Tracking trends and analyzing new and reemerging

infectious disease issues around the world

Apeer-reviewed journal published by the National Center for Infectious Diseases Vol. 5, No. 4, July–Aug 1999

Biological Warfare Dengue Reemergence Cryptospordium Disinfection

DEPARTMENT OF HEALTH AND HUMAN SERVICES

CDC
CENTERS FOR DISEASE CONTROL
AND PREVENTION
 Volume 5, Number 4
July–August 1999

National Symposium on Medical

and Public Health Response to
Bioterrorism
About the First National Symposium D.A. Henderson
on Medical and Public Health Response
to Bioterrorism ...................................................... 491
Cover: John Singer Sargent. Gassed
(1919). Reprinted with permission of the Bioterrorism: How Prepared D.E. Shalala
Imperial War Museum, London. Are We? ........................................................... 492

The Emerging Threat of Bioterrorism ......... 494 J.M. Hughes

Letters View from the Hill: Congressional S.A. McCann

Current Status of Efforts to Address Bioterrorism .................... 496
Smallpox Vaccine ........... 593
J.W. LeDuc and Finding the Right Balance against R.A. Clarke
J. Becher Bioterrorism ................................................... 497

West Nile Fever in Historical Trends Related to Bioterrorism: J.B. Tucker

Czechland ........................ 594 An Empirical Analysis ................................... 498
Z. Hubálek, J. Halouzka,
and Z. Juricová The Threat of Biological Attack: Why D.W. Siegrist
Concern Now? ................................................ 505
Ofloxacin-Resistant
Vibrio cholerae O139 Nuclear Blindness: An Overview of the C.J. Davis
in Hong Kong .................. 595 Biological Weapons Programs of the
K.-M. Kam, K.-Y. Luey, Former Soviet Union and Iraq ...................... 509
T.-L. Cheung, K.-Y. Ho,
K.-H. Mak, and P. Thian
Aum Shinrikyo: Once and Future K.B. Olson
Aun Saw
Threat? ............................................................ 513
Plant Pathology and
Public Health .................. 597 The Prospect of Domestic Bioterrorism ........ 517 J. Stern
K.-B. G. Scholthof
Potential Biological Weapons Threats .......... 523 M.G. Kortepeter
Pet-Associated and G.W. Parker
Zoonoses .......................... 598
L.L. Barton, R. G. Villar, Epidemiology of Bioterrorism ....................... 528 J.A. Pavlin
and M. Connick
Vaccines in Civilian Defense Against P.K. Russell
The opinions expressed by authors Bioterrorism ................................................... 531
contributing to this journal do not
necessarily reflect the opinions of the Vaccines, Pharmaceutical Products, K.C. Zoon
Centers for Disease Control and
Prevention or the institutions with and Bioterrorism: Challenges for the
which the authors are affiliated. U.S. Food and Drug Administration ............ 534
 Volume 5, Number 4
July–August 1999

Dispatches Bioterrorism Symposium cont’d.

Cytotoxin-Producing
Smallpox: Clinical and Epidemiologic D.A. Henderson
Escherichia coli O157 in
Features ....................................................... 537
Wales, 1990 to 1998 ......... 566
R.M. Chalmers, S.M. Parry,
R.L. Salmon, R.M.M. Smith, Smallpox: An Attack Scenario ................... 540 T. O’Toole
G.A. Willshaw, and T. Cheasty
Aftermath of a Hypothetical Smallpox J. Bardi
A Focus of Deer Tick Disaster ....................................................... 547
Virus Transmission in
the Northcentral Clinical and Epidemiologic Principles T.J. Cieslak and
United States ................... 570 of Anthrax .................................................... 552 E.M. Eitzen, Jr.
G.D. Ebel, I. Foppa,
A. Spielman, and S.R. Telford, III Anthrax: A Possible Case History .............. 556 T.V. Inglesby

Dengue Reemergence Applying Lessons Learned from Anthrax J.G. Bartlett

in Argentina ..................... 575 Case History to Other Scenarios................ 561
G. Avilés, G. Rangeón, V.
Vorndam, A. Briones, P. Baroni, Addressing Bioterrorist Threats: Where M.A. Hamburg
D. Enria, and M.S. Sabattini Do We Go From Here? ................................ 564

Chlorine Disinfection of Commentary

Recreational Water Addressing the Potential Threat of J.E. McDade
for Cryptosporidium Bioterrorism: Value Added To an
parvum ............................. 579 Improved Public Health
C. Carpenter, R. Fayer, Infrastructure ............................................ 591
J. Trout, and M.J. Beach
Book Review
Cyclospora cayetanensis
Among Expatriate Clinical Infectious Diseases: A J.M. Miller
and Indigenous Practical Approach ...................................... 599
Populations of West
Java, Indonesia ................ 585 News and Notes
D.J. Fryauff The Epidemiology and Control of
Communicable Diseases .................................... 601
The First Major Antibiotic Resistance in Bacteria of
Outbreak of Dengue Animal Origin ..................................................... 601
Hemorrhagic Fever in Keystone Symposia on Molecular and
Delhi, India ...................... 589 Cellular Biology .................................................. 601
L. Dar, S. Broor, The 5th World Congress on Trauma,
S. Sengupta, I. Xess, Shock, Inflammation and Sepsis-
and P. Seth Pathophysiology, Immune
Consequences and Therapy ............................... 601
International Conference on Emerging
Infectious Diseases ............................................. 602
 Preface

About the First National Symposium on

Medical and Public Health
Response to Bioterrorism

D.A. Henderson
Johns Hopkins Center for Civilian Biodefense Studies

On February director of the U.S. Army Medical Research

16-17, 1999, in Arling- Institute of Infectious Diseases; Thomas V.
ton, Virginia, 950 pub- Inglesby and Tara O’Toole, Johns Hopkins
lic health officials, phy- Center for Civilian Biodefense Studies; and
sicians, and other medi- Philip K. Russell, Johns Hopkins School of Public
cal personnel, along Health.
with government, mili- Federal, state, and local officials reflected on
tary, and intelligence the challenge of coordinating a multidisciplinary
experts gathered for and interagency response to a biological attack.
the first National Symposium on Medical and This array of speakers included Secretary of
Public Health Response to Bioterrorism. Partici- Health and Human Services Donna Shalala;
pants were geographically diverse. Represented Richard Clarke, National Security Council;
were 46 states, plus Washington, D.C., and 10 Michael Osterholm, Minnesota Department of
countries: Australia, Austria, Canada, England, Health; and Jerry Hauer, director of New York
Finland, France, Germany, Israel, Italy, and the City’s Office of Emergency Management.
Netherlands. From their different backgrounds and
The guiding force behind the symposium was perspectives, the more than 20 speakers
the newly established Johns Hopkins Center for addressed the following questions: Why are
Civilian Biodefense Studies, which hopes the current concerns about bioterrorism real? Why
discussions will lead to a framework and must the medical and public health communities
partnership for strategic planning. The other address the issue of bioterrorism? Which
main sponsors were the Department of Health biological threats warrant the most concern?
and Human Services, Infectious Diseases What is the possible aftermath of an act of
Society of America, and American Society for biological terrorism?
Microbiology. Twelve other public health A warning against complacency came from
professional societies supported the conference.1 the symposium’s closing speaker, Margaret A.
The list of speakers included D.A. Henderson, Hamburg, assistant secretary for planning and
director of the Johns Hopkins Center for Civilian evaluation, U.S. Department of Health and
Biodefense Studies; Christopher J. Davis, former Human Services.
senior intelligence analyst for chemical and In making symposium presentations avail-
biological warfare matters on Britain’s Defense able here, the organizers hope to raise awareness
Intelligence staff; Jessica Stern, Council on of the medical and public health threats posed by
Foreign Relations and author of the book The biological weapons and to foster mutual
Ultimate Terrorists; Joshua Lederberg, Nobel understanding and collaboration among the
laureate and professor and president emeritus of diverse groups addressing the threat of
Rockefeller University; Col. Gerald W. Parker, bioterrorism.
1American College of Preventive Medicine, Association for Professionals in Infection Control and Epidemiology, Association of

Public Health Laboratories, Association of Schools of Public Health, Association of State and Territorial Health Officials,
Commissioned Officers Association of the U.S. Public Health Service, Council of State and Territorial Epidemiologists, National
Association of County and City Health Officials, National Association of Local Boards of Health, Partnership for Prevention,
Public Health Foundation, and Society of Hospital Epidemiologists of America.

Vol. 5, No. 4, July–August 1999 491 Emerging Infectious Diseases

 Special Issue

Bioterrorism: How
Prepared Are We?
Donna E. Shalala
U.S. Secretary of Health and Human Services

Richard Preston’s The Cobra Event, which outbreaks, conduct epidemiologic investigations,
he dedicates to public health professionals, perform laboratory tests to identify biological
weaves a chilling, but compelling tale about a agents, and communicate necessary informa-
lone terrorist’s attack on Manhattan with a tion and advisories rapidly through electronic
genetically engineered virus. Preston’s thought- technology.
provoking novel raises a logical question: How do We are enhancing our medical and public
we successfully contain and combat the threat of health response capacity by spearheading an
bioterrorism? To meet this emerging threat, we administrationwide effort to develop infrastruc-
must address four important challenges. ture at the local level by establishing in major
The first challenge is to be aware that an act American cities medical response teams to deal
of bioterrorism could happen. Its likelihood is with the consequences of bioterrorism. We are
entirely unknown, and an attack may never also expanding our capacity to provide prophy-
occur. However, we have seen terrorism emerge laxis, medical care, and infection control on a
as one of the thorniest problems of the post-cold massive scale. We are creating, and will be
war era, and we have seen that terrorists are maintaining, an unprecedented national stock-
always searching for new weapons. We have pile of drugs and vaccines for civilian use in case
already seen sarin nerve gas released in the of a bioterrorist attack.
Tokyo subway. Somewhere, sometime in the Finally, we are accelerating our research and
future, terrorists may well threaten to use, or development of rapid diagnostics, drugs, and
attempt to use, a biological weapon against the vaccines, so we can more effectively address the
United States. When discussing the possibility of threats and consequences of a bioterrorist
a terrorist attack in the next few years, the attack. In addition, we will continue our work on
president unequivocally stated, “This is not a the genome sequencing of organisms most likely
cause for panic. It is cause for serious, deliberate, to be used as bioweapons, so that we can not only
disciplined, long-term concern.” In other words, quickly identify the biological agent, but also
we must not be afraid, but we must be aware. develop effective therapies. Our efforts in
Once we are fully aware that bioterrorism surveillance, medical and public health re-
could happen, our second challenge is to be sponse, stockpile provision, and research and
prepared. That is why the Department of Health development will increase significantly our
and Human Services (HHS) is spending $158 preparedness for bioterrorism.
million this fiscal year to prepare for bioterorrism If we want to be truly prepared, our third
and why the president has proposed increasing challenge is for the public health and medical
that investment by an additional $72 million in communities to take the lead in our fight against
his Fiscal Year 2000 budget. bioterrorism. In a conventional terrorist attack,
This investment will fund our ongoing Anti- local “first responders,” such as the police,
Bioterrorism Initiative. To increase our level of firefighters, and paramedics, constitute the first
preparedness, the initiative is expanding its line of defense. With bioterrorism, the public
activities in a number of key areas: surveillance, health and medical communities stand directly
medical and public health response, building a on the front lines. How well we respond to a
stockpile of drugs and supplies, and research and threat or attack will depend on the preparedness
development. We are improving and strengthen- of our public health and medical communities.
ing the U.S. public health surveillance network For example, if a bioterrorist threat is issued—
by enhancing our capability to detect and report perhaps someone claims to have released a

Emerging Infectious Diseases 492 Vol. 5, No. 4, July–August 1999

 Special Issue

deadly pathogen in a public place—physicians fight against bioterrorism, the federal govern-
must be able to recognize and report cases that ment, particularly HHS, has a leadership role.
come to attention in emergency rooms and Among other things, we need to support state
doctors’ offices; public health officials must be and local planning efforts, provide training at
able to conduct investigations to establish the every level, develop an infrastructure for
likely site/time of exposure, the size and location delivering mass medical care, and offer expertise
of the exposed population, and the prospects for to our communities.
secondary transmission; and appropriately This is a fight we certainly cannot win by
traned laboratory personnel must be available to ourselves. Across the board, we must forge new
identify the biological agent. Whether the working partnerships among health, public
release of a bioweapon is announced or safety, and intelligence agencies. We need
surreptitious, affected persons may not have unprecedented cooperation among the federal
symptoms for days or even weeks, and by then government, state and local health agencies, and
they would be geographically dispersed. Quaran- the medical community. We must ensure that
tine is not practical because only one biological plans for managing the medical consequences of
agent—smallpox—is communicable. Even with terrorist acts are well integrated and coordi-
smallpox, it would be impossible to know whom nated with other emergency response systems.
to quarantine because of the spread of disease by Close collaborative efforts are necessary also
secondary transmission and the difficulty in because microbes do not respect boundaries of
accurately identifying those who have been culture, language, or territory. An act of
exposed. A strong electronic communications bioterrorism cannot be contained by any national
network would be needed to piece together early border or barrier. When it comes to microbes, we
reports, as well as epidemiologic and laboratory are not protected, in the words of the Indian poet
data, to determine what had happened so that Tagore, “by narrow domestic walls.” Since these
public health and law enforcement officials can organisms recognize no boundaries, in our battle
take prompt action. The Centers for Disease against them, neither can we. Because we share
Control and Prevention would play an important a common future, we must share a common
role in this process because of its particular resolve. As Dr. Gro Bruntland, the director-
expertise in surveillance, infectious disease, and general of the World Health Organization, has
public health. Everyone—from the physicians said, when it comes to public health and safety,
who first see victims to the scientists who “Solutions, like the problems, have to be global...”
identify the infectious agents—must coordinate As we work together to counter bioterrorism, we
their efforts. must pool our will and our resources to meet the
That brings me to the fourth, and final, challenges.
challenge: We must all work together. In the

Vol. 5, No. 4, July–August 1999 493 Emerging Infectious Diseases

 Special Issue

The Emerging Threat of Bioterrorism

James M. Hughes
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

The threat of bioterrorism focuses attention capacity in clinical and public health settings.
on overall preparedness to address the The outbreaks have illustrated disruptions of
challenges posed by new and reemerging travel and commerce and potential threats to
infectious diseases. Bioterrorism scenarios national security. The complications of naturally
illustrate the diversity of disciplines and occurring, complex epidemics underline the
perspectives required to confront these threats, global implications of local problems. These
whether naturally occurring or purposely lessons are directly relevant to the threat of
caused. The need to strengthen existing and bioterrorism. The challenges of recognizing
develop new partnerships is clear. disease resulting from the clandestine release of
Since late 1992, a number of large, complex an infectious agent are considerable, given the
outbreaks have occurred in the United States. potential for geographic dispersion of the agent
These include the epidemic of over 400,000 cases (through travel) during the incubation period.
of waterborne cryptosporidiosis in Milwaukee, The public health approach to bioterrorism must
the outbreak of severe, unexplained acute begin with the development of local and state
respiratory disease now known as hantavirus plans formulated collaboratively by the public
pulmonary syndrome in the Spring of 1993, the health, emergency response, and law enforce-
nationwide foodborne salmonellosis outbreak ment communities, which must work together
caused by contaminated ice cream that closely in this phase if an epidemic is to be
accounted for an estimated 250,000 cases in the detected in a timely manner, which is critical to
fall of 1994, and the increasing problems posed its appropriate management. Local health
by antimicrobial-resistant organisms in commu- departments and health-care workers will be on
nity and health-care settings. Epidemics of the front lines in detection and response.
plague in India, Ebola hemorrhagic fever in Infection control practitioners, emergency de-
Central Africa, avian (H5N1) influenza in Hong partment personnel, microbiologists, first re-
Kong, Hendra virus infection in Australia, and sponders, emergency management personnel,
Nipah virus infection recently in Malaysia and and local, state, and federal law enforcement
Singapore required an international response. personnel will play vital roles and must engage
During the hantavirus, plague, and Ebola with each other during the planning stage. Close
investigations, concerns regarding the possibil- collaboration between the clinical and public
ity of bioterrorism were raised early in the health communities will also be critical.
investigations, though these concerns were not From a public health perspective, timely
supported by subsequent findings. surveillance, clinician awareness of syndromes
Investigating these outbreaks in collabora- potentially resulting from bioterrorism, epide-
tion with local, national, and international miologic investigation capacity, laboratory
partners has provided a number of important diagnostic capacity in both clinical and public
lessons, which are reinforced by the threat of health laboratory settings, and the ability to
bioterrorism. We must avoid complacency and rapidly communicate critical information at the
stress preparedness through careful planning local level to those who have a need to know and
and testing of emergency response plans. There to manage public communication through the
is a critical need to strengthen surveillance media will be vital. In addition, ensuring the
systems and epidemiologic and laboratory timely availability of an adequate supply of
antimicrobial drugs, antitoxins, and vaccines is a
Address for correspondence: James M. Hughes, National formidable challenge. Deployment and adminis-
Center for Infectious Diseases, Centers for Disease Control tration of stockpiled components to those
and Prevention, 1600 Clifton Rd NE, Mail Stop C12, Atlanta, affected or at greatest risk are also critical.
GA 30333, USA; fax: 404-639-3039; e-mail: jmh2@cdc.gov.

Emerging Infectious Diseases 494 Vol. 5, No. 4, July–August 1999

 Special Issue

Recognition of the need for local, regional, of emerging infectious diseases. So we will
and national preparedness for bioterrorism benefit even if we are successful in avoiding
provides an opportunity to strengthen the public these attacks”(1).
health system and its linkages with current and
new partners. As President Bill Clinton said in References
his address at the National Academy of Sciences 1. Clinton WJ. Remarks by the President on keeping
in January 1998, “These cutting edge efforts will America secure for the 21st Century. National
Academy of Sciences, Washington, D.C., January 22,
address not only the threat of weapons of mass
1999.
destruction, but also the equally serious danger

Vol. 5, No. 4, July–August 1999 495 Emerging Infectious Diseases

 Special Issue

View from the Hill: Congressional

Efforts to Address Bioterrorism
S. Anthony McCann
U.S. House of Representatives, Washington, D.C., USA

In government—and particularly in the and national levels. Many people equate

federal government—ideas normally come from bioterrorism with chemical or explosive acci-
the bottom up. When finally approved, proposals dents that are obvious and identifiable. The
are reasonably well thought out in terms of what insidious nature of bioterrorist attacks should be
we are going to do and why we are going to do it. better explored and communicated.
Sometimes knowledge of “what” we are going to Finally, over the last 20 or 25 years, efforts to
do far exceeds the ability to explain why we are bring about structural reform in state and local
going to do it. However, for bioterrorism we are governments and in local public health
better able to talk about the “why” than the departments have eroded. Efforts by Congress to
“what.” When Congress received a request from fund the bioterrorism initiative may have a dual
the administration to address bioterrorism, we effect: they may not only improve our ability to
had only the vaguest idea what they wanted to respond to a bioterrorist incident but also may
do. As a result, the availability of funds was strengthen state and local health departments.
delayed until an operating plan was in place. We
are still fleshing out exactly how to approach this S. Anthony McCann is Staff Director for the House Ap-
propriations Subcommittee handling the budgets for the
problem, what the roles of the various agencies
Departments of Labor, Health and Human Services, and
are, and what the legal issues are. Education. In this capacity, Mr. McCann provides sup-
It is incumbent upon the community to spend port and makes policy recommendations to the Chair-
more time studying the proposal and coming man and majority members for over $70 billion in dis-
back to Congress with more detail. cretionary programs under the subcommittee’s jurisdic-
As the scientific community examines the tion. Mr. McCann also served under the Bush Adminis-
issues involved in bioterrorism, an education tration as Assistant Secretary for Finance and IRM and
campaign should be undertaken to inform the Chief Financial Officer of the Department of Veterans
public and the members of Congress at the local Affairs.

Address for correspondence: S. Anthony McCann, U.S. House

of Representatives, Appropriations Committee, Subcommittee
on Labor, Health and Human Services, Education, and Related
Agencies, 2358 Rayburn House Office Building, Washington,
D.C. 20515-6024, USA; fax: 202-225-3509.

Emerging Infectious Diseases 496 Vol. 5, No. 4, July–August 1999

 Special Issue

Finding the Right Balance

against Bioterrorism
Richard A. Clarke
The White House, Washington, D.C., USA

For the first time the Deparment of Health weapons against the United States, we should
and Human Services is part of the national not be raising the specter of horror; instead we
security apparatus of the United States. That should be quietly working in Geneva to improve
reflects a change in our views on chemical and the ban on biological weapons. We are pushing in
biological defense programs. Almost 5 years ago Geneva, but that is not enough. When we learn of
at the bidding of the president we began to look a specific threat, it will be too late to do research
at what has come to be known as “asymmetrical and development, too late to procure medicines,
threats,” ways in which opponents (be they too late to train local authorities.
nations or terrorist groups) could attack us The current bioterrorism initiative includes
without directly engaging our military forces. At a new concept: the first-ever procurement of
the same time we were faced with two events specialized medicines for a national civilian
that drew our attention to chemical and protection stockpile. As new vaccines and
biological threats. Iraq used chemical weapons medicines are developed, that program can be
on Iran and on its own citizens and appeared to expanded. The initiative includes invigoration of
be concealing a biological weapons program. research and development in the science of
Also, the hitherto unknown Japanese cult Aum biodefense; it invests in pathogen genome
Shinrikyo used sarin nerve agent in the Tokyo sequencing, new vaccine research, new thera-
subway; the cult failed in an attempt to use peutics research, and development of improved
biological weapons against Americans in Japan. detection and diagnostic systems. The 2-year
In 1998, the president launched the first program provides for Department of Health and
national effort to create a biological weapons Human Services research, almost tripling the
defense for the United States. While some previous 2-year effort, in addition to ongoing
believe that the response is not strong enough, work in the Defense Department, and it includes
many others think that the proposed program a reinitiation of the federal program to help state
exaggerates the threat, that biological weapons and local public health infrastructure and
are too unpredictable, and that the only big surveillance systems.
biological weapons program died with the Soviet The biological weapons protection program is
Union. However, the former Soviet Union was part of the overall chemical and biological
not the only state engaged in biological weapons protection effort, which includes aid to state and
research and development. Almost every nation local governments for first-responder training,
on the State Department’s list of nations that planning, exercises, and equipment.
sponsor terrorism has engaged in chemical and
Richard A. Clarke serves as the country’s first National
or biological weapons development. If these
Coordinator for Security, Infrastructure Protection and
nations have armed, trained, funded, and Counter-Terrorism. He was Deputy Assistant Secretary
advised terrorist groups, they could cross the line of State for Intelligence in the Reagan Administration
and provide terrorists with chemical or biological and served in the Bush Administration as Assistant
weapons. Finally, some critics say that until we Secretary of State for Politico-Military Affairs.
really know about a specific threat to use these

Address for correspondence: Richard A. Clarke, National

Security Council, 17th and Pennsylvania Avenue, N.W.,
Washington, D.C. 20504; fax: 202-456-9360.

Vol. 5, No. 4, July–August 1999 497 Emerging Infectious Diseases

 Special Issue

Historical Trends Related to Bioterrorism:

An Empirical Analysis
Jonathan B. Tucker
Monterey Institute of International Studies, Monterey, California, USA

Since the Japanese doomsday cult Aum in the frequency of such incidents, the
Shinrikyo released sarin nerve gas on the Tokyo underlying motives, and the choice of agent and
subway in March 1995, killing 12 people, target. The ultimate goal is to identify which
terrorist incidents and hoaxes involving toxic or types of individuals or groups are most likely to
infectious agents have been on the rise. Before acquire and use toxic or infectious materials and
the late 1990s, the Federal Bureau of for what purposes.
Investigation (FBI) typically investigated a Since the Monterey Database has been
dozen cases per year involving the acquisition or compiled from journalistic accounts and other
use of chemical, biological, radiologic, or nuclear unclassified sources, it may not be comprehen-
materials; however, FBI opened 74 such sive or fully accurate. Incidents have been
investigations in 1997 and 181 in 1998 (1). recorded only if they came to the attention of law
Although 80% of these incidents have been enforcement or the news media, so the database
hoaxes, some were unsuccessful attacks (2). does not include events that were not detected or
The vulnerability of civilian populations to whose existence remains secret. Despite these
chemical, biological, radiologic, or nuclear limitations, the information in the database
terrorism has been widely discussed, but indicates trends and patterns of behavior that
information on historical cases is anecdotal and may assist intelligence and law-enforcement
often inaccurate (3). Without a realistic threat personnel in focusing their monitoring efforts.
assessment based on solid empirical data,
government policymakers lack the knowledge Database Findings
they need to design prudent and cost-effective Most of the incidents in the Monterey
programs for preventing or mitigating future Database involve chemical or biological agents
incidents. rather than radiologic or nuclear materials
Responding to this knowledge gap, the (Figure 1). The cases have been divided into
Chemical and Biological Weapons Nonprolifera- three categories: terrorist events, criminal
tion Project at the Monterey Institute’s Center events, and state-sponsored assassinations. To
for Nonproliferation Studies has compiled an be classified as a terrorist event, an incident
open-source database of all publicly known cases must involve an organization or person that
from 1900 to the present in which domestic or conspires to use violence instrumentally to
international criminals or terrorists sought to
acquire or use chemical, biological, radiologic, or
nuclear materials. As of January 31, 1999, the
database contained 415 incidents, both domestic
and international. Each entry draws on multiple
sources and includes a detailed description of the
event and a list of citations.
The project has conducted a preliminary
analysis of the data to discern patterns over time
Address for correspondence: Jonathan B. Tucker, Chemical
and Biological Weapons Nonproliferation Project, Center for
Nonproliferation Studies, Monterey Institute of International
Studies, 425 Van Buren Street, Monterey, CA 93940, USA; fax: Figure 1. Overall database: Distribution of incident
831-647-6534; e-mail: jtucker@miis.edu. by type, 1960–Jan. 31, 1999 (415 cases).

Emerging Infectious Diseases 498 Vol. 5, No. 4, July–August 1999

 Special Issue

advance a political, ideologic, or religious goal. the intent of inflicting mass casualties. Of the
Criminal incidents, in contrast, involve extor- 151 terrorist incidents, a subset of 33 involves
tion, murder, or some other nonpolitical biological agents (22 alleged biological cases were
objective. Of the 415 incidents involving dropped from the analysis because they lacked
chemical, biological, radiologic, or nuclear key pieces of information). Many of the
materials, 151 cases are terrorist events for biological-agent cases are hoaxes.
which information is sufficient to permit cross- Since 1985, the number of terrorist incidents
case comparison. These incidents have been involving the threatened or actual use of
classified according to type of agent, event, chemical, biological, radiologic, or nuclear
target, motive, and group (Figure 2). materials has risen sharply; a more modest
“Type of event” includes the following increase has occurred in efforts to acquire such
categories: 1) conspiracy to acquire and use an agents. When criminal and terrorist incidents
agent, 2) attempted acquisition, 3) possession, involving chemical or biological agents are
4) threatened use, 5) actual use, and 6) hoax or examined, two large peaks become apparent
prank. Most of the 151 incidents involve (Figure 3a). The 1995 peak was associated
threatened or actual use, although rarely with primarily with Aum Shinrikyo and related

Lone psychopaths

Figure 2. Standardized typology used in analysis of politically or ideologically motivated incidents.

Vol. 5, No. 4, July–August 1999 499 Emerging Infectious Diseases

 Special Issue

copycat attacks in Japan; in 1998, incidents of turned out to be a harmless veterinary vaccine
actual use again increased abruptly (Figure 3a). strain, sensational media coverage appears to
Hoaxes involving chemical or biological have had the unintended effect of popularizing
agents have shown two peaks in frequency over this agent among potential perpetrators.
the past 30 years (Figure 3b). The 1986 peak in The categories of terrorist organizations
chemical hoaxes was inspired by the second involved in the acquisition and use of chemical,
series of Tylenol poisonings, while the dramatic biological, radiologic, or nuclear materials have
rise in biological hoaxes in 1998 is attributable to changed over time. Omitting incidents involving
the flurry of anthrax threats in the United lone terrorists, recent years have seen a rise in
States. The first wave of anthrax hoaxes followed cases involving three types of terrorist organiza-
the well-publicized arrest on February 18, 1998, tions: single-issue groups such as those dealing
of Larry Wayne Harris, a microbiologist linked to with abortion and animal rights; nationalist and
white-supremacist groups, after he allegedly separatist groups such as Chechen rebel
threatened to release “military-grade anthrax” organizations, the Kurdistan Workers Party,
in Las Vegas (4). Although Harris’s anthrax and the Tamil Tigers of Sri Lanka; and

Figure 3. (A) Actual chemical and biological incidents vs. hoaxes, 1960–1998 (278 cases). (B) Chemical and
biological hoaxes over time, 1960–1998 (93 cases: 43 chemical, 50 biological).

Emerging Infectious Diseases 500 Vol. 5, No. 4, July–August 1999

 Special Issue

apocalyptic religious cults such as Aum appear to encompass a wide range of objectives.
Shinrikyo (although Aum accounts for nearly all (For each case, two analysts separately
the latter cases). No clear pattern is apparent in determined the “best fit” to a menu of
the types of groups involved in biological motivations.) In descending order, the main
incidents, although religious fundamentalism as motivations are: 1) to promote nationalist or
a motivation has emerged within the past 5 years. separatist objectives; 2) to retaliate or take
The preferred choice of target has also revenge for a real or perceived injury; 3) to
changed over time. If one examines 135 terrorist protest government policies; and 4) to defend
incidents for which the target is known, two animal rights (Figure 4). A similar breakdown of
types of targets have increased in frequency: the motivations is found in the incidents involving
general civilian population (with the apparent biological agents, except for the greater
intent of inflicting indiscriminate casualties) and prominence of apocalyptic prophecy (Figure 5).
a symbolic building or organization. Nearly all the latter cases are linked to Aum
Motivations for the terrorist use of chemical, Shinrikyo, which may be either an outlier or a
biological, radiologic, or nuclear materials trend-setter.

Figure 4. Distribution of motivations for chemical and biological terrorism incidents, 1960–Jan. 31, 1999 (147
cases).

Figure 5. Distribution of motivations for biological terrorism incidents, 1960–Jan. 31, 1999 (33 cases).

Vol. 5, No. 4, July–August 1999 501 Emerging Infectious Diseases

 Special Issue

The motivations underlying terrorist inci- prominence of these three motivations becomes
dents with chemical, biological, radiologic, or even greater when only incidents involving
nuclear materials appear to have shifted over biological agents are examined.
time. The predominant motivation from 1975 to In addition to compiling the incidents
1989 was to protest government policies. Since database, the project commissioned historical
1990, however, the leading motivations have case studies of seven terrorist groups or
been to further nationalist or separatist individuals that acquired or employed biological
objectives and for retaliation or revenge. In 1993, agents (Table 1). Two of the cases appear to be
because of Aum Shinrikyo, apocalyptic prophecy apocryphal, but the five confirmed cases share a
also emerged as an important motivation. The number of characteristics that may be diagnostic

Table 1. Comparison of Values Across Selected Bioterrorist Incidents

Case Motivation/Objective Ideology Target(s) Agent(s) Delivery Outcome
Weather Temporarily incapacitate Revolutionary Urban Reportedly Reportedly Report
Underground U.S. cities to movement op- populations sought to ob- planned to originated with
(1970) demonstrate posed to Ameri- in the tain agents at put incapacita- U.S. Customs
impotence of the can imperialism United Ft. Detrick ting CW/BW informant;
federal government and the States by blackmail agents in ur- case probably
Vietnam War of gay soldier ban water apocryphal

R.I.S.E. (1972) Kill off most of humanity Perpetrators Initially Eight micro- Planned BW Attack aborted
to prevent the destruc- were college entire world bial pathogens aerosol when cultures
tion of nature, then start students population, including attacks were
human race over with a influenced by later nar- agents of (dispersed by discovered; the
select few ecoterrorist rowed to resi- typhoid fever, aircraft) and two main
ideology and dents of five diphtheria, contamination perpetrators
1960s drug states around dysentery, and of urban water then fled to
culture Chicago meningitis supplies Cuba

Red Army Allegedly planned BW Marxist- Specific Group mem- Unknown Probably an
Faction (1980) attacks against West revolutionary targets ber allegedly erroneous
German officials and ideology unknown cultivated botu- report, later
business leaders linum toxin in a repudiated by
Paris safe-house German gov-
ernment (BKA)

Rajneeshee Scheme to incapacitate Indian reli- Residents Salmonella Multiple Plot revealed
Cult (1984) voters to win local gious cult of the town Typhimurium methods, when the cult
election, seize political headed by a of The Dalles mainly con- collapsed and
control of county charismatic and Wasco tamination of members
guru County, restaurant turned
Oregon salad bars informant

Minnesota Cause harm to Anti-govern- IRS offi- Ricin Planned to Group was
Patriots the federal govern- ment tax cials, U.S. extracted deliver ricin penetrated
Council (1991) ment, obtain personal protesters; deputy mar- from castor through skin by FBI
revenge right-wing shal, local beans with DMSO informants;
“patriot” law enforce- obtained by and aloe vera, four key
movement ment mail-order or as dry members
officials aerosol arrested

Aum Shinrikyo Prove an apocalyptic New Age Mass Biological Attempted on Multiple
(1995) prophecy, eliminate doomsday civilian agents at least 10 CW attacks
enemies and rivals, cult seeking populations, (anthrax, occasions to (in Matsumoto,
halt an adverse court to establish individual botulinum disperse BW Tokyo, and
ruling, seize control a theocratic opponents toxin, Q fever agents in assassination
of Japanese government state in Japan, of cult, Ebola virus) aerosol form; campaign)
with a charis- judges ruling and chemical all known killed at least
matic, power- against and agents (sarin, attacks failed 20 people and
hungry leader police inves- VX, hydrogen injured more
tigating cult cyanide) than 1,000

Larry Wayne To alert Americans to Links to Made vague Obtained Discussed Arrested when
Harris (1998) the Iraqi BW threat; Christian threats plague and the dissemi- he talked
seeks separate Identity and against U.S. anthrax (vac- nation of openly about
homeland for whites white federal offi- cine strain), BW agents BW terrorism
in the United States supremacist cials on be- reportedly with crop- and made
groups (e.g., half of right- isolated seve- duster aircraft threatening
the Aryan wing “patriot” ral other and other remarks to
Nation) groups bacteria methods U.S. officials
BW, biological weapons; CW, chemical weapons; DMSO, dimethylsulfoxide; IRS, Internal Revenue Service; FBI, Federal Bureau of
Investigation.

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of groups and individuals most likely to engage rant salad bars in The Dalles, Oregon. This event
in bioterrorism (Table 2). These characteristics caused 751 cases of food poisoning, none fatal (5).
include diffuse objectives, a sense of grandiosity, Incidents of bioterrorism in the Monterey
and a paranoid, conspiratorial, or apocalyptic Database are extremely diverse in terms of type
world view that may lead to “defensive of group and motivation. The trend in recent
aggression.” Such terrorists also lack a domestic years has been away from left-wing terrorism
political constituency that might restrain them and toward nationalist-separatist groups and
from engaging in indiscriminate violence. individuals or ad hoc groups bent on revenge.
Religiously motivated cults such as Aum There has also been an apparent rise in incidents
Shinrikyo and the Rajneeshees are cut off from perpetrated by violent sects or cults that believe
the outside world and are often guided by a in apocalyptic prophecy.
charismatic, all-powerful leader, making them Even if the motivation to inflict mass
less subject to societal norms. Other factors not casualties exists, however, few terrorist groups
listed in the table include a tendency to escalate possess the scientific-technical resources re-
terrorist violence over time and to use innovative quired for the successful large-scale release of a
weapons and tactics. biological agent. Aum Shinrikyo, which had

Table 2. Selected Motivational Factors Associated with Bioterrorism

Loner or Sense of
Charismatic No outside Apocalyptic splinter paranoia and Defensive
Cases leadership constituency ideology group grandiosity aggression
R.I.S.E. X X X X X
Rajneeshee Cult X X X X X
Minnesota Patriots X X X X X X
Council
Aum Shinrikyo X X X X X
Larry Wayne Harris X X X X X

Apparently
Apocryphal
Cases
Weather Underground X X
Red Army Faction X X

Conclusions considerable wealth and scientific expertise,

The Monterey Database indicates that failed in 10 separate attempts to carry out open-
incidents involving biological agents have been air attacks against urban targets with aero-
quite rare, with 66 criminal events and 55 solized anthrax spores or botulinum toxin (6).
terrorist events over the 40-year period from In summary, the historical record suggests
1960 to 1999, although the frequency of such that future incidents of bioterrorism will
incidents (mainly hoaxes) has increased sharply probably involve hoaxes and relatively small-
in recent years. The historical record includes scale attacks, such as food contamination.
few cases in which criminals or terrorists sought Nevertheless, the diffusion of dual-use technolo-
to inflict mass casualties with biological agents, gies relevant to the production of biological and
and none in which they succeeded. Only eight toxin agents, and the potential availability of
criminal attacks with biological agents led to scientists and engineers formerly employed in
casualties, inflicting a total of 29 deaths and 31 sophisticated biological warfare programs such
injuries. Of the terrorist attacks with biological as those of the Soviet Union and South Africa,
agents, only one resulted in casualties: the use by suggest that the technical barriers to mass-
the Rajneeshee cult in 1984 of Salmonella casualty terrorism are eroding.
Typhimurium bacteria to contaminate restau-

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Acknowledgments 3. For a revealing account of the inconsistencies and

The author thanks Jason Pate and Diana McCauley for inaccuracies in the secondary literature on CBW
their outstanding work in compiling and analyzing the terrorism, see Ron Purver, Chemical and biological
Monterey Database of chemical, biological, radiologic, and terrorism: the threat according to the open literature
nuclear incidents. (Ottawa, Canada: Canadian Security Intelligence
Service, June 1995).
Dr. Tucker is director of the Chemical and Biologi- 4. Edwards TM. Catching a 48-hour bug. Time 1998 Mar 2;
cal Weapons Nonproliferation Project, Center for Non- p. 56-7.
proliferation Studies, Monterey Institute of International 5. Török TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow
Studies. R, Mauvais S, et al. A large community outbreak of
salmonellosis caused by intentional contamination of
restaurant salad bars. JAMA 1997;278:389-95.
References 6. WuDunn S, Miller J, Broad WJ. How Japan germ terror
1. Parker-Tursman J. FBI briefed on district’s terror alerted world. New York Times 1998 May 26; Sect A:1
curbs. Pittsburgh Post-Gazette, May 5, 1999. (col 1), A:10 (col 1-5).
2. Weiner T. Reno says U.S. may stockpile medicine for
terrorist attacks. New York Times 1998 Apr 23; Sect. A:12.

Emerging Infectious Diseases 504 Vol. 5, No. 4, July–August 1999

 Special Issue

The Threat of Biological Attack:

Why Concern Now?
David W. Siegrist
Potomac Institute for Policy Studies, Arlington, Virginia, USA

For a biological attack to occur, three chemical weapons, including nerve gas. In
elements must be in place: a vulnerable target, a certain circumstances, biological weapons can be
person or group with the capability to attack, and as devastating as nuclear ones—a few kilograms
the intent (by the perpetrator) to carry out such of anthrax can kill as many people as a
an attack. Much of what can be done to limit the Hiroshima-size nuclear weapon (Figure).
capability and the intent of potential attackers is The United States is unprepared to deal with
already on its way to being accomplished. The a biological attack. Over the past several years,
most work, and the highest return on preparedness strides have been made, especially
investment, involve reducing the vulnerability of in the largest cities. However, much of the
the United States to both intentional and needed equipment is not available. Pathogen
unintentional pathogen releases. sensors are not in place to detect that a biological
attack has taken place. New medicines are
Vulnerability to Biological Attack needed. In combating terrorist attacks, treat-
Among weapons of mass destruction, ment is a more practical approach than
biological weapons are more destructive than prevention; yet many biological agents are
extremely difficult to treat
with existing medicines once
the symptoms appear. In
addition, many of the most
important prophylactic drugs
have limited shelf lives and
cannot be stockpiled. More-
over, their effectiveness could
be compromised by a sophis-
ticated attacker.
Local emergency medical
response capability is lim-
ited. A number of localities
define a “mass casualty
event” as one with more than
a dozen casualties, far fewer
than an intentional biological
release could cause. Emer-
gency room capacity in major
cities can be overwhelmed all
too quickly by more common
emergencies. Much emer-
Figure. Effects of a nuclear and a biological weapons release. gency medical capability is
also located in downtown
areas that may be targeted
Address for correspondence: David W. Siegrist, Potomac
for attack.
Institute for Policy Studies, 1600 Wilson Boulevard, Suite
1200, Arlington, VA 22209, USA; fax: 703-525-0299; e-mail: The National Disaster Medical System has
siegrist@potomacinstitute.com. voluntary access to approximately 100,000

Vol. 5, No. 4, July–August 1999 505 Emerging Infectious Diseases

 Special Issue

hospital beds across the country to cope with a expertise is required to produce high-quality,
large-scale medical emergency. However, not all military-grade biological weapons and reliable
of those beds have the specialized means for means of dissemination, terrorist applications
patient respiration and supportive therapy that are less demanding.
may be needed in a crisis. Such equipment is not Making biological weapons requires sample
available in large numbers (>5,000), even from cultures; the means to grow, purify, and stabilize
deployable field hospital Department of Defense them; and the means to reliably disseminate
war stocks (1). Further, current federal plans them. All these tasks pose substantial but not
favor not evacuating injured people from the insurmountable challenges. More than 1,500
affected area but may relocate patients who were biological culture libraries worldwide, as well as
already in hospitals to free up local bed space (2). numerous research institutions and natural
This indicates that localities need to increase sources, maintain sample cultures (5). Growth
their own capabilities. The federal government media and fermenters to multiply the sample
will augment local efforts, not supersede them. cultures are widely available. Purifying, concen-
Steps are being taken to decrease U.S. trating, and stabilizing agents is demanding and
vulnerability to biological attack. Technical dangerous but not a great technical challenge.
research is being supported, needed medicines Freeze-drying the product and milling it into
and vaccines will be acquired, and emergency particles of a uniform respirable size requires
response templates are being developed. One of even more technical capabilities. A state sponsor
the reforms was setting up the Office of State and may be needed to do it, although companies and
Local Domestic Preparedness Support within institutes regularly spray dry and mill commer-
the Department of Justice. The office has cial microbes. Moreover, a respirable aerosol of
developed a set of objective criteria that measure germs can be achieved through other high-
domestic readiness to deal with an attack by a pressure devices.
weapon of mass destruction. No locality has yet Biological production and weapon-producing
qualified for the top ranking—being prepared for facilities can be small, inexpensive, and
such a crisis (3). inconspicuous. Equipment to develop biological
arms may have legitimate commercial and
Perpetrator Capability research purposes, as well as nefarious ones.
Biological weapons can range in lethality Unlike nuclear weapons, biological weapons do
from salmonella used to temporarily incapacitate not require unique ingredients that are ready
to super bubonic plague engineered for mass objects of arms control.
casualities. Biological weapons include ricin,
which an extremist may use to assassinate a Institutional Capability
single local official, as well as pathogens with Depending on their sophistication, terrorist
high transmissibility and broad potential groups may or may not have the capability to
impact. Biological agents may be used to kill or build broad-impact biological weapons. How-
disable humans or to attack plants or animals to ever, most nations have the capability to make
harm a nation’s economy. Given that broad biological weapons. Some 18 nations are believed
scope, biological attacks have already taken to have done so, including the former Soviet
place and continue to be a distinct probability for Union and several nations the State Department
the foreseeable future (4). However, of greatest lists as supporting terrorism.
concern is the capability to deliver a sizable
lethal attack against a population center. Intention to Use Biological Weapons
Why would anyone wish to use biological
Technical Capability weapons? A leading entity with a motive to
Making reliable biological weapons requires perpetrate a biological attack could be a rogue
art as well as science. Such weapons are not state as an act of clandestine warfare. The very
readily adaptable to “cookbook” type recipes that strength of a superpower may provide an
can be implemented by novices. Nevertheless, incentive to adversaries to challenge this
technical expertise and sophistication about strength unconventionally.
biological processes have become much more If a rogue regime were to mount such an
widespread. Moreover, even though technical unconventional asymmetric attack, they might

Emerging Infectious Diseases 506 Vol. 5, No. 4, July–August 1999

 Special Issue

choose biological weapons because their extreme infectious diseases on the world (Table) (8). An
destructive potential is concentrated in a influenza pandemic was averted 2 years ago by
relatively small and unremarkable package with the alert and energetic actions of epidemiologists
virtually no detectable sensor signature. Be- in Hong Kong and around the world. Slower
cause of the agent’s incubation period, the reactions might have permitted the pathogen’s
perpetrators might be gone before anyone knew genes to shuffle among human and avian
that an attack had been made. Finally, biological infections to make the flu strain readily
agents, unlike ballistic missiles, lend themselves transmissible from person to person. Multidrug-
to clandestine dissemination. resistant tuberculosis is increasing rapidly in
Warfare itself may be becoming more total Russia in part because of lack of adequate
and losing much of its political character in some antibiotics (9). More health challenges are
situations. Biological weapons, which kill people almost certainly in store. Causes contributing to
but leave infrastructure intact, could become the emerging disease outbreaks (overcrowding,
“poor man’s neutron bomb.” deforestation, airline travel) will likely continue
In the past, the essence of terrorism was to (9).
make a political statement through violence. It Health security and national security needs
was a political act designed to influence an overlap. If the United States prepares to confront
audience. Levels of violence were carefully and defeat intentional human releases of
calculated so as to draw attention but not to be so pathogens, we will be better prepared for the
high as to alienate supporters or trigger unpredictable but robust threats likely to occur
overwhelming response from authorities. That from nature. For emergency medical response,
continues to be a main theme of conventional patients need rapid and efficacious treatment,
terrorism. However, in so-called postmodern or whether the source of an outbreak of disease is
superterrorism, the aim is to maximize the intentional or natural. Medical research needs
number of casualties (6). This reflects a shift in drugs that treat disease after symptoms become
the goal of the terrorists, from trying to make a apparent. Such drugs might target common
political statement through violence to maximiz- features of disease (10), e.g., inflammation
ing damage to the target as an end in itself. Such cascade and toxic shock. Aerosol challenge is also
terrorists may be motivated by ethnic or typical of both military threats and other
religious considerations, among others (7). airborne pathogens; vaccines that enhance
Even conventional terrorism tends to mucosal immunity may mitigate them. Expres-
escalate levels of violence to keep garnering sion of specific genes that may be critical and
attention. The threat of biological weapons unique to a number of pathogens might one day
imparts high levels of fear that may make them be inhibited by medicine.
desirable to perpetrators who wish to terrorize, Effective and safe multipurpose and specific
even more than to kill. Threats have to become drug treatments would help in the battle against
increasingly credible after the initial shock of both naturally occurring and intentional
specious threats has diminished. Even a minor releases of infectious disease. Through advanced
biological attack, made to demonstrate credibil- biotechnology, we could begin to reverse the
ity, could have a disproportionate impact. Thus, offense-defense mismatch that now greatly
a certain subset of terrorists may be motivated to favors disease over cure.
commit mass casualty terrorism, including
biological terrorism. Conclusions
Vulnerability and capability, two prerequi-
Nonintentional Pathogen Releases sites of bioterrorism, are in place. Enhancing
Certain kinds of biological assaults can be emergency medical preparedness and support-
predicted with even higher confidence than ing advanced pharmaceutical research for
bioterrorist attacks. Stephen Morse, Defense multivalent drugs, among other measures, will
Advanced Research Projects Agency, has said help us deter and defeat deliberate and
that Mother Nature is the greatest terrorist. naturally occurring pathogen releases, as well
Since infectious diseases were widely dismissed as increase the general health and well-being
as a world health threat some 30 years ago, of the population. The intention of potential
nature has loosed some 30 new or reemerging attackers is difficult to manage. Therefore,

Vol. 5, No. 4, July–August 1999 507 Emerging Infectious Diseases

 Special Issue

Table. New and reemerging viruses (8)

Viruses Date Family Comments
New
Human herpesvirus 6 (HHV-6) 1986 Herpesvirus
Human herpesvirus 7 (HHV-7) 1990 Herpesvirus
GS viruses (hepatitis) 1994 Flavivirus
Human herpesvirus 8 (HHV-8) 1995 Herpesvirus

Reemerging
Cocoa swollen shoot Badnavirus Destroyed 200 million cocoa trees in West
Africa.
Dengue Bunyavirus
Ebola Flavivirus
Equine morbillivirus 1994 Morbillivirus Emerged in Brisbane, Australia. Causes
acute respiratory disease with high
mortality in horses. Believed to cause a
fatal encephalitis in humans.
Hantaan group Bunyaviruses
Phocine distemper 1987 Morbillivirus Caused death rates in seals in the Baltic
and North Sea. Similar viruses
subsequently recognized as responsible
for porpoise and dolphin deaths
in the Irish Sea and the Mediterranean.
Rabbit calicivirus disease 1985 Calicivirus Emerged in China, spread naturally
/Viral hemorrhagic through UK and Europe. Introduced to
disease Wardang Island off the coast of South
Australia to test potential for rabbit
population control, accidentally spread to
mainland decimating rabbit
populations.
Rift Valley fever Bunyaviruses
Tomato spotted wilt Bunyavirus
Whitefly-transmitted Geminivirus
geminiviruses (group III
geminiviruses)

Emergency Response,” Washington, DC, March 10, 1999.

limiting our vulnerability is the most
3. Mitchel A. Office of State and Local Domestic
promising way to prevent or mitigate biological Preparedness Support, U.S. Department of Justice. Panel
attacks on the United States. discussion at conference “Integrating Medical and
Emergency Response,” Washington, DC, March 10, 1999.
Mr. Siegrist is research fellow at the Potomac Insti- 4. Carus S. Bioterrorism and biocrimes: the illicit use of
tute for Policy Studies and is director of Studies for Coun- biological agents in the 20th Century. Washington:
tering Biological Terrorism. He is also an adjunct fac- Center for Counterproliferation Research, National
ulty member at Georgetown University, where he was Defense University; 1998.
National Strategy Public Policy Fellow and where he 5. Broad W, Miller J. The threat of germ weapons is rising.
teaches classes on national security. He is the project Fear, too. The New York Times, December 27, 1998.
leader of Countering Biological Terrorism in the U.S., 6. Laqueur W. Postmodern terrorism. Foreign Affairs;
from Oceana Press (May 1999). Sep/Oct 1996.
7. Ikle F. Waiting for the next Lenin. The National
Interest; spring 1997.
References 8. Cann AJ. Principles of molecular virology. 2d ed. San
1. Army Reserve National Guard. Stakeholders III Diego: Harcourt Brace & Co. Academic Press; 1997. p. 230.
Conference Medical Panel. National Guard Bureau, 9. Lee C. US can’t ignore implications of TB plaguing
Arlington, VA, December 1998. Russia. USA Today, February 8, 1999, p. 16A and 232.
2. Tonat K. Office of Emergency Preparedness, U.S. 10. Committee on R&D Needs for Improving Civilian Medical
Department of Health and Human Services. Panel Response to Chemical and Biological Terrorism Incidents,
discussion at conference “Integrating Medical and Chemical and Biological Terrorism: Research and
Development to Improve Civilian Medical Response,
Institute of Medicine, National Research Council, National
Academy Press, Washington: 1999; pp. 129-32.

Emerging Infectious Diseases 508 Vol. 5, No. 4, July–August 1999

 Special Issue

Nuclear Blindness: An Overview of the

Biological Weapons Programs of the
Former Soviet Union and Iraq
Christopher J. Davis
Johns Hopkins University Center for Civilian Biodefense Studies

The demise of the biological weapons not simply rely on reacting to events. We must
capability of the United States in 1969 and the learn to think like our potential adversaries if we
advent of the Biological and Toxin Weapons are to avoid conflict or blunt an attack, because
Convention in 1972 caused governments in the only superior thinking and planning (not just
West to go to sleep to the possibility of biological better technology) will enable us to survive
weapons development throughout the rest of the biological warfare.
world, as technically knowledgeable workers
were transferred and retired, intelligence desks The Former Soviet Union
were closed down, and budgets were cut. By The origins of the biological weapons
1979, despite the Sverdlovsk anthrax release, a program of the former Soviet Union stretch back
senior British government policy official de- to statements by Lenin, and experimental work
scribed any biological weapons threat as was under way by the late 1920s. The modern era
nebulous. President Nixon’s biological weapons was ushered in, however, only with the postwar
disarmament declaration in 1969 had conveyed military building program, which established
the impression that biological weapons were infrastructure for research, development, test-
uncontrollable and that the U.S. program had ing, production, and delivery of a variety of
not been successful in producing usable weapons agents and weapons.
(when in fact the opposite was true). Add to this On the other side of the globe, the allied
the rise of truly intercontinental ballistic missile biological weapons program had grown from the
delivery of nuclear weapons, and the stage was fledgling efforts of British research into anthrax
set for what I have termed “nuclear blindness” and the development of the World War II–
and defined as “the tunnel vision suffered by anthrax cattlecake retaliation weapon into a
successive governments, brought on by the large U.S.-based research and development
mistaken belief that it is only the size of the bang (R&D) and production capability. By 1969, the
that matters.” Throughout this period, both the U.S. military had accepted seven type-classified
former Soviet Union and Iraq conceived, albeit in agents, and, at plants such as the one at Pine
different ways, their new biological weapons Bluff in Arkansas, they could produce 650 tons of
programs. It took until 1989-1991 for govern- agent per month for filling into weapons. This
ment technical experts in the West to persuade thriving offensive program was unilaterally
the world and their own governments that these abandoned in 1969 as a result of a complicated
programs were real and of enormous potential mixture of politics, secret intelligence informa-
importance to the security of the West, if not the tion, new technological developments, and the
whole world. Vietnam War. These developments gave impetus
Too many times in the past we have failed to to the creation of the Biological and Toxin
anticipate future developments; refused to think Weapons Convention, originally drafted by the
the unthinkable and expect the unexpected. Too British but finalized by the Soviet Union.
many times we have been out maneuvered by Although the Soviet Union signed the Conven-
those who take the time to think and plan and do tion at its inception in 1972, it did not believe that
the United States would be so foolish as to
Address for correspondence: Christopher J. Davis, Og House,
Ogbourne St. George, Marlborough, Wiltshire, SN8 1TF,
abandon its biological weapons capability,
United Kingdom; fax: 44-(0)-1672-841418; e-mail: regarding the disarmament agreement as a
christopher.davis1@virgin.net. ‘worthless piece of paper.’

Vol. 5, No. 4, July–August 1999 509 Emerging Infectious Diseases

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In 1973 and 1974, the Soviet Politburo civilian biotechnology and pharmaceutical en-
formed and funded the organization known most terprises. The two systems, the former Ministry
recently as Biopreparat (Chief Directorate for of Defense complex of biological weapons
Biological Preparations), designed to carry out facilities and the new Biopreparat facilities,
offensive biological weapons R&D and produc- continued to operate side-by-side. The Ministry
tion concealed behind legal and civil biotechnol- of Defense facilities themselves probably
ogy research. At no time did civilian biotechnol- employed another 15,000 workers and had a
ogy work ever comprise much more than 15% of separate budget, so that the potential within the
the activity at any of the 52 sites under the aegis system as a whole, which is how it should be
of Biopreparat. Ultimately it was controlled by considered, was large and dwarfed the by-then
the Ministry of Defense, the Military Industrial long-abandoned U.S. offensive program. Its
Commission, and other state organs, all the way capacity for production of agent was measured
up to the Central Committee and what became not in tons but in hundreds of tons for each of at
eventually the Office of the President. Its head, a least nine separate sites, primarily plague,
general, retained special access to the Central tularemia, glanders, anthrax, smallpox, and
Committee from its inception, and through its Venezuelan equine encephalomyelitis.
links with the Academies of Science and Medical Another mission of Biopreparat was to apply
Science, Ministry of Health, and the Anti-Plague advances in biotechnology (genetic engineering,
Institutes, recruited a generation of scientists in particular) to improving the biological
who elsewhere in the world underpinned the weapons capability of the former Soviet Union.
expanding pharmaceutical and biotechnology This mission took several forms, supported
industries and academic life-sciences research. primarily by the then vice-president of the
The whole system probably employed at its Academy of Sciences, Yuri Ovchinnikov, the
height at least 50,000 people, many of whom most influential Soviet biomedical scientist of
were scientists and technicians with very high the 1970s. He saw a way around arms control
security clearance that identified them as part of treaties and weapons conventions by using
a biological weapons program more closely held microbes to produce biologically active sub-
and more secret than its nuclear weapons stances that would replace classic chemical
counterpart. The system was always able to draw weapons; their production could then be
on the best from any source but was, to a certain concealed in the biotechnology or pharmaceuti-
extent, self-sufficient. Not all of the 52 cal industry. He also envisaged that the
establishments were occupied with microbiology government would use genetic engineering to
or weapons—some were workshops, garages, produce a new generation of biological weapons
and cover operations; others supported the agents with enhanced capability for expressing
program directly with fermenter design and toxins and other biologically active substances
construction or building of weapons test and to improve overall weapons effectiveness.
chambers; while yet others carried out advanced The outcome of the first of these two programs is
research, which would then be given to other not known, but the latter was very successful.
institutes for development. Often there was Moreover, the new Biopreparat-based program
internal competition, with one project being was able to address all aspects of agent
given to a number of facilities to see who would production and delivery, not just the most
come up with the best idea. In its first 15 years advanced microbiological ones. It built strength
alone, Biopreparat probably cost at least 1.5 in depth, having as its main aims to improve
billion rubles to create and run—a large sum for industrial production scale-up techniques, mi-
life-sciences R&D but relatively modest com- crobial production rates, yields of viable
pared with the cost of nuclear weapons R&D and, microorganisms, virulence, and resistance of
therefore, in terms of strategic weapons, microorganisms to antibiotics; to maximize
extremely cost-effective. viability of agent during dissemination and
The main purpose of the enormous increased survivability of biological aerosols; and
Biopreparat capability was to hide biological to enhance the ability of microorganisms to
weapons research, development, and production degrade the target’s natural defenses. The
formerly carried out solely in Ministry of Defense leaders of the program foresaw increasing
establishments behind a facade of nominally encroachment of international arms control

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 Special Issue

processes into the territory of sovereign states. which were categorized as strategic weapons and
Thus, they perceived the need for its weapons to destined for use against enemy population centers.
become invulnerable to first strike or counterat- What happened after Vladimir Pasechnik
tack. Key technical targets associated with such (the former general director of Science Produc-
an approach were the development of dry solid tion Organisation Farmpribor and director of
particulate agent formulations, miniaturized The All Union Scientific Research Institute of
production facilities, mobile production and Ultra Pure Biopreparations in Leningrad [St.
filling facilities, strains resistant to multiple Petersburg]) defected in 1989 constitutes a long
antibiotics, cruise missile dissemination system, and complex story, but in January 1991 the first-
and combination organisms. ever visit to Biopreparat facilities was under-
By addressing every aspect of weapon taken, by a joint U.K./U.S. technical team, under
production, from selection of new strains of a cloak of secrecy. After the subsequent defection
organisms to the behavior of biological aerosols of Kanadjan Alibekov (a former senior deputy
under every possible condition of climate and director of Biopreparat) in 1992, the United
topography, through the genetic engineering of States and the United Kingdom were certain
antibiotic resistance and the design of optimum enough that the offensive biological weapons
dissemination and delivery systems, the former program was continuing that they challenged
Soviet Union was able to envisage the the new Russian regime openly about it as late as
achievement of a miniaturized mobile produc- 1993. By then substantial changes had taken
tion and weapon-making capability invulnerable place within Biopreparat, and today a concerted
to clandestine monitoring, invasive arms effort is under way to help the Russians
inspection, or attack in the event of war (because civilianize these former biological weapons R&D
it was beyond identification); agents precisely establishments. However, questions remain
matched to particular scenarios and human about the Russian program: What happened to
targets and incapable of being treated; a variety the part of the program in Ministry of Defence
of dissemination systems, including cruise facilities that western experts have been unable
missiles; agents resistant to degradation by heat, to visit? What happened to plans detailing every
light, cold, UV radiation, ionizing radiation, and aspect of production and deployment? What
various antibiotics; and dry formulations of agents happened to the Ovchinnikov bioregulator
capable of remaining viable in long-term storage. program? What happened to the thousands of
By the time of the breakup of the former personnel involved in the Biopreparat program?
Soviet Union, from which the Russian Confed- What happened to the R&D centered on
eration emerged in 1992, much had been anticrop, antiplant, and antilivestock biological
achieved and war mobilization plans were in weapons? What happened to the stocks of seed
place for the surge production of huge quantities cultures of biological weapons agents designed to
of the agents mentioned earlier, as well as a be used to fuel the mobilized production of
number of others, such as Marburg virus. Of weapons? Was there space-based biological
overwhelming importance has been the capabil- weapons capability? Was there any human
ity to undertake a strategic attack using plague genetics-related biological weapons research?
or smallpox. Intercontinental ballistic missiles Despite the passage of nearly 10 years, the
with MIRVed warheads containing plague were fundamental change in political structure of
available for launch even before 1985, and SS-11 Russia, the extreme economic upheaval and
and SS-18 missiles have been mentioned in this budget restrictions, the reorientation of
connection. Concepts of use had been developed Biopreparat’s work, and the help and support
for each of the biological agents formally given by the West to civilianize programs and
accepted into use by the army. For instance, the stop the transfer of technology and scientists into
principal agents designated as tactical or illegal biological weapons programs, the capabil-
operational for use on the battlefield were ity of the old Russian Ministry of Defence sites
tularemia and Venezuelan equine encephalomy- remains largely unknown.
elitis, whereas anthrax and Marburg virus were
nominated for attacking rear areas. The third Iraq
category of agents comprised the highly Iraq has stated that its biological weapons
transmissible agents smallpox and plague, program dates to at least 1974. It was carried out

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in great secrecy, after the Biological and Toxin 380,000 liters of Botulinum toxin were manufac-
Weapons Convention had been signed. The tured, along with 84,250 liters of anthrax spores
program was first conducted in an ostensibly and 3,400 liters of C. perfringens spores. In
civilian organization called the State Organiza- addition, 2,200 liters of aflatoxin were produced.
tion for Trade and Industry until this was All these figures represent preconcentration
superseded by the Military Industrial Commis- totals and may be underestimates. Ricin toxin
sion. As with all other major military programs, and the antiplant agents wheat bunt and corn
biological weapons R&D was able to call upon smut were also produced. Camel pox is known to
many of its leading scientists who undertook have been under development as well. This
undergraduate or postgraduate training in the disparate list of biological agents, which at first
west. Much of what happened between the seems to contain substances not previously
supposed inception of the program in 1974 and conceived as potential offensive biological
the establishment of a group of biologists within weapons agents, on closer inspection reveals a
the Al-Muthanna chemical weapons complex in rationale based on the possession of a
1984 is unknown. multipotent arsenal having lethal, incapacitat-
In 1987, the Al-Muthanna research group ing, oncogenic, ethnic, economic, terror, and
was transferred to the Al-Salman facility, and variable time-onset capabilities. In addition,
work was expanded to include the investigation these agents are capable of being used to attack
of fungal and antiplant agents; 1988 saw the people through the lungs and the skin, as well as
establishment of the Al-Hakam Factory, an with carriers such as triethylamine, CN or CS, or
industrial-scale production facility designed to as a toxic coating in fragmentation weapons.
produce anthrax and botulinum toxin for filling Agents were filled into various weapons for
into weapons. This project was completed dissemination. By the end of 1990, according to
quickly by using equipment from nominally Iraqi statements, 25 SCUD/Al-Hussein missiles
civilian facilities, such as those used to produce were readied for use with biological weapons
vaccines; the factory itself produced biological warheads (each carrying 145 liters of agent) and
agent, which was filled into weapons and deployed for action. At least 160 R400 retarded
deployed in late 1990. The program was further aerial bombs, carrying the distinctive black-
expanded in 1990 when viruses were added to stripe identification around them, may also have
the range of agents under development and been filled with 90-liter charges of Botulinum
production capacity was enhanced by the toxin and ready for use. UNSCOM has evidence
acquisition and integration of civilian biotech- to corroborate the Iraqi claim. The Iraqis also
nology facilities by the Military Industrial intended to fill R400 bombs with anthrax and
Commission. aflatoxin. Originally designed and filled with
According to the Iraqis, the program was chemical agents, 155-mm shells were also tested
terminated in 1991, after the adoption of UN with a ricin toxin fill. At least three fuel drop
SCR687, and agents, weapons, munitions, and tanks were completely modified and fitted with
documents were destroyed. However, the United Venturi mechanisms to facilitate aerosol release,
Nations Special Commission (UNSCOM) be- for dispersal of 2,200-liter loads of anthrax and
lieves that from 1991 to 1995 Iraq actively possibly Botulinum toxin, using F1 aircraft as
preserved biological weapons capability. the delivery means.

The Agents, Weapons, and Means of Delivery Postscript

The UNSCOM belief that three biological UNSCOM has no confidence that Iraq has
agents were filled into weapons is supported by abandoned its biological weapons program. The
Iraqi statements concerning the filling of true scale and scope of the Iraqi biological
munitions and their deployment ready for weapons program are, despite all UNSCOM’s
delivery. For one of these agents, Botulinum efforts, still not known.
toxin, UNSCOM also possesses objective evi-
Dr. Davis is consultant in Pharmaceutical Medicine
dence; the other two were probably anthrax and
and Applied Physiology and director of the ORAQ
Clostridium perfringens spores. Approximately Consultancy Ltd., United Kingdom.

Emerging Infectious Diseases 512 Vol. 5, No. 4, July–August 1999

 Special Issue

Aum Shinrikyo: Once and Future Threat?

Kyle B. Olson
Research Planning, Inc., Arlington, Virginia, USA

On March 20, 1995, members of the Aum hundred others were transported to local
Shinrikyo cult entered the Tokyo subway system hospitals, where approximately 200 would
and released sarin, a deadly nerve agent. The require at least one night’s hospitalization.
subway attack was the most deadly assault in an After successfully completing their mission,
ongoing campaign of terror waged by this the cultists drove off to Kamakuishki, a rural
mysterious cult. Four years later, with Aum community at the foot of Mount Fuji, home to golf
Shinrikyo attempting to rebuild itself, many in courses, parks, dairy farms, small villages, and
Japan and around the world are asking whether the headquarters of Aum Shinrikyo in Japan.
the “Supreme Truth Sect” poses a current or The cult’s facilities consisted of a number of
future threat. Answering this question may motley buildings, factories, and dormitories.
further our understanding, not only of the Aum Aum Shinrikyo’s next major act of violence
but also of other extremist and terrorist groups. would serve as a wake-up call to the world
Aum Shinrikyo began its public campaign of regarding the prospects of weapons of mass
terror on June 27, 1994. On that Monday in destruction and terrorism. On the morning of
Matsumoto, a city of 300,000 population 322 March 20, 1995, packages were placed on five
kilometers northwest of Tokyo, a group of cult different trains in the Tokyo subway system. The
members drove a converted refrigerator truck packages consisted of plastic bags filled with a
into a nondescript residential neighborhood. chemical mix and wrapped inside newspapers.
Parking in a secluded parking lot behind a stand Once placed on the floor of the subway car, each
of trees, they activated a computer-controlled bag was punctured with a sharpened umbrella
system to release a cloud of sarin. The nerve tip, and the material was allowed to spill onto the
agent floated toward a cluster of private homes, a floor of the subway car. As the liquid spread out
mid-rise apartment building, town homes, and a and evaporated, vaporous agent spread through-
small dormitory. out the car.
This neighborhood was targeted for a specific Tokyo was experiencing a coordinated,
reason. The dormitory was the residence of all simultaneous, multi-point assault. The attack
three judges sitting on a panel hearing a lawsuit was carried out at virtually the same moment at
over a real-estate dispute in which Aum five different locations in the world’s largest city:
Shinrikyo was the defendant. Cult lawyers had five trains, many kilometers apart, all converg-
advised the sect’s leadership that the decision ing on the center of Tokyo. The resulting deaths
was likely to go against them. Unwilling to and injuries were spread throughout central
accept a costly reversal, Aum responded by Tokyo. First reports came from the inner
sending a team to Matsumoto to guarantee that suburbs and then, very quickly, cries for help
the judges did not hand down an adverse began to flow in from one station after another,
judgment. A light breeze (3 to 5 knots) gently forming a rapidly tightening ring around the
pushed the deadly aerosol cloud of sarin into a station at Kasumagaseki. This station serves the
courtyard formed by the buildings. The deadly buildings that house most of the key agencies of
agent affected the inhabitants of many of the the Japanese government. Most of the major
buildings, entering through windows and ministries, as well as the national police agency,
doorways, left open to the warm night air. Within have their headquarters at Kasumagaseki.
a short time, seven people were dead. Five By the end of that day, 15 subway stations in
the world’s busiest subway system had been
affected. Of these, stations along the Hbiya line
Address for correspondence: Kyle B. Olson, Research were the most heavily affected, some with as
Planning, Inc., 6400 Arlington Blvd., Suite 1100, Arlington, VA many as 300 to 400 persons involved. The
22042, USA; fax: 703-237-8085; e-mail: kolson@rpihq.com.

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number injured in the attacks was just under The cult attempted several apparently
3,800. Of those, nearly 1,000 actually required unsuccessful acts of biological terrorism in Japan
hospitalization—some for no more than a few between 1990 and 1995. As early as April 1990,
hours, some for many days. A very few are still the cult had tried to release botulin toxin from a
hospitalized. And 12 people were dead. vehicle driving around the Diet and other
Within 48 hours of the subway attack, police government buildings in central Tokyo. In early
were carrying out raids against Aum Shinrikyo June of 1993, another attempt was made to
facilities throughout Japan. Police entered cult release botulin toxin, this time in conjunction
facilities carrying sophisticated detection sys- with the wedding of the crown prince. A vehicle
tems and wearing military-issued chemical gear equipped with a spray device was driven around
(which was issued to the Tokyo police the week the imperial palace as well as the main
before the subway attack). government buildings in central Tokyo.
The real target of the raids that began on Later that month, pursuing an alternative
March 17 was the building known as Satyan 7, a technology, the cult attempted to release
supposed shrine to the Hindu god Shiva, the anthrax spores from its mid-rise Tokyo office
most prominent figure in the Aum Shinrikyo building laboratory. At that time, police and
religious pantheon. In reality, the building media reported foul smells, brown steam, some
housed a moderately large-scale chemical pet deaths, and stains on cars and sidewalks.
weapons production facility, designed by cult Then, in March 1995, just before the sarin
engineers, with first-rate equipment purchased subway attack, an attempt to spray botulin toxin
over-the-counter. in the subway at Kasumagaseki Station was
Although the facility’s design was crude by preempted by a cult member who opted not to
industry standards, it was nonetheless very load the improvised briefcase sprayers with
capable of producing the sarin used in the actual agent.
Matsumoto attack. At the time of the Tokyo No injuries were reported in any of these
attack, however, Satyan 7 was not in service, biological events despite the fact the cult was
having been mothballed after an accident during dealing with very toxic materials. The cult’s
the previous summer. In an effort to get the plant failures can be attributed to a variety of factors.
back into production, the cult had, during the fall The cult may not have had the right agents or the
of 1994, unsuccessfully attempted to recruit right technologic facilities; they could have
Russian chemical-weapons engineers. The cult overcooked the bioagents or not known how to
was adept at recruiting educated professionals use them. While the cult was well financed, it
(scientists and engineers), but most were young was not very successful in its efforts to recruit
and largely inexperienced. Satyan 7 was biological scientists. Still, the possibility exists
designed to produce sarin, not on a small that casualties associated with some of these
terrorist scale, but in nearly battlefield releases might have not been detected or were
quantities: thousands of kilograms a year. attributed to other causes.
Chemical weapons were not, however, the The cult’s operations were worldwide,
only option available to the Aum. The first cult promoting a theology drawn from different
laboratory for toxin production was actually in sources, including Buddhism, Christianity,
place by 1990 and was subsequently replaced Shamanism, Hinduism, and New Age beliefs.
with two new laboratories, one at Kamakuishki Cult membership around the world was likely
and the other in Tokyo. Aum dabbled in many 20,000 to 40,000. One cult leader estimated the
different biological agents. They cultured and cult’s net worth in March of 1995 at about $1.5
experimented with botulin toxin, anthrax, billion. The money was collected through
cholera, and Q fever. In 1993, Ashahara led a donations, tithing, sales of religious parapherna-
group of 16 cult doctors and nurses to Zaire, on a lia, videotape and book sales, and other sources.
supposed medical mission. The actual purpose of The cult conducted seminars and hosted training
the trip to Central Africa was to learn as much as courses for members, offering indoctrination in
possible about and, ideally, to bring back samples Aum’s teachings, charging believers from
of Ebola virus. In early 1994, cult doctors were hundreds to tens of thousands of dollars for
quoted on Russian radio as discussing the attending these sessions. Aum Shinrikyo also
possibility of using Ebola as a biological weapon. had a number of commercial enterprises, even a

Emerging Infectious Diseases 514 Vol. 5, No. 4, July–August 1999

 Special Issue

company that manufactured computers. Im- work for Aum, where he very quickly rose
ported components from Taiwan were assembled through the ranks, ultimately to head the cult’s
in a cult factory at Kamakuishki and sold in operations in Russia. Joyu oversaw this
Aum’s computer store in downtown Tokyo. The important cult expansion, among other things
cult also ran a chain of restaurants in Tokyo and “investing” as much as $12 million in the form of
several other Japanese cities. payoffs to well-placed officials. The cult’s
Another source of income was the practice of investment paid off with expedited access to
green mail. Aum would threaten to establish a office buildings, dormitories, and other facilities
cult compound in a city and, if the city fathers did throughout Russia. At the time of the Tokyo
not bribe them to go away, the cult would set up subway attack, the cult’s principle venture in
shop. Several cities paid rather than have Aum Russia was the Moscow-Japan University, with
establish operations there. The cult manufac- headquarters in offices across the street from the
tured illegal drugs and had a marketing Bolshoi Ballet. Their senior Russian partner in
agreement with the Japanese Mafia (the the university was a man by the name of Oleg
Yakuza). In 1996, the Yakuza would be found Lobov, at that time also chairman of Russia’s
responsible for the assassination of the cult’s National Security Council and a close confidant
lead scientist, Dr. Hideo Murai, in the days of Boris Yeltsin.
following the Tokyo subway attack. Concerned Joyu was convicted of perjury after the
at his frequent televised appearances, the subway investigation, but he received an
Yakuza silenced him for fear that he would extremely light sentence (3 years) for his
betray the linkage between the two shadowy involvement in the cult’s activities. Joyu has
groups. Extortion, theft, and murder were also apparently maintained close ties to the cult, and
part of the cult’s fund-raising activities. Among he is slated for release toward the end of this
the cult leaders, “Doomsday guru” Shoko year. After leaving prison, he may make a play
Ashahara is the undisputed head. Ashahara for leadership of the remaining cult elements. He
(born Chizuo Matsumoto) had numerous exalted is the most charismatic member of the cult, other
titles, including venerated master, yogi, and holy than Ashahara. In the days right after the Tokyo
pope. Highly charismatic, this partially blind, subway attack, he was on Japanese television so
apparently very talented yoga instructor was frequently, and featured in magazines and
very ambitious politically and financially. He newspapers so often, that he became a teen
and more than 20 of his followers ran for heartthrob.
Parliament in 1989. They were defeated, which In the days and weeks immediately following
some Japanese analysts have suggested marks the gas attack, more than 200 key members of
the moment when the cult’s leader elected to the cult were arrested. Approximately 120 are
pursue weapons of mass destruction and the still in jail, on trial, or have been convicted.
violent overthrow of the established order. Ashahara himself has been on trial for 3 years.
Millennial visions and apocalyptic scenarios The trial may continue for 5 or 6 years, a judicial
dominate the group’s doctrine, evidenced by the timetable that is aggressive by Japanese
prominent role of Nostradamus as a prophet in standards in cases where the defendant refuses
Aum Shinrikyo teaching. Ashahara has, on to cooperate with the prosecution. Three cult
many occasions, claimed to be the reincarnated members involved in the attack are still at large.
Jesus Christ, as well as the first “enlightened Russian operations were ended by legal action
one” since the Buddha. He has frequently and the assets seized by the government. The
preached about a coming Armageddon, which he cult’s legal status in Japan as a church has been
describes as a global conflict that would, among revoked, but many of its assets are unaccounted
other things, destroy Japan with nuclear, for.
biological, and chemical weapons. According to Today, Aum Shinrikyo is once again
Ashahara, only the followers of Aum Shinrikyo soliciting donations, collecting tithes, selling
will survive this conflagration. materials to members, holding seminars,
Another cult leader, Fumihiro Joyu, now 35 conducting training, and selling computers.
years old, was a bright young engineer with the Active recruiting is under way. Aum Shinrikyo is
Japanese space program, specializing in artifi- holding 50 “educational” seminars a month for
cial intelligence. He left that organization to go to current and potential members. The cult has

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offices throughout Japan, around Tokyo and and military might, one can argue that
other cities, and, according to Japanese sources, developing and even using an asymmetric
they maintain 100 hide-outs throughout that capability was a logical consequence of their
country as “safe houses.” These sources estimate situation. Unable to achieve their objective—
that at least 700 members are live-in, fully political power—through legitimate means, they
committed devotees. Mind control is still a part of determined that a preemptive strike was
the cult’s package. Cult members can be seen in necessary.
Aum-owned houses wearing bizarre electric Is Aum Shinrikyo a potential threat? Is
headsets, supposedly designed to synchronize Shoko Ashahara just the first of many, or has he
their brain waves with those of the cult’s leader. been relegated to the scrap heap? These are open
What is the message that these events to questions we will be forced to grapple with for
impart policy-makers? The objective of the Tokyo many years to come.
subway attack was not irrational. The objective
Mr. Olson is adviser, consultant, and writer on
that day was to kill as many policemen as
high-technology terrorism, the threat of chemical and
possible; Aum Shinrikyo had become aware of biological weapons, and the practical challenges of
police plans to conduct raids against cult arms control; member of the Central Intelligence’s
facilities, beginning on March 20. The cult’s Nonproliferation Advisory Panel; guest lecturer on
timetable could not permit that interruption. chemical and biological weapons terrorism at the
Aum’s actions were perfectly logical within Defense Nuclear Weapons School, Air War College,
the context of their value system. They were a Naval War College, and U.S. Air Force Special Opera-
self-legitimized group that had rejected and, tions School, and an adjunct faculty member at George
ultimately, felt obliged to confront society. Washington University.
Outnumbered as they were by Japanese police

Emerging Infectious Diseases 516 Vol. 5, No. 4, July–August 1999

 Special Issue

The Prospect of Domestic Bioterrorism

Jessica Stern
Council on Foreign Relations, Washington, D.C., USA

Would domestic terrorists use biological Candidates for successful use of biological
weapons?1 The conventional wisdom among weapons represent the intersection of three sets:
experts has been that terrorists “want a lot of groups that want to use these weapons despite
people watching, not a lot of people dead” and are formidable political risks; groups that can
unlikely to turn to weapons of mass destruction.2 acquire the agent and a dissemination device
A new school of thought proposes that improved (however crude); and groups whose organiza-
technology has made biological attacks resulting tional structure enables them to deliver or
in hundreds of thousands or millions of deaths all disseminate the agent covertly. The intersection
but inevitable. While terrorists are increasingly of these sets is small but growing, especially for
interested in weapons of mass destruction, low-technology attacks such as contaminating
proponents of the latter view exaggerate the food or disseminating biological agents in an
threat. Using biological weapons to create mass enclosed space. Major attacks are also becoming
casualties would require more than having more likely. In the sections that follow, we
biological agents in hand. The terrorists would consider eroding motivational, technical, and
need to disseminate the agent, which presents organizational constraints.
technical and organizational obstacles that few
domestic groups could surmount. In addition, Motivational Factors
relatively few terrorists would want to kill
millions of people, even if they could. Getting Attention
For most terrorists, the costs of escalation to Some terrorists may turn to biological
biological weapons would seem to outweigh the weapons because they believe it would attract
benefits. Most modern terrorists have had more attention to their cause than conventional
substantively rational goals, such as attaining attacks. Studies of perceived risk show an
national autonomy or establishing a government inexact correlation between scientists’ assess-
purportedly more representative of the people’s ment of risk and the level of fear invoked by risky
will. Escalating to such frightening weapons technologies and activities.4 Biological weapons
would result in a massive government crack- are mysterious, unfamiliar, indiscriminate,
down and could alienate the group’s supporters. uncontrollable, inequitable, and invisible, all
Biological weapons are also dangerous to characteristics associated with heightened fear.
produce. A number of Aum Shinrikyo members
reportedly damaged their own health while Economic Terrorism
working on biological agents. Additionally, some Unlike conventional weapons, radiologic,
terrorists may perceive moral constraints.3 chemical, and biological agents could be used to
destroy crops, poison foods, or contaminate
pharmaceutical products. They could also be
used to kill livestock. (Conventional weapons
Address for correspondence: Jessica Stern, Council on Foreign
Relations, 1779 Massachusetts Ave. NW, Washington, D.C. could be used for the same purposes, albeit less
20007, USA; fax: 202-986- 2984; e-mail: jessicas@alum.mit.edu. efficiently.) Terrorists might use these agents to

1 This essay summarizes Jessica Stern, “Terrorist Motivations and WMD,” in Peter Lavoy, Scott Sagan, and Jim Wirtz, ed.,

Planning the Unthinkable, in press, 2000.

2 Brian Jenkins has made this statement about terrorists on numerous occasions. For example, see Brian Michael Jenkins,

“International Terrorism: A New Mode of Conflict,” in David Carlton and Carolo Schaerf, eds., International Terrorism and
World Security (London: Croom Helm, 1975), 15. On terrorists’ purported aim to harass, see Kenneth Waltz, “Waltz Responds
to Sagan,” in Scott D. Sagan and Kenneth Waltz, The Spread of Nuclear Weapons: A Debate (New York: Norton, 1995), 94-96.
3 For examples, see Jessica Stern in Lavoy.
4 See for example Paul Slovic, Baruch Fischoff and Sarah Lichtenstein, “Facts and Fears: Understanding Perceived Risk,” in

Richard Schwing and Walter Albers, eds., Societal Risk Assessment: How Safe is Safe Enough? (New York: Plenum Press, 1980),
181-216.

Vol. 5, No. 4, July–August 1999 517 Emerging Infectious Diseases

 Special Issue

attack corporations perceived to be icons of the Larry Wayne Harris, a white supremacist and
target country, for example, by contaminating born-again Christian, predicts that the Y2K bug
batches of Coca-Cola, Stolichnaya vodka, or will cause a civil war in the United States and
Guinness stout. Terrorists could attempt to that after January 1, 2000, the government will
disseminate anthrax with the explicit goal of be unable to deliver welfare checks and food
imposing expensive clean-up costs on a target stamps for at least 3 years.8 He predicts that
government. biological attacks could be carried out by domestic
groups fighting for their heritage, traditions, and
Millenarianism communities, causing devastating plagues like
The millenarian idea is that the present age those described in the Bible’s Book of
is corrupt and that a new age will dawn after a Revelation.9 He urges all U.S. citizens to
cleansing apocalypse. Only a lucky few (usually prepare. For some domestic groups, preparation
selected on the basis of adherence to doctrine or involves stockpiling weapons and training to use
ritual) will survive the end of time and them.
experience paradise.5 Some millenarians believe
that the saved will have to endure the 7 years of Exacting Revenge or Creating Chaos
violence and struggle of the apocalypse, and they Politically motivated terrorists who desire to
want to be prepared.6 Shoko Asahara, leader of change societies rather than destroy them might
the doomsday cult that released sarin gas in the avoid killing very large numbers of people
Tokyo subway in 1995, killing 12, told his because the political costs would exceed the
followers that in the coming conflict between benefits.10 Some terrorists, however, want to
good and evil they would have to fight with every annihilate their enemies or demolish the societal
available weapon.7 A similar belief system order. William Pierce, leader of the neo-Nazi
explains the attraction to survivalism by Identity organization National Alliance, aims to initiate a
Christians, white supremacists who believe in an worldwide race war and establish an Aryan
imminent Armageddon. state. “We are in a war for the survival of our
race,” he explains, “that ultimately we cannot
Premillennial Tension win... except by killing our enemies... It’s a case
Slight tension connected with the millen- of either we destroy them or they will destroy us,
nium presumably affects most people. Many are with no chance for compromise or armistice.”11
concerned about the Y2K problem, the prospect Creating social chaos is thus a worthwhile
that computer systems will malfunction or fail at objective in Pierce’s view. Ramzi Yousef,
the end of 1999. Some fear the breakdown of air- organizer of the World Trade Center bombing,
traffic control systems and are planning to avoid claimed he was exacting revenge against the
traveling around January 1, 2000. Others fear United States.12 Osama bin Laden seems to have
an accidental launch of Russian nuclear missiles similar motives.
due to malfunctioning computers. Many are
stockpiling food and medicine or will have extra Mimicking God
cash on hand in case automated banking systems Terrorists hoping to create an aura of divine
fail. Some feel vague religious fears. Members of retribution might be attracted to biological
antigovernment groups and religious cults are agents. The fifth plague used by God to punish
often vulnerable psychologically and appear to the Pharaoh in the Bible’s Book of Exodus was
be especially affected by premillennial tension. murrain, a group of cattle diseases that includes

5While millenarian doctrines are generally religiously based, some are not. See Jean E. Rosenfeld, “Pai Marire: Peace and

Violence in a New Zealand Millenarian Tradition,” Terrorism and Political Violence, 7, no. 3 (autumn 1995), 83.
6“End Times Jitters,” interview with Michael Barkun, Klanwatch Intelligence Report (summer 1997), 17.
7FBIS-SOV-97-09, 6 May 1997. Source Moscow Trud, 6 May 1997, 1-2.
8Author Interview with Larry Wayne Harris, 9 February 1999.
9Testimony of Larry Wayne Harris, State of Ohio v. Stephen Michael Wharf.
10The nature of the constituency is a key variable here. If the terrorists’ constituents see the targeted group as subhuman, or

if terrorists have no clear constituency, political constraints against macro-terrorism are less likely to bind.
11Quotes from Klanwatch Intelligence Report (May 1996), 6-8.
12Gail Appleson, “Bomb Mastermind Gets Life in US Prison,” Reuters, 9 January 1997.

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anthrax. In the fifth chapter of Samuel I, God still small—of ‘lone offender’ and extremist
turned against the Philistines and “smote them splinter elements of right wing groups have been
with emerods.” Medical historians consider these identified as possessing or attempting to develop
emerods a symptom of bubonic plague.13 Some or use” weapons of mass destruction.16
terrorists may believe they are emulating God by In February 1998, Harris boasted to an
employing these agents. informant that he had enough military-grade
anthrax to wipe out all of Las Vegas. Eight bags
The Aura of Science marked “biological” had been found in the back of
Terrorists may want to impress their target a car he and his accomplice were driving.17
audience with high technology or with weapons Several days later, federal authorities learned
that appear more sophisticated than conven- that the anthrax Harris had brought to Las
tional ones. Terrorists may find technology Vegas was a vaccine strain not harmful to
appealing for various reasons. William Pierce, human health. Nevertheless, the incident
who studied physics at California Institute of frightened many people and sparked a
Technology, is interested in high-technology proliferation of anthrax hoaxes and threats in
weapons. In his novel The Turner Diaries, right- the second half of 1998 continuing into 1999 by
wing extremists use nuclear, chemical, biologi- groups including Identity Christians and other
cal, and radiologic weapons to take over the antigovernment groups, extortionists, anti-
world. Pierce believes he can attract more abortion activists, and presumed prochoice
intelligent recruits to his organization over the groups. In many cases, the perpetrator’s
Internet than through radio or leaflets.14 motives were unknown, but some incidents
appear to have been student pranks, demon-
The Copycat Phenomenon strating the extent to which the threat of
Domestic extremists have shown greater anthrax has entered U.S. consciousness
interest in chemical and biological weapons in (Table).
the last 5 years. For example, in 1998, members
of the Republic of Texas were convicted of Technical Factors
threatening to assassinate with biological agents With the end of the cold war and the breakup
President Clinton, Attorney General Janet Reno, of the Soviet Union, weapons of mass destruction
and other officials.15 In May 1995, 6 weeks after and their components have become easier to
the Aum Shinrikyo incident on the Tokyo acquire. Underpaid former Soviet weapons
subway, Larry Wayne Harris bought three vials experts may be providing biological weapons and
of Yersinia pestis, the bacterium that causes expertise to Iran.18 South African biological
bubonic plague. No law prohibited Harris or any weapons scientists have offered their expertise to
other U.S. citizen from acquiring the agent. The Libya.19 State-sponsored groups are most
law has been tightened up since, although many capable of overcoming technical barriers to
fear it is still not restrictive enough. The Federal mass-casualty attacks, but the sponsor would
Bureau of Investigation (FBI) Director Louis presumably weigh the risk for retaliation before
Freeh reports that “a growing number—while supporting this type of terrorist attack.

13Hans Zinsser, Rats, Lice and History (Boston: Little Brown and Company, 1963), 110.
14Author interview with William Pierce, 22 April 1997.
15 Madeline Baro, “FBI: Men Knew of Cactus Weapons, Threats,” Associated Press/Corpus Christi Online, 27 October 1998;

found at: http://www.callertimes.com/autoconv/newstexmex98/newstexmex57.html.

16 Statement for the Record of Louis J. Freeh, Director, Federal Bureau of Investigation, before the United States Senate

Committee on Appropriations; Subcommittee for the Departments of Commerce, Justice, and State, the Judiciary, and Related
Agencies; February 4, 1999.
17One informant said that Harris said he had “military-grade anthrax.” Another said Harris referred to a vaccine or a placebo.

Proceedings before the Regular Federal Grand Jury, Testimony of Robert James, February 25, 1998, United States District
Court, District of Nevada, p. 17. United States of America v. Larry Wayne Harris, Complete Transcript of Proceedings, CR-2-
95-093, March 6, 1998, United States District Court, Southern District of Ohio.
18Judith Miller and William J. Broad, “Bio-Weapons in Mind, Iranians Lure Needy Ex-Soviet Scientists,” New York Times, 8

November 1998, A1 and Miller and Broad, “Germ Weapons: In Soviet Past or in the New Russia’s Future?” New York Times, 28
December 1998, A1.
19James Adams, “Gadaffi Lures South Africa’s Top Germ Warfare Scientists,” Sunday Times, 26 February 1995; Paul Taylor,

“Toxic S. African Arms Raise Concern; US Wants Assurance ‘80s Program is Dead,” Washington Post, 28 February 1995.

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Table. Anthrax incidents in the United States, 1992–1999a

Year
1992 1997 1998
No. incidents 1 1 37
No. persons affectedb 20 100 5,529
Persons decontaminated, 20 30 1,202
treated, or
quarantinedb
Targets Residence Religious Government
organization buildings and
officials, indivi-
duals, clinics,
religious insti-
utions, antiabor-
tion activists,
financial insti-
tutions, schools,
retail establish-
ments, office
buildings, media,
nightclub
Purported motivators Malicious Anti-Semitism Antigovernment,
alleged research,
antiabortion, pro-
choice retaliation,
student pranks,
delay court
appearance
Dissemination Splattering Mail Dispersal on
technique(s) premises,
modified ciga-
rette lighter,
moist towelettes,
mail (envelope),
explosive device,
ventilation
systems
Responses Perimeter sealed, Perimeter sealed, On-site inspec-
medical decontami- tion, evaluation
treatment nation, medical perimeter sealed,
treatment pamphlets
provided,
quarantine,
decontamination,
medical treatment
aThese data are presumed incomplete and may contain errors. Numbers are based on press reports and are not available for all

years. Data not independently confirmed.

bFigures do not include incidents in which numbers are not available; actual totals, therefore, may be understated.

Chart prepared by Darcy Bender.

College-trained chemists and biologists could substantial development, involving skilled

presumably produce biological agents, although personnel and sophisticated equipment. Mill-
they might have trouble disseminating them as ing biological agents would require a level of
aerosols. Microorganisms can be disseminated sophistication unlikely to be found among
by air in two forms: as liquid slurries or as dry many domestic terrorist groups. Far more
powders. While producing liquid slurries is likely are low-technology incidents such as
relatively easy, disseminating them as respi- contaminating foods, poisoning livestock, or
rable infectious aerosols over large open areas is disseminating industrial poisons in an en-
not. Although dry powders can be disseminated closed space. Such attacks could still be lethal.
far more easily, high-quality powders require Major attacks cannot be ruled out; however,
governments need to prepare.

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Organizational Factors biological agents act on their own or in small,

In the mid-1980s, a little-known survivalist secretive groups, FBI may have difficulty
group called The Covenant, the Sword, and the apprehending them.
Arm of the Lord (CSA) acquired a large drum of One of CSA’s objectives was to establish a
cyanide with the intention of poisoning water computerized, nationwide system linking right-
supplies in major U.S. cities. At the time, CSA wing groups. This goal has been achieved,
was unusual among terrorist groups in that its although CSA is not exclusively—or even
sole objective was large-scale murder rather principally—responsible for this achievement.
than influencing government policies. CSA The nationwide linking of right-wing groups has
overcame two of three large obstacles to implications that have not been adequately
successful employment of a chemical agent. It appreciated by the law enforcement community.
had the motivation to use a chemical agent to kill The Internet makes terrorist acts easier to carry
large numbers and no political or moral out. It facilitates leaderless resistance by
constraints. The group had acquired a chemical allowing leaders of the movement to communi-
agent, although not in sufficient quantity to cate with sympathizers worldwide without
contaminate city water supplies. The group’s having to meet face-to-face with their followers.
leaders had not recruited technically trained
personnel and chose an unworkable dissemina- The Likeliest Perpetrators
tion technique. Moreover, the group lacked A small but growing number of domestic
discipline and was easily penetrated by FBI. It is terrorists could attempt to use biological
unlikely that CSA would make such mistakes if it weapons in the belief that doing so would
were operating today, when antigovernment advance their goals. The most likely are religious
groups are so much more aware of the potential and extreme right-wing groups and groups
of poison weapons for inflicting mass casual- seeking revenge who view secular rulers and the
ties.20 law they uphold as illegitimate. They are
CSA was run as a relatively open compound. unconstrained by fear of government or public
Some members wrote articles in local papers backlash, since their actions are carried out to
espousing antigovernment beliefs, and some please God and themselves, not to impress a
worked in neighboring towns. Several former secular constituency. Frequently, they do not
CSA members became informants, often because claim credit for their attacks since their ultimate
they hoped to get their sentences reduced for objective is to create so much fear and chaos that
other, unrelated, crimes. In recent years, the government’s legitimacy is destroyed. Their
however, antigovernment groups have become victims are often viewed as subhuman since they
more aware of the danger of penetration by law- are outside the group’s religion or race.
enforcement authorities and have devised a new Religiously motivated groups are increasing.
way of organizing themselves called “leaderless Of 11 international terrorist groups identified by
resistance.”21 Members are encouraged to act on the Rand Corporation in 1968, none were
their own, minimizing their communication with classified as religiously motivated. By 1994, a
the leadership of the movement. Timothy third of the 49 international groups recorded in
McVeigh operated according to this model. His the Rand-St. Andrews Chronology were classi-
bombing of the Oklahoma City Federal Building fied as religious.22 Religious groups are not only
was originally conceived of by CSA, although it is becoming more common; they are also more
not clear that McVeigh knew of CSA’s earlier violent than secular groups. In 1995, religious
plot. If future terrorists with chemical or groups committed only 25% of the international
incidents but caused 58% of the deaths.23

20For example, Kerry Noble claimed that if CSA leader James Ellison met someone who knew something about biological agents,

he might consider using them. Author interview with Kerry Noble, March 2, 1998.
21See Louis Beam, “Leaderless Resistance,” The Seditionist, Issue 12, February 1992. Found at: http://www.louisbeam.com/

leaderless.htm.
22Bruce Hoffman, “Viewpoint: Terrorism and WMD: Some Preliminary Hypotheses,” Nonproliferation Review (spring-summer

1997): 45-52. Hoffman provides slightly different numbers in “Holy Terror”: The Implications of Terrorism Motivated by a
Religious Imperative (Santa Monica: Rand Corporation, P-7834, 1993).
23Hoffman, “Viewpoint,” 48.

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Identity Christians believe that the Book of making pipe bombs. Bioweapons are more
Revelation is to be taken literally as a description accessible than are nuclear weapons.”27
of future events. Many evangelical Protestants
believe in a doctrine of rapture: that the saved Conclusions
will be lifted off the earth to escape the Terrorism with biological weapons is likely to
apocalypse that will precede the Second Coming remain rare. This is especially the case for
of Christ. Followers of Christian Identity (and attacks intended to create mass casualties,
some other millenarian sects), however, expect which require a level of technologic sophistica-
to be present during the apocalypse.24 Because of tion likely to be possessed by few domestic
this belief, some followers of Christian Identity groups. While state-sponsored groups are most
believe they need to be prepared with every likely to be capable of massive biological weapons
available weapon to ensure their survival. attacks, the state sponsor would presumably
Organizational pressures could induce some have to weigh the risk for retaliation. As in the
groups to commit extreme acts of violence. case of other low-probability high-cost risks,
Followers tend to be more interested in violence however, governments cannot ignore this
for its own sake than in the group’s purported danger; the potential damage is unacceptably
goals, making them less inhibited by moral or high. Because the magnitude of the threat is so
political constraints than the leaders. Leaders difficult to calculate, however, it makes sense to
may have difficulty designing command and focus on dual-use remedies: pursuing medical
control procedures that work. Offshoots of countermeasures that will improve public health
established groups may be particularly danger- in general, regardless of whether major
ous. Groups may also become most violent when biological attacks ever occur. This would include
the state is closing in on them, potentially posing strengthening the international system of
difficulties for those fighting terrorism. Another monitoring disease outbreaks in humans,
factor is the nature of the leader. Charismatic animals, and plants and developing better
leaders who isolate their followers from the rest pharmaceutical drugs.
of society often instill extreme paranoia among The risk for overreaction must be considered.
their followers. Such groups can be susceptible to If authorities are not prepared in advance, they
extreme acts of violence. will be more susceptible to taking actions they
Asked who he thought the most likely will later regret, such as revoking civil liberties.
domestic perpetrators of biological terrorism Attacks employing biological agents are also
were, John Trochman, a leader of the Montana more likely and will be far more destructive if
Militia, said that extremist offshoots of Identity governments are caught unprepared.
Christian groups are possible candidates, as are
disaffected military officers.25 Some antigovern- Acknowledgments
ment groups are attempting to recruit inside the I thank Darcy Bender for research assistance and Peter
Lavoy, Scott Sagan, and James Wirtz for comments.
U.S. military.26 William Pierce also foresees the
use of biological weapons by antigovernment Dr. Stern is a Fellow at the Council on Foreign Re-
groups. “People disaffected by the government lations. She is the author of The Ultimate Terrorists
include not only the kind of people capable of (Harvard University Press, 1999). She is currently writ-
ing a book on religious extremism worldwide.

24Author interview with Pastor Millar, 21 April 1998.

25Author interview with Trochman, 9 February 1999.
26Author interview with William Pierce, 22 April 1997.
27Author interview with William Pierce.

Emerging Infectious Diseases 522 Vol. 5, No. 4, July–August 1999

 Special Issue

Potential Biological Weapons Threats

Mark G. Kortepeter and Gerald W. Parker
U.S. Army Medical Research Institute of Infectious Diseases,
Fort Detrick, Maryland, USA

The list of agents that could pose the greatest Aum Shinrikyo in Japan is an example of a well-
public health risk in the event of a bioterrorist financed organization that was attempting to
attack is short. However, although short, the list develop biological weapons capability. However,
includes agents that, if acquired and properly they were not successful in their multiple
disseminated, could cause a difficult public attempts to release anthrax and botulinum
health challenge in terms of our ability to limit toxin (4). On this end of the spectrum, the list of
the numbers of casualties and control the biological agents available to cause mass
damage to our cities and nation. casualties is small and would probably include
The use of biological weapons has occurred one of the classic biological agents. The
sporadically for centuries, culminating in probability of occurrence is low; however, the
sophisticated research and testing programs run consequences of a possible successful attack are
by several countries. Biological weapons prolif- serious.
eration is a serious problem that is increasing the Smaller, less sophisticated organizations
probability of a serious bioterrorism incident. may or may not have the intent to kill but may
The accidental release of anthrax from a military use biological pathogens to further their specific
testing facility in the former Soviet Union in goals. The Rajhneeshees, who attempted to
1979 and Iraq’s admission in 1995 to having influence local elections in The Dalles, Oregon,
quantities of anthrax, botulinum toxin, and by contaminating salad bars with Salmonella
aflatoxin ready to use as weapons have clearly Typhimurium, are an example (5). Rather than
shown that research in the offensive use of having a sophisticated research program, these
biological agents continued, despite the 1972 organizations could use biological pathogens
Biological Weapons Convention (1,2). Of the that are readily available.
seven countries listed by the U.S. Department of The third type are smaller groups or
State as sponsoring international terrorism (3), individuals who may have very limited targets
at least five are suspected to have biological (e.g., individuals or buildings) and are using
warfare programs. There is no evidence at this biological pathogens in murder plots or to
time, however, that any state has provided threaten havoc. The recent anthrax hoaxes are
biological weapons expertise to a terrorist examples of this. Many biological agents could be
organization (4). used in such instances and the likelihood of their
A wide range of groups or individuals might occurrence is high, but the public health
use biological agents as instruments of terror. At consequences are low.
the most dangerous end of the spectrum are There are many potential human biological
large organizations that are well-funded and pathogens. A North Atlantic Treaty Organiza-
possibly state-supported. They would be ex- tion handbook dealing with biological warfare
pected to cause the greatest harm, because of defense lists 39 agents, including bacteria,
their access to scientific expertise, biological viruses, rickettsiae, and toxins, that could be
agents, and most importantly, dissemination used as biological weapons (6). Examining the
technology, including the capability to produce relationship between aerosol infectivity and
refined dry agent, deliverable in milled particles toxicity versus quantity of agent illustrates the
of the proper size for aerosol dissemination. The requirements for producing equivalent effects
Address for correspondence: Mark G. Kortepeter, Operational
and narrows the spectrum of possible agents that
Medicine Division, U.S. Army Medical Research Institute of could be used to cause large numbers of
Infectious Diseases, Fort Detrick, MD 21702-5011, USA; fax: casualities. For example, the amount of agent
301-619-2312; e-mail: Mark_Kortepeter@DET.AMEDD. needed to cover a 100-km2 area and cause 50%
ARMY.MIL.

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 Special Issue

lethality is 8 metric tons for even a “highly toxic” of bioterrorism is that it involves the use of
toxin such as ricin versus only kilogram “violence on behalf of a political, religious,
quantities of anthrax needed to achieve the same ecologic, or other ideologic cause without
coverage. Thus, deploying an agent such as ricin reference to the moral or political justice of the
over a wide area, although possible, becomes cause.” The balance of incidents involved an
impractical from a logistics standpoint, even for a expressed interest, threat of use, or an attempt to
well-funded organization (7). The potential acquire an agent. In the 1990s, incidents
impact on a city can be estimated by looking at increased markedly, but most have been hoaxes.
the effectiveness of an aerosol in producing The pathogens involved present a wide
downwind casualties. The World Health Organi- spectrum, from those with little ability to cause
zation in 1970 modeled the results of a disease or disability, such as Ascaris suum, to
hypothetical dissemination of 50 kg of agent some of the familiar agents deemed most deadly,
along a 2-km line upwind of a large population such as B. anthracis, ricin, plague, and
center. Anthrax and tularemia are predicted to botulinum toxins (Table). During this period, the
cause the highest number of dead and number of known deaths is only 10, while the
incapacitated, as well as the greatest downwind total number of casualties is 990. However, the
spread (8). numbers should not give a false sense of security
For further indication of which pathogens that mass lethality is not achievable by a
make effective biological weapons, one could look determined terrorist group. The sharp increase
at the agents studied by the United States when in biological threats, hoaxes, information, and
it had an offensive biological weapons research Internet sources on this subject seen in recent
program. Under that program, which was years indicates a growing interest in the possible
discontinued in 1969, the United States use of biological pathogens for nefarious means (4).
produced the following to fill munitions: Bacillus In general, the existing public health
anthracis, botulinum toxin, Francisella systems should be able to handle most attempts
tularensis, Brucella suis, Venezuelan equine to release biological pathogens. A working group
encephalitis virus, staphylococcal enterotoxin B, organized by the Johns Hopkins Center for
and Coxiella burnetti (9). As a further indication Civilian Biodefense Studies recently looked at
of which pathogens have the requisite physical potential biological agents to decide which
characteristics to make good biological weapons, present the greatest risk for a maximum credible
one need only look next at the agents that former event from a public health perspective. A
Soviet Union biological weapons experts consid- maximum credible event would be one that could
ered likely candidates. The agents included cause large loss of life, in addition to disruption,
smallpox, plague, anthrax, botulinum toxin, panic, and overwhelming of the civilian health-
equine encephalitis viruses, tularemia, Q fever, care resources (12).
Marburg, melioidosis, and typhus (10,11). To be used for a maximum credible event, an
Criteria such as infectivity and toxicity, agent must have some of the following
environmental stability, ease of large-scale properties: the agent should be highly lethal and
production, and disease severity were used in easily produced in large quantities. Given that
determining which agents had a high probability the aerosol route is the most likely for a large-
of use. Both the United States before 1969 and scale attack, stability in aerosol and capability to
the former Soviet Union spent years determining be dispersed (1 µm to 5 µm particle size) are
which pathogens had strategic and tactical necessary. Additional attributes that make an
capability. agent even more dangerous include being
The National Defense University recently communicable from person to person and having
compiled a study of more than 100 confirmed no treatment or vaccine.
incidents of illicit use of biological agents during When the potential agents are reviewed for
this century (W.S. Carus, pers. comm. [4]). Of the these characteristics, anthrax and smallpox are
100 incidents, 29 involved agent acquisition, and the two with greatest potential for mass
of the 29, 19 involved the actual nongovernmen- casualties and civil disruption. 1) Both are highly
tal use of an agent, and most were used for lethal: the death rate for anthrax if untreated
biocrimes, rather than for bioterrorism. In the before onset of serious symptoms exceeds 80%;
context of this study, the distinguishing feature 30% of unvaccinated patients infected with

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Table 1. Biological agents involved in bioterrorism or biocrimesa

Traditional biological Agents associated with
warfare agents biocrimes and bioterrorism
Pathogens Bacillus anthracisb Ascaris suum
Brucella suis Bacillus anthracisb
Coxiella burnetiib Coxiella burnetiib
Francisella tularensis Giardia lamblia
Smallpox HIV
Viral encephalitides Rickettsia prowazekii
Viral hemorrhagic feversb (typhus)
Yersinia pestisb Salmonella Typhimurium
Salmonella typhi
Shigella species
Schistosoma species
Vibrio cholerae
Viral hemorrhagic
fevers (Ebola)b
Yellow fever virus
Yersinia enterocolitica
Yersinia pestisb
Toxins Botulinumb Botulinumb
Ricinb Cholera endotoxin
Staphylococcal enterotoxin B Diphtheria toxin
Nicotine
Ricinb
Snake toxin
Tetrodotoxin
Anti-crop agents Rice blast
Rye stem rust
Wheat stem rust
aIncludes agents which were used, acquired, attempted to acquire, involved in a threat of use or an expressed interest in using.

Reprinted with permission from Carus WS. Table 6: Biological agents involved. In: Carus WS. Bioterrorism and biocrimes: the
illicit use of biological agents in the 20th Century. Working Paper, Center for Counterproliferation Research, National Defense
University. August 1998, revised March 1999.
bThese agents appear on both lists.

variola major could die. 2) Both are stable for diseases is likely to be delayed. For anthrax, this
transmission in aerosol and capable of large- is secondary to the rare occurrence of inhalation
scale production. Anthrax spores have been anthrax. Only 11 cases of inhalation anthrax
known to survive for decades under the right have been reported in the United States from
conditions (13). WHO was concerned that 1945 to 1994 (15), and recognition may be
smallpox might be freeze-dried to retain delayed until after antibiotic use would be
virulence for prolonged periods (8). 3) Both have beneficial. For smallpox, given that few U.S.
been developed as agents in state programs. Iraq physicians have any clinical experience with the
has produced anthrax for use in Scud missiles disease, many could confuse it for more common
and conducted research on camelpox virus, diseases (e.g., varicella and bullous erythema
which is closely related to smallpox (2). A Soviet multiforme) early on, allowing for second-
defector has reported that the former Soviet generation spread (12,16). 6) Availability of
Union produced smallpox virus by the ton (11). 4) vaccines for either disease is limited. Anthrax
Use of either agent would have a devastating vaccine, licensed in 1970, has been used for
psychological effect on the target population, persons at high risk for contact with this disease.
potentially causing widespread panic. This is in The U.S. military has recently begun vaccinat-
part due to the agents’ well-demonstrated ing the entire force; however, there is limited
historical potential to cause large disease availability of the vaccine for use in the civilian
outbreaks (14). 5) Initial recognition of both population. Routine smallpox vaccination was

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discontinued in the United States in 1971. Other agents of concern include the
Recent estimates of the current number of doses botulinum toxins and viral hemorrhagic fevers.
in storage at CDC range from 5 to 7 million (12), Once again, both are highly lethal. Botulinum
but the viability of stored vaccine is no longer toxin is a commonly cited threat, and Iraq has
guaranteed. admitted to producing it. Since intensive care
Obtaining smallpox virus as opposed to other would be required in treating both illnesses and
agents (e.g., anthrax, plague, and botulinum ventilator management is life-saving for botuli-
toxin) would be difficult, but if obtained and num, both would easily tax existing medical care
intentionally released, smallpox could cause a facilities. However, botulinum toxin may be a
public health catastrophe because of its less effective agent because of relatively lower
communicability. Even a single case could lead to stability in the environment and smaller
10 to 20 others. It is estimated that no more than geographic coverage than other agents demon-
20% of the population has any immunity from strated in modeling studies. Producing and
prior vaccination (12). There is no acceptable dispensing large amounts are also difficult (W.C.
treatment, and the communicability by aerosol Patrick, pers. comm.,19).
requires negative-pressure isolation. Therefore, A number of different viruses can cause
these limited isolation resources in medical hemorrhagic fever. These include (but are not
facilities would be easily overwhelmed. limited to) Lassa fever, from the Arenaviridae
Anthrax can have a delayed onset, further family; Rift Valley fever and Crimean Congo
leading to delays in recognition and treatment. hemorrhagic fever, from the Bunyaviridae
In the outbreak of inhalation anthrax in family; and Ebola hemorrhagic fever and
Sverdlovsk in 1979, some patients became ill up Marburg disease, from the Filoviridae family.
to 6 weeks after the suspected release of anthrax These organisms are potential biological agents
spores (1). The current recommendation for because of their lethality, high infectivity by the
prophylaxis of persons exposed to aerosolized aerosol route shown in animal models, and
anthrax is treatment with antibiotics for 8 weeks possibility for replication in tissue culture (16).
in the absence of vaccine or 4 weeks and until In summary, we know that biological
three doses of vaccine have been given (17). The pathogens have been used for biological warfare
amount of antibiotics required for postexposure and terrorism, and their potential for future use
prophylaxis of large populations could be is a major concern. Therefore we must be
enormous and could easily tax logistics prepared to respond appropriately if they are
capabilities for consequence management. used again. The technology and intellectual
Other bacterial agents capable of causing a capacity exist for a well-funded, highly
maximum credible event include plague and motivated terrorist group to mount such an
tularemia. Plague, like smallpox and anthrax, attack. Although the list of potential agents is
can decimate a population (as in Europe in the long, only a handful of pathogens are thought to
Middle Ages). An outbreak of plague could easily have the ability to cause a maximum credible
cause great fear and hysteria in the target event to paralyze a large city or region of the
population (as in the 1994 outbreak in India), country, causing high numbers of deaths, wide-
when hundreds of thousands were reported to scale panic, and massive disruption of commerce.
have fled the city of Surat, various countries Diseases of antiquity (including anthrax,
embargoed flights to and from India, and smallpox, and plague), notorious for causing
importation of Indian goods was restricted (18). large outbreaks, still head that list. In addition,
Both plague and tularemia are potentially lethal other agents, such as botulinum toxin, hemor-
without proper treatment; however, the avail- rhagic fever viruses, and tularemia, have
ability of effective treatment and prophylaxis potential to do the same. By focusing on a smaller
may reduce possible damage to a population. list of these low-likelihood, but high-impact
Both are infectious at low doses. Pneumonic diseases, we can better prepare for potential
plague’s person-to-person communicability and intentional releases, and hope to mitigate their
untreated case-fatality rate of at least twice that ultimate impact on our citizens.
of tularemia make it more effective than Many other pathogens can cause illness and
tularemia as an agent to cause mass illness. death, and the threat list will always be dynamic.

Emerging Infectious Diseases 526 Vol. 5, No. 4, July–August 1999

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We must, therefore, have the appropriate 8. World Health Organization Group of Consultants.
surveillance system and laboratory capability to Health aspects of chemical and biological weapons.
Geneva: The Organization; 1970.
identify other pathogens, and we must improve
9. Department of the Army. U.S. army activity in the U.S.
our public health and medical capabilities to biological warfare programs. Vol II. Publication DTIC
respond to the short list of the most dangerous B193427L. Washington: The Department; 1977.
naturally occurring biological pathogens that 10. Vorobjev AA, Cherkassey BL, Stepanov AV, Kyuregyan
could be used as bioterrorism weapons. AA, Fjedorov YM. Key problems of controlling
especially dangerous infections. In: Proceedings of the
Dr. Kortepeter is a preventive medicine officer in International Symposium of Severe Infectious Diseases:
the Operational Medicine Division at the U.S. Army Epidemiology, Express-Diagnostics and Prevention;
Medical Research Institute of Infectious Diseases, where 1997 Jun 16-20; Kirov, Russia. State Scientific
he teaches the medical management of biological weap- Institution, Volgo-Vyatsky Center of Applied
Biotechnology; 1997.
ons casualties.
11. Alibek K, Handelman S. Biohazard. Random House.
New York, NY; 1999.
Dr. Parker is Commander, U.S. Army Medical Re- 12. Henderson DA. The looming threat of bioterrorism.
search Institute of Infectious Diseases (USAMRIID) at Science 1999;283:1279-82.
Fort Detrick, MD. USAMRIID conducts research to de- 13. Manchee RJ, Stewart WDP. The decontamination of
velop vaccines, medications, and diagnostics to protect Gruinard Island. Chemistry in Britain 1988;690-1.
U.S. service members from biological warfare threats 14. The Holy Bible, new international version. Exodus
and endemic infectious diseases. Chapter 9. Indianapolis and Grand Rapids: B.B.
Kirkbride Bible Company, Inc. and The Zondervan
Corporation; 1978.
References 15. Centers for Disease Control and Prevention. Summary
1. Meselson M, Gillemin J, Hugh-Jones M, Langmuir A, of notifiable diseases, 1945-1994. MMWR Morb Mortal
Popova I, Shelokov A, et al. The Sverdlovsk anthrax Wkly Rep 1994;43:70-8.
outbreak of 1979. Science 1994;209:1202-8. 16. Franz DR, Jahrling PB, Friedlander AM, McClain DJ,
2. Zilinskas RA. Iraq’s biological weapons: the past as Hoover DL, Byrne WR, et al. Clinical recognition and
future? JAMA 1997;278:418-24. management of patients exposed to biological warfare
3. U.S. Department of State. 1996 Patterns of Global agents. JAMA 1997;278:399-411.
Terrorism Report. Available from: URL: http:// 17. Centers for Disease Control and Prevention.
www.state.gov. Bioterrorism alleging use of anthrax and interim
4. Carus WS. Bioterrorism and biocrimes: the illicit use of guidelines for management—United States, 1998.
biological agents in the 20th Century [working paper]. MMWR Morb Mortal Wkly Rep 1999;48:69-74.
Washington: Center for Counterproliferation Research, 18. Campbell GL, Hughes JM. Plague in India: a new
National Defense University; Aug 1998, revised Mar 1999. warning from an old nemesis. Ann Intern Med
5. Torok TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow 1995;122:151-3.
R, Mauvais S, et al. A large community outbreak of 19. McNally RE, Morrison MB, Berndt JE, Fisher JE,
salmonellosis caused by intentional contamination of Bo’Berry JT, Puckett V, et al. Effectiveness of medical
restaurant salad bars. JAMA 1997;278:389-95. defense interventions against predicted battlefield
6. Departments of the Army, Navy, and Air Force. NATO levels of botulinum toxin A. Joppa (MD): Science
Handbook on the Medical Aspects of NBC Defensive Applications International Corporation; 1994.
Operations. Washington: The Department; 1996.
7. Spertzel RO, Wannemacher RW, Patrick WC, Linden
CD, Franz DR. Technical ramifications of inclusion of
toxins in the chemical weapons convention (CWC).
Technical report no. MR-43-92-1. Fort Detrick (MD):
U.S. Army Medical Research Institute of Infectious
Diseases; 1992.

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 Special Issue

Epidemiology of Bioterrorism
Julie A. Pavlin
Walter Reed Army Institute of Research, Washington, D.C., USA

Since the discovery of Iraq’s biological Differential Diagnosis

weapons program, concern regarding the threat Any small or large outbreak of disease should
of biological warfare has increased (1). Anthrax be evaluated as a potential bioterrorist attack.
immunizations; increased nuclear, biological, This initial investigation does not have to be time
and chemical defense training; improved consuming or involve law enforcement. A look at
detection systems and protective gear; and the facts surrounding the outbreak to determine
increased vigilance have been instituted to if anything seems unusual or indicative of
protect the military. bioterrorism should suffice. Since a disease
However, the military is not the only outbreak can be the result of intentional
population at risk for biological attack. To contamination, the differential diagnosis of an
effectively counter the potentially devastating outbreak should first be considered. The
effects of an attack, we need to understand the possibilities include a spontaneous outbreak of a
basic epidemiologic principles of biological known endemic disease, a spontaneous outbreak
agents used as weapons. of a new or reemerging disease, a laboratory
A biological agent is commonly portrayed as accident, or an intentional attack with a
a genetically engineered organism resistant to biological agent. Epidemiologic tools can assist in
all known vaccines and drugs, highly contagious, differentiating between these possibilities.
and able to harm thousands of people. However, The cause of a disease or even the occurrence
alleged attacks by the Aum Shinrikyo did not of something unusual may be very difficult to
result in a single illness from a biological agent determine, especially if the initial cases are few.
(2), and the successful 1984 contamination of Surveillance needs to be more than routine. Not
salad bars in The Dalles, Oregon, by a religious only unusually high rates of illness but also
cult involved a common salmonella strain that unusual diseases should signal a warning. For
was not lethal or contagious and was susceptible example, even one case of inhalation anthrax
to antibiotics (3). should cause immediate concern and action.
Therefore, our level of suspicion and Unlike chemical terrorism, biological terror-
diligence in identifying and reacting to a ism is not immediately obvious but may appear
biological attack must remain high, since the insidiously, with primary-care providers wit-
attack may not follow an expected pattern. nessing the first cases. However, it may not even
Furthermore, a small outbreak of illness could be be emergency room personnel who first detect a
an early warning of a more serious attack, and problem. The first to notice could be a hospital
recognition and prompt institution of preventive laboratory seeing unusual strains of organisms,
measures (such as effective vaccines and or the county epidemiologist keeping track of
antibiotics) could save thousands of lives. hospital admissions, or even pharmacists
To facilitate the rapid identification of a distributing more antibiotics than usual, 911
bioterrorist attack, all health-care providers and operators noticing an increase in respiratory
public health personnel should have basic distress calls, or funeral directors with increased
epidemiologic skills and knowledge of what to business. All epidemiologic data should be
expect in such a setting. tracked and aggressively followed to ensure the
most rapid recognition and response.

Address for correspondence: Julie A. Pavlin, Department of Epidemiologic Approach

Field Studies, Division of Preventive Medicine, Walter Reed The basic epidemiologic approach in the
Army Institute of Research, Washington, D.C. 20307-5100,
evaluation of a potential bioterrorist or
USA; fax: 202-782-0613; e-mail: pavlinj@wrsmtp-ccmail.army.mil.
biowarfare attack is not different from any

Emerging Infectious Diseases 528 Vol. 5, No. 4, July–August 1999

 Special Issue

standard epidemiologic investigation. The first exposure. From this information, a possible
step is to use laboratory and clinical findings to incubation period can be calculated, which can
confirm that a disease outbreak has occurred. A assist in determining the potential cause of
case definition should be constructed to illness, as well as suggesting a possible
determine the number of cases and the attack intentional attack (if the incubation period is
rate. The use of objective criteria in the shorter than usual as a result of an unusually
development of a case definition is very high inoculum or more effective exposure route).
important in determining an accurate case Calculating the incubation period may also help
number, as both additional cases may be found determine if the disease is spread from person to
and some may be excluded, especially as the person, which is extremely important to effective
potential exists for hysteria to be confused with disease control measures.
actual disease. The estimated rate of illness
should be compared with rates during previous Epidemiologic Clues
years to determine if the rate constitutes a As steep epidemic curves can be seen in
deviation from the norm. natural point-source exposures, additional
Once the case definition and attack rate have characteristics of the outbreak should be
been determined, the outbreak can be character- investigated in determining whether it is the
ized in the conventional context of time, place, result of a biological attack (4,5). None of the
and person. These data will provide crucial following clues alone constitute proof of
information in determining the potential source intentional use of a biological agent, but together
of the outbreak. they can assist greatly in determining if further
investigation is warranted. 1) The presence of a
Epidemic Curve large epidemic, with greater case loads than
Using data gathered on cases over time, an expected, especially in a discrete population.
epidemic curve can be calculated. The disease 2) More severe disease than expected for a given
pattern is an important factor in differentiating pathogen, as well as unusual routes of exposure,
between a natural outbreak and an intentional such as a preponderance of inhalational disease
attack. In most naturally occurring outbreaks, as was seen in Sverdlovsk after the accidental
numbers of cases gradually increase as a release of aerosolized Bacillus anthracis spores
progressively larger number of people come in (6). 3) A disease that is unusual for a given
contact with other patients, fomites, and vectors geographic area, is found outside the normal
that can spread disease. Eventually, most of the transmission season, or is impossible to transmit
population has been exposed and is immune to naturally in the absence of the normal vector for
further disease, and the number of cases, or transmission. 4) Multiple simultaneous epidem-
epidemic curve, gradually decreases. Con- ics of different diseases. 5) A disease outbreak
versely, a bioterrorism attack is most likely to be with zoonotic as well as human consequences, as
caused by a point source, with everyone coming many of the potential threat agents are
in contact with the agent at approximately the pathogenic to animals. 6) Unusual strains or
same time. The epidemic curve in this case would variants of organisms or antimicrobial resistance
be compressed, with a peak in a matter of days or patterns disparate from those circulating.
even hours, even with physiologic and exposure 7) Higher attack rates in those exposed in certain
differences. If the biological agent is contagious, areas, such as inside a building if the agent was
it is possible to see a second curve peak after the released indoors, or lower rates in those inside a
first, as original cases expose originally sealed building if an aerosol was released
unexposed persons to the agent. The steep outdoors. 8) Intelligence that an adversary has
epidemic curve expected in a bioterrorism attack access to a particular agent or agents. 9) Claims
is similar to what would be seen with other point by a terrorist of the release of a biologic agent.
source exposures, such as foodborne outbreaks. 10) Direct evidence of the release of an agent,
Therefore, the compressed epidemic curve is still with findings of equipment, munitions, or
not pathognomonic for an intentional bioterrorism tampering.
attack. Even with the presence of more than one of
If a specific group has been exposed, the the above indicators, it may not be easy to
epidemic curve may indicate the time of determine that an attack occurred through

Vol. 5, No. 4, July–August 1999 529 Emerging Infectious Diseases

 Special Issue

nefarious means. For example, it took months to further exposure, which should be the key
determine that the outbreak of salmonellosis in driving force behind any epidemiologic investi-
Oregon was caused by intentional contamination gation. Through strong epidemiologic training, a
of salad bars (3). Other outbreaks, such as the close attention to disease patterns, and a healthy
hantavirus outbreak in the Four Corners area of respect for the threat of biological terrorism,
the United States, have been thought of as potential problems can be discovered rapidly,
possible results of intentional contamination (7). and actions can be taken to decrease the impact
Even if no conclusive answer can be derived of disease, regardless of its origin.
quickly, the means employed in determining the
Major Pavlin is chief of the Field Studies Depart-
cause of an attack will still provide medical
ment, Division of Preventive Medicine, Walter Reed Army
personnel with information that may prevent Institute of Research. She has worked in the area of
illness and death. medical biodefense education. Currently she is develop-
ing national and international surveillance systems for
Recommendations for Preparedness emerging diseases with the Department of Defense’s
Improved awareness and readiness should a Global Emerging Infections Surveillance and Response
bioterrorism attack occur include education of all System.
medical personnel, especially primary-care
providers and emergency personnel first to see References
patients affected by a biological attack. Training 1. Proliferation: threat and response. Office of the
should include basic epidemiologic principles as Secretary of Defense; November 1997.
well as clinical information on diagnosing and 2. Broad WJ, Miller J. The threat of germ weapons is
rising. Fear, too. New York Times 1998 Dec 27; sec. 4,
treating agents that pose the highest threat. col. 1, pg. 1.
Training should be refreshed periodically to 3. Torok TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow
ensure that skills remain current. R, Mauvais S, et al. A large community outbreak of
Improved surveillance efforts should be salmonellosis caused by intentional contamination of
instituted with as close to real-time data restaurant salad bars. JAMA 1997;278:389-95.
4. Weiner SL. Strategies of biowarfare defense. Mil Med
gathering as possible. All facets of surveillance 1987;152:25-8.
should be used, to include emergency visits, 5. Noah DL, Sobel AL, Ostroff SM, Kildew JA. Biological
laboratory data, pharmacy use, school absentee- warfare training: infectious disease outbreak
ism, or any other data that correlate with an differentiation criteria. Mil Med 1998;163:198-201.
increase in infectious disease. Robust surveil- 6. Meselson M, Guillemin J, Hugh-Jones M, Langmuir A,
Popova I, Shelokov A, et al. The Sverdlovsk anthrax
lance systems are essential to detecting any outbreak of 1979. Science 1994;266:1202-8.
emerging or reemerging disease. Quick recogni- 7. Horgan J. Were Four Corners victims biowar
tion of any change in disease patterns will casualties? Sci Am 1993;269:16.
facilitate determining the source and preventing

Emerging Infectious Diseases 530 Vol. 5, No. 4, July–August 1999

 Special Issue

Vaccines in Civilian Defense

Against Bioterrorism
Philip K. Russell
Johns Hopkins School of Public Health, Baltimore, Maryland, USA

In the United States, over the past half epidemic and prevention of a global pandemic,
century, we have lived under the protective postexposure prophylaxis against anthrax (with
umbrella of vaccination programs that shield our antibiotics), and preexposure prophylaxis in
population from a dozen serious and sometimes first-responders at high risk, laboratory work-
fatal naturally transmitted illnesses. Vaccina- ers, and health-care providers.
tion has been the single most cost-effective public Smallpox and anthrax, which pose the
health intervention. However, the value of greatest risk for causing large numbers of
vaccines in protecting the population against the casualties in the event of an effective release by a
deliberate release of infectious organisms is not terrorist group, are at the top of the list of threat
so clear-cut. agents. Licensed vaccines against both anthrax
The U.S. armed forces have recognized the and smallpox that protect against aerosol
military value of vaccines against biological transmission are available. An existing licensed
threats and have a long-standing research and plague vaccine is protective against flea-
development program for a series of vaccines to transmitted disease but not against aerosol
protect service members from hostile use of a challenge in animal experiments or against
biological agent. Vaccination against anthrax is pneumonic plague. This vaccine is in limited
under way in all three armed services. The supply, and the manufacturer has recently
Department of Defense has a large program to ceased production.
develop and license additional vaccines for The Department of Defense Joint Vaccine
biological defense. For the military, vaccination Acquisition Program has several experimental
is an effective means of countering a known vaccines in development (Table). These vaccines
threat because the population at risk is easily will be further developed and tested with the
defined and a high level of vaccine coverage can intent of obtaining products licensed by the U.S.
be achieved. Food and Drug Administration.
In evaluating the role of vaccines for
protecting the civilian population, quite different
Table. Vaccines against biological agents
answers are reached. Despite the protective
efficacy of vaccines against individual organ- Licensed Vaccines in research
vaccines and development
isms, the very high costs and the great
difficulties involved in vaccinating large popula- Anthrax Vaccinia (cell culture)
Smallpox (vaccinia) Botulinum toxoids
tions, along with the broad spectrum of potential
Plague Tularemia
agents, make it impossible to use vaccines to Q fever
protect the general population against VEE, EEE, WEE
bioterrorism. Thus, vaccines cannot be consid- VEE, Venezuelan equine encephalitis; EEE, Eastern equine
ered a first line of defense against bioterrorism encephalitis; WEE, Western equine encephalitis.
for the general population, as they can be for the
relatively small military population. However, if
suitable vaccines can be made available, they Smallpox
have several potential uses: control of a smallpox One vaccine in development that is of great
importance to civilian biodefense is the vaccinia
Address for correspondence: Philip K. Russell, Johns Hopkins
Center for Civilian Biodefense Studies, Candler Building, virus vaccine made in cell culture. A new
Suite 850, 111 Market Place, Baltimore, MD 21202, USA; fax: national stockpile of vaccinia vaccine is urgently
410-223-1665; e-mail: biodefen@jhsph.edu. needed to respond to the possible threat of a

Vol. 5, No. 4, July–August 1999 531 Emerging Infectious Diseases

 Special Issue

deliberate release of smallpox virus. Even Anthrax

though such release is unlikely, the conse- Anthrax is the second threat that requires a
quences of being unprepared would be a global major research and development effort to meet
catastrophe. An unchecked epidemic in today’s civilian needs. A covert attack, which exposes an
unvaccinated, densely packed urban populations urban population to an anthrax spore aerosol, is
linked by rapid air travel could kill millions. The thought by some to be the most likely scenario for
only possible course of action would be to mount a bioterrorism attack. If the release is detected or
a global effort to control the spread and eradicate the first cases are rapidly diagnosed, rapid action
the disease using vaccinia virus vaccine. The can save many lives. Providing the exposed
number of deaths due to secondary and population with antibiotics followed by vaccina-
subsequent spread of this highly contagious tion could be lifesaving for exposed persons who
virus would be determined by the rapidity of the would otherwise become ill with untreatable
public health response, the effectiveness of a inhalation anthrax in the subsequent few weeks.
vaccination campaign, and, most importantly, Prophylactic antibiotics alone will prevent
the availability of vaccine. disease in persons exposed to antibiotic-
The national stockpile (fewer than 7 million susceptible organisms, but incorporating vacci-
doses of vaccinia virus vaccine) is insufficient to nation into the treatment regime can greatly
meet national and international needs in this reduce the length of treatment with antibiotics.
scenario. The stockpile is also deteriorating and Without vaccination, antibiotics must be
has a finite life span. The vaccine was made continued for 60 days; if effective vaccination can
using the traditional method of scarifying and be provided, this can be reduced to 30 days.
infecting the flanks and bellies of calves and Vaccination of persons affected by an attack will
harvesting the infected lymph. No manufacturer also face the issue of environmental contamina-
exists today with the capability to manufacture tion of urban areas after an attack. Stockpiling a
calf lymph vaccine by the traditional method. vaccine capable of inducing protective immunity
Replacing the stockpile will require the with two doses could be extremely valuable in
development and licensure of a new vaccine reducing the impact of a terrorist release of
using modern cell-culture methods. This anthrax.
development program, which will include process The current anthrax vaccine manufactured
development, validation of a new manufacturing by Bioport (formerly the Michigan Department
process, and extensive clinical testing, will be of Public Health Laboratory) is an alum-
expensive and may take several years (1). adsorbed, partially purified culture filtrate of
Obstacles to the development of the vaccine Bacillus anthracis with a high protective
include the lack of satisfactory stocks of vaccinia antigen content. The schedule for administra-
immune globulin necessary for managing tion is 0, 2, and 4 weeks and 6, 12, and 18 months.
complications of vaccination. Clinical testing This vaccine is safe and efficacious and is being
cannot proceed without a supply of vaccinia used by the armed forces to protect personnel
immune globulin. As part of the development against the use of anthrax as a weapon.
effort, the problems associated with manufac- Immunization of rhesus monkeys followed by a
ture of sufficient quantities of vaccinia immune high-dose aerosol challenge has convincingly
globulin will have to be addressed and solved. demonstrated the capability of this vaccine to
The Department of Defense program is moving protect against aerosol challenge with B.
ahead with development of a cell-culture vaccine anthracis spores. The multiple dose require-
by using a cloned strain of vaccinia derived from ment, however, is a drawback for civilian use.
another strain. Both civilian and military Studies in progress may find ways to allow
requirements could be met by a combined and modification of the schedule. Vaccine supply is
expanded development effort using either the limited, as is production capacity. As a result, at
cloned strain or one of the licensed vaccinia least for the immediate future, the armed forces
strains. The development costs will undoubtedly will require the entire available supply. This
be high, as for any new biologic product, but the vaccine is made by a method developed before the
cost of preparedness is insignificant when advent of molecular biology and requires
weighed against the costs of an unchecked dedicated facilities because B. anthracis is a
smallpox epidemic. spore-forming organism. In addition to having a

Emerging Infectious Diseases 532 Vol. 5, No. 4, July–August 1999

 Special Issue

multiple-dose requirement, the vaccine is not The value of vaccinating law-enforcement

highly purified and contains multiple extraneous and emergency response personnel, who must
proteins. The characteristics of the vaccine and respond to threats (real or otherwise), depends
the constraints on the present method of on the nature of their work and the immediacy of
manufacturing argue strongly against procuring the threat. Laboratory personnel who must work
large amounts for civilian use when the with unknown materials and with high
technology and the science base exist to rapidly concentrations of known infectious materials
develop a second-generation, improved anthrax must be vaccinated. These are additional
vaccine. justifications for moving ahead with a vigorous
Anthrax depends on two toxins (lethal factor development program for anthrax and smallpox
and edema factor) for virulence. A protein called vaccines.
protective factor is an essential component of
Dr. Russell is professor, Center for Immunization
both toxins. The protective factor content is the
Research, Johns Hopkins School of Public Health; former
basis for the effectiveness of the current vaccine. Commander, United States Army Medical Research and
A vaccine based on purified protective factor Development Command.
made by recombinant technology has been
protective in animals (2). Use of a modern
adjuvant with purified recombinant protective References
1. Committee on R&D Needs for Improving Civilian
factor should make it possible to have a very Medical Response to Chemical and Biological
effective two-dose vaccine. A recent report of the Terrorism Incidents. Institute of Medicine, National
Institute of Medicine Committee on Research Academy of Sciences. Chemical and Biological
and Development to Improve Civilian Medical Terrorism. Research and Development to Improve
Response to Chemical and Biological Terrorism Civilian Medical Response. Washington: National
Academy Press; 1999.
makes a strong case for a major research and 2. Zajtchtchuk R, Bellamy RF, editors. Textbook of
development effort leading to an improved military medicine: medical aspects of chemical and
second-generation vaccine (1). biological warfare. Office of the Surgeon General,
Questions regarding the ability of existing Department of the Army. Washington, D.C.; 1997.
anthrax vaccines to protect against anthrax 3. Pomeratnsev AP, Startsin NA, Mockov YV, Marnin LI.
Expression of cereolysin AB genes in Bacillus
strains engineered to contain additional viru- Anthracis vaccine strain ensures protection against
lence genes have been raised in Russia (3). experimental hemolytic anthrax infection. Vaccine
Research is needed to address this and related 1997;15:1846-50.
questions about the pathogenesis of anthrax and
protective immunity.

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 Special Issue

Vaccines, Pharmaceutical Products, and

Bioterrorism: Challenges for the U.S.
Food and Drug Administration
Kathryn C. Zoon
U.S. Food and Drug Administration, Rockville, Maryland, USA

In regards to bioterrorism, the goal of the and sponsor compliance are executed in
U.S. Food and Drug Administration (FDA) is to accordance with regulations.
foster the development of vaccines, drugs and FDA’s regulation of medical products is
diagnostic products, safeguards of the food based on science, law, and public health
supply, and other measures needed to respond to considerations (Figure 1). Research conducted at
bioterrorist threats. Many products (vaccines, FDA (in particular at the Center for Biologics
therapeutic drug and biological products, food, Evaluation and Research) contributing to
devices, and diagnostics) regulated by FDA could biological warfare defense and other
be affected by bioterrorism. Pathogens or pathogen counterbioterrorism efforts is in the following
products adapted for biological warfare include areas: design of new vaccines (e.g., pox viruses);
smallpox (variola), anthrax (Bacillus anthracis), pathogenesis and mechanism of replication of
plague (Yersinia pestis), tularemia (Francisella biological warfare agents; new methods and
tularensis), brucellosis (Brucella abortus, standards to expedite the review of new vaccines
B. melitensis, B. suis, B. canis), Q fever (Coxiella and immunoglobulins (e.g., mucosal protection
burnettii), botulinum toxin (produced by against a pathogen); and stem cell protection and
Clostridium botulinum) and staphylococcal en- chemokine/cytokine and angiogenic agent defense
terotoxin B. New products are needed to diagnose, mechanisms. The development framework of
prevent, and treat these public health threats.
FDA is participating in an interagency group
preparing for response in a civilian emergency.
This group includes representatives of the Review Research Surveillance
Department of Defense; the Veterans Adminis-
tration; and components of the Department of
Health and Human Services (DHHS), such as Policy Compliance
the Centers for Disease Control and Prevention
(CDC), National Institutes of Health (NIH), and
Office of Emergency Preparedness. In addition,
FDA will be proposing standards for the use of Figure 1. Regulation of medical products.
animal efficacy data in approving new products
to counter chemical and biological agents. The most biological and traditional drug products is
agency is also participating in setting a broad- shown in Figure 2. The principal evaluation and
based federal research agenda to facilitate the research and development phases before a drug
government’s preparedness against bioterrorism; is submitted to FDA for approval can take 1 to 3
is identifying facilities and activities suitable for years. The clinical research and development
the production of biological weapons; is involved program (investigational phase), depending on
in product development, review, and testing; and is the agent and clinical indication, can take 2 to 10
ensuring that appropriate product surveillance years. The marketing application review period
generally is 2 months to 3 years (average 1 year).
Address for correspondence: Kathryn C. Zoon, Center for Once a product is approved, long-term
Biologics Evaluation and Research, Food and Drug
Administration, Mailstop HFM-1, 1401 Rockville Pike,
postmarketing surveillance, inspections, and
Rockville, MD 20852, USA; fax: 301-827-0440; e-mail: product testing are performed to ensure the
zoon@cber.fda.gov quality, safety, and efficacy of the product, as

Emerging Infectious Diseases 534 Vol. 5, No. 4, July–August 1999

 Special Issue

obtaining clinical efficacy data. For many of

these infectious agents or toxins, human efficacy
trials cannot be performed, as such studies would
involve exposing healthy human volunteers to a
Research and development
lethal or permanently disabling agent without
Principal Evaluation
proven therapy and field trials. In most cases,
such trials are not feasible because pockets of

↓
natural exposure do not exist. To address this
1 to 3 years
dilemma, FDA will be proposing that the use of
animal efficacy data be allowed when appropri-
ate (1). This proposed rule would identify the
Clinical research
types of data required. Safety, pharmacokinetic,
and
and immunogenicity data will still be necessary
development
in humans. Product safety will likely be evaluated
Phases 1, 2, 3
in healthy human volunteers at doses and routes of
administration anticipated in field use.

↓ 2 to 10 years Some scientific considerations for animal

studies include the toxic agent’s pathophysi-
ologic mechanism of toxicity and how the test
drug or biologic product prevents it and the
Product License Application,
validity of the animal study endpoint in humans.
Established License Application,
In addition, data showing that drug effectiveness
New Drug Application,
in animals predicts efficacy in humans would be
New Drug Application
needed. Finally, product recipients should be
Review
given follow-up after treatment to affirm product
safety and efficacy.

↓
2 months to For licensure or other approval, a biological
3 years warfare defense product must have an accept-
able quality, safety, efficacy, and potency profile.
Post-marketing Likewise, the product must have acceptable stability
survellance characteristics and be produced in compliance with
current good manufacturing practices.

↓
A case study of anthrax vaccine can serve as
an example of our capability to respond to a
bioterrorist threat. Only one licensed anthrax
vaccine (Bioport Corp.) is available. This vaccine
Figure 2. Development of biological and tradition consists of a membrane-sterilized culture filtrate
drug products. of B. anthracis V770-NP1-R, an avirulent,
nonencapsulated strain. The culture filtrate is
well as appropriate product labeling. Accelerating adsorbed to aluminum hydroxide and formu-
product development is important in many lated with benzethonium chloride (preservative)
situations, including bioterrorism. Mechanisms and formaldehyde (stabilizer). The administra-
for advancing medicines through the approval tion schedule consists of 0.5 ml injected
process have been developed for severe and life- subcutaneously at 0, 2, and 4 weeks, 6, 12, and 18
threatening illnesses. For drugs and biologic months, and then annually thereafter. The
products, these mechanisms include expedited vaccine was licensed in 1970. The efficacy data in
review and fast-track development, as well as support of the license consisted of a single-blind,
accelerated approval and priority review of well-controlled field study (2). The vaccine
marketing applications. For a priority product, efficacy was 92.5% (lower 95% confidence limit of
complete review of marketing applications is 65%). Of the 26 cases of anthrax in this study, 21
6 months. were cutaneous and 5 (4 fatal) were inhalation (2
Many of the biological warfare defense in the placebo group, 0 in the vaccinated group,
products pose difficult problems with regard to 3 in the unvaccinated group).

Vol. 5, No. 4, July–August 1999 535 Emerging Infectious Diseases

 Special Issue

In December 1985, the Federal Register (3) effective products to treat or prevent toxicity of
published the FDA’s advisory panel review of the biological and chemical agents; methods to
efficacy of anthrax adsorbed. The panel rapidly detect, identify, and decontaminate
recommended that this product be placed in hazardous organisms; a greater ability to ensure
category I (safe, effective, and not misbranded) the safety of the food supply; and a greater ability
and that the appropriate license be continued to provide appropriate medical care and a public
because there was substantial evidence for this health response.
product.
Studies of new anthrax vaccine products are Table. Proposed activities of the U.S. Food and Drug
in progress. They include protective antigen– Administration to counter bioterrorism
based vaccines, e.g., purified protein from 1. Enhancing the expeditious development and
B. anthracis culture or live-attenuated spore licensure of new vaccines and biological
vaccine. Production and product testing will therapeutics through research and review
differ for each of these candidate vaccines. The activities—anthrax vaccine and antisera to
immunogenicity of the product in humans and botulinum toxin, for example.
2. Enhancing the timeliness of application reviews
animal models should be assessed. The cell-
of new drugs and biological products and new
mediated immunity elicited by the vaccine may uses of existing products.
also need to be evaluated. One of the immune 3. Participating in the planning and coordination of
correlates of protection of anthrax vaccines is public health and medical response to a terrorist
likely to be the antibody response to protective attack involving a biological or chemical agent(s).
antigen. However, the quantitative relation of 4. Participating in the development of rapid
antiprotective antigen antibody to protection has detection and decontamination for agents of
not been established in humans but is being bioterrorism such as Clostridium botulinum
investigated by the Department of Defense. toxins, Yersinisa pestis, Bacillus anthracis.
5. Ensuring the safety of regulated foods, drugs,
Animal challenge and protection models,
medical devices, and biological products; arrange
especially rabbit and nonhuman primate models, for seizure and disposal of affected products.
may be particularly useful. Passive transfer of 6. Developing techniques for detection of genetic
protection, also an indication of the importance modifications of microorganisms to make them
of antibodies for protection, has been observed in more toxic or antibiotic- or vaccine-resistant.
animal models. Therefore, human challenge 7. Rapidly determining a microbe’s sensitivity to
protection studies and new field efficacy trials drug therapy.
are not feasible in studying the efficacy of new 8. Determining the mechanism of replication and
anthrax vaccines. Animal challenge and protec- pathogenicity or virulence of identified organisms
including elements that can be transferred to
tion studies against spores will be important for
other organisms to circumvent detection,
new vaccines based on protective antigen. prevention, or treatment.
Comparisons of immune responses in human 9. Enhancing adverse product reporting surveillance
cohorts receiving new or licensed vaccines capabilities.
should be performed.
Data should be obtained on various target Dr. Zoon is director of the Center for Biologics Evalu-
populations, including adults and children, to ation and Research (CBER) at the Food and Drug Ad-
evaluate the safety of new anthrax vaccines. ministration. As former director of the Division of
Systemic and local adverse events are particu- Cytokine Biology in CBER, Dr. Zoon was actively involved
larly important to monitor. For live-attenuated with regulatory issues related to cytokines, growth fac-
tors, studies on interferon purification and character-
and vector vaccine approaches, the potential for
ization, and interferon receptors.
transmission to others will be an important
consideration in clinical development and use.
After these vaccines are licensed and adminis- References
tered, the safety and adverse reactions of these 1. Federal Register Vol 63 #80, Monday, April 27, 1998, p.
21957.
vaccines should be assessed. 2. Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin
In conclusion, FDA will be providing a M, Ingraham NR. Field evaluation of a human anthrax
critical link in access of new medicines for vaccine. Am J Public Health 1962;52:632-45.
biowarfare defense (Table). The expected out- 3. Federal Register. Vol 50 #240, Friday, Dec. 13, 1985, p.
comes of these activities include safe and 51002-17.

Emerging Infectious Diseases 536 Vol. 5, No. 4, July–August 1999

 Special Issue

Smallpox: Clinical and

Epidemiologic Features
D. A. Henderson
Johns Hopkins Center for Civilian Biodefense Studies,
Baltimore, Maryland, USA

Clinical and Epidemiologic later, pustular (Figure 2). The patient remains
Characteristics of Smallpox febrile throughout the evolution of the rash and
Smallpox is a viral disease unique to customarily experiences considerable pain as the
humans. To sustain itself, the virus must pass pustules grow and expand. Gradually, scabs
from person to person in a continuing chain of form, which eventually separate, leaving pitted
infection and is spread by inhalation of air scars. Death usually occurs during the second
droplets or aerosols. Twelve to 14 days after week.
infection, the patient typically becomes febrile The disease most commonly confused with
and has severe aching pains and prostration. smallpox is chickenpox, and during the first 2 to
Some 2 to 3 days later, a papular rash develops 3 days of rash, it may be all but impossible to
over the face and spreads to the extremities distinguish between the two. However, all
(Figure 1). The rash soon becomes vesicular and smallpox lesions develop at the same pace and,
on any part of the body, appear identical.
Chickenpox lesions are much more superficial
and develop in crops. With chickenpox, scabs,
vesicles, and pustules may be seen simulta-
neously on adjacent areas of skin. Moreover, the
rash in chickenpox is more dense over the trunk
(the reverse of smallpox), and chickenpox lesions
are almost never found on the palms or soles.
In 5% to 10% of smallpox patients, more
rapidly progressive, malignant disease develops,
which is almost always fatal within 5 to 7 days. In
such patients, the lesions are so densely
confluent that the skin looks like crepe rubber;

Figure 1. Most cases of smallpox are clinically typical

and readily able to be diagnosed. Lesions on each area
of the body are at the same stage of development, are
deeply embedded in the skin, and are more densely
concentrated on the face and extremities.
Figure 2. The lesions of chickenpox develop as a
Address for correspondence: D. A. Henderson, Johns Hopkins series of “crops” over several days and are very
Center for Civilian Biodefense Studies, 111 Market Place, Ste. superficial. Papules, vesicles, pustules, and scabs
850, Baltimore, MD 21202, USA; fax: 410-223-1665; e-mail: can be seen adjacent to each other. The trunk is
dahzero@aol.com. usually more affected than the face or extremities.

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 Special Issue

some patients exhibit bleeding into the skin and Another outbreak occurred in Yugoslavia in
intestinal tract. Such cases are difficult to February 1972 (1). Despite routine vaccination
diagnose, but they are exceedingly infectious. in Yugoslavia, the first case in the 1972 outbreak
Smallpox spreads most readily during the resulted in 11 others; those 11, on average, each
cool, dry winter months but can be transmitted infected 13 more. Other outbreaks in Europe
in any climate and in any part of the world. The from 1958 on showed that such explosive spread
only weapons against the disease are vaccination was not unusual during the seasonal period of
and patient isolation. Vaccination before high transmission, i.e., December through April.
exposure or within 2 to 3 days after exposure One can only speculate on the probable rapidity
affords almost complete protection against of spread of the smallpox virus in a population
disease. Vaccination as late as 4 to 5 days after where no one younger than 25 years of age has
exposure may protect against death. Because ever been vaccinated and older persons have
smallpox can only be transmitted from the time little remaining residual immunity.
of the earliest appearance of rash, early detection Where might the virus come from? At one
of cases and prompt vaccination of all contacts is time, it was believed that the smallpox virus was
critical. restricted to only two high-security laboratories,
one at the Centers for Disease Control and
Smallpox Vaccination Prevention in Atlanta, Georgia, and one at the
Smallpox vaccination is associated with some Russian State Centre for Research on Virology
risk for adverse reactions; the two most serious and Biotechnology, Koltsovo, Novosibirsk Re-
are postvaccinal encephalitis and progressive gion. By resolution of the 1996 World Health
vaccinia. Postvaccinal encephalitis occurs at a Assembly (WHA), those stocks were slated to be
rate of 3 per million primary vaccinees; 40% of destroyed at the end of June 1999. The
the cases are fatal, and some patients are left desirability of such an action was reaffirmed by a
with permanent neurologic damage. Progressive World Health Organization Expert Committee in
vaccinia occurs among those who are immuno- January 1999. On May 22, 1999, WHA, however,
suppressed because of a congenital defect, passed a resolution postponing destruction until
malignancy, radiation therapy, or AIDS. The 2002, by which time any promise of the variola
vaccinia virus simply continues to grow, and virus stocks for public health research could be
unless these patients are treated with vaccinia determined. Destruction of the virus would be at
immune globulin, they may not recover. least one step to limit the risk for the
Pustular material from the vaccination site may reemergence of smallpox. However, despite
also be transferred to other parts of the body, widespread acceptance of the 1972 Bioweapons
sometimes with serious results. Convention Treaty, which called for all countries
Routine vaccination is only recommended for to destroy their stocks of bioweapons and to cease
laboratory staff who may be exposed to one of the all research on offensive weapons, other
orthopoxviruses. There are two reasons for this. laboratories in Russia and perhaps in other
First is the risk for complications. Second, U.S. countries maintain the virus. Iraq and the Soviet
national vaccine stocks are sufficient to Union were signatories to the convention, as was
immunize only 6 to 7 million persons. This the United States. However, as reported by the
amount is only marginally sufficient for former deputy director of the Russian Bioweapons
emergency needs. Plans are now being made to Program, officials of the former Soviet Union
expand this reserve. However, at least 36 months took notice of the world’s decision in 1980 to
are required before large quantities can be cease smallpox vaccination, and in the atmo-
produced. sphere of the cold war, they embarked on an
The potential of smallpox as a biological ambitious plan to produce smallpox virus in
weapon is most dramatically illustrated by two large quantities and use it as a weapon. At least
European smallpox outbreaks in the 1970s. The two other laboratories in the former Soviet
first occurred in Meschede, Germany, in 1970 Union are now reported to maintain smallpox
(1). This outbreak illustrates that smallpox virus virus, and one may have the capacity to produce
in an aerosol suspension can spread widely and the virus in tons at least monthly. Moreover,
infect at very low doses. Russian biologists, like physicists and chemists,

Emerging Infectious Diseases 538 Vol. 5, No. 4, July–August 1999

 Special Issue

may have left Russia to sell their services to pox eradication campaign (1966-1977) and helped ini-
rogue governments. tiate WHO’s global program of immunization in 1974.
Smallpox is rated among the most dangerous He also served as deputy assistant secretary and senior
of all potential biological weapons, with far- science advisor in the Department of Health and Hu-
man Services.
reaching ramifications.
Dr. Henderson is a distinguished service professor Reference
at the Johns Hopkins University, holding an appoint- 1. Henderson DA. Bioterrorism as a public health threat.
ment in the Department of Epidemiology. Dr. Henderson Emerg Infect Dis 1998;4:488-92.
directed the World Health Organization’s global small-

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 Special Issue

Smallpox: An Attack Scenario

Tara O’Toole
Johns Hopkins School of Public Health, Baltimore, Maryland, USA

Smallpox virus, which is among the most equipment. FBI decides its information is too
dangerous organisms that might be used by vague and too sensitive to pass on to the
bioterrorists, is not widely available. The Department of Health and Human Services,
international black market trade in weapons of local law enforcement authorities, or the state
mass destruction is probably the only means of health department.
acquiring the virus. Thus, only a terrorist
supported by the resources of a rogue state would April 8
be able to procure and deploy smallpox. An FBI informants report rumors that some-
attack using the virus would involve relatively thing happened while the vice-president was in
sophisticated strategies and would deliberately Northeast.
seek to sow public panic, disrupt and discredit
official institutions, and shake public confidence April 12
in government. A 20-year-old university student goes to the
The following scenario is intended to provoke university hospital emergency room with fever
thought and dialogue that might illuminate the and severe muscle aches. She is pale, has a
uncertainties and challenges of bioterrorism and temperature of 103°F, and is slightly leukopenic,
stimulate review of institutional capacities for but the physical exam and laboratory results are
rapid communication and coordinated action in otherwise normal. She is presumed to have a
the wake of an attack. viral infection and is sent home with instructions
to drink fluids and take aspirin or ibuprofen for
Capacity To Detect a Bioterrorist Attack muscle aches. Later that day, a 40-year-old
and To Diagnose an Unusual Disease electrician arrives at the emergency room with
severe lower backache, headache, shaking chills,
April 1 and vomiting. He appears pale and has a
The vice-president visits Northeast, a city of temperature of 102°F and a pale erythematous
2.5 million. His itinerary includes an awards rash on the face. The patient is a native of Puerto
ceremony, an appearance at a local magnet Rico, where he visited 10 days earlier. A
school, and a major speech at the local diagnosis of dengue fever is considered, and the
university. A crowd of 1,000 people, including patient is discharged with ibuprofen and
students, is gathered in the university audito- instructions to drink fluids.
rium. Hundreds more wait outside, where the
vice-president stops to shake hands and respond April 13
to queries from the media. Over the course of the day, four young adults
The Federal Bureau of Investigation (FBI) in their twenties come to the university hospital
has information suggesting a possible threat emergency room with influenzalike symptoms
against the vice-president from a terrorist group and are sent home.
with suspected links to a rogue state. The group
is known to have made inquiries about acquiring April 14
biological pathogens, including smallpox, and is The female student returns to the emergency
suspected of having procured aerosolization room after collapsing in class. She now has a red,
vesicular rash on the face and arms and appears
Address for correspondence: Tara O’Toole, Johns Hopkins
Center for Civilian Biodefense Studies, Candler Building,
acutely ill. Her temperature is 102°F; her blood
Suite 850, 111 Market Place, Baltimore, MD 21202, USA; fax: pressure is normal. She is admitted to an
410-223-1665; e-mail: biodefen@jhsph.edu. isolation room with presumptive diagnosis of

Emerging Infectious Diseases 540 Vol. 5, No. 4, July–August 1999

 Special Issue

adult chickenpox. She has had no contact with hospital) is discussed, but no decisions are made
others known to have chickenpox. because the hospital’s legal authority for doing
this is unclear.
April 15 Half an hour later, the state health
The electrician first seen on April 12 returns commissioner calls FBI. He also contacts CDC to
to the emergency room by ambulance. He too has request that smallpox vaccine be released for
a vesicular rash and appears very ill. He is also hospital staff and patient contacts. Because
admitted to an isolation room with presumptive vaccine supplies are limited, CDC requests that
diagnosis of chickenpox. the diagnosis of smallpox first be confirmed at
That evening at 6 p.m. the infectious disease CDC. CDC calls FBI and arranges to fly a three-
consultant and the hospital epidemiologist meet person Epidemic Intelligence Service team to
on the elevator. The infectious disease specialist Northeast for assistance.
has just finished examining the student and the By 9:30 p.m., an FBI special agent arrives at
electrician, both of whom have vesicular rash on the hospital, secures biological samples taken
the face, arms, hands, and feet. The skin lesions from the patients, and drives them to Andrews
are evolving in phase. The possibility of smallpox Air Force Base, where a military aircraft flies the
is raised. The infectious disease specialist takes a samples to CDC’s Biosafety Level 4 laboratory in
swab specimen from the electrician’s skin Atlanta, Georgia. FBI requests that city police be
lesions, sends it to the laboratory, and requests called to help maintain order and ensure that no
that it be examined by electron microscopy by an patients, staff, or visitors leave the hospital until
experienced technician. The doctor assures the all occupants have been identified and their
technician that he will be vaccinated if the addresses have been recorded. More FBI agents
specimen shows smallpox. At 7:00 p.m., electron and city police arrive on the hospital grounds.
microscopy shows an orthopoxvirus consistent Hospital visitors are confused and angered
with variola—the smallpox virus. by police refusal to allow anyone to leave the
At 7:15 p.m. the hospital epidemiologist hospital. No explanation is given for the
declares a contagious disease emergency. The containment to staff, visitors, or the police.
two patients are moved to negative-pressure Ambulances are rerouted to other hospitals. The
rooms with HEPA filters. Visitors and hospital rumor that smallpox has broken out rapidly
staff not already caring for and in contact with spreads through the building, as do rumors that
patients are forbidden to enter the floor. a terrorist wanted by FBI is in the building. A
Infection-control nurses begin interviewing staff fight erupts between people trying to leave the
to determine who has been in face-to-face contact facility and the police. Three people are injured
with the patients during initial emergency room and sent to the emergency room. More police and
visits and admission. The hospital epidemiologist FBI agents arrive and surround the building.
calls the chair of the department of medicine and The local television networks report the
the hospital vice-president for medical affairs. scene outside the hospital on the late night news.
Within 45 minutes the chair of the The hospital public relations representative
department of medicine and the president of the explains that the lock-in is temporary and
hospital are meeting with the infectious disease intended only to gather names and addresses so
physician, the hospital epidemiologist, the that people can be contacted and treated if a
hospital vice-president for public relations, and suspected, but unnamed, contagious disease is
the hospital’s general counsel. The city and state confirmed. CNN arrives and demands access to
health commissioners join the meeting by phone. the hospital and affected patients. Rumors about
The need to vaccinate and isolate all contacts of what the contagious disease might be include
the patients is recognized and discussed. It is Hong Kong flu, meningitis, Ebola virus,
decided to secure the hospital. No one is allowed smallpox, and measles.
to leave until all persons are identified so that The mayor and state attorney general’s office
they can be vaccinated as soon as vaccine can be are contacted by the health commissioner. There
obtained from the Centers for Disease Control is a phone discussion with the hospital’s general
and Prevention (CDC). The possibility of counsel and epidemiologist about the right to
identifying and vaccinating other patient impose quarantine. Visitors, nonessential per-
contacts (e.g., family members not now in the sonnel, and new patients are blocked from

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 Special Issue

entering the hospital, but visitors already in the sioner presses for enough vaccine for the entire
building are allowed to leave after their names city of Northeast.
and addresses are recorded. FBI and CDC are reluctant to begin mass
FBI, however, is reluctant to allow anyone to vaccination until the dimensions of the outbreak
leave the building. This provokes a lengthy are better understood. It is decided to vaccinate
exchange among the FBI agent-in-charge, the all hospital staff and any visitors to the floor
city police chief, and hospital administrators and where the patients were located. All direct
attorneys. The dispute is resolved after a series contacts of the patients will also be vaccinated.
of phone calls between FBI headquarters and the By the end of the long phone conference, the
state attorney general’s office. decision is made to vaccinate all health-care
personnel, first responders, police, and firefighters
Early Response in any city with confirmed cases of smallpox.
CDC Epidemic Intelligence Service officers
11:30 p.m. arrive in Northeast to assist the state
The specimen arrives at CDC. At midnight, epidemiologist, who is establishing a statewide
the diagnosis of smallpox is confirmed. A phone surveillance and case investigation system.
conference with hospital staff, the city police Efforts begin to develop a registry of all face-to-
chief, the state health commissioner, the state face contacts of smallpox patients and to
attorney general, the governor, CDC, FBI, an monitor, daily, all contacts for fever. Anyone who
assistant secretary of the Health and Human has fever >101°F is to be isolated, at home if
Service (HHS), and staff from the National possible, and be followed for rash.
Security Council and the White House (32 people The state health department activates a
in all) focuses on whether and how to release the prearranged phone tree to query all hospitals
information to the media. The mayor and the and walk-in clinics in the state about similar
governor will go on television in the morning cases and counsels immediate isolation of all
with the health commissioner. The FBI director suspected patients.
will also make a statement. The president will An additional eight admissions for fever and
address the country at noon. vesicular rash are discovered. All patients are
CDC makes arrangements to release extremely ill; two are delirious. The university
smallpox vaccine early the next morning for use hospital emergency room records are searched,
by patient contacts and the health-care teams and staff attempt to contact all patients who had
caring for hospitalized victims. fever during the previous week. Three more
probable smallpox cases are discovered. Tele-
April 16 phone follow-up reveals that one has been
Morning conference calls between CDC, FBI, admitted to another hospital out of state.
HHS, the National Security Council, and state CDC and state health officials discuss
health authorities are set up. Federal officials possible strategies for managing the epidemic if
now assume that a bioterrorist attack has there is insufficient vaccine for all patient
occurred in Northeast. There is concern that contacts, as seems likely. Home isolation of
other attacks might also have taken place but not nonvaccinated patient contacts is considered,
yet come to light or that further attacks might be but the legal authorities, practical logistics, and
imminent. ethical implications of such a strategy remain
A representative from the counterterrorism unclear and unresolved.
office of the National Security Council asks if it is After discussion among state health authori-
necessary or desirable to attempt a complete ties and university hospital staff, it is decided
quarantine of Northeast, including closure of the that the university will serve as the city’s
city airport and a ban on rail traffic leaving from smallpox hospital and will accept transfers of
or stopping in the city. The group agrees that smallpox patients now hospitalized at other
such a step is neither feasible nor warranted. A facilities in the state. Other hospitals will refer
heated debate follows about the advisability of patients to the university hospital or to the state
vaccinating all hospital staff and visitors at all armory but will not admit patients with
facilities where a single case of smallpox is suspected smallpox. Physicians will be urged to
clinically suspected. The state health commis- avoid seeking admission for most smallpox

Emerging Infectious Diseases 542 Vol. 5, No. 4, July–August 1999

 Special Issue

patients and to care for patients in their homes. vaccination of all employees whose jobs involve
Arrangements are made by the state health direct patient contact.
commissioner to activate a state disaster plan,
which establishes the armory as an emergency April 18
hospital for the quarantine of smallpox patients, An additional 20,000 residents of Northeast
in case the number of smallpox patients exceeds are vaccinated.
hospital isolation capabilities.
April 19
Quarantine and Vaccination CDC and the U.S. Army Medical Research
During the morning interagency phone Institute of Infectious Diseases (USAMRIID)
conference, Department of Justice representa- determine that the infecting strain of smallpox
tives raise questions about potential legal was not bioengineered. The genomic sequence is
liabilities associated with adverse vaccine entirely typical of known smallpox strains.
effects. The questions remain unresolved, but The student with the first diagnosed case
vaccination will proceed. dies. Ten more smallpox cases have been
On the evening of April 16, the president identified, bringing the number of confirmed
goes on television to inform the nation of the cases to 50. The patients are located in four
bioterrorist attack by unknown terrorists, vows states, all in the mid-Atlantic area. Suspected
that the assailants will be identified and brought cases are identified in five other states.
to justice, and urges calm and cooperation with
health authorities. April 20
The initial epidemiologic evidence and FBI Governors of affected and unaffected states
information suggest that the smallpox release press, both behind the scenes and publicly, for
likely occurred during the vice-president’s emergency vaccine stocks to be distributed to
January speech at the university in Northeast. states so that immediate action can be taken
Efforts are begun to identify and vaccinate should an outbreak occur.
everyone who attended the speech. Additional At the close of day 4 of the vaccination
health department personnel are detailed to help campaign, 80,000 have been vaccinated.
in the epidemiologic investigation. Media reports
say that the government does not know how April 22-27
many people are sick or how widespread the No new cases of smallpox with onset after
outbreak might be. April 19 have been confirmed, although many
By evening, 35 more cases are identified in suspected cases with fever and rash due to other
eight emergency rooms and clinics around the causes are being seen. In the states reporting
city; 10 cases are reported in an adjoining state. confirmed smallpox cases, thousands of people
CDC alerts all state health departments to be on are seeking medical care because of worrisome
alert for possible smallpox; CDC also urges symptoms. CDC and state health authorities
prompt and strict isolation measures and decide to issue a recommendation that patients
instructs states to send specimens from with fever who cannot be definitively diagnosed
suspected patients to its headquarters in Atlanta be strictly quarantined and observed until the
for definitive laboratory diagnosis. fever subsides. CDC and state health depart-
ments are flooded with calls from health-care
April 17 providers seeking guidance on isolation proce-
In Northeast, 10,000 residents are vacci- dures.
nated by the city and state health departments Some hospitals and health maintenance
with assistance from volunteer physicians and organizations (HMOs) complain to HHS that
nurses. Vaccination of the entire university they cannot afford to isolate the many patients
student body, faculty, and staff is discussed and with fever and rash at their facilities and
rejected by federal officials for fear that vaccine demand that the government pay quarantine
supplies will be needed for contacts of confirmed costs. State health departments are similarly
cases. State health officials continue to press for worried about the costs of quarantine.
a statewide vaccination effort. Unions represent- Local media report an outbreak of sick
ing nurses and other health-care workers call for children with rash in an area elementary school.

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 Special Issue

It is unclear whether the illness is chickenpox or Another 200 probable cases are reported
smallpox. Television stations show film of during the day. CDC receives thousands of
parents arriving at school in midday to remove requests for vaccine from individual physicians
children from classrooms. A college basketball and announces that vaccine will be distributed
star is rushed to hospital by ambulance with an only through state health departments. Gover-
unknown illness. Local television reports that nors of a dozen states are calling the White
the athlete has high fever but no rash. Both House, demanding vaccine. One state attorney
stories are covered on the national evening news. general announces a suit against the federal
government to force release of vaccine for a
April 28 large-scale vaccination campaign.
Smallpox is diagnosed in two young children The federal government announces that 90%
in Megalopolis, a large city in another state. FBI of available vaccine stocks will be distributed to
and the National Security Council worry that affected states, but cautions that the available
these cases might signal another attack since the quantity of vaccine can cover only 15% of those
children have had no discernible contact with a states’ populations. Governors are to determine
smallpox patient or contacts. The possibility that their own state-specific priorities and mecha-
there has been a new attack is weighed against nisms of vaccine distribution. Federal officials
the possibility that the children were infected by also announce an accelerated crash vaccine-
a contact of one of the first wave of patients who production program that will reduce vaccine-
was missed in the epidemiologic investigation. manufacturing time to 24 months.
Members of the state congressional delega-
tion demand that the federal government April 30
implement a massive citywide vaccination A well-known college athlete dies of
program. CDC notes that a Megalopolis-wide hemorrhagic smallpox. The rumor is reported
vaccination program would deplete the entire that he was the victim of a new biological attack
civilian vaccine supply. using a different organism since he did not
The media report that the president, vice- develop the rash associated with classic
president, cabinet representatives, and prominent smallpox. Television commentators misinterpret
members of Congress have been vaccinated, and technical statements from a health-care expert;
the military has already begun to vaccinate the the commentators report that the athlete died of
troops in affected states and Washington, D.C. hemorrhagic fever, and they read clinical
descriptions of Ebola virus infection on the air.
The Epidemic Expands The White House and CDC receive dozens of
calls from furious governors, mayors, and health
April 29 commissioners, demanding to know why they
Over the course of the day, CDC receives were not informed of additional bioterrorist
reports of an additional 100 new cases of attacks using Ebola. Nurses, doctors, and
potential smallpox. Sixty of these are in the hospital-support personnel in health centers
original state. The others are scattered over walk off the job. Thousands of people who
eight states. It is not immediately clear if these attended college basketball games where the
are truly smallpox or mistaken diagnoses. By deceased athlete played call the health
evening, laboratory confirmation of smallpox is department and ask for treatment.
obtained at CDC. Two cases in Montreal and one HHS issues a press release explaining that
in London are also reported. CDC and health the athlete did not have Ebola virus. FBI affirms
agencies now recognize that they are seeing a that there is no reason to believe that an attack
second generation of smallpox cases. It is using any hemorrhagic fever virus has occurred,
presumed that the latest victims were infected but FBI refuses to rule out the possibility that
by contact with those who attended the vice- there has been more than a single bioterrorist
president’s speech, but a second bioterrorism attack using smallpox.
attack cannot be immediately ruled out. CDC
enlists additional epidemiologists from around April 31
the country to join teams tracking patients and The widely publicized death of the college
their contacts. basketball star, plus dramatic footage of young

Emerging Infectious Diseases 544 Vol. 5, No. 4, July–August 1999

 Special Issue

children covered with pox, drive thousands of called in to help police keep order and to guard
people to emergency rooms and doctors’ offices the facilities where smallpox cases and contacts
with requests for vaccination and evaluation of are isolated. The mayor of Northeast is
fever and other symptoms. This escalation in hospitalized with a heart attack.
requests for evaluation and care hampers the
ability of state health authorities and CDC to Conclusions
confirm the number of actual new cases. The rate of development of new smallpox
cases reported worldwide now appears to be
May 1 stabilizing and perhaps subsiding. Vaccination
The number of smallpox cases continues to of contacts has undoubtedly been of benefit.
grow. There are now >700 reported cases Perhaps more important is the seasonal decrease
worldwide. In Northeast, the capacity of local in the spread of virus as warmer weather
hospitals to accommodate patients needing returns.
isolation has long been exceeded. Smallpox cases Many business conventions scheduled to
and suspected contacts are being isolated in the convene in Northeast during the early summer
local armory and convention center, where are canceled. Tourist trade, a major source of
volunteer physicians and nurses are providing state income, is at a standstill. Many small
care. businesses in the city have failed because
suppliers and customers are reluctant to visit the
May 5 area. Attendance at theaters and sports events is
Epidemiologists are working around the down markedly. In several states, public schools
clock to interview patients, trace the chain of are dismissed 1 month early, in part because
infection, place contacts under surveillance, and parents, fearful of contagion, are keeping their
isolate smallpox victims. The evidence continues children home, and partly because teachers are
to indicate that the vice-president’s visit to refusing to come to work. Across the country,
Northeast was the occasion for the release, but people refuse to serve on juries or attend public
some authorities remain concerned about meetings for fear of contracting smallpox. In
multiple releases. hospitals and HMOs where staff have not been
vaccinated, health-care personnel have staged
May 15-29 protests, and some have walked off the job.
The third generation of the epidemic begins. The exponential increase in cases around the
Cases are reported in Northeast, parts of the globe has caused some governments to institute
country far beyond Northeast, and worldwide. strict, harshly enforced isolation and quarantine
The death rate remains 30%. Vaccine supplies procedures. Human rights organizations report
are exhausted. Public concern is mounting numerous cases of smallpox patients being
rapidly. The president has declared states with abandoned to die or of recovering patients being
the largest numbers of victims and people in denied housing and food.
quarantine to be disaster areas. Congress votes Domestic and international travel is greatly
to release federal funds to pay for costs of reduced. Travelers avoid countries known to
quarantine. Over the next 2 weeks, 7,000 cases have smallpox. Some countries refuse to admit
will have been reported. U.S. citizens without proof of recent smallpox
vaccination. Others have imposed 14-day
May 30 quarantines on all persons entering the country
The fourth generation of cases begins. By from abroad. A lucrative black market in falsified
mid-June, 15,000 cases of smallpox will be vaccination certificates has sprung up.
reported in the United States. Twenty states Congress has begun oversight investigations
report cases, as do four foreign countries. More into the epidemic. A congressman accuses the
than 2,000 will have died. The deceased include U.S. Food and Drug Administration of deliber-
two members of the vice-president’s staff and a ately obstructing the development of smallpox
secret service agent. vaccine and vows to hold hearings into the
The city of Northeast, which is hardest hit by matter. Congressional investigations of what
the epidemic, has experienced several outbreaks FBI knew, when they knew it, and whom they
of civil unrest. The National Guard has been talked with, are ongoing. Multiple lawsuits have

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been filed on behalf of and against HMOs, Smallpox continues to spread in many parts
hospitals, and state and federal governments. of the world, echoing its formerly endemic
Several large HMOs refuse to pay states for costs character. Without vaccine, the only control
associated with caring for patients in isolation method is isolation, which hinders, but cannot
wards and quarantine facilities. The states with halt, the spread of the disease. By year’s end,
largest numbers of cases have spent millions of endemic smallpox is reestablished in 14
dollars on the epidemic, including establishing countries. The World Health Assembly schedules
quarantine operations, paying for added public a debate on reenacting a global smallpox
health personnel, and overtime pay for police. eradication campaign.
In the United States, periodic rumors of
Dr. O’Toole is a senior fellow at the Johns Hopkins
miracle treatments, many fueled by the media,
University Center for Civilian Biodefense Studies. The
provoke ardent demands on a beleaguered Center, sponsored by the Hopkins Schools of Public
health-care system. Since vaccine supplies were Health and Medicine, is dedicated to informing policy
depleted, many people seeking protection have decisions and promoting practices that would help pre-
turned to ancient techniques. Some physicians vent the use of biological weapons.
are practicing arm-to-arm transfer of vaccinia,
with a few attempting immunization with
inoculation of smallpox virus from pustules.

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 Special Issue

Aftermath of a Hypothetical
Smallpox Disaster
Jason Bardi
Johns Hopkins University, Baltimore, Maryland, USA

The second day of the symposium featured a tion; Robert Knouss, Office of Emergency
discussion of a scenario in which a medium-sized Preparedness, Department of Health and
American city is attacked with smallpox. Four Human Services; and Scott Lillibridge, Centers
panels represented various time milestones after for Disease Control and Prevention. Joanne
the attack, from a few weeks to several months. Rodgers, Johns Hopkins Medical Institutions
Panelists discussed what they and their Public Affairs, spoke to the response of the
colleagues might be doing at each of these media. George Strait, the medical news director
milestones. The goal of the responses was to for ABC News, acted as moderator for each of the
communicate the complexity of the issues and to panels scheduled on day two. D.A. Henderson
explore the diverse problems that might arise also helped to moderate.
beyond the care and treatment of patients.
The scenario itself was a step-by-step Identifying the Agent
account of a smallpox epidemic in the fictional At the start of the epidemic, 2 weeks after the
city of Northeast. Tara O’Toole, the scenario’s bioterrorist attack, confusion reigns. There is
lead author, read the narrative account before uncertainty as to what the infection is and
each panel. reluctance to diagnose smallpox even when it is
The panelists responded to the events as if suspected. It is unclear who is in charge of
the epidemic were real and they were actually investigating and containing the epidemic.
trying to identify, contain, communicate, and Outside, reporters are knocking on the hospital
otherwise deal with it. Panel members included doors. The question of what took so long to
experts on hospital, city, state, federal, and identify the agent opens the panel. Smallpox, a
media responses. Representing the hospitals nonspecific flulike illness, is hard to diagnose,
were John Bartlett and Trish Perl, Johns replies an emergency medicine physician. The
Hopkins Hospital; Julie Gerberding, Hospital disease is not suspected because it was
Infections Program, Centers for Disease Control eradicated in the late 1970s. Any laboratory
and Prevention; and Gregory Moran, Emergency work on the first cases would initially be testing
Medicine, University of California at Los for a battery of other causes, such as other viral
Angeles. Jerome Hauer represented New York infections (e.g., monkeypox) or reactions to
City’s response. Representing the state were recent vaccinations. A window of 2 weeks before
Michael Ascher, California Department of positive identification of smallpox may even be
Health Services Laboratory; Arne Carlson, optimistic. The diagnosis would probably take
former governor of Minnesota; Terry O’Brien, a much longer because of physicians’ lack of
Minnesota State Assistant Attorney General; familiarity with the disease.
and Michael Osterholm, Minnesota Department When all the tests for other infections turn
of Public Health. The federal representatives on up negative and smallpox is strongly suspected,
the panels were Robert Blitzer, former suggests a state laboratory chief, a conclusive
counterterrorism chief with the Federal Bureau result from the laboratories at the Centers for
of Investigation; Robert DeMartino, Substance Disease Control and Prevention (CDC) or the
Abuse and Mental Health Services Administra- U.S. Army Medical Research Institute of
Infectious Diseases (USAMRIID) would still be
Address for correspondence: Jason Bardi, Johns Hopkins needed. These are the only two places in the
University, Center for Civilian Biodefense Studies, 111
Market Place, Ste. 850, Baltimore, MD 21202, USA; fax 410- United States equipped to identify smallpox
223-1665; jsb14@jhunix.hcf.jhu.edu. virus in tissue samples. This part of the diagnosis
is fairly straightforward but it would take at

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least 1 day before the definitive results could be management teams, as well as the city health
obtained. commissioner, the city health department, and
the mayor, are involved.
Responding at the Hospital Level The problems of the city become state
Hospitals would probably isolate the early problems immediately, counters the former
cases presumptively, even if smallpox was not governor, because the news media treat any
suspected, since the symptoms would appear potential infectious disease outbreak as a
infectious. This is the opinion of a hospital regional problem. This forces the governor’s
infections expert. In the city, argues a state hand. The governor has to move in because there
health department professional, several hospi- is a need for one person to be in charge.
tals would each see one or two of the first few The most difficult situation is how to deal with
cases. The city health department would quickly the hospital patients. One danger in the early
become aware of the similarity of the cases in the days is losing control of the crisis through panic.
various hospitals, recognize a potential outbreak Once rumors about smallpox start to spread,
(probably measles) and mobilize early to contain it. many workers within the hospital walk off the
Once smallpox is identified, the following job. Understaffing also leads to increased stress
organizations within city government would be and confusion for patients and providers alike.
notified: the police department, the local Even before federal and state command
emergency management office, the city health structures are in place, suggests a hospital
commissioner’s office, and, ultimately, the infections control expert, hospital epidemiolo-
mayor’s office. This process may be difficult since gists would already be addressing infection
it requires integrating the health department control issues. She notes that hospital infection
into emergency management plans, an event with control specialists would be on the phone to
little precedent, notes a city emergency official. colleagues in other city hospitals alerting one
another. Hospital epidemiologists, adds a state
Coordinating Response Efforts health official, would have a contact list of state,
Who is in charge, agree panelists, is one of local, and federal public-health authorities who
the most important questions yearly in the also would be notified.
epidemic, because any large-scale relief effort Another problem in coordination becomes
would require good management. Complicating clear to panelists: the difficulty in sharing
the answer, however, are various levels of classified risk information among agencies and
government, each with its own responsibilities various levels of government. Any early
and perspective on response, as reflected in warning, which could have contributed to a more
panelists’ remarks. effective response, was missing in the scenario.
Acts of domestic terrorism are under the Even though the FBI had some early intelligence
jurisdiction of the federal government, so several of the attack, the alerting of health care workers
federal agencies become involved, starting with was nonexistent. The problem lies in the fact,
FBI. FBI is involved from the very beginning assesses a state health department official, that
since any cases of smallpox would indicate a health departments have never been seen as
deliberate terrorist attack. A criminal investiga- intelligence communities, nor has there ever
tion begins immediately. CDC is involved as soon been a precedent for passing such information to
as samples are sent for laboratory diagnosis. them.
The state government becomes involved at On the federal level, CDC addresses the
the outset, since major threats to public health public health issues of the epidemic, and FBI
are dealt with on the state level. The state health addresses the law enforcement issues. These
department starts its own investigation, and to aims are not necessarily exclusive of one
reassure the public, the governor may act as a another, and the possibility of linking efforts is
spokesperson for the management of the epidemic. raised. Everyone interviewed as a part of the
The city is involved from the outset, explains epidemiologic investigation may have to be
the city emergency management official, interviewed as part of the criminal investigation
understanding that “bioterrorism is a local as well. Perhaps the most effective way to
issue,” which escalates very rapidly to state and accomplish this is to conduct both interviews
federal levels. The local police and emergency simultaneously.

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Some aspects of the two federal agencies may panelists. Reporters on the hospital scene will
overlap, perhaps even conflict, in agendas. quickly become aware of any rumors and will
Specimens that are sent to CDC for positive demand answers of any worker or official who is
identification of the smallpox virus may be handy. Official channels will not be the only
needed by FBI as evidence for any eventual source of information during the epidemic,
prosecution. In many ways, it may appear as if argues the public affairs specialist.
FBI is running the investigation. However, First responders, such as the police or fire
dealing with the sick, obtaining vaccine, and officials, might show up with full biohazard
mobilizing the epidemiologic investigation at the protection; such an image immediately raises
local, state, and federal levels are outside the questions. The media will digest information
scope of FBI. CDC takes the lead on these public from day one, whether or not there is an official
health issues, and together with FBI, coordi- statement from the city, state, or federal level.
nates the management of federal resources. Controlling the message that goes out over
However, who is coordinating activities at the airwaves could be extremely difficult,
the hospitals is still unclear, and the question of especially since there may not even be any
authority on that level is unresolved. Can consensus on what the message should be in the
outsiders come into a hospital and wield power, first place. Several panelists point out the need to
and if so, who are they? Federal responders may ensure that information presented to the media
have ambiguous authority within a hospital and is consistent and credible. The city emergency
may add to the chaos. An FBI offical notes that manager suggests that the mayor will work with
his agency’s role in the hospitals will simply be to federal and state officials to get consistent and
inform the doctors and administrators of what credible information out to the public. One viable
the hospital needs to do to assist in the criminal alternative to speculation and misinformation,
investigation—keeping evidence and coordinat- proposes an FBI official, is to have a centralized
ing interviews with patients. However, this may joint information center, such as the one his
still leave gaps of authority within the hospital. agency set up in Oklahoma City after the
In the scenario under consideration, the bombing, with several experts answering all the
state identifies one hospital as the smallpox questions that arise.
hospital, and this also presents a problem of Regardless of how information is dissemi-
coordination. The hospital itself has to work out nated, the message must be carefully considered.
the details of local quarantine and the distribution If the flulike symptoms of smallpox are identified
of medicine to the patients, and there is a need to on the evening news, a flood of noninfected
protect the health-care workers and other persons with stuffy noses or headaches could
hospital staff. Vaccine should be immediately swell emergency rooms across the state. Other
available to these workers, and its distribution reports, such as upcoming quarantine efforts,
will have to be coordinated with CDC. may also spread panic and should be handled
Outside the hospitals, an epidemiologic carefully. The types of stories the media choose to
investigation will be taking place that will need write present a challenge. The press will not only
to be coordinated with CDC. A CDC official cover the crisis but the managers of the crisis.
points out the need for surveillance in the early Plans for responding to questions about crisis
days of the epidemic. To assist in collecting data management must be in place. Whether or not
necessary to identify the release source and the message that goes out to the public includes
people at risk, he recommends that CDC provide mention of terrorism should be weighed.
additional staff for much of the epidemiologic The hospital infections expert pursues a
work, including mid- and senior-level investiga- different angle to the issue of information
tors. Bringing in these outside experts should exchange. The difficulties in interviewing the
not represent a problem for local officials, he public have not been solved, she points out. Who
suggests, since CDC already has strong ties with will do the interviews? How they will be
state epidemiologists. coordinated with criminal investigations? Who
will receive vaccine? And how will health-care
Informing the Public workers be protected? Will the system be
How to control the message going to the overwhelmed by false cases—people who think
public weighs heavily upon the minds of all they have smallpox? Moreover, a basic problem

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in the early days of the epidemic is the need for sequestered causes them to leave hospitals
an infrastructure to handle the large volume of understaffed. Many people are likely to stay at
calls flooding the hospitals. their posts if they feel they have reliable
information and support, argues a mental health
Handling Logistics provider. Some, however, may leave the front
What will be the plan of action? Hundreds of lines to go home to their own families.
people will have to be mobilized to interview the
public, and hundreds more will be needed to Legal Ramifications
administer vaccine. The distribution of antibiot- According to a 1905 Massachusetts case,
ics and vaccines represents a logistical problem cites a state’s assistant attorney general,
that must be overcome. compulsory vaccinations are not a violation of
As the epidemic grows and spreads to several due process and are therefore legal. So the local,
states, friction between the levels of government state, and federal levels of government have no
grows. Governors are demanding vaccine obstacle to vaccinating those designated at risk.
supplies, fueling a larger debate of how A more difficult legal question is that of
vaccination should be handled. Tens of quarantining smallpox patients. Many of the
thousands of people are vaccinated, but many public health codes used to allocate powers to
more still need vaccine. Media reports begin to be government officials are old and may not be valid
critical of the government’s handling of the or useful. Also, court precedents from HIV cases
crisis. may have heavily weighted matters in favor of
What still needs to be done? With a growing due process. Minnesota, for example, requires a
number of deaths, the rise in the number of separate court hearing for each case of
patients in quarantine, the loss of critical health- quarantine. Thus, quarantine may be possible in
care workers and city emergency workers, a hospital but not in the community.
within the city things are beginning to get out of Another basic legal question is whether the
focus, notes a city official. Asking how leadership lines of legal support are clear to all officials,
will function inside the hospital, the hospital such as hospital guards and police officers. How
epidemiologist identifies a need for official far can police go to detain quarantined patients?
responses that are well thought out, strong, and The limits of emergency powers should be clearly
based on hard science. delineated in any predisaster planning.
The vaccine campaign poses significant The epidemic is threatening to expand
issues. The limited supply of vaccine must be beyond the city into the rest of the country and
divided up and distributed according to greatest even beyond. The World Health Organization
risk—persons who may have been infected or (WHO) will probably become involved, and travel
who care for those infected, argues an official in notifications have to be introduced.
federal emergency management. Political lead-
ers and essential city workers are other priority Vaccine Supply
groups. A consensus must be reached as to how to Even without adequate supplies of vaccine,
proceed with the vaccinations. CDC is best suited much can be done with the existing stocks.
to coordinate vaccine efforts, but the public Prevaccinating some health-care workers is a
health community must work towards an proactive approach. Having a sizable pool of
emergency. The governor, warns the city prevaccinated professionals who can mobilize
emergency manager, may step in and call the and act as emergency responders takes much of
shots. There is a need for a public health the pressure off local hospitals. One way to
emergency plan. Did the outbreak start from a reduce secondary transmission (outside of
single source or from multiple sources? This vaccinating the contacts of the infected person),
determination would help with vaccine manage- instructs the hospital epidemiologist, is good
ment and allocation, but there is no answer. infection control—wearing filter masks and
Moreover, testing facilities at CDC and USAMRIID washing hands well. Another way of controlling
are overwhelmed at this point in the epidemic. the epidemic is through quarantine. While these
Hospitals must deal with quarantine. measures are not a substitute for adequate
Restrictions are imposed in the first days or vaccine supply, they can slow the epidemic.
weeks of an epidemic. Workers’ fear of being

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One problem with the vaccine supply is that Failure of containment has turned the
many more people want to be vaccinated than outbreak from local to national and interna-
limited stores permit. There are not even enough tional. However, the epidemic would have been
stores of vaccine to prevent the spread of the much worse, had it gone unchecked, notes a state
epidemic. The existing 6 to 7 million doses of health official. Containment was significant. The
smallpox vaccine will not last forever, and the 36 15,000 smallpox cases could have easily been
months it takes for additional large-scale more than 100,000.
preparations is prohibitive, argues a vaccine No perpetrators have yet been identified,
campaign expert. Health officials will likely not despite combining the criminal and the
have the time or resources to target precisely epidemiologic investigations. Such methodical
those people who have an actual need for vaccine. work, however, is important because, unless the
The need for vaccine will overwhelm the supply. intelligence community comes up with informa-
The cost of vaccine development may inhibit tion or a tip, there is no other way to identify the
stockpiling, proposes a CDC official. Since an source of the epidemic, explains an FBI offical.
attack with smallpox is of low probability, large- Many of the problems in the epidemic could
scale production may be difficult to justify. A have been avoided or controlled if extensive
partnership between private industry and the plans had existed, panelists agree. The panelist
government would help, however. Also, the cost speaking from a governor’s perspective identifies
of getting caught without an adequate supply leadership as the most pressing void. Should the
could be disastrous. city have been placed under immediate
Possible emergency measures to stretch the quarantine? Should martial law have been
vaccine supply, proposes a smallpox expert, implemented? Is the designation of a single
include arm-to-arm vaccination as pustules form smallpox hospital a reasonable thing for any city
on the arms of vaccinated people; vaccinia could to do? These are difficult questions to face in the
be grown in massive amounts in tissue culture; wake of a disaster. Such issues must be
and 30 million doses of vaccine could be addressed long before trouble strikes.
contracted from South Africa.
Who Will Pay for the Smallpox Epidemic?
The Final Stage The significant cost of curtailing the
The smallpox epidemic has become a major epidemic is debated. How will a smallpox
public health emergency affecting several cities hospital be financed, inquires a physician. The
in many states and at least four other countries. money might come from the federal government
The event is identified as a terrorist attack, as emergency management funding, suggests a
because no other source of smallpox outside a city emergency manager. The infrastructure and
deliberate release exists. For those who have linkages within the public health community
already contracted smallpox, antiviral drugs, could be improved, the capacity for laboratory
such as cydolfivir, may be useful but these testing of samples could be increased, surveil-
medicines may be just as scarce as the vaccines. lance methods could be enhanced, and a health
Secondary transmission got out of hand, information strategy could be developed.
vaccine use did not contain the epidemic, and While the smallpox scenario is certainly
standard planning did not work. Thus a state frightening, experience with earlier epidemics
health official sums up the deficiencies of (smallpox among them), knowledge of the issues,
response. Hospital resources have been over- and expertise to deal with them show that in a
whelmed, with people flooding emergency rooms crisis people from all disciplines pull together.
in the belief they have smallpox. These cases are
Mr. Bardi is a freelance writer in Baltimore who
added to hospitalized cases before and during the
holds degrees in biophysics and science writing from
epidemic; yet there are not even enough beds for Johns Hopkins University.
all the sick. The hospital staff have become
physically and emotionally exhausted from the
long hours and from seeing about a third of
infected patients die.

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Clinical and Epidemiologic

Principles of Anthrax

Theodore J. Cieslak and Edward M. Eitzen, Jr.

U.S. Army Medical Research Institute of Infectious Diseases,
Ft. Detrick, Maryland, USA

Background and Epidemiology weapons program of the 1950s, and the Soviet
Anthrax is one of the great infectious Union and Iraq also admitted to possessing
diseases of antiquity. The fifth and sixth plagues anthrax weapons. An accident at a Soviet
in the Bible’s book of Exodus (1) may have been military compound in Sverdlovsk in 1979
outbreaks of anthrax in cattle and humans, resulted in at least 66 deaths due to inhalational
respectively. The “Black Bane,” a disease that anthrax, an inadvertent demonstration of the
swept through Europe in the 1600s causing large viability of this weapon. The epidemiology of this
numbers of human and animal deaths, was likely inadvertent release was unusual and unex-
anthrax. In 1876, anthrax became the first pected. None of the persons affected were
disease to fulfill Koch’s postulates (i.e., the first children (7). Whether this is due to differences in
disease for which a microbial etiology was firmly susceptibility between children and adults or
established), and 5 years later, in 1881, the first purely to epidemiologic factors (children may not
bacterial disease for which immunization was have been outdoors at the time of release) is
available (2). Large anthrax outbreaks in unclear.
humans have occurred throughout the modern Anthrax is caused by infection with Bacillus
era—more than 6,000 (mostly cutaneous) cases anthracis, a gram-positive spore-forming rod.
occurred in Zimbabwe between October 1979 and The spore form of this organism can survive in
March 1980 (3), and 25 cutaneous cases occurred the environment for many decades. Certain
in Paraguay in 1987 after the slaughter of a environmental conditions appear to produce
single infected cow (4). “anthrax zones,” areas wherein the soil is heavily
Anthrax, in the minds of most military and contaminated with anthrax spores. Such
counterterrorism planners, represents the single conditions include soil rich in organic matter (pH
greatest biological warfare threat. A World <6.0) and dramatic changes in climate, such as
Health Organization report estimated that 3 abundant rainfall following a prolonged drought.
days after the release of 50 kg of anthrax spores Partly because of its persistence in soil, anthrax
along a 2-km line upwind of a city of 500,000 is a rather important veterinary disease,
population, 125,000 infections would occur, especially of domestic herbivores. In addition to
producing 95,000 deaths (5). This number encountering anthrax while grazing in areas of
represents far more deaths than predicted in any high soil contamination, these herbivores may
other scenario of agent release. Moreover, it has also acquire the disease from the bite of certain
been estimated (6) that an aerial spray of flies (8). Vultures may mechanically spread the
anthrax along a 100-km line under ideal organism in the environment (9). Anthrax zones
meteorologic conditions could produce 50% in the United States closely parallel the cattle
lethality rates as far as 160 km downwind. drive trails of the 1800s (10).
Finally, the United States chose to include Anthrax spores lend themselves well to
anthrax in the now-defunct offensive biological aerosolization and resist environmental degra-
dation. Moreover, these spores, at 2-6 microns in
diameter, are the ideal size for impinging on
Address for correspondence: Theodore J. Cieslak, Operational
Medicine Division, USAMRIID, 1425 Porter Street, Ft.
human lower respiratory mucosa, optimizing the
Detrick, MD 21702, USA; fax: 301-619-2312, e-mail: chance for infection. It is the manufacture and
Ted_Cieslak@Detrick.Army.Mil. delivery of anthrax spores in this particular size

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 Special Issue

range (avoiding clumping in larger particles) in virulence. These proteins are known as edema
that presents a substantial challenge to the factor (EF), lethal factor (LF), and protective
terrorist attempting to use the agent as a antigen (PA). Following the A-B model of toxicity
weapon. The milling process imparts a static (13), PA serves as a necessary carrier molecule
charge to small anthrax particles, making them for EF and LF and permits penetration into cells.
more difficult to work with and, perhaps, Edema toxin results from the combination of EF
enabling them to bind to soil particles (11). This, + PA, lethal toxin results from the combination of
in part, may account for the relatively low LF + PA. These toxins result in necrosis of the
secondary aerosolization potential of anthrax, as lymphatic tissue, which in turn causes the
released spores bind to soil, now clumping in release of large numbers of B. anthracis. The
particles substantially in excess of 6 microns. organisms gain access to the circulation, and an
This clumping tendency, together with a high overwhelming fatal septicemia rapidly ensues.
estimated ID50 of 8,000-10,000 spores may help At autopsy, widespread hemorrhage and
explain the rarity of human anthrax in most of necrosis involving multiple organs is seen.
the Western world, even in areas of high soil Inhalational anthrax generally occurs after
contamination. Other potential bioweapons, an incubation period of 1 to 6 days (14). During
such as Q fever and tularemia, have ID50 values the Sverdlovsk outbreak, however, spontaneous
as low as 1 and 10 organisms, respectively. cases appeared to arise as late as 43 days after
the assumed release date (7). Such late cases are
The Disease unexplained but have potentially serious
Most endemic anthrax cases are cutaneous implications for postexposure management of
and are contracted by close contact of abraded victims of aerosol exposure. After the incubation
skin with products derived from infected period, a nonspecific flulike illness ensues,
herbivores, principally cattle, sheep, and goats. characterized by fever, myalgia, headache, a
Such products might include hides, hair, wool, nonproductive cough, and mild chest discomfort.
bone, and meal. Cutaneous anthrax is readily A brief intervening period of improvement
recognizable, presents a limited differential sometimes follows 1 to 3 days of these prodromal
diagnosis, is amenable to therapy with any symptoms, but rapid deterioration follows; this
number of antibiotics, and is rarely fatal. While second phase is marked by high fever, dyspnea,
common in parts of Asia and sub-Saharan Africa, stridor, cyanosis, and shock. In many cases,
cutaneous anthrax is very rare in the United chest wall edema and hemorrhagic meningitis
States; the last case was reported in 1992 (12). (present in up to 50% of cases [15]) may be seen
Inhalational anthrax, also known as woolsorters’ late in the course of disease. Chest radiographs
disease, has been an occupational hazard of may show pleural effusions and a widened
slaughterhouse and textile workers; immuniza- mediastinum, although true pneumonitis is not
tion of such workers has all but eliminated this typically present. Blood smears in the later
hazard in Western nations. As a weapon, stages of illness may contain the characteristic
however, anthrax would likely be delivered by gram-positive spore-forming bacilli. Death is
aerosol and, consequently, be acquired by universal in untreated cases and may occur in as
inhalation. A third type of anthrax, acquired many as 95% of treated cases if therapy is begun
through the gastrointestinal route (e.g., consum- more than 48 hours after the onset of symptoms.
ing contaminated meat) is exceedingly rare but While early recognition of anthrax is likely to
was initially offered by Soviet scientists as an require a heightened degree of suspicion, the
explanation for the Sverdlovsk outbreak. diagnosis is supported by gram-positive bacilli in
Inhalational anthrax begins after exposure skin biopsy material (in the case of cutaneous
to the necessary inoculum, with the uptake of disease) or in blood smears. A preponderance of
spores by pulmonary macrophages. These gram-positive bacilli in swabs of the nares or in
macrophages carry the spores to tracheobron- appropriate environmental samples might sup-
chial or mediastinal lymph nodes. Here, port a diagnosis of anthrax where intentional
B. anthracis finds a favorable milieu for growth release is suspected. Chest radiographs exhibit-
and is induced to vegetate. The organism begins ing a widened mediastinum in the proper setting
to produce an antiphagocytic capsule and at least of fever and constitutional signs and in the
three proteins, which appear to play a major role absence of another obvious explanation (such as

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 Special Issue

blunt trauma, deceleration injury, or postsurgi- was licensed (for preexposure prophylaxis) by
cal infection) should also lead to a diagnosis of the U.S. Food and Drug Administration in 1970
anthrax. This finding is only likely to occur late and is prepared from a formalin-treated culture
in the course of disease. Confirmation is obtained supernatent of an avirulent B. anthracis strain.
by culturing B. anthracis from blood. It is given in a preexposure regimen at 0, 2, and
4 weeks, and at 6, 12, and 18 months. Persons at
Disease Management continuing risk for exposure should receive
While endemic strains of B. anthracis are yearly boosters. Exposed persons should receive
typically sensitive to various antibiotics, includ- at least three doses (at 0, 2, and 4 weeks),
ing penicillin G, antibiotic-resistant strains do assuming no further exposure is likely, before
(on rare occasion) occur naturally (16) and can be discontinuing chemoprohylaxis.
readily isolated in laboratories. For this reason, Recently, a number of hoaxes involving a
as well as the convenience of twice-daily dosing, threatened release of anthrax have been
many experts consider ciprofloxacin (400 mg promulgated (19,20), and guidelines have now
intravenously (i.v.) q 12 h) the drug of choice for been published to assist in the management of
treating victims of terrorism or warfare. such threats (19). When evaluating a threatened
Doxycycline (100 mg i.v. q 12 h) is an acceptable release of anthrax, the lack of volatility of the
alternative, although rare doxycycline-resistant disease, as well as its inability to penetrate intact
strains of B. anthracis are known. Conversely, skin, should be taken into account. These factors
however, the much lower cost of tetracyclines make it unlikely, in most cases, that persons
compared to quinolones may factor into coming in contact with letters, packages, and
therapeutic decisions, especially where large other devices purported to contain anthrax will
numbers of patients are involved. These be at risk for aerosol exposure. Moreover,
recommendations are based solely on in vitro because energy is required to aerosolize anthrax
data and data from animal models (17); no spores, opening a letter, even if it contained
human clinical experience with these regimens anthrax, would be unlikely to place a person at
exists. In cases of endemic anthrax, or where substantial risk. For these reasons, postexposure
organisms are known to be susceptible, penicillin prophylaxis may not be necessary in many cases
G (2 million units i.v. q 2 h or 4 million units i.v. of threatened anthrax dissemination.
q 4 h) is recommended. Anthrax has little potential for person-to-
Postexposure prophylaxis against anthrax person transmission; standard precautions are
may be achieved with oral ciprofloxacin (500 mg thus adequate for health-care workers treating
orally q 12 h) or doxycycline (100 mg orally q 12 anthrax patients. Anthrax, as well as other
h), and all persons exposed to a bioterrorist bacteriologic and viral weapons, has an
incident involving anthrax should be adminis- incubation period of >24 hours. This characteris-
tered one of these regimens at the earliest tic is not shared by conventional, chemical, and
possible opportunity. In cases of threatened or nuclear weapons and makes decontamination of
suspected release of anthrax, chemoprophylaxis infected persons admitted to hospitals days after
can be delayed 24 to 48 hours, until the threat is exposure unnecessary in most cases. However,
verified. Chemoprophylaxis can be discontinued in certain cases, such as exposure to a threat
if the threat is found to be false. Levofloxacin and letter involving an unidentified substance,
ofloxacin would be acceptable alternatives to where anthrax cannot readily be ruled out by
ciprofloxacin. In addition to receiving chemopro- Gram stain or other rapid diagnostic procedures,
phylaxis, exposed persons should be immunized. decontamination may be warranted. In such
On the basis of animal data (wherein an cases, decontamination may be accomplished by
appreciable number of unvaccinated primates removing clothing, sealing it in a plastic bag, and
died when antibiotics were withdrawn after 30 showering with copious amounts of soap and
days of therapy) (18), chemoprophylaxis is best water. Environmental surfaces and personal
continued until the exposed persons has received effects may be treated with 0.5% hypochlorite
at least three doses of vaccine (thus, for a after the area in which the agent was released is
minimum of 4 weeks). If vaccine is unavailable, investigated (19).
some recommend that chemoprophylaxis be In summary, even though anthrax may be
continued for 8 weeks (19). The available vaccine among the most viable of biological weapons, it is

Emerging Infectious Diseases 554 Vol. 5, No. 4, July–August 1999

 Special Issue

also a weapon for which a licensed vaccine and 6. Science Applications International Corporation.
good antimicrobial therapy and postexposure Effectiveness of medical intervention against battlefield
prophylaxis exist. Given the relatively short levels of Bacillus anthracis. 1993.
7. Meselson M, Guillemin J, Hugh-Jones M, Langmuir A,
incubation period, and rapid progression of Popova I, Shelokov A, Yampolskaya O, et al. The
disease, however, identification of the exposed Sverdlovsk anthrax outbreak of 1979. Science
population within 24 to 48 hours and 1994;266:1202-7.
employment of therapeutic and prophylactic 8. Turell MJ, Knudson GB. Mechanical transmission of
strategies are likely to present a challenge. Good Bacillus anthracis by stable flies and mosquitoes. Infect
Immun 1987;55:1859-61.
intelligence regarding the capabilities of terror- 9. Titball RW, Turnbull PCB, Hutson RA. The monitoring
ist groups, as well as heightened awareness of and detection of Bacillus anthracis in the environment.
the threat on the part of clinicians, first Journal of Applied Bacteriology 1991; Suppl 70:9S-18.
responders, and public health personnel remains 10. Coker PR, Smith KL, Hugh-Jones ME. Anthrax in the
a cornerstone of bioterrorism defense. USA. Proceedings of the Third International Conference
on Anthrax, Plymouth, England, September 7-10,
Dr. Cieslak is chief of Field Operations Department 1998:44 [abstract].
in the Division of Operational Medicine at the U.S. Army 11. Sidell FR, Patrick WC, Dashiell TR, editors. Jane’s
Medical Research Institute of Infectious Diseases at Ft chem-bio handbook. Alexandria (VA): Jane’s Information
Group; 1998. p. 229-44.
Detrick, MD. Dr. Cieslak is working in the area of medi-
12. Centers for Disease Control and Prevention. Summary
cal defense against biological warfare and terrorism. of notifiable diseases, United States, 1997. MMWR
Morb Mortal Wkly Rep 1998;46:74.
Dr. Eitzen is chief of the Division of Operational 13. Gill DM. Seven toxic peptides that cross cell
Medicine at the U.S. Army Medical Research Institute membranes. In: Jeljaszewicz J, Walstrom T, editors.
of Infectious Diseases and adjunct associate professor Bacterial toxins and cell membranes. New York:
of pediatrics and of military and emergency medicine at Academic Press; 1978. p. 291-332.
the Uniformed Services University of the Health Sci- 14. Brachman PS, Friedlander AM. Anthrax. In: Plotkin &
ences in Bethesda, Maryland. He has worked in the area Mortimer, editors. Vaccines. Philadelphia (PA): W.B.
of medical defense against biological warfare and ter- Saunders; 1994. p. 730.
rorism for the past 8 years. 15. Abramova FA, Grinberg LM, Yampolskaya OV, Walker
DH. Pathology of inhalational anthrax in 42 cases from
the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci U
References S A 1993;90:2291-4.
16. Lightfoot NF, Scott RJD, Turnbull PCB. Antimicrobial
1. Exodus 9:1-12. susceptibility of Bacillus anthracis. Salisbury Medical
2. Pasteur L, Chamberlain C-E, Roux E. Compte rendu Bulletin Suppl 1990;68:95-8.
sommaire des experiences faites a Pouilly-le-Fort, pres 17. Kelly DJ, Chulay JD, Mikesell P, Friedlander AM.
Melun, sur la vaccination charbonneuse [French]. Serum concentrations of penicillin, doxycycline, and
Comptes Rendus des seances De L’Academie des ciprofloxacin during prolonged therapy in rhesus
Sciences 1881;92:1378-83. monkeys. J Infect Dis 1992;166:1184-7.
3. Turner M. Anthrax in humans in Zimbabwe. Cent Afr J 18. Friedlander AM, Welkos SL, Pitt MLM, Ezzell JW,
Med 1980;26:160-1. Worsham PL, Rose KJ, et al. Postexposure prophylaxis
4. Harrison LH, Ezzell JW, Abshire TG, Kidd S, against experimental inhalation anthrax. J Infect Dis
Kaufmann AF. Evaluation of serologic tests for 1993;167:1239-42.
diagnosis of anthrax after an outbreak of cutaneous 19. Centers for Disease Control and Prevention.
anthrax in Paraguay. J Infect Dis 1989;160:706-10. Bioterrorism alleging use of anthrax and interim
5. Report of a WHO group of consultants. Health aspects guidelines for management-United States, 1998.
of chemical and biological weapons. Geneva: World MMWR Morb Mortal Wkly Rep 1999;48:69-74.
Health Organization; 1970. p. 97-9. 20. Sanchez R. California anthrax threats spawn costly
wave of fear. Washington Post, January 11, 1999,
section A, page 1.

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Anthrax: A Possible Case History

Thomas V. Inglesby
Johns Hopkins School of Medicine, Baltimore, Maryland, USA

Federal Bureau of Investigation (FBI) offices Two days after the game, hundreds of people
in five U.S. cities have received warnings of an in and around Northeast become ill with fever,
imminent bioterrorist attack. Each threat cough, and (in some cases) shortness of breath
indicated that a “shower of anthrax would rain and chest pain. Some of the sick self-administer
on U.S. cities,” unless certain demands were met over-the-counter cold remedies; some seek phone
immediately. One of these calls was in advice from physicians and nurses; others are
Northeast, a large city on the Eastern Seaboard seen in clinics, doctors’ offices, and emergency
with a metropolitan population of 2 million. The departments throughout the city.
threats were credible, but no information was Influenza cases had been seen in Northeast 2
relayed to city officials in Northeast or elsewhere. weeks before the game. Health-care providers
On the evening of November 1, a professional seeing the new patients recommend bed rest and
football game is being played in Northeast’s fluids for presumed flu. Specimens are sent to
outdoor stadium before an audience of 74,000. confirm influenza. A few of the sickest patients
The evening sky is overcast, the temperature get chest radiographs to exclude pneumonia.
mild, a breeze blows from west to east. During Only in retrospect, after the source of illness is
the first quarter of the game, an unmarked truck clear, will the widened mediastinum seen on a
drives along an elevated highway a mile upwind number of chest radiographs be recognized for
of the stadium. As it passes the stadium, the the signal it carries. A few patients are
truck releases an aerosol of powdered anthrax hospitalized; some have blood cultures drawn.
over 30 seconds, creating an invisible, odorless The 400 ill persons in the region are receiving
anthrax cloud more than a third of a mile in care from so many different sources that the
breadth. The wind blows the cloud across the health emergency is not detected.
stadium parking lots, into and around the By November 4, nurses and physicians note
stadium, and onward for miles over the the increased volume of serious upper respira-
neighboring business and residential districts. tory illness, and some contact the city health
After the anthrax release, the truck continues department for treatment recommendations and
driving and is more than 100 miles away from the a regional flu update. Blood cultures from the
city by the time the game is finished. The earliest patients grow gram-positive bacilli in
anthrax release is detected by no one. seven laboratories around the city. The laborato-
Approximately 16,000 of the 74,000 fans are ries identify these as Bacillus species. No further
infected by the anthrax cloud; another 4,000 in identification is requested, and none is pursued.
the business and residential districts downwind By the evening of November 4, patients with
of the stadium also are infected. After the game, the earliest symptoms are dying. The illness has
the fans disperse to their homes in the greater been rapidly fatal, killing previously healthy
Northeast metropolitan area; some return to young adults within 24 to 48 hours. Members of
homes in neighboring states. A few are from the medical community, now alarmed by these
other countries. The driver of the truck and his unexpected and unexplained deaths, urgently
associates leave the country by plane that night. contact the state and city health departments.
They will be many time zones away by the time Health department officials contact the Centers
the first symptoms of anthrax appear 2 days for Disease Control and Prevention (CDC). By
later. midnight November 4, 1,200 people around the
Address for correspondence: Thomas V. Inglesby, Johns
city have fallen ill, 80 of whom have died.
Hopkins Center for Civilian Biodefense Studies, Candler Word that previously healthy persons are
Building, Suite 850, 111 Market Pl., Baltimore, MD 21202, dying of a rapidly fatal illness spreads quickly
USA; fax: 410-223-1665; e-mail: tvi@welchlink.welch.jhu.edu. among health-care providers in the state, and is

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featured on local and national morning news The specimen is transferred to the U.S. Army
shows. News media interview families of the Medical Research Institute of Infectious Dis-
deceased, physicians, and city health officials. eases (USAMRIID), where within hours experts
Expert consultants appear on television to report that rapid diagnostic tests support the
discuss potential diagnoses, including the new preliminary diagnosis of anthrax.
Spanish flu, Hong Kong bird flu, and many other The mayor of Northeast consults with
infectious and noninfectious diseases. A rapid officials from the city and state health
survey of city emergency departments and departments, CDC, FBI, and USAMRIID. The
health clinics finds that persons of all ages and working assumptions are that the disease in
from all sectors of the city continue to come down Northeast is anthrax and that it is the result of a
with similar illness. The numbers have doubled bioterrorist attack. Widespread exposure to an
since the previous day, inundating many health- anthrax aerosol is feared.
care facilities. The mayor is outraged to learn that the FBI
The mayor convenes an emergency meeting had not informed her of the credible anthrax
of leading medical experts and health officials as threat to Northeast. She is also shocked that it
reporters gather outside city hall. The assembled has taken more than 80 deaths and hundreds of
experts debate possible causes and responses to illnesses before anyone from the medical
the illness. Many express great concern that a community came up with the diagnosis. She is
virulent strain of influenza or another highly informed that an anthrax vaccine exists, but it is
contagious disease may be present. Isolation of unclear whether any will be made available for
all persons with fever, cough, or chest pain; civilian use in Northeast. No one can yet
expanded laboratory analyses; and rapid estimate the probable scale of the epidemic or
epidemiologic investigation are recommended. whether there has been a single or multiple
Blood and tissue specimens are sent to CDC for attacks. CDC is seeking news of similar
urgent analysis. CDC investigators are en route. syndromes in other locations around the
During a news conference, the mayor describes country. The mayor’s medical advisors recom-
the city’s response to what appears to be a serious mend that quinolone antibiotics be used for
influenza outbreak, appeals for public calm, and initial treatment of the sick. They also advise the
is surprised by questions about the possibility of same antibiotics for those exposed to anthrax but
bioterrorism. not yet sick, even though identifying the exposed
By noon November 5, intensive-care units will take time and requires more information. All
and isolation beds across the city are full. Even that is known is that many (but not all) of the dying
patients receiving the most advanced medical had been at the football game on November 1.
care are dying. Patients are febrile, hypotensive, The mayor also is told that to prevent death,
and seem to be in septic shock; some have antibiotics must be given before symptoms occur,
meningitis. Still, there is no diagnosis. At some or at the latest, in the earliest hours after
locations, the shock of rapid and unexplained symptoms begin. Patients with serious symp-
deaths has created an atmosphere of desperation toms are likely to die, no matter what anyone
and confusion among hospital and clinic staff. does. Available information suggests that the
The recommended isolation protocols quickly local supply of needed antibiotics will soon be
fall apart as hospital and clinic staffs struggle to exhausted; many local pharmacies were already
cope with the surge of patients. Fears of a emptied of antibiotics as the initial news of a
contagious disease prompt hospital staff to don lethal epidemic spread through the city. Given
protective positive-pressure hoods; the news this shortage of antibiotics, one senior advisor
shows physicians working in this gear and asks the mayor to consider a triage plan that uses
explains that there are only two dozen or so such all available antibiotics to protect the exposed
hoods available per hospital. who are not yet sick. In this plan, antibiotics
In the early evening of November 5, a would be kept from those already sick and thus
university laboratory makes a preliminary likely to die, regardless of treatment. The mayor
diagnosis of anthrax from the blood culture of a requests immediate federal assistance in
young patient who died. The laboratory obtaining and distributing large supplies of
immediately notifies city and state health antibiotics. Antibiotic shipments from other
departments, which in turn notify CDC and FBI. states are also urgently requested.

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State officials notify hospitals around the longer accommodate new patients. The National
city of the anthrax epidemic and warn them to Guard will keep order. The Office of Emergency
prepare for a new surge of patients in the wake of Preparedness, Department of Health and
the mayor’s forthcoming TV address. Recom- Human Services, and the Federal Emergency
mendations for the care of infected patients are Management Agency will provide some logistical
sent to hospitals and clinics around the region. support. The city has temporarily run out of
The late night news is interrupted by the antibiotics, but supplies from neighboring states
mayor announcing that anthrax had been are expected. Meanwhile, the media report that
released in the city. She outlines the recom- some of the dead were not at the football game
mended medical response and describes assis- and in fact were miles away from the stadium
tance Northeast is seeking from state and federal that day. Some reporters openly speculate that
agencies. She urges that the needed antibiotics “antibiotics are being held back by city officials”
be taken by all those attending the football game. and that “local authorities are losing control of
For those who attended the game and remain the epidemic.” They also report that false rumors
well, arrangements are being made to distribute of arriving antibiotic shipments have sparked
antibiotics at 20 police stations and schools mobs and violence at antibiotic distribution
around the city starting immediately. Antibiotics centers.
will be distributed in packages sufficient for a 1- At midday November 6, epidemiologists
week supply. A second phase of distribution will report that some anthrax patients had not
commence with the arrival of new supplies of attended the game, suggesting that exposure
antibiotics. Eventually all those exposed will had occurred over a wider area. In addition,
need to receive enough antibiotics to take for 60 computer models show that wind patterns may
days. have blown anthrax spores downwind of the
Persons feeling ill are instructed to report stadium for some miles. The antibiotic recom-
immediately to hospitals for treatment. The mendations are now being expanded to include
mayor reports that an official request for vaccine all persons living or working within an area
has been made to the federal government. She defined by 8 miles east and 1 mile north or south
underscores that anthrax is not contagious. She of the stadium on November 1. The mayor is told
again appeals for calm. by her advisors that, in fact, no antibiotic
Tens of thousands rush to police stations and arrivals are imminent. Some states report they
distribution centers before the antibiotics arrive. have no antibiotics to give, some are refusing to
Communication between the distribution cen- send shipments, and the federal government
ters, the mayor’s office, and the antibiotic reports that it will be at least another 6 hours
suppliers is haphazard. No city plan exists or had before its antibiotic resources arrive. Despite
even been considered for mass distribution of assurances that anthrax is not contagious,
antibiotics. Some centers receive almost no people with the ability to do so flee Northeast,
antibiotics. At other centers, antibiotic supplies causing traffic jams and increasing panic. Some
are rapidly exhausted. train conductors, bus drivers, and pilots refuse to
At this point, there are effectively no travel to Northeast, citing personal safety
antibiotics left in the city. Approximately 50,000 concerns and threatening to walk off the job if
persons had obtained some quantity before forced. As a result, train, bus, and plane traffic to
supplies ran out, but there is no record of who and from Northeast is sharply disrupted. By
has received them. Health-care facilities are midnight November 6, anthrax has sickened
unprepared to cope with the continually rising 3,200 people, 900 of whom have died.
number of patients. By the early hours of Federal shipments of antibiotics have begun
November 6, 2,700 persons have become ill with to arrive by November 7. The distribution
anthrax, 300 of whom have died. Thousands centers, now increased to 40, continue to be
more flood doctors’ offices, clinics, and emer- variably stocked with medicine. A heavy
gency departments, fearing that they are National Guard presence is now evident at
infected with anthrax. distribution centers to prevent violence. FBI
On the morning of November 6, the mayor officials report preliminary evidence that a truck
announces that schools and homeless shelters was the source of the dispersal, though no
will be opened to the ill because hospitals can no suspects have been arrested and no group has

Emerging Infectious Diseases 558 Vol. 5, No. 4, July–August 1999

 Special Issue

claimed responsibility. They confirm that after the attack. Some anthrax cases occurred in
threats of an anthrax attack were made in the other cities, states, and countries where citizens
week before the event. On televised interviews, attending that football game had returned home.
families of the deceased promise legal action Occasional cases occur beyond 10 days among
against the FBI for not revealing the threats, and persons refusing or discontinuing the long
against local and federal government for not course of antibiotics. In all, approximately
supplying sufficient antibiotics and vaccine. 250,000 persons receive antibiotics.
Management of dead bodies becomes a growing The media report that hundreds, if not
crisis. Hospital and city mortuaries are full. thousands, needlessly died because of delays in
Many funeral homes have closed. The state antibiotic distribution, and further, that lifesav-
health department and CDC report that the ing antibiotics would have cost $100 per person—
deceased must be cremated. Some citizen and a price local and federal authorities had not been
religious groups threaten that if cremation is willing to pay. Military intervention in the form
enforced, there may not be full reporting of the of martial law is avoided, despite calls by some
dead, and private burial ceremonies would federal authorities for a “modest military
continue. By nightfall, 4,000 persons have fallen presence to keep peace and stability in a region
ill, 1,600 of whom have died. clearly under attack.” No group can be identified
By November 8, increasing numbers of the as the perpetrator, though FBI continues one of
city’s critical work force are absent, including the largest investigations in its history. Many
police, firefighters, bus and subway operators, refuse to return to their homes downwind of the
building managers, sewage treatment workers, stadium and demand official compensation.
electricity and water officials, and supermarket Businesses downwind of the stadium are shut
staff. Some are absent because of illness or death down. The stadium is largely abandoned.
due to anthrax. Some skip work fearing contagious Newspapers brand the downwind area “the dead
spread despite official statements to the contrary. zone.” Overall, city commerce suffers tremen-
Some simply fear violence in the city. Many of dous losses. The tourism industry collapses. City
those with the means to leave the city do so. officials estimate it will be months or years before
National Guardsmen are able to fill some the city resumes a normal routine. Fear of
roles, but many tasks require specialized anthrax may keep some away from Northeast
expertise. As a result, the public transit system is indefinitely. On December 1, FBI receives a
barely operational; some of the city’s office threat that anthrax will be released in five major
buildings are shut down; response time for calls U.S. cities over the next week.
made to fire, police, and ambulance lengthens. This scenario is ominous. Such an epidemic
Schools and universities are closed. State and would create extraordinary challenges for a
city officials become increasingly concerned about modern American city. However, there is no
an imperiled city infrastructure. Looting erupts. need to give in to the ending of this story.
The mayor holds a press conference to Practical, modest preparedness efforts could
address false allegations that anthrax vaccine is make a difference and change the outcome.
being administered to select individuals in the Many of the most useful efforts may be the result
city. She reports that federal authorities will of ingenuity and depend on collaboration of
make available some vaccine for those deemed at experts from many disciplines.
highest risk. But due to a national shortage of Could the outcome have changed if state and
vaccine and military concerns that this attack local health officials had prior notification of the
may herald further attacks, there is only a highly anthrax threats? Should laboratory practices be
limited amount of vaccine available. For the most changed to increase the chance of early detection
part, the city will have to manage with of anthrax? Should health-care workers become
antibiotics alone. familiar with the early symptoms and signs of
By evening, a total of 4,800 persons have anthrax? What could hospitals do to prepare for
become ill; 2,400 have died. epidemics of seriously ill patients? Could
communities have plans for rapid mass antibiotic
Aftermath acquisition and distribution? Should anthrax
Of the 20,000 persons originally infected in vaccine be more widely available? How might
Northeast, 4,000 died, most in the first 10 days health professionals and government officials

Vol. 5, No. 4, July–August 1999 559 Emerging Infectious Diseases

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interact with the media to best inform the public Dr. Inglesby is assistant professor in the Division
and avoid misunderstanding and panic? What of Infectious Diseases at the Johns Hopkins University
should the community, hospitals, and profes- School of Medicine. He works primarily with the Johns
sional societies be doing? What should you be Hopkins Center for Civilian Biodefense Studies. He is
doing? also a physician, treating patients with human immu-
nodeficiency virus at the Moore Clinic of the Johns
Hopkins Hospital.

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 Special Issue

Applying Lessons Learned from Anthrax

Case History To Other Scenarios
John G. Bartlett
Johns Hopkins School of Medicine, Baltimore, Maryland, USA

Northeast, the city described in the anthrax I then went to radiology; I showed the
scenario (Inglesby, this issue, pp. 556-60) is radiologist a classic case of inhalation anthrax
actually Baltimore, a metropolitan area of 2 and asked him how he would interpret the X-ray.
million population, with a football stadium that He said that he would read it as widened
holds 74,000. Route 95 would be where the mediastinum; the differential diagnosis did not
anthrax dispersion took place. include anthrax.
My test case started on February 13 at 6 a.m. Then I went to the laboratory and asked the
when I went to the emergency room at Johns lead technician who has been in the laboratory
Hopkins University Hospital and asked to see for 25 years. He said that Bacillus anthraxis had
the physician in charge. I described the typical never been isolated during his tenure. If it was
case and asked what the procedure would be if a recovered in blood cultures, it would be called
patient came down with these symptoms. The “Bacillus species, a probable contaminant.”
physician in charge had actually taken the However, more than three cases of Bacillus
specialized 8-hour training course on bioterrorism species would prompt a full identification, which
(one of five physicians in Maryland to have would be available in 48 hours. That would
completed this course entitled “Train the trigger a call to the chief of Infectious Disease
Trainer”). Nevertheless, she confessed that the and to Infection Control. It would take 72 hours
typical early case of inhalation anthrax would to get sensitivity test results—which is
have a presumed diagnosis of flu, and the patient important since this information would drive the
would probably be sent home. Despite the subsequent decisions regarding antibiotic pro-
emphasis on emergency room physicians as the phylaxis to those patients or persons who had
“early response team,” the actual diagnosis been exposed. My own response (if given the
would be made after hospitalization. Many possibility of a case of inhalation anthrax) would
seriously ill patients arriving at the same time be to call the state health department—the
might arouse suspicion, but the initial cases Maryland Department of Health and Mental
would likely be isolated events or would be Hygiene.
dispersed in multiple emergency rooms. I got a recording and left a message that I had
There was a further problem. At the time of a query about bioterrorism, and it was
my visit, the emergency room was on “blue alert,” important. The call was returned 3 days later.
meaning that all 28 beds were filled; the hospital The state does have a response mechanism that
was also filled. Furthermore, the whole city was is far along in planning and can be activated with
on blue alert, probably because of the flu a single phone call. The problem is that I did not
epidemic. Hospitals routinely run on marginal know the number. No one else seemed to know
excess capacity. The pressures of managed care the number; it is not in the hospital directory or
have resulted in a health-care system that has on 911 listings.
minimal elasticity, so on February 13, there were How were we set in Baltimore to deal with
no beds for an anthrax epidemic. antibiotics? What was the supply? At any
moment, the city of Baltimore had 69,000
capsules of ciprofloxicin and 99,000 capsules of
doxycycline. We could probably use a number of
Address for correspondence: John G. Bartlett, Johns Hopkins
Center for Civilian Biodefense Studies, Candler Building, other flouroquinolones, and if the sensitivities
Suite 850, 111 Market Place, Baltimore, MD 21202, USA; fax: proved that penicillin was active, we could use
410-223-1665; e-mail: biodefen@jhsph.edu. that as well. Access to antibiotics would not be a

Vol. 5, No. 4, July–August 1999 561 Emerging Infectious Diseases

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major problem in this scenario of anthrax The great need is for deploying antibiotics in an
contamination. expeditious way to thousands, presumably by
Then I reviewed the statewide facilities and using regional care sites and the thousands of
planning for a bioterrorist attack. One phone call physicians’ offices; 3,000 emergency medical
to the state health department would set into service providers could be available to assist, but
motion a cascade of events that would include an the mainstay of care in any large epidemic would
immediate effort by state epidemiologists to come from the private sector.
review the data and confirm the diagnosis. They How does all this work? The good news is
would then contact the Maryland Emergency that we have a system set up where there is one
Management Agency, the Federal Bureau of person or one group that is coordinating the
Investigation, Maryland Institute for Emer- events and one point of contact that initiates the
gency Medical Services System, and other relevant cascade of events necessary for a
appropriate agencies. The Maryland Emergency response. Can this system respond the way it is
Medical Agency coordinates relevant state expected to respond? The system has worked in
agencies and also acts as spokesperson to the natural disasters, but it may break down in a
press. large outbreak of inhalation anthrax. For
Maryland Institute for Emergency Medical example, during a pfisteria crisis, many groups
Services System has the capability for flash faxes took the outbreak on as their issue. Representa-
to emergency rooms throughout the state but tives of Congress and influential citizens
does not communicate with infection control bypassed the governor, the mayor, the Maryland
programs and other parts of the hospital because Emergency Management Agency and every
somebody in the emergency room can always get other system to contact the White House, CDC,
that information. My perception is that other agencies and various medical experts to
Maryland does not have a good system to reach deal with it. Many did not like the answers they
its practicing physicians, whose involvement is got, so they bypassed standard channels, and
critical. To give antibiotics to tens or hundreds of many are unaware of the rules. A system with a
thousands of persons in several days, it will be single voice for communication with the press
necessary to use more than the health and providers is needed. The state has 13,000
department clinics and personnel. Notification beds, but a flu epidemic recently overwhelmed
and direction would have to be done through the hospital capacity, and this was not even a big
press and through the medical society, but it is year for influenza. A recent large fire in
not clear how well this would work. There had Baltimore demonstrated that the city could not
been a few examples, however, of how this handle 100 casualties.
system would work in other settings. The Finally, there is the issue of medical-care
Maryland Emergency Medical Agency, the personnel resources to respond. Maryland has
system for public communication, is active about 16,000 physicians, 262 members of the Infectious
two to three times a year, primarily for ice storms Disease Society, and 400 emergency room
and hurricanes. It has not been tested for a major physicians; in addition, every hospital has
epidemic, but at least it is a system that is infection control personnel. In the event of a
established. The capacity for bodies in a morgue bioterrorist attack, these will be the first
would be approximately 100, but there are responders. They are the front line for patient
contracts to get refrigerated trucks that would contact with the health system. They will
hold 40 bodies per truck. The system is set up so suspect or establish the diagnosis, develop
that Maryland Institute for Emergency Medical systems to regulate hospital flow, make
Services System can readily identify bed capacity therapeutic policy, give treatment, and will
for every hospital in Maryland including the provide prophylactic antibiotics and vaccines.
number of available intensive care unit beds to Federal, state, and local health agencies play a
facilitate referrals. No plan is available for central role in planning but do not have the
stockpiling antibiotics or vaccines. Stockpiling of facilities or field forces necessary to deal with
antibiotics is not necessary because the city could sick patients and the thousands who need
get an adequate supply from regional sites, and vaccines or antibiotics.
the Centers for Disease Control and Prevention The gap in planning at the federal level has
has a $50 million budget allocated to this need. been the failure to include these diverse groups

Emerging Infectious Diseases 562 Vol. 5, No. 4, July–August 1999

 Special Issue

at the table. We anticipate two responses. representative of hospitals. Thus, enthusiastic

Different groups will make territorial claims on participation by the critical players from the
the issue; infectious disease physicians will say private sector is unlikely.
bioterrorism is what they are trained for, The major mechanism for recruitment is a
infection control practitioners will claim that carrot or a stick. Possibilities include making
epidemics are their special skill, emergency room bioterrorism plans by hospitals a Joint Commis-
physicians will claim that they will be the first to sion on Accreditation of Organization require-
see those patients, and microbiologists will claim ment, requiring this in RRC selected training
that they make the diagnosis. All have a role, and programs, asking it on American Board of
all should be included. The second response Internal Medicine boards, and incorporating it in
seems diametrically opposed. We suspect that it medical school curricula. These possibilities
will be difficult to engender participation by would increase visibility of the issue but would
relevant groups, despite their claims regarding not provide the proper regional training needed.
discipline relevance. A bioterrorist attack is a The resources that now total $20 million should
low-probability event for nearly all cities when include an allocation to the private sector to
considered individually. Cleveland, Tulsa, or permit training and planning programs that
Sacramento are unlikely targets, just as represent a true partnership between public and
Oklahoma City was an unlikely target. Medical private sources.
providers are busy, and most of us have
Dr. Bartlett is professor and chief of the Division of
volunteered to the breaking point. It is not
Infectious Diseases, Johns Hopkins University School
surprising that the “Train the Trainers” sessions of Medicine and president of the Infectious Diseases So-
on bioterrorism in Baltimore were attended by ciety of America.
only five emergency room physicians and no

Vol. 5, No. 4, July–August 1999 563 Emerging Infectious Diseases

 Special Issue

Addressing Bioterrorist Threats:

Where Do We Go from Here?
Margaret A. Hamburg
Department of Health and Human Services, Washington, D.C., USA

In discussing the threat of bioterrorism, public health and health-care community as well
planning, coordination, and preparedness are as with outside partners. We need to develop
recurrent themes. State and local planning are of shared understandings and mechanisms of
particular concern to me, having served as a local communication. All of these efforts are best
health officer and as health commissioner in undertaken before an emergency or crisis.
New York City during the World Trade Center We need to strengthen our nation’s public-
bombing. I have no doubts that the threat of health infrastructure. This means enhancing
terrorism within our borders is real. And several our surveillance and epidemiologic capacity; our
years later, when the sarin attack occurred in laboratory capacity to support surveillance
the Tokyo subway system, it was hard not to efforts; and our communications systems to
imagine what such an event would have meant collect, analyze, and share data. A strong and
in the New York subway system. A fundamental robust public health system requires effective
step toward addressing the threat of bioterrorism working partnerships with the medical care
is comprehensive planning that focuses first and community. For a host of reasons over many
foremost on local preparedness and response years, the worlds of public health and medicine
capacity—integrating the role of state, regional, have existed too far apart, even though they
and federal governments, as well as state, share a common set of goals and the mission of
regional, and national assets. To plan effectively, promoting health and preventing disease. We
we have to think through the different types of need to build linkages and understanding.
scenarios that may confront us, including the We also need to make sure that the public
announced release of a biological agent, the health community works with medical providers
silent release of a biological agent, or some kind to give them the kind of information they need to
of hybrid event, such as having a bomb go off, respond to infectious disease threats in the
that is followed by the release of a biological or community, understand emerging disease trends,
chemical agent. In addition, we have to think and implement appropriate prevention and
about the scenarios where person-to-person control strategies. Improvements to health can
transmission can occur or those with noncommu- be achieved through more effective daily
nicable infectious diseases. Bioterrorism covers a working relationships and even through a
very broad spectrum of concerns, from cata- crisis. In addition, we have to link with other
strophic terrorism with mass casualties, to partners beyond the public health and medical
microevents using low technology but producing community, particularly law enforcement and
civil unrest, disruption, disease, disabilities, and intelligence. Through working together, we
death. All these scenarios must be considered. learn to share common understanding and
We need to identify the assets and capabilities at language. Federal Bureau of Investigation
all different levels and identify the gaps, critical surveillance is different from public health
players, policymakers, and stakeholders, and we surveillance; yet, if we are going to be able to
must forge working relationships within the rapidly detect, diagnose, and control a
bioterrorist event, we need to use both types of
surveillance to inform our activities and
Address for correspondence: Margaret A. Hamburg, Office of ensure adequate preparedness.
Planning and Evaluation, Department of Health and Human Communication is vital. We must learn how
Services, HHH Building, Room 415F, 200 Independence
Avenue, S.W., Washington, D.C. 20201, USA; fax: 202-690-
to educate and communicate with policymakers.
7383. We should define policies to support our

Emerging Infectious Diseases 564 Vol. 5, No. 4, July–August 1999

 Special Issue

preparedness efforts, the true needs for new Another crucial aspect of effective medical
resources, and the places in which to invest. consequence management requires access to
Legal and regulatory issues dealing with necessary therapeutic products. We are in the
quarantine laws and jurisdictional concerns, as process of creating a national stockpile of drugs
well as with the availability or use of certain and pharmaceutical products for civilian use.
drugs or vaccines not licensed by the U.S. Food Given that a bioterrorist event is low probability
and Drug Administration for use in certain and high consequence for any given locality, the
populations in an epidemic context, need to be federal government can step in and provide the
addressed. leadership for creating and administering a
And lastly, we must address the challenge of national stockpile.
informing the public and educating them about A related concern is the need to develop new
the reality of bioterrorism. We must develop the tools for the medical management of bioterrorist
framework of understanding and support threats. The research and development agenda
required to both put in place the systems to needs to be addressed both through governmen-
respond effectively in a crisis and to achieve a tal efforts, including the National Institutes of
level of understanding that can form the Health, the Centers for Disease Control and
foundation for sharing information and develop- Prevention, and the U.S. Army Medical
ing knowledge when a crisis occurs. Research Institute of Infectious Diseases, but
Hoaxes, a growing problem, offer an also through private industry and other research
opportunity to examine our coordination and institutions. Improved and more rapid diagnos-
response. Thinking through the different types tic methods, new and better drugs for treatment
of hoaxes helps us develop protocols and or prophylaxis, and new vaccines, especially
strategies that lead to recognition of a true event. against anthrax and smallpox, are needed. In
Medical consequence management is an area addition to biomedical research, further research
to be explored. The conventional bomb—where into such diverse concerns as defining appropri-
something blows up, you come in, respond, take ate personal protective gear or decontamination
care of the injured, clean up, and then return, procedures is fundamental to our overall
more or less, to life as it was before—is not going preparedness for a bioterrorist attack.
to be the case in a bioterrorist attack, The public health and medical community
particularly in a scenario with human-to-human must look to the issue of prevention in terms of
transmission. Instead, cases will initially appear how to reduce access to dangerous pathogens.
in a scattered, sporadic manner, but rapidly Are there strategies to prevent these often-
increasing and overwhelming the capacity of the frightening microbes from getting into the hands
health-care system and continuing in concentric of those who might want to misuse them, and
circles of infection and disease. We cannot how can we reduce the likelihood that they will
address consequence management in the way be misused? This means being concerned on an
emergency plans traditionally have for earth- international level about such issues as the need
quakes, fires, or bomb blasts. We need to build a to support the strengthening and enforcement of
system that brings together local, state, and the Biological Weapons Convention. Finally, as a
national capacities in an ongoing way. We also scientific community we should play a proactive
must recognize the need to supplement our role in scientific research. We need to shape
health-care delivery capacity with nonmedical policies against the nefarious use of biological
support that may come in the form of police, agents, while safeguarding legitimate research.
National Guard, or possibly military support, We need to ensure that research institutions and
both to assist in the provision of services and individual researchers keep track of the
for crowd control and the maintenance of whereabouts of dangerous pathogens, handle
order. New systems of delivering care and them safely, and store them securely.
treating patients will be needed. For example,
Dr. Hamburg is assistant secretary for Planning and
how are we going to deliver off-site care? How
Evaluation, U.S. Department of Health and Human
are we going to ensure proper infection-control Services, and former commissioner of health for the
measures in that context and provide ancillary City of New York.
support services for medical care?

Vol. 5, No. 4, July–August 1999 565 Emerging Infectious Diseases

 Dispatches

The Surveillance of Vero Cytotoxin-

Producing Escherichia coli O157 in
Wales, 1990 to 1998
Rachel M. Chalmers,* Sharon M. Parry,† Roland L. Salmon,*
Robert M.M. Smith,* Geraldine A. Willshaw,‡ and Tom Cheasty‡
*Public Health Laboratory Service Communicable Disease Surveillance
Centre, Cardiff, United Kingdom; †Welsh Combined Centres for Public
Health, Cardiff, United Kingdom; ‡Central Public Health Laboratory,
Colindale, London, United Kingdom

Population-based surveillance for Vero cytotoxin-producing Escherichia coli

(VTEC) O157 has been carried out in Wales since 1990. The annual incidence has
remained stable during the 9-year period (mean: 1.6 cases per 100,000 population); the
rate is highest in children younger than 5 years of age. Blood in the stool is reported in
fewer than half the cases, indicating the importance of screening all fecal specimens for
VTEC O157.

Vero cytotoxin-producing Escherichia coli the microbiologic characteristics of the isolates.

serogroup O157 (VTEC O157) was first We report on 9 years of surveillance through the
recognized as a human pathogen in 1982 (1). end of 1998. Since the system is population-
Infection results in symptoms ranging from mild based, the figures differ from those in some
diarrhea to hemorrhagic colitis (abdominal pain, published reports of specimens submitted to the
diarrhea, and blood in the stool). Hemolytic reference laboratory (4,7,8).
uremic syndrome (HUS), characterized by Fecal samples were cultured on Sorbitol
microangiopathic hemolytic anemia, thrombocy- MacConkey agar (Oxoid, Basingstoke, UK) and
topenia, and renal failure, develops in 2% to 7% incubated at 37°C for 18 hours (3). Sorbitol
of cases (2). The number of laboratory isolations nonfermenting colonies were tested for latex
of VTEC O157 from human infections in England agglutination with O157 antiserum (Oxoid) and
and Wales has risen from 76 in 1986 (3) to 1,087 were biochemically confirmed as Escherichia coli
in 1997 (4). However, the number of laboratories by API 20E (BioMerieux sa69280 Marcy L’Etoile,
examining feces for VTEC O157 has increased in France). Laboratories were asked to send all
England, as have protocols emphasizing the presumptive VTEC O157 isolates to the
importance of laboratory examination. Many Laboratory of Enteric Pathogens, Central Public
surveillance networks worldwide have selection Health Laboratory, London, for confirmation,
criteria for testing for VTEC O157, such as the phage-typing, and Vero cytotoxin typing (8).
presence of blood in the stools and clinical or age Cases, defined as “isolation of VTEC,
parameters (5). In contrast, population-based confirmed by standard methods, from a fecal
surveillance has been undertaken in Wales since specimen submitted by a resident of Wales,” were
February 1990, with all first-time acute-phase reported to the Public Health Laboratory Service
fecal specimens tested for VTEC O157 (6). The Communicable Disease Surveillance Centre
objectives of this surveillance are to measure the (CDSC) (Wales). Nine cases were excluded
incidence of VTEC O157, identify outbreaks of because the E. coli O157 isolate did not express
infection, and describe the persons involved and Vero cytotoxin genes. Epidemiologic and clinical
information was recorded on a standard
Address for correspondence: Rachel Chalmers, PHLS CDSC
(Wales), Abton House, Wedal Road, Cardiff CF4 3QX, United structured questionnaire. Household contacts
Kingdom; fax: 44-1-222-521-987; e-mail: rachel.chalmers were screened where practicable and were
@cdsc.wales.nhs.uk. included if they met the case definition. HUS,

Emerging Infectious Diseases 566 Vol. 5, No. 4, July–August 1999

 Dispatches

which in the United Kingdom is defined as renal reported from each household) (from 72.3% in
impairment including oligouria and plasma 1998 to 96.2% in 1993). Fifty-eight (17.0%)
creatinine elevated for age, microangiopathic sporadic cases were in household contacts; 26 of
hemolytic anemia, and thrombocytopenia, was these patients had diarrhea, including five with
diagnosed clinically. blood in the stools.
The annual incidence was calculated by Of 415 patients, 207 (49.9%) were males,
using as the denominator the mid-year ages 3 months to 89 years (mean = 25 years,
population estimates for Wales (Office of median = 18 years, mode = 1). The incidence of
National Statistics [ONS]), and the age and sex VTEC O157 was highest in children younger
distribution of patients was calculated by using than 5 years (8.8 per 100,000 population) (Table
the mid-1996 population estimate (ONS). The 2). The number of cases peaked in August, and
Poisson distribution was used to calculate 95% more than half (227) of the cases occurred during
confidence intervals (CI) for age-specific rates. July, August, and September. Only four cases
To assess seasonality, the frequency of cases by occurred during December. Cases were reported
month of onset was examined. (For asymptom- from all five health authority areas in Wales. The
atic cases, the date of the sample was used.) highest incidence was in the northern and
Incidence by health authority areas was western areas (North Wales and Dyfed/Powys)
calculated by using post-1996 boundaries. The (mean annual incidences 2.5 and 2.4 per 100,000
proportions of cases with various symptoms were population, respectively). The lowest incidences
determined, and 95% CI were calculated by were reported in the more densely populated
using standard error of proportions. The areas of Gwent (1.1 per 100,000), Bro Taf (1.1 per
duration of illness (up to the date of interview), 100,000), and Iechyd Morgannwg (1.0 per
admission to hospital and length of stay, and 100,000).
proportion with HUS (95% CI) were calculated. Of the 415 patients, 339 (81.7%, CI = 78.3%-
From 1990 through 1998, 415 cases were 85.7%) had diarrhea, 259 (62.4%, CI = 57.3%-
reported (mean = 1.6 per 100,000 population per 66.7%) reported abdominal pain, and 192 (46.3%,
year), with little change in incidence (1.0 per CI = 41.3%-50.7%) had blood in the stool; 172
100,000 population in 1994 to 2.8 per 100,000 (41.4%, CI = 36.3%-45.7%) had hemorrhagic
population in 1995, when an outbreak of 49 cases colitis. One third of the patients reported
occurred) (Table 1) (9). Seventy-four cases vomiting (32.3%, CI = 27.5%-36.5%) or feeling
(17.8%) were part of six outbreaks involving feverish (34.0%, CI = 29.5%-38.5%); 62 (14.9%, CI
Welsh residents (Table 1). Three of the outbreaks = 11.5%-18.5%) were asymptomatic. The highest
have been reported elsewhere (9-11). The proportion of asymptomatic cases was in the 25-
remaining 341 (82.2%) were sporadic cases, of to 34-year-old age group (18 [40.1%] of 44) who
which 283 (83.0%) were index cases (the first are often the caretakers of symptomatic patients;

Table 1. Occurrence and annual incidence of VTEC O157 in Wales, 1990–1998

Total no.
of cases
(rate per No. of No. of
100,000 sporadic cases outbreak Outbreak summary
Year population) (no. of index cases) cases (setting, mode of spread, phage and verotoxin types)
1990 32 (1.1) 28 (24) 4 Psychogeriatric ward, person to person, PT14,
VT1&2.
1991 39 (1.3) 30 (28) 9 Day nursery, person to person, PT49, VT2.
1992 41 (1.4) 41 (33) 0 -
1993 34 (1.2) 26 (25) 8 Community, Meat from 1 shop, PT49, VT2.
1994 29 (1.0) 29 (24) 0 -
1995 82 (2.8) 33 (30) 49 Day nursery, person to person, PT2 VT2.
1996 38 (1.3) 38 (31) 0 -
1997 55 (1.9) 51 (41) 3 Home for the elderly mentally infirm, person to
person, PT2, VT2.
1 Part of a European outbreak
1998 65 (2.2) 65 (47) 0

Vol. 5, No. 4, July–August 1999 567 Emerging Infectious Diseases

 Dispatches

Table 2. Age and sex distribution of cases of VTEC from cases of HUS had the VT2 gene only. These
O157, Wales, 1990–1998 isolates were predominantly PT2 (n = 10), but
Age also included PT49 (n = 4), PT21 (n = 1) and
range Total Male Female RDNC (n = 1).
<1 24 (7.9, CI = 4.9-11.9) 13 (8.3) 11 (7.5) Foreign travel in the week before onset of
1-4 117 (9.0, CI = 7.4-10.7) 71 (10.7) 46 (7.2)
5-14 56 (1.6, CI = 1.2-2.1) 32 (1.8) 24 (1.4)
symptoms was reported by 37 (8.9%) patients (0
15-24 44 (1.4, CI = 1.0-1.8) 19 (1.1) 25 (1.6) in 1990 to 12 in 1998 [18.5%] of cases). The PTs
25-34 44 (1.2, CI = 0.8-1.6) 19 (1.0) 25 (1.3) among those who had traveled abroad differed
35-44 30 (0.9, CI = 0.6-1.2) 14 (0.8) 16 (0.9) from the overall pattern, the most common being
45-54 33 (1.0, CI = 0.7-1.3) 11 (0.6) 22 (1.3)
55-64 25 (0.9, CI = 0.6-1.5) 10 (0.7) 15 (1.1)
PT8 (10 cases), RDNC (5 cases), and PT21 (4 cases).
$65 35 (0.9, CI = 0.5-1.1) 15 (0.9) 20 (0.8) Population-based surveillance of VTEC O157
Total 415 (1.6, CI = 1.4-1.7) 207 (1.6) 208 (1.5)
in Wales has been undertaken since 1990 and is
(mean) the most complete in the world. There is no
Figures in parentheses are mean annual rates per 100,000 evidence that pathology referrals have changed
population, followed by 95% confidence intervals (CI) for age- during the study period. General practitioners
specific rates. (primary-care physicians) were given no specific
in 17 cases HUS developed (4.1%, CI = 2.4%- incentives for submitting specimens. Palmer
6.5%), age range: 1 to 50 years (mean = 9 years, et al. (12) showed that in 1996, 26% patients with
median = 3 years); 10 HUS patients were less suspected food poisoning attending general-
than 1 to 4 years of age, for a complication rate in practitioner clinics submitted fecal specimens.
this age group of 8.5%. This is similar to the 27% reported during a
Diarrheal illness lasted as long as 330 days study of patients with infectious gastroenteritis
(median and mode = 6 days); 118 (28.4%) patients reporting to general practitioners in England
were admitted to hospital. The length of stay, (13). Although VTEC O157 is regarded as an
first recorded in 1994, was from 1 to 71 days emerging pathogen, in Wales its incidence has
(mode 1 day, median 4.0 days). The highest rate remained stable through 1998, and VTEC O157
of hospitalization was among those >65 years old is a rare (1.6 cases per 100,000 population) but
(25 [62.5%] of 40). The mean annual proportion of serious disease.
index cases hospitalized was 36.1% (24.0% in Public health policy concerning VTEC O157
1993 to 48.5% in 1992). From 1994 through 1998, has been driven by the circumstances surround-
only one person, an 88-year-old woman with ing outbreaks (14). However, in Wales most cases
diarrhea, died as a result of the infection. (82.2%) occur sporadically, and because all first-
Three hundred seventy-eight (91.1%) iso- time specimens and PTs are examined and
lates were sent to the Laboratory of Enteric epidemiologic investigations are conducted, it is
Pathogens for confirmation and typing. Of these, unlikely that outbreaks were missed. The
62 (16.4%, CI = 6.4%-26.4%) had both verotoxin surveillance data, as well as providing a
type (VT) 1 and VT2 genes, and 316 (83.6%, CI = background against which to measure changes
79.9%-87.3%) had VT2 only. Isolates belonged to in incidence, have provided useful information
at least 19 phage types (PT). The two most about VTEC O157 infections. The presence of
common PT were PT2 (160 isolates [42.3%]) and blood in the stool is often used in many countries
PT49 (48 isolates [12.7%]). Other PT accounting as a criterion for examining for VTEC O157, yet
for 5% (19) or more isolates were PT1, PT4, PT8, fewer than half the Welsh patients reported the
and PT14. PT2 was the most common type in presence of blood, demonstrating the value of
each year, with the exception of 1993, when PT49 screening all acute-phase fecal specimens.
predominated. PT and verotoxin type were Although 14.9% of cases were asymptomatic, the
linked: VT2-only strains included 98% (158 of risk for transmission is still present because of
160) of the PT2 and all the PT49 isolates. the low infectious dose (11).
No relationship was found between the Strains of VTEC O157 can be differentiated
major PTs and clinical symptoms. More cases rapidly by PT and Vero cytotoxin typing,
with strains producing VT1+2 had hemorrhagic although even from apparently sporadic cases a
colitis (39 [63.9%] of 61) than cases with VT2 only large number of isolates belonged to a few types,
(120 [42.9%] of 280) (relative risk = 1.69, 95% CI predominantly PT2/VT2 and PT49/VT2. Deter-
= 1.18-1.88). In contrast, 16 of the 17 isolates mining the VT produced appears to be a

Emerging Infectious Diseases 568 Vol. 5, No. 4, July–August 1999

 Dispatches

microbiologic marker of severity, since hemor- References

rhagic colitis was more often associated with 1. Riley LW, Remis RS, Helgerson SD, McGee HB, Walls
VT1+2 strains, and all the cases complicated by J, Davis BR, et al. Hemorrhagic colitis associated with
a rare Escherichia coli serotype. N Engl J Med
HUS had VT2-only strains. These strains are
1983;308:681-5.
consistently more prevalent than other VT types 2. Tarr PI. Escherichia coli O157:H7: clinical, diagnostic
in cases of HUS in the United Kingdom (7) and and epidemiological aspects of human infection. Clin
elsewhere. Demonstration of VT by phenotypic Infect Dis 1995;20:1-10.
tests or the presence of VT genes is definitive for 3. Advisory Committee on the Microbiological Safety of Food.
Report on Vero cytotoxin-producing Escherichia coli.
VTEC O157. The presence of the H7 antigen is
London: The Committee; 1995.
closely associated with VT positivity but is of 4. Vero cytotoxin producing Escherichia coli O157 in England
secondary importance, as a significant minority and Wales. Commun Dis Rep CDR Wkly 1998;8:169.
of VTEC O157 isolated in England and Wales 5. Parry SM. The incidence and sources of Vero cytotoxin
(14%-20% in 1992-1994) are nonmotile (8). There producing Escherichia coli O157 in Wales and the English
Borders [Ph.D. thesis]. University of Leeds; 1997.
was some annual variation in PTs, although as in
6. Salmon RL, Smith RMM. How common is Escherichia
England the predominant phage type was PT2. coli O157 and where is it coming from? Total population
As with other surveillance reports, the surveillance in Wales 1990-1993. In: Karmali MA,
highest incidence was in children younger than 5 Golglio AG, editors. Recent advances in Vero-cytotoxin-
years of age (8). Although fecal specimens are producing Escherichia coli infections. Amsterdam:
Elsevier Science BV; 1994.
more likely to be available for this age group, the
7. Thomas A, Chart H, Cheasty T, Smith HR, Frost JA,
isolation rate is also high (6), and person-to- Rowe B. Vero cytotoxin-producing Escherichia coli,
person spread is most likely (15). In Wales, particularly serogroup O157, associated with human
person-to-person spread was the most important infections in the United Kingdom: 1989-1991.
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8. Thomas A, Cheasty T, Frost JA, Chart H, Smith HR,
those in the children’s day nurseries, which were
Rowe B. Vero cytotoxin-producing Escherichia coli,
the setting for the two largest outbreaks. particularly serogroup O157, associated with human
Continued surveillance for VTEC O157 will infections in England and Wales: 1992-1994. Epidemiol
provide timely reporting of cases and detection Infect 1996:117;1-10.
and containment of outbreaks. Ongoing surveil- 9. Al-Jader L, Salmon RL, Walker AM, Williams HM,
Willshaw GA, Cheasty T. An outbreak of Vero cytotoxin
lance over the last 9 years in Wales has provided
producing Escherichia coli O157 in a private nursery in
valuable information about VTEC O157 infec- North Wales: lessons for prevention. Arch Dis Child
tions and demonstrated the wide range of 1999: 81;60-3.
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Acknowledgments
The authors thank the microbiology laboratories and
d’Epidemiologie de Terrain le Bulletin d’Epiter;11;90.
their link personnel, District Environmental Health 11. Willshaw GA, Thirwell J, Jones AP, Parry S, Salmon RL,
Departments, Health Authority Consultants in Communi- Hickey M. Vero cytotoxin-producing Escherichia coli O157
cable Disease Control, and the Welsh Office Standing in beefburgers linked to an outbreak of diarrhoea,
Specialist Advisory Group (Microbiology). Unipath/Oxoid haemorrhagic colitis and haemolytic uraemic syndrome in
organized the distribution of reagents to participating Britain. Letts Appl Microbiol 1994;19:304-7.
laboratories. 12. Palmer S, Houston H, Lervy B, Ribiero D, Thomas P.
Problems in the diagnosis of foodborne infection in
This work was funded by grants from the Department of general practice. Epidemiol Infect 1996;117:479-84.
Health, London (DH code 145 and 254) and a PHLS Small 13. Wheeler JG, Sethi D, Cowden JM, Wall P, Rodrigues
Projects grant. LC, Tompkins DS, et al. Study of infectious intestinal
disease in England: rates in the community, presenting
Dr. Chalmers is a senior scientist with the U.K. to general practice, and reported to national
Public Health Laboratory Service Communicable Dis- surveillance. BMJ 1999;318:1046-50.
ease Surveillance Centre in Cardiff. She has a research 14. Pennington Group. Report on the circumstances leading to
background in veterinary microbiology and protozool- the 1996 outbreak of infections with E. coli O157 in central
ogy and current interests in the epidemiology of occu- Scotland. The implications for food safety and the lessons
pational and food- and waterborne zoonoses. to be learned. Edinburgh: The Stationery Office; 1997.
15. Parry SM, Salmon RL. Sporadic STEC infection:
secondary household transmission in Wales. Emerg
Infect Dis 1998;4:657-61.

Vol. 5, No. 4, July–August 1999 569 Emerging Infectious Diseases

 Dispatches

A Focus of Deer Tick Virus Transmission

in the Northcentral United States
Gregory D. Ebel, Ivo Foppa, Andrew Spielman, and
Sam R. Telford, III
Harvard School of Public Health, Boston, Massachusetts, USA

We screened salivary glands from adult deer ticks collected near Spooner and
Hayward, Wisconsin, to determine whether deer tick virus, a recently described
flavivirus, occurs with other tickborne agents in the upper Midwest. Intraacinar
inclusions suggestive of replicating virus were detected in 4 (4.6%) of 87 ticks. The virus
was isolated by suckling-mouse inoculation.

Pathogens transmitted by deer ticks (Ixodes organisms and were removed after 4 to 5 days.
dammini) affect the health of residents in areas Ticks were dissected individually on acid-
of the northcentral United States. The diversity washed microscope slides by using flame-
of infecting agents, the intensity of their sterilized forceps and razor blades. One of each
transmission, and the concomitant risk for pair of salivary glands was stained by the
human infection are well documented and Feulgen reaction and examined by bright-field
approach levels found in the Northeast (1-4). In microscopy. The other was pooled with the
northwestern Wisconsin, the risk to health from salivary glands of four other ticks in Hanks’
these ticks may increase as human recreational Balanced Salt Solution supplemented with fetal
and industrial activities more frequently bovine serum (HBSS/FBS) for mouse inoculation
intersect with areas of enzootic transmission. In and polymerase chain reaction (PCR) analysis.
addition to the agents of Lyme disease (Borrelia The slides used for dissection were examined for
burgdorferi), human granulocytic ehrlichiosis B. burgdorferi by direct fluorescent antibody (6).
(Ehrlichia microti), and human babesiosis Male ticks were assayed for spirochetal infection
(Babesia microti), deer ticks in these foci might only; they were homogenized in 50 µl PBS, and
be infected with deer-tick virus (DTV), a recently 10 µl of the resulting suspension was applied to
described Powassan (POW)-like agent of the 12-well microscope slides, air dried, and stained.
genus Flavivirus (5), and might pose an Deer ticks sampled near Spooner and
additional threat to human health in this region. Hayward, Wisconsin, maintain pathogens simi-
To determine whether this newly recognized lar to those found in New England ticks and in
agent infects deer ticks in a focus outside New comparable proportions (Table). In addition to
England, we sampled ticks from two heavily the three agents enzootic near Spooner (4,7,8),
infested sites in northern Wisconsin and assayed we observed a staining pattern suggestive of
them for all four agents. Host-seeking adult ticks viral replication (5) in the salivary glands of four
were collected by dragging a piece of flannel cloth ticks. To determine whether this agent was viral,
over the vegetation during October of 1997 and we inoculated suckling mice intracerebrally with
1998. We collected 481 adult deer ticks near 0.03 ml of a clarified and sterile-filtered
Spooner and Hayward, Wisconsin, during 8 homogenate of the combined pools containing
hours of sampling. A sample of the female ticks Feulgen-positive salivary glands. A sample of
(87 of 271) was selected for analysis. Nonengorged this homogenate was reserved for reverse
female ticks were fed on uninfected laboratory transcriptase (RT)-PCR analysis. Siblings of
rabbits to stimulate replication of infectious suckling mice received 0.03 ml of sterile HBSS/
FBS. On the morning of day 6 after inoculation,
Address for correspondence: Sam R. Telford, III, Department the mice that received salivary gland homoge-
of Immunology and Infectious Diseases, 665 Huntington
Avenue, Boston, MA 02115, USA; fax: 617-738-4914; e-mail: nate showed signs of profound neurologic
stelford@hsph.harvard.edu. dysfunction: their gait was disrupted, and they

Emerging Infectious Diseases 570 Vol. 5, No. 4, July–August 1999

 Dispatches

Table. Pathogens maintained by deer ticks, Spooner and Hayward, Wisconsin, 1997-98
Agent Assay No. examined No. positive % positive (95% CI)
Borrellia burgdorferi Direct fluorescent antibody 220 83 37.7 (31.3, 44.5)
Babesia sp. Microscopy 87 6 6.9 (2.6, 14.4)
Ehrlichia microti Microscopy 87 4 4.6 (1.3, 11.4)
Deer tick virus Microscopy 87 4 4.6 (1.3, 11.4)

failed to right themselves when placed on their chain termination method and an automated
backs. By mid-afternoon they were moribund DNA sequencer (Applied Biosystems, Foster
and died shortly thereafter. The time between City, CA). Sequences were compared with those
inoculation and death was similar to that seen in accessioned in GenBank. Sequence alignments
DTV and POW infections, which kill suckling mice were generated with the PILEUP program of the
in 5 to 7 days (5,9). Wisconsin Genetics Computer Group and then
To determine whether the putative viral analyzed by the distance method using MEGA
agent was DTV, POW, or a related flavivirus, (10). Third codon positions were omitted to
salivary glands that appeared infected were minimize sequence convergence due to ho-
analyzed by RT-PCR. The clarified homogenate moplasy and to better reflect nucleotide changes
used for mouse inoculation was added to 350 µl of resulting in amino acid differences. Analyses
a lysis buffer, and RNA was extracted by RNEasy including third codon positions resulted in
spin columns (Qiagen) as directed by the identical topologies with higher bootstrap values
manufacturer. The resulting RNA-containing and longer branch lengths. Evolutionary
solution was reverse transcribed by using random distances were computed by the Kimura 2-
hexamers at 42°C for 20 minutes. We added 5 µl of parameter method, including both transitions
cDNA to an amplification mixture containing and transversions. Distance trees were con-
primers (TBE-1[5'-3' ACATGGCAGTACTGGGG) structed by the neighbor-joining method, and
and TBE-2 (5'-3' CCCATCATGTTGTACAC]) their robustness was estimated by performing
designed to amplify an approximately 450-bp 500 bootstrap replicates. Phylogenetic analysis
fragment of the ns5 gene of Central European of this fragment (GenBank accession af135459)
tickborne encephalitis (TBE). Reaction condi- indicated that the virus was most closely related,
tions were as follows: initial denaturation at but not identical, to DTV from northwestern
94°C for 1 minute, followed by 35 cycles of 94°C Connecticut (af135460) (Figure 1). Because the
for 45 seconds, 40°C for 45 seconds, and 72°C for 1 ns5 gene from our Spooner isolate was more
minute. A final extension step of 72°C for 6 closely related to DTV than to POW, this isolate
minutes was also performed. Bands of the correct is provisionally designated as deer-tick virus-
size were excised and sequenced by the dideoxy- Spooner (DTV-SPO).

Figure 1. Phylogenetic relationships among tickborne flaviviruses based on a 376-bp fragment of the ns5 gene.
Distance analysis omitting third position nucleotides. Branch numbers are bootstrap confidence estimates on
the basis of 500 replicates. GenBank accession numbers in parentheses. LI = Louping Ill; TBE-West = Western
subtype tickborne encephalitis (Central European encephalitis); POW = Powassan virus; DTV = deer tick virus.

Vol. 5, No. 4, July–August 1999 571 Emerging Infectious Diseases

 Dispatches

To more completely characterize the Wiscon- subjected to electrophoresis on a 2% agarose gel,

sin viral isolate, we amplified a 650-bp fragment yielding a product of the expected size, which was
of the viral envelope gene from the suckling subsequently excised and sequenced. The nucle-
mouse brain tissue. Extraction and reverse- otide sequence of this fragment differs by 16%
transcription of RNA was conducted as previously and 4% from published POW and DTV sequences,
described; PCR were also conducted as respectively. Phylogenetic analysis of this
described, except that the primers ENV-A and fragment (af135461) confirmed that the Spooner
POW-6 were used (5). PCR products were isolate clusters with DTV and POW (Figure 2).

Figure 2. Phylogenetic relationships among tickborne flaviviruses on the basis of a 575-bp fragment of the envelope
gene. Distance analysis omitting third position nucleotides. Branch numbers are bootstrap confidence estimates on
the basis of 500 replicates. GenBank accession numbers in parentheses. LI = Louping Ill; SSE = Spanish sheep
encephalitis; TSE = Turkish sheep encephalitis; GGE = Greek goat encephalitis; TBE-West = Western subtype
tickborne encephalitis (Central European encephalitis); OHF = Omsk hemorrhagic fever; TBE-East = Eastern
subtype tickborne encephalitis (Russian spring-summer encephalitis); KFD = Kyasanur Forest disease; POW =
Powassan encephalitis; DTV = deer tick virus; SRE = Saumarez Reef virus; TYU = Tyuleniy virus; YF = yellow fever.

Emerging Infectious Diseases 572 Vol. 5, No. 4, July–August 1999

 Dispatches

The resulting topology was virtually identical to presentations. We suspect that in contrast to
that of other published trees analyzed by means infection with POW, human disease caused by
of different optimality criteria (11,12). DTV may be mild or asymptomatic. Although
This is the first report of an isolation of a residents of northeastern and midwestern states
TBE-group flavivirus from Wisconsin, and only are heavily exposed to deer ticks, an associated
the second report of a flavivirus in deer ticks. The severe neurologic disease has not yet been
antigenic relatedness of DTV and POW has not described. Prevalence of DTV in host-seeking
yet been determined. Arboviral classification has adult deer ticks was similar to that of the human
been on the basis of serologic methods granulocytic ehrlichiosis agent (4.3%), which
(International Catalogue). A fourfold or greater indicates that residents of this region may be
difference in titer measured by one or more exposed frequently to the bites of DTV-infected
serologic tests (neutralization, complement ticks, and perhaps even more frequently than
fixation) between homologous and heterologous residents of our New England study sites (5).
antisera raised to the viruses being compared is Alternatively, we may fortuitously have sampled
considered to support novelty (15). However, in Wisconsin in an intense focus of transmission.
molecular phylogenetic analyses are increas- European TBE group viruses persist in such
ingly becoming routine and can rapidly provide enzootic microfoci, located within larger regions
information on relatedness. Initial findings may of lesser overall prevalence (14). Because these
subsequently be complemented by the time- foci are so small, few residents of the region are
tested serologic techniques. This paradigm for exposed. The distribution of DTV, like that of
viral identification, where an agent of unknown babesiosis and Lyme disease, may spread from
pathogenic potential may be initially examined its initial foci to exposing the residents of much
by PCR sequencing, has been recently used with broader regions.
much success with hantaviruses. New York
virus, for example, was suggested to be a distinct Acknowledgments
subtype of Sin Nombre virus because its The authors thank Philip Armstrong for thoughtful
suggestions, Rich Pollack and Heidi Goethert for reading the
nucleocapsid protein gene sequence differed by manuscript, and Melissa Culhane for field assistance. All
10% to 12% (16). Other northeastern U.S. animal experiments were conducted according to the
hantavirus isolates from Peromyscus leucopus approved International Animal Care and Use Committee
clustered with each other in phylogenetic guidelines for the Harvard Medical Area.
analysis (forming a “clade”) rather than with Sin This work was supported by NIH grants AI 39002, AI
Nombre virus from the southwestern United 37993, and AI 19693.
States. Similarly, despite the geographic
distance of their transmission foci, DTV-SPO Mr. Ebel is a doctoral candidate in the Laboratory
forms a clade with the two original DTV isolates of Public Health Entomology, Department of Immunol-
ogy and Infectious Diseases. His research interests fo-
from New England rather than with the sole
cus on the population biology of deer tick- and small-
molecularly characterized POW isolate, which mammal-associated viruses.
derives from nearby Ontario. Accordingly,
although conclusions regarding the novelty of
DTV should be regarded as tentative pending References
serologic studies, molecular evidence strongly 1. Kitron U, Kazmierczak JJ. Spatial analysis of the
distribution of Lyme disease in Wisconsin. Am J
suggests that DTV is a new subtype of POW. Epidemiol 1997;145:558-66.
The clinical implications of human infection 2. Sweeney CJ, Ghassemi M, Agger WA, Persing DH.
with DTV are not known. Powassan encephali- Coinfection with Babesia microti and Borrelia
tis, however, often follows a severe clinical burgdorferi in a western Wisconsin resident. Mayo Clin
course, with a 10.5% case-fatality rate and severe Proc 1998;73:338-41.
3. Tsai TF, Bailey RE, Moore PS. National surveillance of
sequelae (hemiplegia, wasting, severe head- Lyme disease, 1987-1988. Conn Med 1989;53:324-6.
aches) in 47.1% of survivors (9). The genetic 4. Dryer RF, Goellner PG, Carney AS. Lyme arthritis in
distance (Figure 2) between DTV and POW Wisconsin. JAMA 1979;241:498-9.
isolates is roughly similar to the difference 5. Telford SR III, Armstrong PM, Katavolos P, Foppa I,
between eastern TBE isolates (Russian spring- Olmeda Garcia AS, Wilson ML, et al. A new tick-borne
encephalitis-like virus infecting New England deer
summer encephalitis) and Omsk hemorrhagic ticks, Ixodes dammini. Emerg Infect Dis 1997;3:165-70.
fever, viruses with radically different clinical

Vol. 5, No. 4, July–August 1999 573 Emerging Infectious Diseases

 Dispatches

6. Mather TN, Piesman J, Spielman A. Absence of 12. Zanotto PM, Gould EA, Gao GF, Harvey PH, Holmes
spirochaetes (Borrelia burgdorferi) and piroplasms EC. Population dynamics of flaviviruses revealed by
(Babesia microti) in deer ticks (Ixodes dammini) molecular phylogenies [see comments]. Proc Natl Acad
parasitized by chalcid wasps (Hunterellus hookeri). Sci U S A 1996;93:548-53.
Med Vet Entomol 1987;1:3-8. 13. Mandl CW, Holzmann H, Kunz C, Heinz FX. Complete
7. Dumler JS, Bakken JS. Human granulocytic ehrlichiosis genomic sequence of Powassan virus: evaluation of
in Wisconsin and Minnesota: a frequent infection with the genetic elements in tick-borne versus mosquito-borne
potential for persistence. J Infect Dis 1996;173:1027-30. flaviviruses. Virology 1993;194:173-84.
8. Herwaldt BL, Springs FE, Roberts PP, Eberhard ML, 14. Gresikova M, Calisher C. Tick-borne encephalitis. In:
Case K, Persing DH, et al. Babesiosis in Wisconsin: a Monath T, editor. The arboviruses: epidemiology and
potentially fatal disease. Am J Trop Med Hyg ecology. Boca Raton (FL): CRC Press; 1989. p. 177-202.
1995;53:146-51. 15. Calisher C, Karabatsos N, Dalrymple J, Shope RE,
9. Artsob H. Powassan encephalitis. In: Monath T, editor. The Porterfield JS, Westaway EG, et al. Antigenic
arboviruses. Boca Raton (FL): CRC Press; 1989. p. 29-49. relationships between flaviviruses as determined by
10. Kumar S, Tamura K, Nei M. MEGA: Molecular cross-neutralization tests with polyclonal antisera. J
evolutionary genetics analysis. University Park (PA): Gen Virol 1989;70:37-43.
The Pennsylvania State University; 1993. p. 16802. 16. Monroe MC, Morzunov SP, Johnson AM, Bowen MD,
11. Zanotto PM, Gao GF, Gritsun T, Marin Ms, Jiang WR, Artsob H, Yates T, et al. Genetic diversity and
Venugopal K, et al. An arbovirus cline across the distribution of Peromyscus-borne hantaviruses in
northern hemisphere. Virology 1995;210:152-9. North America. Emerg Infect Dis 1999;5:75-86

Emerging Infectious Diseases 574 Vol. 5, No. 4, July–August 1999

 Dispatches

Dengue Reemergence in Argentina

G. Avilés,* G. Rangeón,† V. Vorndam,‡ A. Briones,§ P. Baroni,*
D. Enria,* and M.S. Sabattini*
*Instituto Nacional de Enfermedades Virales Humanas (INEVH) “Dr. J.I.
Maiztegui”, Administración Nacional de Laboratorios e Institutos de Salud
“Dr. C. Malbrán”, Pergamino, Argentina; †Ministerio de Salud, Salta,
Argentina; ‡Centers for Disease Control and Prevention, San Juan, Puerto
Rico; and §Delegación Sanitaria Federal, Salta, Argentina

Aedes aegypti, eradicated from Argentina in 1963, has now reinfested the
country as far south as Buenos Aires. In 1997, four persons with travel histories to
Brazil, Ecuador, or Venezuela had confirmed dengue, and surveillance for
indigenous transmission allowed the detection of 19 dengue cases in Salta
Province. These cases of dengue are the first in Argentina since 1916 and
represent a new southern extension of dengue virus.

Dengue History in Argentina aegypti was considered eradicated from the

Several cases of dengue fever were reported country (1), but in 1986 the National Ministry of
in Argentina at the beginning of this century. Health reported reinfestation in the north (2).
Indigenous cases were reported in 1905, 1911, The reinfested area is the area that was infested
and 1916 in northern Argentina (Chaco, in 1955, including Salta Province. Buenos Aires
Corrientes, Formosa, and Misiones Provinces) Province was reinfested in 1991 and the Federal
(1). In February and March 1916, an epidemic District in 1995 (2,3). In autumn 1997, high
with 15,000 reported cases occurred in Entre infestation levels (35% in 1996 and 18% in 1997)
Rios Province along the Uruguay and Paraná were found in houses in Buenos Aires Province
Rivers in eastern Argentina. None of these and the Federal District (3). In Villa María,
patients had hemorrhagic symptoms. Since this Córdoba Province (32 degrees south), Ae. aegypti
epidemic, no indigenous cases had been reported was found in summer (February) of 1995,
until 1997 (1). disappeared in winter, and reappeared in early

Aedes aegypti
In 1955, when the Aedes aegypti eradication
campaign began in Argentina, an estimated
1,500,000-km2 area was infested (Figure 1) (1).
Santiago del Estero Province had the highest
infestation rate, with Ae. aegypti found in 9.4% of
localities and 5.3% of houses. This province is
characterized by a warm summer and low
socioeconomic conditions, with many houses
lacking running water (1). The southern
extension of Ae. aegypti distribution was 35
degrees south, the latitude of Buenos Aires (1).
Buenos Aires was only minimally affected, with
only 6 of 199,172 houses infested. By 1963, Ae.

Address for correspondence: G. Avilés, Instituto Nacional de

Enfermedades Virales Humanas “Dr. Julio I. Maiztegui”,
Monteagudo 2510 (2700) Pergamino, Argentina; fax: 54-24- Figure 1. Geographic distribution of Aedes aegypti,
774-33045; e-mail: Gaby@inevh.sld.ar. 1955: Dengue risk area in Argentina.

Vol. 5, No. 4, July–August 1999 575 Emerging Infectious Diseases

 Dispatches

summer (December 1995) (4). The mosquito was

also found in Buenos Aires Province (Zárate and
Campana, 34.2 degrees and 34.4 degrees south,
respectively) in February 1996 and October 1996
(early spring) (Avilés G, unpublished data).
These findings indicate that Ae. aegypti may
spend winter in refuges in temperate areas and
may not necessarily be reintroduced during
summer.
The presence of Ae. aegypti in most of the
country and the reappearance of dengue fever in
neighboring countries (Brazil, Paraguay, and
Bolivia) increases the risk for dengue infection in
Argentina. The Instituto Nacional de
Enfermedades Virales Humanas “Dr. J.I.
Maiztegui” is the National Reference Center of
Dengue Diagnosis. This article summarizes the Figure 2. Surveillance for dengue virus infections in
first dengue cases diagnosed in Argentina in Salta Province: Localities with cases.
recent years and documents the southernmost
expansion of dengue in South America.
also conducted in Tartagal. Median tempera-
The Study tures in northern localities (Tartagal and Orán)
DEN 1 HAW, DEN 2 NGC, DEN 3 H87, and are 26°C in summer and 19°C in winter. In Salta
DEN 4 H241 strains were obtained from the city the median temperatures are 22°C in
Centers for Disease Control Laboratory, San summer and 15°C in winter.
Juan, Puerto Rico. Plaque reduction neutraliza-
tion tests (PRNTs) were performed as described Study Participants
by Russel et al. (5), with an 80% plaque reduction Blood samples were collected at regional
endpoint. The enzyme-linked immunosorbent hospitals from patients seeking treatment for
assay (ELISA) capture IgM test was done as any illness.
described by Innis et al. (6) and Kuno et al. (7).
Polymerase chain reaction (PCR) was done Surveillance of Imported Cases
according to the protocol of Lanciotti et al. (8). During the epidemiologic surveillance of the
The isolation attempts and immunofluorescence cases compatible with dengue, from January to
tests were done by injecting sera into C6/36 cells November 1997 our laboratory received 16
and using monoclonal antibodies against each of samples from returning travelers who had
the serotypes (9). suspected dengue (Table 1). Sera of four
patients, returning from Brazil, Ecuador, and
Study Area Venezuela, were positive by IgM-capture-
Salta Province is located in northwestern ELISA. Cases from Ecuador and Venezuela
Argentina (Figure 2) in the subtropical area were positive by PRNT, but the serotype could
between 22° and 26°, 30 minutes south. A not be determined because of cross-reactions,
serosurvey was done in Orán, Salvador Mazza, possibly indicating secondary flavivirus
and Guemes (Figure 2). Active surveillance was infections.

Table 1. Imported dengue cases-Argentina, 1997

Patient Travel Onset of Plaque reduction neutralization tests
no. history symptoms MAC-ELISA D1 D2 D3 D4
1 Brazil 02/14/97 Pos --- --- --- ---
2 Ecuador unknown/97 Pos 1,280 1,280 80 <20
3 Venezuela 11/16/97 Pos --- --- --- ---
4 Venezuela unknown/97 Pos >1,280 >1,280 >1,280 >1,280
---Not done

Emerging Infectious Diseases 576 Vol. 5, No. 4, July–August 1999

 Dispatches

Surveillance of Cases in Salta Province Epidemiologic and Clinical Data

A total of 404 sera were studied from Orán, We obtained epidemiologic and clinical
Salvador Mazza, Santa Victoria, Tartagal, information from nine patients. One, a man from
General Mosconi, Salta city, Junta del San Salvador Mazza, had fever, retroocular pain,
Antonio, Aguaray, and Guemes during April malaise, muscle pain, and arthralgias and had
through November 1997. Nineteen serologi- traveled to Santa Cruz de la Sierra, Bolivia,
cally positive samples were detected from four before onset of symptoms. Seven other patients
of these locations (Orán, Salvador Mazza, reported symptoms including headache, muscle
Tartagal, and Guemes) (Table 2). Twelve pain, abdominal pain, arthralgias, rash, pharyn-
samples were positive by MAC-ELISA, indicat- gitis, and epistaxis. No hemorrhagic manifesta-
ing current or recent infections, and three of tions were reported. Six of these patients
these had PRNT titers indicating primary reported no travel history and must have become
DEN 2 infections. Three other samples had infected in Orán or Tartagal. Travel histories
cross-reactive antibody patterns indicative of were not available from the other two patients.
secondary flavivirus infections. Seven other
samples were immunoglobulin (Ig)M negative, Conclusions
but positive by PRNT. Three of these showed Laboratory results show that imported cases
PRNT titers indicating DEN 2 infections. Six of dengue arrived in Argentina during 1997,
additional samples were positive by PRNT, but enabling local transmission in cities like Rosario
the serotype could not be determined. Virus and Buenos Aires. In northern Argentina, there
isolation attempts on 36 acute-phase samples is continuous traffic with Bolivia, Paraguay, and
had negative results, but one sample was Brazil, where dengue is known to occur. We
diagnosed as dengue 2 by reverse tran- report early evidence of DEN 2 virus circulating
scriptase-PCR. in northern Argentina, where indigenous cases

Table 2. Surveillance for dengue virus infections, Salta Province, Argentina

positive/ ELISA PRNT
Locality* tested Onset IgM D1 D2 D3 D4
Orán 6/161 -- Pos 20 320 80 <20
-- Neg 80 80 160 20
04/22/97** -- <20 80 <20 <20
04/28/97 -- 20 >160 20 40
05/16/97 Pos 640 1,280 640 80
11/16/97 Pos -- -- -- --
Salvador 7/113 -- Pos <20 20 <20 <20
Mazza -- Pos <20 80 20 <20
-- Pos 160 >640 >640 20
-- Neg <20 80 40 <20
-- Neg -- 80 80 20
-- Neg 20 40 -- <20
-- Pos <20 <20 <20 <20
Tartagal 3/7 08/30/97 Pos 80 >160 >160 <20
10/26/97 Pos <20 160 <20 <20
11/23/97 Pos 640 >1,280 640 40
Guemes 1/100 -- Neg <20 40 <20 <20
Unknown 2/6 -- Pos <20 <20 <20 <20
Pos 40 >160 80 <20
*Samples from the following localities were negative by IgM capture -enzyme-linked immunosorbent assay: Santa Victoria (2),
General Mosconi (2), Salta city (11), Junta del San Antonio (1) and Aguaray (1).
**An acute-phase sample from this case was positive for DEN 2 by RT-PCR.

Vol. 5, No. 4, July–August 1999 577 Emerging Infectious Diseases

 Dispatches

have occurred in Orán, Tartagal, Guemes, and References

Salvador Mazza. These cities are generally 1. Sabattini MS, Avilés G, Monath TP. Historical,
located along a highway going north into Bolivia, epidemiological and ecological aspects of arboviruses in
Argentina: Flaviviridae, Bunyaviridae and
where DEN is endemic. Clinically, all cases were
Rhabdoviridae. In: An overview of arbovirology in
classic dengue fever. High PRNT antibody titers Brazil and neighboring countries. Travassos da Rosa
in the acute-phase samples indicated that APA, Vasconcelos PFC, Travassos da Rosa JFS, editors.
dengue or other flavivirus infections had Belem, Brazil: Instituto Evandro Chagas; 1998. p. 113-
probably been present but had gone undetected. 34.
2. Boffi R. Programa de prevención del dengue y control
Only sporadic cases were found in the area under
del Aedes aegypti. In: Temas de zoonosis y
active surveillance, as in Texas in 1995 when enfermedades emergentes. 2do Congreso Argentino de
isolated cases of indigenous transmission were Zoonosis, 1er Congreso Argentino y Latinoamericano
detected (10). de Enfermedades Emergentes y Asociación Argentina
The reestablishment of dengue in Argentina de Zoonosis, editors. 1998;413-419, Buenos Aires.
3. Schweigmann N, Boffi R. Aedes aegypti y Aedes
is of concern because of the following risk factors
albopictus: situación entomológica en la región. In:
(11): 1) the presence of Ae. aegypti vector in high Temas de zoonosis y enfermedades emergentes. 2do
densities in several places (3); 2) the low levels of Congreso Argentino de Zoonosis, 1er Congreso
immunity in the human population in all areas Argentino y Latinoamericano de Enfermedades
that have been studied (1); 3) endemic virus in Emergentes y Asociación Argentina de Zoonosis (eds.)
1998;259-263, Buenos Aires.
neighboring countries (12); and 4) the wide-
4. Avilés G, Cecchini R, Harrington ME, Cichero J, Asis R,
spread presence of substandard living condi- Rios C. Aedes aegypti in Córdoba Province, Argentina. J
tions, including the lack of running water, in Am Mosq Control Assoc 1997;13:255-8.
areas where the virus is most likely to be 5. Russel PK, Nisalak A, Sukhavachana P, Vivona S. A
introduced. Air conditioning is uncommon plaque reduction test for dengue virus neutralizing
antibodies. J Immunol 1967;99:291-6.
throughout the country, and the climate is
6. Innis BL, Nisalak A, Nimmannitya S, Kusalerdchariya
subtropical in the north and temperate in the S, Chongwasdi V, Suntayakorn S, et al. An enzyme-
central region, where conditions are suitable for linked immunosorbent assay to characterize dengue
dengue transmission in summer. Surveillance infections where dengue and Japanese encephalitis co-
should be continued and expanded in the most circulate. Am J Trop Med Hyg 1989;40:418-27.
7. Kuno G, Gómez I, Gubler DJ. An ELISA procedure for
susceptible areas to monitor introduction and
the diagnosis of dengue infections. J Virol Methods
spread of this reemerging disease. 1991;33:101-13.
8. Lanciotti RS, Calisher CH, Gubler DJ, Chang GJ,
Acknowledgments Vorndam AV. Rapid detection and typing of dengue
The authors thank Robert Shope and Elsa Segura for viruses from clinical samples by using reverse
revising this manuscript; Liliana Canini, Nora M. Mellano, transcriptase-polymerase chain reaction. J Clin
Milton Bejarano, José A. Rodriguez, Silvia Gonzalez Ayala, Microbiol 1992;30:545-51.
and Roque Brun, who attended patients and provided 9. Gubler DJ, Kuno G, Sather GE, Velez M, Oliver A.
samples; and Cristina C. Bono and Maria Luisa Cacase, who Mosquito cell cultures and specific monoclonal
also provided samples. antibodies in surveillance for dengue viruses. Am J
Trop Med Hyg 1984;33:158-65.
Dr. Avilés is a biologist in charge of the Arbovirus 10. Centers for Disease Control and Prevention. Dengue
Laboratory, National Reference Center of Dengue Di- fever at the U.S.—Mexico border, 1995-1996. MMWR
agnosis, Collaborative Center PAHO/WHO, Instituto Morb Mortal Wkly Rep 1996;45:841-4.
Nacional de Enfermedades Virales Humanas “Dr. J.I. 11. Gubler DJ. Dengue. In: The arboviruses: epidemiology
Maiztegui”-Administracion Nacional de Laboratorios and ecology. Monath TP, editor. II. Boca Raton, FL:
e Institutos de Salud, Pergamino, Argentina. Her ar- CRC Press; 1988. p. 223-60.
eas of expertise are arbovirology and medical ento- 12. Pan American Health Organization. Dengue and
mology (mosquitoes). Her research interests include dengue hemorrhagic fever in the Americas: guidelines
arboviruses (in humans and vertebrates), DEN, YF, for prevention and control. Washington, D.C. 1994;
Scientific publication No. 548.
WEE, EEE, VEE, and the competence of mosquitoes
as vectors for arboviruses.

Emerging Infectious Diseases 578 Vol. 5, No. 4, July–August 1999

 Dispatches

Chlorine Disinfection of Recreational

Water for Cryptosporidium parvum
Colleen Carpenter,* Ronald Fayer,*
James Trout,* and Michael J. Beach†
*U.S. Department of Agriculture, Beltsville, Maryland, USA; and
†Centers for Disease Control and Prevention, Atlanta, Georgia, USA

We examined the effects of chlorine on oocyst viability, under the conditions of

controlled pH and elevated calcium concentrations required for most community
swimming pools. We found that fecal material may alter the Ct values (chlorine
concentration in mg/L, multiplied by time in minutes) needed to disinfect swimming
pools or other recreational water for Cryptosporidium parvum.

The small size of the Cryptosporidium C. parvum oocysts, and therefore on pool water
parvum oocyst (4-6 µm) and its resistance to quality and the potential for disease transmission.
many chemical disinfectants (e.g., chlorine) pose
a challenge for standard filtration and disinfec- Study Design
tion procedures (1). Moreover, the low dose Oocysts of the AUCP-1 isolate were extracted
required for infection and the prolonged from the feces of experimentally infected calves
excretion of high numbers of oocysts make and cleaned of fecal debris with cesium chloride
C. parvum ideal for waterborne transmission. (32). The short exposure to cesium chloride
Chlorinated recreational water facilities, such as followed by thorough rinsing with deionized
public swimming pools and water parks water has no deleterious effects on the oocyst
frequently used by large numbers of diapered wall or oocyst survival. Oocysts cleaned by this
children, have been implicated in numerous method appear free from all organic fecal debris
outbreaks of cryptosporidiosis during the last and other microorganisms and thus are
decade (Table 1). potentially more susceptible to disinfectants
Previous studies of chlorine inactivation of than are oocysts surrounded by debris. Oocysts
oocysts have used oxidant demand-free water were stored at 4°C until use and were less than
and glassware or chlorine demand-free reactors 1 month old when used.
(1,24-31); none were performed in simulated Two experiments were conducted to deter-
recreational water (i.e., pH balanced, CaCl2 mine how long oocysts would remain infectious
added for hardness, organic material added). when exposed to two concentrations of chlorine
Therefore, Ct values (chlorine concentration in at two temperatures. Stock solutions of 2.0 ppm
mg/L multiplied by time in minutes) calculated and 10.0 ppm HOCl in demineralized water
under oxidant demand-free laboratory condi- (resistance measured 18 mega-ohm) were
tions for disinfection of microorganisms such as prepared with commercial laundry bleach
Cryptosporidium may not be directly applicable (CLOROX). Chlorine concentrations were moni-
to recreational water environments where tored with a digital chlorine colorimeter kit
additional organic material, such as urine, feces, (LaMotte model no. DC 1100, Chestertown, MD).
hair, sweat, sloughed cells, and lotion, is present, In experiment 1, one centrifuge tube (15 ml
pH is controlled, and calcium concentration is polypropylene, screw-top Falcon, Becton
elevated. We report that under recreational Dickinson, Franklin Lakes, NJ) was prepared
water conditions fecal material alone has a large containing 1 x 106 oocysts for each of the 28
negative effect on chlorine inactivation of temperature and time combinations. Tubes were
Address for correspondence: R. Fayer, USDA, ARS, LPSI,
centrifuged at 1,500 g for 15 minutes;
10300 Baltimore Avenue, Bldg 1040, Beltsville, MD 20705, supernatants were decanted, and oocyst pellets
USA; fax: 301-504-5306; e-mail: rfayer@lpsi.barc.usda.gov. were resuspended in 12 ml of stock chlorine

Vol. 5, No. 4, July–August 1999 579 Emerging Infectious Diseases

 Dispatches

Table 1. Outbreaks of cryptosporidiosis in recreational water facilities

No. of cases
estimated/ Date
Facility Location Disinfectant confirmed) (year) Ref.
Pool Doncaster, UK Chlorine a/79 1988 2
Pool Los Angeles County Chlorine 44/5 1988 3
Pool British Columbia Chlorine 66/23 1990 4
Pool Gloucestershire, UK Ozone/chlorine a/13 1992 5
Water slide Idaho Chlorine 500/a 1992 6
Pool (wave) Oregon Chlorine a /52 1992 7
Pool (motel) Wisconsin Chlorine 51/22 1993 8,9
Pool (motel) Wisconsin Chlorine 64/b 1993 9
Pool Wisconsin Chlorine 5/b 1993 9
Pool Wisconsin Chlorine 54/b 1993 9
Pool (motel) Missouri Chlorine 101/26 1994 10
Lake New Jersey None 2,070/46 1994 11
Pool Sutherland, New South Wales Chlorine a/70 1994 12
Pool Kansas a 101/26 1995 13
Water park Georgia Chlorine 2,470/62 1995 13
Water park Nebraska a a/14 1995 13
Pool Florida a 22/16 1996 14c
Water park California Chlorine 3,000/29 1996 13,15c
Pool Andover, UK Chlorine 8/a 1996 16
Lake Indiana None 3/a 1996 13
River NW England & Wales None 27/7 1997 17c
Pool SW England & Wales Ozone & chlorine a/9 1997 17c
Fountain Minnesota Sand filter 369/73 1997 18
Three pools Canberra, Australia a a/210 1998 19c,20c
Pool Oregon a 51/8 1998 21c
Pools Queensland a 129/a 1997 21c
Pools New South Wales a 370/a 1998 22c
Pools Hutt Valley, New Zealand a a/171 1998 23c
aNo data available.
bReference did not identify cases as estimated or confirmed.
cReference is not peer reviewed and may not reflect a rigorous investigation of the outbreak.

solution. Tubes were then placed in controlled were counted with a hemacytometer to verify
temperature water circulators (model 9101; dosage levels. Individual oocysts were counted in
Polyscience, Inc., Niles, IL) and incubated at the clumps of 2 to 4 oocysts observed on days 5
20oC or 30oC. For all mice to be the same age at through 7. Mice were euthanized by CO2
the time of infection, tubes were prepared on 7 overexposure 96 hours after intubation. To
successive days and placed in the water assess infectivity, hematoxylin- and eosin-
circulators so that all incubations ended and all stained histologic sections of ileum from each
mice were inoculated on the same day (Table 2). mouse were examined by brightfield microscopy
Because of the small volume in each tube, it for developmental stages of C. parvum (24).
was not possible to monitor the chlorine Because the results from experiment 1
concentration daily. Therefore, readings were indicated a need to examine shorter times of
taken initially and after incubation, immediately oocyst exposure to chlorine, a second experi-
before the mice were inoculated. Upon removal ment was conducted in which oocysts were
from the water circulators, all tubes were tested for viability after exposure to chlori-
centrifuged at 1,500 g for 15 minutes, nated water for 6, 12, 24, 48, and 72 hours
supernatant was aspirated, and pelleted oocysts (Table 2). To simulate actual pool conditions
were resuspended in 1 ml of demineralized (33), chlorinated water was balanced between
water. Oocysts in each tube were then pH 7.2 and 7.8, and CaCl 2 was added to a
administered orally to four neonatal BALB/c concentration of 200 ppm to 400 ppm.
mice by gastric intubation. Each mouse received To simulate a swimming pool fecal incident
150,000 oocysts. Oocysts remaining in each tube and thereby test the effectiveness of chlorine on

Emerging Infectious Diseases 580 Vol. 5, No. 4, July–August 1999

 Dispatches

Table 2. Contact times and infectivity for purified Crytosporidium parvum oocysts subjected to chlorination
(Experiments 1 and 2)a
2 ppm 10 ppm
Ctb Infectivity Ctb Infectivity
Expt. Days (min.) value 20ºC 30ºC value 20ºC 30ºC
2 (360) 720 4/4 4/4 3,600 4/4 0/4
2 (720) 1,440 4/4 3/4 7,200 0/4 0/4
1 1 (1440) 2,880 4/4c 0/4 14,400 0/4 0/4
2 1 (1440) 2,880 4/4 0/4 14,400 0/4 0/4
1 2 (2880) 5,760 0/4 0/4 28,800 0/4 0/4
2 2 (2880) 5,760 0/4 0/4 28,800 0/4 0/4
1 3 (4320) 8,640 4/4 0/4 43,200 0/4 0/4
2 3 (4320) 8,640 0/4 0/4 43,200 0/4 3/4
1 4 (5760) 11,520 0/4 0/4 57,600 0/4 0/4
1 5 (7200) 14,400 0/4 0/4 72,000 0/4 0/4
1 6 (8640) 17,280 0/4 0/4 86,400 0/4 0/4
1 7 (10,080) 20,160 0/4 0/4 100,800 0/4 0/4
aTreatments in which mice were found infected are shown in bold.
bHypothetical Ct value calculated by assuming constant chlorine concentration.
cFraction represents number of mice showing developmental stages of C. parvum in the intestinal epithelium over the total

number of mice inoculated, e.g., 4/4 indicates 4 mice were found infected out of 4 mice inoculated.

oocysts in the presence of organic material, three dispersed feces, dialysis tubing (SPECTRUM
aquariums were each filled with 30 L of tap water Medical Industries, Inc., Los Angeles, CA) with a
balanced to meet standard pool regulations (33). molecular weight cutoff of 6,000 to 8,000 was
The pH was maintained by adding NaOH or HCl, used to contain the oocysts and fecal mixture.
and the calcium level was maintained by adding Fecal material came from a calf that tested
CaCl2. In one aquarium, sufficient chlorine was negative for C. parvum. Feces were mixed with
added to achieve and maintain 2.0 ppm, a normal water to form a diarrhea-like consistency. To
pool concentration. In another aquarium used to ensure the recovery of sufficient oocysts for later
represent a response to water contamination, bioassay in mice, 2 x 106 oocysts in 20 mg of the
chlorine was maintained at 10 ppm. In the third fecal slurry were introduced into the dialysis
aquarium, calcium and pH were held at standard tubing and then filled with water from the
pool conditions, but no chlorine was added. The appropriate aquarium. Time points of 0, 6, 12, 24,
aquariums were maintained at room temperature and 48 hours of exposure were tested. Therefore,
and were covered with a glass plate to prevent additional dialysis tubing containing oocysts and
evaporation. Chlorine, pH, and calcium values fecal material was added to each aquarium at
were monitored 4 times a day between 8:00 a.m. specified intervals, and all were removed at the
and 4:30 p.m. and adjusted to target levels when end of the incubation time. Oocysts were
necessary. aspirated from the dialysis tubing, they were
Calculations for simulating a pool fecal concentrated by centrifugation (1,500 g, 15
accident in an aquarium were based on a minutes), and 150,000 were intubated into each
700,000-L swimming pool and an infected person of 3 to 5 neonatal BALB/c mice as before.
excreting approximately 500 g of fecal material Necropsy of mice and assessment for infectivity
into the water (490,000 mg feces per 700,000 L were performed as in the previous experiment.
pool = 0.7 mg/L; 0.7 mg/L x 30/L aquarium = 20
mg feces). The estimated ratio of fecal mass to Findings
water volume necessarily correlates with large In the first experiment, oocysts maintained
contamination to maintain a ratio based on the at 20°C in 2 ppm chlorine for 1 and 3 days were
small size of the aquarium and the need for a infectious for mice. Oocysts maintained at higher
sufficient quantity of feces and oocysts for temperatures or chlorine concentrations were
testing. The number of oocysts added was based not infectious for mice (Table 2).
on laboratory experience for recovery of oocysts In the second experiment, oocysts main-
from numerous 5-g fecal samples of bovine feces. tained at 20°C in 2 ppm chlorine remained
To simulate a loose fecal mass but not fully infectious after exposure of 6 to 24 hours (Table

Vol. 5, No. 4, July–August 1999 581 Emerging Infectious Diseases

 Dispatches

2). At 20°C and 10 ppm chlorine, oocysts exposed oocysts in experiment 2 infected 3 of 4 mice after
for 6 hours infected mice, whereas those exposed exposure to 10 ppm chlorine at 30°C for 72 hours
longer did not. At 30°C and 2 ppm chlorine, but not for shorter periods underscores the
oocysts exposed for 6 hours infected all mice, difficulty of performing these experiments. Such
those exposed for 12 hours infected 3 of 4 mice, findings may be explained by the stickiness of
and those exposed longer were not infectious. At the oocyst surface, which leads to clumping that
30°C and 10 ppm chlorine, oocysts held for 6, 12, can result in nonuniform sampling or possibly
24, and 48 hours did not initiate infection; protection from inactivation. However, these
however, those held for 72 hours were infectious outlying datapoints in experiments 1 and 2 are
for 3 of 4 mice. inconsistent with total oocyst inactivation
In the third experiment, tissues from all mice observed in the shorter incubation times under
inoculated with the oocysts exposed to all the same conditions. It is unclear whether a few
incubation time points at 0, 2, or 10 ppm chlorine oocysts survived the exposure period or whether
were found to contain developmental stages of the infections were experimental artifacts.
the parasite in the intestinal epithelium. These Environmental contamination of the mouse
findings indicated that oocysts in the presence of colony used for the bioassays is unlikely because
fecal material remained infectious even after no mice from the negative control litter used for
exposure to 10 ppm chlorine for 48 hours. this study or from >1,000 previous negative
control mice used in this laboratory had
Conclusions developed a C. parvum infection. These data
Swimming is the second most popular suggest that disinfection of C. parvum, in the
recreational activity in the United States, with absence of feces or other organic contaminants,
more than 350 million persons participating each may be less difficult than thought, particularly
year (34). The emergence of C. parvum as a major at the higher temperatures found in chlorinated
cause of recreational waterborne disease has recreational venues.
prompted public health workers to reevaluate In contrast to experiment 2, in which fecal
existing recommendations and regulations for matter was absent, oocysts in experiment 3 were
water quality and use. Frequent fecal contami- incubated under identical water and chlorine
nation of recreational water and the high level of conditions but in the presence of feces (i.e., a
C. parvum oocyst resistance to chlorine, the low simulated fecal accident) and remained infec-
oocyst dose required for infection, and high tious at all time points through 48 hours.
numbers of bathers make it imperative that we Because this simulated accident was contained
understand how oocyst inactivation is affected in a dialysis bag rather than being dispersed, it
by recreational water conditions, including fecal may not represent the best model for a dispersed
contamination. diarrheal accident. Containment of oocysts with
In our first experiment, to become noninfec- the organic material may actually have afforded
tious, purified C. parvum oocysts in chlorine some protection from inactivation. This high-
demand-free deionized water required exposure lights our incomplete understanding of C. parvum
to chlorine at a Ct value higher than 8,640. This inactivation and the detrimental effect that
value is relatively close to that obtained for organic or fecal contamination can play in
disinfection under similar chlorine demand-free recreational water.
conditions (Ct = 7,200-9,600) (28). Purified Although the fecal accident simulated here
C. parvum oocysts in chlorine demand-free water could be considered major, the decrease in
balanced to meet swimming pool standards effective chlorine action is probably a conserva-
(experiment 2) required even less time to be tive measure for recreational water since the
rendered noninfectious, i.e., exposure to 2 ppm simulation did not include additional biologic
chlorine for 2 days at 20°C or 1 day at 30°C. contaminants found in recreational water (i.e.,
Incubation in 10 ppm chlorine rendered oocysts sweat, hair, skin cells, lotion, urine, and algae).
noninfectious in 6 hours or less at both Because oocysts attach readily to biologic
temperatures, respectively. particles (35), such particles may provide a
The findings that oocysts in experiment 1 protective surrounding. The retarded inactiva-
were infectious when exposed to 2 ppm at 20oC tion of an already chlorine-resistant organism
for 1 and 3 days but not for 2 days and that suggests that the current recommendation (36)

Emerging Infectious Diseases 582 Vol. 5, No. 4, July–August 1999

 Dispatches

for responding to fecal accidents (20 mg chlorine/ 5. Hunt DA, Sebugwawo S, Edmondson SG, Casemore
L for 9 hours to achieve a Ct value of 10,800) DP. Cryptosporidiosis associated with a swimming pool
complex. Commun Dis Rep CDR Rev 1994;4:R20-2.
needs to be tested under appropriate conditions
6. Moore AC, Herwaldt BL, Craun GF, Calderon RL,
of water quality (33) in the presence of fecal and Highsmith AK, Juranek DD. Surveillance for waterborne
organic contaminants (both as tested here or disease outbreaks—United States, 1991-1992. MMWR
dispersed in a pool) and revised as necessary. Morb Mortal Wkly Rep 1993;42(SS-5):1-22.
Routine use of recreational venues by 7. McAnulty JM, Fleming DW, Gonzalez AH. A
community-wide outbreak of cryptosporidiosis
diapered children from day-care facilities, who
associated with swimming at a wave pool. JAMA
have an elevated prevalence of C. parvum 1994;272:1597-600.
infection, increases the potential for waterborne 8. MacKenzie WR, Kazmierczak JJ, Davis JP. An
disease transmission. Prevention plans that outbreak of cryptosporidiosis associated with a resort
combine engineering changes (improved filtra- swimming pool. Epidemiol Infect 1995;115:545-53.
9. Kramer MH, Herwaldt BL, Craun GF, Calderon RL,
tion and turnover rates, separate plumbing and
Juranek DD. Waterborne disease: 1993 and 1994. J Am
filtration for high-risk “kiddie” pools), pool policy Water Works Assoc 1996;88:66-80.
modifications (fecal accident response policies, 10. Wilberschied L. A swimming-pool-associated outbreak
test efficacy of barrier garments such as swim of cryptosporidiosis. Kansas Medicine 1995;96:67-8.
diapers), and patron and staff education should 11. Kramer M, Sorhage F, Goldstein S, Dalley E, Wahlquist
S, Herwaldt B. First reported outbreak in the United
reduce the risk for waterborne disease transmis-
States of cryptosporidiosis associated with a recreational
sion in public recreational water venues. lake. Clin Infect Dis 1998;26:27-33.
Education efforts should stress current knowl- 12. Lemmon JM, McAnulty JM, Bawden-Smith J.
edge about waterborne disease transmission and Outbreak of cryptosporidiosis linked to an indoor
suggest simple prevention measures such as swimming pool. Med J Aust 1996;165:613-6.
13. Levy DA, Bens MS, Craun GF, Calderon RL, Herwaldt
refraining from pool use during a current or
BL. Surveillance for waterborne disease outbreaks-
recent diarrheal episode, not swallowing United States, 1995-1996. MMWR Morb Mortal Wkly
recreational water, using proper diaper chang- Rep 1998;47(SS-5):1-34.
ing and handwashing practices, instituting 14. Past water-related outbreaks in Florida. Crypto
frequent timed bathroom breaks for younger Capsule 1998;3:3.
children, and promoting a shower before pool use 15. Effects of last summer’s outbreak on Wild Water
Adventure’s theme park. Crypto Capsule 1997;2:1-3.
to remove fecal residue. 16. Sundkvist T, Dryden M, Gabb R, Soltanpor N,
Casemore D, Stuart J, et al. Outbreaks of
Ms. Carpenter is a graduate student at Virginia
cryptosporidiosis associated with a swimming pool in
Commonwealth University’s Center for Environmen- Andover. Commun Dis Rep 1997;7:R190-2.
tal Studies. She is studying amoebae in Asian freshwa- 17. Outbreaks in England and Wales: first half of 1997.
ter clams as biologic indicators of runoff from combined Crypto Capsule 1998;3:4.
sewer outfalls into the James River. Ms. Carpenter’s 18. Outbreak of cryptosporidiosis associated with a water
interests include the epidemiology of foodborne and sprinkler fountain-Minnesota, 1997. MMWR Morb
waterborne parasitic protozoa. Mortal Wkly Rep 1998;47:856-60.
19. Swimming pools implicated in Australia’s largest
cryptosporidiosis outbreak ever reported. Crypto
References Capsule 1998;3:1-2.
1. Fayer R, Speer CA, Dubey JP. The general biology of 20. Number of cryptosporidiosis cases increase in
Cryptosporidium. In: Cryptosporidium and Australia. Crypto Capsule 1998;3:1-2.
cryptosporidiosis. Fayer R, editor. Boca Raton (FL): 21. Most cases in Australia linked to swimming pool
CRC Press; 1997. p. 1-41. exposure. Crypto Capsule 1998;3(7):5-6.
2. Joce RE, Bruce J, Kiely D, Noah ND, Dempster WB, 22. Recreational outbreak in Oregon. Crypto Capsule
Stalker R, et al. An outbreak of cryptosporidiosis 1998;4(1):1.
associated with a swimming pool. Epidemiol Infect 23. New Zealand’s pool related outbreak is over. Crypto
1991;107:497-508. Capsule 1998;3(9)5-6.
3. Sorvillo FJ, Fujioka K, Nahlen B, Tormey MP, 24. Fayer R. Effect of sodium hypochlorite exposure on
Kebabjian RS, Mascola L. Swimming-associated infectivity of Cryptosporidium parvum oocysts for
cryptosporidiosis. Am J Public Health 1992;82:742-4. neonatal BALB/c mice. Appl Environ Microbiol
4. Bell A, Guasparini R, Meeds D, Mathias RG, Farley JD. 1995;61:844-6.
A swimming pool-associated outbreak of 25. Finch GR, Black EK, Gyurek LL. Ozone and chlorine
cryptosporidiosis in British Columbia. Canadian J inactivation of Cryptosporidium. Proceedings of the
Public Health 1993;84:334-7. AWWA Water Quality Technical Conference, San
Francisco, CA 1994; 1303-8.

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26. Venczel LV, Arrowood M, Hurd M, Sobsey MD. 31. Campbell I, Tzipori S, Hutchison G, Angus KW. Effect
Inactivation of Cryptosporidium parvum oocysts and of disinfectants on survival of Cryptosporidium oocysts.
Clostridium perfringens spores by a mixed-oxidant Vet Rec 1982;111:414-15.
disinfectant and by free chlorine. Appl Environ 32. Kilani RT, Sekla L. Purification of Cryptosporidium
Microbiol 1997;63:1598-601. oocysts and sporozoites by cesium chloride and percoll
27. Gyurek LL, Finch GR, Belosevic M. Modeling chlorine gradients. Am J Trop Med Hyg 1987;36:505-8.
inactivation requirements of Cryptosporidium parvum 33. ANSI/NSPI 1 Standards for public swimming pools. In:
oocysts. J Environ Eng 1997;123:865-75. Pool and spa water chemistry. Taylor Technologies,
28. Korich DG, Mead JR, Madore MS, Sinclair NA, Sterling Inc., Sparks, MD. 1994. p. 40.
CA. Effects of ozone, chlorine dioxide, chlorine, and 34. U.S. Bureau of the Census, Statistical Abstract of the
monochloramine on Cryprosporidium parvum oocyst United States: 1995. 115th ed. Washington: The
viability. Appl Environ Mirobiol 1990;56:1423-7. Bureau; 1995. p. 260.
29. Parker JFW, Smith HV. Destruction of oocysts of 35. Medema GJ, Schets FM, Yeunis PFM, Havelaar AH.
Cryptosporidium parvum by sand and chlorine. Water Sedimentation of free and attached Cryptosporidium
Res 1993;27:729-31. oocysts and Giardia cysts in water. Appl Environ
30. Pavlasek I. Effect of disinfectants in infectiousness of Microbiol 1998;64:4460-6.
oocysts of Cryptosporidium sp. Cs Epidemiol 1984;33:97- 36. Kebabjian RS. Disinfection of public pools and
101.1. management of fecal accidents. J Environ Health
1995;58:8-12.

Emerging Infectious Diseases 584 Vol. 5, No. 4, July–August 1999

 Dispatches

Cyclospora cayetanensis Among

Expatriate and Indigenous Populations of
West Java, Indonesia
David J. Fryauff,* Reinhard Krippner,† Purnomo Prodjodipuro,*
Christa Ewald,† Shirley Kawengian,‡ Katrin Pegelow,§
Thomas Yun,¶ Claudia von Heydwolff-Wehnert,‡
Buhari Oyofo,* and Rainer Gross#
*U.S. Naval Medical Research Unit No. 2, Jakarta, Indonesia; †Embassy of
the Federal Republic of Germany, Jakarta, Indonesia; ‡University of
Indonesia, Jakarta, Indonesia; §SEAMEO-TROPMED Regional Center for
Community Nutrition, Jakarta, Indonesia; ¶Embassy of the United States of
America, Jakarta, Indonesia; #Deutsche Gesellschaft für Technische
Zusammenarbeit (GTZ) GmbH, Eschborn, Germany

From January 1995 through July 1998, we investigated the occurrence of

Cyclospora cayetanensis infection associated with gastrointestinal illness or diarrhea in
foreign residents and natives of West Java, Indonesia. We found that C. cayetanensis
was the main protozoal cause of gastrointestinal illness and diarrhea in adult foreign
residents during the wet season. The parasite rarely caused illness in the indigenous
population or in children.

Cyclospora cayetanensis is a newly recog- center for an estimated 300 European expatri-
nized coccidian parasite associated with sudden ates, screened for ova and parasites in cases of
onset of gastrointestinal illness and chronic gastrointestinal illness and diarrhea from
diarrhea. In developing countries, cases occur January 1995 through July 1998. The Parasitol-
sporadically, in a seasonal pattern, and ogy Department of the U.S. Naval Medical
primarily among western expatriates and Research Unit No. 2 (NAMRU-2) provided
travelers (1,2). diagnostic services for U.S. military staff and
We recently reported multiple symptomatic their families living in Jakarta during January
cases of C. cayetanensis infection among 1996 to January 1998. The U.S. Embassy Medical
European expatriates living in Jakarta, Indone- Unit in Jakarta performed diagnostic parasitic
sia; C. cayetanensis and Giardia lamblia were tests for approximately 500 U.S. expatriate
the intestinal parasites most frequently identi- residents from January to December 1998.
fied (6.4%) in cases of gastroenteritis or chronic All three laboratories performed wet-mount
diarrhea (3). We report here the results of a microscopy of fresh and formalin-ethyl acetate-
longitudinal evaluation of Cyclospora infection concentrated feces stained with dilute iodine or
among expatriate populations of Jakarta and the merthiolate-iodine-formalin solution. All speci-
results of two recent surveys of intestinal mens were from persons with self-reported cases
parasite infections in Indonesian children. of gastrointestinal illness and diarrhea who
Three clinical diagnostic laboratories, each sought medical attention. Confirmation of
serving subpopulations of expatriate residents of Cyclospora was based primarily on size and
Jakarta, Indonesia, participated in the longitudi- morphologic features relative to reference slides
nal evaluation. The medical unit of the Embassy of provided by J.H. Cross, Uniformed Service
the Federal Republic of Germany, a diagnostic University of Health Sciences, Washington,
Address for correspondence: David J. Fryauff, U.S. NAMRU-2, D.C., and secondarily on acid-fast staining
Box 3, APO AP 96520-8132; fax: 62-21-424-4507; e-mail: characteristics. The NAMRU-2 laboratory also
fryauff@smtp.namru2.go.id. routinely applied a modified, 22 mm x 40 mm

Vol. 5, No. 4, July–August 1999 585 Emerging Infectious Diseases

 Dispatches

Kato thick-smear technique to estimate parasite/ 1998 (Table). C. cayetanensis was the most
ova density. Analyses were limited to autochtho- frequently identified pathogenic intestinal
nous cases by evaluating patient histories and parasite each year, accounting for 8.6% to 15.1%
excluding those that were probably acquired of the annual diagnoses. All but one of these
outside Indonesia. cases were in adults (30 years of age or older).
All 8- to 10-year-old Indonesian children Cases were clustered during the wet season
attending 10 public schools in rural Sukaraja (November–May), suggesting a seasonality of
District, West Java, Indonesia, were examined risk (Figure).
for parasites and ova during December 1995. The second Jakarta-based laboratory that
Direct wet-mount microscopy and modified Kato performed parasitologic screening on predomi-
thick-smear examination of a fresh fecal specimen nantly American families identified
were performed. Two independent examinations C. cayetanensis in 9 (9.1%) of 99 persons with
were performed on each sample by clinical gastrointestinal illness or diarrhea who sought
parasitologists. After informed parental consent, care during a 24-month period. Cyclospora
a subsample of 83 children was enrolled into a oocyst counts per gram of feces from these
prospective study to monitor episodes of diarrhea symptomatic C. cayetanensis cases were 100 to
following mebendazole de-worming. Stool samples 327,600/gm; the highest counts were associated
were collected weekly or during gastrointestinal with early onset and acute symptoms. All nine
illness or diarrhea over 13 consecutive weeks of C. cayetanensis cases were in adults.
posttreatment observation (March to June The U.S. Embassy Health Unit in Jakarta
1996). Specimens were screened for parasites identified 28 C. cayetanensis infections among
and ova as described above. 206 patients (13.6%) with gastrointestinal illness
A hospital-based study to determine the or diarrhea who were examined during an
causes of diarrhea among Indonesian residents 11-month period in 1998. Pediatric infections,
of Jakarta was initiated in July 1997 as a seen only in teenagers, accounted for 2 of the 28
collaborative study between the Departments of cases. An apparent association was found
Microbiology and Parasitology, the Health between expatriates’ risk for infection and the
Research Branch of the Indonesian Ministry of cooler wet season (October-May) (Figure).
Health, and several participating Jakarta A well population of 348 Indonesian
hospitals. A single stool sample was collected for schoolchildren was screened for intestinal
testing from study participants who reported to parasite infections. The prevalence of intestinal
the clinic with diarrhea lasting >72 hours. helminth and protozoan infections among the
Preliminary analysis for parasitic causes children was 84% and 77%, respectively.
associated with diarrhea was done in cases of Asymptomatic, low-density C. cayetanensis
children < 3 years old who were screened during infections were found in 2 (0.6%) children.
the first 12 months (July 1997 to June 1998) of A prospective study of 83 of these children
this 3-year study. was performed for 1,006 weeks of follow-up
C. cayetanensis was the dominant patho- (average 12.2 weeks per child). Single or multiple
genic intestinal parasite, present in 29 (11.5%) of samples of loose or watery stool (230 per 1,006
253 cases of gastrointestinal illness and diarrhea total samples) were collected from 71 of the 83
among European expatriates who sought children. Although generally well and attending
medical care during January 1995 to January school, 26 (31.3%) of these 71 children had loose
Table. Parasites associated with self-reported gastrointestinal illness or diarrhea, German Embassy Health Unit,
Jakarta, Indonesia
Entamoeba
Cyclospora histolytica/ Giardia Trichuris Ascaris Blastocystis
No. cayetanensis E. dispar lamblia trichiura lumbricoides hominis
Year examined No. (%) No. (%) No. (%) No. (%) No. (%) No. (%)
1995 104 9 (8.6) 8 (7.7) 4 (3.8) 5 (4.8) 1 (1.0) 23 (22.1)
1996 96 12 (12.5) 4 (4.2) 2 (2.1) 2 (2.1) 0 10 (10.4)
1997 53a 8 (15.1) 4 (7.5) 1 (1.9) 2 (3.8) 1 (1.9) 5 (9.4)
Total 253 29 (11.5) 16 (6.3) 7 (2.8) 9 (3.5) 2 (0.8) 38 (15)
aNo laboratory diagnoses were performed during June and July 1997.

Emerging Infectious Diseases 586 Vol. 5, No. 4, July–August 1999

 Dispatches

for parasites; 170 (64.6%) of these were

children younger than 3 years of age (ave. =
10.9 months, SD = 7.5 months). No Cyclospora
infections were found.
The relatively sudden appearance, since
1995, of C. cayetanensis infections among long-
term expatriate residents of Jakarta may
indicate either a new ability of local diagnostic
laboratories to recognize an established parasite
or new establishment of this pathogen in the
urban environment of Indonesia. Recent parasi-
tologic surveys conducted throughout Indonesia
may not have been undertaken with sufficient
sensitivity to detect C. cayetanensis and may
have been conducted during periods of low
transmission.
The high frequency with which C.
cayetanensis infections were found in expatriate
patients cannot be attributed to new staining or
concentration methods. Three laboratories ap-
plied direct wet-mount microscopy to identify
this agent, and each laboratory independently
classified C. cayetanensis as the dominant
pathogenic parasite associated with diarrhea.
Despite moderately enhanced recovery of
C. cayetanensis oocysts by formalin-ethyl acetate
sedimentation, virtually all diagnoses were made
from the initial findings of the direct wet-mount
or the modified Kato thick smear and were not
dependent on the concentration step.
Cyclospora infections were identified in the
cross-sectional prevalence survey and the
prospective study of rural schoolchildren but not
in the diarrhea specimens from Jakarta infants
during the year-long study. Unlike the
C. cayetanensis infections among foreign
residents of Jakarta, infections by this parasite
in rural Indonesian children were rare and
characterized by low parasite density, absence of
symptoms, and sporadic appearance.
These disparate findings suggest various
Figure. Monthly profiles of Cyclospora infection possibilities: 1) The absence of Cyclospora
among gastrointestinal illness/diarrhea cases at infection in young children with diarrhea, both
private health laboratories serving expatriate expatriate and native Indonesian, may result
populations of Jakarta, Indonesia. from their lack of exposure to foods or other risk
factors to which older children and adults are
or watery stools at least four times during follow- exposed. Additionally, Indonesian infants may be
up. Low-density C. cayetanensis infections were protected by maternally acquired passive
identified in two (2.4%) children, for an immunity. 2) Fecal contamination of food and
incidence of two infections per 19.3 person- water in rural Indonesia may be sufficiently high
years. that local children, by the age of 8 to 10 years,
In the first year of the 3-year Jakarta have effective clinical and parasitologic immu-
diarrhea study, 263 Indonesians were screened nity to Cyclospora and other pathogens. Infection

Vol. 5, No. 4, July–August 1999 587 Emerging Infectious Diseases

 Dispatches

of Indonesian children by other enteric Acknowledgments

pathogens may confer cross-protective immu- The authors thank Aftab Ansari for critical review of the
manuscript. They also thank Wolfgang Benkel, Regional
nity. 3) Urban transmission of Cyclospora may Medical Officer of the German Embassy, Jakarta, Indonesia;
predominate among expatriate residents of Carol Francis, Registered Medical Technologist, American
Jakarta because of their atypical food prefer- Embassy, Jakarta, Indonesia; and collaborating investigators
ences (imported, varied, fresh fruit and of the Health Research Branch of the Indonesian Ministry of
Health (LITBANGKES), Harapan Kita, Sumber Waras, and
vegetables, restaurant-prepared) and prepara- Persahabatan Public Hospitals of Jakarta, Indonesia, for
tions (prepared by servants, frequent use of raw their contributions. This work was conducted in accordance
garnish and salads). with U.S. Navy and Republic of Indonesia regulations
The paucity of Cyclospora infections associ- governing the protection of human subjects in medical
research.
ated with loose stool or diarrhea in the rural and
urban Indonesian children may not be atypical Portions of this work were supported by U.S. Naval
for these age groups. Among children of Bangkok Medical Research and Development Command work unit
(#5) who were screened for diarrheal causes number 623002A.
during 1985 to 1986, Cryptosporidium was the Dr. Fryauff heads the Parasitic Disease Program of the
only protozoon associated with illness (4). If U.S. Navy Medical Research Unit No. 2 in Jakarta, In-
Cyclospora was also present in this population donesia. His principal research interest is in malaria:
but classified as Cryptosporidium spp., these drug trials for prevention and treatment, monitoring
organisms collectively accounted for only 1.8% of drug resistance, evaluating rapid diagnostics, and im-
cases and 0.3% of controls. munologic and epidemiologic studies.
Among nearly 900 Jakarta expatriates of all
ages, we saw relatively few pediatric cases of References
Cyclospora and suspect that infections in this 1. Ortega YR, Sterling CR, Gilman RH, Cama VA, Diaz F.
age group may also go undetected. Our methods Cyclospora species—a new protozoan pathogen of
humans. N Engl J Med 1993;328:1308-12.
may not have been sufficiently sensitive to detect 2. Mintz ED, Long EG. CLB: an emerging infectious cause
mild infections of Cyclospora in highly suscep- of chronic diarrhea. CDC/NCID report. Infect Dis Clin
tible young persons or in asymptomatic older Pract 1994;3:315-20.
persons who have been sensitized, even without 3. Fryauff DJ, Krippner R, Purnomo, Ewald C, Echeverria
prior exposure to C. cayetanensis, by repeated P. Case report of Cyclospora infection acquired in
Indonesia and treated with cotrimoxazole. Am J Trop
new contact and long-term maintenance of other Med Hyg 1996;55:584-5.
commensal and pathogenic parasite infections. 4. Echeverria P, Taylor DN, Lexsomboon U, Bhaibulaya
Despite the likelihood that pathogenic M, Blacklow NR, Tamura K, et al. Case-control study of
bacterial and viral agents are the principal endemic diarrheal disease in Thai children. J Infect Dis
causes of gastrointestinal illness and diarrhea 1989;159:543-8.
5. Subekti D, Lesmana M, Komalarini S, Tjaniadi P, Burr D,
among native and expatriate residents of Pazzaglia G. Enterotoxigenic Escherichia coli and other
Indonesia (5,6), our results clearly identify causes of infectious pediatric diarrheas in Jakarta,
C. cayetanensis as commonly associated with Indonesia. SE Asian J Trop Med Pub Hlth 1993;24:420-4.
these health problems. 6. Richie E, Punjabi NH, Corwin A, Lesmana M, Rogayah
I, Lebron C, et al. Enterotoxigenic Escherichia coli
diarrhea among young children in Jakarta, Indonesia.
Am J Trop Med Hyg 1997;57:85-90.

Emerging Infectious Diseases 588 Vol. 5, No. 4, July–August 1999

 Dispatches

The First Major Outbreak of Dengue

Hemorrhagic Fever in Delhi, India
L. Dar, S. Broor, S. Sengupta, I. Xess, and P. Seth
All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

An outbreak of dengue hemorrhagic fever/dengue shock syndrome (DHS/DSS)

occurred in 1996 in India in and near Delhi. The cause was confirmed as dengue virus
type 2, by virus cultivation and indirect immunofluorescence with type-specific
monoclonal antibodies. This is the largest such outbreak reported from India, indicating
a serious resurgence of dengue virus infection.

An outbreak of dengue hemorrhagic fever/ Medical Sciences from patients with suspected
dengue shock syndrome (DHF/DSS) occurred in dengue fever or denguelike illness from Delhi
Delhi, India, and its adjoining areas, from and its adjoining areas, along with a profile of the
August through November 1996. We confirmed culture-confirmed cases.
the etiologic agent of this outbreak as dengue Virus isolation was carried out on 149
virus type 2 by virus cultivation and indirect samples received on ice from patients with acute
immunofluorescence with type-specific mono- illness. Serum was separated aseptically and
clonal antibodies. This is the largest culture- stored at -70o C. The standard method of virus
confirmed outbreak of DHF/DSS in India and cultivation, which used the C6/36 clone of Aedes
indicates a serious resurgence of dengue virus albopictus cell line, was followed with some
infection in this country. modifications (10).
Dengue fever occurs worldwide, in nearly all On days 5 and 10, cells were tested by
tropical and subtropical countries (1). Dengue indirect immunofluorescence assay (IFA) by
virus was first isolated in India in 1945 (2). All using monoclonal antibodies to dengue virus
four virus types circulate and cause epidemics, types 1-4. If IFA was negative for dengue viruses
but only occasional cases of DHF/DSS have been on first passage, a second passage was made, and
reported in India (3). cells were again harvested on days 5 and 10 for
Delhi, situated in the northern part of IFA. All four dengue virus types (from the
India, had outbreaks of dengue virus infection National Institute of Virology, Pune, India) were
due to different dengue virus types in 1967, included as positive controls, and uninfected
1970, 1982, and 1988, but no culture-confirmed C6/36 cells were kept as negative controls.
cases of DHF/DSS were reported during these Dengue viruses were isolated in C6/36 cells
epidemics (4-7). Some cases of DHF were seen from 27 (18.1%) of 149 samples processed for
for the first time in 1988 (7). These were virus isolation. Of the 27 isolates, 26 were
confirmed only serologically, by the hemagglu- identified as dengue virus type 2 and one as
tination inhibition test. dengue virus type 1. Sixteen of the 27 isolates
Delhi had its largest outbreak of DHF/DSS in were from patients with DHF/DSS, while 11
1996. The outbreak started the last week of were isolated from patients with uncomplicated
August and continued until the end of dengue fever. Of the 27 culture-positive patients,
November, peaking in mid-October (8,9). A total 11 (40.7%) were in the 5- to 12-year age group
of 8,900 cases were reported, with a death rate of (Table). However, the isolates were nearly
4.2% (9). We report results of virologic testing of equally distributed among children (<12 years)
samples received at the All India Institute of and adults. The ratio of male to female in these
27 cases was 12:15. The median duration of fever
Address for correspondence: Shobha Broor, Department of
Microbiology, All India Institute of Medical Sciences, Ansari
at the time of viral isolation was 4 days, on the
Nagar, New Delhi-110 029, India; fax: 91-11-686-2663; e-mail: basis of 24 culture-positive cases for which the
broor@hotmail.com. duration of fever was available. After 5 days of

Vol. 5, No. 4, July–August 1999 589 Emerging Infectious Diseases

 Dispatches

Dr. Dar is associate professor in the virology sec-

Table. Age distribution of patients with culture-positive
tion of the Department of Microbiology at the All India
dengue
Institute of Medical Sciences, New Delhi, India. His in-
Age (years) No. of cases terests include diagnostic virology, viral immunology, and
0-1 2 tuberculosis.
>1-5 1
>5-12 11
>12-20 7
References
>20-30 4 1. Thongcharoen P, Jatanasen S. Dengue haemorrhagic fever
and dengue shock syndrome—introduction, historical and
>30 2
epidemiological background. In: Thongcharoen P, compiler.
Monograph on dengue haemorrhagic fever. WHO,
fever, virus isolation was possible only from one Regional Office for South-East Asia; 1993. p. 1-8.
2. Sabin AB. Research on dengue during World War II. Am
patient. The median duration of viremia in
J Trop Med Hyg 1952;1:30-50.
dengue type 2 infection was also found to be 3. Rao CVRM. Dengue fever in India. Indian J Pediatr
4 days in a detailed study on dengue viremia 1987;54:11-4.
from Jakarta, Indonesia (11). Testing for 4. Balaya S, Paul SD, D’Lima LV, Pavri KM.
immunoglobulin (Ig) M antibodies to dengue Investigations on an outbreak of dengue in Delhi in
1967. Indian J Med Res 1969;57:767-74.
virus was performed on 270 serum samples by
5. Diesh P, Pattanayak S, Singha P, Arora DD, Mathur
MAC-ELISA according to a standard protocol PS, Ghosh TK, et al. An outbreak of dengue fever in
(12). Of 270 sera tested for antibodies to dengue Delhi—1970. J Commun Dis 1972;4:13-8.
virus by MAC-ELISA, 140 (51.9%) showed anti- 6. Rao CVRM, Bagchi SK, Pinto BD, Ilkal MA, Bharadwaj
dengue IgM antibodies. All samples from M, Shaikh BH, et al. The 1982 epidemic of dengue fever
in Delhi. Indian J Med Res 1985;82:271-5.
patients with a duration of fever ≥ 5 days were
7. Kabra SK, Verma IC, Arora NK, Jain Y, Kalra V.
tested for anti-dengue IgM antibodies. In some Dengue haemorrhagic fever in children in Delhi. Bull
samples, antibodies could be detected as early as WHO 1992;70:105-8.
the fifth day of fever. Three of the culture- 8. Broor S, Dar L, Sengupta S, Chakraborty M, Wali JP,
positive acute-phase samples were also positive Biswas A, et al. Recent dengue epidemic in Delhi, India.
In: Saluzzo JE, Dodet B, editors. Factors in the
by MAC-ELISA.
emergence of arbovirus diseases. Paris: Elsevier; 1997.
Analysis of the outbreaks of dengue virus p. 123-7.
infection in Delhi indicates a seasonal trend. All 9. Sharma PL, Sood OP, editors. Round table conference
outbreaks (including the one reported here) series—dengue outbreak in Delhi: 1996. Gurgaon,
occurred during the monsoon (rainy) season India: Ranbaxy Science Foundation; 1996.
10. Gubler DJ, Kuno G, Sather GE, Valez M, Oliver A.
(August to November) and subsided with the
Mosquito cell and specific monoclonal antibodies in
onset of winter. Dengue virus types 1, 2, and 3 surveillance for dengue viruses. Am J Trop Med Hyg
have been isolated during dengue fever 1984;33:158-65.
outbreaks (without DHF/DSS) in Delhi. Sero- 11. Gubler DJ, Suharyono W, Tan R, Abidin M, Sie A.
logic studies have also shown that dengue Viraemia in patients with naturally acquired dengue
infection. Bull WHO 1981;59:623-30.
infection has been endemic in this region (13).
12. Monath TP, Nystrom RR, Bailey RE, Calisher CH,
During the 1996 outbreak of DHF/DSS, we were Muth DJ. Immunoglobulin M antibody capture enzyme
able to identify dengue virus type 2 as the linked immunosorbent assay for the diagnosis of St
etiologic agent. This is the first culture- Louis encephalitis. J Clin Microbiol 1984;20:784-90.
confirmed outbreak of DHF/DSS from Delhi and 13. Mathew T, Nayar M, Gupta JP, Suri NK, Bhola SR,
Ghosh TK, et al. Serological investigations on arbovirus
its adjoining areas and the largest reported
activity in and around Delhi—a five year study. Indian
outbreak of DHF/DSS from India. J Med Res 1979;69:557-66.

Acknowledgments
We thank Duane J. Gubler for supplying diagnostic
reagents and protocols for our work and the director,
National Institute of Virology, Pune, India, for providing
known strains of all dengue virus types. We also thank Milan
Chakraborty and Raj Kumar for excellent technical support.

Emerging Infectious Diseases 590 Vol. 5, No. 4, July–August 1999

 Commentary

Addressing the Potential Threat of systems; and insufficient training of physicians,

Bioterrorism—Value Added to an epidemiologists, and laboratorians. The deficien-
Improved Public Health Infrastructure cies may be more pressing in certain disease
areas than in others. Some diseases that are
The use of biological weapons was banned in considered bioterrorist threats, such as anthrax
1972 by the Convention on the Prohibition of the and plague, are no longer important public
Deployment, Production, and Stockpiling of health problems in most industrialized nations,
Bacteriological and Toxin Weapons (1). Caches of so the capabilities and capacities for responding
biological weapons still exist, however, and their to outbreaks of these diseases may be at historic
illegal use in military operations cannot be lows. These deficiencies in response capacity can
discounted entirely (2). be traced to the 1960s and 1970s, when
The threat of biological warfare seems complacency began to erode essential compo-
remote to industrialized nations, which have nents of the public health infrastructure. Since
enjoyed decades of peace and prosperity. In the early 1970s, at least 25 previously unknown
contrast, the threat of bioterrorism, in which pathogenic agents and diseases have been
biological agents are used by extremists as identified, and in recent years mounting
weapons against civilian populations, generates resistance to antimicrobial agents has con-
considerable anxiety. Although the likelihood of founded the treatment of many illnesses (3).
a bioterrorist attack is difficult to predict, the A strategic plan for reducing the conse-
consequences of a successful attack could be quences of new and reemerging infectious
devastating and cannot be ignored. Unlike diseases (4) proposes corrective measures for
attacks involving conventional or even chemical addressing the infrastructure deficiencies:
weapons, which could be readily detected and instituting better surveillance systems, improv-
limited to a specific geographic area, an attack ing diagnostic techniques, developing new
with a biological agent (and the resulting vaccines and drugs, and conducting research and
symptoms of exposed persons) could remain providing training in several areas. The
undetected for days, would be widely scattered, measures needed to prevent and control
and depending on the etiologic agent, might not emerging infections are strikingly similar to
be identified immediately as a manmade event. those needed to check the threat of bioterrorism.
Secondary cases would confound epidemiologic Improving capabilities and capacities for
investigations as well. responding to one issue will almost certainly
Regardless of the source, surveillance of benefit the other. For example, developing rapid
infectious diseases, detection and investigation diagnostic techniques that would make it
of outbreaks, identification of etiologic agents possible to quickly detect bioterrorist attacks
and their modes of transmission, and the involving anthrax, plague, or Q fever would have
development of prevention and control strategies considerable usefulness in the routine clinical
are responsibilities of public health agencies. diagnosis of pneumonia. Distribution systems
Acquiring and sustaining the capability for an set up to deliver antimicrobial agents and
adequate response to bioterrorism requires vaccines after bioterrorist attacks would be
thoughtful analysis and carefully integrated indispensable in delivering antiviral compounds
planning by these agencies, as well as law and influenza vaccine during a large pandemic.
enforcement officials, emergency response phy- Surveillance and communication systems are
sicians and other first responders, the military, fundamental components of an adequate public
and others. New partnerships will need to be health infrastructure, so an electronic, inte-
forged and old ones strengthened. grated surveillance system based on standard
Preliminary assessments of our nation’s architecture and vocabulary would serve all
capabilities for responding to possible bioterrorist needs.
attacks have identified many deficiencies. From A value-added approach to infrastructure
the public health perspective, these deficiencies development is not a new concept in public
include inadequate surveillance systems; lack of health. In 1951, at the beginning of the cold war,
rapid diagnostic techniques; insufficient stock- the Epidemic Intelligence Service (EIS) was
piles and distribution systems of antimicrobial founded at the Center for Disease Control (CDC)
agents and vaccines; inefficient communication (5,6). The EIS concept originated with Joseph W.

Vol. 5, No. 4, July–August 1999 591 Emerging Infectious Diseases

 Commentary

Mountin, founder of CDC, and was implemented public health system for detecting and respond-
by Alexander D. Langmuir. Noting the “dearth of ing to this threat. Also as in 1951, we have an
trained epidemiologists,” Langmuir proposed opportunity to ensure that improvements made
training a corps of young physicians that could in response to the threat of bioterrorism have
“investigate outbreaks of disease in strategic multiple uses and can be applied to other public
areas.” He also noted, “A broader but equally health emergencies. Planning efforts to date
pressing need is to make available competent have adopted this viewpoint. Developing a
epidemiologists to assist in the planning and separate infrastructure for responding to acts of
organization of the total civil defense program at bioterrorism would be poor use of scarce
all levels.” Langmuir also observed that while resources, particularly if this infrastructure is
“this dearth exists even in peacetime, defense never used. “Value added” should be the
needs exaggerate this deficiency.” watchwords of the current initiative.
In 1951, 22 young physicians and one
sanitary engineer signed on as EIS Officers at Joseph E. McDade
CDC, where they received several weeks of Centers for Disease Control and Prevention,
instruction in epidemiology, biostatistics, and Atlanta, Georgia, USA
public health administration and then served for
2 years as field epidemiologists, either at CDC or References
in state health departments. EIS has been in 1. Smart JK. History of chemical and biological warfare:
operation since then, and as the purview of CDC an American perspective. In: Medical aspects of
chemical and biological warfare. Sidell FR, Takafuji ET,
expanded beyond infectious diseases, so have the
Franz DR, editors. Washington: Office of the Surgeon
size and composition of EIS and the training of General; 1997. p. 9-86.
EIS Officers. Surveillance, outbreak investiga- 2. Zilinskas RA. Iraq’s biological weapons: the past as
tions, and research on the epidemiology of new future? JAMA 1997;278:418-24.
diseases remain standard activities, however. 3. McDade JE. Global infectious disease: surveillance and
response. Australian Journal of Medical Science
EIS has rarely had occasion to investigate
1997;18:2-9.
outbreaks caused by the intentional release of 4. Centers for Disease Control and Prevention. Preventing
microorganisms (7,8). However, as Langmuir emerging infectious diseases: a strategy for the 21st
predicted in 1951, the program has increased century. Atlanta: U.S. Department of Health and
public health preparedness and made important Human Services; 1998.
5. Langmuir AD, Andrews JM. Biological warfare
contributions to the control of communicable
defense. 2. the Epidemic Intelligence Service of the
diseases. EIS now has more than 2,000 alumni, Communicable Disease Center. Am J Public Hlth
including nearly 200 scientists from abroad. 1952;42:235-8.
Many alumni have moved on to distinguished 6. Thacker SB, Goodman RA, Dicker RC. Training and
careers in academia, industry, and clinical service in public health practice, 1951-90—CDC’s
Epidemic Intelligence Service. Public Health Rep
practice, but many others have filled key
1990;105:599-604.
positions at federal and state public health 7. Török TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow
agencies. Trained to consider diseases as R, Mauvais S, et al. A large community outbreak of
problems of populations, EIS alumni remain a salmonellosis caused by intentional contamination of
valuable resource when disease outbreaks occur. restaurant salad bars. JAMA 1997;278:389-95.
8. Kloavic SA, Kimura A, Simons SL, Slutsker L, Barth S,
As in 1951, civil defense, and particularly the
Haley CE. An outbreak of Shigella dysenteriae Type 2
use of biological agents against civilian among laboratory workers due to intentional food
populations, is of utmost concern. Efforts are contamination. JAMA 1997;278:396-8.
under way to improve the capabilities of the

Emerging Infectious Diseases 592 Vol. 5, No. 4, July–August 1999

 Letters

Current Status of Smallpox Vaccine tions is 0.6 ml per kg of body weight. This volume
is sufficient to treat adverse reactions in
To the Editor: The possible use of smallpox virus approximately 675 adults. Further, the entire
as a weapon by terrorists has stimulated growing stockpile of VIG has been placed on hold while
international concern and led to a recent review the cause of a slight pink discoloration is
by the World Health Organization of the global investigated. Until the cause of the discoloration
availability of smallpox vaccine. This review is determined or another approved supply of VIG
found approximately 60 million doses worldwide, is obtained, no vaccinia vaccine is being released.
with little current vaccine manufacture, al- While unknown, the rate of adverse reactions in
though limited vaccine seed remains available (1). today’s population is likely to be greater than
Ongoing discussions in the United States seen during the global eradication campaign
suggest that the national stockpile should because of recent increases in the number of
contain at least 40 million doses to be held in immunocompromised persons. The Department
reserve for emergency use, including in case of a of Defense has recently contracted the process-
terrorist release of smallpox virus (O’Toole, this ing of new lots of VIG (to be administered
issue, pp. 540-6). intravenously rather than by the intramuscular
The current U.S. stockpile contains approxi- route like existing VIG stocks); however,
mately 15.4 million doses of vaccinia vaccine maintaining adequate stocks of VIG will remain
(Dryvax) made from the New York City Board of a challenge.
Health strain of vaccinia and was produced by In the event of release of smallpox virus,
Wyeth Laboratories in 13 separate lots. The persons at high risk and persons exposed but not
vaccine is lyophylized in glass vials with rubber yet showing clinical illness would be vaccinated
stoppers and sealed with a metal band. When immediately. Intensive case detection and
rehydrated, each vial contains 100 doses and has vaccination of contacts and other persons at risk
a potency of at least 108 plaque-forming units would follow. All vaccine, including lots retained
(pfu)/ml. Some vials of the vaccine stockpile have after failed quality control tests, would be made
shown elevated moisture levels and thus failed available for emergency use. Previous studies
routine quality control testing; however, the have found that more than 90% of susceptible
vaccine in these vials remains potent, and the persons respond to vaccinia virus with a titer of
failed lots have not been discarded. 107 pocks/ml (2). In an emergency, consideration
The diluent used to rehydrate the vaccine would be given to diluting the existing vaccine as
contains brilliant green, which makes the much as 10-fold, so that each vial could
vaccine easier to visualize when administered conceivably contain 1,000 doses of vaccine,
with bifurcated needles. Over time, the brilliant rather than the current 100 doses. The present
green has deteriorated, and most of the available vaccine container is sufficiently large to
diluent does not pass quality control. Discussions accommodate the added diluent. The absence of
are under way with Wyeth to begin production of sufficient quantities of VIG to protect against
sufficient new diluent for the entire stockpile. adverse reactions during a mass immunization
The vaccine is administered by superficial campaign would necessitate careful screening of
inoculation (scarification) with a bifurcated those receiving the vaccine; some persons with
needle. Fewer than 1 million bifurcated needles adverse reactions would likely go untreated.
are held as part of the stockpile. As with the While the intentional release of smallpox
diluent, Wyeth has been requested to produce virus would represent a global emergency, the
additional bifurcated needles. existing national stockpile could be effectively
Vaccinia virus produces adverse reactions in used to limit the spread of disease and buy time
a small percentage of vaccinated persons. while the pharmaceutical industry begins
Adverse reactions are treated with vaccinia emergency vaccine production.
immune globulin (VIG), currently only available
James W. LeDuc and John Becher
from Baxter Healthcare Corporation (5,400 vials
Centers for Disease Control and Prevention, Atlanta,
of VIG in stock). Each vial contains 5 ml of VIG; Georgia, USA
the recommended dose for postvaccine complica-

Vol. 5, No. 4, July–August 1999 593 Emerging Infectious Diseases

 Letters

References 50% PFU reduction was regarded as the titer.

1. World Health Organization. Report of the meeting of Antibodies neutralizing West Nile virus were
the ad hoc committee on Orthopox virus infections. detected in 13 (2.1%) persons: 2.8% of 179 male
Department of Communicable Disease Surveillance
and 1.8% of 440 female. Persons with detectable
and Response. WHO, 14-15 January 1999.
2. Cockburn WC, Cross RM, Downie AW, Dumbell KR, West Nile virus antibody were questioned about
Kaplan C, Mclean D, et al. Laboratory and vaccination their health history during the previous 5 years,
studies with dried smallpox vaccines. Bull World and their medical records were reviewed; none
Health Organ 1957;16:63-77. recalled having had tickborne encephalitis
(Central-European encephalitis [CEE] virus is
the only other flavivirus present in Czechland) or
West Nile Fever in Czechland having been vaccinated against CEE or yellow
fever virus. Titers of PRN antibodies to CEEV
To the Editor: After heavy rains in July 1997, were all below 16. Two of the seropositive
extensive floods occurred along the Morava persons had traveled abroad during the last 5
River, Czech Republic. Populations of Aedes years: one to Croatia in 1996, and one to South
mosquitoes increased rapidly in the flooded Australia during 1951 to 1994.
areas, prompting surveillance for mosquito- Paired serum samples were obtained from 72
borne virus infections in the Breclav area, South of the 619 persons examined. A significant
Moravia. We collected 11,334 female mosquitoes increase (≥4 times) in antibody titer against West
(9,100 Aedes vexans, 917 Ae. cinereus, 11 Nile virus between the first (acute-phase) and
Ae. cantans, 1,074 Ae. sticticus, and 232 Culex p. second (convalescent-phase) samples was de-
pipiens) from July through September 1997 and tected four times: in 2 of 41 young persons (≤16
tested them for virus in 117 monospecific pools years of age) and in 2 of 31 adults (>16 years of
by intracranial inoculation of suckling mice. age). Among the four seroconverting persons,
Seven virus isolates were obtained and identified only the two children had clinical symptoms
by complement-fixation and neutralization tests. compatible with West Nile fever. A 9-year-old
Six isolates (five from Ae. vexans, one from Ae. boy had fever (39oC) for 4 days, sore throat,
cinereus) were identified as the bunyavirus headache, muscle ache, pronounced fatigue, and
Tahyna, California serogroup, and one (strain nausea lasting approximately 6 days, with
97-103 from 57 C. p. pipiens collected at Lanzhot, recovery after 13 days. Neutralizing antibodies
48o40'N, 16o56'E, on September 17) was to West Nile virus, Eg-101 and 97-103, were 64
identified as the flavivirus West Nile (1). A and 32 on July 22 and 512 and 256 on August 4,
crossed comparison of 97-103 and topotype Eg- respectively. A 9-year-old girl had fever (38°C-
101 (2) West Nile virus strains and their antisera 39°C) for 3 days, sore throat, headache, muscle
(prepared in mice by three intraperitoneal doses ache, pronounced fatigue, nausea, vomiting,
at weekly intervals) by plaque reduction maculopapular rash (including flushed face),
neutralization (PRN) on XTC-2 cells (3,4) showed and slightly enlarged inguinal lymph nodes. The
their antigenic relationships: reciprocal titers of illness lasted approximately 7 days, with
homologous/heterologous sera were 512/512 in complete recovery after 17 days. Neutralizing
Eg-101 and 512/64 in 97-103. Strain 97-103 has antibodies to West Nile virus, Eg-101 and 97-103,
lower virulence than Eg-101 in that it does not were 64 and 32 on August 6 and 256 and 128 on
kill adult ICR mice and may represent a subtype August 20, respectively. Of the remaining nine
of West Nile virus. seropositive persons lacking paired serum
Blood samples were obtained from 619 samples, one had severe headache, muscle ache,
persons seeking treatment at hospital and prolonged fatigue, nausea, pain on eye move-
outpatient clinics in the Breclav area from June ment, maculopapular rash, and insomnia in
23 through September 29, 1997. Sera were summer of 1997. Two other persons had had
inactivated at 56°C for 30 minutes, diluted 1:8, “summer fever” (sore throat and lymphadenitis;
and assayed by PRN for antibodies against c. 30 headache with pain on eye movement) in 1997.
plaque-forming units (PFU) per well of West Nile The other persons who seroconverted did not
virus strains Eg-101 and 97-103. All sera causing report any substantial illness. In total, clinical
90% reduction of PFU at 1:8 dilution were symptoms in five persons are compatible with
titrated, and the highest serum dilution showing West Nile fever.

Emerging Infectious Diseases 594 Vol. 5, No. 4, July–August 1999

 Letters

These are the first reported human cases of with the El Niño phenomenon (1). Outbreaks
West Nile fever in Central Europe (5); an caused by antibiotic-resistant Vibrio cholerae O1
extensive outbreak occurred in Romania in 1996, and O139 have been documented in the Indian
with approximately 500 patients hospitalized subcontinent (2-4), Africa (5), and Ukraine (6).
and a 4% to 8% fatality rate (6,7). West Nile virus In Hong Kong, nonduplicate bacterial
should be viewed as a potential agent of local strains of V. cholerae O1 and O139 isolated from
sporadic cases, clusters, or outbreaks, even in patients and environmental sources and re-
temperate Europe. Environmental factors (in- ceived in the Public Health Laboratory between
cluding human activities) that enhance vector January 1, 1993, and June 30, 1998, were
population densities (heavy rains followed by identified by conventional biochemical tests (7,8)
floods, irrigation, higher than usual tempera- and API 20E (bioMerieux, France); serotyped by
tures due to global warming) might produce an slide agglutination with polyvalent O1 and
increased incidence of West Nile fever and other mono-specific Inaba and Ogawa antisera
new or reemerging mosquito-borne diseases. (Murex, Dartford, United Kingdom); and
Surveillance for West Nile fever should monitor checked with O139 antiserum (Denka Seiken,
population density and infection rate of principal Tokyo, Japan). Biotyped and antibiotic suscepti-
vectors, antibodies in vertebrates and exposed bilities were determined by the Kirby-Bauer
human groups, and routine diagnosis of human disk-diffusion assay (8-10). Antibiotics tested
infections. included chloramphenicol and tetracycline (from
1993 to 1996) and ofloxacin (added in routine
Zdenek Hubálek, Jirí Halouzka, and
testing from 1997). V. cholerae isolates available
Zina Juricová
Institute of Vertebrate Biology, Academy of Sciences,
for further study were tested with the standard
Brno, Czech Republic broth microdilution method (11) to measure
minimum inhibitory concentrations (MICs) of
susceptibilities to chloramphenicol, tetracycline,
References and ofloxacin.
1. Hubálek Z, Halouzka J, Juricová Z, Šebesta O. First
isolation of mosquito-borne West-Nile virus in the
No antibiotic resistance was seen in
Czech Republic. Acta Virol 1998;42:119-20. V. cholerae isolates in testing conducted from
2. Melnick JL, Paul JR, Riordan JF, Barnett VHH, 1969 to 1995. The first V. cholerae isolate with
Goldblum N, Zabin E. Isolation from human sera in reduced susceptibility to chloramphenicol but
Egypt of a virus apparently identical to West Nile virus. sensitive to tetracycline was encountered in
Proc Soc Exp Biol Med 1951;77:661-5.
3. de Madrid AT, Porterfield JS. The flaviviruses (group B
Hong Kong in 1996. This O1 El Tor Ogawa strain
arboviruses): a cross-neutralization study. J Gen Virol was imported from Nepal. Since then, more O1
1974;23:91-6. strains were isolated that exhibited reduced
4. Leake CJ, Varma MGR, Pudney M. Cytopathic effect antibiotic susceptibilities to chloramphenicol
and plaque formation by arboviruses in a continuous and tetracycline but not to ofloxacin (12). In May
cell line (XTC-2) from the toad Xenopus laevis. J Gen
Virol 1977;35:335-9.
1998, seven V. cholerae O139 strains were
5. Hubálek Z, Halouzka J. Arthropod-borne viruses of verte- isolated that displayed patterns of antibiotic
brates in Europe. Acta Scientiarum Naturalium Aca- susceptibilities strikingly different from those of
demiae Scientiarum Bohemicae Brno 1996;30, no. 4-5:1-95. O1 isolates; the former were all sensitive to
6. Le Guenno B, Bougermouh A, Azzam T, Bouakaz R. tetracycline but showed reduced susceptibilities
West Nile: a deadly virus? Lancet 1996;348:1315.
7. Tsai TF, Popovici F, Cernescu C, Campbell GL, Nedelcu
to chloramphenicol and ofloxacin. All V. cholerae
NI. West Nile encephalitis epidemic in southeastern O1 strains tested have been susceptible to
Romania. Lancet 1998;352:767-71. ofloxacin; O1 isolates falling into intermediate
categories for chloramphenicol and tetracycline
susceptibilities (31% and 27.6%, respectively)
Ofloxacin-Resistant Vibrio cholerae O139 were common.
in Hong Kong The first isolate of V. cholerae O139 in Hong
Kong came from the imported case of a patient
To the Editor: Unexpected outbreaks of cholera who had traveled to other provinces of China
occurred in many areas of the world in 1997-98, (13,14). Isolation of O139 continued sporadically
partly because of weather changes associated since then, with six cases between 1993 and the

Vol. 5, No. 4, July–August 1999 595 Emerging Infectious Diseases

 Letters

1st quarter of 1998. In May 1998, a cluster of antimicrobial therapy and prophylaxis for cholera
seven imported cases of V. cholerae O139 were and other enteric diseases to decrease the
reported with strains isolated from seven selection of more resistant clones in our locality.
persons who became ill with severe diarrhea
Kai Man Kam, Kit Yee Luey, Tze Leung
after visiting Zhuhai in Guangdong Province,
Cheung, Kwan Yee Ho, Kwok Hang Mak, and
China. Of 13 V. cholerae O139 isolates tested, 7 Paul Thian Aun Saw
showed intermediate resistance to chloram- Department of Health, Hong Kong SAR Government
phenicol and high-level resistance to ofloxacin
(MIC 16 µg/ml) but no resistance to tetracycline
(MIC 50s and MIC 90s were 0.25 µg/ml). This is References
1. World Health Organization, Geneva. Cholera in 1997.
the first evidence of a quinolone-resistant strain Wkly Epidemiol Rec 1998;73:201-8.
of V. cholerae O139 in Hong Kong. Of the O1 2. Gharagozloo RA, Naficy K, Mouin M, Nassirzadeh MH,
isolates, none were resistant to chloramphenicol Yalda R. Comparative trial of tetracycline,
and ofloxacin, but six were resistant to chloramphenicol, and trimethoprim/sulphamethoxazole
tetracycline (MIC 50s and MIC 90s were 0.25 µg/ in eradication of Vibrio cholerae El Tor. BMJ
1970;4:281-2.
ml and 8 µg/ml, respectively). 3. Glass RI, Huq I, Alim AR, Yunus M. Emergence of
Although all O1 isolates were sensitive to multiply antibiotic-resistant Vibrio cholerae in
chloramphenicol, there was only a twofold Bangladesh. J Infect Dis 1980;142:939-42.
difference in MIC90 to chloramphenicol between 4. Ramamurthy T, Garg S, Sharma R, Bhattacharya SK,
O1 and O139 isolates. MIC90s of ofloxacin for Nair GB, Shimada T, et al. Emergence of novel strain of
Vibrio cholerae with epidemic potential in southern and
O139 were nearly 10 times higher than those for eastern India. Lancet 1993;341:703-4.
O1 strains. 5. Finch MJ, Morris JG Jr, Kaviti J, Kagwanja W, Levine
The novel appearance of O139 resistant to MM. Epidemiology of antimicrobial resistant cholera in
ofloxacin with MICs of 16 µg/ml from Guangdong Kenya and east Africa. Am J Trop Med Hyg
Province, China, was of special concern. 1988;39:484-90.
6. Clark CG, Kravetz AN, Alekseenko VV, Krendelev
Preliminary results using pulsed-field gel YuD, Johnson WM. Microbiological and epidemiological
electrophoresis analysis of chromosomal DNA investigation of cholera epidemic in Ukraine during
showed that these ofloxacin-resistant O139 1994 and 1995. Epidemiol Infect 1998;121:1-13.
strains had identical fingerprint patterns and 7. Cowan ST, Steel KJ. Manual for the identification of
probably belonged to the clone that had caused medical bacteria. 2nd ed. Cambridge: Cambridge
University Press; 1974.
severe diarrheal disease in the region. Two 8. Bradfold AK, Bopp CA, Wells JG. Isolation and
previous surveys of V. cholerae antibiotic identification of Vibrio cholerae O1 from fecal
susceptibilities had not described any ofloxacin- specimens. In: Wachsmuth IK, Blake AB, Olsvik Ø,
resistant O139 strains (15,16). The potential for editors. Vibrio cholerae and cholera: molecular to global
rapid spread of these strains threatens cholera perspectives. Washington: American Society for
Microbiology; 1994. p. 3-26.
prevention and control efforts that may still rely 9. National Committee for Clinical Laboratory Standards.
on chemotherapy. Performance standards for antimicrobial disk susceptibility
Different antimicrobial resistance patterns tests approved standard. NCCLS document M2-A6.
of V. cholerae O1 and O139 were noted. Among Villanova (PA): The Committee; 1997.
the resistant O1 isolates, four were local, one was 10. National Committee for Clinical Laboratory Standards.
Performance standards for antimicrobial susceptibility
from other provinces of China, and one was from testing; NCCLS document M100-S8, 18(1). Villanova
Thailand. All the resistant O139 isolates were (PA): The Committee; 8th information supplement,
imported from Guangdong Province, China. 1998.
Antibiotic resistance was found in strains from 11. National Committee for Clinical Laboratory Standards.
local isolates and from neighboring countries. Methods for dilution antimicrobial susceptibility tests for
bacteria that grow aerobically. 4th ed. NCCLS document
The unique patterns of antimicrobial resistance M7-A4. Villanova (PA): The Committee; 1997.
for the O1 and O139 isolates suggest different 12. Wong W, Ho YY. Imported cholera cases among tours
mechanisms of resistance. As quinolones are used returning from Thailand. Public Health & Epidemiology
heavily in this region to treat cholera and other Bulletin, Department of Health, Hong Kong. 1998;7:21-4.
enteric diseases, selective pressure could encour- 13. Kam KM, Leung TH, Ho PYY, Ho KY, Saw TA.
Outbreak of Vibrio cholerae O1 in Hong Kong related to
age emergence of ofloxacin resistance. Prudent contaminated fish tank water. Public Health
use of antibiotics should be exercised during 1995;109:389-95.

Emerging Infectious Diseases 596 Vol. 5, No. 4, July–August 1999

 Letters

14. Lee SH, Lai ST, Lai JY, Leung NK. Resurgence of of the environment, including the quality of our
cholera in Hong Kong. Epidemiol Infect 1996;117:43-9. drinking water, opportunities may exist for
15. Yamamoto T, Nair GB, Albert MJ, Parodi CC, Takeda
physicians to interact with plant pathologists.
Y. Survey of in vitro susceptibilities of Vibrio cholerae
O1 and O139 to antimicrobial agents. Antimicrob Concern is growing about the use of Burkholderia
Agents Chemother 1995;39:241-4. cepacia, a bacterial phytopathogen, for the
16. Sciortino CV, Johnson JA, Hamad A. Vitek system biologic control of seedling diseases (9). Although
antimicrobial susceptibility testing of O1, O139, and non- B. cepacia is effective for the biologic control of
O1 Vibrio cholerae. J Clin Microbiol 1996;34:897-900.
fungal diseases in the agricultural environment
(10), this bacterium could contaminate the public
water supply and subsequently influence the
Plant Pathology and Public Health health of the immunosuppressed or persons with
The day will come when the sign of the plant
cystic fibrosis (9-11). This risk exemplifies the
pathologist will stand forth in the street alongside need to integrate plant health measures with
that of the physician and surgeon. . . . For what will human and veterinary health guidelines.
it profit us if all the ills and diseases of the human Plant pathology and public health also
race be banished and we then face starvation
because of diseases and pests in our food (1).
intersect with post-harvest fungal infections of
seed and grain, particularly Aspergillus flavus and
To the Editor: Every year plant diseases affect Fusarium moniliforme (2), which produce aflatox-
human society, resulting in inadequate nutrition in and fumonisin, respectively. During the past 2
and economic loss. The potato famine in the mid- drought years in Texas, aflatoxin in contaminat-
1800s is the best-known example of a fungal ed corn and peanuts has become a public health
plant pathogen’s effect on history (2-4); problem. In 1998, more than 50 pet dogs died of
Phytopthora infestans has recently reemerged in aflatoxicosis, perhaps by eating aflatoxin B1-
the Americas (5). Among the silent problems that contaminated corn used in dog food (12).
have enormous effects on human society each Although the veterinary and medical
year are crop infections by geminiviruses and communities are well aware of the risks
tomato spotted wilt virus (6). These plant viruses associated with plant pathogens when they enter
are transmitted by whiteflies, leafhoppers, or the animal or human food supply, more routine
thrips to hundreds of species of plants. They interactions with plant pathologists could
cause diseases of crops and ornamental plants benefit public health. For example, plant
around the world. pathologists can often predict impending plant
More obvious problems include ergotism, disease outbreaks. This information can be used
caused by the alkaloids produced by the fungus by epidemiologists to sound a warning about
Claviceps purpurea. Ergotism was associated impending food shortages or poor food quality,
with the growth of rye, particularly in cool particularly in developing countries. Plant
climates that cannot support wheat, and was pathologists are also developing new types of
implicated in the aberrant human behavior resistance in host plants and alternative
responsible at least in part for the Salem witch strategies for managing plant diseases. These
trials and St. Anthony’s fire (2,7). In the last 5 measures should improve food quality and
years, a new plant disease, sorghum ergot reduce the negative public health impact
(Claviceps africana), has spread north from associated with plant diseases.
Brazil into the United States. This fungus also Karen-Beth G. Scholthof
causes disease in Australia, a sudden change Texas A&M University, College Station, Texas, USA
from its known occurrence in Africa (8).
Sorghum is the fifth most important cereal crop
References
in the world, with approximately 45 million 1. Whetzel HH. The relation of plant pathology to human
hectares under cultivation for food, beverages, affairs. Mayo Foundation Lectures 1926-1927.
feed, and fodder (8). Ergot alkaloid toxicity has Philadelphia: W.B. Saunders Co.; 1928. p. 151-78.
not yet been demonstrated, but potential 2. Hudler GW. Magical mushrooms, mischievous molds.
nutritional and economic losses could have Princeton: Princeton University Press; 1998.
3. Woodham-Smith C. The great hunger: Ireland 1845-
substantial impact on public health. 1849. New York: Old Town Books; 1962.
With our increased awareness of the fragility

Vol. 5, No. 4, July–August 1999 597 Emerging Infectious Diseases

 Letters

4. Schumann GL. Plant diseases: their biology and social Pet-Associated Zoonoses
impact. St. Paul: American Phytopathological Society
Press; 1993.
To the Editor: We read with interest the article
5. Goodwin SB, Smart CD, Sandrock RW, Deahl KL,
Punja ZK, Fry WE. Genetic change within populations by Grant and Olsen on preventing zoonotic
of Phytopthora infestans in the United States and diseases in immunocompromised persons (1). We
Canada during 1994 to 1996—role of migration and completely agree with the benefits of communi-
recombination. Phytopathology 1998;88:939-49. cation between physicians and veterinarians.
6. Prins M, Goldbach R. The emerging problem of
However, we want to emphasize that pet-
tospovirus infection and nonconventional methods of
control. Trends Microbiol 1998;6:31-5. associated illnesses are not limited to the
7. Matossian MK. Poisons of the past: molds, epidemics, immunocompromised; pregnant women and
and history. New Haven: Yale University Press; 1989. young infants should be included in this high-
8. Bandyopadhyay R, Frederickson DE, McLaren NW, risk category. Our recently published survey (2)
Odvody GN, Ryley MJ. Ergot: a new disease threat to
reaffirms the need for education of the general
sorghum in the Americas and Australia. Plant Disease
1998;82:356-67. public, parents, and—to a lesser extent—
9. Holmes A, Govan J, Goldstein R. Agricultural use of pediatricians regarding pet-associated hazards.
Burkholderia (Pseudomonas) cepacia: a threat to
human health? Emerg Infect Dis 1998;4:221-7. Leslie L. Barton,* Rodrigo G. Villar,† and
10. Park JL. Burkholderia cepacia: friend or foe? 1998. Megan Connick‡
Available from: URL: http://www.scisoc.org/feature/ *University of Arizona Health Sciences Center,
BurkholderiaCepacia/ Tucson, Arizona, USA; †Indian Health Service,
11. King EB, Parke JL. Population density of the biocontrol Gallup, New Mexico, USA; and ‡Washington
agent Burkholderia cepacia AMMDR1 on four pea University School of Medicine, St. Louis,
cultivars. Soil Biology and Biochemistry 1996;28:307-12. Missouri, USA
12. Texas Veterinary Diagnostic Medical Laboratory.
Epidemiol Bull 1998. Available from: URL: http://
www.tvmdl.tamu.edu/. References
1. Grant S, Olsen CW. Preventing zoonotic diseases in
immunocompromised persons: the role of physicians
and veterinarians. Emerg Infect Dis 1999;5:159-63.
2. Villar RG, Connick M, Barton LL. Parent and
pediatrician knowledge, attitudes, and practices
regarding pet-associated hazards. Arch Pediatr Adolesc
Med 1998;152:1035-7.

Emerging Infectious Diseases 598 Vol. 5, No. 4, July–August 1999

 Book Review

Clinical Infectious Diseases: A Practical cotton-tipped swabs), some of which are

Approach. K.R. Root, F. Waldvolgel, L. Corey, specifically recommended for use with certain
W.E. Stamm, editors. Oxford University Press, agents or tests. More could have been presented
New York, 1999,1,013 pages. regarding specimen transport, in light of the
emergence of central core laboratory facilities for
This new text presents updated and valuable multihospital health systems and the use of
information to the clinician and brings to the distant facilities for microbiology analysis.
forefront issues important for diagnosing and The 22 chapters on antimicrobial drugs and
managing infectious diseases in an era of their appropriate use are complete and up to
competing demands on resources and rapidly date. For example, a brief discussion of the
evolving health-care delivery systems. While recently emerged glycopeptide-intermediate Sta-
other books on infectious diseases are available, phylococcus aureus is presented, as is informa-
the speed with which new diagnostic methods tion on inappropriate use of antimicrobial drugs,
are developed and the unpredictable nature of particularly vancomycin, and the emergence of
microbial pathogens require that the clinical and extended-spectrum beta-lactamases. Pharmaco-
health-care community be kept informed of new kinetics, clinical indications and use, mode of
approaches to diagnosis. This is particularly true action, clinical experience, adverse reactions,
in today’s medical environment, where interna- mechanisms of resistance, and other useful
tional travel and world events compel the local information are described, along with a generous
medical community to broaden its scope beyond array of very helpful summary tables and charts.
its former comfort zone. The editors and The primary diagnostic portion of the text is
contributors to this book have successfully presented by syndrome, not by organism or
presented the diagnosis, management, and individual disease. For example, tuberculosis is
prevention of infectious diseases in a context covered in the chapter on “Cavitary Pulmonary
that promotes the best of patient care and Disease,” while varicella is discussed in
outcome. “Infections with Rash.” The annotated bibliogra-
The text has 1,013 pages of information, phy at the end of each chapter is very helpful:
tables, charts, algorithms, and photographs recent literature references are included where
provided by 150 contributors representing a possible, along with italicized notes about the
broad array of internationally recognized content and value of each reference selected.
expertise. The book’s 103 chapters are logically Pathogenesis is appropriately discussed in the
divided into seven parts: Pathophysiology of section for each disease or agent rather than in an
Infectious Diseases, Diagnostic Methods in introductory section. The complexity of patho-
Infectious Diseases, Antimicrobial Drugs: Prin- genic mechanisms and host-parasite relationships
ciples and Usage, Vaccines and Immunomodulary within the microbial groups makes this approach
Agents, Infectious Disease Syndromes, Infec- a sound one. This section of the book is nicely
tions in Special Patient/Risk Groups, and introduced by valuable discussions on fever that
Human Immunodeficiency Virus and AIDS. The set the stage for the subsequent syndrome
first four provide sufficient background for presentations.
focusing on the final three sections. The text The section on infections in special patient
includes 49 color plates with 54 photos that are populations and in special groups at risk is
bright, colorful, descriptive, and large enough for appropriate and informative and recognizes the
detail to be appreciated. unique needs and problems associated with these
Specimen management is covered nicely in populations. Infections in immunocompromised
the chapters on bacteria, viruses, parasites, and patients, postsurgical wound infections, trauma,
fungi, although the apparent assumption is that in-dwelling medical devices, transplantation,
the patient will usually be an adult. In some travelers, and alcohol and drug abuse are some of
cases, specimens from pediatric patients may the special risks and groups presented. AIDS and
require different approaches to collection and to HIV are considered separately in a seven-
the amount of material to collect. In addition, the chapter section.
role of the swab as a collection device is not There are few negatives about this book. For
detailed enough, since there are so many types ease of use, it might have been helpful for all
(e.g., Dacron-, rayon-, calcium alginate-, and information about specimen management to be

Vol. 5, No. 4, July–August 1999 599 Emerging Infectious Diseases

 Book Review

summarized in a single chapter. There were some This book, while not inexpensive, will be an
controversial recommendations for blood collec- important addition to the resources available to
tion at 1-hour intervals, and some may question clinicians and laboratorians alike.
the proposed use of direct antigen tests in spinal
J. Michael Miller
fluid for pediatric patients. Today vaginosis is
Centers for Disease Control and Prevention,
recognized with more accuracy in the microbiol-
Atlanta, Georgia, USA
ogy laboratory by Gram stain evaluation rather
than by culture (as recommended in the book),
which can often be inconclusive.

Emerging Infectious Diseases 600 Vol. 5, No. 4, July–August 1999

 News and Notes

The Epidemiology and Control of Information on this program and the topic of
Communicable Diseases antibiotic resistance in bacteria of animal origin
Surveillance and Investigating Outbreaks is available at http://www.fougeres.afssa.fr/arbao.
(November 22–23) To receive conference materials, please
Control of Communicable Diseases forward your name, affiliation, postal address,
(November 24–25) phone and fax number, and e-mail address to P.
Sanders, AFSSA-Fougères, La Haute Marche-
Presented by the University of Western Javené, BP 90203, 35302 Fougeres Cedex,
Australia (UWA), Department of Public Health’s France; phone: 33-29-994-7876; fax: 33-29-994-
Summer School Program 1999, this interactive 7877; e-mail: arbao@fougeres.afssa.fr.
course will provide both an overview of com-
municable disease control and practical skills in
surveillance, investigation, health outcomes, Keystone Symposia on Molecular and
role of government, policy development and Cellular Biology
analysis, value, and limitations of legislation in Genetics, Pathogenesis and Ecology of
the context of infectious disease control. Emerging Viral Diseases (J1)
The presenter, Dr. Aileen Plant, is a medical Taos Civic Center, Taos, NM, January 24–30, 2000
epidemiologist with UWA and recently under- Organizers: Michael J. Buchmeier and
took a 6-month study leave with WHO, working Clarence J. Peters
with a new international surveillance and Abstract Deadline: September 24, 1999
investigative network, TEPHINET. Early Registration: November 23, 1999
Cost is $400 AUD per module with discounts Pathogen Discovery: From Molecular Biology
for registration before August 31. Participants may to Diseases (J2)
enrol in one or both modules. Prior epidemiologic Taos Civic Center, Taos, NM, January 24–30, 2000
experience is not necessary. CME points for Organizers: Georg Hess and Helen H. Lee
general practioners have been applied for. Sponsored by Roche Diagnostics
To register, contact Serena Angelo at Abstract Deadline: September 24, 1999
serena@dph.uwa.edu.au. Early Registration: November 23, 1999
For information on UWA’s Summer School Biological Threats and Emerging Diseases (F3)
go to http://www.publichealth.uwa.edu.au/events/ Beaver Run Resort, Breckenridge, CO, April 8–13,
summer/ or contact Melodie Kevan, Dept. of Public 2000
Health, The University of Western Australia Organizers: Gregory Milman, Joseph E.
Nedlands WA 6907; phone: 61-8-9380-1286; fax: McDade and Gail H. Cassell
61-8-9380-1188; e-mail: melodie@dph.uwa.edu.au. Abstract Deadline: December 8, 1999
Early Registration: February 8, 2000
For information or registration visit
Antibiotic Resistance in Bacteria of Keystones’s Web site: http://www.symposia.com.
Animal Origin
Institut Pasteur, Paris, France,
November 29–30, 1999 The 5th World Congress on Trauma,
Shock, Inflammation and Sepsis-
This international symposium, organized as Pathophysiology, Immune Consequences
part of a European Concerted Action, will gather and Therapy
scientists from diverse disciplines (microbiology, Munich, Germany, February 29–March 4, 2000
epidemiology, ecology) to share data and actual
knowledge on antibiotic resistance, especially in Deadline for abstracts is October 30, 1999.
the veterinary field. For further information contact: Eugen Faist,
Objectives of this congress are the presenta- Dept. of Surgery, Ludwig-Maximilians-Univer-
tion of current recommendations of Concerted sity Munich, Klinikum Grosshadern,
Action members, of current knowledge on Marchioninistrasse 15, 81377 Munich, Germany;
antibiotic resistance, and of existing monitoring phone: 49-89-7095-5461/2461; fax: 49-89-7095-
strategies, and the promotion of research funded 2460; e-mail: faist@gch.med.uni-muenchen.de.
by the European Union.

Vol. 5, No. 4, July–August 1999 601 Emerging Infectious Diseases

 News and Notes

ICEID 2000

Hold the dates of July 16–19,

2000 for the International
Conference on Emerging
Infectious Diseases, a meet-
ing of 2,500 specialists in
infectious diseases. The pro-
gram will include plenary
sessions and symposia with
invited speakers, presenta-
tions on emerging infections
activities, and oral and
poster presentations. Major
topics will include current
work on surveillance, epide-
miology, research, commu-
nication and training, as
well as prevention and
control of emerging infectious diseases, both in the United States and abroad. Abstracts are
invited and will be accepted beginning in September 1999.

The Call for Abstracts and Preliminary Program will be mailed in August 1999.

For more information, call ICEID management at 202-942-9248, e-mail meetinginfo@asmusa.org,

or www.cdc.gov/ncidod/iced2k.htm.

Emerging Infectious Diseases 602 Vol. 5, No. 4, July–August 1999

 Access EMERGING INFECTIOUS DISEASES at www.cdc.gov/eid
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Editorial Policy and Call for Articles

Emerging Infectious Diseases is a peer-reviewed journal established expressly to promote the recognition of new and reemerging infectious
diseases around the world and improve the understanding of factors involved in disease emergence, prevention, and elimination.
The journal has an international scope and is intended for professionals in infectious diseases and related sciences. We welcome contributions from
infectious disease specialists in academia, industry, clinical practice, and public health, as well as from specialists in economics, demography, sociology,
and other disciplines. Inquiries about the suitability of proposed articles may be directed to the Editor at 404-639-4856 (tel), 404-639-3075 (fax), or
eideditor@cdc.gov (e-mail).
Emerging Infectious Diseases is published in English and features the following types of articles: Perspectives, Synopses, Research Studies, Policy
Reviews, and Dispatches. The purpose and requirements of each type of article are described in detail below. To expedite publication of information,
we post journal articles on the Internet as soon as they are cleared and edited.
Spanish and French translations of some articles can be accessed through the journal’s homepage at www.cdc.gov/eid. Articles by authors from non-
English-speaking countries can be made simultaneously available in English and in the author’s native language (electronic version of the journal only).

Instructions to Authors
Manuscript Preparation Types of Articles
Follow “Uniform Requirements for Manuscripts Submitted to
Perspectives, Synopses, Research Studies, and Policy Reviews:
Biomedical Journals” (Ann Int Med 1997:126[1]36-47) (http://
www.acponline.org/journals/resource/unifreqr.htm). Articles should be approximately 3,500 words and should include
Begin each of the following sections on a new page and in this order: references, not to exceed 40. Use of subheadings in the main body of
title page, abstract, text, acknowledgments, references, tables, figure the text is recommended. Photographs and illustrations are encour-
legends, and figures. aged. Provide a short abstract (150 words) and a brief biographical
Title page. Give complete information about each author (i.e., full sketch.
name, graduate degree(s), affiliation, and the name of the institution in Perspectives: Articles in this section should provide insightful analysis
which the work was done). Also provide address for correspondence and commentary about new and reemerging infectious diseases or
(include fax number and e-mail address). related issues. Perspectives may also address factors known to influence
Abstract and key words. Avoid citing references in the abstract. the emergence of diseases, including microbial adaptation and change;
Include up to 10 key words; use terms listed in the Medical Subject human demographics and behavior; technology and industry; economic
Headings from Index Medicus (http://www.nlm.nih.gov/tsd/serials/ development and land use; international travel and commerce; and the
lji.html). breakdown of public health measures. If detailed methods are included,
Text. Double-space everything, including the title page, abstract, a separate section on experimental procedures should immediately
references, tables, and figure legends. Type only on one side of the paper follow the body of the text.
and number all pages, beginning with the title page. Indent paragraphs Synopses: This section comprises concise reviews of infectious diseases
5 spaces; leave no extra space between paragraphs. After a period, leave or closely related topics. Preference is given to reviews of new and
only one space before beginning the next sentence. Use Courier font size emerging diseases; however, timely updates of other diseases or topics
10 and ragged right margins. Italicize (rather than underline) scientific are also welcome. Use of subheadings in the main body of the text is
names when needed. recommended. If detailed methods are included, a separate section on
Electronic formats. For word processing, use WordPerfect or MS experimental procedures should immediately follow the body of the text.
Word. Send graphics in either (TIFF), or .EPS (Encapsulated Postscript) Photographs and illustrations are encouraged.
formats. The preferred font for graphics files is Helvetica. Convert
Research Studies: These articles report laboratory and epidemiologic
Macintosh files into one of the suggested formats. Submit slides or
results within a public health perspective. Although these reports may
photographs in glossy, camera-ready photographic prints.
be written in the style of traditional research articles, they should
References. Follow the Uniform Requirements style. Place reference
explain the value of the research in public health terms and place the
numbers in parentheses, not in superscripts. Number citations in order of
findings in a larger perspective (e.g., “Here is what we found, and here is
appearance (including in text, figures, and tables). Cite personal
what the findings mean”).
communications, unpublished data, and manuscripts in preparation or
submitted for publication in parentheses in text. Consult List of Journals Policy Reviews: Articles in this section report public health policies
Indexed in Index Medicus for accepted journal abbreviations; if a journal is that are based on research and analysis of emerging disease issues.
not listed, spell out the journal title in full. List the first six authors followed Dispatches: These brief articles are updates on infectious disease
by “et al.” trends and research. The articles include descriptions of new methods
Tables and figures. Create tables within the word processing for detecting, characterizing, or subtyping new or reemerging
program’s table feature (not columns and tabs within the word pathogens. Developments in antimicrobial drugs, vaccines, or infectious
processing program). For figures, use color as needed; send files, slides, disease prevention or elimination programs are appropriate. Case
photographs, or prints. Figures, symbols, lettering, and numbering reports are also welcome. Dispatches (1,000 to 1,500 words) need not be
should be clear and large enough to remain legible when reduced. Place divided into sections. Provide a short abstract (50 words); references, not
figure keys within the figure. to exceed 10; figures or illustrations, not to exceed two; and a brief
biographical sketch.
Manuscript Submission Book Reviews: Short reviews (250 to 500 words) of recently published
Include a cover letter verifying that the final manuscript has been books on emerging disease issues are welcome.
seen and approved by all authors. Letters: This section includes letters that give preliminary data or
Submit three copies of the original manuscript with three sets of comment on published articles. Letters (500 to 1,000 words) should not be
original figures and an electronic copy (on diskette or by e-mail) to the divided into sections, nor should they contain figures or tables.
Editor, Emerging Infectious Diseases, Centers for Disease Control and References (not more than 10) may be included.
Prevention, 1600 Clifton Rd., MS C-12, Atlanta, GA 30333, USA; e-mail
News and Notes: We welcome brief announcements (50 to 150 words)
eideditor@cdc.gov.
of timely events of interest to our readers. (Announcements can be
posted on the journal web page only, depending on the event date.) In
this section, we also include summaries (500 to 1,500 words) of
conferences focusing on emerging infectious diseases. Summaries may
provide references to a full report of conference activities and should
focus on the meeting’s content.