the Uni-
versity of Wisconsin–Madison.
MICHAEL T. OSTERHOLM, Ph.D., M.P.H., is Director of the Center for

Infectious Disease Research and Policy at the University of Minnesota where he
is also Professor at the School of Public Health. Previously, Dr. Osterholm was
the state epidemiologist and Chief of the Acute Disease Epidemiology Section
for the Minnesota Department of Health. He has received numerous research
awards from the National Institute of Allergy and Infectious Diseases and the

Centers for Disease Control and Prevention (CDC). He served as principal inves-
tigator for the CDC-sponsored Emerging Infections Program in Minnesota. He
has published more than 240 articles and abstracts on various emerging infectious
disease problems and is the author of the best selling book, Living Terrors: What
America Needs to Know to Survive the Coming Bioterrorist Catastrophe. He is
past president of the Council of State and Territorial Epidemiologists. He cur-
rently serves on the National Academy of Sciences, Institute of Medicine (IOM)
Forum on Emerging Infections. He has also served on the IOM Committee, Food
Safety, Production to Consumption and the IOM Committee on the Department
of Defense Persian Gulf Syndrome Comprehensive Clinical Evaluation Program,
and as a reviewer for the IOM report on chemical and biological terrorism.
GEORGE POSTE, Ph.D., D.V.M., is Director of the Arizona Biodesign Institute

and Dell E. Webb Distinguished Professor of Biology at Arizona State University.
From 1992 to 1999 he was Chief Science and Technology Officer and President,
Research and Development of SmithKline Beecham (SB). During his tenure at SB
he was associated with the successful registration of 29 drug, vaccine and diagnos-
tic products. He is Chairman of diaDexus and Structural GenomiX in California
and Orchid Biosciences in Princeton. He serves on the Board of Directors of
AdvancePCS and Monsanto. He is an advisor on biotechnology to several venture
capital funds and investment banks. In May 2003 he was appointed as Director of
the Arizona Biodesign Institute at Arizona State University. This is a major new
initiative combining research groups in biotechnology, nanotechnology, materials
science, advanced computing and neuromorphic engineering. He is a Fellow of
Pembroke College Cambridge and Distinguished Fellow at the Hoover Institution
and Stanford University. He is a member of the Defense Science Board of the U.S.
Department of Defense and in this capacity he Chairs the Task Force on
Bioterrorism. He is also a member of the National Academy of Sciences Working
Group on Defense Against Bioweapons. Dr. Poste is a Board Certified Pathologist,
a Fellow of the Royal Society and a Fellow of the Academy of Medical Sciences.
He was awarded the rank of Commander of the British Empire by Queen Elizabeth
II in 1999 for services to medicine and for the advancement of biotechnology. He
has published over 350 scientific papers, co-edited 15 books on cancer, biotechnol-
ogy and infectious diseases and serves on the Editorial Board of multiple technical
journals. He is invited routinely to be the keynote speaker at a wide variety of
academic, corporate, investment and government meetings to discuss the impact of
biotechnology and genetics on healthcare and the challenges posed by bioterrorism.
Dr. Poste is married with three children. His personal interests are in military his-
tory, photography, automobile racing and exploring the wilderness zones of the
American West.
GARY A. ROSELLE, M.D., received his M.D. from Ohio State University
School of Medicine in 1973. He served his residency at Northwestern University

APPENDIX F 349
School of Medicine and his Infectious Diseases fellowship at the University of

Cincinnati School of Medicine. Dr. Roselle is the Program Director for Infec-
tious Diseases for the VA Central Office in Washington, D.C., as well as the
Chief of the Medical Service at the Cincinnati VA Medical Center. He is a pro-
fessor of medicine in the Department of Internal Medicine, Division of Infec-
tious Diseases at the University of Cincinnati College of Medicine. Dr. Roselle
serves on several national advisory committees. In addition, he is currently head-
ing the Emerging Pathogens Initiative for the Department of Veterans Affairs.
Dr. Roselle has received commendations from the Cincinnati Medical Center
Director, the Under Secretary for Health for the Department of Veterans Affairs,
and the Secretary of Veterans Affairs for his work in the infectious diseases
program for the Department of Veterans Affairs. He has been an invited speaker
at several national and international meetings, and has published over 80 papers
and several book chapters.
JANET SHOEMAKER, is director of the American Society for Microbiology’s

Public Affairs Office, a position she has held since 1989. She is responsible for
managing the legislative and regulatory affairs of this 42,000-member organiza-
tion, the largest single biological science society in the world. She has served as
principal investigator for a project funded by the National Science Foundation
(NSF) to collect and disseminate data on the job market for recent doctorates in
microbiology and has played a key role in American Society for Microbiology
(ASM) projects, including the production of the ASM Employment Outlook in
the Microbiological Sciences and The Impact of Managed Care and Health Sys-
tem Change on Clinical Microbiology. Previously, she held positions as Assistant
Director of Public Affairs for ASM, as ASM coordinator of the U.S./U.S.S.R.
Exchange Program in Microbiology, a program sponsored and coordinated by the
National Science Foundation and the U.S. Department of State, and as a freelance
editor and writer. She received her baccalaureate, cum laude, from the University
of Massachusetts, and is a graduate of the George Washington University pro-
grams in public policy and in editing and publications. She has served as commis-
sioner to the Commission on Professionals in Science and Technology, and as the
ASM representative to the ad hoc Group for Medical Research Funding, and is a
member of Women in Government Relations, the American Society of Associa-
tion Executives, and the American Association for the Advancement of Science.
She has co-authored published articles on research funding, biotechnology, bio-
logical weapons control, and public policy issues related to microbiology.
P. FREDERICK SPARLING, M.D., is J. Herbert Bate Professor Emeritus of

Medicine, Microbiology and Immunology at the University of North Carolina
(UNC) at Chapel Hill, and is Director of the North Carolina Sexually Transmitted
Infections Research Center. Previously, he served as chair of the Department of
Medicine and chair of the Department of Microbiology and Immunology at UNC.

He was president of the Infectious Disease Society of America in 1996-1997. He

was also a member of the Institute of Medicine’s Committee on Microbial Threats
to Health (1991-1992). Dr. Sparling’s laboratory research is in the molecular
biology of bacterial outer membrane proteins involved in pathogenesis, with a
major emphasis on gonococci and meningococci. His current studies focus on the
biochemistry and genetics of iron-scavenging mechanisms used by gonococci
and meningococci and the structure and function of the gonococcal porin pro-
teins. He is pursuing the goal of a vaccine for gonorrhea.
SPEAKERS
ABU SALEH M ABDULLAH, M.D., M.P.H., Ph.D., is a Research Assistant
Professor in the Department of Community Medicine, The University of Hong
Kong. Trained as a family physician, he completed his Ph.D. in Community Medi-
cine and specializes in Public Health Medicine. He is a Diplomat member of the
Faculty of Public Health Medicine, the Royal College of Physicians, United King-
dom. He is a counsellor of the Asia Pacific Travel Health Society, a member of
the Editorial Board of the Journal of Travel Medicine and the regional editor of
the International Society of Travel Medicine Newsletter. He is a regular manu-
script reviewer for several national and international journals. Currently, he is
also the Director of the Hong Kong Smoking Cessation Health Centre at Ruttonjee
Hospital and an active member of the Advisory Council on AIDS of the Govern-
ment of the Hong Kong Special Administrative Region. He also serves as mem-
ber to several other national and international organizations including Interna-
tional Society for Infectious Disease, Asia Pacific Travel Health Society, Asia
Pacific AIDS Society and the Society for Research on Nicotine and Tobacco
(USA). Dr. Abdullah has written few book chapters and his research work has
been published in several prestigious journals including the Lancet, Emerging
Infectious Disease, Sexually Transmitted Diseases, International Journal of STD
& AIDS, Annals of Tropical Medicine & Parasitology and Preventive Medicine.
ROBERT BREIMAN, M.D., is seconded since 2000 from the Centers for Dis-
ease Control and Prevention the International Centre for Diarrheal Disease Re-
search, Bangladesh (ICDDR,B)—Centre for Health and Population Research
where he is the head of the Programme on Infectious Diseases and Vaccine Sci-
ences. Before joining ICDDR,B, Dr. Breiman was the Director of the United
States National Vaccine Program Office from 1995-2000, and was the Chief of
the Bacterial Respiratory Diseases Branch Epidemiology Section at CDC from
1989-1997. Dr. Breiman’s research focus includes emerging and re-emerging in-
fectious diseases, including respiratory infections, encephalitis, dengue, typhoid,
tuberculosis, and leishmaniasis and the evaluation of new, promising vaccines to
prevent disease in developing countries; currently, he is working on studies to
evaluate new rotavirus, cholera, and influenza vaccines. In March and April 2003,

APPENDIX F 351
Dr. Breiman was the leader of a World Health Organization team of international
expert consultants which provided assistance to WHO and the government of
China on addressing the public health threat from severe acute respiratory disease
(SARS); in January 2004, he returned to Beijing and Guangzhou, China,at the
request of WHO to lead a team of experts in providing assistance in assessing the
reappearance of SARS in Guangdong Province.
MARTIN S. CETRON, M.D., received his B.A. from Dartmouth College in

1981, and his M.D. from Tufts University in 1985. He trained in Internal Medi-
cine at the University of Virginia and Infectious Diseases at the University of
Washington before becoming a Commissioned Officer in the U.S. Public Health
Service (PHS) in 1992. Dr. Cetron is currently the Deputy Director for the Divi-
sion of Global Migration and Quarantine (DGMQ) at the U.S. Centers for Disease
Control and Prevention (CDC) whose mission is to prevent introduction and
spread of infectious diseases in the U.S. and to prevent morbidity and mortality
among immigrants, refugees, migrant workers, and international travelers. Dr Cetron
holds faculty appointments in Division of Infectious Disease at the Emory Uni-
versity School of Medicine and Department of Epidemiology at Rollins School of
Public Health. His primary research interest is international health and global
migration with a focus on emerging infections, tropical diseases, and vaccine-
preventable diseases in mobile populations. Dr. Cetron has worked at CDC since
1992 where he has lead numerous domestic and international outbreak investiga-
tions, conducted epidemiologic research throughout the world, and been involved
in several domestic and international emergency responses to provide medical
screening and disease prevention programs to refugees prior to U.S. resettlement.
Recently, Dr Cetron has played a principal role in high profile CDC responses to
intentional and naturally-acquired emerging infectious disease outbreaks includ-
ing the anthrax bioterrorism incident in the Fall of 2001, the Global SARS
epidemic in Spring 2003 and Monkeypox Outbreak in Summer 2003.
PETER DRAGOVICH, Ph.D., is Senior Director, Head of Viral Diseases Drug

Discovery at the La Jolla laboratories of Pfizer Global Research and Develop-
ment. He was previously employed by Agouron Pharmaceuticals (1993-1999)
and, via a corporate merger, the Warner-Lambert company (1999-2000). Prior to
joining PGRD-La Jolla, Dr. Dragovich served in a number of capacities in the
Agouron and Warner-Lambert organizations including Senior Scientist, Project
Leader, and Group Leader (medicinal chemistry). Dr. Dragovich received a B.S.
degree in Chemistry from the University of California, Berkeley in 1988 and a
Ph.D. in Chemistry (Biology minor) from the California Institute of Technology
in 1993.
YANZHONG HUANG, Ph.D., is assistant professor in the John C. Whitehead

School of Diplomacy and International Relations at Seton Hall University, where

he directs the school’s Center for Global Health Studies. His current research
interests include health politics in post-Mao China, the impact of infectious dis-
eases on state capacity, and SARS and the political economy of contagion in
Pacific Rim. His most recent publications include a monograph “Mortal Peril:
Public Health in China and Its Security Implications” (Chemical and Biological
Arms Control Institute, 2003). In May of 2003, he appeared before the Congres-
sional-Executive Commission on China to testify about the politics of SARS in
China. Dr. Huang received a Ph.D. degree in political science from the University
of Chicago.
NATHANIEL HUPERT, M.D., M.P.H., is an Assistant Professor of Public

Health and Medicine at Weill Medical College of Cornell University in New York
City. In addition to maintaining a primary care internal medicine practice, Dr.
Hupert has directed a number of federally funded studies since 2000 using com-
puter modeling to improve public health response strategies for intentional and
natural outbreaks of disease. Using tools developed by Dr. Hupert and colleagues
such as the Weill/Cornell Bioterrorism and Epidemic Outbreak Response Model
(BERM, available online at www.ahrq.gov/research/biomodel.htm), public health
and emergency response planners from around the country can customize resource
deployment strategies to suit local needs for mass prophylaxis or vaccination strat-
egies. Dr. Hupert is a member of both local and national expert panels on
bioterrorism response and has provided computer modeling support to the New
York City Office of Emergency Management and to the NYC Department of Health
and Mental Hygiene since the spring of 2001. He has served as a lecturer for the
CDC Strategic National Stockpile Program and the US Public Health Service Com-
missioned Corps Readiness Force on antibiotic dispensing strategies. Currently he
is a member of the New York Presbyterian Hospital Biological Pathogens Task
Force.
ANN MARIE KIMBALL, M.D., M.P.H., is currently Associate Professor,

Health Services and Epidemiology, Adjunct in Medicine, University of Washing-
ton. She also serves as the Director and Graduate Program Coordinator, M.P.H.
Program, School of Public Health and Community Medicine, University of Wash-
ington. Dr. Kimball has devoted her career to studying health issues and has
worked in numerous positions in the United States and abroad. Her research in-
terests are primarily in international health, HIV/AIDS, emerging infections, and
maternal and child health. She has previously served as a panelist on the IOM
Forum on Emerging Infections, as a member of the Department of Health Emerg-
ing and Reemerging Diseases Strategic Planning Task Force, as regional adviser
for PAHO in HIV/AIDS, and as the Chair of the National Alliance of State and
Territorial AIDS Directors in the United States.
JAMES W. LEDUC, Ph.D., is the Director, Division of Viral and Rickettsial

APPENDIX F 353
Diseases at the Centers for Disease Control and Prevention where he coordinates
research activities, prevention initiatives and outbreak investigations for viral and
rickettsial pathogens of global importance, including viral hemorrhagic fevers,
influenza and other respiratory infections, childhood viral diseases, and newly
emerging diseases such as SARS. Prior to becoming Director of the Division, he
served as the Associate Director for Global Health (1996-2000) in the Office of
the Director, National Center for Infectious Diseases at CDC, and was a Medical
Officer in charge of arboviruses and viral hemorrhagic fevers at the World Health
Organization in Geneva, Switzerland (1992-1996). He also held leadership posi-
tions during a 23-year career as a U.S. Army officer in the medical research and
development command, with assignments in Brazil, Panama and at various loca-
tions in the United States, including the Walter Reed Army Medical Center and
the U.S. Army Medical Research Institute of Infectious Diseases. He is a native
of southern California and earned his doctoral degree from the University of Cali-
fornia at Los Angeles.
DONALD E. LOW, M.D., F.R.C.P.C., holds a Fellowship in Medical Microbi-

ology, Internal Medicine and Infectious Diseases. He is a Professor of Laboratory
Medicine and Pathobiology and Medicine at the University of Toronto where he
is the Head of the Division of Microbiology in the Department of Laboratory
Medicine and Pathobiology. He is Chief of the Toronto Medical Laboratories and
Mount Sinai Hospital Department of Microbiology; a laboratory which provides
diagnostic services to eleven hospitals in the Toronto area. He is also Chair of the
National Advisory Committee on Chemical, Biological, Radio-nuclear Safety,
Security and Research, Health Canada; and Member of the National Committee
on Clinical Laboratory Standards. Dr. Low’s primary research interests are in the
study of epidemiology and the mechanisms of antimicrobial resistance in com-
munity and hospital pathogens. Other research interests include the epidemiol-
ogy, pathogenesis, and treatment of severe invasive streptococcal diseases.
JOHN MACKENZIE, Ph.D., is presently Professor of Microbiology (from

1995) and Professor of Tropical Infectious Diseases (from 1999), University of
Queensland, Australia. He was previously Professor (1994), Associate Professor
(1980-1994), and Senior Lecturer (1973-1999) at the University of Western Aus-
tralia, Perth, Australia, Head of Genetics Department at the Animal Virus Re-
search Institute, Pirbright, England (1990-1992), and Research Fellow at the Pub-
lic Health Research Institute, New York (1969-1970). He was appointed to a
short-term consultancy as Professional Officer at the World Health Organization
(WHO) in 2003-2004 to convene the WHO International SARS Research Advi-
sory Committee, and to chair the WHO SARS Laboratory Network. Honorary
and elected positions have included Secretary-General, International Union of
Microbiological Societies (IUMS) (1999-2005); Member-at-Large, Executive
Board of IUMS (1994-1999); Member of the WHO Global Outbreak Alert and

Response Network Steering Committee (since 2000); Member of the WHO Sci-
entific Advisory Committee for Global Health Security (since 2001); President of
the Asian-Pacific Society for Medical Virology (2000-2003); President of the
Australian Society for Microbiology (1992-1994). He was leader of the first WHO
mission into China in March 2003 to investigate cases of atypical pneumonia in
Guangdong Province, and the etiological relationship of these cases to SARS.
Recent research has been concerned with the ecology, epidemiology, and mo-
lecular phylogeny of mosquito-borne viruses, especially Japanese encephalitis
virus, and emergent zoonotic viruses. He received the award of Officer in the
Order of Australia (AO) in 2001.
GENE MATTHEWS, J.D., as the Legal Advisor to CDC in Atlanta and, as the
manager of the legal staff there for 25 years, has handled a wide range of public
health law issues. His initial work at CDC coincided with the beginning of the
HIV/AIDS epidemic. His experience has included questions of patient confiden-
tiality, access to records, liability for vaccine-related injuries, occupational health
protection, environmental concerns, and chronic disease prevention strategies.
He has litigated important public health lawsuits and civil discovery questions.
Mr. Matthews is widely published and is frequently called upon to lecture on
cutting-edge legal issues facing CDC, such as AIDS, livable communities, and
bioterrorism preparedness. Most recently, Mr. Matthews has also provided lead-
ership for CDC’s development of a newly created Public Health Law Program
designed to improve the understanding of the use of laws as tools of public health
in the 21st century. He has guided this exciting initiative to reach out both to the
legal community and to public health practitioners through research, training,
information, and partnerships. Mr. Matthews is a graduate of the University of
North Carolina School of Law and is an avid distance swimmer.
PROFESSOR WARWICK J. MCKIBBIN, Ph.D., is Professor of International

Economics and Convenor of the Economics Division in the Research School of
Pacific and Asian Studies at the Australian National University. He is also a Pro-
fessorial Fellow at the Lowy Institute for International Policy; a nonresident Se-
nior Fellow at the Brookings Institution in Washington D.C. and President of
McKibbin Software Group. He is a member of the Board of the Reserve Bank of
Australia. Professor McKibbin has worked at the Reserve Bank of Australia, Japa-
nese Ministry of Finance, US Congressional Budget office and World Bank. He
has been a consultant for many international agencies and a range of governments
on issues of macroeconomic policy, international trade and finance and green-
house policy issues. Professor McKibbin has published widely in technical jour-
nals and the popular press including the book “Global Linkages: Macroeconomic
Interdependence and Cooperation in the World Economy” written with Professor
Jeffrey Sachs of Harvard University and the new book “Climate Change Policy
after Kyoto: A Blueprint for a Realistic Approach” with Professor Peter Wilcoxen

APPENDIX F 355
of the University of Texas. He received his B.Com. (Honours 1) and University

Medal from University of NSW (1980) and his A.M. (1984) and a Ph.D. (1986)
from Harvard University. He is a Fellow of the Australian Academy of Social
Sciences and a founding member of the Harvard University Asian Economic
Panel. He was awarded the Centenary medal in 2003 “For Service to Australian
Society through Economic Policy and Tertiary Education.”
KAREN J. MONAGHAN, joined the National Intelligence Council as the

Deputy National Intelligence Officer for Economics and Global Issues in May
2002. She was named Acting NIO in September 2002. Prioir to her assignment
with the NIC, she served in the Department of State and in the Central Intelli-
gence Agency’s Directorate of the Intelligence (DI) in a variety of managerial
and analytic positions. Most recently she supervised current and long-term analy-
sis of Asian Economic developments. Ms. Monaghan also spearheaded a corpo-
rate outreach program, tapping into corporate and financial sector expertise to
help bolster financial vulnerability analysis and the impact of international capi-
tal flows on national and regional stability among emerging market countries.
Ms. Monaghan is a graduate of Vassar College and undertook graduate studies in
international relations and economics at St. Antony’s College, Oxford Univer-
sity, where she earned an M.Phil. degree in 1982. Currently, Ms. Monaghan is an
adjunct professor at the School of Foreign Service at Georgetown University. She
has published extensively on issues of economic development and global issues.
AMY PATICK, Ph.D., is Senior Director, Head of Virology, at Pfizer Global

Research and Development, La Jolla (formerly Agouron Pharmaceuticals, Inc.).
Amy earned her Ph.D. in Medical Microbiology from the University of Wiscon-
sin in1987. She has been involved in antiviral drug research since 1990 initially at
Bristol-Myers Squibb Co. and subsequently (1994–present) at Pfizer Global Re-
search and Development, La Jolla. Her research efforts are currently focused on
antiviral chemotherapy and the emergence of resistance to antiviral agents. She
has published more than 100 articles and abstracts in prominent scientific jour-
nals in the area of antiviral research. She is the Secretary for the International
Society for Antiviral Research and has served as a member on the HIV Inter-
company Collaborative Committee, HIV Resistance Collaborative Group, and
the Scientific Subcommittee, International Workshop on HIV Resistance and
Treatment Strategies. Amy is a regular ad hoc reviewer for several journals in-
cluding Antimicrobial Agents and Chemotherapy, AIDS Research and Human
Retroviruses, and Antiviral Therapy.
LINDA J. SAIF, Ph.D., is Professor and Researcher at the Ohio State

University’s Ohio Agricultural Research and Development Center (OARDC). Dr.
Saif brings to the committee her contributions to the study of virology, disease
pathogenesis, and immunity, in both animal and human health, and mechanisms

of immunity against intestinal infections. Dr. Saif’s research focuses on enteric

viruses, including rotaviruses, caliciviruses, and coronaviruses, which cause mor-
tality and morbidity in both food-producing animals and humans. During the past
30 years, she has identified new intestinal viruses and developed diagnostic tests
and research methods for working with them in the laboratory. Furthermore, she
discovered viruses that cause intestinal diseases in livestock, and developed meth-
ods for their control. She is also credited with discovering the potential of enteric
viral infections in animals to infect human populations in epidemic proportions.
One example is Dr. Saif’s ongoing effort to develop safe and effective vaccines
for rotavirus diarrhea, which kills nearly a half million children every year. In
2002, Dr. Saif became the first Ohio State researcher not based on the Columbus
campus to be recognized as a Distinguished University Professor, and was
awarded an honorary doctorate by Belgium’s Ghent University. She was elected
a member of the National Academy of Sciences in 2003. Dr. Saif earned her
bachelor’s degree from the College of Wooster in 1969, and received her master’s
degree (1971) and doctorate (1976) in microbiology/immunology from the Ohio
State University.
RANGA SAMPATH, Ph.D., is the Director of Genomics and Computational

Biology at Ibis Therapeutics, a division of Isis Pharmaceuticals. He leads Ibis’s
genomics efforts, both in RNA-based drug discovery and in microbial detection
and diagnosis. Dr. Sampath has over 7 years of experience in the pharmaceutical
industry and has been the lead genomics investigator on several DARPA pro-
grams related to bioinformatics, drug discovery and biological warfare agent de-
tection and treatment. He has several publications and patents in RNA structure
and target discovery, computational algorithms for RNA structure prediction, and
pathogen and infectious agent diagnostics. Prior to joining Ibis Therapeutics, Dr.
Sampath was a postdoctoral fellow at the Indiana University School of Medicine.
He received his Ph.D. in chemical engineering from Rice University (Houston,
Texas), and bachelor’s in chemical engineering from the Indian Institute of Tech-
nology (Chennai, India).
JEROME J. SCHENTAG, Pharm.D., is Professor of Pharmaceutical Sciences

and Pharmacy, at the University at Buffalo School of Pharmacy and Pharmaceuti-
cal Sciences. He is also Chief Executive Officer at CPL Associates LLC, a private
CRO. His Research emphasis has been in the clinical applications of pharmacoki-
netic/pharmacodynamic models to anti-infectives and other classes of pharmaceuti-
cals used in seriously ill patients. Earlier work established correlations between
pharmacokinetic parameters and biologic response to disease, drug efficacy and
toxicity and managing antimicrobial resistance. Dr. Schentag received his Pharm.D.
degree from the Philadelphia College of Pharmacy and Science and postdoctoral
fellowship in clinical pharmacokinetics from SUNY Buffalo School of Pharmacy.
A member of numerous professional societies, including the American Society for

APPENDIX F 357
Microbiology and American Society of Hospital Pharmacists, Dr. Schentag is a

Fellow of American College of Clinical Pharmacy and the American College of
Clinical Pharmacology. He has authored over 300 original research papers in pres-
tigious journals, including the Journal of Antimicrobial Chemotherapy, Pharmaco-
therapy, Antimicrobial Agents and Chemotherapy, Annals of Pharmacotherapy and
Journal of the American Medical Association. He has lectured extensively, both
nationally and internationally, on a wide variety of topics, notably the clinical ap-
plication of PK/PD and managing antimicrobial resistance.
ALAN R. SHAW, Ph.D., is the Executive Director of Virus & Cell Biology at
Merck Research Laboratories, and is responsible for all aspects of live virus vac-
cine research, as well as technical aspects of development and production. He is
also responsible for research and early development of recombinant protein-based
vaccines. Prior to joining Merck, Dr. Shaw worked on vaccines for hepatitis B
and Plasmodium falciparum as well as cytokines and natural inhibitors of
interleukin-1 at Biogen, SA in Geneva, Switzerland. Dr. Shaw received a B.A.
from Rice University, a M.S. in molecular biology from the University of Texas
at Dallas, and a Ph.D. in molecular biology at the Medical College of Ohio. He
had postdoctoral fellowships at the International Institute of Cellular Pathology
in Brussels and the Rockefeller University. Dr. Shaw is the past Chairman of the
International Federation of Pharmaceutical Manufacturers Association
Biologicals Committee.
ROBERT G. WEBSTER, Ph.D., is Professor in the Division of Virology, De-

partment of Infectious Diseases at St. Jude Children’s Research Hospital. A na-
tive of New Zealand, Dr. Webster received his B. Sc. and M. Sc. in Microbiology
from Otago University in New Zealand. In 1962, he earned his Ph.D. from the
Australian National University and spent the next two years as a Fullbright
Scholar working on influenza in the Department of Epidemiology at the Univer-
sity of Michigan, Ann Arbor. Since 1968, Dr. Webster has been with St. Jude
Children’s Research Hospital, Memphis, Tennessee. In 1988, he was appointed
to the Rose Marie Thomas Chair in Virology. In 1989, he was admitted to the
Royal Society of London in recognition for his contribution to influenza virus
research. In 1998 he was appointed to the National Academy of Sciences of the
United States. In 2002 he received the Twelfth Annual Bristol-Myers Squibb
Award for Distinguished Achievement in Infectious Disease Research. Dr.
Webster is Director of the World Health Organization Collaborating Center for
Studies on the Ecology of Influenza in Animals and Birds. His interests include
the structure and function of influenza virus proteins and the development of new
vaccines and antivirals. The major focus of his research is the importance of
influenza viruses in wild aquatic birds as a major reservoir of influenza viruses
and their role in the evolution of new pandemic strains for humans and lower

animals. His curriculum vitae contains over 450 original articles and reviews on
influenza viruses.
FORUM STAFF
STACEY L. KNOBLER, is Director of the Forum on Microbial Threats at the
Institute of Medicine (IOM) and a senior program officer for the Board on Global
Health (BGH). She has served as the director of the BGH study, Neurological,
Psychiatric, and Developmental Disorders in Developing Countries and as a re-
search associate for the Board’s earlier studies on The Assessment of Future Sci-
entific Needs for Live Variola (Smallpox) Virus and Cardiovascular Disease in
Developing Countries. Previously, Ms. Knobler has held positions as a Research
Associate at the Brookings Institution, Foreign Policy Studies Program and as an
Arms Control and Democratization Consultant for the Organization for Security
and Cooperation in Europe in Vienna and Bosnia-Herzegovina. She has also
worked as a research and negotiations analyst in Israel and Palestine. Ms. Knobler
received her baccalaureate, summa cum laude, in political science and molecular
genetics from the University of Rochester, and her M.P.A from Harvard Univer-
sity. She has conducted research and published on issues that include, biological
and nuclear weapons control, foreign aid, health in developing countries, poverty
and public assistance, and the Arab-Israeli peace process.
KARL GALLE, Ph.D., is a research associate for the president’s office at the
Institute of Medicine. He received his Ph.D. in the history and philosophy of
science from the University of London in 2002, prior to joining the National
Academies through the Christine Mirzayan internship program in science and
technology policy. He has worked at the Institute of Medicine since 2003 and
also holds a B.A. in international development from Williams College, an M.A.
in the conceptual foundations of science from the University of Chicago, and an
M.Sc. in the history of science and medicine from the University of London.
KATHERINE A. OBERHOLTZER, is research assistant for the Institute of

Medicine’s Board on Global Health. She recently played a key role in the devel-
opment and production of the BGH study, Microbial Threats to Health: Emer-
gence, Detection, and Response. Katherine received her B.S. in Integrated Sci-
ence and Technology with a concentration in Biotechnology from James Madison
University in 2000. She is currently pursuing her Professional Editing Certificate
at the George Washington University. Katherine has worked as the Meeting Co-
ordinator for the Maryland AIDS Education and Training Center of the Institute
of Human Virology at the University of Maryland, Baltimore. Katherine joined
the staff at the Institute of Medicine in December 2000.
LAURA SIVITZ, M.S.J., joined the staff of the Institute of Medicine in 2002 as

APPENDIX F 359
the research associate in an 18-month study on prion diseases. She played a lead-
ership role in the development, production, and dissemination of the report Ad-
vancing Prion Science: Guidance for the National Prion Research Program. In
November 2003, she joined the staff of the Forum on Microbial Threats in the
Board on Global Health at IOM. Previously, Ms. Sivitz had served as a technol-
ogy reporter for Washington Techway magazine; as the science-writer intern for
Science News; as the Washington correspondent for the York Daily Record of
Pennsylvania; and as a science, legal, and business reporter for the Medill News
Service of Chicago. She won a National Science Foundation fellowship in 1994
to conduct research at the University of Pennsylvania on piezoelectric ceramics
for use in mammography systems. Ms. Sivitz received her bachelor of arts in
physics from Bryn Mawr College in 1996 and her master of science in journalism
from Northwestern University in 2001.


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Learning from SARS: Preparing for the Next

Disease Outbreak -- Workshop Summary

Copyright © National Academy of Sciences. Permission is granted for this material to be

Stacey Knobler, Adel Mahmoud, Stanley Lemon, Alison Mack,

Forum on Microbial Threats

Board on Global Health

Copyright © National Academy of Sciences. All rights reserved.

Library of Congress Cataloging-in-Publication Data

Copyright 2004 by the National Academy of Sciences. All rights reserved.

Copyright © National Academy of Sciences. All rights reserved.

“Knowing is not enough; we must apply.

Adviser to the Nation to Improve Health

Copyright © National Academy of Sciences. All rights reserved.

The National Academy of Sciences is a private, nonprofit, self-perpetuating society

The Institute of Medicine was established in 1970 by the National Academy of

Copyright © National Academy of Sciences. All rights reserved.

FORUM ON MICROBIAL THREATS

Copyright © National Academy of Sciences. All rights reserved.

GEORGE POSTE, Director, Arizona BioDesign Institute, Arizona State

Copyright © National Academy of Sciences. All rights reserved.

BOARD ON GLOBAL HEALTH

Copyright © National Academy of Sciences. All rights reserved.

Roy M. Anderson, Imperial College London, London, United Kingdom

The review of this report was overseen by Enriqueta C. Bond, President,

Copyright © National Academy of Sciences. All rights reserved.

The Forum on Emerging Infections was created in 1996 in response to a request

ABOUT THE WORKSHOP

1Representatives of federal agencies serve in an ex officio capacity. An ex officio member of a

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ORGANIZATION OF WORKSHOP SUMMARY

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Adel Mahmoud, Chair

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SUMMARY AND ASSESSMENT 1

1 SARS: EMERGENCE, DETECTION, AND RESPONSE 41

2 POLITICAL INFLUENCES ON THE RESPONSE TO

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SARS: Political Pathology of the First Post-Westphalian Pathogen 110

3 MICROBIOLOGY, ECOLOGY, AND NATURAL

4 DIAGNOSTICS, THERAPEUTICS, AND OTHER

5 PREPARING FOR THE NEXT DISEASE OUTBREAK 206

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SARS: Lessons from a New Disease 234

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Summary and Assessment1

The emergence of a novel human coronavirus in late 2002 alarmed popula-

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2 LEARNING FROM SARS

Disease Outbreak on September 30 and October 1, 2003. Participants discussed

OVERVIEW OF THE SARS EPIDEMIC

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SUMMARY AND ASSESSMENT 3

improvements in how the world responds to an outbreak of infectious dis-

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4 LEARNING FROM SARS

November 2002: First case of SARS occurs in Guangdong Province, China.