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Volume 4 • Number 3 July–September 1998
About the International Conference 353 The Emergence of Bovine Spongiform 390
on Emerging Infectious Diseases Encephalopathy and Related Diseases
S.A. Morse J. Pattison
Explaining the Unexplained in Clinical 395
About Emerging Infectious Diseases Infectious Diseases: Looking Forward
Collaboration in the Fight Against 354 B. Perkins and D. Relman
Infectious Diseases
The Secretary of Health and The Global Threat
Human Services Donna Shalala Malaria: A Reemerging Disease in Africa 398
Effective Global Response to Emerging 358 T. Nchinda
Infectious Diseases Vaccine-Preventable Diseases 404
C. Broome A. Mawle
Addressing Emerging Infectious Disease 360 Travelers’ Health 405
Threats—Accomplishments and Future Plans M. Cetron, J. Keystone, D. Shlim, R. Steffen
J. Hughes Global Tuberculosis Challenges 408
Global Surveillance of Communicable Diseases 362 K. Castro
D. Heymann and G. Rodier Blood Safety 410
M.E. Chamberland, J. Epstein, R.Y. Dodd,
Emerging Infections: An Evolutionary Perspective 366
D. Persing, R.G. Will, A. DeMaria, Jr.,
J. Lederberg
J.C. Emmanuel, B. Pierce, and R. Khabbaz
Emerging Infectious Diseases: 372
Confronting Emerging Infections: Lessons 412
A Brief Biographical Heritage
from the Smallpox Eradication Campaign
P. Drotman
W. Foege
New and Reemerging Diseases: The Importance 374
The Guinea Worm Eradication Effort: 414
of Biomedical Research Lessons for the Future
A. Fauci D. Hopkins
Health Policy Implications of Emerging Infections 379
K. Hein
Populations at Risk
Nosocomial Infection Update 416
New Agents and Disease Associations R. Weinstein
Detection and Identification of Previously 382 Opportunistic Infections in 421
Unrecognized Microbial Pathogens Immunodeficient Populations
D. Relman J. Kaplan, G. Roselle, and K. Sepkowitz
Host Genes and Infectious Diseases 423
J. McNicholl
Immigrant and Refugee Health 427
S. Cookson, R. Waldman, B. Gushulak, D. MacPherson,
F. Burkle, Jr., C. Paquet, E. Kliewer, and P. Walker

Zoonotic and Vector-borne Issues

Emerging Zoonoses 429
F. Murphy
Influenza: An Emerging Disease 436
R.G. Webster
Resurgent Vector-Borne Diseases 442
as a Global Health Problem
D. Gubler
Global Climate Change and Infectious Diseases 451
R. Colwell, P. Epstein, D. Gubler, M. Hall, P. Reiter,
J. Shukla, W. Sprigg, E. Takafuji, and J. Trtanj
David Satcher, U.S. Surgeon General; Donna Shalala, U.S. Emerging Zoonoses 453
Secretary of Health and Human Services. J. Childs, R.E. Shope, D. Fish, F.X. Meslin,
C. J. Peters, K. Johnson, E. Debess,
D. Dennis, and S. Jenkins
Cover: T. Moore (1941), Phantasmagoria, oil on board. From the collection of Abdu Azad.

Conference photos by Jim Gathany.



Volume 4 • Number 3 July–September 1998

Emerging Foodborne Pathogens Bioterrorism as a Public Health Threat 488

New Approaches to Surveillance and Control 455 D.A. Henderson
of Emerging Foodborne Diseases Bioterrorism as a Public Health Threat 493
R. Tauxe J. McDade and D. Franz
FoodNet and Enter-net: Emerging Surveillance 457 Who Speaks for the Microbes? 495
Programs for Foodborne Diseases S. Falkow
S. Yang Emerging Diseases—What Now? 498
Enhancing State Epidemiology and Laboratory 459 G. Alleyne
Capacity for Infectious Diseases
D. Deppe Summaries from satellite partnership meetings
(March 8-12)
Communicating the Threat Plague Diagnostic Workshop 501
International Cooperation 461 M.C. Chu
J. LeDuc The U.S.-EU Conference on Extension of the 502
Public Health Surveillance and 462 Salm/Enter-net Surveillance System for Human
Information Technology Salmonella and E. coli O157 Infections
R. Pinner A. Levitt
Innovative Information-Sharing Strategies 465 ASM/CDC/NIH Training in Emerging and 504
B. Kay, R.J. Timperi, S.S. Morse, Reemerging Infectious Diseases
D. Forslund, J.J. McGowan, and T. O’Brien K. Western
Getting the Handle off the Proverbial 467
Pump: Communication Works Letters
L. Folkers, M.T. Cerqueira, R.E. Quick, Outbreak of Suspected Clostridium butyricum 506
J. Kanu, and G. Galea Botulism in India
Communicating Infectious Disease 470 R. Chaudhry, B. Dhawan, D. Kumar, R. Bhatia,
Information to the Public J.C. Gandhi, R.K. Patel, and B.C. Purohit
E. Abrutyn Molecular Analysis of Salmonella paratyphi A 507
APEC Emerging Infections Network: 472 From an Outbreak in New Delhi, India
Prospects for Comprehensive Information K. Thong, S. Nair, R. Chaudhry, P. Seth, A. Kapil,
Sharing on Emerging Infections within D. Kumar, H. Kapoor, S. Puthucheary, and T. Pang
the Asia Pacific Economic Cooperation Unrecognized Ebola Hemorrhagic Fever at 508
A.M. Kimball, C. Horwitch, P. O’Carroll, Mosango Hospital during the 1995 Epidemic in
S. Arjoso, C. Kunanusont, Y. Lin,
Kikwit, Democratic Republic of the Congo
C. Meyer, L. Schubert, and P. Dunham
M. Bonnet, P. Akamituna, and A. Mazaya
Classification of Reactive Arthritides 510
Critical Issues for the Future
D.R. Blumberg and V.S. Sloan
Controversies in the Prevention and 473
Reply to Drs. Blumberg and Sloan 512
Control of Antimicrobial Resistance J. Lindsay
D. Bell
Cost of Blood Screening 512
Infectious Causes of Chronic Inflammatory 475
O. Chang
Diseases and Cancer
G. Cassell
Book Review
James M. Hughes, Director, Emerging Infections 513
National Center for Infectious B. Mahy
Diseases, Centers for Disease
Control and Prevention, Atlanta, News and Notes
Georgia, USA CDC To Release Updated Emerging 514
Infectious Disease Plan
First Congress of the European Society 514
for Emerging Infections, September
13-16, 1998, Budapest, Hungary
Foodborne Illness: A Disease for All 514
Seasons, October 27 and 28, 1998,
Newark, Delaware
December 1998 International Conference 515
on Antiretroviral Therapy
Erratum 515
Special Issue

About the International Conference on

Emerging Infectious Diseases
Stephen A. Morse
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

More than 2,500 researchers, clinicians, causes of chronic disease, blood safety, host
laboratorians, veterinarians, and other public genetics, vaccines, global climate change, and
health professionals from all 50 states and more immigration and travel.
than 70 countries convened in Atlanta on March In delivering the keynote address, Nobel
8-11, 1998, for the International Conference on laureate Joshua Lederberg reviewed the scien-
Emerging Infectious Diseases. The conference, tific basis for the emergence of infectious
organized by the Centers for Disease Control and diseases. U.S. Health and Human Services
Prevention (CDC), the Council of State and Secretary Donna Shalala and Assistant Secre-
Territorial Epidemiologists, the American Soci- tary for Health and Surgeon General David
ety for Microbiology, and the National Founda- Satcher, along with representatives from the
tion for CDC along with 62 other cosponsors,1 World Health Organization, the Pan American
provided a forum for the exchange of ideas and Health Organization, and the U.S. Agency for
possible solutions to the problems of new and International Development, and representatives
reemerging infectious diseases, including poten- from academia and industry addressed the
tial threats presented by bioterrorism. Several national and international ramifications of
agencies and organizations sponsored satellite emerging infections. In closing the conference,
partnership meetings on March 8 and March 12. James Hughes, director, National Center for
More than 85 sessions (12 plenary sessions, 17 Infectious Diseases, CDC, stressed the impor-
invited panels, 35 poster sessions, and late- tance of building bridges and forging new
breaking abstracts) were presented on surveil- partnerships to prevent and control the
lance, epidemiology, prevention, and control of emergence of infections into the next millennium.
emerging infectious diseases, as well as emergency In publishing the conference presentations
preparedness and response and reemerging or and discussions in this journal, the organizers
drug-resistant infectious diseases. Topics included hope to capture the energy expressed by all
foodborne diseases, infectious diseases transmitted participants, further disseminate new informa-
by animals and insects, nosocomial infections, tion on emerging infections, and stimulate more
infections in immunocompromised patients and research and other initiatives against this
persons outside the health-care system, infectious important public health threat.

1Alliance for the Prudent Use of Antibiotics, American Academy of Pediatrics, American Association of Blood Banks, American

Association of Health Plans, American Cancer Society, American College of Preventive Medicine, American Hospital
Association, American Medical Association, American Mosquito Control Association, American Public Health Association,
American Sexually Transmitted Diseases Association, American Society of Clinical Pathologists, American Society of Tropical
Medicine and Hygiene, American Veterinary Medical Association, Association of American Veterinary Medical Colleges,
Association of Schools of Public Health, Association of State and Territorial Directors of Health Promotion and Public Health
Education, Association of State and Territorial Health Officials, Association of State and Territorial Public Health Laboratory
Directors, Association of Teachers of Preventive Medicine, Burroughs Wellcome Fund, Emory University School of Medicine,
Fogarty International Center, Food and Drug Administration, Indian Health Service, Infectious Diseases Society of America,
International Life Sciences Institute, International Society for Infectious Diseases, International Society of Travel Medicine,
International Union for Health Promotion and Education, International Union of Microbiological Societies, Minority Health
Professions Foundation, Morehouse School of Medicine, National Aeronautics & Space Administration, National Association
of City and County Health Officials, National Association of State Public Health Veterinarians, National Council for
International Health, National Foundation for Infectious Diseases, National Hispanic Medical Association, National Institute
of Allergy and Infectious Diseases, National Medical Association, National Oceanographic & Atmospheric Administration,
Office of Science and Technology Policy, Pan American Health Organization, Rollins School of Public Health of Emory
University, Society for Healthcare Epidemiology of America, Society for Occupational and Environmental Health, Society for
Public Health Education, The Carter Center, The Henry J. Kaiser Family Foundation, The HMO Group, The Robert Wood
Johnson Foundation, The Rockefeller Foundation, The World Bank, U.S. Agency for International Development, U.S.
Department of Agriculture, U.S. Department of Defense, U.S. Department of State, U.S. Department of Justice (INS), U.S.
Department of Veterans Affairs, U.S. Environmental Protection Agency, World Health Organization.

Vol. 4, No. 3, July–September 1998 353 Emerging Infectious Diseases

Special Issue

Collaboration in the Fight Against

Infectious Diseases
Donna E. Shalala
U.S. Secretary of Health and Human Services

Two hundred years ago, the U.S. Public Life returned to normal. The great flu was soon
Health Service, of which the Centers for Disease pushed off the front pages and out of the public
Control and Prevention (CDC) is an essential eye. When avian flu first appeared last year, we
part, began as a humble maritime hospital in wondered if perhaps another pandemic had
New York City. Its mission was simply to stop begun. An influenza subtype that had never
infectious disease from coming in on ships and before produced illnesses or deaths in humans
spreading across our country. Today, as we now did. While it appears that the spread of avian
celebrate the anniversary of the Public Health flu has halted without the appearance of human-
Service, another historic event has occurred. One to-human transmission, the danger is far from
of the great detective hunts of the 20th century over because the critical period may be just
came to an end. Scientists at the U.S. beginning—this is the start of the traditional flu
Department of Defense confirmed that tissue season in Hong Kong.
from a woman’s body buried near the Bering The emergence of avian flu points up a
Strait contains genetic material from the 1918 broader concern: complacency over infectious
Spanish flu virus—the virus that caused the disease. It is easy to assume that modern
worst pandemic the world has ever known. This medicine has defeated this enemy once and for
discovery will help us map the genetic structure all. Our comfort is a natural byproduct of our
of the microbe that sent a wave of death crashing progress and success—the remarkable break-
around the globe 80 years ago. throughs in antibiotics and vaccines, thanks to
It is hard to believe today that flu could be so the work of scientists and researchers worldwide.
nearly apocalyptic. In just 11 months, at least 24 We eradicated smallpox—consigning one of
million people died, and most of humanity was history’s deadliest killers from the medical books
infected. The infected often never knew what hit to the history books. But infectious disease
them; in the morning they felt fine; by night they remains the leading cause of death worldwide
could be dead—drowned as the lungs filled with and the third leading cause in the United States.
fluid. There was no explanation, no protection, While we may be winning some old battles, we are
no cure. The pandemic produced scenes from a struggling with some new adversaries—emerg-
gothic horror novel—but it was all too real. In ing infectious diseases such as Ebola, hantavirus
Philadelphia alone, 11,000 died of the flu in a infection, new strains of tuberculosis (TB), AIDS,
single month. The dead were left in gutters, and and Lassa fever, to name a few. In fact, the World
death carts roamed the city in a surreal scene Health Organization (WHO) has labeled the
from medieval times. As the deaths mounted all growing threat of infectious disease a global
over the world, orderly life began to break crisis.
down. Schools and churches closed; farms and The time has come to replace complacency
factories shut down; homeless children wan- with a new sense of urgency—to launch a
dered the streets; their parents vanished. The renewed, unified, global effort against infectious
acting U.S. Army Surgeon General, Victor disease. Nature may have the power to create a
Vaughn, calculated that if the pandemic pandemic—but together we have the power to
continued its mathematical rate of acceleration, prevent it, to stop it, to overcome it, to cure it. And
it soon could spell the end of humankind. there is no time like the millennium. For today,
But then, as silently, as mysteriously, as history and human progress have created an
quickly as it came, the terror began to fade away. “ironic contradiction” in the fight against
People stopped dying. The victims were buried. infectious disease: some of the same forces that

Emerging Infectious Diseases 354 Vol. 4, No. 3, July–September 1998

Special Issue

invite pandemics can also be harnessed to fight the first antibiotic to fight a new generation of
pandemics. With the globalization of travel and “super bugs,” Synercid, won limited approval
trade, immigration, communication, and indus- from a Food and Drug Administration (FDA)
trialization, we have a smaller world with porous advisory panel. If it wins full approval, it will be
borders. Nations are more interconnected, people the first drug in a new arsenal of weapons. FDA
are more interdependent, and humanity is less continues to work with drug manufacturers to
divided by what the Indian poet Tagore called our bring new antibiotics to market as safely and
“narrow domestic walls.” So the bad news is that rapidly as possible.
we have fewer barriers against the spread of Antibiotic resistance is not just a medical
infectious disease; yet the good news is that those problem; it is also a behavioral problem. Patients
fewer barriers mean new avenues to progress and too often demand antibiotics for every illness—
the potential for sharing information and efforts even for viral infections (like the flu) that do not
to stop infectious disease. respond; patients often do not finish the course of
We now have the power to push infectious medication, allowing the remaining bacteria to
diseases off the world stage but only if develop resistance; many doctors overprescribe;
governments, world health organizations, the and the pharmaceutical industry has limited its
private sector, scientists, and researchers work antibiotic development because of cost. The
together with a global strategy. How do we widespread use of antibiotics in farm animals
successfully wage this global battle against may also be helping the spread of drug-resistant
infectious disease? The answer lies in what we genes. Given the consequences, we must act now to
can learn from the 1918 pandemic; it provides combat the diminishing effectiveness of antibiotics.
three important lessons—challenges for all of us. That is why CDC is strengthening surveillance and
The first lesson is that we must assume it implementing education campaigns about the
could happen again. Influenza pandemics have problem, why the National Institutes of Health
regularly swept the world every 10 to 40 years, (NIH) is studying resistance, and why FDA is
and it has been 30 years since the last influenza promoting judicious antibiotic use. But this is not
pandemic, Hong Kong flu, killed 700,000. Nature is a job for government agencies alone. Each and
creative, and the flu has great potential for every one of us who understands the risks needs
mutating. If a strain changes dramatically, we to spread the message that antibiotics are being
could suddenly have a virus for which we may misused, abused, and overused.
have no immunity, no vaccine, and no cure. The The next pandemic could also result not from
threat is not just the flu—the spectrum of new a mutating bug or ineffective antibiotics but from
infectious diseases is constantly expanding, an act of bioterrorism. Whether bioterrorism is
while old diseases, such as TB, have evolved into state sponsored or undertaken by a lone terrorist,
entirely new killers because they developed it is not just a problem for the military or law
antibiotic resistance. enforcement; it is also a challenge for the entire
The advent of antibiotics in the 1940s was one public health community. If a specific threat is
of the chief reasons we began to defeat infectious issued—perhaps someone claims to have released a
disease. However, almost as soon as antibiotics toxic agent in a public place—trained public health
were available, microbes mutated and developed officials must first verify that an incident has
resistance. In the 1950s to 1970s, we produced so occurred. They may need to decontaminate the
many new antibiotics that there was always an area, identify exposed populations, and deliver
alternative medication; today, the flood of new preventive measures and treatments. Too often,
antibiotics has diminished to a trickle, while the a threat is not issued, no warning is given. In such
microbes have continued to grow resistant. a situation, public health officials must first
Antibiotic-resistant bacteria are becoming more quickly determine the deadly agent, the route of
common in hospitals and among patients with exposure, and the likely source.
depressed immune systems. In Japan in 1996 and The U.S. Department of Health and Human
in the United States last year, we started to see a Services (DHHS) is coordinating with our
strain of staphylococcus infection, the most partners in other agencies and the military to
common hospital-acquired infection, which could ensure the proper training of state and local
sometimes withstand vancomycin—our most health officials, the availability of vaccines and
potent treatment. But almost simultaneously, drugs, and the enhancement of our surveillance

Vol. 4, No. 3, July–September 1998 355 Emerging Infectious Diseases

Special Issue

capacity and expertise. There is also an monitoring and surveillance system needed
administrationwide effort to train emergency worldwide is the excellent system that stopped
response teams and health-care providers in 120 the avian flu outbreak in Hong Kong. On a
cities. We must enhance our ability now to routine basis, officials collect throat swabs from
address the growing threat of bioterrorism. people with flulike symptoms. The samples are
The second lesson concerns preparation for a analyzed, and if suspicious, they are immediately
potential pandemic. We cannot wait until the sent to CDC, which functions as one of the WHO
next deadly microbe appears on the world stage. International Reference Laboratories for East
Therefore, since 1993, HHS has been leading a Asia. When the first known case of avian flu was
federal, state, and local effort to develop a diagnosed in a 3-year-old boy, warning bells went
“pandemic influenza plan.” As a result of the off immediately. When a second case appeared in
avian flu episode, we have sped up the process to November, health officials around the world went
complete the plan and pursue its full implemen- on alert, and a team from CDC left for Hong Kong.
tation. Meanwhile, CDC is studying the impact of Over the next 2 months, work continued to define
antiviral medications and alternative ways to the extent of the outbreak, including who was
produce vaccines. NIH is working with the becoming ill, why they were becoming ill, and
pharmaceutical industry to develop and test whether the virus could spread from person to
innovative vaccines, including a nasal spray that person and cause a pandemic. The slaughter of
delivers an inoculation dose of the virus. FDA is more than one million chickens seems to have
issuing new drug permits for experimental halted the virus at least for now.
influenza vaccines. With new viruses knocking at Hong Kong’s surveillance system proved that
the door, we cannot afford to be caught unprepared. early detection of infectious diseases can prevent
Because only in the movies can we save the world their spread. David Heymann of WHO once asked
from a deadly disease in just 24 hours. a provocative question: What would have
We need commitment in responding to all happened if we had had an excellent surveillance
emerging infectious disease. We need a world- system in place in Africa when the AIDS outbreak
wide “surveillance and response network” that first occurred? Perhaps we could also have halted
can quickly identify and stop an outbreak. We that virus in its tracks. Perhaps we would have
have already laid the groundwork for such a spared ourselves the second great pandemic of
system with bilateral and multilateral talks on the 20th century. AIDS taught us that regardless
disease monitoring with our partners in Europe, of a person’s sexual orientation, color, wealth, or
Japan, Asia, and Africa. For example, at the home, if we hesitate in our fight against
Denver Summit in 1997, the group of eight infectious diseases and fail to detect and track
industrialized nations, including the United them early, they will eventually affect us all.
States, pledged to help develop a global disease We cannot simply deal with each potential
surveillance network and coordinate an interna- pandemic as it arises. We must also look over the
tional response to infectious disease. Working horizon and seize new possibilities to head off
through the Trans-Atlantic Agenda with the infectious diseases before they can occur. We
European Union (EU), the United States and EU must fully harness this golden age of global
countries have begun to share surveillance data telecommunications (from satellites to the
on Salmonella infections. Additionally, through Internet) to create a truly global surveillance and
the U.S.-South Africa Bilateral Commission, our monitoring network and find new ways to
two countries are training health personnel in prevent, stop, overcome, and cure infectious
South Africa in surveillance and applied disease. That is one of the reasons that President
epidemiology. I look forward to working closely Clinton proposed the 21st Century Research
with WHO to further globalize our approach to Fund—a historic national effort to spur the best
surveillance and response. minds of this generation to unlock scientific
U.S. agencies are already supporting the discoveries, unravel scientific mysteries, and
efforts of WHO to improve communications uncover scientific advances. Today, the pace of
networks and to build regional centers for medical discovery is not limited by science or
monitoring disease. CDC and WHO jointly run 12 imagination or intellect but by resources. Thus,
world monitoring stations for the flu alone. the research fund will provide a US$1.1 billion
Perhaps the best example of the kind of budget increase for NIH next year. It is the first

Emerging Infectious Diseases 356 Vol. 4, No. 3, July–September 1998

Special Issue

down payment on an unprecedented 50% If we truly want to end the threat of infectious
expansion of NIH over the next 5 years. This diseases, we must do even more together. We
funding will enable NIH to do more to develop must inject into global gatherings—no matter
new ways to diagnose, treat, and prevent disease. where they are, no matter what the subject—the
We are also seeking a boost in CDC funding to urgency of working together to defeat infectious
step up our ability to identify and investigate disease. We must never let research into
infectious disease outbreaks, including foodborne infectious disease become a forgotten step-child.
outbreaks. CDC will play a key role in a new We must continue to invest in vaccine research
initiative by the U.S. Agency for International and development and ensure that preventive
Development to develop programs in targeted vaccines are available, affordable, and effective
countries to fight the growing threat of bacterial everywhere. We must work with all our
resistance, TB, and malaria. This new American partners in the private sector to ensure that
investment in fighting infectious disease will not drugs, vaccines, and tests are available during
only pay off in America, because in this world an infectious disease emergency. We must
without borders, a discovery by any one nation ensure that all urban populations have access to
will benefit us all and brings us a little closer to essential facilities, especially clean water,
preventing the next pandemic. because vaccines and medicines can do little if
The third lesson of the great pandemic of water is unclean. We must work together to deal
1918 is that we have the power to prevent the with urban overcrowding, poverty, and poor
next pandemic and defeat emerging infectious sanitation, which are spreading infectious disease
diseases, but only if our nations step up the fight in many parts of the world. Finally, we must pool
together. Because diseases recognize no borders, our greatest resources—our imagination and
in our fight against them, neither can we. Or as intellect—to fight this collective fight. For as
Dr. Bruntland of WHO has stated, when it comes Joshua Lederberg once noted, “Pitted against
to public health, “solutions, like the problems, microbial genes, we have mainly our wits.”
have to be global in scope.” That is why U.S. and Let us pit our wits (and our will) to this battle,
Japanese scientists have held three international together, to heed the lessons of the great
conferences together on infectious diseases and pandemic and so ensure that it does not happen
research. It is why some members of the Asian- again, that we are prepared, and that we always
Pacific Economic Cooperation Area, including work together. If we do, our children—the children
Thailand, Indonesia, and the Philippines, have of the millennium—will remember the 21st century
developed a communications network to track cases as a time of health and hope, a time of promise and
of multidrug-resistant TB. And it is why CDC, FDA, possibility, a time of medical miracles and
and other U.S. agencies are providing assistance to scientific marvels. I have absolutely no doubt that
the Russian Federation and the Newly Indepen- we can do it, that we must do it, that we will do it.
dent States, which have faced a large increase in
infectious disease in the post-Soviet era.

Vol. 4, No. 3, July–September 1998 357 Emerging Infectious Diseases

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Effective Global Response to

Emerging Infectious Diseases
Claire V. Broome
Centers for Disease Control and Prevention, Atlanta, GA, USA

To discuss the global efforts needed to detect reagents had to be available and the reference
and control emerging infections, I will begin with laboratories had to be able to make a definitive
a personal experience. In 1987, a large epidemic identification, not just of that initial strain, but of
of meningococcal meningitis occurred during the the hundreds of other strains evaluated. In this
haj, the annual pilgrimage of Moslems to Mecca. case, H5 reagents (the result of National
The Centers for Disease Control and Prevention Institutes of Health [NIH] research) had been
(CDC) sent a team of epidemiologists and distributed (by CDC) to reference laboratories
laboratorians to Kennedy Airport to meet the internationally. The capacity to respond to
thousands of pilgrims returning to the United potential outbreaks with expert epidemiologic
States. Returning pilgrims were given chemopro- investigation also had to be in place. The team
phylaxis; nasopharyngeal cultures showed that that went to Hong Kong consisted of epidemiolo-
11% of the pilgrims carried the epidemic strain of gists, laboratorians, a public affairs specialist,
group A Neisseria meningitidis, the causative and an expert in animal influenza. The team
agent. Only 25% of the returning pilgrims were worked closely with Hong Kong colleagues to
intercepted and treated; thousands of others detect new cases by implementing an enhanced
dispersed throughout the country (presumably surveillance system. They targeted not only
with the same 11% carriage rate of this highly hospitals but also outpatient settings. Most
virulent strain). Were U.S. surveillance systems importantly, they designed studies to rapidly
adequate to rapidly detect any subsequent determine whether the strain could be transmit-
outbreaks? We were completely dependent on ted from human to human. Would the H5N1
local physicians to diagnose cases, on laboratories isolates share the pathogenic potential of human
to isolate and serotype the organism, on the influenza, which is so readily transmissible from
notification systems to inform the state and human to human, or was this strain relatively
federal agencies. In this instance, the United limited in its ability to spread? The kind of rapid
States was fortunate and did not see any but rigorous epidemiologic studies undertaken by
secondary outbreaks. Other countries were not so the outbreak response team were invaluable in
fortunate; large epidemics occurred in Chad, answering this question; fortunately, the strain
Kenya, and Tanzania as a result of the same had limited potential for human-to-human
virulent clone of N. meningitidis. The importa- transmission. Still, we cannot become compla-
tion of this epidemic clone illustrates the central cent; given the genetic recombination potential of
importance of local capacity to diagnose, report, influenza viruses, we need to maintain and
and control emerging infectious diseases. enhance our surveillance systems worldwide.
A more recent example is the 1997 influenza Through the U.S. emerging infections
H5N1 outbreak in Hong Kong: the outbreak initiative, the number of laboratory surveillance
illustrates what systems are needed to detect a sites supported to look for new influenza strains
new organism and to respond appropriately. has been increased. In China, sites had been
First, the Hong Kong public health system had to expanded from 6 to 12, which improved the
have the capacity to isolate the organism and to ability of the World Health Organization (WHO)
recognize that it was not an ordinary influenza system to monitor evidence of dissemination of
strain. Because infections emerge at the local this strain on the Chinese mainland. Through
level, the capacity to detect new threats when the CDC WHO Collaborating Center on
they arise should be available throughout the Influenza, we made diagnostic kits based on the
world. Secondly, the specialized diagnostic NIH H5 reagents available to reference

Emerging Infectious Diseases 358 Vol. 4, No. 3, July–September 1998

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laboratories around the world so that many secretariat to facilitate collaboration and provide
different areas can detect H5N1 should it emerge. regional expertise. WHO and CDC are working
At the same time, the WHO Collaborating Center with these countries to ensure necessary support
was actively engaged in training activities. and coordination with international surveillance.
The H5N1 example shows that we are The second area is communication systems. The
somewhat better able to deal with emerging Internet globally facilitates our ability to share
infections in 1997 and 1998 than we were in 1987. technical and surveillance information.
The example also underscores what is needed: We are better able in 1998 to address the
dramatically strengthened local surveillance, threats of emerging infections, but we are by no
including both laboratory and epidemiologic means fully prepared. We must have the capacity
capacity; commitment on the part of local to identify new or reemerging threats and to
governments; and a strong collaborative interna- respond successfully. We need to be creative and
tional research and response system. efficient in identifying necessary resources; for
Two other areas of international capacity example, the polio eradication program has
development contribute to effective response to developed a global network of laboratories and is
emerging infections. The first is Field Epidemiol- strengthening the surveillance systems needed
ogy Training Programs. These programs operate to identify poliomyelitis cases. Eradication
on the assumption that the best way to develop activities also contribute to health capacity
epidemiologic capacity in a country is to train development, and the laboratory and surveil-
local professionals who are committed to lance capacities created for polio eradication
continuing to work with the government in should also be useful in detection of and response
surveillance, outbreak response, epidemiology, to emerging infectious diseases. Many other
and other aspects of public health management. creative approaches and collaborations are
Field Epidemiology Training Programs have needed for an effective global response to
been developed in 17 countries. These programs whatever our microbial adversaries may produce.
are now planning to create an executive

Anthony S. Fauci Karen Hein Claire V. Broome

National Institutes of Health, National Academy of Sciences, Centers for Disease
Bethesda, Maryland, USA Washington, D.C., USA Control and Prevention,
Atlanta, Georgia, USA

Vol. 4, No. 3, July–September 1998 359 Emerging Infectious Diseases

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Addressing Emerging Infectious Disease

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

In 1962, Sir McFarland Burnet wrote, “One Addressing Emerging Infections in the
can think of the middle of the 20th century as the United States: Implementation of CDC’s
end of one of the most important social Plan
revolutions in history—the virtual elimination of
the infectious disease as a significant factor in Emerging Infections Programs
social life” (1). This statement is at the core of Seven Emerging Infections Programs have
many years of neglect of infectious diseases—it been established through cooperative agreement
represents complacency with a capital “C,” and awards (California, Connecticut, Georgia, Mary-
we are now paying the price. land, Minnesota, New York, and Oregon). These
Infectious diseases, the leading cause of programs share core projects on invasive bacterial
death worldwide (2) and the third leading cause and foodborne diseases. The California program is
of death in the United States, have returned with a focused on the San Francisco Bay Area. Four of the
vengeance (3). Between 1980 and 1992, infectious seven programs also focus on identifying the causes
disease deaths increased by 58% (39% after age of unexplained deaths and severe illnesses in
adjustment); the major contributors were HIV previously healthy persons ages 1 to 49 years.
infection and AIDS, respiratory disease (primarily
pneumonia), and bloodstream infection. Epidemiology and Laboratory Capacity
In 1994, the Institute of Medicine published Cooperative Agreements
Emerging Infections: Microbial Threats to Thirty awards established cooperative agree-
Health in the United States (4). This report ments with 28 states and two large cities (Los
broadly defined as emerging “new, reemerging, Angeles and New York) (Figure). Funds are used
or drug-resistant infections whose incidence in in different ways in different locales, but each
humans has increased within the past two recipient works toward strengthening infectious
decades or whose incidence threatens to increase disease surveillance capacity and improving
in the near future.” This report, which detailed laboratory capacity and the reporting and
the factors involved in emergence, reminds us analysis of infectious disease surveillance data.
that we live in a global village. In addition, CDC has established three new
Spurred on by the Institute of Medicine’s
report and by outbreaks of Escherichia coli O157
(January 1993), cryptosporidiosis (April 1993),
and hantavirus pulmonary syndrome (May
1993), the Centers for Disease Control and
Prevention and its partners produced a strategic
plan for addressing emerging infectious diseases
(5). The plan focused on increasing surveillance
and response capacity; addressing applied
research priorities; strengthening prevention
and control programs; and repairing the public
health infrastructure at local, state, regional,
national, and global levels. Incremental imple-
mentation of this plan is ongoing. An update plan Figure. Epidemiology and laboratory capacity coop-
will be published in the fall of 1998. erative agreements (shown in gray).

Emerging Infectious Diseases 360 Vol. 4, No. 3, July–September 1998

Special Issue

provider-based sentinel surveillance systems The Emerging Infectious Diseases Journal

with several partners. One network is based in To better track trends and analyze new and
emergency departments in academic medical reemerging infectious disease issues around the
centers (Emergency ID Network); a second, world, CDC established a quarterly, peer-
involving infectious disease clinicians, is in reviewed international journal (
collaboration with the Infectious Diseases Society eid/). The journal, a part of the communications
of America; and the third involves collaboration component of the strategy against emerging
with the International Society of Travel Medicine infections, has facilitated the exchange and
(Geo-Sentinel), which involves travel medicine dissemination of scientific information about
clinics in the United States and other countries. these infections.

The National Food Safety Initiative Future Plans

Because of inadequate foodborne disease Antimicrobial resistance, new and reemerg-
surveillance in the United States, the safety of ing infections, and a strong public interest in
the food supply could not adequately be assessed. health will demand vigilance, renewed efforts,
Six million to 81 million cases have been and strengthened partnerships in infectious
estimated (M. Osterholm, unpub. data). Food diseases. An update of CDC’s strategic plan along
Safety from Farm to Table (6), released in 1997, with cooperative efforts across government and
underlines the Clinton Administration’s commit- private organizations all over the world will drive
ment to improving food safety. future efforts for the control of new and
reemerging infections.
The National Molecular Subtyping Network
The national molecular subtyping network References
(7) for foodborne disease surveillance (PulseNet) 1. Burnet M, White DO. Natural history of infectious
represents a model of disease surveillance that disease. London: Cambridge University Press; 1962.
2. World Health Organization. The World Health Report
takes into account the globalization of the world’s
1997: conquering suffering, enriching humanity.
food supply. During the summer of 1997, the Report of the Director-General. Geneva, Switzerland:
state public health laboratory in Colorado using The Organization; 1997.
molecular fingerprinting techniques (pulsed- 3. Pinner RW, Teutsch SM, Simonsen L, Klug LA, Graber
field gel electrophoresis) recognized a cluster of JM, Clarke MJ, Berkelman RL. Trends in infectious
diseases mortality in the United States. JAMA
15 cases of E. coli O157:H7 infections from widely
scattered areas in the state (8). Rapid epidemiologic 4. Institute of Medicine. Emerging infections: microbial
investigation implicated undercooked ground beef threats to health in the United States. Washington:
from a single company, resulting in the recall of 25 National Academy Press; 1992.
million pounds of ground beef and the closing of the 5. Centers for Disease Control and Prevention. Addressing
emerging infectious disease threats: a prevention
plant that produced it. This outbreak illustrates the
strategy for the United States. Atlanta (GA): U.S.
critical role of public health laboratory capacity and Department of Health and Human Services, Public
rapid public health action in outbreak detection and Health Service; 1994.
response. Before the recent advances, this outbreak 6. U.S. Department of Health and Human Services, U.S.
probably would not have been detected. Department of Agriculture, U.S. Environmental
Protection Agency. Food safety: from farm to table. A
national food-safety initiative. A Report to the
The Emerging Infectious Diseases Laboratory President, May 1997. Washington: Government
Fellowship Program Printing Office; 1997.
In an effort to strengthen public health 7. Stephenson J. New approaches for detecting and
laboratory capacity, CDC in collaboration with curtailing foodborne microbial infections. JAMA
the Association of State and Territorial Public
8. Centers for Disease Control and Prevention. Escherichia
Health Laboratory Directors will be providing coli O157:H7 infections associated with eating a
opportunities for training state public health nationally distributed commercial brand of frozen
laboratory workers (9). Forty-five fellows have ground beef patties and burgers—Colorado, 1997.
participated in this program. An international MMWR Morb Mortal Wkly Rep 1997;46:777-8.
9. Emerging Infectious Diseases Fellowship Program.
track will be inaugurated in the summer of
Emerg Infect Dis 1995;1:105.
1998 with the support of the CDC Foundation
and Eli Lilly and Company.

Vol. 4, No. 3, July–September 1998 361 Emerging Infectious Diseases

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Global Surveillance of
Communicable Diseases
David L. Heymann and Guénaël R. Rodier
World Health Organization, Geneva, Switzerland

Globalization and Health: The Need for source of communicable diseases such as
Global Surveillance hepatitis and other bloodborne infections. Social
A recent report of A/Sydney/05/97-like and environmental changes linked to urbaniza-
(H3N2) influenza on a cruise ship from New York tion, mobility, and deforestation have created
to Montreal demonstrates the ease with which new opportunities for infection, while rapid
communicable diseases can be transferred across adaptation of microorganisms has facilitated the
international borders (1). In this outbreak 2.7% of return of old communicable diseases and the
passengers and 0.5% of crew had acute febrile emergence of new ones. With the rapid evolution
respiratory illness during or after the cruise and of antimicrobial resistance, treatments for a wide
introduced this antigenic variant of influenza A range of parasitic, bacterial, and viral infections
into both Canada and the United States. have become less effective. Today, a communi-
Other viral infections and parasitic diseases cable disease in one country is a global concern.
are also associated with population movements. In industrialized countries, where deaths due
During 1996, fatal yellow fever infections were to communicable diseases have greatly decreased
imported into the United States and Switzerland over the past century, the concern is to prevent
by tourists who traveled to yellow fever–endemic diseases from entering and causing an outbreak
areas without yellow fever vaccination (2,3). or reemergence. In developing countries, the
During the same year approximately 10,000 concern is to detect communicable disease
cases of malaria were imported into the European outbreaks early and to stop their mortality,
Community, one fourth of them from the United spread, and potential harm to trade and tourism.
Kingdom (4). Had mosquito vectors been present, When cholera entered Peru in 1991, it spread
these diseases could have set up endemic cycles. through the existing sanitation and water
Misdiagnosed by an unsuspecting health worker, systems, causing more than 3,000 deaths (9).
they could have been fatal. Seafood export embargoes and decreased tourism
Bacterial infections such as meningococcal cost an estimated loss of US$770 million to the
meningitis and cholera are also spread with ease Peruvian economy in 1 year. Negative economic
by international travelers. Among the pilgrims impact can also occur in the more robust
for the Haj in 1987, 7.7 per 100,000 returned to industrialized economies, the most recent example
their countries of origin with meningitis (5). being bovine spongiform encephalopathy and the
Cholera, often associated with religious pilgrim- new variant of Creutzfeldt-Jakob disease in the
age and movement of refugees, resulted in 70,000 United Kingdom.
cases and a 22% fatality rate in 1995 among Concerns about communicable diseases in
recently arrived Rwandese refugees in Goma, both industrialized and developing countries can
Democratic Republic of the Congo (formerly best be addressed through strong surveillance
Zaire) (6). Rickettsial diseases such as louse- systems, renewed commitment to public health,
borne typhus have also recently caused illness and strong international partnerships to
and death among refugee and prison populations strengthen national and international coopera-
of Burundi and Rwanda (7,8). tion in communicable disease prevention and
Population movement is only part of the control. In view of the disparity among national
globalization fallout. Expansion in international surveillance systems, partnerships in global
travel and commerce in food and medicinal surveillance are a logical starting point in this
biologic products provides another potential area of common commitment.

Emerging Infectious Diseases 362 Vol. 4, No. 3, July–September 1998

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Global Surveillance: An Essential Public Refugees and the United Nations Children’s
Health Instrument Fund. International military networks such as
With globalization, strengthened communi- the U.S. Department of Defense Global Emerging
cable disease surveillance at the global level has Infections System, private clinics, individual
become an essential public health instrument. In scientists, and public health practitioners complete
addition to providing necessary information for the network of formal information sources.
monitoring communicable diseases and evaluat- Geographic gaps and deficiencies in expertise
ing control measures, global surveillance serves in these networks must be rectified. These
as an early warning system for epidemics and networks must develop means of including the
provides the rationale for public health interven- private sector as well as other sources of valid
tion. Early detection of communicable diseases information such as military and research
and immediate public health intervention can laboratories. They must represent both human
curtail the numbers of communicable illnesses and and animal infections and provide information
deaths and negative effects on international travel on antimicrobial resistance and the environ-
and trade. At the close of the 20th century, which ment, including water, insect vectors, and
has seen the affairs of all countries become ever animal reservoirs.
more intertwined, global communicable disease
surveillance and response is a decisive element in Informal Sources of Information
controlling communicable disease. Telecommunications, media and Internet
Global surveillance provides health advice access, and rapid information exchange across
for international travelers and guidance to those the globe permit public health professionals
involved in international transport and trade, around the world to communicate more effec-
including the food, plant, animal, and animal tively. Many groups, including health profession-
products industries. At the same time, it supplies als, nongovernmental organizations, and the
crucial data to support the Biological Weapons general public, have access to reports on disease
Convention and to prevent or anticipate outbreaks, challenging national disease surveil-
bioterrorism. To be effective, global surveillance lance authorities, which were once the sole source
must be free of, and be perceived as free of, of such information. Public Internet sites are
political bias. Global surveillance requires a dedicated to disease news and include sites for
neutral reporting and response environment, and medicine and biology as well as major news
the World Health Organization (WHO) is agencies and wire services.
strengthening the framework within which it can Such electronic discussion sites, accessible
be fostered. through free and unrestricted subscription, are
valuable sources of information. Their scope
Global Networking may be worldwide (ProMed, TravelMed),
regional (PACNET in the Pacific region), or
Formal Sources of Information national (Sentiweb in France). They exemplify
Government and university centers such as unprecedented potential for increasing public
the U.S. Centers for Disease Control and awareness on public health issues.
Prevention, the U.K. Public Health Laboratory The Global Public Health Information
Service, the French Instituts Pasteur, the global Network is a second generation electronic
network of schools of public health, and the surveillance system developed and maintained
Training in Epidemiology and Public Health by Health Canada. Its powerful search engines
Intervention Network (TEPHINET) provide actively crawl the World-Wide Web looking for
confirmed reports of communicable diseases. reports of communicable diseases and communi-
Most of these sites are or will become part of the cable disease syndromes in electronic discussion
WHO Collaborating Centre network. This groups, news wires, and elsewhere. Searches are
network, as well as the WHO Regional Offices, in English and French and will eventually
WHO country representatives, and other WHO expand to all official languages of the WHO, to
and UNAIDS reporting sites, contributes to which it has created close links for verification.
global surveillance along with reporting net- Other network sources for communicable
works of other United Nations agencies such as disease reporting include nongovernmental
the United Nations High Commissioner for organizations such as the Red Cross and Crescent

Vol. 4, No. 3, July–September 1998 363 Emerging Infectious Diseases

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societies, Médecins sans Frontières, and Medical Requirements for monitoring the intentional
Emergency Relief International (Merlin), and use of pathogenic microbes have also been
Christian religious organizations such as the addressed in the network, specifically in the
Catholic and Protestant mission networks. revision of the IHR, in collaboration with the ad
hoc Group of States Parties to the Biological
Legally Mandated Sources of Information Weapons Convention.
The International Health Regulations (IHR) Nonverified information about communi-
are a legal instrument that requires WHO cable diseases coming from within the networks,
member states to report diseases of international including that from IHR, requires rapid
importance: currently plague, cholera, and verification from multiple sources other than the
yellow fever. Countries have not uniformly originator. Such “disease intelligence” requires
complied, often fearing unwarranted reactions information management skills, knowledge of
that affect travel and trade. In addition, the field conditions, and commonly used, standard-
official international reporting mechanism has ized medical language compatible with modern
not evolved with the new communications communication technology. WHO has therefore
environment and does not include many created an electronic verification system based on
communicable diseases of importance to interna- its internationally accepted norms and stan-
tional public health. A revision of IHR is therefore dards. This user-friendly system consists of an
being directed toward a stronger role in global electronic repository for ready information
communicable disease surveillance and control. access, regular electronic communication with
Currently being evaluated in a pilot study in 21 network members, and a tracking and follow-up
countries, the revised IHR emphasizes immedi- mechanism to verify each piece of information.
ate notification of all disease outbreaks of urgent The power of the verification system is its
international importance. Electronic reporting of network of contributors, which includes official
specific clinical syndromes of importance to government channels and all participating
public health will help countries report immedi- networks. Electronic mail provides immediate
ately, facilitating rapid alert and appropriate follow-up with easy-to-archive responses at low
international response while awaiting laboratory cost. Communications keep the focus on diseases
verification. Once the diagnosis is confirmed, it with international implications to avoid informa-
will also be fed into the system, permitting any tion overload. The criteria used to determine
necessary adjustments to the international international implication include suddenness of
response. When the revision is complete, IHR will onset, illness and death, potential for interna-
constitute an important public health tool as a tional spread, and likely effects on international
source of information linked to an appropriate travel and trade. Timely sharing of relevant
international response. information strengthens networking and contrib-
utes to common awareness of current events,
Pulling the Networks Together: Exchange thus increasing international preparedness.
and Verification of Global Surveillance
Information Epidemic Preparedness and Response
A neutral environment, internationally Once a communicable disease outbreak has
accepted surveillance standards and norms, and been confirmed, pertinent information is placed
wider use of modern communication tools is on the World Wide Web, available to the general
required to bring all these networks into a global public. At the same time, an international
surveillance system—a true “network of net- response including technical and humanitarian
works.” The network has been developed partners is mounted if required. A WHO team
together with the 191 WHO member states and arrives on site within 24 hours of outbreak
other partners, including the European Union- confirmation to make an initial assessment and
U.S. Task Force on Emerging Communicable begin immediate control measures and prepare
Diseases and the U.S.-Japan Common Agenda the ground for the larger international response
and has been cited as an area of collaboration by if needed. By linking the international response
the G-7/G-8 member countries at both the Lyon to systematic global surveillance, a worldwide
(1996) and the Denver (1997) Summit Meetings. “network of networks” is available from which to

Emerging Infectious Diseases 364 Vol. 4, No. 3, July–September 1998

Special Issue

solicit support, thus ensuring that no one epidemiologic and laboratory studies, prompt
country, technical, or humanitarian partner dissemination of public information, develop-
must bear the entire burden. ment of diagnostic test kits for international
distribution, and identification of a virus line
How It Works in Practice: Global Influenza suitable for vaccine development, all contrib-
Surveillance uted to a timely, ordered, and effective
Influenza surveillance, one of the most response to the outbreak.
developed global surveillance and monitoring WHO will celebrate the 50th anniversary of
systems of WHO, started in 1948 and developed global influenza surveillance with a meeting
over the years into a highly successful global bringing together participants from the national
partnership. The network now involves 110 influenza laboratories and WHO Collaborating
collaborating laboratories in 82 countries, Centers and other experts. Participants will look
constantly monitoring locally isolated influenza back over past successes and lessons learned and
viruses and providing information on true ahead to needs for improved surveillance and
emergence and spread of different strains. control of influenza in the 21st century, including
National case detection systems and labora- research priorities. The success of the global
tories have been strengthened using internation- influenza program can serve as a model for the
ally accepted norms; virus isolates from national continued development and strengthening of
laboratories are analyzed in more detail in one of international collaboration in the surveillance
the four WHO Collaborating Centers for and control of other communicable diseases.
Influenza. The data are then used by experts
associated with the surveillance system to make References
recommendations on the three virus strains to be 1. Centers for Disease Control and Prevention. Update:
included in the next season’s influenza vaccine. influenza activity—United States, 1997-98 season.
MMWR Morb Mortal Wkly Rep 1997;46:1094-8.
Thus, information generated from global surveil-
2. World Health Organization. Yellow fever in a traveller.
lance results in an important and unified public Wkly Epidemiol Rec 1996;30:342-3.
health response each year. The annual design of 3. Office Fédéral de la Santé Publique. Information EPI.
the vaccine also represents outstandingly Berne, Switzerland; 1996; Bulletin 28:5.
successful collaboration between the public and 4. Commission of the European Communities. Imported
malaria. European Communicable Disease Bulletin
private sectors.
In parallel to the surveillance program, 5. Moore PS, Reeves MW, Schwartz B, Gellin EG, Broome
national and global plans are being developed to CV. Intercontinental spread of an epidemic group of
systematically address the next influenza Neisseria meningitidis strain. Lancet 1989;8657:260-3.
pandemic. Both the surveillance system and the 6. Goma epidemiology group. Public health impact of
Rwandan refugee crisis: what happened in Goma,
elements of the global pandemic plan were tested
Zaire. Lancet 1995:345:339-44.
during the outbreak of the avian influenza 7. Bise G, Cominx R. Epidemic typhus in a prison in Burundi.
A(H5N1) virus in humans in Hong Kong in late Trans Royal Soc Trop Med Hyg 1997;91:133-4.
1997. The rapid identification of the virus strain 8. A large outbreak of epidemic louse-borne typhus in
in one of the collaborating laboratories in the Burundi. Wkly Epidemiol Rec 1997;21:152-3.
9. World Health Organization. Cholera in Peru. Update.
Netherlands, mobilization and coordination of an
Wkly Epidemiol Rec 1991;20-141-6.
investigating team from WHO Collaborating
Centers in the United States, extensive

Vol. 4, No. 3, July–September 1998 365 Emerging Infectious Diseases

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Emerging Infections: An
Evolutionary Perspective
Joshua Lederberg
The Rockefeller University, New York, New York, USA

Our relationship to infectious pathogens is the fidelity of replication; therefore, the concept
part of an evolutionary drama (1). Here we are; of the quasispecies swarm was recently gener-
here are the bugs. They are looking for food; we ated. For many RNA viruses, retroviruses in
are their meat. How do we compete? They particular, the rates of mutation are so high that
reproduce so quickly, and there are so many of to a close approximation, every particle is
them. They tolerate vast fluctuations of genetically different (in at least one nucleotide)
population size as part of their natural history; a from every other particle. They are rapidly
fluctuation of 1% in our population size is a major evolving as swarms of genotypes, no single
catastrophe. Microbes have enormous potential genotype being totally representative. Natural
mechanisms of genetic diversity. We are different selection plays a substantial role. The role of
from them in every respect. Their numbers, rapid cooperativity in infection of these viruses,
fluctuations, and amenability to genetic change particularly among retroviruses and HIV, has not
give them tools for adaptation that far outpace been adequately investigated. Rous sarcoma
what we can generate on any short-term basis. virus is a case in point. It may be difficult for a
So why are we still here? With very rare single particle, many generations removed from
exceptions, our microbial adversaries have a the original competent infector, to consummate
shared interest in our survival. With very few an infection by itself, but it can be complemented
exceptions (none among the viruses, a few among by other helper viruses present in the same cell.
the bacteria, perhaps the clostridial spore-
forming toxin producers), almost any pathogen Haploid Organisms
reaches a dead end when its host is dead. Truly Most of the organisms we are dealing with are
severe host-pathogen interactions historically haploid, so they have no delay in expressing new
have resulted in elimination of both species. We genetic factors. The prompt expression may
are the contingent survivors of such encounters potentially augment cumulative genetic alter-
because of this shared interest. ations, but in the short run, a resistance mutation
will manifest itself almost immediately and will
Microbial Resources be subject to natural selection very promptly.
Multicopy plasmids, which would behave differ-
Intraclonal Processes ently, are exceptions.
DNA Replication
Microbial intraclonal methods of variation Phase Variation
are legion. DNA replication is error prone, and Phase variation occurs in almost every
often the constraints of precise replication are pathogenic bacterium, in malaria parasites, in
turned off in the presence of DNA damage or other trypanosomes, and in Borrelia. Changes that
injury. Microbes often live in a sea of mutagens, appear to be mutational, on closer examination
chemical and physical. If we go out in the sun, our turn out to be microbial access to an archive of
skin is damaged; in microbes, UV irradiation goes genetic information, much of which has been
unimpeded to the very core of their DNA. Those silenced and then reappears as an adaptive
that are not killed are rapidly mutated. change. The flagellar antigens of salmonella
provide the historic example; they can exist in
RNA Replication either so-called specific phase or group phase,
RNA replication is particularly error prone. going back to H1 or H2 loci. We now know that
There are no editing mechanisms for examining they are the result of silencing one of these loci by

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the position of a piece of DNA that can be inverted (e.g., in animal husbandry). The mechanisms
to move the promoter from one locus to another exist to make it easy not only for single antibiotic
and give a very sudden transformation of the resistance but whole blocks of resistance to be
serotype from type 1 to type 2. This is a moved from one bacterium to another.
completely reversible phenomenon; the same
event can reinvert that DNA. Many species of Host-Parasite Coevolution
site-specific recombinases are capable of scram- Microbes’ shared interest in our survival will
bling and rescrambling the bacterial genome in dominate the overall picture of their evolution.
order to silence and unsilence genes that may be Can this help us predict the outcome of the
then carried in an archival state. I pondered why balance between the host and the pathogen? The
bugs use this mechanism for keeping genes in a possible outcomes are so divergent that it is very
cryptic state when gene expression can be (and difficult to predict in detail what is going to
often is) regulated in other ways. The simplest happen in any particular confrontation.
speculation is that phase variation very often The long-term trend is coadaptation, in which
entails controlled antigenic factors. A bug does the host acquires factors for resistance and the
not want to telegraph to its host in advance that it parasite acquires factors for mitigation and
is carrying even a tiny relic of an alternative longer survival of (and thereby in) the host. These
epitope because that will provoke immunity on factors may be genetic mutations, which will
the part of the host even before it has undergone certainly be selected.
that phase variation. Other factors include human cultural
Genetic factors also control the rates of changes, such as hygienic procedures. The
mutability; whether these factors do or do not human species outdoes all other species in
directly influence adaptability to virulence is adopting behavior that is self-destructive rather
controversial. Preliminary reports suggested than self-protective. I am not convinced that
that virulent bacteria had a higher incidence of every nuance of human behavior has been
mutators. We now realize that mutators are quite specifically evolved. Most of our behavior, even
prevalent, and therefore bacteria are constantly the maladaptive self-destructive kind, is learned:
facing environmental challenges. the pity and the hope of our species.
Pathogens find it to their advantage to
Interclonal Processes mitigate their virulence, provided they can do so
Recombination mechanisms are quite pro- without compromising their livelihood. That is
miscuous. Conjugation, which can occur between the tightrope they walk. Rhinovirus, the agent of
bacteria of widely varying kinds, is most often the common cold, is an extremely successful
recognized by plasmid transfer and every now pathogen. We do little to get rid of it. We go to
and then by mobilization of chromosomes. work and school with our runny noses. The virus
Conjugation can even occur across kingdoms, has a number of adaptations (including the very
between a bacterium and a yeast, or between a moderation of its disease process) that tend to
bacterium and a plant. In the case of the facilitate its spread. I worry that a rhinovirus
rhizobium-like parasite, the crown gall bacte- may some day mutate into a somewhat more
rium, genetic material is transferred from the virulent form, given that it is capable of very
bacterium into the chromosomes of the host rapid spread.
plant. Similar phenomena probably occur in
eukaryotic infections. Some genes in viruses and Evolutionary Strategies
bacteria almost certainly were of eukaryotic The parasite’s dilemma is that if it
origin. Some bacteria can deliver DNA intercellu- proliferates rapidly, it may kill the host; that
larly to their host animals. would be a winning strategy if transmission were
Plasmid interchange (movement of tiny bits easy, vectors readily available, the host’s
of DNA from one species to another) is not just a behavior obliging, and mosquitoes abundant for
laboratory curiosity; it is the mechanism for rapid high-density spread. Such circumstances are
spread of antibiotic resistance from widely present in northwest Thailand where Plasmo-
different species, one to another. It adds even dium falciparum would be unlikely to survive for
greater cogency to our concerns about the less very long (because of its profound effects on its
than optimally advantageous use of antibiotics host) if the density of spread to new hosts were

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not favorable. In modern hospitals, the own devices, HIV would not kill its host; but by
mosquitoes are health-care attendants who knocking down the host’s immune system, the
inadvertently facilitate the transfer of infection virus opens the door for other organisms,
from one patient to another. including commensals, opportunists that can
thrive only when the immune defenses are
Toxins attenuated.
It is a wonder that the inexhaustible
reservoir of potent toxins has not spread much Symptoms
further. Botulinum toxin, one of the deadliest Vectors are rarely symptomatic, almost never
compounds, is produced in abundance by severely symptomatic. The plasmodium would
Clostridium botulinum, whose spread to other not benefit from killing the mosquitoes that
organisms and potential for becoming a major transmit it. If a rabid dog can be considered a
public health threat can easily be imagined. Why vector, its behavioral anomaly illustrates another
is this toxin so confined? The underlying biologic adaptation that serves the purposes of the
mechanisms are not confining it; rather, its parasite.
lethality keeps it under control. The microbe kills This line of thinking, what some people have
its host rapidly, and if it cannot continue to multiply called evolutionary medicine—call it common
even in the dead host, it reaches a dead end. sense—leads us to look at symptoms. To what
In specific physiologic circumstances, these extent should we be treating them? Some we
rules of natural selection might not apply. treat because they are life-threatening. But is
Escherichia coli O157 is a case in point. O157 has fever, for example, a host defense? Is it a mode of
little to do with E. coli; it is a shigella with a little bacterial attack? Is the bacterium or virus
cloak of E. coli antigens. O157 should not be used producing pyrogens because a higher tempera-
as the sole diagnostic criterion for the spread of ture will promote its own replication? Are
shigelloid disease. The toxin genes can inhabit pyrogens just side effects of other evolutionary
other vectors. The ecologic implications of its adaptations that have not come to equilibrium? It
human and bovine virulence are not clear. is hard to avoid models that assume equilibrium;
Perhaps polymorphism (changes in bacterial few complex physiologic systems are so obliging.
genotype) alters its virulence in human and bovine We should question symptoms from an evolution-
species. The human loop is quite incidental to its ary perspective. How did they come to be there?
overall survival, as far as we know. The attack rate This approach may open the door to new avenues
in humans is only 1%. How has E. coli O157 of thought in examining the disease process.
evolved? We understand that as poorly as we Cough, diarrhea, or hemorrhage may serve the
understand the sporadic emergence of Legionella purposes of the parasite; even so, we may still have
from the soil into our air-conditioner ducts. to treat hemorrhage, but how far should we go in
treating cough? On the one hand, if not too severe,
Proliferation Rate cough may eliminate some of the infectious load
If the parasite adopts another strategy and from the body; on the other hand, cough generates
proliferates slowly, we have an evolutionary an aerosol that further disseminates the organism.
mechanism in which our own immune system is Cough may have to be treated as a public health
looking for deviants; this mechanism will be measure as much as a therapeutic measure.
presenting new epitope receptors waiting to be Diarrhea is another example; it may be a way of
stimulated. Most acute infections produce a full eliminating the parasite or a special adaptation
immune response at a humoral and a cellular enhancing dissemination.
level within a week or 10 days. So the microbe Other symptoms (malaise, headache, pain,
that proliferates slowly is laying the groundwork itching) probably have different answers. Pain is
for its own vulnerability unless it adopts some a puzzling symptom, which plays an indispens-
further tactics (e.g., phase variation, stealth able role by drawing attention to a disease. Once
tactics, antigenic mimicry, exploiting the the disease is acknowledged, there is no reason in
autotolerance that the host needs to survive its the world not to treat pain. Yet I know of no
own immune system). Parasites also compete infection (other than chronic leprosy) that
with commensals, with probiotic organisms. This induces anesthesia. It would seem to me that a
is where HIV runs into severe trouble. Left to its microbe bent on thriving would impart a sense of

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euphoria (rather than pain) to its host; we would the late 1950s and the early planning of our space
welcome it and infect ourselves with it. Analgesia program. Would it be permissible to move
may be the eventual moral hazard of biotechnology, contaminated spacecraft from one planet to
the internalized moonshine still or poppy patch. another? Certainly proliferating organisms on
The ultimate symptom, death of the host, is Earth could be easily carried to Mars. What
almost never to the advantage of the parasite. would happen if we brought back Mars samples?
Death signals a breakdown in the equilibrium These considerations resulted in an international
(the contract between parasite and host) that convention for the conservation of the microbial
could have had a better outcome had both sides virginity of celestial bodies. Sterilization proto-
been more witting. cols were applied to the Viking Mars spacecraft
and by the Russians in the 1970s.
Zoonotic Interactions
Many lessons of evolutionary relationships Maternal Immunity
come from zoonotic interactions. Infections that One mechanism of accommodation is not
break out of their host of origin often have a very genetic but physiologic: maternal immunity. The
severe impact on their new host. Hantavirus is an recent outbreak of canine distemper in the lions
outstanding recent example. The pathologic of the Serengeti (1) demonstrates a
processes in the rodent carriers hardly compare quasihereditary cycle that does not involve the
with those in humans. Most zoonotic transfers genes at all but rather is the propagation of
simply do not work. They are host specific; many are maternal immunity, partial immunity on the
neutral. Every now and then, a zoonotic transfer part of the offspring, easier adaptation to
has enormously larger pathologic implications for infection by the host.
the host; these are the transfers we focus on. We
presume that the filoviruses and perhaps HIV are Mitochondria—the Ultimate Pathogens
in that category. Many, not all, simian immunodefi- What are the ultimate pathogens, the
ciency viruses are perceptibly less virulent in their ultimate symbionts? The mitochondria. A
natural host than HIV is in humans, perhaps bacterial invader probably 2.5 billion years ago
another example of equilibrium breakdown. got into the first eukaryotic cells and conferred
How could the zoonoses be pathogenic when oxidative machinery. Who is serving whom? We
they require so many subtle adaptations to come generally think mitochondria are to our
into a host and really cause disease? Dozens, if advantage, but think how hard we work to shovel
not hundreds, of bacterial genes would have to the coal into the furnace that the mitochondria
work in concert to be pathogens. Microbes make have provided in every cell of our body. Symbiosis
proteins and carbohydrates, familiar to our is a fact of life, not always friendly or mutually
systems of immunity. Therefore, if the parasite accommodating. In bacteria, plasmids confer
does not know how to live in the earthly host and great advantages for some functions, but many
the host cannot cope with totally alien parasites, plasmids also convey a “leave me and you die”
we end up with a wash. message. The plasmid encodes simultaneously
Consider tsutsugamushi fever, scrub typhus. for a toxin and an antitoxin but makes sure that
Bangkok is reporting intermediate levels of drug the toxin has a longer lifespan. So a bacterium
resistance in Orientalia in tsutsugamushi in careless enough to drop its plasmid will suffer.
central and eastern Thailand. The life cycle is one The plasmid has the long-term advantage of
of essentially a hereditary symbiont; the tick is ensuring that only cells able to continue to
transmitted transovarially and can be communi- proliferate will continue to have the plasmid. So
cated from tick to microbe or humans, where it knowing who is serving whom in these kinds of
rapidly proliferates. Reinfection back to the tick relationships is very complicated.
is not of consequence, which must be a fairly
recent spillover of pathogenicity for which there Patterns of Evolution
is not ongoing selection. Nothing in the life Thanks to the wonders of genomics and DNA
history of Orientalia would sustain its pathoge- analysis, we have a good overall model of the tree
nicity to maintain its high infectivity. of life and the overall patterns of evolution. By
Years ago planetary quarantine became a the criterion of 16S RNA, extraordinary
policy consideration, beginning with Sputnik in evolutionary changes have occurred within the

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multicellular branch, but these changes are not The rare nonfamilia incidence of sporadic
at the level of fundamental housekeeping Creutzfeldt-Jakob disease (CJD) poses a possible
machinery; they have to do with growing brains, example, although it is difficult to exclude some
eyes, branches, and flowers, incidental items not contact with prions in individual cases. We might
at the level of cellular physiology. watch for CJD-like disease as an incident to other
kinds of toxic insults. One implication of the
Viruses protein-prion model, not discussed hitherto, is
Where do viruses come from? Certainly in the that conformer alterations may ensure from
world of eukaryotic viruses, no one can say with chemical or physical trauma to preexisting prp-c;
confidence what the evolutionary provenance is. heat, toxins, side effects of other infections are
We believe that viruses originated from some candidates (2). Let us carefully label this as wild
kind of cellular organelle, perhaps ultimately speculation, pending badly needed assays for this
from the nuclear DNA, perhaps from the other conformer-altering capacity. Other protein-
organelles. Many of them would have to have aggregate or amyloid-based diseases (like
undergone enormous changes, and we cannot say Alzheimer’s) likely have a nucleating episode in
which came from where in any tangible example. their pathogenesis, even if there is no means of
This complexity can be illustrated (in the contagion from one person to another. At least in
prokaryotic systems) by the ease with which viral the pancreas, amyloid aggregation is a side effect
genomes can be integrated into bacterial chromo- of protein injury by glycation (3).
somes. These are all double-stranded DNA
bacterial viruses, so they have the same Emerging Pathogens
fundamental structure as bacterial chromosomes. What are we going to do about new, mutant,
They go in and out with ease and can be integrated and recombinant pathogen strains? What can we
and mobilized, sometimes as viruses, sometimes anticipate about new major outbreaks? How
as bacterial genes. It is impossible to say which should we be defending ourselves? The good news
came first. If one could point to an evolutionary of course is the wonderful technology in the
progression of clusters of genes in a bacterium on offing, one marvelous innovation after another in
the way to generation of a new virus, it would be every field of prophylaxis, vaccines, understand-
of some help, but how would one know it was not ing of pathogenic phenomena. The genomics
the relic of a very old one coming back again? Our work on bacteria is paying off and may even
most fundamental knowledge is very primitive. justify the overall project of human genomics all
by itself with its insights into microbial evolution
Prions and potential targets for new discoveries in
Prions offer a new paradigm, much of which disease management.
we do not understand. Stan Prusiner has argued At a very high strategic level, we have the
that prions are pure proteins. Trying to basic knowledge to control foodborne epidemics,
understand how a pure protein can propagate waterborne epidemics, and fecal-borne diseases.
confounds our conceptions of the transmission of At a technologic level, even sexually transmitted
biological information. So let us say that prion diseases can be controlled. One neglected
protein (e.g., scrapie prion protein) is a medium is air. Can we do as well in preventing
conformational modification of a normal protein, airborne transmission? Effective control may
prp-c, coded for by an endogenous gene, a part of come down to something as elementary as a face
the normal genome, not an essential gene. mask like that worn by police in 1918. Control of
Infected mice show some functional disorders but even a vicious airborne epidemic like influenza
can survive. One might argue that we do worse should not be above our technical capability. Tens
with this gene than without it as long as we are or even hundreds of millions of lives might be at
susceptible to this modification. stake over such elementary matters.
Not much new sequence information is The introduction of a new hemolysin into
imparted to the normal prion to convert it to the existing anthrax strains in a demonstration of
infective agent. The change may be merely in their pathogenicity in golden hamsters (4)
the prion’s conformation. We must consider required additional epitopes to vaccinate those
other mechanisms that might cause that same hamsters against this anthrax. This first example
conversion. of an artificially contrived new human pathogen

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illustrates additional challenges in the fight References

against emerging infections. 1. Lederberg J. Infectious disease as an evolutionary
Natural infection and disease are enough of a paradigm. Emerg Infect Dis 1997;3:417-23.
2. Causette M, Planche H, Delepine S, Monsan P,
challenge and should not be compounded by Gaunand A., Lindet B. The self catalytic enzyme
human-made agents of death. Biological warfare inactivation induced by solvent stirring: a new example
cannot be endured and must not be tolerated. of protein conformational change induction. Protein
Eng 1997;10:1235-40.
Dr. Lederberg, Nobel laureate in physiology or medi- 3. Kapurniotu A, Bernhagen J, Greenfield N, Al-Abed Y,
cine, is a research geneticist, Sackler Foundation scholar, Teichberg S, Frank RW, et al. Contribution of
and president emeritus at the Rockefeller University. Dr. advanced glycosylation to the amyloidogenicity of islet
Lederberg currently conducts research on genetic ex- amyloid polypeptide. Eur J Biochem 1998;251:208-16.
change mechanisms in bacteria. 4. Pomerantsev AP, Staritsin NA, Mockov YV, Marinin
LI. Expression of cereolysine AB genes in Bacillus
anthracis vaccine strain ensures protection against
experimental hemolytic anthrax infection. Vaccine

Gail H. Cassell (L)

Lilly Research Laboratories, Indianapolis, Indiana,

Helene Gayle (L)

Centers for Disease Control and
Prevention, Atlanta, Georgia, USA
Barbara Murray
University of Texas Medical
School, Houston, Texas, USA

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Emerging Infectious Diseases: A Brief

Biographical Heritage
D. Peter Drotman
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

The concept that infectious (and other) Even though Virchow was working before the
diseases emerge and reemerge is not new, and germ theory of disease was accepted, at a time
neither is the search for causes of disease when disease causation was highly debated and
emergence. However, societies frequently over- microbes were not well described, he seems to
look or forget that microbes evolve, adapt, and have correctly diagnosed typhus (or possibly
emerge in response to nonmicrobial and even relapsing fever) as the cause of the Silesian
nonbiologic changes in the physical and social epidemic (1). Even though Virchow’s diagnosis
environment. Sometimes we need to be rudely cannot be confirmed, it is consistent with clinical
reminded of this lesson. Two scientists who descriptions and epidemiologic inference. He
have delivered such reminders, both in the clearly demonstrated that the conditions and
form of landmark reports, are Rudolf Virchow, vectors for typhus and relapsing fever (famine
a 19th century German pathologist, statesman, and malnutrition, humid climate, poor housing,
and anthropologist, and Joshua Lederberg, the poverty) were present in Upper Silesia in 1847 to
American microbiologist who coined the phrase 1848. The agents that cause epidemic louse-borne
“emerging infectious diseases” within the last typhus fever (Rickettsia prowazekii) and relaps-
decade (Photo). We owe much to the pioneering ing fever (Borrelia recurrentis) were not
vision of these scientists. described until many years later.
Infectious diseases have been emerging for at Virchow’s report was a scathing criticism of
least as long as humans have inhabited the earth. the Prussian government, which he squarely
Every student of microbiology, medicine, and blamed for the epidemic. Virchow considered the
public health learns about the triangle of host, Silesian outbreak investigation a defining
environment, and agent; what is not clear is how
the three change over time, often in response to
changes in another side of the triangle. Factors
that influence such changes do evolve, but many
are surprisingly constant. How easily and often
some of these factors are overlooked is often both
consequential and tragic; a historical example
illustrates this point.
Rudolf Virchow, the founder of cellular
pathology, wrote the first textbook in that field
and established the principle that disease results
from disturbed cellular function. As a young
physician and anatomic pathologist in Berlin, he
was assigned by the central government to
investigate an epidemic in Upper Silesia, a sector
of the Prussian Empire populated by a Polish-
speaking minority. He completed the field
portion of his investigation on March 10, 1848
(exactly 150 years before the International
Conference on Emerging Infectious Diseases).
The report he wrote was remarkable. Rudolf Virchow and Joshua Lederberg.

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episode in his life and career, so when the 2). Each regarded control of diseases as primarily
government largely ignored the report and his social, political, and environmental. We overlook
recommendations (Table 1), he became a this common theme at our collective peril.
passionate voice in politics, albeit in a minority Unlike Virchow’s report, the words of Joshua
role. He died in 1902, a revered scientist with a Lederberg are being translated into actions.
lifetime of magnificent achievements, but also Those actions can be spurred by disseminating
with desires to have done more to improve public information and building partnerships to effec-
health and social conditions. We still have a lot to tively address the ongoing threat of emerging
learn from Virchow’s life and work. infectious diseases.
Joshua Lederberg was awarded the Nobel
Prize for medicine in 1958 for his discoveries References
concerning genetic recombination and the 1. Eisenberg L. Rudolf Ludwig Karl Virchow: Where are
organization of the genetic material of bacteria. you now that we need you? Am J Med 1984;77:524-32.
2. Silver GA. Virchow, the heroic model in medicine:
He is President Emeritus of The Rockefeller
Health policy by accolade. Am J Public Health
University in New York, a member of the 1987;77:82-8.
Institute of Medicine, an advisor to presidents, 3. Virchow RL. Report on the Typhus Epidemic in Upper
and a 20th century Rudolf Virchow. Like Silesia. Translated in: Rather LJ, editor. Rudolf
Virchow, Lederberg recognized that micro- Virchow: Collected Essays on Public Health and
Epidemiology, 2 vols. Canton (MA): Science History
scopic changes make much larger differences,
Publications 1985:311.
particularly when viewed in the context of 4. Taylor R, Rieger A. Medicine as a social science: Rudolf
global changes. Like Virchow, he coauthored a Virchow on the typhus epidemic in Upper Silesia. Int J
prescient report that associated a pressing Health Services 1985;15:547-59.
health emergency with larger social, political, 5. Lederberg J, Shope RE, Oaks SC, editors. Emerging
Infections: Microbial Threats to the United States.
and environmental changes. The similarities
Washington: National Academy Press, 1992.
between the two reports are striking (Tables 1,

Table 1. Virchow’s recommendations to the Prussian

government regarding the typhus epidemic in Upper
Silesia, 1848 (2)
Political reform and local self-government, including
local coordination of relief efforts
“Education, with its daughters, liberty and
prosperity” (3)
Economic reform
Agricultural reforms, including development of
Building of roads
Acceptance of Polish as an official language (while
most Silesians spoke Polish, nearly all the
physicians and school teachers assigned by the
central government spoke only German)
Separation of church and state (he criticized the
Catholic hierarchy) (4)

Table 2. Factors in disease emergence—The Institute of

Medicine’s 1992 report on emerging infections (5)
Human demographics and behavior
Technology and industry
Economic development and land use
International travel and commerce
Microbial adaptation and change
Breakdown of public health measures

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New and Reemerging Diseases: The

Importance of Biomedical Research
Anthony S. Fauci
National Institutes of Health, Bethesda, Maryland, USA

A generation ago, it was suggested that the awareness that we live a global community, that
threat of infectious diseases would soon become an diseases do not recognize borders, and that the
artifact of history. Today, as we approach the new U.S. public health community has an important
millennium, the folly of this position is role to play in fostering global health.
increasingly clear. My 87-year-old father recently
reminded me of this. In the course of his lifetime, The Importance of Research
spent almost entirely in New York City, he has The infectious diseases community faces a
witnessed two pandemics of extraordinary impact: difficult challenge: coping with ongoing problems
the global influenza pandemic of 1918–1919, which such as malaria and TB while preparing for the
killed more than 20 million people worldwide, and inevitable emergence of diseases that are
the HIV/AIDS pandemic, which began to unknown or are recognized but will reemerge in a
accelerate in the early 1980s and continues more threatening form. Available resources must
unabated in some parts of the world. In addition, be maximized by sustaining and increasing
at least 30 other new and reemerging diseases and collaboration between federal agencies, academia,
syndromes have been recognized since the 1970s, industry, and nongovernmental agencies, all of
including liver disease due to hepatitis C virus, which play important roles in the fight against
Lyme disease, foodborne illness caused by infectious diseases.
Escherichia coli O157:H7 and Cyclospora, water- Within the federal government, the Centers
borne disease due to Cryptosporidium, hantavirus for Disease Control and Prevention’s (CDC) work
pulmonary syndrome, and human disease caused by in detecting and tracking pathogens is critical,
the avian H5N1 influenza virus (Figure 1). Clearly, especially with regard to diseases that have
we remain vulnerable to new and reemerging recently emerged or have the potential for
diseases. emergence. Equally important, and complemen-
New diseases are superimposed on endemic tary to CDC’s efforts, is basic and clinical research
diseases such as diarrheal diseases, malaria, supported by the National Institutes of Health
tuberculosis (TB), and measles, which continue (NIH) and other agencies. Historically, basic
to exact a huge toll. Indeed, malaria and TB, research has led to important, often serendipi-
among others, are reemerging in a drug-resistant tous, advances that have illuminated the etiology
form. Today, infectious diseases remain the leading of sometimes mysterious diseases and facilitated
cause of death worldwide and the third leading the development of diagnostics, therapies, and
cause of death in the United States. Many vaccines (Figure 2).
pathogens are becoming increasingly resistant At the National Institute of Allergy and
to standard antimicrobial drugs, making Infectious Diseases (NIAID) at NIH, we have
treatment difficult and in some cases impos- increased funding for emerging diseases from
sible. Moreover, chronic conditions generally $39.3 million in fiscal year 1993 to an estimated
considered noninfectious actually have been (president’s budget) $85.0 million in fiscal 1999
found to have a microbial etiology. (Figure 3). Approximately 21% of the NIAID non-
AIDS infectious diseases budget is devoted to
Awareness of Emerging Infections emerging infectious diseases.
The challenges posed by infectious diseases With the help of our advisory committees, we
are recognized by the public and the media, as well have defined five priorities in emerging and
as by political leaders and policy makers at the reemerging diseases research: 1) supporting the
highest levels of government. There is a growing application of relevant scientific knowledge and

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Figure 1. Examples of new and reemerging diseases.

new technologies to the detection, identification, these diseases is greatest. It is essential to

and interdiction of emerging diseases, by expanding engage scientists in host countries and work
research on ecologic and environmental factors with them collaboratively, both to tap their
influencing disease emergence and transmission; 2) expertise as well as to help them build research
supporting the application of recent discoveries and infrastructure on their home soil.
new biomedical technologies to the identifica-
tion, management, and control of emerging Successful Partnerships
diseases, by expanding research on microbial The public and private sectors, including
changes and adaptations that influence disease government, academia, and industry, bring
emergence; 3) providing fundamental information complementary skills and perspectives to the
for developing prevention and treatment strate- research endeavor. Cross-sector collaboration can
gies that can be employed to ameliorate disease yield extraordinary dividends. A cogent example is
impact, by expanding research on host susceptibil- the development of protease inhibitors for the
ity to emerging or reemerging pathogens; 4) treatment of HIV disease.
supporting the development and validation of After HIV was identified in 1983, research-
vaccines, therapeutics, and other control ers funded by NIH and others began to
strategies for specific diseases with the potential intensively study the structural and regulatory
to emerge or reemerge; and 5) strengthening the genes of HIV and the role these genes and their
current U.S. research and training infrastructure products play in the replication cycle of the
for detecting and responding to outbreaks of virus. This work led to an understanding of the
infectious diseases. importance of the HIV protease enzyme and
Among many studies domestically and methods to express, purify, and crystallize the
internationally, NIAID sponsors five interna- enzyme. Building on these findings, researchers
tional programs in tropical infectious diseases, in the private sector designed and produced
most of which have components both in the United specific inhibitors of HIV protease and worked
States and in the countries where the incidence of closely with the Food and Drug Administration,

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Figure 2. Emerging infectious diseases: a research ap- Figure 3. Emerging diseases funding (National Insti-
proach. tute of Allergy and Infectious Diseases).

NIH, and others to assess protease inhibitors in organizations and donor agencies from around the
clinical trials. world to form a coalition called the Multilateral
The first of four licensed protease inhibitors Initiative on Malaria. This unprecedented
reached the market in December 1995. Given in initiative will enhance international collabora-
combination with at least two other antiretroviral tions, encourage the involvement in malaria
drugs, protease inhibitors dramatically reduce research of scientists from malaria-endemic
levels of plasma viremia in a substantial proportion countries, and identify additional malaria
of patients. Both controlled and observational research resources. In addition, NIH has
studies show that these potent regimens can provide bolstered its long-term commitment to malaria
a substantial clinical benefit. research. NIH-supported malaria projects—many
Although drug combinations that include in collaboration with other government and
protease inhibitors have helped many patients, it international agencies—include 1) a new reposi-
is far too soon to become complacent or declare tory of materials available to researchers
victory. Many patients have not benefited from the worldwide; 2) basic, field-based, and clinical
new drugs or cannot tolerate their side effects, and research on all phases of malaria research; and 3)
drug resistance will inevitably become more projects to determine the genetic sequences of
widespread. The development of the next important malaria species.
generation of antiretroviral agents is crucial and
will require the skills of investigators in both the Responding to Avian H5N1 Influenza
public and private sectors. However, the cost of An outbreak of avian H5N1 influenza in Hong
antiretroviral drugs will probably keep them Kong recently alarmed the medical community
beyond the reach of much of the developing world; and the world. The multinational response to
therefore, the development of an HIV vaccine is of this outbreak has involved the close collabora-
paramount importance. tion of many organizations (Figure 4). As part of
NIH’s long-standing research into respiratory
Malaria Initiatives at NIH viruses, we had in our reagent repository the
Until relatively recently, AIDS was virtually specific antisera needed to quickly develop test
the only emerging disease with global impact that kits that were used effectively by CDC and
was widely discussed in the United States; others for detecting and tracking the virus. We
however, other diseases such as malaria and TB also have supported the rapid production of a
have actually caused more illnesses and deaths recombinant vaccine against avian influenza
over the past 2 decades. virus for use in laboratory and health-care
Malaria kills up to three million persons each personnel at risk. Without a strong research
year, most of them children in sub-Saharan Africa. base, the rapid response to this emergency
In the past year, NIH has worked with research would not have been possible.

Emerging Infectious Diseases 376 Vol. 4, No. 3, July–September 1998

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Vaccine Development important pathogens, such as Plasmodium spp.,

With avian flu, malaria, AIDS, and other Mycobacterium spp., Chlamydia trachomatis, Vibrio
new and reemerging diseases, an important goal cholerae, and Neisseria gonorrhoeae, are under way.
of NIH is the development of vaccines. If just
four recently developed vaccines (hepatitis B, Conclusion
rotavirus, Haemophilus influenzae type b, and The importance of basic research to the
acellular pertussis) were universally adminis- control of emerging and reemerging diseases
tered, more than three million deaths could be cannot be overemphasized. Emerging diseases
prevented each year. research encompasses many disciplines, and
Historically, scientific advances in microbiol- research advances that fall under the rubric of
ogy and related disciplines have driven the emerging diseases will be relevant not only to
development of new vaccines. For example, the specific diseases being studied but to a broad range
identification of microbial toxins, as well as of disciplines such as vaccinology, immunology,
methods to inactivate them, allowed the and drug development (Figure 5). In turn,
development of some of our earliest vaccines, research in these areas is critical to advances in
including those for diphtheria and tetanus. In the emerging and reemerging diseases. With a
1950s, new tissue culture techniques ushered in a sustained commitment to basic research and
new generation of vaccines, including measles, cross-sector collaboration, important scientific
mumps, and rubella. In recent years we have seen findings and technological advances can be
rapid advances in our understanding of the translated into improved global health and
immune system and host-pathogen interactions, reduced susceptibility to new microbial threats.
as well as technical advances such as recombinant
DNA technology, peptide synthesis, and gene Acknowledgment
sequencing. Each of these has facilitated the The author thanks Greg Folkers for helpful
development of new vaccines and vaccine discussion related to the preparation of this
candidates for important pathogens. manuscript.
Sequence information can be used in many
ways and promises to be useful in identifying References
antigens to incorporate into vaccines, as well as 1. Institute of Medicine, Board on International Health.
determining the factors that influence the America’s vital interest in global health. Washington:
National Academy Press; 1997.
antigenicity or virulence of a microbe. The
2. Centers for Disease Control and Prevention.
complete genetic sequences of more than 13 Staphylococcus aureus with reduced susceptibility to
microorganisms have now been published. More vancomycin—United States, 1997. MMWR Morb
than 60 other sequencing projects for medically Mortal Wkly Rep 1997;46:765-6.

Figure 4. Response to H5N1 avian influenza outbreak Figure 5. Benefits of emerging diseases research.
in Hong Kong.

Vol. 4, No. 3, July–September 1998 377 Emerging Infectious Diseases

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3. Centers for Disease Control and Prevention. Update: 5. Two cheers for the multilateral malaria initiative.
isolation of avian influenza A (H5N1) viruses from [editorial]. Nature 1997;388:211.
humans—Hong Kong, 1997-1998. MMWR Morb Mortal 6. Fauci AS. Biomedical research in an era of unlimited aspi-
Wkly Rep 1998;26:1245-7. rations and limited resources. Lancet 1996;348:1002-3.
4. The CVI strategic plan: managing opportunity and 7. The Institute for Genomic Research. TIGR Microbial
change: a vision of vaccination for the 21st century. Database [database online] [cited 1998 Apr 1]. Available
Geneva: Children’s Vaccine Initiative, 1997. Sponsored from: URL:
by UNICEF, United Nations Development Program, 8. World Health Organization. World Health Report
World Health Organization, World Bank, Rockefeller 1997—conquering suffering, enriching humanity.
Foundation. Geneva: The Organization; 1997.

Emerging Infectious Diseases 378 Vol. 4, No. 3, July–September 1998

Special Issue

Health Policy Implications of

Emerging Infections
Karen Hein
Institute of Medicine, National Academy of Sciences, Washington, D.C., USA

The solutions to emerging disease problems Emerging Infections: Microbial Threats to

involve politics and policy issues, as well as solid Health in the United States (1992)(3) identified
science. The National Academy of Sciences’ significant emerging infectious diseases, deter-
Institute of Medicine (IOM), whose mission is to mined what might be done to deal with them, and
“improve the health of people of the nation and recommended how similar future threats might
the world,” draws upon the expertise of elected be confronted to lessen their impact on public
members as well as others in the United States health. The document focused on factors
and other nations to make policy recommenda- contributing to disease emergence, not the
tions. Groups convene to debate contentious diseases themselves: human demographics and
issues and publish evidence-based reports with behavior, technology and industry, economic
recommendations to government, academia, development and land use, international travel
industry, and the public. and commerce, microbial adaptation and change,
Evidence-based reports are the foundation and the breakdown of public health measures.
upon which policy can be built. In this last decade, Sexually Transmitted Diseases: The Hidden
IOM has produced several documents that have Epidemic (1997) (4) focused on the need for a new
focused on emerging infections and provided a social norm of healthy sexual behavior. The small
springboard for policy on a local, nationwide, and investment in prevention efforts was contrasted
international scale. The U.S. Capacity to Address with the very high costs of care for treating
Tropical Infectious Disease Problems (1987) (1) sexually transmitted diseases (STDs) (Figure 1).
concluded that U.S. capacity was barely adequate The report also examined the obstacles and
and that improvement in policies and modest opportunities presented by managed care.
additional funding could make a substantially Limitations include the low priority for STD
stronger contribution to the field. Required prevention, emphasis on short-term cost savings,
efforts included sustained support for basic and
applied research; accelerated development and
testing of new preventive, therapeutic, and
diagnostic technologies; sustainable career struc-
tures for tropical disease professionals; increased
capacity to train U.S. tropical disease profession-
als and those from developing countries in research
and public health service; development of disease
surveillance capabilities; strengthened institu-
tional capabilities in developing countries; and
flexible, responsive administration of programs.
The Future of Public Health (1988) (2) report
made three basic recommendations regarding
the mission of public health and defined its core
functions to be assessment, policy development,
and assurance. It also included guidance for the
Figure 1. Estimated annual direct and indirect costs
government’s role in fulfilling the public health for selected sexually transmitted diseases (STDs) and
mission and the responsibilities unique to each their complications in 1994 versus national public
level of government. The report has been a useful investment in STD prevention and research in federal
blueprint for the past decade. fiscal year 1995 (4).

Vol. 4, No. 3, July–September 1998 379 Emerging Infectious Diseases

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varying technical capabilities for diagnosis and Institutes of Health described research and
treatment, and patient concerns about confiden- training issues relevant to the national strategy
tiality and treatment of partners not enrolled in for confronting the threat of emerging and
the same health plan. Lastly, opportunities for reemerging infections and related its approach to
training and continuing education in STD control addressing these issues.
and prevention are not built into most managed In 1996, the Department of State established
care settings. The report called for several steps an Emerging Infectious Diseases and HIV/AIDS
including a national campaign to heighten Program to serve as a focal point for the
awareness of the human and financial costs of development and implementation of U.S. foreign
STDs and to promote the use of social marketing policy objectives to improve the health of U.S.
techniques for their prevention. A recent citizens and to stem the spread of infectious
innovative informational campaign used a niche diseases worldwide through various interna-
approach and a social marketing strategy with tional bilateral and multilateral negotiations.
the spot video Hittin’ the Skins and the public This program has received $50 million in
service announcement Knockin’ Boots (D. funding. Other government agencies, including
Futterman, pers. comm.), geared toward FDA, U.S. Agency for International Develop-
alerting 16- to 21-year-olds of the need for HIV ment, Department of Defense, National Oceanic
testing. and Atmospheric Administration, National Aero-
Many related activities, in addition to the nautics and Space Administration, and U.S.
IOM reports, have underscored the danger of Department of Agriculture, have also examined
emerging infectious diseases and reiterated the the issue of U.S. vulnerability to epidemics and
warnings about the overall erosion of the U.S. resurgence of infectious disease threats.
public health system during the 1990s. The The IOM’s Forum on Emerging Infections is
reports also provided specific, detailed recom- the most recent activity within the National
mendations for action by individual agencies. In Academy of Sciences to keep sustained attention
1994, the Centers for Disease Control and on these issues. The forum was established in
Prevention (CDC) published Addressing Emerg- 1996 to provide a structured opportunity for
ing Infectious Disease Threats: A Prevention discussion and to scrutinize critical, and possibly
Strategy for the United States. In the same year, contentious, scientific and policy issues related to
the U.S. National Science and Technology research on and the prevention, detection, and
Council’s Committee on International Science, management of new and reemerging infections.
Engineering, and Technology (an interagency The forum has organized a series of workshops to
working group) was convened to consider the be conducted over 30 months. Workshop topics
global threat of emerging and reemerging include costs of infectious diseases, surveillance,
infectious diseases and in 1995 published the antimicrobial resistance, effects of health-care
report Infectious Disease—A Global Health restructuring on public health and basic research
Threat. In 1995, the National Security Council related to infectious diseases, capacity for
asked the federal government to examine its emergency response to emerging and reemerging
preparedness to respond to global epidemics. infectious diseases, education and training needs,
In 1995, the Food Safety and Inspection predicting the future, and behavioral interventions.
Service, CDC, and the Food and Drug Orphans and Incentives (5), a 1998 report, is
Administration (FDA) developed the Sentinel the first publication of the forum; it focused on
Site Study, which evolved into FoodNet and constraints that have left an undefined group of
now includes collection of more precise “urgently needed medical products in an
information on the incidence of foodborne orphaned condition which demands special
disease in the United States. In 1996, President attention.” The authors examined these products
Clinton’s administration set out a new policy to across the product cycle and then classified them
establish a worldwide infectious disease into categories for which incentives might be
surveillance and response system and expand developed to bolster the competitiveness of such
certain federal agency mandates to better products in industrial portfolios.
protect American citizens. The 1998 report Antimicrobial Resistance (6),
In the 1996 NIAID Research Agenda for the second publication of the forum, examined
Emerging Infectious Diseases, the National increases in the number of pathogens, multidrug-

Emerging Infectious Diseases 380 Vol. 4, No. 3, July–September 1998

Special Issue

resistant strains, compromised persons (includ-

ing HIV-infected patients), deaths from infection
with resistant organisms, speed of the global
spread, and costs of health care. The report also
examined decreases in the antimicrobial arma-
mentarium, amount of research and develop-
ment expended when resistance was not seen as a
major threat, and funding for public health
infrastructure and addressed the following
topics: expansion, coordination, and improve-
ment of the diverse elements of surveillance;
need for relatively small but thoughtful
investments in research, clinical management
and practice, and policy; use of antibiotics in food
production; ways to prolong the effectiveness of
Figure 2. The growing role of the World Bank in
existing antibiotics; basic research and incentives health (7).
for new antibiotics; and legal and regulatory
mechanisms in key areas of need.
A soon-to-be-published report on a March
1998 workshop on managed care will examine the Acknowledgments
implications of managed care systems on The author thanks Carol Bock for her assistance in
preparing this manuscript and Jonathan Davis for collecting
emerging infections by reviewing basic and background materials.
clinical research, clinical practice guidelines,
surveillance and monitoring, prevention, educa- References
tion and outreach, and product development. 1. The U.S. capacity to address tropical infectious disease
These reports and events have examined problems. Washington: National Academy Press; 1987.
research on emerging infectious diseases and p. 88. Sponsored by the Board on Science and
crafted a series of policy recommendations. They Technology for International Development, Office of
put forth a rationale for why the United States International Affairs, National Research Council and
Institute of Medicine, National Academy of Sciences.
should invest in global health. The 1997 report, 2. The future of public health. Washington: National
entitled America’s Vital Interest in Global Health Academy Press; October 1988. p. 240. Sponsored by the
(7), provided a new framework for thinking about Institute of Medicine, Division of Health Care Services.
the benefits to the United States, as well as to the 3. Lederberg J, Shope RE, Oaks SC Jr, editors. Emerging
infections: microbial threats to health in the United
rest of the world, of our increased participation.
States. Washington: National Academy Press; October
The movement of two million people each day 1992. p. 312. Sponsored by the Institute of Medicine,
across national borders and the growth of Division of Health Sciences Policy and Division of
international commerce are inevitably associated International Health.
with transfers of health risks (e.g., infectious 4. Eng TR, Butler WT, editors. The hidden epidemic:
confronting sexually transmitted diseases. Washington:
diseases, contaminated food, terrorism, and legal
National Academy Press; 1997. p. 392. Sponsored by
or banned toxic substances). U.S. commitment to the Institute of Medicine, Board on Health Promotion
global health serves to protect our people, enhance and Disease Prevention.
our economy, and advance our international 5. Harrison PF, Lederberg J, editors. Orphans and
interests. Moreover, governments are no longer the incentives: developing technology to address emerging
infections, Workshop Report. Washington: National
sole agents in the global health arena (Figure 2).
Academy Press; 1997. Sponsored by the Institute of
The United States can contribute not only Medicine.
with funding, but also with the scientific and 6. Antimicrobial resistance: issues and options. Workshop
technical expertise in its health sector. The Report. Washington: National Academy Press; 1998.
United States should lead from its strengths Sponsored by the Institute of Medicine, Forum on
Emerging Infections.
(medical science and technology) in the areas of
7. America’s vital interest in global health, protecting our
research and development, surveillance, educa- people, enhancing our economy, and advancing our
tion and training, global partnerships, and international interests. Washington: National Academy
coordination and leadership. In this way, the Press; 1997. Sponsored by the Institute of Medicine,
United States “can do well by doing good.” Board on International Health.

Vol. 4, No. 3, July–September 1998 381 Emerging Infectious Diseases

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Detection and Identification of Previously

Unrecognized Microbial Pathogens
David A. Relman
Stanford University, Stanford, California, USA, and Veterans Affairs Palo
Alto Health Care System, Palo Alto, California, USA

Features of a number of important but poorly explained human clinical syndromes

strongly indicate a microbial etiology. In these syndromes, the failure of cultivation-
dependent microbial detection methods reveals our ignorance of microbial growth
requirements. Sequence-based molecular methods, however, offer alternative
approaches for microbial identification directly from host specimens found in the setting of
unexplained acute illnesses, chronic inflammatory disease, and from anatomic sites that
contain commensal microflora. The rapid expansion of genome sequence databases and
advances in biotechnology present opportunities and challenges: identification of
consensus sequences from which reliable, specific phylogenetic information can be
inferred for all taxonomic groups of pathogens, broad-range pathogen identification on the
basis of virulence-associated gene families, and use of host gene expression response
profiles as specific signatures of microbial infection.

For 100 years, efforts to detect and identify Microbial cultivation methods opened up an
microorganisms have generally begun with the unsuspected world of microscopic life and
inoculation and incubation of growth media in the presumed causative agents of human illness.
laboratory. Colony purification and preparation of However, much of this world remained
limiting dilutions of liquid culture media have uncharacterized. In the external environment,
provided at least two benefits: amplification of certain biochemical activities could best be
microbial material and purification of single explained by the presence of microorganisms,
organisms along with their direct descendants. although they could not be cultivated in vitro.
Because some microorganisms are not particular in Sergei Winogradsky, a pioneering soil microbiolo-
their growth requirements, these efforts have gist of the early 20th century, spoke about the “less
yielded an array of diverse microbial cultivation docile” organisms that were not satisfied with
types. Serial propagation of microorganisms in the laboratory cultivation conditions. In the internal,
presence of varied energy sources, analysis of their privileged niches of animals, microorganisms were
macromolecular composition and their metabolic sometimes visualized in diseased tissues, and
by-products, and use of specific immunologic persons with typical clinical signs of infection would
reagents have created a variety of systems for respond to antibiotics, despite unsuccessful efforts
microbial classification and identification. Some at microbial propagation. That conserved genomic
isolates purified from diseased tissues of animal sequences might be used to infer evolutionary
and human hosts produced identical disease when ancestry and be amplified directly from natural
injected into other, previously healthy hosts. By the sites of infection provided the framework for
latter half of the 20th century, these findings had cultivation-independent approaches for micro-
led to optimism about our ability to detect and bial detection and identification. In a few years, it
recognize microscopic life forms, particularly forms became clear that most extant microorganisms in
that can cause disease. the external environment had been completely
overlooked because of their resistance to
Address for correspondence: David A. Relman, VA Palo Alto cultivation on artificial media.
Health Care System 154T, 3801 Miranda Avenue, Palo Alto, CA
94304, USA; fax: 650-852-3291; e-mail:

Emerging Infectious Diseases 382 Vol. 4, No. 3, July–September 1998

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Sequence-Based Methods for Pathogen region of sequence. For example, a newly

Discovery discovered hantavirus was identified as a cause of
What features of a genetic sequence make it acute pulmonary disease by using broad-range
useful for identifying uncharacterized micro- primers directed at a conserved region of a coat
organisms? (1). First, the sequence should be protein-encoding genomic segment (8). A collec-
conserved among a relatively large number of tion of family-restricted broad-range primers is
known organisms. Second, its rate of change necessary to identify unrecognized viral patho-
should be constant over long periods and among gens; this collection is not yet comprehensive.
diverse organisms and should allow inferences of Two other independent sequence-based meth-
evolutionary distance among a wide range of life ods are available for pathogen discovery. One relies
forms; the sequence should not be subject to widely upon subtractive hybridization to isolate fragments
discrepant degrees of evolutionary pressure. Third, of nucleic acid that are unique (different) to one
the sequence should not have been shared among member of an otherwise matched pair of specimens;
different organisms by horizontal transmission. these “difference” molecules are then selectively
Finally, the sequence should be amenable to broad- amplified by using linker sequences that had been
range amplification or detection. ligated to all fragments derived from the infected
The sequence of the small subunit ribosomal specimen. Multiple rounds of subtraction and
RNA or DNA (ssu rDNA), among other genomic amplification are required to find rare fragments
sequences, meets these criteria. Ssu rRNA within a complex common background. Although
sequences were the first to reveal a tripartite tree better suited than differential display or suppres-
of cellular life, one that includes the bacteria, sive subtractive hybridization for low copy targets
archaea, and eukarya (2); few genetic sequences and highly complex backgrounds (such as human
reliably reflect the ancestry of such a wide array genomic DNA), this method, known as repre-
of cellular life as the ssu rRNA. Since this sentational difference analysis (RDA) (9), is labor-
realization nearly two decades ago, a large ssu intensive and cumbersome. Nonetheless, it identi-
rRNA sequence database has accumulated (3), fied for the first time the presumed causative agent
further enhancing the usefulness of this of Kaposi sarcoma, human herpesvirus 8 (9). RDA
particular locus. (More than 7,000 bacterial 16S enables detection of any class of microorganism;
rDNA sequences are now available). Highly however, it may be most useful for DNA viruses.
conserved regions of the ssu rDNA and ssu rRNA The third sequence-based pathogen discovery
provide priming sites for broad-range polymerase method takes advantage of host immunologic
chain reaction (PCR) (or RT-PCR) and obviate the recognition of an exogenous microbial agent.
need for specific information about a targeted Immune sera are used to screen an expression
microorganism before this procedure. Thus, a genomic library created from an infected
previously uncharacterized bacterium, for ex- specimen. While laborious, this method has also
ample, can be identified from an infected site or uncovered an important previously unrecognized
tissue by broad range bacterial 16S rDNA pathogen for humans: hepatitis C virus (10).
amplification, sequencing, and phylogenetic Sequence-based approaches take advantage
analysis (4). This approach was applied to the of the speed and sensitivity of rapidly evolving
uncultivated bacteria of bacillary angiomatosis in molecular biologic methods and the specificity of
1990 and of Whipple’s disease soon thereafter genotypic characterization. Consensus PCR has
(5,6). Because of the usual presence of host DNA, the additional advantage of being able to target
eukaryotic pathogens (parasites, fungi) must be families of sequences preselected for their
approached either with domainwide primers and reliability in the inference of evolutionary
partially purified pathogens or with range (e.g., relationships. However, all approaches have
kingdom)-restricted eukaryotic primers (7). limitations. One of the most important for
Broad-range PCR as a method for “pathogen sequence-based methods involves the processing
discovery” is not limited to ssu rDNA as a target of clinical specimens. Difficulties include hetero-
or to cellular life. Any phylogenetically reliable geneity of sample, wide variation in the numbers
family of orthologous gene sequences found of microbial targets in any given sample,
among a coherent group of microorganisms can resistance of some microorganisms to digestion
be targeted, as long as conserved priming sites and subsequent release of nucleic acid, and
can be defined at sites that flank the informative presence of PCR inhibitors in varying amounts

Vol. 4, No. 3, July–September 1998 383 Emerging Infectious Diseases

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and types—not to mention ubiquitous microbial niches had not been recognized or ever cultivated in
nucleic acid contamination of PCR reagents, the laboratory. Novel kingdoms of life have been
specimen collection materials, and externally discovered with these genotypic methods (12,13). It
exposed surfaces of the host. These problems has been estimated that only 0.4% of all extant
reflect the intrinsic biologic variability of a highly bacterial species have been identified. Does this
complex, partially characterized host. Standard- remarkable lack of knowledge pertain to the subset
ized procedures that produce consistent results of microorganisms both capable and accomplished
with large numbers of clinical specimens are rare. in causing human disease? The molecular methods
Despite increasing attention to these issues, described above could be applied in several settings
particularly in the private and commercial in which one might expect to find uncharacterized
sectors, resource commitment and technology microbial pathogens.
advances have lagged behind the development of
methods for sequence acquisition and analysis. In Acute, Life-Threatening Unexplained Illness
fact, it is far easier to generate a putative All clinicians are aware of cases character-
microbial sequence from a clinical specimen than ized by sudden onset of fever, flu-like syndrome,
it is to understand its clinical relevance. and hemodynamic instability, often accompanied
As the process of pathogen discovery and by leukocytosis or leukopenia and rapid
detection turns to the fundamental signature deterioration of one or more organ systems. In
macromolecules of all life forms and away from some cases, despite the strong suggestion of a
reliance on cultivation, we increasingly rely on microbial etiology, conventional diagnostic meth-
our ability to understand a putative microorgan- ods cannot determine the cause. The dramatic
ism from its genetic sequence. Many families of nature of these illnesses belies their potential
virulence-associated genes and gene products are importance to public health and their value in
recognizable from their sequence, and their revealing “emerging” agents of disease. An
targets are predictable. To predict whether the Unexplained Deaths and Critical Illnesses
microorganism whose presence is inferred from Project has been designed to identify and
amplified genomic fragments is the cause of the characterize these illnesses (14). Laboratory
disease under study, however, is far more investigations include the application of broad-
problematic. A replicating organism with which range ssu rDNA PCR. RDA is planned for
to observe behavior (e.g., drug resistance) and carefully selected cases with matched control
reproduce disease is not available. In fact, the samples. Appropriate specimens have been
viability of the putative microorganism may not obtained in only a minority of cases, but positive
be certain. Although detection of different results from cerebrospinal fluid samples are
molecular markers (e.g., specific mRNAs, rRNA/ encouraging. Two lessons have been learned. 1)
rDNA ratio, resistance-encoding loci) might help Well-recognized pathogens may be the cause of
resolve some of these questions, it is difficult to some critical illnesses that cannot be explained
determine whether these genotypes and markers with traditional diagnostic methods. 2) The
all derive from the same organism in that clinical process of clinical specimen selection and
specimen. From a practical standpoint, proof of collection may need to be rethought jointly by
disease causation from sequence-based investi- molecular biologists and clinicians.
gations will require data that address strength
and specificity of association, target dosage Chronic Idiopathic Disease
effects, temporal considerations, response to Adaptation and cooptation, features that
therapy, and use of in situ hybridization (11). The favor long-term survival of both participants,
selection of proper experimental and control dominate most host-pathogen relationships.
specimens is paramount. Persistent or intermittent inflammation indi-
cates host perturbation and a subtle imbalance to
Settings for Pathogen Discovery the relationship and gives rise to clinical
Explorations of microbial diversity within the manifestations. In fact, the epidemiologic,
external environment have yielded surprising clinical, and pathologic features of many chronic
results. Nearly all bacteria and archaea revealed inflammatory diseases are consistent with a
by broad-range sequence “mining” in fresh water microbial cause, but intimate or symbiotic host-
sites, oceans, surface soils, and deep geologic pathogen relationships are among the most

Emerging Infectious Diseases 384 Vol. 4, No. 3, July–September 1998

Special Issue

difficult to decipher and mimic in the laboratory. microbial diversity within the human-associated
Thus, it is not surprising that although microbial commensal flora is as limited as it was of external
etiologies are attractive hypotheses for many environments, these clinical observations may
chronic diseases, culture-dependent methods have not be surprising. That is, the inability to
not produced much evidence. Serologic approaches cultivate some of the commensal flora may
have been useful in providing some leads. For explain the failure to diagnose related disease. In
example, the first clues of a possible chlamydial addition to revolutionizing environmental micro-
etiology for coronary atherosclerosis were serologic biology, molecular methods may offer rewards for
findings. Corroborating data then became available clinical microbiology and the study of internal
from the use of molecular and in situ methods. environmental niches.
The list of chronic inflammatory diseases Recent research has compared culture-
with possible microbial etiologies is extensive dependent and culture-independent methods of
(15); it includes sarcoidosis, various forms of characterizing human commensal flora (16-19).
inflammatory bowel disease, rheumatoid arthri- The results suggest that members of at least some
tis, systemic lupus erythematosus, Wegener phylogenetic groups, e.g., the spirochetes, have
granulomatosis, diabetes mellitus, primary been ignored by traditional approaches. Direct
biliary cirrhosis, tropical sprue, and Kawasaki comparisons of these two methods will likely show
disease. In this discussion, the concept of biases and deficiencies with each; nonetheless,
pathogenic mechanism should be viewed broadly. important aspects of microbial diversity will be
Many chronic diseases may result from damage revealed by one and not the other. A complete
or disruption of local immunologic surveillance enumeration of complex microbial communities is
systems by microbial infection or products; the not the primary goal. Key members play crucial
microorganism is subsequently cleared away, but roles in maintaining the health of the ecosystem
autoimmune responses or responses directed (20,21), and understanding community interac-
against commensal flora persist. By the time tions and function may be the more important goal.
typical pathologic and clinical findings are
produced and the disease is recognized, the Arthropod Vectors and Small Animal
inciting agent or its nucleic acids may be gone. Reservoirs
Under these circumstances, the optimal time for Several prominent, recently described culti-
specimen collection may be well before the disease vation-resistant pathogens are transmitted to
takes on its characteristic features. Clinical humans from small animal reservoirs through
suspicion, astute observation, and identification of airborne or vector-borne routes. These pathogens
disease-predisposing factors are critical. Surpris- include borreliae (22), bartonellae (23), ehrlichiae,
ingly few published studies describe the application rickettsiae, babesiae, and hantaviruses. These
of broad-range molecular pathogen discovery reservoirs and the relevant vectors are attractive
methods to the diseases listed above or to other targets for pathogen discovery. Searches for
enigmatic chronic disease syndromes. With the restricted groups of microorganisms, searches
finding of microbial sequences in these disease within restricted host anatomic niches, or
settings, experimental criteria for identifying searches that include subtractive or differential
disease causation must be rigorously pursued (11). techniques may be warranted, since all these
targets are also hosts for their own commensal
Commensal Microbial Flora (e.g., intestinal) flora. Microorganisms that use
The human body harbors a 10-fold greater arthropod vectors often express different sets of
number of microbial cells than human cells. The genes within vector versus animal host (e.g.,
commensal flora includes microorganisms that human). Human immune recognition of differen-
occasionally cause disease, especially when host tially expressed gene products might help
defenses are impaired (due to immunosuppres- distinguish vector-associated pathogens from
sive drugs, disruption of anatomic barriers, nonpathogenic vector-associated flora.
suppression of bacterial flora with antibiotics, or
insertion of artificial surfaces). However, in many Phylogenetic Diversity of Microbial
hosts with impaired conditions and signs and Pathogens
symptoms of infectious disease, an etiologic agent Nearly all kingdoms within the domain
is not identified. If our understanding of Bacteria contain recognized human pathogens

Vol. 4, No. 3, July–September 1998 385 Emerging Infectious Diseases

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(Figure). Of those bacterial pathogens identi- 50 microorganisms by the year 2000. This
fied only by molecular methods, many are massive infusion of primary sequence data
clustered within some kingdoms and divisions, unleashes the potential to identify new families
such as the alpha-proteobacteria, which of broadly conserved orthologous genes that could
include many organisms that form endosymbi- be used to infer accurate phylogenies at every
otic relationships with their hosts. level and sector of the evolutionary tree. The
Nearly all humans harbor in the intestinal number of completed genome sequences is too
tract Archaea—among the most diverse and small to effect this goal (25). The sequence data
numerous cellular life forms on earth (24)—most sets for newly characterized genes are too small
to assess the reliability of the phylogenies they
predict. The problem imposed by horizontal gene
transfer is now more apparent with the analysis
of multitudes of gene families. To identify a well-
characterized microorganism, an exact genotypic
“hit” with a highly variable locus is sufficient.
Likewise, clonality and clone identification can
be determined with sequences from collections of
polymorphic, but conserved loci, e.g., “housekeep-
ing genes” (26). But for an unrecognized
organism, the sequence locus or loci selected for
genotyping must be highly conserved and
phylogenetically informative and reliable. Over
the next 5 years, with the increasing use of large-
scale comparative genomic techniques, microbial
sequence databases will represent the broad
diversity among distant ancestral relatives, as
well as the fine differences among closely related
Figure. Evolutionary tree of the domain Bacteria cousins. Assessment of putative universal
based upon comparative analysis of nearly complete sequences can be undertaken. All these develop-
16S rDNA sequences.
ments and future trends apply equally well to the
wide array of animal viruses and viral genomes
notably methanogens. So why are there no known (Table 1). As genotypes become more easily
archaeal pathogens? Although some of the most interpreted, they will continue to displace
well-known archaea were first identified in (and phenotypic characterization as the basis for
were assumed to require) extreme environments, pathogen recognition.
they are also found in environments similar to Often the only difference between a
those found within the human body. However, in pathogenic and a nonpathogenic strain of the
vitro cultivation methods for many archaea are same species, e.g., enteropathogenic and
unavailable, so how would we know if archaeal nonenteropathogenic Escherichia coli, is a small
pathogens existed? Molecular reagents for archaeal set of virulence genes. These differences are not
detection and identification, i.e., rDNA-based reflected in the ancestry inferred from more
primers and probes, have not been systematically stable chromosomal markers (Table 2). Yet
applied to human disease-associated specimens. detection of these genes is a fundamental aspect
Without such analyses, finding these organisms in
Table 1. Newer diagnostic technologies
clinical samples would be unlikely. 1. High-density DNA microarrays
• broad-based pathogen detection and
Genomics and Newer Technologies
characterization: bacteria, eukarya, viruses
The ultimate genotype of a microorganism is
its complete genome sequence. Approximately 15 • virulence-associated gene families
microbial genomes have been sequenced in their • comprehensive host gene expression profiles
entirety, and the rapid evolution of and large- 2. Improved nucleic acid subtractive methods
scale investment in DNA sequencing technology 3. Novel bioassays for toxin activity
predict full genome sequencing of approximately • neurons– or myocytes–on-a-chip

Emerging Infectious Diseases 386 Vol. 4, No. 3, July–September 1998

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Table 2. Pathogens that may be difficult to detect or

of pathogen identification. Microbial virulence is
a phenotype whose genetic basis is rapidly being 1. Pathogens that establish intimate relationships
revealed. Families of virulence-associated genes with the host
responsible for microbial adherence, toxicity, • endosymbionts and intracellular organisms
specialized secretion, environmental sensing, 2. Chimeras: natural versus man-made?
and subversion of immune defenses have been 3. “Nonpathogens” that acquire virulence-associated
defined, albeit with many sequence variations on genes
a theme (27,28). One of the most important features 4. Microorganisms without “universal” sequences?
of these genes is their proclivity toward horizontal
transfer and over relatively rapid time scales.
Genome sequencing efforts have facilitated, and measure changes in individual members as a
will continue to facilitate, this approach to pathogen function of varying environmental conditions.
discovery. Physical clusters (or islands) of The second theoretical use of DNA microarray
virulence genes are being identified, and their technology for pathogen detection would focus on
distinctive composition and boundaries are being host gene responses. Arrays in current use at
defined (29). One might well imagine the academic and commercial research laboratories
development of a comprehensive set of consensus are capable of quantitating expression responses
primers and probes for detecting these gene by 10,000 to 20,000 human genes simultaneously
families, clusters, and islands (Table 1). (30-34). During most infectious diseases, directly
With increasing value placed on genotypic affected tissues, secondary sites, and circulating
information and increasing numbers of poten- leukocytes will likely display sets of common
tially useful genotyping loci, the technology of nonspecific expression responses; however, since
sequence determination and primary genomic each microbial pathogen interacts with and
characterization has assumed center stage. Goals manipulates the host in a complex and unique
include speed, convenience, and large-scale manner, within these highly complex patterns
sequencing. High density DNA microarray technol- there will also likely be critical diagnostic
ogy is one of the most promising in this context signatures that distinguish infection by one
(Table 1). Depending on the format, microarrays pathogen from infection by another. Further-
can be used to detect nucleic acid polymorphisms or more, these stereotypic expression patterns will
to sequence de novo; they can also quantitate evolve. The time of initial host exposure to a
mRNA. At least two basic applications of DNA pathogen might be determined by comparing new
microarray technology are available for pathogen expression patterns with a suitable preexisting
detection and identification; neither has been fully set of timed profiles. Patterns will provide clues
developed or tested clinically (Table 1). The first about the pathogenesis of chronic inflammatory
would consist of a set of probes designed to assess disease (35). Through the identification of key
ssu rDNA sequence diversity of all known response genes might emerge novel diagnostic
monophyletic groups of bacteria, archaea, viruses, assays for their putative protein products and
and nonanimal eukarya. Other phylogenetically novel strategies for interfering with or blocking
reliable loci might be substituted for rDNA or disease pathogenesis.
included as well. In addition, consensus probes for In many cases, infection-associated tissue
families of virulence-associated genes, as described damage occurs in the absence of intact
above, would facilitate identification of unsus- microorganisms. Toxin-mediated disease is a
pected or newly acquired pathogenic attributes in prominent example. Often, microbial toxins act
organisms not usually associated with these traits. at a distance from the original site of microbial
Differential hybridizations and multiple toxin production and release. In this setting,
fluorophores allow easy detection of hybridized genotypic approaches for microbial detection may
target and normalization of quantified values to a not be appropriate; in addition to the assessment
reference sample. This sort of broad-range of host responses, novel bioassays for toxin
“pathogen detection chip” would identify mixed activity are attractive options (Table 1). For
infections, as well as chimeric or novel microorgan- example, in a system designed by Greg Kovacs at
isms (Table 2); it could rapidly create an inventory Stanford University, neurons or myocytes are
of highly complex microbial communities and cultivated on the electrical contacts of a

Vol. 4, No. 3, July–September 1998 387 Emerging Infectious Diseases

Special Issue

miniaturized circuit board. The electrical output 2. Woese CR, Kandler O, Wheelis ML. Towards a natural
and properties of these cells can be monitored and system of organisms: proposal for the domains
Archaea, Bacteria, and Eucarya. Proc Natl Acad Sci U
analyzed as they are exposed to diverse
S A 1990;87:4576-9.
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that such cells are extremely sensitive to Database Project). Nucleic Acids Res 1997;25:109-11.
chemical toxins, and this sensitivity can be 4. Relman DA, Loutit JS, Schmidt TM, Falkow S,
Tompkins LS. The agent of bacillary angiomatosis. An
recorded in the form of altered action potentials
approach to the identification of uncultured pathogens.
and changes in impedance and cell movement. N Engl J Med 1990;323:1573-80.
Experiments are under way to test cell responses 5. Relman DA, Schmidt TM, MacDermott RP, Falkow S.
to biologic toxins in a variety of clinically relevant Identification of the uncultured bacillus of Whipple’s
experimental conditions. disease. N Engl J Med 1992;327:293-301.
6. Wilson KH, Blitchington R, Frothingham R, Wilson JA.
Phylogeny of the Whipple’s-disease-associated
Relationships between Pathogen and Host bacterium. Lancet 1991;338:474-5.
As more sensitive and comprehensive 7. Santamaria-Fries M, Fajardo LF, Sogin ML, Olson PD,
methods for uncovering human-associated patho- Relman DA. Lethal infection by a previously unrecognised
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8. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE,
pected host-pathogen relationships, the nature of
Ksiazek TG, Feldmann H, et al. Genetic identification
these relationships may need to be rethought of a hantavirus associated with an outbreak of acute
(36,37). Parasitism and commensalism are respiratory illness. Science 1993;262:914-7.
probably not the complete story; mutualism may 9. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J,
be more common in the human host than is Knowles DM, et al. Identification of herpesvirus-like
DNA sequences in AIDS-associated Kaposi’s sarcoma.
usually taught. Evidence of coevolution between
Science 1994;266:1865-9.
host and microbe suggests codependence. The 10. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW,
endosymbiont theory for the origin of eukaryotic Houghton M. Isolation of a cDNA clone derived from a
organelles is consistent with the same (38). blood-borne non-A, non-B viral hepatitis genome.
Microbial remnants and cryptic genomic frag- Science 1989;244:359-62.
11. Fredricks DN, Relman DA. Sequence-based
ments may not be so uncommon within the
identification of microbial pathogens: a reconsideration
human genome; for example, approximately 1% of Koch’s postulates. Clin Microbiol Rev 1996;9:18-33.
of the human genome is retrovirus sequence (39). 12. Barns SM, Delwiche CF, Palmer JD, Pace NR.
Some of these viral genes may be expressed Perspectives on archaeal diversity, thermophily and
during local inflammation. The real challenges in monophyly from environmental rRNA sequences. Proc
Natl Acad Sci U S A 1996;93:9188-93.
pathogen discovery will be the problems of
13. Hugenholtz P, Pitulle C, Hershberger KL, Pace NR.
sequence interpretation, clinical relevance, and Novel division level bacterial diversity in a Yellowstone
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Only with the coordinated interaction of epidemi- AL, Klug LA, et al. Unexplained deaths due to possibly
infectious causes in the United States: defining the
ologists, pathologists, and clinicians will the role of
problem and designing surveillance and laboratory
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Emerg Infect Dis 1996;2:47-53.
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cine and of microbiology and immunology at Stanford etiology of chronic idiopathic diseases. In: Remington
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velopment and application of molecular methods for patient with severe destructive periodontitis. Infect
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in the natural environment: a molecular phylogenetic
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Thomas C. Nchinda (L)

David Heymann
World Health Organization,
Geneva, Switzerland.

Vol. 4, No. 3, July–September 1998 389 Emerging Infectious Diseases

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The Emergence of Bovine Spongiform

Encephalopathy and Related Diseases
Sir John Pattison
Medical School of University College London, London, United Kingdom

Since 1986, approximately 170,000 cases of bovine spongiform encephalopathy

(BSE) have occurred among approximately one million animals infected by
contaminated feed in the United Kingdom. A ruminant feed ban in 1988 resulted in the
rapid decline of the epidemic. Transmissible spongiform encephalopathies due to
agents indistinguishable from BSE have appeared in small numbers of exotic zoo
animals; a small outbreak among domestic cats is declining. Creutzfeldt-Jakob disease
(CJD) has been intensively monitored since 1990 because of the risk BSE could pose to
public health. In 1995, two adolescents in the United Kingdom died of CJD, and through
the early part of 1996, other relatively young people had cases of what became known
as new variant CJD, whose transmissible agent (indistinguishable from that of BSE) is
responsible for 26 cases in the United Kingdom and one in France. Areas of concern
include how many cases will appear in the future and whether or not use of human blood
and blood products may cause a second cycle of human infections.

Before the 1980s, a number of diseases of decline (Table 1). Approximately two thirds of
animals (scrapie, chronic wasting disease, and the dairy herds in the United Kingdom have
transmissible mink encephalopathy) and hu- had at least one case of BSE compared with
mans (Creutzfeldt-Jakob disease, Gerstmann- only one sixth of the beef suckler herds.
Straussler-Scheinker syndrome, and kuru), in Furthermore, most of the affected suckler
spite of distinctive individual features, could be herds contained animals originating from dairy
unified by the term transmissible spongiform herds, which are fed differently.
encephalopathies (TSEs). In 1986, bovine Shortly after the recognition of BSE,
spongiform encephalopathy (BSE) was first epidemiologic studies indicated that the source of
identified in indigenous cattle in the United infection was the meat and bone meal used in
Kingdom (1). A variety of clinical signs have been concentrated cattle feed (5). Subsequently, in
observed, but the three cardinal features of the July 1988, ruminant protein in ruminant feed
disease are nervousness, heightened reactivity to was banned. This ban immediately reduced the
external stimuli, and difficult movement, particu-
larly of the hind limbs (2). Spongiform change is
evident in the brain (1), and neuropathologic tests Table 1. Annual incidence of bovine spongiform
encephalopathy in the United Kingdom, 1985–1997
remain the mainstay of a BSE diagnosis. The
Year Number of cases
disease was transmitted experimentally to mice (3) 1985 14
and cattle (4) by use of brain homogenates from 1986 60
cattle with clinical BSE; thus BSE has all the 1987 630
features that define classical TSEs. 1988 2,184
1989 7,137
The BSE Epidemic 1990 14,181
Some 1985 cases were diagnosed retrospec- 1991 25,032
tively; other cases occurring before 1986 probably 1992 36,682
1993 34,370
went unnoticed. Since BSE was recognized, more
1994 23,945
than 170,000 cases were reported in the United 1995 14,300
Kingdom through the end of 1997. The epidemic 1996 8,016
curve, which peaked in 1992, is now in rapid 1997 4,052

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incidence of new infections, which began to be very few new infections by the beginning of the
reflected in a diminution in the incidence of next decade. The predictions have been validated
clinical cases 5 years later (the average by the actual numbers in 1996 and 1997, which
incubation period) in 1993. Nevertheless, almost were 8,016 and 4,149, respectively (9).
36,000 cattle with BSE were born after the
ruminant feed ban (a few as late as 1994), which Infection in Other Animals
indicates that the ban was not completely BSE has also been transmitted to exotic
effective. Ruminant protein could be included in ruminants in zoos in the United Kingdom.
pig and poultry feed, and cross-contamination of Between 1986 and 1992, cases have occurred in
cattle feed in the production mills and perhaps bison, nyala, gemsbok, two species of oryx,
accidental exposure of cattle on the farm were greater kudu, and eland. These animals became
possible until the feeding of mammalian protein infected by eating the same meat and bone meal-
to all farm animal species in the United Kingdom containing concentrated feed responsible for the
was prohibited in 1996. disease in cattle. BSE infection in species other
The average age at which clinical BSE than ruminants was always considered possible.
manifests itself is 4 to 5 years (6). Many animals Careful watch was kept on the packs of hounds
in the national U.K. herd are slaughtered at used for hunting in the United Kingdom because
significantly younger ages, and those infected they are often fed carcasses unfit for human
with BSE would not have had a chance to develop consumption. Spongiform encephalopathy has
the disease. Using methods developed for the not occurred in dogs; however, in 1990, a case of
retrospective analysis of the AIDS epidemic, spongiform encephalopathy was diagnosed in
Anderson and colleagues (7) calculated that domestic cats; 81 additional cases in cats have
approximately one million animals in the U.K. occurred with a wide geographic spread
herd must have been infected to have produced throughout the United Kingdom. The true
170,000 clinical cases of BSE. These same incidence is probably many times higher than
workers predicted the number of cases of BSE observed because diagnosis is patchy and the
that would occur in 1996 and in subsequent years disease was not statutorily notifiable until 1994.
(Table 2). The calculations are based on a The annual incidence at the height of the
dominant feedborne source of infection; a small outbreak was probably 10 to 15 cases per million
amount of cow-to-calf transmission was included cats (Wilesmith, pers. comm.). The most likely
because a long-term study, conducted by the U.K. source of the infection was commercially
Ministry of Agriculture, Fisheries and Food, produced cat food. In 1989, the pet food industry
indicated an increased incidence of BSE in calves removed the dangerous bovine tissues, the
born to mothers in the late stages of the specified bovine offal, before a statutory ban in
incubation period of the disease (8). The results 1990. The number of cases of feline spongiform
are compatible with a cow-to-calf transmission of encephalopathy (FSE) diagnosed in the United
approximately 10%, which in itself is not Kingdom has been declining since 1994 (1994, 16
sufficient to perpetuate the BSE epidemic. The cases; 1995, 6 cases; 1997, 6 cases) (Table 3). Only
calculations predict a small number of cases and one cat, an adopted stray, was apparently born

Table 3. Number of cases of feline spongiform

Table 2. Predictions of new infections and cases of
encephalopathy in the United Kingdom by year of
BSEa from 1996-2001b
diagnosis (MAFF, personal communication)
New infections Cases
Year Number of cases
95% 95%
1990 12
Expected Prediction Expected Prediction
1991 12
Year value interval value interval
1992 10
1996 189 (155-11,300) 7,386 (6,541-8,856)
1993 11
1997 95 (63-236) 4,111 (3,006-7,664)
1994 16
1998 38 (21-214) 1,864 (1,153-7,052)
1995 8
1999 12 (5-162) 682 (388-5,909)
1996 6
2000 3 (1-86) 221 (128-3,660)
1997 6
2001 1 (0-33) 72 (45-1,592)
aBovine 1998a 4
spongiform encephalopathy. aTo
bInformation extracted from (7). May 1, 1998.

Vol. 4, No. 3, July–September 1998 391 Emerging Infectious Diseases

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after the ban on specified bovine offal in pet food. the second half of 1997, the long-term
A TSE indistinguishable from BSE has also been pathogenesis experiment indicated that the
found in puma, cheetah, ocelot, and a tiger in zoos in transmissible agent of BSE could be recovered
the United Kingdom between 1992 and 1995. These from the dorsal root ganglia of experimentally
animals became infected as a result of being fed raw infected animals toward the end of the incubation
meat, which would have included bovine central period. Also, in one animal the agent was
nervous system, a practice which has now ceased. transmitted by intracerebral inoculation of mice
with bovine bone marrow. Accordingly, in
Human Disease and BSE December 1997 the U.K. government introduced
legislation to ban the sale of beef on the bone,
Control Measures even from animals under 30 months of age. Many
The risk to human health from BSE was in the United Kingdom thought that this
always recognized. The principal protective regulation to prevent an extremely small risk of
measure was the November 1989 ban on the use transmitting BSE in T-bone steaks and rib of beef
of certain specified bovine offal in human food. As was unnecessary. Nevertheless, the introduction
with scraple, the tissues banned were those likely of the specified bovine offal ban in 1989 and its
to contain the highest concentrations of the subsequent refinements have ensured the safety
transmissible agent (brain, spinal cord, tonsil, of beef and beef products that now enter the
spleen, thymus, and intestine of cattle older than human food chain in the United Kingdom. Even
6 months of age). The intestine and thymus of so, as a consequence of the emergence of new
calves was added to the list in 1994 when a long- variant CJD, a worldwide ban on the sale of U.K.
term pathogenesis study in cattle by the Ministry beef and beef products was introduced by the
of Agriculture, Fisheries and Food indicated that European Union in March 1996 and is still in
the transmissible agent could be found in the force with the exception of a recent (March 1998)
terminal ileum (it is assumed that the agent was relaxation for certain herds in Northern Ireland.
present in Peyer’s patches). In 1996 the whole
head, other than the tongue, was formally New Variant CJD
banned because of concern about possible Clearly, the first measures to protect human
contamination with brain. Since the banned health were introduced before any human
tissues now contain more than offal, the tissues disease could be related to BSE. To guard against
are referred to as specified bovine material. the possible emergence of such disease (or
During 1995, it became clear that spinal cord was diseases), the U.K. Department of Health set up a
not being completely removed from a small CJD Surveillance Unit in 1990. The purpose of
number of carcasses that were subsequently the unit was to monitor the trends in incidence of
certified as fit for human consumption. Conse- CJD and any unusual features among cases.
quently, in December 1995 the U.K. government Concern was first focused on the 1995 cases of the
banned the use of bovine vertebral column for the third and fourth U.K. farmer since 1990 to be
production of mechanically recovered meat. In confirmed as having CJD. Statistically, the
March 1996, when it became clear that human chances of four such cases occurring in 6 years in
disease related to BSE was “probable” rather the United Kingdom were very small. However,
than “theoretical,” the U.K. government intro- the clinical features of the disease were typical of
duced the over-30–month scheme, which allowed classical CJD, and collaboration between the CJD
only animals under the age of 30 months to be Surveillance Unit and other European countries
used for human food, provided that all the banned indicated that farmers were overrepresented
specified bovine material had been removed. This compared with CJD cases in countries with no
added an extra margin of safety because cattle BSE. Subsequently, classic CJD was confirmed in
can be reasonably accurately aged by their these farmers; no further cases have been
dentition at 30 months and because BSE is diagnosed in U.K. farmers, and the significance of
relatively rare under the age of 30 months. Only the high incidence in 1995 is diminishing.
265 cases occurred in cattle younger than 30 The death in May 1995 of the first adolescent
months, and during 1997, the youngest animal ever to be diagnosed with CJD in the United
with BSE was 37 months of age (Ministry of Kingdom was followed in October 1995 by the
Agriculture, Fisheries and Food, pers. comm.). In death of a second adolescent; by January 1996,

Emerging Infectious Diseases 392 Vol. 4, No. 3, July–September 1998

Special Issue

three other young (29 years of age) persons evidence, only a working hypothesis, that
became ill. Atypical pathologic results were transmission was likely from inclusion in the
beginning to be defined in these patients; and on human food chain of tissues that contain the
March 8, 1996, eight cases of what came to be highest concentration of the transmissible agent.
known as new variant CJD or variant CJD The major differences in human exposure to
(vCJD) were reported to the Spongiform these tissues would have occurred first when sick
Encephalopathy Advisory Committee. The cases animals were banned from the human food chain
were distinguished by the relatively young age at in 1988 and again in 1989 when the specified
which the symptoms started (10,11). That age bovine offals of otherwise healthy animals were
range is now 16 years to 52 years. The duration of removed from the human food chain.
the illness is relatively long, averaging approxi- Studies continue in an attempt to answer the
mately 14 months as opposed to the 4 to 5 months third question, “How many vCJD cases will there
in classic CJD. The early symptoms are often be in the future?” So far, 26 cases have been
psychiatric, and it may be 6 or 7 months before diagnosed in the United Kingdom (Table 4) and 1
any neurologic signs appear. The characteristic in France. Incidence has not increased since
electroencephalogram pattern of sporadic CJD is vCJD was first diagnosed in 1995. If instead of
not seen in vCJD, and pathologic results show looking at the date of death one looks at the date
florid plaques and extensive cerebellar involve- of onset of the symptoms in the 26 patients, two
ment with multiple PrP deposits. As with BSE new cases occurred on average every quarter
and FSE, the neuropathologic appearances are the since 1994. All cases have been methionine
mainstay of laboratory confirmation. Magnetic homozygotes at codon 129 of the PrP gene. In the
resonance imaging scanning and detection of 14-3- general population approximately 40% have such
3 protein can be helpful. Early evidence indicates a genotype; 10% are valine homozygotes, and 50%
that the diagnosis can often be made from tonsil are heterozygotes. An analysis of classic sporadic
biopsies (12). Otherwise, diagnosis must depend CJD indicates that 80% of those cases are
upon brain biopsy or postmortem examination. methionine homozygotes, 10% valine homozy-
When on March 20, 1996, the U.K. gotes, and 10% heterozygotes. It is perhaps not
government announced the existence of 10 cases surprising, therefore, that the first cases of vCJD
of vCJD and the opinion of the Spongiform to be seen are methionine homozygotes.
Encephalopathy Advisory Committee that these Only one published analysis has predicted
were probably related to BSE, three questions the number of future nvCJD cases after
immediately arose. The first was, “Is there really constraining the models used to the known and
any link with BSE?” Additional evidence surmised facts at the time (15). The total number
emerged from the work of Collinge and his of future cases will depend critically on the
colleagues (13) on the analysis of the PrP average incubation period of vCJD. At present,
fragments after protease digestion. The position we have no way of determining that; therefore, it
of the three fragments and the relatively high remains too early to predict with any accuracy
concentrations of the di-glycosylated form the total number of future cases. It remains
indicated that vCJD was distinct from the possible that the outbreak of vCJD cannot be
previously recognized forms of CJD and that regarded as a single curve and that the small
similarities existed between the cases of vCJD
and BSE and FSE. In 1997, the first results were
Table 4. Creutzfeldt-Jakob disease in the United Kingdom
published from the classic strain typing Deaths of definite and probable cases
experiments initiated during 1996 (14). The Refer- Spora- Iatro- Fami-
characteristics of material from cases of vCJD, in Year rals dic genic lial GSSa nvCJDb Total
terms of incubation period and lesion profile in 1994 116 52 1 3 3 0 59
RIII mice, were identical to those from cases of 1995 86 34 4 2 3 3 46
BSE and FSE. These observations are confirmed 1996 133 40 4 2 4 10 60
now in C57 black mice. Thus, vCJD can now be 1997 152 42 6 3 0 10 61
regarded as human BSE in the same way that 1998c 35 3 0 1 0 2 6
aGerstmann-Straussler-Scheinker syndrome.
FSE is regarded as feline BSE. The second bNew variant Creutzfeldt-Jakob disease.
question was, “What is the route of transmission cTo Apr 30, 1998. Figures released by U.K. Department of

from cattle to humans?” So far we have no Health Jun 1, 1998.

Vol. 4, No. 3, July–September 1998 393 Emerging Infectious Diseases

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number of cases have occurred in persons who are References

extremely susceptible for unknown reasons. 1. Wells GAH, Scott AC, Johnson CI, Gunning RF,
Hancock RD, Jeffrey M, et al. A novel progressive
spongiform encephalopathy in cattle. Vet Rec
The Future 1987;121:419-20.
Much has happened already as a consequence 2. Wilesmith JW, Hoinville LJ, Ryan JBM, Sayers AR.
of the emergence of BSE in U.K. cattle. The Bovine spongiform encephalopathy: aspects of the
appropriate measures are in place to protect clinical picture and analyses of possible changes. Vet
public health and end the BSE epidemic in cattle Rec 1992;130:197-201.
3. Fraser H, McConnell I, Wells GAH, Dawson M.
and other affected species. These measures are
Transmission of bovine spongiform encephalopathy to
more rigorously enforced than ever before. It is mice. Vet Rec 1988;123:472.
difficult to see what could be done to make the 4. Dawson M, Wells GAH, Parker BNJ. Preliminary evi-
BSE epidemic decline more rapidly than it dence of the experimental transmissibility of bovine spon-
already has, short of slaughtering the entire U.K. giform encephalopathy to cattle. Vet Rec 1990;126:112-3.
5. Wilesmith JW, Wells GAH, Cranwell MP, Ryan JBM.
herd, which would be unnecessary and impracti-
Bovine spongiform encephalopathy: epidemiological
cal. From now the question is likely to be how to studies. Vet Rec 1988;123:638-44.
withdraw some of the restrictions on U.K. beef 6. Stekel DJ, Nowak MA, Southwood TRE. Prediction of
and beef products. The exemptions are likely to future BSE spread. Nature 1996;381:119.
be herd based (as is the case with Northern 7. Anderson RM, Donnelly CA, Ferguson NM, Woolhouse
MEJ, Watt CJ, Udy HJ, et al. Transmission dynamics
Ireland) or date based after the total ban on the
and epidemiology of BSE in British cattle. Nature
use of meat and bone meal in the feed of any farm 1996;382:779-88.
animals in the United Kingdom in 1996. In terms 8. Donnelly CA, Ghani AC, Ferguson NM, Wilesmith JW,
of the protection of public health, all the Anderson RM. Analysis of the bovine spongiform
necessary measures are in place. Two further encephalopathy study: evidence for direct maternal
transmission. Appl Statist 1997;43:321-44.
concerns remain and are actively under
9. Lawson C, Herd L, editors. BSE Enforcement Bulletin
consideration: whether or not BSE exists in the 1998. Ministry of Agriculture, Fisheries and Food;
sheep flocks and whether the cases of vCJD in the Bull. No. 20; p. 2.
United Kingdom will be sufficient to generate 10. Will RG, Ironside JW, Zeidler SN, Cousens SN, Estibeiro
concern about a second wave of transmission K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob
disease in the UK. Lancet 1996;347:921-5.
within the human population as a consequence of
11. Zeidler M, Stewart GE, Barraclough CR, Bateman DE,
the use of blood and blood products. With respect Bates D, Burn DJ, et al. New variant Creutzfeldt-
to the former, the detection of sheep with scrapie- Jakob disease: neurological features and diagnostic
like diseases in the United Kingdom and the tests. Lancet 1997;350:903-7.
typing of strains from affected animals are being 12. Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of
new variant Creutzfeldt-Jakob diseases by tonsil
intensified. With respect to blood and blood
biopsy. Lancet 1997;349:99-100.
products, some restrictions on the use of U.K. raw 13. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF.
materials for the production of blood products are Molecular analysis of prion strain variation and the
already in place, and a detailed risk assessment aetiology of ‘new variant’ CJD. Nature 1996;383:685-90.
in relation to blood transfusion is awaited. 14. Bruce ME, Will RG, Ironside JW, McConnell I,
Drummond D, Suttie A, et al. Transmissions to mice
Sir John Pattison is a virologist and dean of the indicate that ‘new variant’ CJD is caused by the BSE
Medical School, University College London, and Chair, agent. Nature 1997;389:498-501.
U.K. Spongiform Encephalopathy Advisory Committee. 15. Cousens SN, Vynnycky E, Zeidler M, Will RG, Smith
PG. Predicting the CJD epidemic in humans. Nature

Emerging Infectious Diseases 394 Vol. 4, No. 3, July–September 1998

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Explaining the Unexplained in Clinical

Infectious Diseases: Looking Forward
Bradley A. Perkins* and David Relman†
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; and
†Palo Alto VA Medical Center, Palo Alto, California, USA

We examined the need to improve our ability proportion was 62%; in the 1980s, 40%; and in
to explain the unexplained in clinical infectious 1991, 18%. Why has the recovery of pneumococci
diseases, primarily through improvements in from patients with community-acquired pneumo-
diagnostic technology. Part of the motivation for nia changed so dramatically? Have the causes of
this effort came from an Emerging Infectious community-acquired pneumonia changed? Stan-
Disease Program (funded by the National Center dard “gumshoe” microbiology to isolate pneumo-
for Infectious Diseases, Centers for Disease cocci has taken a devastating hit in the 1990s due
Control and Prevention [CDC]) to conduct to outsourcing of microbiology services or just
surveillance for unexplained deaths and critical decreased emphasis on standard microbiology
illnesses due to possibly infectious causes. This practices (e.g., collection and handling of clinical
project has found that the number of such specimens). Newly recognized agents such as
patients in the United States is substantial and Legionella pneumophila may also explain some
that a probable causative agent can be identified of the decrease in the proportion of pneumo-
in only a small fraction of these patients. cocci isolated.
John Bartlett, Johns Hopkins University, Recommendations for the evaluation and
Baltimore, Maryland, and Sherif Zaki, CDC, management of community-acquired pneumo-
Atlanta, Georgia, addressed the current status nia, developed by the Infectious Disease Society
and offered their perspectives on pneumonia, of America, were published in the April issue of
particularly acute respiratory distress syndrome Clinical Infectious Diseases. These recommenda-
(ARDS) and hemorrhagic pneumonia, syndromes tions detail diagnostic tests as well as inadequa-
frequently associated with unexplained critical cies in diagnostic technologies for several of the
illness. Greg Kovacs, Stanford University, Stanford, common causes of community-acquired pneumo-
California, and Michael Eisen, Stanford University nia, including Chlamydia pneumoniae, L.
School of Medicine, Stanford, California, presented pneumophila, and Mycoplasma pneumoniae.
possible technologies and approaches to improving
diagnostic capabilities—a sensitive biologic detec- Pathologic Approach to the Diagnosis of
tion system (for toxins and host gene expression Infectious Causes of Pulmonary
responses) for diagnosing infectious diseases. Hemorrhage and Acute Respiratory
Distress Syndrome
Pneumonia—Evolving Diagnostic Pathologists should recognize patterns of
Practices tissue injury (especially in the lung parenchyma)
Pneumonia, the most common infectious that react in specific and predictable ways. This
cause of death in the United States, accounts for approach narrows diagnostic options and focuses
approximately 45,000 deaths annually. In large testing efforts. Acute lung injury (e.g., diffuse
hospital-based studies, no causative agent can be alveolar damage or ARDS) and air space filling
identified in 35% of community-acquired pneu- patterns (e.g., hemorrhage and pulmonary
monia cases. In actual practice, this proportion is edema) of lung injury are two important patterns
probably 50% to 75%. manifesting infectious disease. Examples include
Over the last three decades, the proportion of diffuse alveolar damage associated with adenovi-
community-acquired pneumonia cases in which rus infection (smudge cells may be seen); measles
Streptococcus pneumoniae was isolated has (giant cells); respiratory syncytial virus (RSV)
substantially declined. In the 1970s, the infection; influenza infections; Rocky Mountain

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spotted fever; typhus; legionnella; mycoplasma; cell monolayer is incredibly responsive because of
and hemorrhage associated with aspergillosis, its diffusion characteristics; this responsiveness
mucormycosis, leptospirosis, dengue, yellow can be tuned by selection of cells and through
fever, Lassa, and Ebola virus infection. The engineering. The use of cocultures can allow
recognition of these patterns (combined with diversity in detection and response characteris-
application of special stains, immunohistochemi- tics. In addition to detecting chemical and
cal reagents, and in situ hybridization) is a biological warfare agents, these systems can
powerful tool in the diagnosis of unexplained screen for antidotes by challenging the system
critical infectious diseases. with the toxin and adding a putative antidote.
Two examples of the application of these Pharmaceutical companies are interested in
combined methods to the identification of using this system for early screening of drug
infectious agents are the 1993 hantavirus actions on cell physiology.
epidemic in the southwestern United States and Chick myocardial cells and NG108 neuro-
the 1995 leptospirosis epidemic in Nicaragua. In blastoma hybrid cell lines were used to examine
the hantavirus epidemic, healthy young adults the shape and frequency of action potentials.
contracted fever and rapidly progressive pulmo- Exposure of these cells to agents with known
nary disease consistent with ARDS, and many effects on cell physiology (e.g., epinephrine,
died within days of the onset of illness. Testing for verapamil, and tetrodotoxin) causes predictable
a wide variety of agents was negative. Lung changes (depending on the interaction of these
tissue showed interstitial pneumonitis and toxins with transmembrane channels) on the
interalveolar edema; these patterns were consis- shape of action potential curves when deviation
tent with viral pneumonia or toxic change. After from baseline is used as the internal control on
serum samples from these patients were found to response. Impedance measurement (alteration in
cross-react with known hantaviruses, antibodies electrical current after passage through a cell)
were used to demonstrate hantavirus in the lung, can also be used to reflect changes in the cell
kidney, and muscle tissues. In the leptospirosis membrane as a result of exposure to a toxin. The
epidemic, after heavy rains in northern Nicara- effect of toxins on the cytoskeleton can also be
gua, a number of persons became ill with fever, measured by cell motility through impedance.
headache, muscle aches, hemorrhage, and severe When this technology was first developed, it
ARDS; no prominent renal or hepatic manifesta- required approximately 1 m3 of electronics support,
tions were observed. Initial testing focused on but with silicon chips a laptop computer can now
hantavirus, dengue, and other viral agents, but support the operation. A Windows application can
results were negative. Pathologic examination of handle the data processing, and the technology can
tissue from fatal cases showed pulmonary be transferred to other laboratories.
hemorrhage and diffuse alveolar damage, as well
as renal and hepatic changes. In the 1980s, Cellular Scouts: Genome-Wide Expression
reports of leptospirosis epidemics in Korea and Monitoring of Peripheral Blood to Detect and
China prompted investigators to develop an Characterize Pathogens
immunohistochemical test for leptospirosis; the Using an easily constructed robot, we have
disease was subsequently found in kidney, liver, been building DNA microarrays in which each
and lung specimens of Nicaraguan patients. dot represents different open reading frames. In
the fully sequenced genome of Saccharomyces
Novel Bioassay for Detecting Toxin-Mediated cerevisiae, there are 6,200 dots or open reading
Illness frames. The Human Genome Project has
The impetus for this project has been identified approximately 50,000 distinct cDNA
twofold: military detection of chemical and sequences, and we have been using microarrays
biological warfare agents and pharmaceutical with approximately 15,000 of these. By the end of
screening. Cells are cultured on silicon chips, and 1998, we will have all 50,000 genes on a
their response to toxins is monitored in several microarray. For these assays we use a control and
ways (e.g., action potential for electrically active an experimental sample. From these samples, we
cells, impedance, and motility). These systems isolate polyadentylated RNA by using any of a
complement other approaches because they allow variety of kits, and then make fluorescently
detection of unknown or unrecognized toxins. A labeled cDNA copies, with each of the two

Emerging Infectious Diseases 396 Vol. 4, No. 3, July–September 1998

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samples labeled with a different color (e.g., one patterns of human gene response to different
green and the other red). RNA is degraded to stimuli, including T-cells stimulated with
avoid any confounding signals; the samples are mitogens, cells exposed to DNA damaging agents,
mixed and then hybridized to the microarray. The and cells infected with polio and cytomegalovirus
microarray is imaged by using a scanning laser have distinct DNA expression patterns, or “bar
confocal microscope, and through a process of codes,” that change over time. Although we have
quantitation, the relative representation of every not processed a wide selection of infectious agents,
gene in sample 1 versus sample 2 is calculated. we have evaluated approximately 60 distinct
These data provide a very high resolution human tumor cell lines using a common control cell
fingerprint of what is going on in any cell(s) of line. When we used these data for phylogenetic
interest. So when a sample from a healthy person is reconstruction, we found very good clustering with
compared with one from an ill person, differences in respect to the tissue of origin. Specific signatures
gene expression should be sufficiently unique to are related to central nervous system tumors,
diagnose particular infections. kidney tumors, melanomas, and leukemias.
First, however, we would like to know that We would like to focus on the use of peripheral
cells respond to internal and external stimuli by blood cells as a sort of infectious disease sensor.
at least some differences in expression of their There are a number of reasons to believe that this
genes, that specific stimuli result in distinct gene may work. We have data from human lymphocytes
expression patterns, and that the response to harvested from whole blood (where one sample is
stimuli evolves in a stereotypic temporal manner. exposed to interleukin-2 and the other is not) and
Ideally, we would like not only to diagnose a we can demonstrate many changes in gene
particular infection but also to determine the expression. To make this approach useful, we will
stage of that infection. Preliminary data from our need a broad range of gene array data from
laboratory support these hypotheses. The persons with known causes of illness.

Vol. 4, No. 3, July–September 1998 397 Emerging Infectious Diseases

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Malaria: A Reemerging Disease in Africa

Thomas C. Nchinda
World Health Organization, Geneva, Switzerland

A recent upsurge of malaria in endemic-disease areas with explosive epidemics in

many parts of Africa is probably caused by many factors, including rapidly spreading
resistance to antimalarial drugs, climatic changes, and population movements. In Africa,
malaria is caused by Plasmodium falciparum and is transmitted by Anopheles gambiae
complex. Control efforts have been piecemeal and not coordinated. Strategies for control
should have a solid research base both for developing antimalarial drugs and vaccines and
for better understanding the pathogenesis, vector dynamics, epidemiology, and
socioeconomic aspects of the disease. An international collaborative approach is needed
to build appropriate research in a national context and to effectively translate research
results into practical applications in the field. The Multilateral Initiative for Malaria in Africa
can combine all of the above strategies to plan and coordinate partnerships, networking,
and innovative approaches between African scientists and their Northern partners.

The global malaria eradication program of the dysfunction (e.g., respiratory distress syndrome).
1950s and 1960s suffered serious setbacks in the Persons repeatedly exposed to the disease acquire
early 1970s, and the disease was slowly increasing a considerable degree of clinical immunity, which
in areas of Asia and South America where the is unstable and disappears after a year away from
number of cases had been reduced to low levels. the endemic-disease environment. Immunity
This article discusses malaria and, more reappears after malarial bouts if the person
specifically, malaria in Africa, where the global returns to an endemic-disease zone. Most likely to
eradication program was never started and the die of malaria are persons without previous
disease is reemerging at an alarming and immunity, primarily children or persons from
unprecedented rate. parts of the same country (e.g., high altitudes)
where transmission is absent, or persons from
The Disease more industrialized countries where the disease
Malaria in humans is caused by a protozoon does not exist.
of the genus Plasmodium and the four
subspecies, falciparum, vivax, malariae, and Why Is Malaria Reemerging?
ovale. The species that causes the greatest illness In the last decade, the prevalence of malaria
and death in Africa is P. falciparum. The disease has been escalating at an alarming rate,
is transmitted by the bites of mosquitoes of the especially in Africa. An estimated 300 to 500
genus Anopheles, of which the Anopheles million cases each year cause 1.5 to 2.7 million
gambiae complex (the most efficient) is respon- deaths, more than 90% in children under 5 years
sible for the transmission of disease in Africa. of age in Africa (1). Malaria has been estimated to
Fever is the main symptom of malaria. The most cause 2.3% of global disease and 9% of disease in
severe manifestations are cerebral malaria Africa (1); it ranks third among major infectious
(mainly in children and persons without previous disease threats in Africa after pneumococcal
immunity), anemia (mainly in children and acute respiratory infections (3.5%) and tubercu-
pregnant women), and kidney and other organ losis (TB) (2.8%). Cases in Africa account for
approximately 90% of malaria cases in the world
(1). Between 1994 and 1996, malaria epidemics in
Address for correspondence: Thomas C. Nchinda, Global 14 countries of sub-Saharan Africa caused an
Forum for Health Research, World Health Organization, 1211 unacceptably high number of deaths, many in
Geneva 27, Switzerland; fax: 41-22-791-4394; e-mail:
areas previously free of the disease (2).

Emerging Infectious Diseases 398 Vol. 4, No. 3, July–September 1998

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Adolescents and young adults are now dying of adequate? Are governments and populations of
severe forms of the disease. Air travel has endemic-disease countries adequately prepared?
brought the threat of the disease to the doorsteps
of industrialized countries, with an increasing Knowledge About the Disease and Its
incidence of imported cases and deaths from Determinants
malaria by visitors to endemic-disease regions. Falciparum malaria is a complex disease with
The estimated annual direct and indirect costs of a patchy nonuniform distribution and clinical
malaria were US$800 million in 1987 and were manifestations that vary from one area to
expected to exceed US$1.8 billion by 1995 (3). another within an endemic-disease zone, often
A number of factors appear to be contributing showing space-time clustering of severe malaria
to the resurgence of malaria: 1) rapid spread of in the community (4). The relationship between
resistance of malaria parasites to chloroquine fevers, clinical disease, anemia, and cerebral
and the other quinolines; 2) frequent armed malaria remains the subject of current research.
conflicts and civil unrest in many countries, The determinants of severe life-threatening
forcing large populations to settle under difficult malaria need further elucidation. Present
conditions, sometimes in areas of high malaria research, focusing on the disease rather than the
transmission; 3) migration (for reasons of infection and the dynamics of its transmission, is
agriculture, commerce, and trade) of nonimmune bringing in new vision about the disease,
populations from nonmalarious and usually high particularly the immunologic aspects. Persons with
to low parts of the same country where asymptomatic parasitemia constitute an important
transmission is high; 4) changing rainfall reservoir. The epidemiology of malaria (particu-
patterns as well as water development projects larly the relationship between the clinical patterns
such as dams and irrigation schemes, which of the disease in different locations, the pattern of
create new mosquito breeding sites; 5) adverse severe disease, and causes of deaths due to malaria)
socioeconomic conditions leading to a much needs future research (5).
reduced health budget and gross inadequacy of
funds for drugs; 6) high birth rates leading to a Tools for Malaria Control
rapid increase in the susceptible population The present strategy for malaria control,
under 5 years of age; and 7) changes in the adopted by the Ministerial Conference on
behavior of the vectors, particularly in biting Malaria in Amsterdam in 1992, is to prevent
habits, from indoor to outdoor biters. death, reduce illness, and decrease social and
economic loss due to the disease (6). Its practical
What Knowledge Is Needed for Effective implementation requires two main tools: first,
Control? drugs for early treatment of the disease,
Continental sub-Saharan Africa was never a management of severe and complicated cases,
part of the global malaria eradication program. and prophylactic use on the most vulnerable
The severity of the disease, the density and population (particularly pregnant women); sec-
efficiency of An. gambiae, the problem of ond, insecticide-treated nets for protection
eradicating the disease over such a large land against mosquito bites. Each tool has its own
mass with recurrent reinvasions, high costs, and problems in regard to field implementation.
subsequent maintenance must have all contrib- Chloroquine remains the first-line therapy
uted to the lack of will to undertake an for malaria. However, the alarming increase in
eradication program. Also, the eradication resistance in eastern and southern Africa
program period coincided with the colonial and requires that sulfadoxine-pyrimethamine re-
immediate postcolonial period, during which place chloroquine as the first-line drug. Cur-
little or no indigenous capacity was available to rently, 20% to 30% of strains are highly resistant
initiate and sustain malaria eradication. After a (RIII) with in vivo levels of 40% to 60%. Resistance
period of laissez faire regarding malaria control, has been spreading westward, attaining levels of
these countries have had to face the reemergence 20% to 35% in West Africa. Chloroquine remains
of the disease. Important questions about control the drug of choice in most of sub-Saharan Africa.
include the following. Is there enough knowledge Resistance to mefloquine, another first-line
about the disease and its determinants? Are drug, developed in the early 1980s, was noticed
there enough tools? Are existing resources soon after its introduction and is now almost at

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the same level as chloroquine. Sulfadoxine- to malaria in endemic-disease areas should be

pyrimethamine (Fansidar, Hoffman la Roche) is evaluated. The old vector-control method of house
the second-line drug in many countries of West spraying persists in some countries. The relative
and Central Africa, but so much resistance merits and cost-effectiveness of house spraying
appears to be rising in countries of East Africa that versus the use of treated nets should be evaluated.
atovaquone/dapsone (Malarone, Glaxo Wellcome)
is being developed as a replacement. Intravenous The Challenge of Malaria Control to
quinine is still the main therapy for cerebral Communities and Governments
malaria, although resistance is increasing. The best tools will not necessarily lead to
Development by the African strains of malaria malaria control. African populations have
parasites of the pattern of drug resistance now traditional perceptions about disease causation
seen in Southeast Asia would be a major disaster. and management. Some diseases are considered
More research is needed. For example, it is suitable for management by western medicine,
necessary to initiate systematic monitoring of while others are considered the exclusive domain
drug resistance in Africa using standardized of local traditional health practitioners. Deci-
methods. Drug efficacy studies using in vivo sions to seek western medicine for any illness are
methods have now been standardized by the often considered a last resort. Studies on health-
World Health Organization (WHO)/Regional seeking behavior, perceptions of malaria, treat-
Office for Africa (AFRO) and carried out in a large ments, and decision making for health care at the
number of countries in West, Central, and East household level are crucial to malaria control.
Africa. Sentinel sites have also been established Such studies must be accompanied by improved
for monitoring resistance. No new methods are public awareness of the importance of seeking
being developed. The feasibility of using appropriate treatment and complying with
polymerase chain reaction techniques should be recommended regimens.
explored. Also, management guidelines should be Management of disease in the household
developed concerning when and under what devolves on mothers. Fever remains the most
conditions to change the treatment regimen for recognized symptom of malaria. Studies are
different levels of resistance at the district, ongoing to determine the proportion of fevers
regional, and central level. Development and actually due to malaria. Mothers should be
field testing of inexpensive, effective new malaria taught to recognize the symptoms of malaria, to
drugs are urgently needed to replace present provide home management, and to know when to
drugs when resistance patterns make them refer cases to health centers. Four countries in
unusable. Drugs developed because of the more Africa have developed and tested teaching guides
serious problem of drug resistance in Asia should to facilitate home management of malaria (11).
be field tested in Africa. The most promising ones, Also, guidelines for the management of fever at
artemisinin and its derivatives artemether, the periphery have been developed and field tested
arteether, and artesunate, are being tested for within the Sick Child Initiative and have been
use in cerebral malaria and cases of proven recommended for wide-scale application. Socioeco-
resistance to chloroquine (12); some are already nomic and community studies are needed to
used in some countries. understand the extent to which the communities
Research carried out in Dakar (7) demon- will participate in new malaria control measures.
strated the efficacy of insecticide-treated nets for Finally, cost recovery of health care, including
reducing infant death; subsequent large-scale costs of drugs (the Bamako Initiative), has been
multicenter studies in six countries across Africa the subject of many recent studies and probably
confirmed this finding (8-10). However, costs of holds the key to health care in rural populations.
the nets and treatment still inhibit wide-scale Some study results indicate an initial fall in
use. Ongoing research seeks ways of reducing use of services following the introduction of cost-
these costs, such as social marketing, possible recovery schemes (12). However, a recent study
involvement of the private sector, cost-effective indicates the opposite. Community health
methods for net treatment, the most appropriate workers were trained to administer prepackaged
nets, and proper procurement of insecticides and antimalarial drugs only when paid. They also
treatment of the nets. Eventually, the long-term received direct remuneration for their work
effects on natural acquisition of partial immunity rather than being supported by the village on a

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voluntary basis (13). This plan seems to have quently, all candidate vaccine trials must be
increased attendance. This subject needs large- closely linked to studies on how humans acquire
scale multicenter studies. immunity and the correlation between protective
immunity and immunologic assays. Such studies
Governments’ Response—Peripheral Health should be carried out longitudinally in multiple
Services sites where future vaccines will be tested.
Health service organization, function, and On the vector side, studies in Mali have
governing policies are important to malaria shown that malaria transmission in this Sahel
control. Health policy and systems research have country is maintained by a relay transmission
been recently identified as neglected areas of pattern, whereby the three main vectors appear at
research in need of international effort (1). Many different times of the year, thus ensuring that
studies are researching different ways to vectors are always present (Y. Toure, pers. comm.).
integrate vertical malaria control programs into More research is in progress concerning the
the general health-care system. Economic potential of using genetic engineering to make
evaluation of different interventions is impor- the main malaria vector, An. gambiae, refractory
tant, and the techniques are continually being to the malaria parasite and releasing this refractory
refined and improved. They require much local parasite into the wild population to replace the
capacity since they tend to be country specific. active vectors. Despite potential ethical problems,
Studies in this area have now caught up with the this approach probably constitutes a long-term
current trend favoring decentralization of future method for interrupting malaria transmis-
services, giving more power to the districts. Such sion (14). Finally, the much-neglected issue of the
studies include ways of improving case manage- pathogenesis of malaria anemia both in children
ment where health services have been decentral- and pregnant women, as well as the link of anemia
ized, sustaining effective interventions, and in pregnancy and HIV/AIDS, needs further study
ensuring that drug supply chains function and is likely to be multifactorial.
optimally. Extensive research is examining Mapping malaria transmission intensity
health sector reform on malaria control (12). using geographic information systems and
Health sector reform holds great potential for geographic positioning systems has developed
controlling malaria and all other diseases, as it is into a Pan-African research collaboration for
the focal point of the central and local Mapping the Malaria Risk in Africa, which has
governments and the populations themselves. received international funding. It plays a major
Other needed research includes different health role in time-spatial mapping of malaria across the
policies, access to health services, and the issues continent with a strong potential for predicting
of equity in health care. malaria epidemics (15) and monitoring control.

Is There a Place for Biomedical Research? What Is the Response of the World Health
If the emphasis appears to be on epidemio- Organization?
logic and socioeconomic research and studies on WHO developed global and regional strate-
health policies and systems, it is because these gies for malaria control after the Ministerial
results have immediate importance to malaria Conference on Malaria in Amsterdam in 1992.
control. The argument is for better use of existing WHO/AFRO has multiplied efforts to encourage
tools. However, tools alone will not provide all the countries to embark seriously on malaria control.
knowledge needed for sustainable malaria A WHO/AFRO Task Force for Malaria comprising
control. Recent research by the Wellcome Trust a selected sample of malaria control managers,
and the National Institutes of Health on malaria experts from Africa, and technical
sequencing the genome of P. falciparum is likely representatives from bilateral and multilateral
to lead to development of new antimalarial drugs agencies funding malaria control in Africa was
and vaccines. Similarly, DNA technologies are set up in 1994. This task force has met regularly
being used to search for candidate molecules for to provide guidance on malaria control strategies
vaccines and new targets for drug development. and to recommend criteria for monitoring and
The development of a malaria vaccine is still evaluation as well as operational research. Some
in the laboratories, and no effective vaccine is in of these agencies have recently increased their
sight despite promising candidates. Subse- malaria control funding directly to some

Vol. 4, No. 3, July–September 1998 401 Emerging Infectious Diseases

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countries of Africa; others have preferred funding institutes and universities, with no exclusion.
through the regional office. Flexible training programs would be developed to
In addition, the WHO Director General made meet the needs of individual research centers and
a generous grant of US$10 million from the WHO countries. A good start has been made. Using
regular budget for 1997 for intensified malaria funds provided late in 1997 to WHO’s Tropical
control efforts. Momentum is building, strongly Diseases Research Programme, a task force was
supported by the World Bank, for more concerted set up for Malaria Research Capability Strength-
efforts at malaria control. ening in Africa. The money funded North/South
and South/South collaborative research in
The Way Forward malaria. All the principal investigators were to be
The Multilateral Initiative on Malaria in from Africa. Training was central to the projects
Africa (MIM) was created in Dakar in January so that more hands-on and practical research
1997 from the realization that success in training would be given to trainees, and practical
controlling malaria in the future would be greatly refresher training and technology transfer would
enhanced by cooperation and collaborative be given to experienced scientists.
efforts in research to support strategies for Research centers also need to be strength-
control (5). MIM capitalized on the important ened. Laboratories need refurbishing and
1992 Ministerial Conference, which led to the equipment and supplies (including computer
adoption of a Global Plan of Action for Malaria equipment and software), and vehicles are
Control and the World Health Assembly Resolution needed for field studies. Suitable research
on this subject (WHA 49.11), urging increased careers should be created to encourage the best
efforts on malaria control. Composed of scientists scientists to remain in research.
from Africa and their colleagues from industrial- Because scientific isolation constitutes a
ized countries as well as representatives from major major constraint to African scientists, communi-
funding agencies, MIM plans to facilitate collabora- cation facilities need urgent attention. One of
tion between governments, research scientists, MIM’s highest priorities is to enhance the capacity
research funding agencies, and the private of African scientists to communicate electronically
(pharmaceutical industry) sector for concerted with each other and with colleagues around the
action through research to combat malaria. world and to access needed scientific information
Like other diseases of low-income countries, from local and remote libraries and the Internet.
malaria has been grossly underfunded. From NIH’s National Library of Medicine is playing a
1990 to 1992, $58 million a year was spent on lead role in this critical area.
malaria research, while $56 billion was spent on
health research worldwide. Expressed as re- The Future
search investment per death, malaria research Malaria is an important social, economic, and
receives about US$42 per fatal case, much less developmental problem affecting individuals,
than for other diseases such as HIV/AIDS families, communities, and countries. The best
(US$3,270) and asthma (US$789) (3). Rather chance for successfully combating the disease
than the duplicative efforts of the past, MIM requires a collaboration particularly of those
encourages a common goal with common responsible for control and research. Such
research priorities, which should create a greater collaboration, particularly between South and
spirit of cooperation. North, is being actively developed, and MIM
presents itself as a worthwhile initiative (16).
Strengthening Research Capability Important factors are 1) placing the control
MIM took a firm stand on indigenous capacity strategy on a strong research base, 2) strong
building for malaria research in Africa, an international collaboration, and 3) sustained
important prerequisite for sustainable research government support.
and control of malaria in that continent. Training Smallpox was eradicated because of the
would be carried out in Africa as far as possible development of freeze-dried vaccine, the develop-
but not exclusively so. Training would be carried ment of the multiple-use nozzle jet injector and
out for all health-care workers within the malaria bifurcated needle, and the replacement of mass
research and control pyramid, including Ministry vaccination by selective vaccination, coupled
of Health personnel and those in research with a strong international effort. Onchocercia-

Emerging Infectious Diseases 402 Vol. 4, No. 3, July–September 1998

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online] Available from: url: http://www.niaid.nih/dmid/

sis is being controlled because research results malafr/.
were immediately applied to control. Translat- 6. World Health Organization. Control of Tropical
ing research findings into control methods has Diseases: 1. Progress Report. Geneva: The Organization,
also been pursued for Chagas disease and Division of Control of Tropical Diseases; 1994. Report
leprosy. Concerted action between the research No.: CTD/MIP/94.4
7. Alonso PL, Lindsay SW, Armstrong JRM, Conteh M,
and control communities is needed to ensure Hill AG, David PH, et al. The effect of insecticide-
that malaria follows the same path. MIM treated bed nets on mortality of Gambian children.
strongly advocates this approach. Research Lancet 1991;337:1499-502.
must be a constant feature throughout the 8. Nevill CG, Some ES, Mung’ala VO, Mutemi W, New L,
entire process of malaria control. Marsh K, et al. Insecticide treated bednets reduce
mortality and severe morbidity among children in the
Kenyan Coast. Trop Med Int Health 1996;1:139-46.
Dr. Nchinda is senior health specialist at the 9. Binka FN, Kubaje A, Adjuik M, Williams LA, Lengeler
Global Forum for Health Research based at the World C, Maude CH, et al. Impact of Permethrine
Health Organization headquarters in Geneva. His impregnated bednets on child mortality in Kassena-
research interests are in tropical diseases research Nankana district of Ghana: a randomized controlled
and control, particularly malaria, training and trial. Trop Med Int Health 1996;1:147-54.
utilization of health personnel, research capacity 10. Lengeler C, Cattani J, de Savigny D, editors. Net gain:
strengthening, health services research, and organi- a new method for preventing malaria deaths. Ottawa,
zation of community health services. Canada: International Development Centre/World
Health Organization; 1996.
11. World Health Organization. Toward healthy women
References counseling guide: ideas from the gender and health
1. World Health Organization. Investing in health research group. Geneva: The Organization, UNDP/
research for development. Report of the Ad Hoc World Bank/WHO Special Programme for Research
Committee on Health Research Relating to Future and Training in Tropical Diseases (TDR). Report No.:
Intervention Options. Geneva:The Organization; 1996. TDR/GEN/95.1
Report No.: TDR/Gen/96.1 12. World Health Organization. Tropical diseases research:
2. Harare declaration on malaria prevention and control progress 1995-96. 13th Programme Report. Geneva:
in the context of African economic recovery and The Organization, UNDP/World Bank/WHO Special
development. In: Proceeding of the 33rd Ordinary Programme for Research and Training in Tropical
Session of the Assembly of Heads of State and Diseases(TDR), Geneva.
Government, Organization of African Unity; 1997 2-4 13. Pagnoni F, Convelbo N, Tiendrebeago H, Cousens S,
June; Harare, Zimbabwe. Esposito F. A community-based programme to provide
3. Anderson J, MacLean M, Davies C. Malaria research: prompt and adequate treatment of presumptive malaria
an audit of international activity. Prism Report No. 7, in children. Trans R Soc Trop Med Hyg 1997;91:512-7.
The Wellcome Trust; 1996. 14. Carlson J, Olson K, Higgs S, Beaty B. Molecular
4. Snow RW, Schellenberg JR, Peshu N, Foster D, genetic manipulation of mosquito vectors. Annu Rev
Newton CR, Witstanley PA, et al. Periodicity and Entomol 1995;40:359-88.
space-time clustering of severe childhood malaria on 15. Omumbo J, Ouma J, Rapouda B, Craig M, le Sueur D,
the coast of Kenya. Trans R Soc Trop Med Hyg Snow RW. Mapping malaria transmission intensity
1993;87:386-90. using geographic information systems: an example
5. Final report: International Conference on Malaria in from Kenya. Ann Trop Med Parasitol. In press 1998.
Africa, 6-9 January 1997, Dakar, Senegal. [document 16. Mons B, Klasen E, van Kessel R, Nchinda T.
Partnerships between South and North crystallizes
around malaria. Science 1998;279:498-9.

Vol. 4, No. 3, July–September 1998 403 Emerging Infectious Diseases

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Vaccine-Preventable Diseases
Alison C. Mawle
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

The panel addressed four main areas of epidemiologic characteristics are different from
vaccine development and use: diseases of public those of usual strains (e.g., the 1918 strain killed
health importance for which no vaccine is young adults). Vaccine production problems pose
available; diseases for which an existing licensed another challenge. Identifying an appropriate
vaccine is not optimal and alternative vaccines seed strain can delay initiation of production for 4
are under development; diseases for which a to 6 months after the need for a vaccine has been
vaccine exists but is not being used optimally; and identified, and growing sufficient quantities of
diseases requiring vaccines of specialized or vaccine is difficult. The issue of an appropriate
limited use, such as those needed for controlling vaccine regimen (one dose or two) was also
outbreaks or for military use. The specific addressed. The many vaccination issues involved
diseases chosen to illustrate each area were in a pandemic situation make the adoption of a
malaria, influenza, meningitis, and filovirus credible pandemic plan imperative. The emer-
infections (Ebola and Marburg), respectively. gence of the H5N1 strain in Hong Kong has
Lee Hall, National Institute of Allergy and underlined this imperative.
Infectious Diseases, addressed the basic chal- Brad Perkins, Centers for Disease Control
lenges in developing a malaria vaccine. The and Prevention, presented the challenge of the
historical norm of vaccine development has been African meningitis belt, where periodic large
an empirical process; in contrast, modern epidemics affect approximately 1% of the
vaccines take advantage of basic knowledge of the population with a 10% death rate. Since the
organism and of the immune response to it. In current vaccine does not confer lasting protection,
vaccine development, certain elements are prediction of these epidemics can trigger vaccina-
prerequisite: demonstrable protective immunity tion campaigns to prevent deaths. A model using an
and intimate knowledge of the organism’s life epidemic threshold of 15 cases per 100,000
cycle, including the DNA sequence. Vaccine demonstrated potential lives saved. Obstacles to
development has three potential goals: prevent the use of the vaccine include inadequate
infection, prevent disease, and prevent transmis- surveillance, high cost of the vaccine, inadequate
sion. A successful vaccine may address any or all delivery systems, and inadequate vaccine supply.
these areas; for malaria, a vaccine able to perform Vaccines for agents such as Marburg and
any of these would have a significant impact. Ebola were discussed by Alan Schmaljohn, U.S.
Vaccine development, often thought of as a flow, is Army Medical Research Institute of Infectious
in fact an iterative process; it addresses scientific, Diseases. Limited-use vaccines do not have a
technical, manufacturing, and clinical issues and is global market but are potentially important
affected by economic, political, and social issues against the threat of biological weapons or
usually outside the scientific sphere of influence. epidemics. These vaccines have unique problems,
Several downstream gaps in vaccine development such as inadequate efficacy testing (since there is
include resource limitation, lack of standardization, no disease-endemic area) and high production
and problems in clinical and industrial interest. costs (since there is no target population).
Claude Hannoun, Institut Pasteur, ad- All the presentations addressed public policy
dressed problems in influenza vaccine develop- issues: who will use the vaccine and under what
ment. Influenza, the quintessential emerging circumstances, what is the time frame for
infectious disease, needs a new vaccine each year vaccine development (short-term versus long-
to protect against the predominant strains. The term), what is the cost of a vaccine (who bears
disease poses additional challenges; one is the the brunt of development costs), how are these
need for vaccine against a potential pandemic costs recouped, and what is the role of
strain, particularly a pandemic strain whose partnerships in determining vaccine need and

Emerging Infectious Diseases 404 Vol. 4, No. 3, July–September 1998

Special Issue

Travelers’ Health
Martin Cetron,* Jay Keystone,† David Shlim,‡ and Robert Steffen§
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †The
Toronto Hospital, Toronto, Ontario, Canada; ‡The Canadian International
Water and Energy Consultants Clinic Travel Medicine Center, Kathmandu,
Nepal; §University of Zurich and World Health Organization Collaborating
Centre for Travelers’ Health, Zurich, Switzerland

Over the last century and a half, the world’s If travelers are responsible for the spread of
population has grown from one billion to almost infectious agents, they are also ideal sentinels for
six billion, and the time required to circumnavi- the arrival of an infectious agent in a new
gate the globe has decreased from 365 days to community. In 1969, the first documented
fewer than 3. Currently, 1.4 million persons outbreak of Lassa fever was noted among
travel internationally by air every day. The speed American missionaries in Lagos, Nigeria. In
and volume of international travel are cited by 1992, two Peace Corps volunteers contracted
the Institute of Medicine as principal factors neuroschistosomiasis; a subsequent investiga-
contributing to the global emergence of infectious tion confirmed that Lake Malawi was an
diseases. This panel assessed the effect of travel important source for the transmission of
on emerging infections from the perspectives of Schistosoma haematobium. More recently, chlo-
both industrialized (Jay Keystone) and develop- roquine-resistant Plasmodium vivax was docu-
ing countries (David Shlim), discussed the role of mented for the first time in North Africa in U.S.
vaccination in preventing travel-related infec- Army troops returning from Somalia.
tions (Robert Steffen), and explored unique These and many other examples show that
health issues associated with travel into space travel is instrumental in the spread of new and
(David Shlim and Thomas Marshburn, National reemerging infectious diseases. As international
Aeronautics and Space Administration [NASA]). travel grows by more than 10% per year and
major population shifts continue because of
Travel and the Spread of Emerging political, economic, and social instability, public
Infectious Diseases health agencies will have to focus their infectious
In the past decade, international travel has disease surveillance programs on travelers,
grown dramatically to the point where more than migrants, and the vehicles of transport.
500 million travelers cross international borders Recognition that travelers are important sentinels
annually by commercial aircraft alone. Mass for emerging infectious diseases has stimulated the
migrations of refugees, workers, and displaced International Society of Travel Medicine and the
persons have led to a steady growth of urban Centers for Disease Control and Prevention to carry
centers at the expense of rural areas. These out a joint surveillance project, Geosentinel, in 22
population movements have been ideal conduits travel clinics around the world.
for the global spread of new and reemerging
infectious diseases. Virtually any place in the Vaccinating Travelers
world can be reached within 36 hours, less than Vaccination is only one of several strategies of
the incubation period for most infectious prophylaxis in travel medicine. Selection of
diseases. Infectious agents can spread from immunizations should be based on requirements
person to person directly or to vectors at the and on risk for infection. According to the
traveler’s destination. Vehicles of human trans- International Health Regulations, many countries
port, such as aircraft and ships, also transport the require proof of yellow fever vaccination on the
infectious agent and its vector. In addition, mass International Certificate of Vaccination. The
migrations have facilitated the rapid and revised International Health Regulations, to be
immediate spread of communicable disease submitted to the World Health Assembly next year,
among refugees and displaced persons. will likely maintain this requirement. Addition-

Vol. 4, No. 3, July–September 1998 405 Emerging Infectious Diseases

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ally, a few countries still require proof of vac- travel medicine clinic. Started in 1982 to provide
cination against cholera, diphtheria, and meningo- western medical care for expatriates and tourists in
coccal disease under specific circumstances. Nepal, the clinic has set a standard for investigating
Recommended immunizations often are more disease risks for tourists in a developing country.
important for travelers’ health than the required Nepal (population 22 million, resident
or routine ones. The most frequent vaccine- foreign population 3,000) has an annual influx of
preventable infection in travelers to developing approximately 250,000 non-Indian tourists a
countries is hepatitis A, with an average year. The Travel Medicine Center is situated in
incidence rate of 0.3% per month in susceptible the capital, Kathmandu, through which 90% of
persons; in high-risk backpackers or foreign-aid tourists enter and exit the country; a high
volunteers, this rate is 2.0%. The World Health percentage of expatriates and tourists use the
Organization and many national expert groups clinic for medical care, creating a favorable
recommend that all travelers visiting developing situation for health-risk studies.
countries be immunized against hepatitis A. Emerging diseases can be divided into three
Several other immunizations are recommended categories: 1) truly new diseases, such as
for special risk groups. Hepatitis B is a problem diarrhea caused by Cyclospora; 2) newly noted or
among expatriates, particularly if they live close increasing diseases, such as meningococcal
to the native population or engage in high-risk meningitis and Japanese encephalitis; and 3)
behavior (e.g., unprotected casual sex or unexplained illnesses, such as a cluster of cases of
intravenous drug use); rabies is also a problem, sudden death among young trekkers in teahouses.
with approximately 0.2% to 0.4% of long-term The Travel Medicine Center has made it possible
residents bitten by animals each month— to observe all three categories. Most of the above
travelers to selected geographic regions with high conditions would likely have remained unnoticed
endemicity (Southeast Asia) and exposure risk and unreported were it not for the presence of a
profiles warrant rabies vaccination; typhoid fever clinic focused on the health risks of foreigners in
(often diagnosed among travelers to the Indian Nepal.
subcontinent, North and West Africa—except The value of a research-oriented travel
Tunisia—and Peru) poses a higher risk in long- medicine center in Kathmandu extends beyond
term residents and in those who consume food the borders of Nepal. Research into diarrheal
and beverages prepared under substandard disease, hepatitis, typhoid fever, rabies
hygienic conditions (estimated incidence 0.03% to immunoprophylaxis, and altitude illness has
0.003% per month); anecdotally, meningococcal been relevant to other locations. Specific disease
disease, Japanese encephalitis, and tick-borne risks for travelers to Nepal have been carefully
encephalitis have been reported in travelers defined. Clinics in other developing countries
(monthly incidence less than one per million should be identified, and similar data gathering
travelers); immunizations against cholera and and observations should be encouraged.
tuberculosis are only rarely recommended.
In the not-too-distant future, travelers will be Travel Medicine in the 21st Century: NASA
offered a variety of oral vaccines against Perspectives
pathogens causing travelers’ diarrhea, including Space travel entails unique circumstances
all enterotoxigenic Escherichia coli as well as that influence the health of astronauts, most
Campylobacter and Shigella. Additionally, im- notably, the limitations imposed by zero-gravity
munization against Lyme disease and dengue environments. The impact of weightlessness on
fever will be available within the next years; human physiology is substantial and affects various
vaccines against malaria and AIDS, the body systems: neurologic, psychologic, vestibular,
infections causing most death in travelers, are cardiovascular, musculoskeletal, endocrine, hema-
much further in the future. tologic, and immunologic. Prominent sequelae of
prolonged weightlessness may include profound
Emerging Diseases in a Developing motor weakness and 1% to 2% loss of mineralized
Country: Observations from a Travel bone for each month in orbit; these effects can be
Medicine Clinic countered by maintaining a vigorous daily
The CIWEC Clinic Travel Medicine Center exercise program while in orbit. In addition,
was the world’s first self-supporting destination recent studies of the immune system have

Emerging Infectious Diseases 406 Vol. 4, No. 3, July–September 1998

Special Issue

documented a decrease in cell-mediated space travel include selecting exceptionally fit,

immunity among astronauts spending ex- healthy crew members and imposing preflight
tended time in space. protective quarantine. Access to the astronauts is
Environmental stressors (prolonged expo- restricted to family members beginning 10 days
sure to increased temperatures, high-velocity before departure, and a strict 7-day prelaunch
travel [17,000 miles per hour], and prolonged quarantine is imposed.
confinement to limited physical space) may also Thus far, infectious diseases have rarely been
affect the health of space travelers. The space an important problem at NASA; launch delays
environment also challenges the growth of due to infectious diseases have occurred in only
microorganisms. Increased antimicrobial resis- two Apollo flights and one shuttle mission. One
tance has been noted among E. coli and instance of infectious prostatitis in an astronaut on
Staphylococcus aureus bacteria in space, and the MIR space station resulted in the premature
fungal overgrowth can be a problem because of termination of his stay. Recent forays into long-
changes in humidity and pockets of increased term habitation in space such as those aboard MIR
condensation aboard spacecraft and space stations. (3 to 6 months) will provide new insights into the
The primary strategies used by NASA to feasibility of extended space travel and human
prevent health-related mishaps associated with colonization beyond our planet.

Vol. 4, No. 3, July–September 1998 407 Emerging Infectious Diseases

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Global Tuberculosis Challenges

Kenneth G. Castro
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Mario Raviglione, World Health Organiza- in 1995. In areas that did not use DOTS, 45% of
tion (WHO), described the epidemiology of global reported TB cases were not evaluated, and
tuberculosis (TB) using surveillance data avail- treatment success remained low (45%). Among
able to WHO from 212 countries and data from a the 22 countries with the highest TB prevalence,
recent survey of antituberculosis drug resistance six showed progress in DOTS implementation,
in 32 countries. Countries were categorized seven showed little progress, and nine did not
according to the degree of TB directly observed implement DOTS. In summary, TB remains an
treatment strategy (DOTS) implementation. important public health problem in many areas of
Performance of national TB programs was the world where DOTS has not been imple-
assessed by using treatment outcome indicators. mented. Because treatment outcomes were
In 1996, 3.8 million TB cases (887,731 from areas better in countries where DOTS has been used,
with DOTS) were reported to WHO. In the strategy needs to be expanded rapidly and
developing countries, the bulk of TB cases are new tools to facilitate its implementation need to
found in all age groups of native-born popula- be developed.
tions, while in many industrialized countries a Barry Bloom, Howard Hughes Medical
large proportion of TB cases are in foreign-born Institute, described advances in TB vaccine
residents. In countries of the former Soviet development. The available bacillus Calmette-
Union, TB cases and deaths have doubled in just Guerin (BCG) vaccine has a demonstrated
a few years. Drug resistance and HIV infection efficacy ranging from no protection to 80%
related to TB are found only in limited foci. protection. Most recently, a meta analysis
Acquired multidrug-resistant TB (MDRTB) was estimated that the overall efficacy of BCG is 50%.
present in 27% to 54% of culture-positive TB Because of case reports of disseminated BCG
cases from the Baltic countries and Russia. The infection, this vaccine is contraindicated in
effect of the HIV epidemic on TB has been major immunocompromised persons, and safer and
in Africa, where HIV seroprevalence among TB more efficacious vaccines are clearly needed.
cases is 50% to 70% and TB case notifications Identifying such new vaccines for use in humans
have at times tripled. Countries with inadequate will take several years. However, recent
TB control are particularly exposed to the advances in this area provide optimism. Recent
consequences of both epidemics. In Southeast research activities have improved our under-
Asia, cases are increasing, and MDRTB is standing of the immunologic response to
common in Thailand, China, and Vietnam. Mycobacterium tuberculosis and identified major
One hundred eighty-one countries and protein antigens of M. tuberculosis and recombi-
territories (97% of the global population) have nant BCG forms that overexpress protective
reported on the status of DOTS to WHO. Of these, antigens. Additionally, avirulent auxotrophic
96 implemented DOTS (63 countrywide). Ap- mutants of both BCG and M. tuberculosis have
proximately 32% of the global population lives in been used in animal models. The recent
areas where DOTS is available. Twenty countries sequencing of the M. tuberculosis genome has
have adopted DOTS since the 1996 survey, and presented additional opportunities to identify
an additional 9% of the global population were virulence factors that could be deleted and other
benefitting from it. However, most of these new target sites that could be genetically engineered.
countries had small populations; DOTS was only DNA constituents can also be used to develop
slowly implemented in countries with high TB candidate vaccines. In animal studies, subunit
prevalence. In areas that used DOTS, treatment vaccines consisting of pooled mycobacterial culture-
outcome evaluation remains high (94%), and filtrate proteins have been protective. Auxotrophic
treatment success rose from 76% in 1994 to 78% mutants may also prove useful in immuno-

Emerging Infectious Diseases 408 Vol. 4, No. 3, July–September 1998

Special Issue

compromised patients, as may recombinant BCG tuberculin skin test studies regarding the risk for
vaccines that secrete host-specific cytokines. TB among health-care workers in Thailand and
Clearly, a major national effort is required for TB Brazil. In Thailand, 35% of 911 health-care
vaccine development, recommendations on policies workers had a positive test at the 15-mm cutoff,
and priorities, and cooperation between the while 69% were positive at the 10-mm cutoff.
government and private sector in these efforts. BCG scar was associated with positive skin test
Christopher Murray, Harvard School of reaction at the lower cutoff value, but not at the
Public Health, described a mathematical model 15-mm cutoff. Additionally, tuberculin skin test
developed to forecast the future impact of reactivity correlated with more than 1 year’s
improvements in TB prevention and control. employment as a health-care worker, and with
Specifically, this model projected the number of occasional or frequent patient contact. In Brazil,
TB cases and deaths averted through the year 48% of 524 health-care workers had a reaction of
2050. Different scenarios were simulated to 10 mm, while 26% had a reaction of 15 mm. As in
project the effect of adding TB vaccines to Thailand, BCG scar correlated only with 10-mm
existing interventions. Six specific scenarios skin test reactivity but not with 15-mm. Workers
assessed the effect of vaccines (with efficacy with occasional or frequent patient contact were
levels of 20%, 50%, and 80%) to protect from M. also more likely to have a positive tuberculin test.
tuberculosis infection, as well as the effect of Factors that appear to contribute to the risk for
vaccines of the same levels of efficacy to protect TB in these workers include delays in the
latently infected persons from “breakdown” to diagnosis of TB, inadequate isolation practices,
active TB. Although a TB infection vaccine with and lack of personal protection during high-risk
20% efficacy would prevent more than 30 million procedures. Important measures to reduce the
TB cases, the best protection is obtained from a risk for TB in these settings include increasing
TB breakdown vaccine with 80% efficacy, which the awareness and training of health-care
would prevent almost 130 million TB cases. The workers about the risk for TB, improving the
breakdown vaccine could be used in the large ability to establish the diagnosis of TB by smear
number of persons with latent M. tuberculosis microscopy, reducing the need for hospitalization
infection, now estimated at almost one third of of TB patients, considering the establishment of
the world’s population. Such anticipated gains chest clinics at separate times or in separate
justify the effort to develop better TB vaccines. areas, and improving ventilation by keeping
Denise Garrett, Centers for Disease Control windows open. Laboratories should contain all
and Prevention, presented the findings of recent needed safety features.

Vol. 4, No. 3, July–September 1998 409 Emerging Infectious Diseases

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Blood Safety
Mary E. Chamberland,* Jay Epstein,† Roger Y. Dodd,‡
David Persing,§ Robert G. Will,¶ Alfred DeMaria, Jr.,#
Jean C. Emmanuel,** Beatrice Pierce,†† and Rima Khabbaz*
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †Food
and Drug Administration, Washington, D.C., USA; ‡American Red Cross,
Washington, D.C., USA; §Western General Hospital, Edinburgh, Scotland;
¶The Mayo Clinic, Rochester, Minnesota, USA; #Massachusetts
Department of Public Health, Boston, Masschusetts, USA;
**World Health Organization, Geneva, Switzerland; and
††National Hemophilia Foundation, New York, New York, USA

The blood supply in industrialized countries likely to have been born in or have traveled to
is safer than ever. However, blood (a human tis- disease-endemic countries were seropositive for
sue) is a natural vehicle for transmission of in- T. cruzi. Moreover, American Red Cross studies
fectious agents. In recent years, numerous of recipients of T. cruzi–seropositive blood and
pathogens have emerged in the United States blood products showed no evidence of transmis-
and worldwide with the potential to affect the sion. Finally, variant forms of recognized patho-
safety of the blood supply. gens can potentially affect the safety of the blood
supply. Current serologic tests do not consistently
International Movement of Infectious detect HIV-1 group O infections, which are com-
Agents mon in some West and Central African countries
Movement of transfusable blood and blood but very rare (two cases) in the United States.
components between countries is relatively un- Efforts are under way to modify existing serologic
common. However, infectious agents can cross tests to improve detection of group O strains with-
international borders through immigration or out compromising sensitivity for the predominant
travel. For example, malaria is an important prob- group M viruses. As an interim measure, the Food
lem in much of the world, with an estimated 300 and Drug Administration has recommended that
to 500 million cases per year. On average, 1,000 donors at increased risk for HIV-1 group O on the
cases are reported each year in the United States, basis of residence and risk exposure be deferred
most in persons who travel to malaria-endemic from donating blood or plasma.
areas. Only a small number of cases (approxi-
mately three per year) are transmitted by expo- Creutzfeldt-Jakob Disease and Blood
sure to infected blood products. Current measures Safety
(which temporarily defer donors with a history of Risk for transmission by transfusion is poorly
origin in a malarious country, clinical malaria, or characterized for a number of emerging agents.
travel to malaria-endemic areas) appear to be ef- One of these is Creutzfeldt-Jakob disease (CJD),
fective. Similarly, Chagas disease, a vector-borne a rare, fatal neurodegenerative disease believed
disease caused by the parasite Trypanosoma cruzi, to be caused by an abnormal form of prion pro-
is endemic in parts of Central and South America tein. CJD has been transmitted iatrogenically
and Mexico, where infected persons can transmit through human pituitary-derived growth hor-
the disease through transfusion. The immigration mones, human dura mater grafts, corneal trans-
of millions of persons from T. cruzi–endemic ar- plants, and contaminated surface electroencepha-
eas and increased international travel have raised logram electrodes and neurosurgical instruments.
concerns about the potential for transfusion-trans- Incubation was as long as 30 years in some cases.
mitted Chagas disease. Five cases of T. cruzi trans- Concerns regarding bloodborne transmission of
mission from transfusions have been reported in the CJD agent derive primarily from laboratory
North America. Recent seroprevalence studies studies, including animal models, which suggest
showed that approximately 0.1% of blood donors such a potential. However, no proven cases of blood

Emerging Infectious Diseases 410 Vol. 4, No. 3, July–September 1998

Special Issue

transmission are reported in humans, and accu- United States, the incidence of transfusion-trans-
mulating epidemiologic information (surveil- mitted babesiosis may increase. The tick vector
lance, follow-up of recipients of blood from do- and animal reservoir of the Babesia more recently
nors who subsequently developed CJD, and found in the northwestern and western United
case-control data) indicates that the risk (if States remain to be defined. The parasite survives
any) for transmission of CJD by blood prod- blood-banking conditions and is transmissible by
ucts is extremely small. At present, CJD is transfusion of red blood cells and platelet concen-
considered a remote, theoretical risk. trates. Although babesiosis classically causes a
In March 1996, health officials in the United febrile illness with hemolytic anemia, infection
Kingdom announced that the agent responsible can also cause chronic asymptomatic or mildly
for the decade-old bovine spongiform encephal- symptomatic parasitemia. Recent studies suggest
opathy epizootic might have spread to humans. that untreated persons have evidence of B. microti
As of March 1998, 24 persons have been reported DNA for longer periods, despite mild or absent
with this apparently new variant form of CJD symptoms, and may transmit infection for months
(nvCJD). The possibility of nvCJD transmission or possibly longer. The potential for transmission
through the blood supply has been debated. Cur- of other tick-borne agents is unclear. Like babe-
rently, this risk is theoretical. However, because siosis, Lyme disease or ehrlichiosis (caused by an
the infectious agent of nvCJD is new in humans, obligate intracellular gram-negative rickettsia)
it may present risks that differ from those of clas- may be asymptomatic or mildly symptomatic; spi-
sic CJD. In addition, important differences have rochetemia or rickettsemia can precede prodro-
been noted in the two diseases. For example, hu- mal symptoms by 24 to 72 hours, making trans-
man spleen and tonsil tissues contain abnormal mission by transfusion a possibility. One case of
prion protein in nvCJD but not in classic CJD. In transfusion-transmitted Rocky Mountain spotted
view of this uncertainty, U.K. health officials have fever has been reported.
undertaken a conservative approach, including
1) withdrawal of blood products donated by per- Summary
sons subsequently confirmed or strongly sus- Since blood is a biologic product, it is unlikely
pected to have nvCJD; 2) discontinuation of the that the risk for transfusion-transmitted infection
use of British plasma in plasma-derived prod- will ever be reduced to zero. The approach to
ucts; and 3) consideration of leukodepletion of emerging infections associated with transfusion
all blood donations, in view of experimental of blood and blood products includes assessing the
studies suggesting that B lymphocytes may play transmissibility of the agent by this route; devel-
a role in the development of scrapie. oping effective prevention strategies, including
screening tests and donor deferral policies; im-
Tick-Borne Agents and Transfusion Risk proving viral and bacterial inactivation proce-
In the United States, the most commonly re- dures; and surveillance for known, as well as
ported transfusion-associated tickborne infection emerging and poorly characterized, transfusion-
is babesiosis. At least 21 reported cases of babe- transmitted agents. Vigilance is needed to help
siosis, mostly caused by Babesia microti but also ensure proper balance between safety and the
by the more recently recognized WA1-type Babe- availability of blood. Finally, vigilance needs to
sia parasite, have been transmitted by transfu- extend to the developing world, where the ba-
sion of blood from asymptomatic infected blood sic elements to reduce transfusion-transmitted
donors. With the expansion of deer populations infections and systems of disease surveillance
(natural host of B. microti) in the northeastern are often not available.

Vol. 4, No. 3, July–September 1998 411 Emerging Infectious Diseases

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Confronting Emerging Infections:

Lessons from the
Smallpox Eradication Campaign
William H. Foege
Emory University, Atlanta, Georgia, USA

Ralph Waldo Emerson in 1860 said, “We Knowledge

learn geology the day after the earthquake.” We did not understand the limitations of
Traditionally, the world learns prevention the smallpox transmission; we knew nothing about
day after the epidemic. Today, we have the fetishes or the role of nomads. As organisms, the
responsibility of preparing for the prevention and environment, people, and tools change, programs
control not only of known but also unknown must change. Appropriate response requires
conditions. Eradication is a focused field exercise good epidemiologic analysis. The epidemiology,
in which approaches have been tested and from in turn, can be no better than the facts assembled.
which public health lessons can be learned. Knowledge is dependent on the information
system; in public health, the surveillance system
Lessons from Eradication forms the foundation of knowledge.

Calculated Risks Vision

It is clear, in retrospect, that we didn’t know With eradication, the vision is no more cases.
how to eradicate smallpox when the eradication With emerging infections, the vision is rapid,
effort began. Thirty years ago, in the middle of appropriate, effective response, being prepared
the smallpox campaign in West and Central to protect the world because you are ready to act.
Africa (charged with ending transmission in 20
countries in 5 years), we tried a new strategy, Performance
converting from mass vaccination to surveillance With eradication, to get global support, we
and containment. Although we were 1 1/2 years into must demonstrate that a disease can be
the campaign when the strategy shift occurred, we eliminated from a geographic area. With
still reached the goal of zero cases on time and emerging infections, the value of surveillance (for
under budget. The lesson is that we do not have the making decisions, for deciding on interventions)
luxury of waiting until we know everything before must be demonstrated.
doing something. We are always called upon to
make decisions with insufficient information and Humility
make corrections midcourse. With all our experience, we have not gone
far on the road to eradicating disease. This
Interdependence knowledge keeps us humble. We have trouble
Disease eradication campaigns illustrate the outthinking a virus. Even smallpox humbled us
value of working as global citizens rather than as until the very end. That virus seemed to have a
a collection of national programs. First promoted better understanding of nature, human behav-
by the Soviet Union in 1958, smallpox eradication ior, and ways to achieve immortality than the
did not get the approval of the World Health entire smallpox eradication team. The emer-
Assembly until 8 years later in 1966, when it gence and reemergence of infections must be
became a joint proposal of the Soviet Union and approached with humility.
the United States. If we could form this alliance
during the cold war, how many alliances can we Enemies
form now? No country alone can prevent or Some anthropologists think conflict is not
control emerging infections. only inevitable but needed. Will Durant once

Emerging Infectious Diseases 412 Vol. 4, No. 3, July–September 1998

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doubted the world could ever combine forces usefulness is limited. Large problems should be
without fear of an alien invasion. Perhaps disease approached with optimism.
could be used as a surrogate enemy? Emerging
infections are a powerful common enemy well Conclusions
suited as a global challenge. Nine hundred years ago, building inventions
converged and reached a peak, leading builders and
Focused Energy architects of the time to try ever bolder structures.
Energy focused on a specific end can also build Cathedrals were built that in turn led to new
infrastructure. Energy focused on eradication innovations. For several hundred years Europe was
improved infrastructure. Surveillance, logistic rewarded not only with cathedrals but also with
systems, evaluation, field teams, and cluster better building techniques for all structures. The
sampling are concepts used during eradication that infrastructure changed. Historians, in a thousand
are now part of primary health care. years, will look on the public health cathedrals that
resulted from better building materials in a period
Optimism of 75 years, from the mid-20th century until the
The pessimists and cynics were not just early 21st century. The control and eradication of
wrong with smallpox; they were harmful. They infectious diseases that once caused great
diverted attention, generated doubts in those trepidation produced better diagnostic systems,
who could provide resources, invented problems treatment, and vaccines, the elements with which
far beyond the vast array of existing ones. Even to strengthen and improve the public health system
though negative news can be of value, their and confront new disease challenges.

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The Guinea Worm Eradication Effort:

Lessons for the Future
Donald R. Hopkins
The Carter Center, Atlanta, Georgia, USA

The dracunculiasis (Guinea worm) eradica- countries, only three or four thousand cases of
tion campaign has specific implications for efforts Guinea worm disease were officially reported;
to control other emerging infectious diseases. but the actual numbers were much higher. In
Guinea worm, a painful disfiguring disease, 1989 when Ghana conducted a nationwide village-
affects primarily adults, who often become ill in by-village search, almost 180,000 cases were found.
very large numbers (usually 30% or more of a Sudan began its eradication program late because
village’s population) during the planting or of civil war. In 1996 and 1997, an apparent decline
harvest season. The disease used to be of cases in Sudan was due to less complete reporting
transmitted in parts of Asia and in Africa in open because of increased fighting in 1997.
standing stagnant water. The intermediate host
of the parasite, the copepod, contains the larva of The Campaign’s Implications for Other
the worm in such open drinking water; these Diseases
organisms are barely visible in a glass of The Guinea worm campaign has demon-
drinking water held up to the light. Thirteen strated very graphically the possibility of village-
years ago, the disease was still endemic in parts based monthly reporting in Africa. In Ghana and
of the Indian subcontinent, a small part of Nigeria at the beginning of this program 10 years
Pakistan and India, Yemen, and the band of ago, such reporting did not exist. Now in those
countries across Africa from east to west. countries, more than 6,000 disease-endemic
villages have volunteers who report to the
The Guinea Worm Eradication Campaign national capital monthly.
Several interventions have been used to end The Guinea worm campaign has also
transmission of Guinea worm disease: health demonstrated very clearly the efficacy of health
education (teaching people to filter their water education. In the beginning, many were skeptical
through a finely woven cloth and not to enter because Guinea worm could not be combated with
water when they or their neighbors are a vaccine, and eradication efforts had to rely on
infectious), safe drinking water from such behavior change. However, behavior has changed.
sources as underground borehole wells, and While we have been successful in helping to bring
vector control (using Abate). safe drinking water to many disease-endemic
The Guinea worm campaign, like other villages, the fastest and most effective interven-
campaigns in the past, has illustrated the tion has been health education, which helped
importance of political mobilization, including people understand where the parasite was
the mobilization of national leaders. For example, coming from, how they were being infected, and
General Amadou Toumani Touré (a charismatic the importance of using cloth filters to protect
former head of state of the Republic of Mali), with themselves and their families.
the encouragement of President Carter in 1992, The campaign has underscored the potential
made the eradication of Guinea worm disease in of local volunteers. Many years ago in the
Mali and in the nine other French-speaking Americas, village volunteers were used as part of
countries in West Africa his personal mission. malaria control efforts. The onchocerciasis
The campaign faces a problem common to control program in Africa is also using village
many other efforts to control infectious diseases volunteers successfully. The Guinea worm
in the industrialized and the developing world: campaign has been another illustration of how
underreporting. For example, in Ghana, as in volunteers can be used to diagnose, report, and
Nigeria 10 years ago, and in many other provide, in this instance, on-the-spot treatment

Emerging Infectious Diseases 414 Vol. 4, No. 3, July–September 1998

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to neighbors for a specific infection. Those eradication, which was in disrepute only 5, 10
responsible for the campaign’s success are often years ago, has been revived. Soon we will confirm
not members of the general health services. that a nonviral disease for which vaccine is not
With the help of the World Bank, the Guinea available can be eradicated.
worm campaign demonstrates the importance of Like the smallpox eradication campaign, the
disease eradication to the national economy. The Guinea worm campaign has illustrated very
World Bank has estimated that the economic rate vividly in many different ways and at many
of return on the investment in Guinea worm different levels (from international to village level)
eradication will be on the order of 29% per year the power of data. In the Guinea worm campaign,
once the disease is eradicated. That figure is we have used surveillance data to promote health
based on a very conservative estimate of the policy. One key lesson from the smallpox campaign
average amount of time infected workers are we are deliberately applying in the Guinea worm
unable to perform agricultural tasks. campaign is to distill what needs to be done in
The campaign has also created a group of terms of interventions to a handful, or almost a
trained health-care workers of a different handful, of indexes (seven on an international
generation from those involved in the smallpox level) to know what is most important and (as
eradication program. These workers have gone rapidly as possible) how well we are doing. That
from beginning to end, from hearing the unleashes inordinate amounts of energy.
doubters and seeing the difficulty of initiating Finally, the Guinea worm eradication
the campaign to tasting victory in their own campaign will have illustrated again the power
countries. These workers can contribute to of demonstration. Eradication can happen
subsequent campaigns. Moreover, the concept of because it has happened.

Vol. 4, No. 3, July–September 1998 415 Emerging Infectious Diseases

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Nosocomial Infection Update

Robert A. Weinstein
Cook County Hospital & Rush Medical College, Chicago, Illinois, USA

Historically, staphylococci, pseudomonads, and Escherichia coli have been the

nosocomial infection troika; nosocomial pneumonia, surgical wound infections, and
vascular access–related bacteremia have caused the most illness and death in
hospitalized patients; and intensive care units have been the epicenters of antibiotic
resistance. Acquired antimicrobial resistance is the major problem, and vancomycin-
resistant Staphylococcus aureus is the pathogen of greatest concern. The shift to
outpatient care is leaving the most vulnerable patients in hospitals. Aging of our
population and increasingly aggressive medical and surgical interventions, including
implanted foreign bodies, organ transplantations, and xenotransplantation, create a
cohort of particularly susceptible persons. Renovation of aging hospitals increases risk
of airborne fungal and other infections. To prevent and control these emerging
nosocomial infections, we need to increase national surveillance, “risk adjust” infection
rates so that interhospital comparisons are valid, develop more noninvasive infection-
resistant devices, and work with health-care workers on better implementation of
existing control measures such as hand washing.

As we enter the next millennium of infection Over the past 25 years, CDC’s National
control, we stand on the shoulders of giants— Nosocomial Infections Surveillance (NNIS) sys-
Jenner, Semmelweis, Nightingale, Oliver Wendell tem has received monthly reports of nosocomial
Holmes, and my own personal favorite, Thomas infections from a nonrandom sample of United
Crapper, the father of indoor plumbing. Modern States hospitals; more than 270 institutions
infection control is grounded in the work of Ignaz report. The nosocomial infection rate has
Semmelweis, who in the 1840s demonstrated the remained remarkably stable (approximately five
importance of hand hygiene for controlling to six hospital-acquired infections per 100
transmission of infection in hospitals. However, admissions); however, because of progressively
infection control efforts were spotty for almost a shorter inpatient stays over the last 20 years, the
century. In 1976, the Joint Commission on rate of nosocomial infections per 1,000 patient
Accreditation of Healthcare Organizations pub- days has actually increased 36%, from 7.2 in 1975
lished accreditation standards for infection control, to 9.8 in 1995 (Table 1). It is estimated that in
creating the impetus and need for hospitals to 1995, nosocomial infections cost $4.5 billion and
provide administrative and financial support for contributed to more than 88,000 deaths—one
infection control programs. In 1985, the Centers for death every 6 minutes.
Disease Control and Prevention’s (CDC’s) Study on
the Efficacy of Nosocomial Infection Control
reported that hospitals with four key infection
control components—an effective hospital epidemi- Table 1. Nosocomial infections, United States (2,3)
ologist, one infection control practitioner for every Nosoco-
250 beds, active surveillance mechanisms, and mial
Nosoco- infections
ongoing control efforts—reduced nosocomial infec-
Year Admis- Patient Length mial (/1000
tion rates by approximately one third (1). sions daysa of stay infection patient
(x106) (x106) (days) (x106) days)
Address for correspondence: Robert A. Weinstein, Cook
1975 38 299 7.9 2.1 7.2
County Hospital, Division of Infectious Diseases, 129 Durand,
1835 W. Harrison St., Chicago, IL 60612, USA; fax: 312-572- 1995 36 190 5.3 1.9 9.8
aPatient days = total inpatient days.
3523; e-mail:

Emerging Infectious Diseases 416 Vol. 4, No. 3, July–September 1998

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Which Nosocomial Infections Are The contribution of antibiotic resistance to

Emerging? excessive death rates in hospitals is difficult to
We have witnessed a cyclical parade of evaluate, often depending on whether studies are
pathogens in hospitals. In Semmelweis’s era, population-based or case-control, but evidence is
group A streptococci created most nosocomial mounting that antimicrobial resistance contrib-
problems. For the next 50 to 60 years, gram- utes to nosocomial deaths.
positive cocci, particularly streptococci and While bacterial resistance is clearly the major
Staphylococcus aureus, were the hospital patho- threat, viral and fungal resistance could become
gens of major concern. These problems culmi- important because of the small number of
nated in the pandemic of 1940 to 1950, when S. therapeutic options for these pathogens. Herpes
aureus phage type 94/96 caused major nosoco- viruses with acquired resistance to acyclovir and
mial problems. In the 1970s, gram-negative ganciclovir have emerged as problems, particu-
bacilli, particularly Pseudomonas aeruginosa larly in HIV-infected patients. Pathogens with
and Enterobacteriaceae, became synonymous intrinsic resistance often have lower pathogenic-
with nosocomial infection. By the late 1980s and ity and have disproportionately affected
early 1990s, several different classes of antimi- immunocompromised patients. For example,
crobial drugs effective against gram-negative Candida spp. with intrinsic resistance to azole
bacilli provided a brief respite. During this time, antifungal agents (e.g., C. krusei) and to
methicillin-resistant S. aureus (MRSA) and amphotericin B (e.g., C. lusitaniae) have emerged
vancomycin-resistant enterococci (VRE) emerged, as problem pathogens in oncology units.
signaling the return of the “blue bugs.” In 1990 to While we are facing the era of opportunists,
1996, the three most common gram-positive including fungi, viruses, and parasites in
pathogens—S. aureus, coagulase-negative sta- immunocompromised patients, the one we fear
phylococci, and enterococci—accounted for 34% most is the postantibiotic era. The first
of nosocomial infections, and the four most nosocomial inkling is MRSA with reduced
common gram-negative pathogens—Escherichia susceptibility to vancomycin (7). Beyond the
coli, P. aeruginosa, Enterobacter spp., and postantibiotic era lies the era of xenogenic
Klebsiella pneumoniae—accounted for 32% (3). infections as organs, transplanted from nonhuman
Bloodstream infections and pneumonias primates, bring with them a variety of potential
have increased in frequency from 1975 to 1996 zoonotic pathogens. Nevertheless, traditional
(Table 2). However, tracking nosocomial infec- respiratory pathogens may yet prove to be our
tions by site has become difficult in the last few greatest challenge; for example, a major shift in
years because of shorter inpatient stays. For strain type (8) could result in devastating pandemic
example, the average postoperative stay, now community and nosocomial influenza A outbreaks.
approximately 5 days, is usually shorter than the
5- to 7-day incubation period for S. aureus Who Is Affected by Emerging Nosocomial
surgical wound infections. Pathogens?
Acquired antimicrobial resistance is the Nosocomial infections typically affect pa-
major anticipated problem in hospitals. VRE and tients who are immunocompromised because of
MRSA are the major gram-positive pathogens of age, underlying diseases, or medical or surgical
concern (5,6). P. aeruginosa, Klebsiella, and treatments. Aging of our population and
Enterobacter that harbor chromosomal or increasingly aggressive medical and therapeutic
plasmid-mediated beta-lactamase enzymes are interventions, including implanted foreign bodies,
the major resistant gram-negative pathogens. organ transplantations, and xenotransplantations,
have created a cohort of particularly vulnerable
Table 2. Sites of nosocomial infections (2,4)
persons. As a result, the highest infection rates
Lower are in intensive care unit (ICU) patients.
respira- Nosocomial infection rates in adult and pediatric
Urinary Surgical tory Blood- ICUs are approximately three times higher than
tract wound tract stream Other elsewhere in hospitals. The sites of infection and
Year (%) (%) (%) (%) (%) the pathogens involved are directly related to
1975 42 24 10 5 19 treatment in ICUs. In these areas, patients with
1990–96 34 17 13 14 21 invasive vascular catheters and monitoring

Vol. 4, No. 3, July–September 1998 417 Emerging Infectious Diseases

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devices have more bloodstream infections due to continue to be a source of emerging infectious
coagulase-negative staphylococci. In fact, most diseases. Moreover, as hospitals age, infrastructure
cases of occult bacteremia in ICU patients are repairs and renovations will create risks of airborne
probably due to vascular access-related infec- fungal diseases caused by dust and spores released
tions. Fungal urinary tract infections have also during demolition and construction. Infections due
increased in ICU patients, presumably because of to other pathogens, such as Legionella, may also
extensive exposure to broad-spectrum antibiot- result from such disruptions.
ics. In the National Nosocomial Infections
Surveillance system, Candida spp. are the main How Can We Prevent and Control
cause of nosocomial urinary infections in ICUs (9). Emerging Nosocomial Infections?
Infection control can be very cost-effective.
Why Are Nosocomial Infections Emerging Approximately one third of nosocomial infections
Now? are preventable. To meet and exceed this level of
Three major forces are involved in nosoco- prevention, we need to pursue several strategies
mial infections. The first is antimicrobial use in simultaneously (12). First, we need to continue to
hospitals and long-term care facilities. The improve national surveillance of nosocomial
increased concern about gram-negative bacilli infections so that we have more representative
infections in the 1970s to 1980s led to increased data. We must assess the sensitivity and
use of cephalosporin antibiotics. As gram- specificity of our surveillance and of our case
negative bacilli became resistant to earlier definitions, particularly for difficult-to-diagnose
generations of cephalosporin antibiotics, newer infections like ventilator-associated pneumonia.
generations were developed. Widespread use of We also need to develop systems for surveillance
cephalosporin antibiotics is often cited as a cause of “nosocomial” infections that occur out of the
of the emergence of enterococci as nosocomial hospital, where much health care is now given.
pathogens. About the same time, MRSA, perhaps Second, we need to ensure that surveillance
also in response to extensive use of cephalosporin uses are valid. The Joint Commission on
antibiotics, became a major nosocomial threat. Accreditation of Healthcare Organization’s ORYX
Widespread empiric use of vancomycin, as a initiative for monitoring health-care processes
response to concerns about MRSA and for and outcomes will lead to core indicators and
treatment of vascular catheter–associated infec- sentinel event monitoring. This initiative will be
tion by resistant coagulase-negative staphylo- followed by increased outpatient surveillance,
cocci, is the major initial selective pressure for which ultimately may lead to systemwide real-
VRE. Use of antimicrobial drugs in long-term time surveillance and reporting. Because we
care facilities and transfer of patients between want to use nosocomial infection rates as a core
these facilities and hospitals have created a large indicator of quality of care, we need to improve
reservoir of resistant strains in nursing homes. our ability to “risk adjust” infection rates so we
Second, many hospital personnel fail to follow know that our interprovider and interhospital
basic infection control, such as hand washing comparisons are valid. Risk stratification will
between patient contacts. In ICUs, asepsis is often ultimately depend on organic-based computer
overlooked in the rush of crisis care (10). systems that will mimic biologic events.
Third, patients in hospitals are increasingly Third, many of our successes in controlling
immunocompromised. The shift of surgical care to nosocomial infections have come from improving
outpatient centers leaves the sickest patients in the design of invasive devices. This is particularly
hospitals, which are becoming more like large ICUs important given the marked increase in
(11). This shift has led to the greater prevalence of frequency of vascular access–associated blood-
vascular access–associated bloodstream infections stream infections, particularly in ICU patients.
and ventilator-associated pneumonias. Given the choice of changing human behavior
Other precipitating factors also can be (e.g., improving aseptic technique) or designing a
anticipated in hospitals. Transplantation is a better device, the device will always be more
double-edged sword because of the combined successful. Of particular importance is the
effects of immunosuppression of transplant development of noninvasive monitoring devices
patients and of infectious diseases that come with and minimally invasive surgical techniques that
some transplanted organs. The blood supply will avoid the high risk associated with bypassing

Emerging Infectious Diseases 418 Vol. 4, No. 3, July–September 1998

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normal host defense barriers (e.g., the skin and The major advances in overall control of
mucous membranes). infectious diseases have resulted from immuniza-
Fourth, forestalling the postantibiotic era will tion and improved hygiene, particularly hand
require aggressive antibiotic control programs (13); washing. We must work with hospital personnel
these may become mandated for hospitals that on better implementation of existing infection
receive federal reimbursements, as happened in the control technologies so that we will not need to
past with infection control programs. Risks for rely solely on technologic advances.
antibiotic-resistant strains also may be reduced in
the future by controlling colonization through use of Dr. Weinstein is chair, Division of Infectious
immunization or competing flora. Diseases, Cook County Hospital; director of Infectious
Fifth, antimicrobial resistance problems and Diseases Services for the Cook County Bureau of Health
Services; and professor of Medicine, Rush Medical
the advent of xenotransplantation emphasize the
College. He also oversees the CORE Center for the
importance of newer microbiologic methods. For Prevention, Care and Research of Infectious Disease and
investigation of outbreaks of multidrug-resistant directs the Cook County Hospital component of the Rush/
pathogens, pulsed-field gel electrophoresis has Cook County Infectious Disease Fellowship Program.
become a routine epidemiologic tool (14). His areas of research include nosocomial infections
Molecular epidemiologic analysis also may help (particularly the epidemiology and control of antimicro-
us better understand the factors that lead to the bial resistance and infections in intensive care units)
emergence of resistant strains. For diagnosis of and health-care outcomes for patients with HIV/AIDS.
syndromes caused by unusual pathogens,
representational difference analysis and specia- References
tion by use of the pathogen’s phylogenetic r-RNA 1. Haley RW, Culver DH, White J, Morgan WM, Amber TG,
Mann VP, et al. The efficacy of infection surveillance and
“clock” may become routine.
control programs in preventing nosocomial infections in
Sixth, control of tuberculosis (TB) in US hospitals. Am J Epidemiol 1985;121:182-205.
hospitals is an excellent example of the successful 2. Haley RW, Culver DH, White JW, Morgan WM, Emori
collaboration of the infection control community, TG. The nationwide nosocomial infection rate: a new need
CDC, and regulatory agencies. But we can for vital statistics. Am J Epidemiol 1985;121:159-67.
3. New York Times 1998 Mar 12; Sect. A12.
anticipate that the Occupational Safety and Health
4. Centers for Disease Control and Prevention, Hospital
Administration may have many new employee Infections Program. National Nosocomial Infections
health issues—beyond TB and bloodborne patho- Surveillance (NNIS) report, data summary from
gens—to evaluate in hospitals, such as health October 1986-April 1996, issued May 1996: A report
problems related to exposure to magnetic fields, to from the NNIS System. Am J Infect Control
new polymers, and to medications that contami-
5. Slaughter S, Hayden MK, Nathan C, Hu TC, Rice T,
nate the environment. Problems of mental stress Van Voorhis J, et al. A comparison of the effect of
due to unrelenting exposure to pagers, faxes, e- universal use of gloves and gowns with that of glove use
mail, holograms, and telephonic implanted alone on acquisition of vancomycin-resistant enterococci
communicators will require special attention. in a medical intensive care unit. Ann Intern Med
6. Bonten MJM, Hayden MK, Nathan C, Van Voorhis J,
Conclusion Matushek M, Slaughter S, et al. Epidemiology of
Several enduring truths characterize the colonisation of patients and environment with vancomycin-
field of infection control. Hospitals will become resistant enterococci. Lancet 1996;348:1615-9.
more like ICUs, and more routine care will be 7. Hiramatsu K, Aritaka N, Hanaki H, Kawasaki S, Hosoda
Y, Hori S, et al. Dissemination in Japanese hospitals of
delivered on an outpatient basis. Given the choice
strains of Staphylococcus aureus heterogeneously
of improving technology or improving human resistant to vancomycin. Lancet 1997;350:1670-3.
behavior, technology is the better choice. All 8. Webster RG. Influenza: an emerging disease. Emerg
infection control measures will need to continue Infect Dis 1998;4(3).
to pass the test of the “four Ps” (15): Are the 9. Fridkin SK, Welbel SF, Weinstein RA. Magnitude and
prevention of nosocomial infections in the intensive
recommendations Plausible biologically (e.g., is it
care unit. Infect Dis Clin North Am 1997;11:479-96.
likely to work)? Are they Practical (e.g., are they 10. Weinstein RA. Epidemiology and control of nosocomial
affordable)? Are they Politically acceptable (e.g., infections in adult intensive care units. Am J Med
will the administration agree)? And, will Personnel 1991;91:179-84.
follow them (e.g., can they and will they)?

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11. Archibald L, Phillips L, Monnet D, McGowan JE, 13. Goldmann DA, Weinstein RA, Wenzel RP, Tablan OC,
Tenover F, Gaynes R. Antimicrobial resistance in Duma RJ, Gaynes RP, et al. Strategies to prevent and
isolates from inpatients and outpatients in the United control the emergence and spread of antimicrobial-
States: increasing importance of the intensive care resistant microorganisms in hospitals. A challenge to
unit. Clin Infect Dis 1997;24:211-5. hospital leadership. JAMA 1996;275:234-40.
12. Scheckler WE, Brimhall D, Buck AS, Farr BM, Friedman 14. Tenover FC, Arbeit RD, Goering RV. How to select and
C, Garibaldi RA, et al. Requirements for infrastructure interpret molecular strain typing methods for
and essential activities of infection control and epidemiological studies of bacterial infections: a review for
epidemiology in hospitals: a consensus panel report. Infect healthcare epidemiologists. Infect Control Hosp Epidemiol
Control Hosp Epidemiol 1998;19:114-24. 1997;18:426-39.
15. Weinstein RA. SHEA consensus panel report: a smooth
takeoff. Infect Control Hosp Epidemiol 1998;19:91-3.

Sir John Pattison (L)

Medical School of University College,
Sherif Zaki
Centers for Disease Control and
Prevention, Atlanta, Georgia, USA

Emerging Infectious Diseases 420 Vol. 4, No. 3, July–September 1998

Special Issue

Opportunistic Infections in
Immunodeficient Populations
Jonathan E. Kaplan,* Gary Roselle,† and Kent Sepkowitz‡
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA;
†Veterans Administration Medical Center, Cincinnati, Ohio, USA; and
‡Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Opportunistic infections occur with greater Robert Hogg, University of British Colum-
frequency or severity in patients with impaired bia, discussed the remarkable changes in the
host defenses. Growing numbers of HIV-infected natural history of HIV in North America,
persons, transplant recipients, and elderly specifically in British Columbia, as a result of
persons are at increased risk. highly active antiretroviral therapy (HAART).
Alison Grant, London School of Hygiene and Of more than 5,000 HIV-infected persons
Tropical Medicine, discussed opportunistic infec- receiving care in British Columbia, more than
tions due to HIV. In 1997, more than 30 million 2,000 are receiving HAART. HIV viral loads
HIV-infected persons lived in the world, with have been reduced to undetectable levels in
more than two thirds of them in sub-Saharan approximately half of these patients, with
Africa and an additional 20% in Asia and Latin corresponding decreases in the incidence of
America. Assessments of the prevalence and opportunistic infections, hospitalizations, and
incidence of opportunistic infections in these deaths. However, even for persons who have
areas and comparability of the available data are access to the therapy, these successes may be
hampered by limited access to care, diagnostic short-lived as resistance to HAART becomes
capabilities, and surveillance data. Despite these more widespread. HAART use has resulted in
limitations, we know that tuberculosis (TB) is the new syndromes that may occur soon after
most frequent serious opportunistic infection in therapy, probably representing preexisting,
the developing world. Other such infections subclinical infections that are unmasked by the
common in sub-Saharan Africa include septice- immunologic improvement that accompanies
mia (of which nontyphoid salmonella is the most HAART; these syndromes include lymphadeni-
common cause), toxoplasmosis, and bacterial tis associated with Mycobacterium avium
pneumonia. Pneumocystis carinii infection, for complex, cytomegalovirus retinitis, and miliary
unknown reasons, is uncommon among adults in TB on chest X-ray. Hepatitis C infection,
East and West Africa but appears to be more common in HIV-infected injection drug users,
common in South Africa. Penicillium marneffei may pose increasing problems as coinfected
infection, common in Thailand, is an example of persons live longer. Therefore, surveillance for
an opportunistic infection of importance in a old and new syndromes remains critical even
specific region; risk factors in these regions are with the reduced incidence of opportunistic
largely unknown. Additional challenges are infections that has been associated with
posed by the different HIV subtypes in the HAART.
developing world and the possibility that some Robert Rubin, Harvard University and
may be associated with a differential risk for Massachusetts Institute of Technology, discussed
opportunistic infections. Prevention efforts in opportunistic infections in hematopoietic stem
developing countries have been limited. More cell (bone marrow) and solid-organ transplant
work is needed to evaluate prophylactic regimens recipients; the number of these transplant
appropriate to different regions. Prevention of TB recipients has increased dramatically in the
with isoniazid; of pneumocystosis, toxoplasmosis, United States in the past decade. The opportunis-
and some bacterial infections with cotrimoxazole; tic infections in these patients originate from
and of pneumococcal infections with 23-valent endogenous flora (e.g, invasive candidiasis), from
pneumococcal vaccine have potential. the general (nonhospital) environment (e.g,

Vol. 4, No. 3, July–September 1998 421 Emerging Infectious Diseases

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histoplasmosis, TB, disseminated strongyloidi- population that is increasing in the United

asis), or from the hospital environment (e.g, States and worldwide. Persons >65 years of age
aspergillosis, legionellosis, and infections with already constitute approximately one eighth of
vancomycin-resistant enterococci or multiply the U.S. population; this proportion is expected
resistant gram-negative bacteria). These infec- to double in the next 50 years. Elderly persons
tions characteristically occur in a time-depen- have defects in T-cell immunity that result in
dent pattern posttransplant, corresponding with increased incidence and death from TB. B-cell
the nature of the immunodeficiency. For defects result in increased susceptibility to
example, in bone marrow transplant recipients, Streptococcus pneumoniae and respiratory
infections within 1 month of transplantation syncytial virus and a decreased response to 23-
(pre-engraftment) occur as a result of neutrope- valent pneumococcal vaccine. Elderly persons
nia and disruption of mucosal surfaces; infections are at increased risk for cancer, so various
that occur in the second or third months are due treatments associated with immunosuppres-
to deficiencies in cell-mediated immunity and are sion (such as organ transplantation and
more frequent in the setting of graft versus host aggressive cancer chemotherapy) are increas-
disease. In solid-organ transplant recipients, ingly being used in this population. Chronic
infections within the first month are generally corticosteroid therapy is frequently used for
associated with technical problems related to treatment of temporal arteritis. Although HIV
surgery; infections that occur later are due to infection is relatively uncommon in the elderly,
immunodeficiency associated with immunosup- when it does occur, it is likely to go undiagnosed.
pressive therapy. These timetables are useful in Because of higher rates of hospitalization, elderly
that infections that are unusual or occur outside persons are more susceptible to nosocomial
the expected time frame may serve as sentinels infections (including those caused by antibiotic-
for emerging opportunistic infections. Research resistant organisms). Moreover, the elderly are
priorities in this area include development of more likely to reside in long-term care facilities,
therapies that will enhance successful transplan- which may serve as sources or amplifiers of
tation without increasing the risk for opportunis- infections such as influenza. Susceptibility to
tic infections, strategies to reduce the risk of infection may be further increased by malnutri-
drug-resistant opportunistic infections, and tion, diabetes, and chronic renal failure. Finally,
greater understanding of the role of cytokines in healthy, more affluent older persons are at risk
the relationship between graft versus host for infections associated with travel.
disease and opportunistic infections. In summary, opportunistic infections are a
Carol Kauffman, University of Michigan and threat in the increasing populations of
the Ann Arbor Veterans Administration Medical immunocompromised persons. In these popula-
Center, discussed infections in the elderly, a tions, opportunistic infections pose challenges for
surveillance and determination of risk factors,
including those for infection with antibiotic-
resistant organisms.

Emerging Infectious Diseases 422 Vol. 4, No. 3, July–September 1998

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Host Genes and Infectious Diseases

Janet McNicholl
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

This panel presented data on host genes that of patients disease may progress to shock, 5%
influence susceptibility to or manifestations of may require dialysis, and some may die. Of those
four infectious diseases: Puumala hantavirus who recover, renal damage may later result in
infection, tuberculosis (TB), Lyme disease, and chronic hypertension. Because hantaviruses are
AIDS. Gus Birkhead, Council of State and variable and are usually transmitted as swarms
Territorial Epidemiologists, introduced the ses- of viruses, it was proposed that host factors, such
sion, highlighting its timeliness in relation to the as HLA genes, might influence the spectrum of
rapidly emerging body of data on our 100,000 disease. Indeed, this has been shown to be the
human genes that stems from the Human case. Persons who express the HLA-B8 genes had
Genome and related projects. more severe disease with lower blood pressures,
The presentations introduced several ap- higher creatinine (1), and more virus in the urine
proaches to identifying a host gene–infectious and blood by polymerase chain reaction (PCR) (2).
disease interaction. Panelists presented case- Persons with HLA-B27 had milder disease (3).
control studies of hantavirus infection, AIDS, TB, The finding of TNF-α expression in the kidney of
and Lyme disease that used the candidate gene infected patients prompted an analysis of the
approach; the new approach, genome scanning by TNF 1 and 2 alleles (at positions -308 and -238) by
microsatellites to identify genes associated with restriction fragment length polymorphism
TB susceptibility, was also described. Candidate (RFLP), and as might have been predicted from
genes were chosen on the basis of pathology of the their linkage to the HLA-A1-B8-DR3 haplotype,
infectious disease (human leukocyte antigen nearly all who progressed to shock expressed the
[HLA], tumor necrosis factor [TNF], the antigen TNF 2 allele (M. Kanerva, unpub. data). This
processing [TAP]), mouse genetic studies of the allele has been linked to high TNF production (4).
pathogen (NRAMP1 in TB), or epidemiologic Because the HLA-A1-B8-DR3 MHC haplo-
findings of disease severity (Vitamin D and TB). type is associated with insulin-dependent
diabetes mellitus and other autoimmune dis-
Susceptibility-Associated Major eases that may have a viral etiology, it was asked
Histocompatibility Complex (MHC) if molecular mimicry could explain the associa-
Haplotype in Severe Puumala Hantavirus tion of this haplotype with the renal disease of
Infection Puumala virus infection. Dr. Vaheri stated that
Annti Vaheri, Haartman Institute, Univer- no such evidence exists and that the association
sity of Helsinki, described the epidemiology of probably reflects a propensity to a particular type
hantavirus infections in Northern Europe. The of immune response that results in disease.
pathogens, enveloped RNA viruses primarily of Whether the genetic associations observed with
the Puumala and Dobrava genotypes, are carried Puumala hantavirus disease are due to a primary
by rodents such as mice and voles and cause a association with the TNF 2 allele or the linked
range of disease in humans. While the epidemics HLA alleles is not known and deserves future
in the United States are of hantaviruses that research. Another important field is the mapping
cause primarily pulmonary disease, in northern of HLA-restricted epitopes in hantaviruses.
Europe, renal disease is the primary pathologic
manifestation, as evidenced by increased capil- Host Susceptibility to TB in Africa
lary permeability, infiltrates of CD8+ T cells, Although TB has been present in human
high levels of ICAM-1, and expression of TNF-α populations for millennia, its reemergence as a
and transforming growth factor (TGF)-ß. Al- public health problem and the new tools of
though most infections with these viruses are molecular genetics have provided an impetus to
probably subclinical or cause mild disease, in 10% study host genetic susceptibility to TB disease.

Vol. 4, No. 3, July–September 1998 423 Emerging Infectious Diseases

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Richard Bellamy, Wellcome Trust Center for patients; persons heterozygous for INT4 GC and
Human Genetics, presented studies that used 3'UTR deletion had a fourfold increased risk of
both candidate- and genome-screening ap- having TB (6). The 3'UTR allele is of unusually
proaches to define these factors in African high prevalence in the West African population
populations. As stated during the question-and- studies but is uncommon in Europeans. This may
answer session, many studies of TB should be partly explain the higher susceptibility to TB in
considered studies of TB disease rather than TB African Americans compared with other ethnic
susceptibility, since most persons, particularly in groups. While the physiologic function of
Africa, are TB infected, but (at least in HIV- NRAMP1 has not been defined, it may affect
negative populations) fewer than 10% become ill. phagolysosome function. Dr. Bellamy’s data
Dr. Bellamy’s studies were carried out in suggest that the polymorphisms they have
populations with low HIV prevalence, HIV- defined or linked polymorphisms may alter
infected persons were excluded, and disease was NRAMP1 function and therefore the host’s ability
defined as smear-positive TB. Historically, in to clear intracellular pathogens. In vitro studies
most populations, particularly in The Gambia to address the effect of these polymorphisms on
and South Africa, the sources of patients and macrophage function are in progress.
controls for these studies, TB is predominantly a Dr. Bellamy also presented unpublished data
disease of males. Previous studies of mono- and on vitamin D receptor genotypes and susceptibil-
dizygotic twins have also suggested a genetic ity to TB disease. This gene was chosen because of
component (reviewed in 5). clinical and laboratory data suggesting vitamin D
One of the studies described by Dr. Bellamy may be important in host defenses against TB
used new tools from the human genome and other (7,8). He observed a low prevalence of the
projects called microsatellite markers (intronic homozygous t vitamin D receptor genotype in TB
sections of cytosine, adenine repeats) and cases but not in controls. This genotype is also
automated robotic DNA typing using four-color associated with increased risk for osteoporosis
fluorescent labels with 20 markers per lane of (9,10). These findings raise the question whether
large gels that are scanned and analyzed by administering vitamin D to populations at risk
software such as GeneScan 672 and Genotyper for TB disease might be a simple public health
1.2. He analyzed 92 sibling-pairs from The measure to reduce the disease. However, the
Gambia and South Africa. Cosegregation with TB effect of such therapy might be hard to estimate
was identified for markers on chromosomes 3, 5, 6, because of the low prevalence of the tt
8, 9, 15, and the X chromosome. A second study of 83 homozygous genotype.
sibling-pairs from the same countries again linked The genes (e.g., HLA) identified in these and
the same sites on Xq and 15p with lod scores of >2. other studies are certainly not the only genes
While these studies do not identify the genes in involved in host susceptibility to TB. Dr. Bellamy
question, further studies of these regions may estimated that together they account for less
reveal the relevant genes (e.g., the microsatellite than 2% of the total familial clustering effect in
region identified on Xq is close to genes encoding the this disease.
CD40 ligand and human LAMP).
Bellamy’s group identified two additional HLA and the Pathogenesis of Lyme
genes associated with TB in candidate gene Arthritis
association studies of African TB cases and Host responses to another bacterium, the
ethnically matched controls (6). The human spirochete Borrelia burgdorferi, and the clinical
homologue NRAMP1 of the mouse Bcg gene that spectrum of Lyme arthritis were discussed by
confers resistance to bacillus Calmette-Guérin Allen Steere, Department of Rheumatology and
has been located on chromosome 2q35. Four Immunology, New England Medical Center,
polymorphisms in NRAMP1 were studied with Boston, Massachusetts. Another vector-borne
microsatellite markers and probes that distin- human pathogen, B. burgdorferi causes a
guished single-base substitutions and a 4-bp multisystem disease that may affect the skin,
deletion in the gene. While all four polymor- nervous system, heart, or joints. Arthritis is a
phisms were associated with TB, two, one major late manifestation of the illness. Although
intronic and another in the 3' untranslated all manifestations are usually treatable with
region, were particularly overrepresented in TB antibiotic therapy, approximately 10% of patients

Emerging Infectious Diseases 424 Vol. 4, No. 3, July–September 1998

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with Lyme arthritis have persistent joint inflam- AIDS was reviewed by Richard Kaslow,
mation for months or even years after antibiotic Department of Epidemiology, University of
therapy. In these patients, PCR tests for B. burg- Alabama, Birmingham, Alabama. The studies
dorferi DNA in joint fluid have been negative after reported by Kaslow and others in the last 2 years
antibiotic treatment, which suggests that joint have greatly benefited from several longitudinal
inflammation may sometimes continue after the cohort studies, some focusing on HIV-infected
spirochete has been eradicated from the joint. seroconverters or HIV-exposed persons in the
Dr. Steere’s group is studying host factors United States and Europe. More than 10 years
that may be important in the pathogenesis of after these cohorts have been established,
chronic, treatment-resistant Lyme arthritis. adequate power to address the role of candidate
Studies of HLA class II alleles have shown that genes in transmitting HIV horizontally and
HLA-DRB1*0401 alleles are associated with vertically and in affecting the rate of disease
chronic Lyme arthritis and lack of response to progression has been obtained, while increased
antibiotic therapy (11). This allele is also knowledge of HIV’s mode of cellular entry has
associated with an increased risk of developing provided new candidate genes to study. HIV
severe rheumatoid arthritis (12). In a study of enters cells through an interaction with both CD4
antibody responses in patients throughout the and a chemokine receptor of the 7 Tm family (14).
course of Lyme disease, immunoglobulin G (IgG) Dr. Kaslow first reviewed the role of genes in
responses to outer-surface protein A (OspA) and encoding chemokine receptors (CCR5 and CCR2)
OspB of the spirochete often developed near the and chemokines (SDF-1) in HIV disease. While
beginning of prolonged episodes of arthritis (13). CCR5 has multiple allelic variants in its coding
Arthritis lasted considerably longer after treat- region (15), the deletion of a 32-bp segment
ment in patients with HLA-DR4 and OspA and results in a nonfunctional receptor (reviewed in
OspB antibody reactivity than in those who 16), thus preventing HIV entry; two copies of this
lacked responses to these proteins (13). The gene provide strong protection against HIV
cellular arm of the immune response has also infection in epidemiologic studies, although the
been examined by Dr. Steere’s group, and persons protection is not absolute. This gene is found in
with treatment-resistant Lyme arthritis usually up to 20% of Europeans but is rare in Africans and
have T cells that react with many OspA epitopes, Asians. Multiple studies of HIV-infected persons
whereas treatment-responsive patients usually do have shown that presence of one copy of this gene
not. A possible explanation for these findings is that delays progression to AIDS by about 2 years. A
the T-cell response to OspA in patients with mutation in another chemokine receptor gene,
treatment-resistant Lyme arthritis may cross-react that coding for CCR2, has also been reported by
with a self antigen in the joint, and the response to several groups to be associated with a delayed
this self antigen may continue to cause joint progression to AIDS (reviewed in 17). This
inflammation for months or even years after the polymorphism (a position 64 Val→Ile substitution)
eradication of the spirochete from the joint. does not appear likely to affect receptor function,
How does one treat patients with Lyme and the mutation may be linked to another
arthritis who do not appear to respond to therapy? polymorphism in the promotor of CCR5 (18).
Dr. Steere recommended that if they have not Nevertheless, studies of persons with both CCR2
responded to antibiotics after 2 months and the 64I polymorphism and CCR5 delta 32 deletion
PCR test on joint fluid is negative for B. burgdorferi suggest the effect of both genes on HIV disease
DNA, patients should be treated with antiinflam- progression is additive (19). A polymorphism in the
matory agents. When asked whether HLA genes chemokine SDF-1, which binds to another HIV
might influence Osp-based vaccines for Lyme entry receptor, CXCR4, also delays HIV progres-
disease, Dr. Steere noted that studies to address sion and similarly appears additive to the effects of
this question have not yet been carried out. the CCR2 and CCR5 polymorphisms (20).
Dr. Kaslow also reviewed studies of the HLA
Host Genes, HIV Susceptibility, and system (at the Class I HLA A, B, C and Class II DR
Disease Course and DQ and the antigen processing [TAP] loci) and
The rapidly growing and complex body of how complex combinations of different HLA alleles
knowledge on the host genes that influence alter the risk of developing AIDS in several cohorts
susceptibility to HIV infection and progression to of HIV-infected persons (21). The effects of different

Vol. 4, No. 3, July–September 1998 425 Emerging Infectious Diseases

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combinations of HLA alleles appear to delay HIV 9. Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF,
progression by a variable number of years and to be Gilsanz V. Vitamin D-receptor gene polymorphisms
additive to the effects of the chemokine gene and bone density in prepubertal American girls of
Mexican descent. N Engl J Med. 1997;337(2):77-82.
polymorphisms described above. 10. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen
These new findings about HIV and host genes TV, et al. Prediction of bone density from vitamin D
have led to new approaches to AIDS treatments, receptor alleles. Nature 1994;367(6460):284-287.
such as those directed at chemokine receptors, 11. Steere AC, Dwyer E, Winchester R. Association of
and hold great promise for advancing our ability chronic Lyme arthritis with HLA-DR4 and HLA-DR2
alleles. N Engl J Med 1990;323:219-23.
to combat this disease. 12. Gregerson PK, Silber J, Winchester RJ. The shared
epitope hypothesis: an approach to understanding the
References molecular genetics of rheumatoid arthritis. Arthritis
1. Mustonen J, Partanen J, Kanerva M, Pietilä K, Rheum 1987;30:1205-13.
Vapalahti O, Pasternack A, et al. Genetic susceptibility 13. Kalish RA, Leong JM, Steere AC. Association of
to severe course of nephropathia epidemica caused by treatment-resistant chronic Lyme arthritis with HLA-
Puumala hantavirus. Kidney Int 1996;49:217-21. DR4 and antibody reactivity with OspA and OspB of
2. Plyusnin A, Hörling J, Kanerva M, Mustonen J, Cheng Borrelia burgdorferi. Infect Immun 1993;61:2774-9.
Y, Partanen J, et al. Puumala hantavirus genome in 14. Murphy PM. Chemokine receptors: structure, function
patients with nephropathia epidemica: correlation of and role in microbial pathogenesis. Cytokine & Growth
PCR positivity with HLA haplotype and link to viral Factor Reviews 1996;7:47-64.
sequences in local rodents. J Clin Microbiol 15. Carrington M, Kissner T, Gerrard B, Ivanov S, O’Brien
1997;35:1090-6. SJ, Dean M. Novel alleles of the chemokine-receptor
3. Mustonen J, Partanen J, Kanerva M, Pietilä K, gene CCR5. Am J Hum Genet 1997;61:1261-7.
Vapalahti O, Pasternack A, et al. Asssociation of HLA 16. McNicholl JM, Smith DK, Qari SH, Hodge T. Host
B27 with benign clinical course of nephropathia genes and HIV: the role of the chemokine receptor gene
epidemica caused by Puumala hantavirus. Scand J CCR5 and its allele (∆32 CCR5). Emerg Infect Dis
Immunol. In press 1998. 1997:3:261-71.
4. Wilson AG, Symons JA, McDowell TL, McDevit HO, 17. Garred P. Chemokine-receptor polymorphisms: clarity
Duff GW. Effects of polymorphism in the tumor or confusion for HIV prognosis [editorial]. Lancet
necrosis factor alpha promoter on transcriptional 1998;351:2-3.
activation. Proc Natl Acad Sci U S A 1997;94:3195-9. 18. Kostrikis LG, Huang Y, Moore JP, Wolinsky SM,
5. Bloom BR, Small PM. Editorial. The evolving relation Zhang L, Guo Y, et al. A chemokine receptor CCR2
between humans and Mycobacterium tuberculosis. N allele delays HIV progression and is associated with a
Engl J Med 1998;338:677-8. CCR5 promotor mutation. Nature Med 1998;4;350-3.
6. Bellamy R, Ruwende C, Tumani C, McAdam PWJ, 19. Smith MW, Dean M, Carrington M, Winkler C, Huttley
Whittle HC, Hill AVS. Variations in the NRAMP1 gene GA, Lomb DA, et al. Contrasting genetic influence of
and susceptibility to tuberculosis in West Africans. N CCR 2 and CCR5 variants on HIV infection and disease
Engl J Med 1998;338:640-4. progression. Science 1997;277;959-65.
7. Davies PD. A possible link between vitamin D 20. Winkler C, Modi W, Smith MW, Nelson GW, Wu X,
deficiency and impaired host defence to Mycobacterium Carrington M, et al. Genetic restriction of AIDS
tuberculosis. Tubercle 1985;66:301-6. pathogenesis by an SDF-1 chemokine gene variant.
8. Rook GA, Steele J, Fraher L, Barker S, Karmali R, Science 1998;279;380-93.
O’Riordan J, et al. Vitamin D3, gamma interferon, and 21. Kaslow RA, Carrington M, Apple R, Park L, Munoz A,
control of proliferation of Mycobacterium tuberculosis Saah AJ, et al. Influence of combinations of human
by human monocytes. Immunology. 1986;57:159-63. major histocompatibility complex genes on the course
of HIV-1 infection. Nature Medicine 1996;2:405-11.

Emerging Infectious Diseases 426 Vol. 4, No. 3, July–September 1998

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Immigrant and Refugee Health

Susan Cookson,* Ronald Waldman,* Brian Gushulak,† Douglas
MacPherson,‡ Frederick Burkle, Jr.,§ Christophe Paquet,¶ Erich
Kliewer,# and Patricia Walker**
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †The
International Organization for Migration, Geneva, Switzerland; ‡St. Joseph’s
Hospital, Hamilton, Ontario, Canada; §University of Hawaii, Honolulu,
Hawaii, USA; ¶Epicentre, Paris, France; #Manitoba Cancer Treatment and
Research Foundation, Winnipeg, Manitoba, Canada; and
**Regions Hospital, St. Paul, Minnesota, USA

Each year, more than 15 million people seek medical interventions for the causative agents of
political asylum or become refugees in various diseases that affect these vulnerable populations.
parts of the world. Most of these displaced Migrant populations have been displaced by
persons are from developing countries where disasters (natural, technologic, and human),
infectious diseases (e.g., tuberculosis, hepatitis, which test the public health resources of a nation
malaria, various parasitic and emerging dis- and expose weaknesses. Public health workers
eases) are prevalent. These persons migrate increasingly appreciate the fragile interaction
mainly to the United States, Australia, and between individual host, environment, and infec-
Canada, nations that receive inflows of migrants tious and noninfectious agents capable of producing
proportional to their mainstream population. disease. The consequences of these relationships,
Because of the speed and efficiency of modern including the real and potential vulnerability of
transportation systems, health interventions populations, are becoming increasingly important
applicable to all persons who cross international indicators of national security.
borders are difficult to introduce and monitor. Cholera, a disease that affects migrant
Identifying and addressing individual and public populations, was examined. In Malawi, 11
health risks necessitate international and outbreaks were documented in Mozambican
quarantine health legislation, health policy and refugees between 1987 and 1991, with attack rates
social economic evaluation, risk-benefit and of 0.6% to 9.3%. In 1994, an estimated 60,000 cases
utility analysis, and risk-predictive modeling. of cholera and 10,000 deaths occurred during a
Ultimately, improving the health of migrants is 1-month massive epidemic among Rwandan
at the heart of reducing the public health risk to refugees (population 800,000) in Goma, Democratic
the international community from infectious Republic of Congo. Epidemic preparedness during
disease spread by travel. the 1996 return of the epidemic proved the
Medical intelligence systems that can survey, cornerstone of cholera control in these refugees.
detect, and confirm the emergence of new Properly implemented, active case-finding and
infectious diseases are still in their infancy. The rehydration therapy in specialized treatment
global ability to generate numerators (cases of centers can keep the case-fatality ratio below 1%.
existing and emerging infectious disease) has In Australia, use of hospital and medical
been limited to the relatively few diseases listed services by immigrants and refugees was
in the old World Health Organization (WHO) examined. Foreign-born persons had lower
International Health Regulations (yellow fever, hospitalization rates than native Australians,
plague, cholera, smallpox); further limitations although some immigrant groups had higher
stem from poor detection systems and incomplete rates for some diagnoses. Hospital data may help
reports (with the exception of smallpox). The define trends in immigrant disease profiles; the
dynamic problem of defining numerators and data, however, do not indicate whether the
denominators (displaced persons at risk) is generally lower hospitalization rates among
compounded by the need for improved diagnos- immigrants were due to better health status or to
tics, heightened recognition, and effective barriers in accessing the medical system. In the

Vol. 4, No. 3, July–September 1998 427 Emerging Infectious Diseases

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United States, Minnesota has been a leader in hepatitis B, tuberculosis, and parasitic diseases,
refugee resettlement since 1979; one center for as well as mental health problems, have been
international health has established a unique diagnosed; and prevention strategies or thera-
multidisciplinary primary and specialty care pies have been implemented.
program for refugees and immigrants. Hmong, Successful integration of migrant popula-
Cambodian, Vietnamese, Russian, Ukrainian, tions into their new communities’ health-care
African, and Latin American refugees and systems is critical to the prevention and control of
immigrants have been seen; diseases such as new and reemerging infectious diseases.

Emerging Infectious Diseases 428 Vol. 4, No. 3, July–September 1998

Special Issue

Emerging Zoonoses
Frederick A. Murphy
University of California, Davis, California, USA

In the past few years, emergent disease episodes have increased; nearly all have
involved zoonotic or species-jumping infectious agents. Because there is no way to
predict when or where the next important new zoonotic pathogen will emerge or what its
ultimate importance might be, investigation at the first sign of emergence of a new
zoonotic disease is particularly important. Such investigation may be described in terms
of a discovery-to-control continuum: from recognition of a new disease in a new setting
to complex phases involving the hard science disciplines pertaining to discovery, the
epidemiologic sciences pertaining to risk assessment, and activities pertaining to risk
management. Today, many activities involving zoonotic disease control are at risk
because of a failed investigative infrastructure or financial base. Because zoonotic
diseases are distinct, their prevention and control will require unique strategies, based
more on fundamental research than on traditional approaches. Such strategies require
that we rebuild a cadre of career-committed professionals with a holistic appreciation of
several medical and biologic sciences.

In the past few years, emergent disease eases whose etiologic agent has long relied on
episodes have increased in the United States and human-to-human transmission for its survival.
globally. The list of important emergent diseases The Centers for Disease Control and Prevention’s
is impressive indeed and, given what we know (CDC) acute infectious disease prevention and
about disease ecology, it will only continue to control strategies were largely developed from
grow. Nearly all of these emergent disease experiences with vaccine-preventable childhood
episodes have involved zoonotic infectious diseases, sexually transmitted diseases, hepati-
agents; that is, they have involved the tis, and other diseases for which traditional clini-
transmission of the etiologic agent to humans cally based or laboratory-based surveillance can
from an ongoing reservoir life cycle in animals or provide the base for intervention activities such
arthropods, without the permanent establish- as vaccination or antimicrobial chemotherapy. For
ment of a new life cycle in humans. Fewer the zoonoses and for diseases caused by species-
episodes have involved species-jumping by the jumping agents, prevention and control strategies
etiologic agent; that is, they derive from an have come from diverse bases. At the heart of this
ancient reservoir life cycle in animals but have research have been individual scientists who have
subsequently established a new life cycle in spent whole careers accumulating highly special-
humans that no longer involves an animal ized knowledge and experience. In fact, the work
reservoir. of these scientists might best be described as fun-
damental research—research seeking the means
Distinct Prevention and Control Strategies for disease control and prevention.
Nearly all of the major topics for discussion
at this conference involve either zoonotic or spe- Predicting the Emergence of Zoonotic and
cies-jumping infectious agents. Prevention and Species-Jumping Pathogens
control strategies for diseases caused by these In general, there is no way to predict when or
agents are different from those required for dis- where the next important new zoonotic pathogen
will emerge or what its ultimate importance
might be. A pathogen might emerge as the cause
Address for correspondence: Frederick A. Murphy, School of
of a geographically limited curiosity, intermittent
Veterinary Medicine, University of California, Davis, CA
95616-8734, USA; fax: 530-752-2801; e-mail: disease outbreaks, or a new epidemic. No one could have predicted the emergence or zoonotic

Vol. 4, No. 3, July–September 1998 429 Emerging Infectious Diseases

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nature of the bovine spongiform encephalopa- humans and animals follow. Population move-
thy prion in cattle in the United Kingdom in ments and the intrusion of humans and domestic
1986, the emergence or zoonotic potential of Sin animals into arthropod habitats have resulted in
Nombre virus as the cause of hantavirus emergent disease episodes, some of which are the
pulmonary syndrome in the Southwest in 1993, stuff of fiction. The classic example is the
and certainly not the species-jumping emer- emergence of yellow fever when humans entered
gence of HIV as the cause of AIDS in 1981. the Central American jungle to build the Panama
Consequently, investigation at the first sign of Canal—many contemporary examples suggest
emergence of a new zoonotic disease is that similar events will continue to occur.
particularly important, although the investiga- Deforestation and settlement of new tropical
tion usually resembles a field- and laboratory- forest and farm margins have exposed farmers
based research project rather than a typical case- and domestic animals to new arthropods and the
control–based outbreak investigation. This reality viruses they carry. Mayaro and Oropouche virus
must drive strategic planning for dealing with new infections in Brazilian woodcutters who cleared
zoonotic diseases. the Amazonian forest in recent years is a case in
point. The opening up of isolated ecosystems has
Factors Contributing to the Emergence of contributed to emergent disease episodes.
Zoonotic Diseases Remote econiches, such as islands, with
Many elements can contribute to the immunologically naive potential reservoir hosts
emergence of a new zoonotic disease: microbial/ and vectors are often particularly vulnerable to
virologic determinants, such as mutation, natural an introduced virus. For example, the initial
selection, and evolutionary progression; individual Pacific island-hopping of Ross River virus in the
host determinants, such as acquired immunity 1980s from its original econiche in Australia
and physiologic factors; host population determi- caused “virgin soil” epidemics of arthritis-
nants, such as host behavioral characteristics myalgia syndrome in Fiji and Samoa—this virus
and societal, transport, commercial, and iatro- will surely reemerge. Increased long-distance air
genic factors; and environmental determinants, travel facilitates the movement of infected
such as ecologic and climatologic influences. persons and exotic arthropod vectors around the
Emergence of new zoonotic pathogens seems world. The introduction of the Asian mosquito
to be accelerating for several reasons: global Aedes albopictus to the United States in water
human and livestock animal populations have contained in used tires represents an unsolved
continued to grow, bringing increasingly larger problem of this kind. Increased long-distance
numbers of people and animals into close contact; livestock transportation facilitates the move-
transportation has advanced, making it possible ment of viruses and arthropods (especially ticks)
to circumnavigate the globe in less than the around the world. The introduction and
incubation period of most infectious agents; emergence of African swine fever virus from
ecologic and environmental changes brought Africa into the Americas in the 1960s and 1970s
about by human activity are massive; and seem prophetic; although this virus is not
bioterroristic activities, supported by rogue zoonotic (it does not infect humans), this
governments as well as organized amateurs, are experience should raise the question concerning
increasing, and in most instances the infectious possible transport of Crimean-Congo hemor-
agents of choice seem to be zoonotic. rhagic fever virus or other tick-borne pathogens
to new locales. Ecologic factors pertaining to
Ecologic Factors Contributing to the uncontrolled urbanization and environmental
Emergence of Zoonotic Diseases, as pollution are contributing to many emergent
Exemplified by Arbovirus Diseases disease episodes. Arthropod vectors breeding in
Contributing to the emergence of zoonotic accumulations of water (e.g., tin cans, old tires)
diseases is the capacity of microorganisms and and sewage-laden water are a problem world-
viruses to adapt to extremely diverse and wide. Environmental chemical toxicants (herbi-
changing econiches. One of the most complex sets cides, pesticides, residues) can also affect vector-
of adaptations concerns the arboviruses and their virus relationships directly or indirectly. Ecologic
transmission by specific arthropods. When factors related to expanding primitive irrigation
ecosystems are altered, disease problems of systems are becoming important in virus

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disease emergence, as exemplified by the again, the response might not be much different.
emergence of Japanese encephalitis in newly If the epidemic in Venezuela and Columbia in 1995
developed rice-growing areas of southern Asia. had progressed and jumped north, which agency
New routings of long-distance bird migrations, would have stepped forward to direct control
brought about by new man-made water impound- activities? What would have been done? Do we have
ments, represent an important yet still untested an interagency plan? The same question might be
risk of introduction of arboviruses into new areas. asked in regard to the possible introduction of Rift
Global warming, which affects sea level, Valley fever virus into the United States. In my
estuarine wetlands, fresh water swamps, and view, our government institutional culture fails in
human habitation patterns, may also be affecting long-term, interdisciplinary, interagency strategy
vector-virus relationships throughout the trop- development—we need strategies that are proof-
ics; however, data are scarce and long-term tested to ensure success.
programs to study the effect of global warming There is another lesson from the 1971 and
have too often not included the participation of 1995 Venezuelan equine encephalitis epidemics.
tropical medicine experts. Thirty years ago the arbovirus community was
Of all the ecologic factors contributing to large, very experienced in field work and disease
arthropod-borne zoonotic viral disease emer- control actions, and holistic in perspective and
gence, uncontrolled urbanization is the most expertise. Arbovirologists were able to bring
important. The mega cities of the tropics, with together all necessary expertise—entomology
their lack of sanitary systems, serve as and vector biology, ecology, mammology, orni-
incubators for emerging zoonoses—they repre- thology, epidemiology, and virology. However,
sent the most difficult zoonotic disease risks of today this community, like so many others
the next century. Who will pay to control disease supporting zoonotic public health programs, is
in these cities? How will the World Health very small, rather poorly experienced in field
Organization (WHO) and the Pan American work, and scientifically fragmented. Experts on
Health Organization (PAHO) serve the needs of mosquito biology, genetics, ecology, and vector
the people in these cities? How will CDC serve the competence are becoming more and more
interests of the people of the United States in separated from the people in local mosquito
preventing emergent zoonotic diseases from control agencies who are expected to terminate
emigrating from these cities? Lessons from the epidemics. We had better fix this, organization-
past suggest that we need a larger national and ally and culturally, if we are to deal with
international enterprise to deal with emergent mosquito-borne diseases in the 21st century.
zoonoses in such settings, but even more we need
an adaptable enterprise, one that can adjust Lessons from the Equine Morbillivirus
quickly to diverse episodes. Outbreak in Australia
Recent experiences in Australia with a new
Lessons from Venezuelan Equine morbillivirus disease add still more lessons in
Encephalitis Epidemics zoonotic disease prevention and control. In 1994,
Past Venezuelan equine encephalitis epidem- horses on a property in Queensland developed
ics provide lessons regarding today’s zoonotic acute respiratory distress with hemorrhagic
disease prevention and control systems. In 1971, manifestations—14 of 21 infected horses died. A
as the virus crossed from Mexico into Texas, horse trainer and a stable-hand became ill after
agricultural disease control authorities were nursing a sick horse—the trainer died. The
prepared to start shooting and burying horses in disease was found to be caused by a previously
a massive slaughter campaign. Scientists from unknown morbillivirus. Remarkably, in 1996
CDC and the Middle America Research Unit (at fruit bats (flying foxes) were found to be the
the time a unit of the National Institutes of natural host of the virus. Studies are under way
Health) provided the virologic and epidemiologic to unravel these findings.
base to override the sanitary rifle strategy of One lesson is similar to that taught by
agricultural authorities, and the U.S. Army experiences with Venezuelan equine encephali-
provided its then new TC83 vaccine. Conflict tis. In Australia, where animal disease research
between agricultural and public health agencies is organized on a national basis but human
was rampant; if this kind of emergency happened disease research (and prevention and control

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activities) on a state basis, this disease was dangerous infectious agents need not be
given over to the Australian Animal Health thought of as so expansive or expensive as to be
Laboratory. One can imagine the public outcry if unrealistic. Field-based epidemiologic studies
it had turned out that humans were at greater are needed; diagnostic systems require better
risk than horses. Again, cooperation across a placement in laboratories in Africa. Training is a
wide range of institutions is required to deal major need—not through short courses, but
with zoonoses, but when human health is at risk, rather through advanced career training and
I cannot imagine our public health institutions experience; transcending these is the need for an
deferring to animal disease and agricultural expanded research base, which in turn requires
institutions. Similar turf issues have been more national laboratory facilities and resources
raised in the United States and in the United for work at biosafety level (BSL) 4. These needs
Kingdom in regard to the recent episode of must be met in all industrialized countries on
H5N1 influenza in chickens and humans in Hong behalf of developing countries.
Lessons from Rabies Epidemics
Lessons from Ebola Hemorrhagic Fever Rabies provides many lessons in how viral
Epidemics adaptation contributes to emergence in new
Should we be concerned about Ebola virus? Is econiches. Often, the necessary ecologic elements
there a risk to Africa that compares with the are in place and the recipe for emergence simply
everyday problems of other zoonoses such as involves the introduction of virus; a dramatic
malaria or yellow fever? Is there a risk to people illustration was the appearance of epidemic
in North America or Europe? If the worst that raccoon rabies in the eastern United States. The
might happen is an occasional importation epidemic was traced to raccoons imported from
resulting in a small cluster of cases, should we be Florida to West Virginia in 1977—as usual,
concerned? If the time and place of such episodes human perturbation of an ecosystem, in this
are unpredictable, should we not just wait and instance involving the transport of wild raccoons
react after the fact? The risk reflected in these from an endemic site, caused trouble. One key to
questions is difficult to evaluate because we know our understanding of this episode was the
so little. However, we can say that as western- discovery that rabies virus is not one virus;
style hospitals become more affordable for rather, it is a set of different genotypes, each
Africans, nosocomial Ebola amplification will transmitted within a separate reservoir host
increase, and epidemics will get larger. econiche. In North America, there are six
These viruses and the diseases they cause terrestrial animal genotypes, including the
need to be understood because the risk they raccoon virus genotype. Raccoons bite raccoons
represent is unknown and the risk for future that bite raccoons, and after some time, their
episodes is so unpredictable—the same should be virus becomes a distinct genotype, highly
said in regard to all similarly lethal zoonotic adapted to the host cycle. When the full
pathogens. For example, we need to find the significance of this discovery was realized, many
natural reservoir of Ebola virus and learn how its mysteries of rabies ecology were clarified. The
prevalence in its natural environment and how lesson here is that modern virologic research is
transmission to humans are regulated. In Africa, the key for prevention and control programs such
the emergence of Ebola virus could dramatically as those carried out by the CDC Rabies
increase if its still unknown reservoir host(s) Laboratory and the Texas State Health Depart-
increased, the virus changed its behavior, or ment, which is achieving much success with its
ecologic factors brought additional reservoir coyote vaccination program.
hosts into play. We need to know enough to detect
such changes quickly. The concerned public Lessons from the Hantavirus Pulmonary
would not be satisfied if public health leaders Syndrome Epidemic
decided on a wait-and-see approach for dealing In 1993, hantavirus pulmonary syndrome
with Ebola hemorrhagic fever or other diseases was first recognized in the southwestern United
with similar pathogenic potential. States. Cases have been found in 28 states; as of
Dealing with Ebola virus and similar very 1997, more than 164 cases had been confirmed in

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the United States and more than 400 than any other recent emergent zoonotic
throughout the Americas—the death rate has disease episode. The disease was first
been approximately 45%. At the beginning of the diagnosed in the United Kingdom in 1986; as of
investigation, serologic tests provided the first 1997, more than 170,000 cattle had been
clue about the nature of the causative virus. reported as infected, but modern statistical
Viral RNA was amplified from patient methods have indicated that about one million
specimens, and a previously unknown hantavirus, cattle had been infected, roughly half of which
now named Sin Nombre virus, was uncovered. entered the human food chain in the United
Later, scientists from CDC, the University of Kingdom.
New Mexico, and elsewhere found that several Today, with the wisdom of hindsight, it might
variant viruses were distributed over large be said that the ministry of agriculture in the
areas of the United States, all previously United Kingdom failed to react in time to what
unknown, all entrenched in specific rodent was clearly a great risk to the livestock and
reservoirs, all capable of zoonotic transmission related food industries of the country—every
to humans. element of its disease prevention and control
The laboratory and field work resembled responsibilities might be called into question. By
fundamental field- and laboratory-based re- 1990, the front pages of British newspapers were
search, not a traditional outbreak investigation. filled with BSE articles, forcing the question
Sin Nombre virus and its relatives could only be “…does BSE pose a risk to human health?”
dealt with in laboratories with the most British government officials responded, “…there
sophisticated molecular biologic and immuno- is nothing to worry about…” This of course led
logic technologies, the most expert staff the public to become more skeptical. The
scientists, and the kind of global perspective seen editors of the journal Nature reacted as follows:
in WHO international reference centers. If
scientists in these laboratories compete rather …Never say there is no danger [risk]. Instead, say that
than collaborate, how will public health be given there is always a danger [risk], and that the problem is
to calculate what it is… Never say that the risk is
priority? How will technology transfer occur as negligible unless you are sure that your listeners
rapidly as needed? How will the full capacity of share your own philosophy of life…
more specialized biomedical research laborato-
ries be brought to bear? In my view, this response sums up one of the
The tradition of public service holds the central precepts of public health practice.
answer. When the rabies immunofluorescence In 1995, the BSE agent was reported to be the
test was developed at CDC, it was made available cause of a new human zoonotic disease, new-
immediately to state and other laboratories. variant Creutzfeldt-Jakob disease. By 1997, 26
When Legionella pneumophila was discovered, cases had been reported in the United Kingdom
cultures and reagents were made available and one in France. A recent report from The
immediately to everyone concerned. This tradi- Royal Society states that there is now a
tion, in turn, has led over the years to the compelling case regarding new-variant
immediate transfer to CDC of new infectious Creutzfeldt-Jakob disease as the human mani-
agents isolated in other laboratories—Marburg festation of BSE. With such a small number of
virus from Germany, Lassa virus from Yale, HIV cases, it is impossible to predict future numbers
from France, poliovirus isolates from every- of cases of the human disease, but clearly the
where. Research competition has never been the damage to the livestock and related food
point—public health has been the purpose at industries of the United Kingdom will continue.
hand. The perpetuation of this tradition seems BSE may be instructive in other ways, especially
extremely important. in its extension into the worlds of macroeconom-
ics, international trade, political science, and
Lessons from the Bovine Spongiform even global governance.
Encephalopathy Epidemic in Cattle and In all these lessons, one of the most important
New-Variant Creutzfeldt-Jakob Disease in points is the need for greater epidemiologic
Humans resources and better trained professionals for
Bovine spongiform encephalopathy (BSE) in dealing with human and animal diseases or with
the United Kingdom may provide more lessons

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the zoonotic interface between the two. This about it? This phase may include expansion of
training component requires consideration of many elements: technology transfer involving
all steps along the discovery-to-control con- diagnostics development and proof testing,
tinuum. vaccine and drug development and proof testing,
sanitation and vector control, and medical and
The Discovery-to-Control Continuum as veterinary care activities and their adaptation to
Applied to Zoonotic Diseases the circumstances of the disease locale; commer-
Initial investigation at the first sign of cialization, where appropriate, of diagnostics,
emergence of a new zoonotic disease must focus vaccines, and therapeutic agents in quantities
on practical characteristics such as death rate, needed and provision of these materials through
severity of disease, transmissibility, and remote nongovernment organizations or government
spread, all of which are important predictors of sources; training, outreach, continuing educa-
epidemic potential and societal risk. Various tion, and public education, each requiring
elements of a discovery-to-control continuum are professional expertise and adaptation to the special
usually called for: discovery, the recognition of a circumstances of the disease locale; and communi-
new zoonotic disease in a new setting; cations, employing the technologies of the day such
epidemiologic field investigation; etiologic inves- as the Internet and professional expertise.
tigation; diagnostics development; focused re- Further along the discovery-to-control con-
search; technology transfer; training and out- tinuum, activities become more complex. Frus-
reach; and ultimately control, elimination, and tration often occurs at intermediate points as
eradication. Of course, not all of these elements administrators and politicians drag their feet in
are appropriate in every emerging zoonotic regard to resource allocation. This frustration, in
disease episode—decisions must be made and turn, drives scientists back to their laboratories,
priorities must be set. to the world of research, to the front end of the
In the initial phases in the discovery-to- continuum. Younger scientists, particularly,
control continuum, people outside the “citadel” become cynical of the harsh political world of risk
(the traditional federal community of investiga- management, even though this is the arena in
tors and officials) must be recognized—local which their discoveries must prove themselves.
clinicians, pathologists (including medical exam- More expensive and specialized expertise and
iners and forensic pathologists), veterinarians resources come into play in the final phases of the
and animal scientists, ecologists, wildlife scien- discovery-to-control continuum: public health
tists, as well as local public health officials, many systems, including rapid case-reporting sys-
of whom have not been enamored of their tems, surveillance systems, vital records and
experiences in dealing with those inside the disease registers, staffing and staff support,
citadel. The important early role of primary logistic support, legislation and regulation, and
diagnostic laboratories and the reference labora- expanded administration; special clinical sys-
tory networks that support them must also be tems, including isolation of cases, quarantine, and
recognized. In this era of the primacy of patient care; and public infrastructure systems,
molecular microbiology and virology, it bears including sanitation and sewerage, safe food and
reminding that many of the early investigative water supplies, and reservoir host and vector
activities surrounding the identification of a control.
possibly emergent zoonotic disease must be The question of facilities needs in the United
carried out in the field, not in the laboratory. This States is an element of our capacity to fulfill the
is the world of shoe-leather epidemiology (the discovery-to-control continuum. What about
logo of CDC’s Epidemic Intelligence Service BSL-3+ and BSL-4 laboratory facilities west of
program is the outline of the sole of a shoe with a the Appalachians? Recent debate makes it clear
prominent hole worn in it), as well as of molecular that having two BSL-4 facilities in the United
microbiology and virology. States (CDC in Atlanta, and the U.S. Army
In the intermediate phases in the discovery- Medical Research Institute of Infectious Diseases
to-control continuum, the continuum progresses in Frederick, Maryland) and one in Canada (at
to the general area of risk management, the area the new center in Winnipeg) is not enough. Plans
represented not by the question what’s going on for a few small BSL-4 labs in U.S. academic
here? but by the question what are we going to do centers may help in expanding basic research

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supported by competitive grants, but they will stake, turf battles are exacerbated, and
not support expanded field-based research. competition rather than cooperation between
Which government agency will step forward to academic institutions and government agencies
solve this problem? And in a related way, which ensues. CDC may be getting new funds, but
government agency will step forward to solve the there is no parallel sense of “good times ahead”
unique problem of career-committed professional out in the country. This is happening in
personnel needs for dealing with emerging contradiction to public expectations. Data
zoonotic diseases? clearly show that the concerned public wants
more disease control and intervention actions,
Conclusions more of the medical research needed to drive
Who will be the world’s doctor? Who will be such actions, and more participation across the
the world’s expert on zoonotic diseases? These country. Numerous surveys of public opinion done
questions are taken from an editorial in the New by Research!America show that the concerned
York Times, May 12, 1995. It seems that many public is willing to pay. In my view, public
authorities, including those at CDC, are saying expectations can only be met by the integration
that they have the answer to these questions in of the nascent global public health emerging
regard to all emerging diseases. Their answers infectious disease network, with networks
have been in the form of proposals and funding focused on threats posed by livestock animal
requests to expand global disease surveillance, diseases, crop plant diseases, and bioterrorism.
diagnostics, communications, and emergency The public would see such an overall system as
response systems, a global training program, and having a high benefit:cost ratio, which would solve
a global stable funding base. However, somewhat several high priority problems most efficiently.
distinct strategies are needed to deal specifically
with emerging zoonotic diseases, and these Frederick Murphy is professor of virology at the
strategies have not been fully developed. School of Veterinary Medicine, University of
Examples have been given in this paper to California, Davis. He has served as director of the
Division of Viral and Rickettsial Diseases as well as
suggest that these strategies must involve more
director of the National Center for Infectious
of a field and laboratory research enterprise than Diseases, Centers for Disease Control, and dean of the
a traditional surveillance and reference diagnos- School of Veterinary Medicine, UC Davis. His
tics enterprise. In some cases, it is not even clear professional interests include the pathogenesis and
who might do the focused applied research that ultrastructural pathology of viral diseases, viral
must underpin advances in zoonotic disease characterization and taxonomy, rabies, arboviruses,
prevention and control. In present circum- viral hemorrhagic fevers, viral encephalitides, public
stances, where the survival of institutions is at health policy, vaccine development, and new and
reemerging infectious diseases.

George Hill (L)

Meharry Medical College,
Nashville, Tennessee, USA
Frederick A. Murphy
University of California,
Davis, California, USA

Vol. 4, No. 3, July–September 1998 435 Emerging Infectious Diseases

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Influenza: An Emerging Disease

Robert G. Webster
St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

Because all known influenza A subtypes exist in the aquatic bird reservoir,
influenza is not an eradicable disease; prevention and control are the only realistic
goals. If people, pigs, and aquatic birds are the principal variables associated with
interspecies transfer of influenza virus and the emergence of new human pandemic
strains, influenza surveillance in these species is indicated. Live-bird markets housing
a wide variety of avian species together (chickens, ducks, geese, pigeon, turkeys,
pheasants, guinea fowl), occasionally with pigs, for sale directly to the public provide
outstanding conditions for genetic mixing and spreading of influenza viruses;
therefore, these birds should be monitored for influenza viruses. Moreover, if pigs are
the mixing vessel for influenza viruses, surveillance in this population may also provide
an early warning system for humans.

The influenza virus continues to evolve, and Since a large number of susceptible young ducks
new antigenic variants (drift strains) emerge are hatched each year throughout the world,
constantly, giving rise to yearly epidemics. In many birds are infected by virus shed into water.
addition, strains to which most humans have no This would explain the high incidence of virus
immunity appear suddenly, and the resulting infection in Canadian ducks, particularly juve-
pandemics vary from serious to catastrophic. niles, when up to 30% can shed virus before fall
Influenza viruses are unique among respira- migration. Transmission by feces also provides
tory tract viruses in that they undergo considerable a way for wild ducks as they migrate through
antigenic variation. Both surface antigens of the an area to spread their viruses to other
influenza A viruses undergo two types of variation: domestic and feral birds (3).
drift and shift (1). Antigenic drift involves minor The avirulent nature of avian influenza
changes in the hemagglutinin (HA) and neuramini- infection in ducks and wading birds may result
dase (NA), whereas antigenic shift involves major from virus adaptation to this host over many
changes in these molecules resulting from centuries, which created a reservoir that ensures
replacement of the gene segment. perpetuation of the virus; therefore, ducks and
wading birds may be occupying an important
The Reservoirs of Influenza A Viruses position in the natural history of influenza
Aquatic birds are the reservoirs of all 15 viruses. Influenza viruses of avian origin have
subtypes of influenza A viruses. In wild ducks, been implicated in outbreaks of influenza in
influenza viruses replicate preferentially in the mammals, such as seals (4), whales (5), and pigs
cells lining the intestinal tract, cause no disease (6), as well as in domestic poultry (7).
signs, and are excreted in high concentrations in
the feces (up to 108.7 50% egg infectious doses/g) Evolutionary Pathways for Influenza
(2). Avian influenza viruses have been isolated Viruses
from freshly deposited fecal material and from Studies on the ecology of influenza viruses
unconcentrated lake water, which indicates that have led to the hypothesis that all mammalian
waterfowl have a very efficient way to transmit influenza viruses derive from the avian influenza
viruses, i.e., by fecal material in the water supply. reservoir. Support for this theory comes from
phylogenetic analyses of nucleic acid sequences of
influenza A viruses from a variety of hosts,
Address for correspondence: Robert G. Webster, St. Jude geographic regions, and virus subtypes. Analyses
Children’s Research Hospital, 332 North Lauderdale St., of the nucleoprotein (NP) gene show that avian
Memphis TN 38105-2794, USA; fax: 901-523-2622; e-mail: influenza viruses have evolved into five host-

Emerging Infectious Diseases 436 Vol. 4, No. 3, July–September 1998

Special Issue

specific lineages: ancient equine, which has not Since the first human influenza virus was
been isolated in over 15 years; recent equine; gull; isolated in 1933, new subtypes of human type A
swine; and human. The human and classic swine influenza viruses have occurred: H2N2 (Asian
viruses have a genetic “sister group” relationship, influenza) replaced H1N1 in 1957, Hong Kong
which shows that they evolved from a common (H3N2) virus appeared in 1968, and H1N1 virus
origin. The ancestor of the human and classic reappeared in 1977. Each of these new subtypes
swine virus appears to have been an intact avian first appeared in China, and anecdotal records
virus that, like the influenza virus currently suggest that previous epidemics also had their
circulating in pigs in Europe, derived all its genes origin in China. Serologic and virologic
from avian sources (8,9). evidence suggests that since 1889 there have
Studies on the NP and other gene lineages in been six instances of the introduction of a virus
avian species show separate sublineages of bearing an HA subtype that had been absent
influenza in Eurasia and the Americas, indicating from the human population for some time.
that migratory birds moving between these Three human subtypes of HA have appeared
continents (latitudinal migration) have little or no cyclically—H2 viruses in 1889, H3 in 1900, H1
role in the transmission of influenza, while birds in 1918, H2 again in 1957, H3 again in 1968,
that migrate longitudinally appear to play a key and H1 again in 1977. Phylogenetic evidence
role in the continuing process of virus evolution. indicates that a totally new H1N1 virus of
Phylogenetic analyses of amino acid changes avian origin (not a reassortant) could have
show that avian influenza viruses, unlike appeared in humans or swine before the 1918
mammalian strains, have low evolutionary rates influenza and replaced the previous human
(8). In fact, influenza viruses in aquatic birds virus strains. Whether the virus was first
appear to be in evolutionary stasis, with no introduced into humans and then transmitted
evidence of net evolution over the past 60 years. to pigs, or vice versa, remains unknown. The
Nucleotide changes have continued at a similar reappearance of the H1N1 Russian 1977
rate in avian and mammalian influenza viruses; influenza virus remains a mystery.
however, these changes no longer result in amino
acid changes in the avian viruses, whereas all How Are Influenza Viruses Spread?
eight mammalian influenza gene segments Avian influenza viruses in wild aquatic birds
continue to accumulate changes in amino acids. are spread by fecal-oral transmission through the
The high level of genetic conservation suggests water supply (10); initial transmission of avian
that avian viruses are approaching or have influenza viruses to mammals, including pigs and
reached optimum, wherein nucleotide changes horses, probably also occurs by fecal contamina-
provide no selective advantage. It also means tion of water. Scholtissek has postulated that the
that the source of genes for pandemic influenza use of fecal material from ducks for fish farming
viruses exists phenotypically unchanged in the in Asia may contribute to transmission of avian
aquatic bird reservoir. The most important influenza viruses to pigs (11). Another direct
implication of phylogenetic studies is that the method of transfer is by feeding pigs untreated
ancestral viruses that caused the Spanish flu in garbage or the carcasses of dead birds. Raising
1918, as well as the viruses that provided gene pigs under chicken houses and feeding them dead
segments for the Asian/1957 and Hong Kong/ avian carcasses has been observed on rare
1968 pandemics, are still circulating in wild occasions in the United States; H5N2 influenza
birds, with few or no mutational changes. virus was isolated from pigs living under chicken
houses in Pennsylvania during the outbreak in
Emergence and Reemergence of “New” 1982. Both pigs and poultry are commonly raised
Influenza A Virus in Humans on the same commercial farms. From the
Over the past two and a half centuries, 10 to 20 perspective of the control of interspecies
human influenza pandemics have swept the globe; transmission of influenza, this is undesirable, for
the most devastating, the so-called Spanish flu of it may facilitate interspecies transmission of
1918 to 1919, caused more than 20 million deaths influenza viruses. After transmission to pigs,
and affected more than 200 million people. Both horses, or humans, the method of spread of
pandemics probably originated from aquatic birds. influenza is mainly respiratory.

Vol. 4, No. 3, July–September 1998 437 Emerging Infectious Diseases

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Emergence of H5N2 Influenza Viruses in eradicated from chickens by quarantine and use of
North America inactivated vaccine.
In 1983 an H5N2 influenza virus infected
chickens and turkeys in Pennsylvania and Live Bird Markets and the Epidemiology of
became highly pathogenic for poultry. Virologic Influenza
and serologic studies provided no evidence of The chicken/Pennsylvania (H5N2) influenza
transmission to humans (12). The virus was outbreak in 1983 to 1984 demonstrated that live
eventually eradicated by quarantine and exter- bird markets play an important part in the
mination of more than 17 million birds at a direct spread of influenza viruses in avian species. In
cost of more than US$60 million and an indirect 1992, Senne et al. (13) described live bird markets
cost to the industry of more than US$250 million. as the “missing link in the epidemiology of avian
More recently, a highly pathogenic H5N2 influenza,” for H5N2 viruses had been isolated from
influenza virus emerged in domestic chickens in live birds until 1986. These H5N2 viruses caused
Mexico (7). In October 1993, egg production subclinical infection in chickens in the markets, as
decreased and deaths increased among Mexican did H5N1 viruses in live bird markets in Hong Kong
chickens in association with serologic evidence of in 1997 (Figure 2). Moreover, ducks in the markets
an H5N2 influenza virus. H5N2 virus was in the United States were infected with many
isolated in May 1994. By the end of 1994, the different subtypes of influenza A viruses, including
virus had mutated to contain a highly cleavable H2N2 viruses related antigenically to the Asian/57
HA, but remained only mildly pathogenic in (H2N2) viruses that have disappeared from humans.
chickens. Within months, however, it had become The live bird markets in the United States
lethal in poultry. Phylogenetic analysis of the HA continue to harbor many influenza viruses. The
of H5 avian influenza viruses, including the ancestor of the H5N2 influenza virus that caused
Mexican isolates, indicated that the epidemic the epidemic in Mexico in 1993 to 1995 was
virus had originated from the introduction of a isolated from market birds, and H7NX subtypes
single virus of the North American lineage into are still found in live bird markets. These viruses
Mexican chickens (Figure 1). This virus was are potentially pathogenic for chickens and are of

Figure 1. Molecular changes associated with emer-

gence of a highly pathogenic H5N2 influenza virus in
chickens in Mexico. In 1994, a nonpathogenic H5N2
influenza virus in Mexican chickens was related to an Figure 2. The emergence of H5N1 influenza in Hong
H5N2 virus isolated from shorebirds (ruddy turn- Kong. It is postulated that a nonpathogenic H5N1
stones) in Delaware Bay, United States, in 1991. The influenza spread from migrating shorebirds to ducks by
1994 H5N2 isolates from chickens replicated mainly fecal contamination of water. The virus was transmitted
in the respiratory tract, spread rapidly among to chickens and became established in live bird markets
chickens, and were not highly pathogenic. Over the in Hong Kong. During transmission between different
next year the virus became highly pathogenic, and the species, the virus became highly pathogenic for chickens
hemagglutinin acquired an insert of two basic amino and occasionally was transmitted to humans from
acids (Arg-Lys), possibly by classic recombination and chickens in the markets. Despite high pathogenicity for
a mutation of Glu to Lys at position – 3 from the chickens (and humans), H5N1 were nonpathogenic for
cleavage site of HA1/HA2. ducks and geese.

Emerging Infectious Diseases 438 Vol. 4, No. 3, July–September 1998

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great concern to chicken farmers in the Characterization of the Human and

northeastern United States. Chicken H5N1 Viruses from Hong Kong
The depopulation of live bird markets and Avian influenza outbreaks occurred in Hong
farms in the New Territories of Hong Kong Kong from late March to early May of 1997. Three
(December 29, 1997) stopped the spread of H5N1 chicken farms were separately affected; the
influenza viruses. An important lesson can be death rate for the total of 6,800 chickens exceeded
learned from this action in Hong Kong. Live 70%. A comparison between the nucleotide
bird markets are potential breeding grounds sequences of the H5 genes from both the human
for both avian and mammalian influenza virus A/Hong Kong/156/97 (H5N1) (HK97) and a
viruses. Serologic monitoring of the chickens in representative of the chicken viruses from the
Hong Kong markets for H5N1 influenza virus March outbreak, A/chicken/Hong Kong/258/97
was an important first step in stopping the (CkHK97), showed a high degree of homology in
spread of the viruses. An even more important their respective H5 HA1 sequences. Only three
step would be to reduce the opportunity for amino-acid differences were observed in the HA1
interspecies transmission by marketing chick- of the HA, confirming the close phylogenetic
ens separately from other avian species. relationship between these viruses, belonging to
the Eurasian lineage of the subtype H5 viruses.
The Index Case of H5N1 in Humans in Sequence analyses of the HA of multiple
Hong Kong human and chicken H5N1 isolates show that they
On May 21, 1997, a 3-year-old boy from Hong form two subgroups with close linkage between
Kong died in an intensive care unit in Hong Kong chicken and human isolates. An analysis of the
on the fifth day of his hospitalization, with a final amino acids expected to be involved in the
diagnosis of Reye syndrome, acute influenza assembly of the receptor binding site showed no
pneumonia, and respiratory distress syndrome differences could be observed between the human
(14). He had no indications of other underlying isolate and avian H5 viruses. Therefore, the H5
disease, including immunodeficiency or car- HA of HK97 had probably not acquired mutations
diopulmonary disease. From a tracheal aspirate, that favor binding to sialic acids with 2,6 linkage
we isolated an influenza virus in MDCK cells but to the galactoside over the 2,3 linked sialic acid
were unable to grow any pathogenic bacteria receptor preferred by human and avian viruses
from respiratory specimens. In hemagglutination respectively. However, the loss of a potential N-
inhibition assays, the virus did not react with linked glycosylation site at amino acid 156 Asn,
ferret antisera to recent isolates of human and close to the receptor binding site, could affect
swine subtypes. binding to the cellular receptor.
Hemagglutination inhibition assays using The amino acid sequence motif at the cleavage
antisera to 14 H subtypes showed that the isolate site of the HA molecule has been associated with
was an H5 influenza A virus. Neuraminidase high virulence of avian influenza viruses.
inhibition tests, using antisera to nine N Experimental infection of chickens with HK97
subtypes, indicated that the neuraminidase was showed that even after passaging in mammalian
of the N1 subtype. Nucleotide sequence analyses cells (once in the child and twice in MDCK cells), the
of parts of the HA and NA genes of the virus virus remained highly pathogenic for chickens: all
allowed a phylogenetic comparison with other eight chickens inoculated intratracheally with
influenza viruses. Our analyses confirmed that the MDCK-grown HK97 died within 3 days after
virus was of the H5N1 subtypes. Each of the eight infection. A comparison of the reactivity of a panel
RNA segments wase of avian origin, and the virus of 17 monoclonal antibodies (MAb) directed against
was highly pathogenic for chickens. The contribu- A/chicken/Pennsylvania/83 (H5N2) with HK97 and
tion of the influenza A H5N1 virus infection to the CkHK97 in a hemagglutination inhibition assay
child’s disease, eventually leading to death, was showed similar antigenic reactivities with all but
complicated by the child’s treatment with aspirin. one MAb, indicating antigenic cross-reactivity
The virus identification is important because it is between these viruses and the usefulness of these
the first documented isolation of an influenza A antibodies for diagnosis.
virus of this subtype from humans (15). The fetuin-cleaving activity of the NA proved
to be inhibited by anti-NA antiserum. Reverse

Vol. 4, No. 3, July–September 1998 439 Emerging Infectious Diseases

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transcriptase polymerase chain reaction using able frequency of transfer between people, pigs,
primer sets that amplified the 5' end of the NA and ducks and if we understand the ecologic and
gene segments showed that this gene was of the agricultural features involved in the transfer,
N1 genotype. Nucleotide sequence analysis and pandemics may be preventable. If pigs are the
comparison to published NA sequences con- major mixing vessel for influenza viruses,
firmed this finding genetically. The NA se- changes in the agricultural practices that
quences unequivocally showed a close molecular separate pigs from people and ducks could
relationship between HK97 and CkHK97, as a prevent future pandemics. Most importantly, we
unique 57-nucleotide deletion was observed in may influence the appearance of pandemics by
the stalk region of the N1 gene of both viruses. changing the methods of live bird marketing by
Each of the eight gene segments showed close separating chickens from other species, espe-
genetic homology between the HK97 and Ck/ cially from aquatic birds.
HK97 viruses, the lowest being 98.2% for the
nucleoprotein; the remaining genes varied from This work was supported by Public Health Service
grants AI-29680 and AI-08831 from the National Institute of
98.8% to 100% homology (16). Allergy and Infectious Diseases, by Cancer Center Support
(CORE) grant CA-21765, and by the American Lebanese
Can the Emergence of Pandemic Strains Syrian Associated Charities.
Be Prevented?
Dr. Webster holds the Rose Marie Thomas Chair
Because all known influenza A virus
in the Department of Virology and Molecular Biology
subtypes are found in aquatic wild birds in at St. Jude Children’s Research Hospital, Memphis,
nature, agricultural authorities have recom- Tennessee. In addition, he is director of the World
mended avoiding direct or indirect contact Health Organization Collaborating Center for Ecology
between domestic poultry and wild birds. A of Influenza Viruses in Lower Animals and Birds. He
classic mistake made by chicken and turkey has devoted his life to the understanding of the
farmers is to raise a few domestic ducks on a pond emergence of pandemic influenza viruses, the structure
near poultry barns; these birds attract wild and function of the viral proteins, and methods for
ducks. The highly pathogenic outbreaks of H5N2 developing new and improved antiviral drugs and
avian influenza in chickens and turkeys in
Pennsylvania and surrounding states in 1983
to 1984 (12) and the H5N2 in Mexico in 1993 (7) References
could probably have been prevented if domestic 1. Murphy BR, Webster RG. Orthomyxoviruses. In: Fields
poultry had been raised in ecologically BN, Knipe DM, Howley PM, Chanock RM, Melnick JL,
Monath TP, Roizman R, Straus SE, editors. Fields
controlled houses with a high standard of virology. New York: Raven Press; 1996. p. 1397-445.
security and limited access. 2. Webster RG, Yakhno MA, Hinshaw VS, Bean WJ,
If we assume that people, pigs, and aquatic Murti KG. Intestinal influenza: replication and
birds are the principal variables associated with characterization of influenza viruses in ducks. Virology
the emergence of new human pandemic stains, 1978;84:268-78.
3. Halvorson D, Karunakaran D, Senne D, Kelleher C,
human pandemics of influenza may be pre- Bailey C, Abraham A, et al. Epizootiology of avian
vented. The principles applied to preventing influenza-simultaneous monitoring of sentinel ducks
outbreaks of influenza in domestic animals and turkeys in Minnesota. Avian Dis 1983;27:77-85.
should apply equally here. Pandemic strains of 4. Geraci JR, St. Aubin DJ, Barker IK, Webster RG,
human influenza emerge only rarely; however, Hinshaw VS, Bean WJ, et al. Science 1982;215:1129-31.
5. Hinshaw VS, Bean WJ, Geraci JR, Fiorelli P, Early G,
interspecies transmission of influenza viruses Webster RG. Characterization of two influenza A
may not be so rare, for up to 10% of persons with viruses from a pilot whale. J Virol 1986;58:655-6.
occupational exposure to pigs develop antibodies 6. Scholtissek C, Burger H, Bachmann PA, Hannoun C.
to swine influenza virus (17). Most transfers of Genetic relatedness of hemagglutinins of the H1
influenza viruses from pigs to humans are dead- subtype of influenza A viruses isolated from swine and
birds. Virology 1983;129:521-3.
end transfers (they do not spread efficiently from 7. Horimoto T, Rivera E, Pearson J, Senne D, Krauss S,
human to human). As indicated above, we do not Kawaoka Y, et al. Origin and molecular changes
know the frequency of virus transfer between the associated with emergence of a highly pathogenic H5N2
suspect species in southern China. If there is an influenza virus in Mexico. Virology 1995;213:223-30.
epicenter for pandemic influenza and a detect-

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8. Gorman OT, Bean WJ, Kawaoka Y, Webster RG. 13. Senne DA, Pearson JE, Panigrahy B. Live poultry
Evolution of the nucleoprotein gene of influenza A markets: a missing link in the epidemiology of avian
virus. J Virol 1990;64:1487-97. influenza. In: Proceedings of the 3rd International
9. Gammelin M, Altmuller A, Reinhardt U, Mandler J, Symposium on Avian Influenza; 1997 27-29 May; The
Harley VR, Hudson PJ, et al. Phylogenetic analysis of Wisconsin Center, The University of Wisconsin-
nucleoproteins suggests that human influenza A Madison. p. 50-8.
viruses emerged from a 19th-century avian ancestor. 14. De Jong JC, Claas ECJ, Osterhaus ADME, Webster RG,
Mol Biol Evol 1990;7:194-200. Lim WL. A pandemic warning. Nature 1997;389:554.
10. Hinshaw VS, Webster RG. The natural history of 15. Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall
influenza A viruses. In: Beare AS, editor. Basic and H, et al. Characterization of an Avian influenza A
applied influenza research. Boca Raton (FL): CRC (H5N1) virus isolated from a child with a fatal
Press; 1982. p. 79-104. respiratory illness. Science 1998;279:393-6.
11. Scholtissek C, Naylor E. Fish farming and influenza 16. Claas ECJ, Osterhaus ADME, van Beek R, De Jong JC,
pandemics. Nature 1988;331:215. Rimmelzwaan GF, Senne DA, et al. Human influenza A
12. Bean WJ, Kawaoka Y, Wood JM, Pearson JE, Webster H5N1 virus related to a highly pathogenic avian
RG. Characterization of virulent and avirulent A/ influenza virus. Lancet 1998;351:472-7.
Chicken/Pennsylvania/83 influenza A viruses: potential 17. Schnurrenberger PR, Woods GT, Martin RJ. Serologic
role of defective interfering RNAs in nature. J Virol evidence of human infection with swine influenza
1985;54:151-60. virus. Am Rev Respir Dis 1970;102:356-61.

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Resurgent Vector-Borne Diseases as a

Global Health Problem
Duane J. Gubler
Centers for Disease Control and Prevention, Fort Collins, Colorado, USA

Vector-borne infectious diseases are emerging or resurging as a result of changes

in public health policy, insecticide and drug resistance, shift in emphasis from prevention
to emergency response, demographic and societal changes, and genetic changes in
pathogens. Effective prevention strategies can reverse this trend. Research on
vaccines, environmentally safe insecticides, alternative approaches to vector control,
and training programs for health-care workers are needed.

In the 120 years since arthropods were fever in Cuba was the first vector-borne disease to
shown to transmit human disease, hundreds of be effectively controlled in this manner, followed
viruses, bacteria, protozoa, and helminths have quickly by yellow fever and malaria in Panama.
been found to require a hematophagous (blood- Over the next 50 years, most of the important
sucking) arthropod for transmission between vector-borne public health problems were
vertebrate hosts (1). Historically, malaria, effectively controlled (Table 1). Most of these
dengue, yellow fever, plague, filariasis, louse- programs established vertically structured vec-
borne typhus, trypanosomiasis, leishmaniasis, tor control organizations that emphasized
and other vector-borne diseases were respon- elimination of arthropod breeding sites (source
sible for more human disease and death in the reduction) through environmental hygiene along
17th through the early 20th centuries than all with limited use of chemical insecticides. By the
other causes combined (1). During the 19th and 1960s, vector-borne diseases were no longer
20th centuries, vector-borne diseases prevented the considered major public health problems outside
development of large areas of the tropics, especially Africa. Urban yellow fever and dengue, both
in Africa; it was not until these diseases were
controlled that engineering feats such as the
Table 1. Successful vector-borne disease control/
Panama Canal could be completed (1,2).
elimination programs
Not long after the 1877 discovery that
mosquitoes transmitted filariasis from human to Disease Location Year(s)
human, malaria (1898), yellow fever (1900), and Yellow fever Cuba 1900-1901
dengue (1903) were shown to have similar Yellow fever Panama 1904
transmission cycles (2). By 1910, other major Yellow fever Brazil 1932
vector-borne diseases such as African sleeping Anopheles gambiae Brazil 1938
sickness, plague, Rocky Mountain spotted fever, infestation
relapsing fever, Chagas disease, sandfly fever, An. gambiae Egypt 1942
and louse-borne typhus had all been shown to infestation
require a blood-sucking arthropod vector for Louse-borne typhus Italy 1942
transmission to humans (2). Malaria Sardinia 1946
Prevention and control programs were soon Yellow fever Americas 1947-1970
based on controlling the arthropod vector. Yellow (Aedes aegypti)
Malaria Americas 1954-1975
Malaria Global 1955-1975
Address for correspondence: Duane J. Gubler, Division of Yellow fever West Africa 1950-1970
Vector-Borne Infectious Diseases, National Center for Onchocerciasis West Africa 1974-present
Infectious Diseases, Centers for Disease Control and
Prevention, P.O. Box 2087, Fort Collins, CO 80522, USA; fax:
Bancroftian filariasis South Pacific 1970s
970-221-6476; e-mail: Chagas disease South America 1991-present

Emerging Infectious Diseases 442 Vol. 4, No. 3, July–September 1998

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transmitted by Aedes aegypti, were effectively of the lack of sustainability of vertically

controlled in Central and South America and structured prevention/control/elimination pro-
eliminated from North America; malaria was grams. Complacency, dwindling financial and
nearly eradicated in the Americas, the Pacific political support, and a change in strategy from
Islands, and Asia. The discovery and effective use vector control to case finding and drug treatment
of residual insecticides in the 1940s, 1950s, and were mainly responsible for the resurgence of
1960s contributed greatly to these successes. malaria in these countries.
However, the benefits of vector-borne disease More recently, vivax malaria has reemerged
control programs were short-lived. A number of in Korea (Figure 2c). Urban malaria in the Indian
vector-borne diseases began to reemerge in the subcontinent and in parts of South America
1970s, a resurgence that has greatly intensified (Figure 2d) is also a major concern. In 1998,
in the past 20 years (3-7). Although the reasons malaria is the most important tropical disease
for the failure of these programs are complex and with more than half of the world’s population
not well understood, two factors played impor- living in areas of risk and with an estimated 200
tant roles: 1) the diversion of financial support million cases and two million deaths each year (11).
and subsequent loss of public health infrastruc- Widespread drug resistance of the parasites and
ture and 2) reliance on quick-fix solutions such as insecticide resistance among anopheline mosquito
insecticides and drugs. vectors have complicated malaria control (4).
Malaria is the most common imported
The Global Emergence/Resurgence of disease in the United States, where anopheline
Vector-Borne Diseases mosquito vectors still exist (12). Approximately
Evidence of the reemergence of vector-borne 1,000 suspected malaria cases are imported into
diseases such as malaria and dengue was first the United States each year, associated with
observed in the 1970s in Asia and the Americas increased frequency of autochthonous cases;
(5-9). Warnings, however, were largely ignored since 1987, 16 incidents of autochthonous
until recently (10), and now it may be difficult to malaria have occurred in nearly all parts of the
reverse the trend. United States. In each incident, however,
Figure 1 shows some vector-borne parasitic, transmission was limited to only a few cases (12).
bacterial, and viral diseases that have caused
epidemics in the 1990s. While malaria is the most African Trypanosomiasis
important vector-borne disease because of its Historically, African sleeping sickness, trans-
global distribution, the numbers of people mitted by the tsetse fly, has been a major
affected, and the large number of deaths, the impediment to the social and economic develop-
vector-borne viruses (arboviruses) are clearly the ment of Central and East Africa. With the use of
most numerous. modern drugs, insecticides, and other control
methods, this disease was effectively controlled
Malaria in most countries by the mid-1960s. In the past 20
The resurgence of malaria in Asia in the late years, however, major epidemics have occurred
1960s and early 1970s provides a dramatic in East and Central Africa, mainly because
example of how quickly vector-borne disease control programs were disrupted by war (13). In
trends can change. Malaria, transmitted to the Sudan, the Republic of Congo, and Angola,
humans by anopheline mosquitoes, had been which have high prevalence, poor surveillance,
nearly eliminated in Sri Lanka in the 1960s, with no drugs, and no vector control, the disease poses
only 31 and 17 cases reported in 1962 and 1963, a major public health threat. Although available,
respectively. By 1967, 3,468 cases were reported. some new drugs, vector control approaches, and
In 1968, however, a major epidemic caused diagnostic tests are not being used because of lack
440,644 cases. In 1969, 537,705 cases were of funding support.
reported (Figure 2a); the disease has never been African sleeping sickness is a low-priority
effectively controlled since then. In India, a rural disease. Effective, sustainable control is
similar resurgence of malaria occurred (Figure unlikely until traditional uses of land change and
2b), with sporadic outbreaks of disease beginning socioeconomic conditions improve in rural Africa
in the early 1970s and nearly seven million cases (13). The primary approach to control is
by 1976. Sri Lanka and India are classic examples treatment with drugs that are expensive and not

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Figure 1. Epidemic vector-borne diseases, 1990–1997. A. parasitic diseases, B. bacterial diseases, C. arboviral

Emerging Infectious Diseases 444 Vol. 4, No. 3, July–September 1998

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Figure 2. The resurgence of malaria. A. Sri Lanka (data from Tissa Vitarana, Office of Science and
Technology, Sri Lanka); B. India (data from Shiv Lal, Director, National Malaria Eradication
Program, India); C. Korea (data from Dan Strickman, Walter Reed Army Institute of Research; D.
Manaus, Brazil (data from Bedsy Dutary, National Institute of Research of the Amazon).

readily available (11). To reverse this trend, an Lyme disease is transmitted by Ixodes ricinus
integrated sustainable control program must be complex hard ticks. In the United States, I.
implemented, including effective surveillance for scapularis, the deer tick, is the vector in the
case finding, a network of treatment centers with eastern and midwestern states, and I. pacificus is
a supply of drugs, and vector control using the vector in the far western states. While human
trapping techniques (13). cases of apparent Lyme disease are reported from
most states and many enzootic cycles of B.
Lyme Disease burgdorferi occur throughout the country, the
Lyme disease, a bacterial tick-borne infec- public health importance of these cases is
tion, is caused by Borrelia burgdorferi. Discov- uncertain. Approximately 90% of reported Lyme
ered in the United States in 1975, the disease has disease cases occur each year in the Northeast
continued to increase in incidence and geographic (Connecticut, Maryland, Massachusetts, New
distribution since national surveillance was Jersey, New York, Pennsylvania, and Rhode
initiated in 1982. At that time, 497 cases were Island), upper Midwest (Minnesota and Wiscon-
reported compared with 11,700 to 16,455 cases each sin), and Northwest (California) (14).
year between 1994 and 1997 (Figure 3) (cumulative
total cases reported more than 109,000) (14). Lyme Plague
disease has a global distribution in the temperate Plague is the original emerging disease, having
regions. Because of the multistage disease and caused major pandemics; the most recent (late
chronic complications associated with B. 19th century) is believed to be responsible for the
burgdorferi infection, Lyme disease has major current global distribution of the disease, which
public health and economic effects. is spread by rats on ships (15). Like many other

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Dengue fever caused major epidemics from
the 17th to the early 20th centuries (18). In most
Central and South American countries, effective
disease prevention was achieved by eliminating
the principal epidemic mosquito vector, A.
aegypti, during the 1950s and 1960s. In Asia,
however, effective mosquito control was never
achieved, and a severe hemorrhagic fever (DHF)
emerged following World War II. During the
1950s, 1960s, and 1970s, this new form of dengue
occurred as periodic epidemics in a few countries.
During the 1980s, however, incidence increased
Figure 3. Reported cases of Lyme disease in the United dramatically, expanding distribution of the virus
States, 1982–1997. and the mosquito vector to the Pacific islands and
tropical America (18). In the latter region, the
vector-borne diseases, plague was controlled with Ae. aegypti eradication program had been
antibiotics, insecticides, and rat control in the disbanded in the early 1970s; by the 1980s, this
latter half of the 20th century. The number of species had reinfested most tropical countries of
cases reported to the World Health Organization the region (Figure 4). Increased disease
decreased to an all-time low of 200 cases in 1981 transmission and frequency of epidemics caused
(15). In recent years, however, epidemic plague by multiple virus serotypes in Asia increased the
has resurged, most notably in Africa, with an movement of dengue viruses into these regions,
average of nearly 3,000 cases reported annually resulting in a dramatic increase in epidemic
(approximately 65% from Africa) (15). dengue fever; hyperendemicity (the cocirculation
The decrease in plague incidence from 1950 of multiple virus serotypes); and the emergence of
to 1980 was followed by decreased financial DHF in the Pacific Islands, the Caribbean, and
support, lowered interest, and ultimately the Central and South America. Thus, in less than 20
deterioration of surveillance systems. Many years, both the American tropics and the Pacific
countries were no longer capable of making a Islands went from not having dengue to having
laboratory diagnosis of plague in the 1990s. For an important dengue/DHF problem in 1998.
example, in 1994 when an outbreak of plague Globally, DHF has emerged as a major cause
occurred in Western India (16) (which had of hospitalization and death. The number of DHF
reported its last case of plague in 1966), lack of cases reported from 1981 to 1995 is four times
laboratory capacity for diagnosis led to higher than that of the previous 30 years. In 1998,
confusion as to the cause of the outbreak and more than 2.5 billion persons live in areas of risk
panic within the population. An estimated (Figure 5). Dengue is the second most important
500,000 people fled Surat for other major cities, tropical disease (after malaria) with approxi-
some of which subsequently reported second- mately 50 to 100 million cases of dengue fever and
ary plague transmission (16). 500,000 cases of DHF each year.
Because effective epidemiologic investigation Because of limited surveillance data and
and an accurate laboratory diagnosis were not gross underreporting in most disease-endemic
made in time, a relatively unimportant, focal countries, the economic and public health impact
public health event turned into an international of dengue is greatly underestimated.
public health emergency costing the Indian and
the global economies billions of U.S. dollars (17). Yellow Fever
Plague can cause explosive epidemics when Like dengue fever, yellow fever caused major
effective laboratory-based surveillance and pre- epidemics from the 17th to the 20th centuries and
vention and control are not maintained in was effectively controlled in the Americas by the
countries with enzootic disease. An important Ae. aegypti elimination program in the 1950s
lesson learned from this incident was that and 1960s. Yellow fever is maintained in forest
laboratory-based international infectious disease cycles involving monkeys and canopy-dwelling
surveillance is cost-effective. mosquitoes in both Africa and the Americas.

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Peru, all urban centers infested with Ae. aegypti.

Moreover, two patients with yellow fever cases
imported to the United States and Switzerland
died; neither patient had been vaccinated.
Thus, the frequency of yellow fever moving
from the American rain forest to tropical urban
areas is increasing, and it is likely only a matter
of time before an urban yellow fever epidemic will
occur. The disease will then likely spread rapidly
to other cities in the Americas and from there to
cities in Asia and the Pacific, much as dengue has
in the past 20 years (18). Because of the
Figure 4. Geographic distribution of Aedes aegypti in similarities in clinical expression between yellow
the Americas, 1930s, 1970, and 1998. fever and other common diseases such as dengue
and leptospirosis and because the surveillance
systems needed to detect yellow fever are very
limited in most countries, widespread epidemic
transmission would likely occur before the
disease is detected. Emergency methods of
controlling Ae. aegypti are ineffective (21,22);
therefore, a major international public health
emergency could occur.
These are only a few examples of emergent/
resurgent vector-borne diseases, but there are
many more that are causing increasingly
frequent epidemics. Many go unreported because
laboratory-based surveillance systems are not
available in many countries.

Factors Involved in Vector-Borne Disease

Figure 5. Global distribution of Aedes aegypti and of Emergence
epidemic dengue, 1980–1998. The factors responsible for the emergence/
resurgence of vector-borne diseases are complex.
They include insecticide and drug resistance,
Human infections since the 1950s have been changes in public health policy, emphasis on
primarily in persons associated with the forest. emergency response, deemphasis of prevention
Since the mid-1980s, however, epidemic yellow programs, demographic and societal changes,
fever has resurged in West Africa, and for the
first time in history, an outbreak occurred in
Kenya in 1992 to 1993 (19).
Although the last urban epidemic in the
Americas was in 1942 (20), urban epidemics may
recur because nearly all major urban centers of
the American tropics have been reinfested by Ae.
aegypti in the past 20 years. Most persons in
tropical American cities are at high risk for
epidemic urban transmission because of low
yellow fever immunity. Of added concern are the
increasingly frequent reports of imported yellow
fever to mosquito-infested urban areas (Figure
6). In the past 2 years, yellow fever cases have Figure 6. Major urban centers of South America
been imported to Santa Cruz, Bolivia; Manaus, recently infested with Aedes aegypti and at high risk
Brazil; Villavicencia, Colombia; and Iquitos, for imported yellow fever.

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and genetic changes in pathogens (10). Public borne, rodent-borne, and water-borne diseases. The
health policy decisions have greatly decreased prospects for the future are not good; nearly all of
the resources for surveillance, prevention, and the world’s population growth in the next 25 years
control of vector-borne diseases in the 1960s and will occur in the urban centers of developing
1970s, primarily because control programs had countries, many of them in tropical areas where
reduced the public health threat from these vector-borne diseases occur most frequently (25).
diseases. Those decisions, the technical problems Other societal changes, such as agricultural
of insecticide and drug resistance, as well as too practices and deforestation (10), increase the risk
much emphasis on insecticide sprays to kill adult for vector-borne disease transmission (Table 2).
mosquitoes, contributed greatly to the resur- Many irrigation systems and dams have been
gence of diseases such as malaria and dengue. built in the past 50 years without regard to their
Decreased resources for infectious diseases in effect on vector-borne diseases. Similarly,
general resulted in the discontinuation or merger tropical forests are being cleared at an increasing
of many programs and ultimately to the rate, and agricultural practices such as rice
deterioration of the public health infrastructure production have also increased.
required to deal with these diseases. Moreover, Consumer products make ideal breeding
good training programs in vector-borne diseases sites for domesticated mosquitoes. Packaged in
decreased dramatically after 1970. Thus, in 1998, nonbiodegradable plastics, cellophanes, and tin,
we are faced with a critical shortage of specialists these products tend to be discarded in the
trained to respond effectively to the resurgence of environment where they collect rainwater.
vector-borne diseases (10,23). A related problem Discarded automobile tires, many in the domestic
is the lack of preventive medicine training in environment, make ideal mosquito breeding
most medical schools. The curative approach and places as well as rat and rodent harborages.
emphasis on high-tech solutions to disease Container shipping and the global used tire
control have led most physicians, health officials, industry have contributed to the increased
and the public to rely on “magic bullets” to cure an geographic distribution of selected mosquito
illness or control an epidemic (21). species that lay their eggs in used tires (26).
Major global demographic and societal Finally, the jet airplane has had a major
changes of the past 50 years have directly influence on global demographics (27). The
affected the emergence/resurgence of vector- airplane provides the ideal mechanism for
borne and other infectious diseases (10,21,23,24). transporting pathogens between population
Unprecedented population growth, mostly in centers (10,18,21,23). The result is a constant
developing countries, resulted in major move- movement of viruses, bacteria, and parasites
ments of people, primarily to urban centers. This among cities, countries, regions, and continents.
unplanned and uncontrolled urbanization (inad- Climate change (e.g., global warming and El
equate housing, deteriorating water, sewage, and Niño Southern Oscillation) is often cited as the
waste management systems) produced ideal cause for the emergence/resurgence of vector-
conditions for increased transmission of mosquito- borne diseases, especially malaria, dengue, and

Table 2. Influences on emergent/resurgent vector-borne diseases

Urbanization Deforestation Agricultural Practices

Dengue fever Loaiasis Malaria
Malaria Onchocerciasis Japanese encephalitis
Yellow fever Malaria St. Louis encephalitis
Chickungunya Leishmaniasis West Nile fever
Epidemic polyarthritis Yellow fever Oropouche
West Nile fever Kyasanur Forest disease Western equine encephalitis
St. Louis encephalitis La Crosse encephalitis Venezuelan equine encephalitis
Lyme disease Eastern equine encephalitis
Ehrlichiosis Lyme disease

Emerging Infectious Diseases 448 Vol. 4, No. 3, July–September 1998

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yellow fever. While meteorologic factors such as References

temperature, rainfall, and humidity influence 1. Gubler DJ. Insects in Disease Transmission. In:
the transmission dynamics of vector-borne Strickland GT, editor. Hunter tropical medicine, 7th
edition. Philadelphia (PA): W. B. Saunders; 1991. p.
diseases, climate change has not yet been
scientifically proven to have caused the emer- 2. Philip CB, Rozenboom LE. Medico-veterinary
gence/resurgence of any of the vector-borne entomology: a generation of progress. In: Smith RF,
diseases described above. Mittler TE, Smith CN, editors. History of entomology.
Palo Alto (CA): Annual Reviews Inc; 1973.
3. Gubler DJ. The global resurgence of arboviral diseases.
The Future Trans Roy Soc Trop Med Hyg 1996;90:449-51.
Reversing the trend of emergent/resurgent 4. Krogstad DJ. Malaria as a reemerging disease.
vector-borne diseases is a major challenge. Epidemiol Rev 1996;18:77-89.
Vaccines, available for only a few diseases (yellow 5. Bruce-Chwatt LJ. The Manson Oration, May 1979.
fever, Japanese encephalitis, tick-borne encepha- Man against malaria: conquest or defeat? Trans Roy
Soc Trop Med Hyg 1979;73:605-17.
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6. Hammon WM. Dengue hemorrhagic fever—do we
Vaccine prospects for major vector-borne dis- know its cause? Am J Trop Med Hyg 1973;22:81-91.
eases are not good. With the exception of malaria, 7. Pan American Health Organization. Dengue in the
few other vector-borne diseases have funding for Caribbean, 1977. Scientific Publication No. 375.
vaccine research. Washington: The Organization; 1979.
8. Reeves WC. Recrudescence of arthropod-borne
In the next decade, therefore, vector control
diseases in the Americas. Washington: Pan American
will be required to interrupt transmission of most Health Organization; 1972. PAHO Scientific Publication
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vironmentally safe insecticides and research on 9. Groot H. The reinvasion of Colombia by Aedes aegypti:
alternative approaches (such as biological control) aspects to remember. Am J Trop Med Hyg 1980;29:330-8.
10. Lederberg J, Shope RE, Oaks SC Jr, editors. Emerging
are needed. Integrated prevention strategies must
infections: microbial threats to health in the United
be developed and implemented in endemic/ States. Washington: National Academy Press; 1992.
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support for research, human resources are fostering development. Geneva: World Health
needed to develop and implement sustainable Organization; 1996.
12. Zucker JR. Changing patterns of autochthonous
prevention programs. Adequately trained per-
malaria transmission in the United States: a review of
sonnel are lacking in most developing countries, recent outbreaks. Emerg Infect Dis 1006;2:37-43.
as are academic institutions with the programs to 13. Molyneux DH. Current public health status of the
train them. Policy changes must be made to trypanosomiases and leishmaniases. In: Hilde G,
support public health approaches to disease Mottram JC, Coombs GH, Holmes PH, editors.
Trypanosomiasis and leishmaniasis. London: CAB
prevention. All these factors are needed to
International; 1997. p. 39-50.
rebuild the public health infrastructure. Ulti- 14. Dennis DT. 1998. Epidemiology, ecology, and
mately, however, demographic trends that have prevention of Lyme disease. In: Rahn DW, Evens J,
resulted in increased population pressure on urban editors. Lyme disease. Philadelphia (PA): American
centers and changes in agricultural practices must College of Physicians; 1998. p. 7-34.
15. Dennis DT. Plague as an emerging disease. Emerging
be reversed. Only then will we be able to effectively
Infections II. In press 1998.
reverse the current trend of emergent/resurgent 16. Ramalingaswami V. The plague outbreaks of India,
vector-borne disease in the 21st century. 1994–a prologue. Current Science 1996;71:781-806.
17. Plague—India 1994: economic loss. Geneva: World
Acknowledgment Health Organization; 1997. p. 14.
The author is grateful to numerous colleagues around 18. Gubler DJ. Dengue and dengue hemorrhagic fever: its
the world for contributing data and information used in history and resurgence as a global public health problem.
preparation of this paper. In: Gubler DJ, Kuno G, editors. Dengue and dengue
hemorrhagic fever. London: CAB International. p. 1-22.
Dr. Gubler is director of the Division of Vector-Borne 19. Sanders EJ, Tukei PM. Yellow fever: an emerging
Infectious Diseases, National Center for Infectious Diseases, threat for Kenya and other East African countries.
CDC, in Fort Collins, Colorado. His research interests East Afr Med J 1996;73:10-2.
include field epidemiology, laboratory diagnosis, surveil- 20. Monath TP. Yellow fever. In: Monath TP, editor. The
lance, prevention, and control of vector-borne diseases, with arboviruses: epidemiology and ecology. Boca Raton
special emphasis on dengue/dengue hemorrhagic fever and (FL): CRC Press; 1988. p. 139-231.
other arboviruses.

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21. Gubler DJ. Aedes aegypti and Aedes aegypti-borne 24. Addressing emerging infectious disease threats: a
disease control in the 1990s: top down or bottom up. Am prevention strategy for the United States. Atlanta (GA):
J Trop Med Hyg 1989;40:571-8. Centers for Disease Control and Prevention; 1994.
22. Reiter P, Gubler DJ. Surveillance and control of urban 25. World resources 1996-97. A guide to the global
dengue vectors. In: Gubler DJ, Kuno G, editors. environment. The urban environment. New York:
Dengue and dengue hemorrhagic fever. London: CAB Oxford University Press: 1996.
International; 1997. p. 425-62. 26. Reiter P, Sprenger D. The used tire trade: a mechanism
23. Gubler DJ. Epidemic dengue and dengue hemorrhagic for the worldwide dispersal of container breeding
fever: a global public health problem in the 21st mosquitoes. J Am Mosq Ctrl Assoc 1987;3:494-501.
century. In: Scheld WM, Armstrong D, Hughes JM 27. Gubler DJ. Arboviruses as imported disease agents:
editors. Emerging infections 1. Washington: ASM the need to increased awareness. Arch Virol
Press; 1997. p. 1-14. 1996;11:21-32.

Emerging Infectious Diseases 450 Vol. 4, No. 3, July–September 1998

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Global Climate Change and

Infectious Diseases
R. Colwell,* P. Epstein,† D. Gubler,‡ M. Hall,§ P. Reiter,‡
J. Shukla¶, W. Sprigg,# E. Takafuji,** and J. Trtanj§
*University of Maryland Biotechnology Institute, College Park, Maryland,
USA; †Harvard Medical School, Boston, Massachusetts, USA; ‡Centers for
Disease Control and Prevention, Atlanta, Georgia, USA; §National Oceanic
and Atmospheric Administration, Washington, D.C., USA; ¶Institute
of Global Environment and Society, Inc., Calverton, Maryland, USA;
#National Research Council, Washington, D.C., USA; **Walter Reed
Army Institute of Research, Washington, D.C., USA

Climate change, if it occurs at the level The second set of papers provided current
projected by current global circulation models, evidence of global climate change and described
may have important and far-reaching effects on how climatologic data might be used to
infectious diseases, especially those transmitted understand geographic spread and transmission
by poikilothermic arthropods such as mosquitoes dynamics of an important emerging infectious
and ticks. Although most scientists agree that disease such as cholera. The speakers concluded
global climate change will influence infectious that global warming is occurring and that
disease transmission dynamics, the extent of the weather events appear to be associated with the
influence is uncertain. This conference session emergence and spread of cholera in the Americas
provided an overview of the issues associated between 1991 and 1998.
with climate change as it relates to the emergence Speakers then focused on the research that
and spread of infectious diseases. will be required to answer the many questions
Two papers set the stage by reviewing data relating to climate change and infectious
that support or do not support the conclusion that diseases. They described an effort initiated by the
climate change has already influenced transmis- National Oceanic and Atmospheric Administra-
sion of infectious diseases. Some studies support tion to take advantage of the strong El Niño
such conclusions as warming at higher eleva- Southern Oscillation (ENSO) signal in 1997 to
tions, including the retreat of tropical summit 1998 to study the effect of ENSO on vector-borne
glaciers, upward plant displacement, elevational diseases. The hypothesis was that ENSO-related
shifts in insect populations and vector-borne changes in precipitation, temperature, and other
diseases, and upward shift of the freezing isotherm environmental variables have both direct effects
(150 m, which is equivalent to 1°C warming) since (through drought, flood, and extreme weather
1970. Other studies, however, point out that in events) and indirect effects (through changes in
centuries past, vector-borne diseases such as transmission and outbreaks of infectious dis-
malaria, dengue, and yellow fever occurred eases, particularly diseases transmitted by
regularly in temperate regions in epidemic form mosquitoes, rodents, or water) on human health.
during the summer months. The diseases were Diseases studied in the ENSO experiment
eliminated from Europe and North America, and include cholera in Bangladesh and Peru,
although many areas still have the mosquito cryptosporidiosis in the United States, water-
vectors, epidemic disease transmission has been borne and water-related diseases in Florida,
prevented by improved living conditions and marine ecologic disturbances in the eastern
effective mosquito control. Also, since malaria has United States, dengue in different parts of the
historically occurred at elevations of 2,400 m to world, malaria in Africa, domestic arboviral
2,600 m, its current transmission at high altitudes encephalitides in the United States, and
does not necessarily prove that transmission at hantavirus pulmonary syndrome in the United
these high altitudes is the result of climate change. States. The National Academy of Sciences and

Vol. 4, No. 3, July–September 1998 451 Emerging Infectious Diseases

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Institute of Medicine plan to appoint a committee placed on public health intervention measures
to review critically the published work on this that are properly implemented and can mitigate
topic and make recommendations for a national the effect of global climate change on infectious
research agenda. A number of U.S. government disease incidence and geographic spread.
agencies will support this committee financially.
The final presentation addressed the need Suggested Bibliography
for cooperation and partnerships in implement- 1. Epstein PR, Diaz HF, Elias S, Grabherr G, Graham NE,
ing this research agenda. The government Martens WJM, et al. Biological and physical signs of
climate change: focus on mosquito-borne disease.
agencies involved have unique expertise and
Bulletin of the American Meteorological Society
perspectives that can be brought to bear on the 1998;78:409-17.
problem of climate change. Emphasis must be

Jagadish Shukla Ernest Takafuji

Institute of Global Walter Reed Army
Environment and Institute of Research,
Society, Inc., Calverton, Washington, D.C,
Maryland, USA USA

Emerging Infectious Diseases 452 Vol. 4, No. 3, July–September 1998

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Emerging Zoonoses
James Childs,* Robert E. Shope,† Durland Fish,‡ Francois X. Meslin,§
Clarence J. Peters,* Karl Johnson,¶ Emilio Debess,#
David Dennis,* and Suzanne Jenkins**
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA;
†University of Texas Medical Branch at Galveston, Galveston, Texas, USA;
‡Yale School of Medicine, New Haven, Connecticut, USA; §World Health
Organization, Geneva, Switzerland; ¶University of New Mexico,
Albuquerque, New Mexico, USA; #National Association of Public Health
Veterinarians; and **Council of State and Territorial Epidemiologists

Zoonotic pathogens cause infections in tion of the northeastern coastal states since the
animals and are also transmissible to humans; early part of this century precipitated a natural
knowledge of the extrahuman reservoirs of these succession of ecologic changes that included
pathogens is thus essential for understanding the increased deer density, expansion of the natural
epidemiology and potential control of human range of the deer-dependent tick Ixodes
disease. Zoonotic diseases are typically endemic scapularis, and increased transmission rates of
and occur in natural foci. However, ecologic tick-borne pathogens. I. scapularis is a compe-
change and meteorologic or climatic events can tent vector of at least four enzootic tick-borne
promote epidemic expansion of host and pathogens (Borrelia burgdorferi, Babesia microti,
geographic range. For practical reasons, surveil- Ehrlichia phagocytophila, and a Powassanlike
lance of zoonotic agents too often relies on the encephalitis virus). Because of its anthropophilic
identification of human cases. Surveillance in nature, I. scapularis is also an excellent bridge
natural hosts may be difficult because of the vector for transmission of these pathogens to
ecologic complexity of zoonoses; multidisciplinary humans. This dramatic expansion in the
teams of ecologists, mammalogists, ornitholo- distribution of I. scapularis in the northeastern
gists, and entomologists, as well as physicians United States has caused the current epidemic of
and epidemiologists, may be required for Lyme disease and has increased the range of
successful investigations. A recent trend in human babesiosis in New England. However, the
studying zoonoses that have strong environmen- recent emergence of human granulocytic
tal correlates includes geographers and math- ehrlichiosis resulted from the recognition of
ematical modelers, who integrate satellite human cases caused by a zoonosis already well
remote sensing and geographic information established within I. scapularis populations. As I.
systems to predict outbreaks. Understanding scapularis continues to expand its range bringing
extrahuman life cycles and predicting zoonotic more people in contact with novel enzootic tick-
disease outbreaks may permit control activities borne pathogens, additional tick-borne diseases
targeted at several points in the cycle of pathogen may emerge as new public health threats.
maintenance before human infection begins. These Since the unprecedented impact of bovine
control efforts are important because most zoonoses spongiform encephalopathy (BSE) and new
are not amenable to eradication, except perhaps variant Creutzfeldt-Jakob disease (nvCJD) on
those in areas where animal reservoirs are targeted animal health and national politics and econo-
for vaccination, e.g., fox rabies in Europe. mies, this new zoonosis has prompted many
In the United States, tick-borne zoonoses questions in the field of foodborne disease control
have emerged at the relatively constant rate of and prevention. BSE and nvCJD, caused by an
one per decade over the past 100 years. However, unconventional agent, the nature of which
the incidence of human tick-borne disease has remains controversial, are invariably fatal. The
increased exponentially over the past two threat to human health is compounded because
decades—primarily because of ecologic change the causative agent is resistant to conventional
caused by reforestation. Large-scale reforesta- physical and chemical methods of decontamina-

Vol. 4, No. 3, July–September 1998 453 Emerging Infectious Diseases

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tion and cannot be fully inactivated by any of the their hosts limit a targeted intervention. The
current food technologies. A preclinical diagnos- prevalence of virus infection in rodent popula-
tic test remains elusive. Traditional food safety tions may be less important than the absolute
programs cannot prevent infection to consumers number and demographic characteristics of
once the agent has entered the food chain. New and infected mice. A single, newly infected, subadult
reemerging conventional or unconventional mouse may shed in its urine and feces the high
foodborne pathogens of animal origin must be quantities of virus needed to infect a person by
better addressed, and food safety programs with the aerosol route. However, effective mainte-
emphasis on the preharvest and harvest food stages nance of virus may hinge on persistent infections
must be developed. Control is best achieved at the in older, dominant, male rodents that survive
feed preparation and farm level and at the over extended periods and have the highest
harvest stage. Consumer health takes prece- prevalence of infection but only shed sufficient
dence over market concerns, and when data are virus in their saliva to perpetuate rodent-to-
incomplete, a conservative response is warranted rodent transmission through intraspecific ag-
until the risk can be accurately assessed. gressive encounters. Recent developments in
Diseases of humans caused by rodent-borne remote sensing and geographic information
viruses in the families Bunyaviridae and systems, coupled with longitudinal studies of
Arenaviridae include the newly recognized virus activity and rodent population dynamics,
hantavirus pulmonary syndrome and the South hold promise for developing models predictive of
American hemorrhagic fevers. Many of these when and where outbreaks of rodent-borne
diseases present control challenges—because zoonoses could occur.
vaccines may not be developed, because of Surveillance of the unknown appears to be a
characteristics of the exposed population, or thankless task, and it is probable that we will
because control of rodent reservoirs in the learn of an “Andromeda” event after an urban
affected areas is impractical or unachievable. population is struck, although the agent is most
Many of these diseases may be increasing in likely to arise in a rural, tropical setting. The
frequency as humans modify forest and natural health and safety of future generations may
savannah environments for agriculture, inad- depend on our ability to rapidly detect, monitor,
vertently promoting human-rodent contact and and control disease caused by novel zoonotic
increasing the number of suitable habitats used agents. Uniform surveillance definitions, reliable
by rodents, which are habitat generalists and also specimen collection, shipping and handling, and
virus reservoirs. Serious gaps in our understand- means for rapid communication will be critical.
ing of the natural history of these viruses and

Emerging Infectious Diseases 454 Vol. 4, No. 3, July–September 1998

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New Approaches to Surveillance and

Control of Emerging Foodborne
Infectious Diseases
Robert V. Tauxe
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Each year in the United States, foodborne developing prevention tools. Dennis Lang,
diseases affect millions of persons, who become ill National Institute of Allergy and Infectious
after exposure to any of a growing spectrum of Diseases, emphasized that NIH-supported inves-
identified agents and toxins. Typhoid fever and tigators who study the organisms responsible for
other foodborne diseases common a century ago foodborne illness represent a national resource
have been controlled by measures that prevent that can be used to address food safety questions
contamination of food and water with human more effectively. New approaches to prevention are
sewage and by technologies (such as milk now being implemented by the food regulatory
pasteurization) that eliminate any remaining agencies, and more approaches, including irradia-
pathogens. Many recently identified foodborne tion, have been approved for industry use.
diseases are caused by contamination with animal Barbara Herwaldt, CDC, reported that
feces and can be prevented by measures that reduce Cyclospora cayetanensis is an archetypical emerg-
contamination and eliminate residual pathogens. ing foodborne pathogen. This recently described
In the future, growing attention will need to be parasitic pathogen sprang to national attention in
directed to the safety of the food and water the nationwide outbreaks in 1996, which were traced to
animals themselves consume. raspberries imported from Guatemala. Outbreaks
New foodborne diseases emerge for many recurred in 1997, leading to a suspension of
reasons, including changes in the pathogens importation, despite efforts of the Guatemalan
themselves, increasingly centralized and concen- raspberry industry to reduce potential contami-
trated food production, globalization of the food nation. With improved surveillance, other
supply, and increases in populations at higher outbreaks were detected, investigated, and
risk. Better surveillance and investigation now traced to mesclun lettuce and basil. CDC
detect outbreaks that a few years ago would have investigation has now documented C. cayetanensis
been missed. The continuing challenges are to as a common cause of springtime diarrhea among
identify new pathogens as they emerge, children in Guatemala. Critical gaps in our
understand how foodborne pathogens contami- understanding of the biology and epidemiology of
nate food and cause illness, and define and this parasite, particularly in the raspberry farm
implement the best prevention strategies. environment, need to be closed before effective
Many efforts are now under way to improve control measures can be developed.
food safety in the United States. In 1997, the B. Swaminathan, CDC, described a new
National Food Safety Initiative outlined an subtyping strategy for public health surveillance
interagency effort to enhance foodborne disease of Escherichia coli O157:H7 that will become
surveillance, research, and prevention. The available electronically later this year. This
Centers for Disease Control and Prevention strategy depends on standardized molecular
(CDC) and state and local health departments fingerprinting in public health and food
have begun to implement improved surveillance regulatory agency laboratories by pulsed-field gel
strategies, including additional resources for electrophoresis (PFGE). With standardized
basic surveillance and investigation, an active methods and equipment, excellent interlaboratory
surveillance network called FoodNet, surveil- comparability of DNA fingerprint patterns has
lance for antimicrobial resistance, and a network been achieved. Twenty-four states, the U.S.
for molecular subtyping called PulseNet. Basic Department of Agriculture, and the Food and
research at the National Institutes of Health Drug Administration are now equipped to use
(NIH) is clarifying virulence mechanisms and CDC’s PFGE method for E. coli O157:H7. These

Vol. 4, No. 3, July–September 1998 455 Emerging Infectious Diseases

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laboratories are being linked to form a prevent E. coli O157:H7 in humans by

collaborative network for molecular subtyping, vaccinating the bovine reservoir.
PulseNet, which will permit rapid comparison of Henrik Wegener, Danish Zoonosis Center,
identified PFGE profiles with the national described the emergence of vancomycin-resistant
database at CDC. Efforts are also under way to enterococci (VRE) in northern Europe, linking it
apply the same strategy to other foodborne to the use of a related glycopeptide antibiotic,
pathogens. In 1997, PFGE results were already avoparsin, in food animals. VRE were common in
critical to epidemiologic investigations of several poultry flocks and swine herds exposed to this
outbreaks of E. coli O157:H7 infections. These antibiotic, and 5% of healthy carnivorous humans
included a Colorado outbreak traced to ground beef were carriers of VRE. Sequencing the resistance
and a multistate outbreak related to alfalfa sprouts. gene showed that one genotype was present in
Alison O’Brien, Uniformed Services Univer- poultry, a second was present in swine, and both
sity of the Health Sciences, described a new were present in humans. Thus, VRE are unlikely
approach to prevention, based on an attachment to have spread from animals to humans rather
protein present in enteropathogenic E. coli as than vice versa. After avoparsin was withdrawn
well as E. coli O157:H7. This protein, intimin, in Denmark in 1995, the prevalence of VRE in
permits the bacteria to attach to mucosal cells chickens dropped; the European Union banned
and produce a characteristic pathologic change. the agent in 1997. In some countries, amplifica-
In a calf model, E. coli O157:H7 can cause diarrhea tion of VRE in hospitals where vancomycin use is
and this change; the change does not occur if the E. frequent may follow introduction of resistance
coli lack the gene for intimin. Intimin is highly strains from food sources. Other antibiotics being
antigenic and acid stable, and antibodies raised to it developed for human use (e.g., streptogramins)
block adherence in vitro. The intimin gene has been have analogues used in agriculture for years, to
introduced into plants, where it is produced in the which resistance may already have emerged.
leaves. This means that an antitransmission Integrated resistance surveillance systems, data
vaccine based on intimin can be produced cheaply on antibiotic use in humans and in agriculture,
in plants and be given to calves. The vaccine could and prudent agricultural use policies are critical
even be fed to animals if intimin were produced in to managing the growing challenge of antibiotic
fodder plants. In the future, we may be able to resistance related to foods and food animals.

Emerging Infectious Diseases 456 Vol. 4, No. 3, July–September 1998

Special Issue

FoodNet and Enter-net: Emerging

Surveillance Programs for
Foodborne Diseases
Samantha Yang
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

The public health challenges of foodborne United States each year. To address these
diseases are changing as a result of newly objectives, FoodNet conducts active surveillance
identified pathogens and vehicles of transmis- and related studies: a population survey, a
sion, changes in food production and distribution, physician survey, and a case-control study of
and an apparent decline in food safety awareness. Escherichia coli O157:H7 infections.
Response to these new challenges requires new
surveillance strategies to monitor the incidence Population Survey
of human illness and provide data for developing Duc Vugia, California Department of Health,
effective prevention strategies. reported the results of the FoodNet population
survey, which was conducted between July 1,
FoodNet 1996, and June 30, 1997, in selected counties of
The Foodborne Diseases Active Surveillance California, Connecticut, Georgia, and the entire
Network (FoodNet), the principal foodborne states of Minnesota and Oregon. This survey
disease component of the Centers for Disease provided an estimate of the prevalence of acute
Control and Prevention’s (CDC) Emerging diarrhea and the frequency with which patients
Infections Program (EIP), is a collaborative with acute diarrhea sought medical care. In 9,003
project with participating EIP sites, the U.S. interviews, 11% of persons reported acute diarrhea
Department of Agriculture (USDA), and the U.S. in the 4 weeks before the interview, 12% of
Food and Drug Administration (FDA). To persons with acute diarrhea called a health-care
determine more precisely the incidence of provider as a result of this illness, and 8% sought
foodborne illness in the United States, FoodNet medical care. These data indicate an estimated
was established in five locations (selected 1.4 acute diarrheal episodes per person each year
counties in California, Connecticut, and Georgia, in the United States, with 1% of the population
and the entire states of Minnesota and Oregon) in seeking medical care because of acute diarrhea.
1995 and was expanded to selected counties in
Maryland and New York in 1997. The population Physician Survey
of these seven FoodNet sites in 1997 was 20.3 In 1996, to obtain information on stool
million (7.7% of the U.S. population). culturing practices, physicians in California,
The objectives of FoodNet are to 1) describe Connecticut, Georgia, Minnesota, and Oregon
the epidemiology of new and emerging bacterial, were surveyed. Results were reported by Thomas
parasitic, and viral foodborne diseases of national Hennessy, CDC. Of the 1,783 physicians
importance; 2) more precisely determine the responding to this survey, 44% reported
frequency and severity of foodborne diseases in requesting a stool culture from the most recent
the United States; and 3) determine the patient they remembered seeing who had acute
proportion of foodborne disease caused by eating diarrhea. Patient factors significantly associated
specific foods. By monitoring foodborne disease with stool culture requests included bloody stools,
incidence over time, FoodNet will document the a diagnosis of AIDS, diarrhea lasting longer than 3
effectiveness of new food safety initiatives, such as days, travel to a developing country, and fever.
the USDA Food and Safety Inspection Service’s Stool culture ordering practices differed by
Pathogen Reduction and Hazard Analysis and physicians’ specialties and geographic site; how-
Critical Control Points (HACCP) Rule, in decreas- ever, culturing practices did not differ by payment
ing the number of cases of foodborne disease in the plan, such as managed care or fee-for-service.

Vol. 4, No. 3, July–September 1998 457 Emerging Infectious Diseases

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Variability in culturing practices by specialty and The international database of laboratory-confirmed

geographic location suggests a need for clinical cases of salmonellosis produced by Enter-net also
diagnostic guidelines for diarrheal illnesses. allows trends in this illness to be observed over
several years. For example, Enter-net is
Case-Control Study documenting the continuing problem of Salmo-
A case-control study was conducted at nella serotype Enteriditis in western Europe.
FoodNet sites to identify risk factors for sporadic Enter-net represents a working model of how
E. coli O157:H7 infections and to explain focused infection-specific international surveil-
variations in the incidence of E. coli O157:H7 lance involving key public health professionals can
incidence among FoodNet sites. Heidi Kassenborg, help monitor and detect international outbreaks
Minnesota Department of Health, presented of foodborne infection.
results from this study, which was conducted
between March 1, 1996, and April 30, 1997, in
selected counties of California, Connecticut,
Georgia, and the entire states of Minnesota and
Oregon. Data were obtained from 200 nonoutbreak
case-patients and 380 controls, matched by age
and telephone exchange. For all sites combined,
illness was associated with eating pink hamburg-
ers or pink ground beef and with visiting a farm.
Regional variation in beef processing and in
exposure to farms may have contributed to the
regional variability of E. coli O157:H7 infections.

Funded by the European Commission,
Enter-net (formerly Salm-Net) is an interna-
tional surveillance system for Salmonella
infections (including data on antibiotic resis-
tance) and E. coli O157 infections. Microbiolo-
gists and epidemiologists responsible for
national laboratory-based surveillance of these
pathogens in 15 European countries form the
Enter-net network. Ian Fisher, Communicable
Disease Control Centre, United Kingdom,
described Enter-net and highlighted interna-
Carol Hardegree
tional outbreaks recognized by the network. Food and Drug Administration,
Investigations of these outbreaks led to public Washington, D.C., USA
health interventions and product recalls in Europe.

Emerging Infectious Diseases 458 Vol. 4, No. 3, July–September 1998

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Enhancing State Epidemiology and

Laboratory Capacity for
Infectious Diseases
Deborah A. Deppe
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

The Epidemiology and Laboratory Coopera- reportable communicable diseases on the HIN.
tive is an agreement that provides state and large Since implementation, reports from local health
local health departments with resources to departments to the state have been more timely.
strengthen and enhance basic capacity for public Counties can easily update and query their own
health surveillance and response for infectious data and can access statewide reports generated
diseases. The funding is used to implement new by the state and posted on the HIN.
technology, upgrade systems, train staff, and The Los Angeles County Department of
purchase office and laboratory equipment. Six of Health Services has used pulsed-field gel
the 30 sites reported on their programs. electrophoresis (PFGE) for outbreak investiga-
The Vermont Department of Health has tions for 2 years. Bacteria caused 140 (24%) of 576
undertaken statewide efforts to improve commu- reported outbreaks, 36% of health facility
nicable disease reporting through legislation. outbreaks, but only 19% of community outbreaks.
Before 1997, public health law required PFGE was used in 32 investigations, of which 29
physicians, nurses, hospital administrators, and (91%) were nosocomial. The most common
school and town health officials to report organisms were staphylococcus and enterococ-
communicable disease (defined by regulation) to cus. In contrast, PFGE was used in only 3 (4%) of
the Commissioner of Health. Legislation pro- 77 investigations of community bacterial out-
posed and passed in 1997 required health breaks. Health departments should consider the
maintenance organizations and managed care number, setting, and causes of outbreaks that
organizations to report as well. This model law they investigate to determine if PFGE will be
defines such information as “confidential and useful in their investigation arsenal.
privileged” and extends protection to investiga- The Washington State Department of Health
tions and studies of disease outbreaks. has developed a pilot electronic laboratory-based
The Kansas Department of Health and reporting mechanism to route infectious disease
Environment is building epidemiology and reports from a large managed care organization
laboratory capacity by expanding electronic to local health agencies. The overall goal is
surveillance and analysis, enhancing surveil- development of a generic electronic reporting
lance for diarrheal disease, and integrating mechanism. For this project, Health Level 7 was
information from other sources into the existing identified as a common ground for sharing data.
surveillance system. The new programs are Preliminary data suggest that timeliness and
flexible so they can meet the challenges posed by completeness of reporting will improve. Adhering
new and emerging infectious diseases as well as to nationally recognized standards and codes
changing needs within public health. may help reduce problems associated with
The New York State Department of Health transferring data; however, no public health
uses electronic communications to enhance rapid software or implementation package was avail-
reporting of communicable disease epidemiologic able, so resource-intensive customization was
and laboratory data within the state. In July necessary.
1997, seven counties began pilot testing the New The Maine Bureau of Health is attempting to
York Health Information Network (HIN), a characterize statewide hepatitis C (HCV) preva-
secure Intranet site. Web forms were designed for lence through a review of existing databases
designated county personnel to submit confiden- (hospital discharges, deaths, Medicaid registry,
tial case and supplemental information on 61 blood donor screening), mandatory laboratory

Vol. 4, No. 3, July–September 1998 459 Emerging Infectious Diseases

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reporting with physician questionnaire follow- 1990s and an unexpectedly high proportion of
up, a blinded seroprevalence survey in sexually patients with injection drug–associated risk
transmitted disease clinics, and a survey of histories. Local surveillance data are useful for
gastroenterologists. Initial data indicate dra- public policy decisions and as educational tools
matic increases in HCV-related hospitalization for physicians and the public.
and in Medicaid expenditures during the mid-

Emerging Infectious Diseases 460 Vol. 4, No. 3, July–September 1998

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International Cooperation
James LeDuc
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Experts from the World Health Organization region to pass several resolutions on prevention
(WHO), the European Union (EU), the U.S. of epidemic infectious diseases, yet frequent
Department of Defense (DoD), and other epidemics continue. Apart from the development
organizations summarized existing and planned of a few disease-specific laboratory diagnostic
collaborations on emerging infectious diseases. networks, laboratory services in Africa remain
The session was chaired by David Heymann, rudimentary and underdeveloped. The WHO
WHO, and James LeDuc, CDC. Regional Office for Africa has recently formu-
One speaker, V. Ramalingaswami, All India lated a strategic plan for integrated disease
Institute of Medical Sciences, India, summarized surveillance and an action plan to strengthen
lessons learned from the plague outbreak in laboratory capacity in Africa; international
Surat, India. The plague outbreak, the first in support is urgently needed to implement these
many years, found the country ill-prepared to plans.
diagnose this disease, and young clinicians Global collaborations were also discussed.
lacked experience in recognizing or managing Nils Daulaire, U.S. Agency for International
plague-infected patients. Development (USAID), described the recently
Two speakers examined regional collabora- announced $50 million initiative to address
tions. Christopher Bartlett, Public Health infectious diseases globally. These funds will be
Laboratory Service, London, summarized the used to focus activities on tuberculosis, malaria,
development of international surveillance within antimicrobial resistance, and surveillance, both
EU. The Maastricht Treaty provided the political in countries with USAID missions, as well as
will to underpin these activities; since the treaty, regionally. Michael McCarthy, DoD, summarized
the heads of European institutes with responsi- the new DoD initiative on emerging infectious
bility for national surveillance have met diseases and explained how the overseas
regularly to assist in strategic development of laboratories in Thailand, Kenya, Peru, Brazil,
surveillance activities. Disease-specific networks Egypt, and Indonesia will work closely with their
have been established, each with an operational host nations and DoD scientists to address
protocol that sets out agreed case definitions and emerging endemic disease threats. Maria Neira,
standard methods and use of information WHO, described recent activities to address
obtained. High quality and timely information is cholera and other diarrheal diseases of epidemic
now being provided on a steadily increasing potential globally. These activities included the
spectrum of infectious diseases through weekly secondment of a CDC medical epidemiologist to the
electronic and monthly surveillance bulletin WHO subregional office for southern Africa, where
publications. Oyewale Tomori, regional virologist in the past several years a plan to improve
for Africa from WHO, explained that despite recognition and response to epidemic diarrheal
substantial advances in disease prevention and diseases has been developed and implemented.
control, communicable diseases still constitute a Included in the program are training on improved
major health problem for Africa. Concern about patient management, strengthened laboratory
the deplorable and worsening state of disease capacity, and better communication both within
control in Africa has led ministers of health in the and between countries of southern Africa.

Vol. 4, No. 3, July–September 1998 461 Emerging Infectious Diseases

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Public Health Surveillance and

Information Technology
Robert W. Pinner
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Applying Modern Information Technology Codes

to Reporting for Public Health—the Role Code standards include Logical Observations
of Standards Identifiers Names and Codes (LOINC), a code
Clement McDonald, Indiana University standard that identifies clinical questions,
School of Medicine, discussed the role of variables, and reports; Systematized Nomencla-
standards in the application of modern informa- ture of Medicine (SNOMED), which identifies
tion technology to public health reporting. He procedures and possible answers to these
pointed to the rich data sources stored questions, such as test results; Current Proce-
electronically in clinical laboratories, pathology dural Terminology, Version 4 (CPT4), which
and cytology reporting systems, pharmacies, and identifies procedures; and the National Library of
hospitals, and emphasized the trend toward Medicine’s Unified Medical Language (UMLS), a
increasing automation. metathesaurus of most code systems.
Interest and demand for electronic delivery of LOINC comprises a database of 15,000
data come from many interested parties—3rd variables with synonyms and cross-mappings
party payers, researchers, physicians, and public and covers a wide range of laboratory and clinical
health officials. However, substantial barriers to subject areas (e.g., blood bank, chemistry,
smooth electronic flow of this information include hematology, microbiology, vital signs, body
the storage of data in isolated areas, varying measurements, obstetric ultrasound, and electro-
internal structures among information systems, cardiograms). LOINC’s formal naming structure
and considerable variation in codes (e.g., for has six parts: component (analyte); property
laboratory tests and results). Overcoming these measured; time aspect; system (specimen,
barriers requires defining, adopting, and imple- organ), precision, method. LOINC is being
menting standards for messages, codes, identifica- adopted by several large reference laboratories,
tion (e.g., persons, providers, places), and security. and it has been incorporated into UMLS.
Additional information about LOINC can be
Messages found at
Health Level Seven (HL7) is a message termcode/loinc.htm.
standard that defines messages for laboratory SNOMED defines code standards in a variety
and other clinical results, immunization report- of clinical areas, called coding axes: topography;
ing, drug usages, patient registration, and morphology; function; living organisms; chemi-
clinical trials. HL7 provides standards for the cals, drugs, and biologic products; physical
structure and organization of clinical messages, agents, activities, and forces; occupations; social
defining data types, and structure of the “records” context; diseases/diagnoses; procedures; general
in the message. A 1997 Healthcare Information linkages/modifiers.
Management System Societies/Hewlett-Packard
Leadership Survey found that HL7 was the most Security and Privacy
important health informatics standard. HL7 is an Privacy issues include both information
American National Standards Institute (ANSI)– technology and policy considerations. For
approved clinical message standard used widely example, security can be addressed by encryption
in the United States and internationally. techniques; policies that strongly discourage
Additional information can be found at the HL7 sharing of passwords are also required for
Internet web site: adequate privacy and security.

Emerging Infectious Diseases 462 Vol. 4, No. 3, July–September 1998

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The public health system has been working to HHS Data Council, a senior level policy guidance
adopt needed standards for immunization data and decision-making group, is the contact for the
transactions using HL7, data elements for National Committee on Vital and Health
emergency department systems, and an ap- Statistics. 2) The Data Council’s Health Data
proach for piloting electronic reporting from Standards Committee provides management of
clinical laboratories (which defines an HL7 the standards activities. 3) Implementation
message with LOINC codes for identifying tests Teams provide research, analysis, and develop-
and SNOMED for identifying results, and a set of ment of standards and implementing regula-
tables that define reportable diseases in terms of tions. The HHS adopts a standard by publishing
specific tests and results) (1). in the Federal Register a Notice of Intent to
The “rules” for achieving public health goals for gather information when no consensus exists and a
electronic clinical data are as follows. 1) Take Notice of Proposed Rule Making, which provides a
advantage of the momentum of the existing draft final rule. Publication of a Final Rule marks
standards in hospitals and laboratories. 2) Recog- the “adoption” by HHS of a particular standard.
nize that this is difficult and will take a long Standards proposed for adoption include
time. 3) Consider the source system data X12N Version 4010 for all transactions except
structures when defining data needs. pharmacy claims, for which the National Council
for Prescription Drug Program Version 3.2 is
Opportunities and Pitfalls for Surveillance proposed. Coding standards proposed for adop-
William Braithwaite, Department of Health tion include ICD-9-CM, followed by ICD-10-CM
and Human Services, described the Administra- in 2001 for diagnoses, and ICD-9-CM Vol. 3 and
tive Simplification provision of the Health Health Care Financing Administration Common
Insurance Portability and Account Act of 1996 Procedure Coding System (HCPCS) for proce-
(HIPAA), which is intended to standardize the dures. Proposed identifier standards are the
electronic data interchange of certain adminis- National Provider Identifier Health Care Financ-
trative and financial transactions while protect- ing Administration (HCFA) for providers, the
ing the security and privacy of transmitted PAYERID (HCFA) for health plans; and the
information. The act mandates nine transaction Employer Identification Number (Internal Rev-
standards (e.g., claims, encounters, enrollment) enue Service) for employers. A Notice of Intent
including code sets; coordination of benefits will be published to seek input regarding the
information; unique identifiers (including defin- individual identifier.
ing allowed uses) for individuals, employers, Important issues for public health surveil-
health plans, and health-care providers; and lance in the next phases include participating in
security, confidentiality, and electronic signa- development of the data content of these
tures. Once standards are adopted, all health standards, the standard for claim attachments,
plans, clearinghouses, and those providers who and the electronic medical records standards, and
choose to conduct transactions electronically will developing health information privacy that
be required to implement them. The time line for maintains appropriate access to data for public
implementation calls for adoption by the health purposes. Additional information about
Secretary of Health and Human Services (HHS) the Administrative Simplification provisions of
during 1998 of all standards except claim HIPAA can be found at
attachments. (“Claim attachments” refers to admnsimp/.
information requested by an insurance payer
from a health-care provider to justify submitted Public Health Surveillance for the 21st
charges and is difficult to standardize because of Century
the diversity of requests.) The Secretary will look Paul Stehr-Green, Washington Department
first to industry for a consensus standard of Health, emphasized public health surveillance
developed by an ANSI-accredited standards as the foundation of public health practice. Public
development organization and will rely upon health surveillance needs to adapt to changing
advice of the National Committee on Vital and health practice, such as requiring assessment of
Health Statistics. The HHS implementation the risks for new and reemerging infectious
strategy involves a three-tiered approach. 1) The diseases or environmental hazards.

Vol. 4, No. 3, July–September 1998 463 Emerging Infectious Diseases

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Public health should use the array of new Information and Surveillance Systems Board to
information tools available. The Blueprint for integrate a number of current surveillance
Surveillance is a document prepared by the systems; updating the agency’s inventory of
Council of State and Territorial Epidemiologists; surveillance systems; developing a policy to
it outlines the National Public Health Surveil- monitor and evaluate proposals to develop new or
lance System. This conceptual framework to substantially modify existing surveillance
approaches surveillance for not only reportable systems; developing an investment analysis
diseases, but also for a variety of health policy, which may allow the use of some portion of
outcomes, costs, and risk factors important to funds to support the development and mainte-
public health. The National Public Health nance of integrated surveillance and information
Surveillance System would involve other ap- systems by state health departments; and
proaches (taking into account available funding developing resources that have been made
levels and the particular goals of surveillance at available to state health departments for
each level of the public health system) in addition to enhancing infectious diseases surveillance capac-
the traditional reportable diseases surveillance ity. Washington State is formally reviewing the
model. The primary goals of the National Public regulatory foundation for surveillance and is
Health Surveillance System include 1) coordinat- developing and piloting electronic systems for the
ing new and existing public health surveillance collection, management, analysis, and dissemi-
systems and linking them to facilitate the nation of surveillance data and information,
exchange of data; 2) encouraging partnerships of including a collaboration between the health
federal, state, and local public health profession- department and Group Health Puget Sound
als in decision-making about surveillance Cooperative to electronically send selected labora-
activities; 3) reviewing existing surveillance (and tory data to the department of health for
other data collection efforts that have a surveillance. State and local health departments
surveillance component) and making decisions should commit to changing from old to modern
about new surveillance efforts and changes in ways of approaching surveillance, and CDC should
existing systems; 4) monitoring the adequacy of provide leadership to bring together disparate
methods and processes involved in current stakeholders and to provide flexible resources to
surveillance systems; and 5) developing a help state and local health departments effect
comprehensive description of conditions under modernization and integration of surveillance.
surveillance to bring attention to public health
surveillance activities and justify the need to Reference
support these activities. Recent accomplishments 1. McDonald CF, Overhage JM, Dexter P, Takesue BY,
include an effort coordinated by the Centers for Dwyer DM. A framework for capturing clinical data
sets from computerized sources. Ann Intern Med
Disease Control and Prevention’s (CDC) Health

Emerging Infectious Diseases 464 Vol. 4, No. 3, July–September 1998

Special Issue

Innovative Information-Sharing Strategies

Bradford A. Kay,* Ralph J. Timperi,† Stephen S. Morse,‡ David
Forslund,§ Julie J. McGowan,¶ and Thomas O’Brien#
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †The
Massachusetts State Laboratory Institute, Jamaica Plain, Massachusetts,
USA; ‡Defense Advanced Research Projects Agency, Arlington, Virginia,
USA; §Los Alamos National Laboratory, Los Alamos, New Mexico, USA;
¶University of Vermont, Burlington, Vermont, USA; and #Brigham and
Women’s Hospital, Boston, Massachusetts, USA

National and global health issues accentuate and discussions on how to improve surveillance
the need for health professionals to rapidly and and response capabilities are especially encour-
effectively acquire and disseminate information. aged. To subscribe to the ProMED-mail electronic
This session highlighted four innovative systems conference, send an e-mail message to
for communicating health information., and write “sub-
scribe promed” in the text space.
Many experts, both within and outside TeleMed
government, have warned of the need to improve The Advanced Computing Laboratory at Los
capabilities for dealing with emerging infectious Alamos National Laboratory, Los Alamos, New
diseases; development of an effective global Mexico, developed TeleMed, an electronic
infectious disease surveillance system has been medical record for managing tuberculosis
the primary recommendation. ProMED, a project patients through a collaboration with the
of the Federation of American Scientists, was National Jewish Center for Immunology and
inaugurated in 1993 at a conference in Geneva as Respiratory Medicine in Denver, Colorado.
a vehicle for developing, coordinating, and TeleMed provides a snapshot of patient data,
promoting plans for a global program to identify presented chronologically with access to labora-
and respond to emerging infectious diseases. tory test results, clinical history, radiology
Members of the ProMED Steering Committee images, reports, and treatment history. A
include (among others) representatives of the particularly valuable feature allows physicians to
Centers for Disease Control and Prevention, the annotate the medical record, either orally or in
National Institutes of Health, the World Health writing, for collaborating physicians to retrieve.
Organization (WHO), the Pan American Health Medical expertise can also be exchanged in real
Organization, and the International Office of time, with both users sharing the same screen
Epizootics. and with each having the capability to drive the
In 1994, in cooperation with SatelLife/ mouse-pointer. TeleMed, now available on the
HealthNet, ProMED developed an e-mail confer- Internet using Java-based technology, enables
ence system, ProMED-mail, on the Internet. physician specialists to support primary care
Originally developed to allow worldwide scien- providers in the management of complex medical
tist-to-scientist communications on emerging problems. The technology creates a “virtual
infectious diseases, the system rapidly evolved patient record” that allows the integration of
into a prototype for an open-architecture, real- databases from multiple clinics and multiple
time outbreak reporting system intended to providers across geographically separated areas.
complement official surveillance systems. Today, This permits individual health-care facilities to
with more than 10,000 subscribers from more continue to own and manage their own data while
than 125 countries, ProMED-mail is increasingly making the data accessible to others treating the
providing the first reports of infectious disease same patient. TeleMed provides a time-oriented
outbreaks. All items are read by scientists before record of the patient’s medical history but only
posting. Reporting of incidents or outbreaks, retrieves the actual data on demand, thereby
infectious disease problems of emerging interest, minimizing the bandwidth requirements of the

Vol. 4, No. 3, July–September 1998 465 Emerging Infectious Diseases

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networking capabilities. Distributed ownership results. Its primary goals are to enhance local
of the data means that only one copy of the data capabilities for analysis and to facilitate the
exists, and that copy remains where it was created. exchange of microbiologic data between centers.
Location of the data is obtained from a master WHONET is a DOS-based application that may
patient index that provides pointers to the data. be used alone on personal computers or in
Security and access to the data are controlled and conjunction with existing mainframe- or mini-
protected with encryption technology. computer-based clinical information systems.
Data conversion (“downloading” or “translating”)
VTMedNet from hospital systems or commercial automated
Vermont MedNet has been described as the susceptibility test machines can usually be
“first comprehensive statewide health informa- accomplished with BACLINK software, also
tion network in the nation.” VTMedNet was available free of charge from WHO. WHONET is
developed to provide timely access to medical not a complete laboratory management system
information in support of health-care delivery but can be used for simple clinical reporting of
across the state of Vermont. The system was results. Software development has concentrated
unique, not because it used advanced technology, on data analysis, particularly of the results of
but because it used basic technology. VTMedNet antimicrobial susceptibility tests. The analytic
Plus, the network’s evolution into voice, image, tools aid the selection of antimicrobial agents, the
and video, has already garnered national identification of hospital outbreaks, and the
recognition for its initiatives in the area of recognition of quality control problems in the
telemedicine. The network’s home page has laboratory. Review of antimicrobial results also
become a primary resource for the dissemination permits characterization of resistance mecha-
of information about Vermont’s health-care nisms and the epidemiology of resistant strains.
community and information for Vermont’s The software consists of three sections. 1)
health-care consumer. It is also being used to Data Entry. In addition to the routine entry of
collect data for research and public health susceptibility test results (disk diffusion, MIC,
reporting and to distribute aggregate informa- and/or E-test), this program permits printing,
tion to improve health-care delivery in one of the retrieval, and correction of clinical records as well
nation’s most rural states. VTMedNet is the as immediate feedback on test results. If data are
culmination of a partnership among all major converted from an existing laboratory system, for
health-care organizations in Vermont, including example with BACLINK, direct entry of data into
the University of Vermont, Fletcher Allen Health WHONET is unnecessary. 2) Data Analysis.
Care, Vermont State Medical Society, and the Currently supported analyses include listings
Vermont Hospital Association. To access the and summaries of isolates by user-defined
network, users must have their own computers criteria; tabulation of the percentages of
and modems. A simple, configured, shareware resistant, intermediate, and susceptible isolates
communications script is provided to those who by species; zone diameter and MIC histograms;
request it. VTMedNet is primarily an intranet scatterplots of zone diameter versus zone
and provides e-mail and Internet access for the diameter or MIC versus MIC; scatterplots of zone
state’s health-care providers and access to health diameter versus MIC scatterplots and the
information from around the world. It is also calculation of zone diameter/MIC regression
designed to serve as a “virtual colleague,” curves; listings and summaries of isolates by
encouraging communication among all of Vermont’s resistance profile; and automated screening of
health-care providers through targeted listservs. the data for unusual isolates. 3) Configuration
Program. This program permits the user to enter
WHONET and modify laboratory-specific information such
WHONET is database software for the as patient-care areas, antibiotics and interpre-
management of routine microbiologic test tive breakpoints, language, and hardware.

Emerging Infectious Diseases 466 Vol. 4, No. 3, July–September 1998

Special Issue

Getting the Handle off the Proverbial

Pump: Communication Works
Lela F. Folkers,* Maria Teresa Cerqueira,† Robert E. Quick,* James
Kanu,* and Gauden Galea‡
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA;
†Pan American Health Organization, Washington, D.C., USA; and
‡University of Malta, Zebbug, Malta

Health Promotion, Communication, and guide policies, plans, and activities for
Education, and Community Participation: health. Health education, communication, and
A Theory-Based Framework community participation have a wide range of
During the last decades of this century, we theoretical frameworks. Among the more impor-
have come to recognize that human and social tant are 1) participatory community development
development are affected by the health status of political theories that explain capacity building,
the population and that medical care alone democratic organization, and management styles;
cannot fully address all the determinants of 2) community-based social support networks that
health. Health promotion strengthens primary facilitate interpersonal communication and
health care and contributes to public health by consensus around healthy lifestyles; 3) learner-
enabling people to become involved in community centered cognitive theories that describe and
action for health while working to maintain explain the process of acquiring and updating
healthy lifestyles and behavior. Health promo- values, knowledge, and skills; and 4) the behavior
tion is part of the communications effort involved change framework, especially persuasion theo-
in the prevention and control of emerging ries that describe and explain the process of
infections. adoption of healthy lifestyles, both individually
Health promotion, as defined by various and collectively. These theories create supportive
international and regional health promotion environments, strengthen community action,
conferences (Ottawa 1986, Adelaide 1988, develop personal health skills, and sustain
Sundsvall 1991, Bogota 1992, Port of Spain 1993, positive behavior change.
and Jakarta 1997), enhances intersectoral action
by increasing the focus on community involve- Diarrhea Prevention through Point-of-Use
ment and action for health, placing healthy Disinfection and Safe Storage of Water:
public policy on the agenda, creating supportive The Need for Innovative Interventions to
environments, and developing personal health Change Behavior
skills. Health promotion is one of five policy In many parts of the developing world,
directives of the Pan American Health Organiza- drinking water is collected from unsafe sources
tion (PAHO) Strategic and Programmatic and is further contaminated during storage in
Orientations for 1995-1998. The PAHO/World household vessels. Simple, inexpensive disinfec-
Health Organization (WHO) Regional Plan of tant generators, better storage vessel designs,
Action for Health Promotion includes the and community education allow families to
following objectives: 1) promote social develop- disinfect drinking water immediately after
ment based on principles of equity and the right collection and to store treated water in narrow-
of citizens to health and well-being; 2) strengthen mouth, lidded vessels designed to prevent
the concept of a health culture based on healthy recontamination. This three-component preven-
environments, behavior, and lifestyles; and 3) tion strategy has been field tested in Bolivia and
develop the health sector’s capacity to recognize, Guatemala with remarkable success. Urban and
support, and lead intersectoral processes for rural families readily accepted the vessels and
promoting health. disinfectant, operated disinfectant generators,
To fully meet the goals of health promotion reliably obtained adequate levels of free chlorine
and disease prevention, programs must inform in stored water, and produced from contaminated

Vol. 4, No. 3, July–September 1998 467 Emerging Infectious Diseases

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sources potable water that met WHO standards disease and prevent transmission. Additional
for microbiologic quality. One study showed that education and training provided information on
the intervention reduced diarrheal disease how to reduce contact between humans and
episodes in children and infants by 44%. rodents. These promising approaches were
Guatemalan street vendors added a soap dish disrupted by civil war.
beside the water vessel to produce safer drinks A January 1996 outbreak lasted until April
and attract more customers. In Bolivia, water 1997. Of 664 reported cases, 427 were confirmed
vessels and disinfectant are now commercially Lassa fever cases; 82 patients died. In response to
produced and marketed. Although the interven- the outbreak, an isolation and referral network
tion costs less than US$1.00 per person per year was established and an emergency training
and water vessels have been well accepted, in workshop on surveillance, case management,
several projects the use of chlorine disinfectant prevention, and control of Lassa fever was
has decreased over time. Health communication organized for 40 health-care workers in two
and initial adoption of water vessels alone has not districts in Eastern Province. Lassa fever
changed the long-term water treatment behavior continues to be a major health problem in
in a large percentage of the population. Eastern Province of Sierra Leone.
Formative research is needed prior to implement-
ing these projects, and innovative behavioral Healthy Islands and Emerging Infectious
techniques are needed to motivate and sustain Diseases
behavioral change. In March 1995 in Yanuca Island, Fiji, the
Western Pacific Regional Office of WHO
Lassa Fever Prevention In Endemic and introduced the Healthy Islands program. This
Epidemic Situations—Sierra Leone program recognizes the peculiar character of
Lassa fever, a viral disease prevalent in West island settings and seeks to reorient health and
Africa, was first described in a village called developmental planning in a manner that
Lassa in northern Nigeria. The disease affects addresses this character. This approach to health
healthy persons of all ages and both sexes and promotion, which takes into account the setting
results in severe acute illness with a 16% death of a particular health problem, has become
rate. The virus is transmitted from rodents to prevalent since the Ottawa Health Promotion
humans and from person to person. The disease is Conference in 1986.
a major cause of illness and death in disease- Island states have contributed to the
endemic areas in Sierra Leone. epidemiologic study of infectious diseases in
In 1976, the Lassa Fever Research Project areas such as the delineation of area-species or
was established as a collaborative effort between population-disease relationships and the history
the Centers for Disease Control and Prevention of infectious disease. This contribution stands to
and the Ministry of Health in Sierra Leone. The repeat itself as many modern island nations exhibit
mandate was to study all aspects of the disease the factors that have been linked to the emergence
including epidemiology, diagnosis, treatment, of infectious disease, including economic vulner-
prevention, and control. In the intervening years ability; unsustainable resource use; substantial
much has been learned about the virus and the internal migration; breakdown of water, sanitation,
disease it causes. Ribavirin, a drug effective and public health services (especially in areas of
against the disease, is not easily accessible, and rapid urbanization); and large inflows of tourists.
no vaccine is available; therefore, prevention of Healthy Islands projects aimed at holistic solutions
endemic Lassa fever is vital. A multidisciplinary to these problems have addressed, for example,
strategy for prevention and control has been malaria control in the Solomon Islands, environ-
developed and includes three components: mental health protection in Fiji, and water supply
clinical therapy, public education, and rodent and sanitation in Tonga. These projects have
control. Physicians at regional hospitals and included health communication with community
village health workers have been trained to development approaches directed at the peculiar
recognize the disease and its symptoms and to problems of the island setting.
isolate and treat Lassa fever patients. Public The Internet helps promote some of the
education and communication activities have principles of the Healthy Islands approach. The
helped the general population recognize the Internet promises to be an excellent tool for

Emerging Infectious Diseases 468 Vol. 4, No. 3, July–September 1998

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overcoming professional isolation, a major skills to effectively use the technology are scarce
shortcoming of the island setting, and providing and the cost of introduction great. Solutions
authoritative and timely access to information. like the Internet, appropriate in larger
Two projects demonstrate this approach: The countries, are relatively costlier and may be
SYNAPSE is a network of health-care profession- less appropriate in smaller contexts.
als in the Mediterranean island of Malta, and The Internet is a good metaphor for
Pacnet is an electronic mailing list run by the Healthy Islands programs that seek to apply
Secretariat of the Pacific Community as a forum technology imported from larger countries and
for public health practitioners with an interest in adopt it within cost-effective, holistic frame-
the Pacific. The Internet also serves to illustrate works for health promotion. These solutions
the “small-scale syndrome.” The logistic prob- are relevant to the small isolated context,
lems that render small economies vulnerable address issues that cut across sectoral and
increase the cost of bandwidth per head of health service boundaries, and tend to be
population in small isolated communities. The potentiated by concerted regional action.

Vol. 4, No. 3, July–September 1998 469 Emerging Infectious Diseases

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Communicating Infectious Disease

Information to the Public
Elias Abrutyn
Allegheny University of the Health Sciences Philadelphia,
Pennsylvania, USA

At one time, information about the science of particularly diseased animals, into animal feed,
medicine was almost the sole purview of can cause problems.
physicians and scientists, and the vehicle of Laurie Garrett, science and medical writer
communication was predominantly the scientific for Newsday magazine, highlighted the ability to
journal. Today, a broad audience is interested in place events within a historical perspective,
the results of scientific investigations, which are discussed reasons for differing viewpoints of the
disseminated widely in a variety of media. This same events (particularly differences between
session sought to provoke discussion about journalists and scientists), and suggested ways in
scientific communication in the broadest sense which journalists and scientists can broaden
and to describe the roles and perspectives of public perspective.
science writers and journalists. Paraphrasing Barbara Rosenberg of the
Robin Cook, a science fiction writer, Harvard School of Public Health, Laurie Garrett
described two experiences during his medical noted public health professionals cannot see their
training that prompted him to become an author: work in a historical light. At the same time,
He realized that medicine involved high drama seeing events in such light may not be possible.
with star quality, and he noted a tremendous gulf Further, each person’s perspective is determined
between what physicians knew and what the by cultural, educational, and other factors;
public knew about medicine. therefore, alternative views of the same event
Physicians and scientists need to recognize should be allowed.
basic differences between the goals of medical Like public health professionals, journalists
professionals and the goals of the media. need to consider the historical perspective as they
Physicians and scientists seek to transmit deal with the task of reporting daily events.
information; the media, on the other hand, seek Journalists and scientists should gauge the
to entertain in addition to transmitting informa- current and future import of an event and
tion. Fiction is a powerful tool because it places examine how it reflects on events of the past. The
information in an emotional context that people Heisenberg principle of uncertainty also applies
remember, and its message has lasting influence. to epidemiology. When you see an event, you alter
Nichols Fox, a free-lance writer, discussed it—in particular, you bring your cultural
her interest in foodborne infectious diseases, perspective to it. Cultural perspective and
particularly Escherichia coli diarrheal disease. scientific training affect interpretation of events
Sometimes, in their research, reporters arrive at and should be taken into account when making
conclusions that are not entirely objective. The observations.
following are some of the conclusions Nichols Fox Journalists and authors of science fiction may
shared with the panel. 1) When you close the door make the scientific community uncomfortable
on one microbe, you open the door for another. 2) with probing questions. Sometimes they simply
Measures that make food more affordable may reflect a different point of view or perspective;
also increase disease risk. 3) Efficiency may not sometimes they make historical connections not
be the most important issue in food production, plainly obvious to everyone. With a broad view in
and in a cost-benefit analysis, the people mind, scientists and journalists can bring a larger
benefitting are not always the ones sharing the perspective to the public.
cost. 4) Treatment of food animals and risk for Patricia Cornwell, a crime novelist, noted
disease are related. 5) Recycling food animals, that two sayings are wellknown in the morgue:

Emerging Infectious Diseases 470 Vol. 4, No. 3, July–September 1998

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the case is only as good as the evidence (a book is disseminate a story to the public by translating
only as good as the existing research), and as technical language into accessible terms.
forensic pathologists say, people often die in the Scientists, like science writers, should cultivate
way that they lived—a saying not true about good sources and pick stewards who will
infectious diseases and bioterrorism in which the communicate the information accurately. The
randomness is striking. world wants to know about emerging threats to
The session’s message was that scientists health, and writers can help.
should view science writers as the scribes who can

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APEC Emerging Infections Network:

Prospects for Comprehensive Information
Sharing on Emerging Infections within
the Asia Pacific Economic Cooperation
Ann Marie Kimball,* Carrie Horwitch,* Patrick O’Carroll,†
Sumarjati Arjoso,‡ Chaiyos Kunanusont,§ Ya-Shin Lin,* Clifford
Meyer,* Laura Schubert,* and Phillip Dunham*
*University of Washington, Seattle, Washington, USA; †The Centers for
Disease Control and Prevention, Atlanta, Georgia, USA; ‡Ministry of Health,
Indonesia; and §Ministry of Public Health, Thailand

Trading blocs realize the strategic impor- ingly useful. The Emerging Infections Network
tance of and threats from emerging infections, (EINet) Web site includes project information,
particularly those related to travel and food. Like surveillance data, policy discussion, prevention
the European Union, the Asia Pacific Economic guidelines, and distance learning resources about
Cooperation (APEC) is undertaking an initiative emerging infections.
in emerging infections. Human networking is as important as
The APEC Emerging Infections Network technology-based networking in addressing
project builds on an existing Internet-based emerging infections. Technology is adequate to
educational network (APEC EduNet), created to support communications if a comprehensive
help link APEC “study centers” at designated telecommunications strategy is used. APEC,
universities. Use of collaborative tools, such as unlike the European Union, does not have the
e-mail and the World Wide Web, helps bridge treaty basis to support this intercountry
the broad geographic expanse and diversity of collaboration, so memoranda of understanding
APEC economies, permitting scientists and are needed to facilitate sustainable surveillance
policy makers to share information and more information flow and scientific cooperation.
effectively combat emerging infectious disease Numerous member economies are eager to be
through surveillance, prevention, research, included in project activities. In the second year
and control measures. the project is expanding both in terms of breadth
In the project’s first year, staff made site of information and geography of economies.
visits to Thailand, Indonesia, the Philippines,
and Canada, and compiled information regarding Additional Information
Internet access in these selected economies. 1. Kimball AM. Pacific Rim economic ties spur emerging
Multidrug-resistant tuberculosis (MDRTB) was infections network. Washington Public Health 1997;22.
2. Lance CR, Joseph CA, Bartlett CLR. European
selected as a disease priority by the partner
surveillance of travel-associated Legionnaires disease.
economies. Accurate, prospective surveillance Slide presentation at the International Conference on
data on MDRTB are not generally available. Emerging Infectious Diseases, Atlanta.
Information sharing by e-mail and automated e- 3. WHO/IUATLD. Global project on anti-tuberculosis
mail lists has been successful, and feedback drug resistance surveillance, 1994-1997. Geneva:
World Health Organization;1997. p. 1-227.
suggests these strategies will become increas-

Emerging Infectious Diseases 472 Vol. 4, No. 3, July–September 1998

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Controversies in the Prevention and

Control of Antimicrobial Drug Resistance
David Bell
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

In Hospitals approach. In Pakistan, laboratory data indicate

William Jarvis, Centers for Disease Control that 78% of pneumococci are resistant to co-
and Prevention (CDC), discussed antimicrobial trimoxazole, yet the clinical treatment failure
resistance related to hospitalization. Two major rate is only 15%. The reasons for this discrepancy
factors contribute to the emergence and spread of are unknown, but the issue is important because
antimicrobial resistance in hospitals: a high rate alternative drugs are more expensive. Standard-
of antimicrobial drug use and inadequate ization of laboratory methods and appropriate
infection control practices. Much antimicrobial surveillance methods are essential.
drug use in hospitals is inappropriate (e.g., the Another controversial area involves anti-
use of vancomycin to treat a staphylococcal biotic use and how to improve it. For many
infection susceptible to methicillin, or the infections, the optimal dose and duration of
continuation of perioperative prophylaxis beyond therapy are unknown. Antibiotics are often
24 to 48 hours). Educational efforts on prescribed inappropriately because physicians
antimicrobial drug use in hospitals have had are uncertain when antibiotics are indicated and
mixed success. More aggressive and controver- patients demand them; educating both of these
sial approaches to improve the use of these drugs groups is a challenge. Better diagnostics to
have been proposed; for example, excluding reduce empiric therapy would be helpful. Other
certain drugs (such as vancomycin) from the areas of uncertainty include the use of vaccines to
routine reporting of susceptibility results; decrease colonization and infection with resis-
monitoring antimicrobial use with feedback to tant organisms and the extent to which
physicians concerning inappropriate use; anti- antibiotics given for a specific indication might
biotic-use audits targeting problem areas (e.g., no lead to resistance in different organisms.
diagnostic test done, more than four drugs used
during one hospitalization, use for more than 3 In Veterinary Medicine
weeks continuously); regulating drug promotion; Klaus Stoehr, World Health Organization
requiring justifications for use; using computer- (WHO), addressed controversies related to use of
generated stop orders; and developing formular- antibiotics (preventive, therapeutic, growth-
ies, restrictions, and protocols by a promoting) in food animals. Some antibiotic use
multidisciplinary team. contributes to the pool of resistant human
pathogens. Both medical and nonmedical uses of
In Communities antibiotics should be reduced. More scientific
Keith Klugman, South African Institute of data are needed to address issues related to
Medical Research, spoke on community-acquired antibiotic use in food animals, including
infections, focusing on respiratory pathogens. elucidating the human health impact, e.g., the
One controversial area concerns the extent to percentage of resistance genes or resistant
which drug resistance identified in the microbiol- organisms originating in animals and the extent
ogy laboratory correlates with clinical failure. to which therapy of zoonotic bacterial infections
Since clinical trial data are frequently unavail- in humans has been compromised because of
able, assessment of drug efficacy is often based on resistance. The economic benefits of
pharmacodynamics; i.e., a drug is believed subtherapeutic antimicrobial use for growth
efficacious if its concentration at the site of promotion are also controversial; one study
infection exceeds the organism’s MIC. Otitis estimates that production costs without such use
media and meningitis studies support this would increase by up to 8%, but recent experience

Vol. 4, No. 3, July–September 1998 473 Emerging Infectious Diseases

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in Sweden indicates that meat produced without In Clinical Laboratories

growth promotants can be priced competitively. Fred Tenover, CDC, addressed antibiotic
A WHO meeting in 1997 on the medical impact of resistance issues in the microbiology laboratory.
antibiotic use in livestock production recom- Laboratorians must move from susceptibility
mended antimicrobial resistance monitoring and testing to finding resistance. A common
prudent use of antibiotics in food animals. misconception is that new resistance mecha-
nisms are easily identified because they result in
In Developing Countries high MICs and low zone sizes. However, many
Antonio C. Pignatari, Escola Paulista da new resistance mechanisms lead to MICs close to
Medicina, São Paulo, Brazil, discussed antibiotic the breakpoint for resistance. More sensitive
resistance issues in developing countries. More screening tests are being introduced to detect
than two thirds of the world’s population lives in resistance, but they cannot replace MICs;
developing countries, where the contrast be- therefore, laboratory workload is increasing in an
tween wealth and poverty is extreme. Infectious era of downsizing.
diseases represent the main public health Several “drug-bug” combinations are prob-
problem. Because of inadequate resources for lematic and require new approaches. For
surveillance, control, and treatment, antimicro- detecting nonsusceptibility (intermediate or full
bial-resistant infections have become a major resistance) of staphylococci to vancomycin, the
problem with serious implications for the health traditional method of disk diffusion testing is not
system and the economy. The main problems reliable. Acceptable methods include the Brain
with drug resistance are seen in the treatment of Heart Infusion vancomycin agar screening test
diarrheal diseases, sexually transmitted dis- developed for enterococci or broth microdilution
eases, pneumococcal infections, tuberculosis, tests held 24 hours. For pneumococci, testing for
nosocomial infections, and malaria. Restrictive susceptibility to both penicillin and extended
antimicrobial use policies (which are controver- spectrum cephalosporins is important because
sial) can be effective in the hospital but are resistance to these drugs is becoming more
difficult to implement in the community. In many common. For invasive isolates where the need to
areas, the availability of medical care is limited; detect resistance is urgent, the oxacillin
thus, laws requiring a physician’s prescription for screening test should not be used; MIC methods
antibiotics are difficult to enforce. Pharmacies should be used directly. For gram-negative
provide an important service in dispensing bacilli, traditional methods to detect resistance to
medications, yet most developing country extended spectrum beta-lactam drugs are
pharmacists have limited training. The use of inadequate, although the latest National Com-
antimicrobial drugs in food animals is also a mittee for Clinical Laboratory Standards guide-
problem in developing countries, and no controls lines present effective screening tests. Finally,
are in place to address it. Control of antimicrobial sensitivity must be determined for clinically
resistance and emerging infections in developing important isolates treated with fluoroquinolones,
countries cannot be achieved without addressing since selective pressure for resistance is
closely related social and economic issues. increasing as a result of widespread use.

Emerging Infectious Diseases 474 Vol. 4, No. 3, July–September 1998

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Infectious Causes of Chronic

Inflammatory Diseases and Cancer
Gail H. Cassell
Lilly Research Laboratories, Indianapolis, Indiana, USA

Powerful diagnostic technology, plus the realization that organisms of otherwise

unimpressive virulence can produce slowly progressive chronic disease with a wide
spectrum of clinical manifestations and disease outcomes, has resulted in the discovery of
new infectious agents and new concepts of infectious diseases. The demonstration that
final outcome of infection is as much determined by the genetic background of the patient
as by the genetic makeup of the infecting agent is indicating that a number of chronic
diseases of unknown etiology are caused by one or more infectious agents. One well-
known example is the discovery that stomach ulcers are due to Helicobacter pylori.
Mycoplasmas may cause chronic lung disease in newborns and chronic asthma in adults,
and Chlamydia pneumoniae, a recently identified common cause of acute respiratory
infection, has been associated with atherosclerosis. A number of infectious agents that
cause or contribute to neoplastic diseases in humans have been documented in the past
6 years. The association and causal role of infectious agents in chronic inflammatory
diseases and cancer have major implications for public health, treatment, and prevention.

The belief that infectious agents are a cause chronic disease with a wide spectrum of clinical
of chronic inflammatory diseases of unknown manifestations and disease outcomes. Increased
etiology and of cancer is not new. Approximately understanding of the body’s defense mechanisms
100 years ago, doctors noted a connection and the demonstration that final outcome of
between cervical cancer and sexual promiscuity infection is as much determined by the genetic
that transcended mere coincidence (1). By 1911, a background of the host as by the genetic makeup
connection between viruses and cancers in of the infecting agent suggest that a number of
animals had become well established (2). As early chronic diseases of unknown etiology may be
as the 1930s, mycoplasmas were proposed as a caused by an infectious agent.
cause of rheumatoid arthritis in humans, and Recent data suggest a role for one or more
shortly thereafter, they were proven to be the infectious agents in the following chronic diseases:
most common cause of naturally occurring chronic lung diseases (including asthma), cardio-
chronic arthritis in animals (3). Proof of causality vascular disease, and cancer. Many of the agents
of cancer and arthritis in humans was more implicated are commonly transmissible and are
difficult. When searches for infectious agents in either treatable with existing antibiotics or are
cancer and arthritis found none, research began potentially treatable with antiviral drugs. Thus,
to focus on mechanisms of inflammation, proof of causality in any one of these diseases
tumorogenesis, and drug discovery. More re- would have enormous implications for public
cently, however, scientists have renewed searches health, treatment, and prevention. Few areas of
for infectious agents. research hold greater promise of contributing to
Advances in molecular biology and medical our understanding of infectious diseases and the
devices have revolutionized our ability to detect eventual relief of human suffering.
very low numbers of infectious agents in The intent of this paper is not to provide a
specimens collected directly from the affected comprehensive review of chronic inflammatory
site. HIV has demonstrated the ability of diseases of unknown etiology and the agents
infectious agents to produce slowly progressive, implicated but rather to utilize several models to
discuss available data and to illustrate the
Address for correspondence: Gail H. Cassell, Lilly Research difficulty in proving causality in chronic
Laboratories, Lilly Corporate Center, Indianapolis, IN 46285,
USA; fax: 317-276-1743; e-mail:
inflammatory diseases. The discussion is based

Vol. 4, No. 3, July–September 1998 475 Emerging Infectious Diseases

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upon the following assumptions. Most chronic early 1970s was M. pulmonis alone shown to
inflammatory diseases are likely multifactorial. consistently reproduce all of the characteristic
Heredity, environment, and nutrition are critical clinical and pathologic features of the natural
determinants of disease expression with heredity respiratory disease when inoculated into animals
being the most important. maintained under germ-free conditions (7).
Theoretically, chronic inflammatory diseases Subsequent studies provided explanations for
currently of unknown etiology could result from previous difficulties in reproducing the disease.
three different types of pathogens: 1) those that The respiratory disease caused by M.
are fastidious and previously recognized but pulmonis is slow to begin and long-lasting.
because of their fastidiousness or lack of Consequently, the disease has various stages of
appreciation of their disease-producing potential pathologic lesions and a lack of uniform lesions,
are not included in the differential diagnosis, and even among animals in the same cages (due
2) infectious agents previously not recognized partly to variables that can affect development of
that therefore go undetected. Infection with the disease in the lower respiratory tract, such as
either group can result in misdiagnosis and lack intracage ammonia produced by bacterial action
of treatment. Depending upon the biology of the on soiled bedding, synergy with murine respira-
organism and intrinsic and extrinsic factors of tory viruses and other bacterial pathogens, and
the host the organism can persist, resulting in nutritional factors) (7). However, comparison of
chronic inflammation. The third group of animals matched for age, sex, and microbial and
pathogens would be those that elicit an environmental factors indicates that heredity is
autoimmune response resulting in persistent the most critical determinant of susceptibility,
inflammation without the persistence of the lesion character, and disease severity. Suscepti-
inciting agent. Examples of the first two groups of bility among animal species and among strains of
pathogens will be discussed here using mycoplas- the same species differ dramatically (8-11).
mas to typify the first group and Chlamydia Intranasal inoculation of M. pulmonis
pneumoniae the second. Finally, recent advances produces markedly different lesions in F344 rats
in our understanding of the role of infectious and in CD-1 mice, even when the dose is
agents in cancer will also be summarized. comparable on the basis of lung and body weight.
In rats the lesions progress slowly from the upper
Chronic Lung Diseases respiratory tract distally, with alveolar involve-
ment occurring days to months following
Murine Chronic Respiratory Disease as a inoculation, whereas in mice, alveolar lesions
Model System develop within hours after infection and are
The difficulty in establishing the infectious responsible for acute alveolar disease and death
etiology of a chronic obstructive lung disease is within 3 to 5 days. Depending on their genetic
well illustrated by Mycoplasma pulmonis and background, mice that survive the acute disease
murine chronic respiratory disease. Proof that M. develop chronic lung disease characterized by
pulmonis can cause this disease took nearly 50 bronchiectasis that persists for up to 18 to 24
years and required inoculation of germ-free months or the lifetime of the animal.
animals (4). Chronic bronchopneumonia in rats Studies of naturally occurring and experi-
was first described in 1915 when this species mentally induced disease indicate that M.
came into general use for experimental purposes pulmonis also causes a slowly progressing upper
(5). In approximately 1940, a Mycoplasma, later genital tract disease in LEW and F344 rats (18).
identified as M. pulmonis, was recognized as a Pups can become infected in utero, at the time of
possible cause (6), but the ubiquity of the birth due to cervical and vaginal infection of the
organism and its frequent isolation from healthy dams, or via aerosol from dams shortly after
as well as diseased rats and mice (even from birth. Even though the organisms can be shown
trachea and lungs) soon gave it the reputation of to colonize the ciliated epithelium of the upper
being a commensal with little pathogenic and lower respiratory tracts of pups, microscopic
potential. The failure of pure cultures of this lesions are not detectable for 2 to 6 months
organism to consistently produce disease of the depending on the strain of rat. Development of
lower respiratory tract also precluded its obstructive lung disease can require as long as 12
acceptance as the etiologic agent. Only in the to 18 months.

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Differences in severity and progression of the viruses, fungi, and bacteria and in the presence of
lung lesions due to M. pulmonis in LEW and F344 chorioamnionitis and funisitis (40) and has been
rats are related to differences in the degree of demonstrated within fetal membranes by
nonspecific lymphocyte activation in the two immunofluorescence (24) and in lung lesions of
strains or an imbalance in regulation of newborns by electron and immunofluorescent
lymphocyte proliferation in LEW rats (12). M. microscopy (20). The specific immunoglobulin (Ig)
pulmonis possesses a potent B cell mitogen, and, M response in several cases of pneumonia in
in addition, the organism is chemotactic for B newborns further documents in utero infection (20).
cells (13). Interestingly, LEW rats are also more We have found that U. urealyticum is the
susceptible to other chronic inflammatory single most common microorganism isolated
diseases, including streptococcal cell-wall in- from endotracheal aspirates of infants who weigh
duced arthritis, adjuvant-induced arthritis, and ≤2,500 g and who require supplemental oxygen
allergic encephalomyelitis (12). within the first 24 hours after birth (19). Infants
weighing ≤1,000 g and from whom U. urealyticum
Ureaplasma urealyticum as a Cause of is isolated from the endotracheal aspirate are
Pneumonia in Newborns and Its Association twice as likely to die as infants of similar birth
with Chronic Lung Disease (CLD) in Premature weight but who are uninfected or infected infants
Infants ≥1,000 g. These findings support the hypothesis
Respiratory dysfunction represents the most that only a select group of infants, i.e., those with
common life-threatening problem in premature very low birth weights, is subject to disease due to
infants and one of the largest costs of neonatal U. urealyticum. This fact may account for the
intensive care (14). Infants weighing less than seeming disparities in conclusions regarding the
1,000 g at birth are more likely than those with role of U. urealyticum in neonatal respiratory
greater birth weights to die within the first few disease reached in earlier prospective studies
days of birth of respiratory-related problems; that failed to distinguish this subpopulation at
those who survive are at an increased risk of CLD high risk from the whole (25,26).
(15). Approximately 20% of stillborn babies and That endotracheal isolations of U. urealyticum
infants dying within 72 hours of delivery have represent true infection of the lower respiratory
histologic evidence of pneumonia (16). Yet the tract is supported by initial isolation of
true incidence of lower respiratory infection ureaplasmas in numbers exceeding 1,000 CFUs
acquired either in utero or at the time of delivery (and sometimes exceeding 10,000 CFUs) and
and its contribution to death or development of repeated isolations of the organism from tracheal
CLD are unknown. The cause of lower aspirates for weeks and even months in some
respiratory disease in newborn babies is a infants that continue to require mechanical
diagnostic dilemma because pneumonia in early ventilation. That the tracheal isolates are not
neonatal life is usually clinically and radiologi- merely a reflection of contamination from the
cally indistinguishable from surfactant-defi- nasopharynx is supported by the discrepancy in
ciency syndrome (17). Furthermore, meaningful isolation rates between the two sites and recovery
cultures from the lung are not easily obtained, of U. urealyticum in pure culture from
whereas cultures of the throat, nasopharynx, and endotracheal aspirates in more than 85% of the
blood are unrevealing or misleading. infants (19). Concomitant recovery of the
organism from blood of up to 26% of those with
Pneumonia positive endotracheal aspirates and from cere-
The mycoplasma U. urealyticum, a common brospinal fluid (CSF) of some infants indicate
commensal of the lower female genital tract, has that in some infants the organism is invasive (19).
recently been shown to cause respiratory disease Fourteen percent of U. urealyticum endotracheal
in newborn infants. Retrospective (18) and isolates were from infants born by cesarean
prospective (19-21) studies indicate an associa- section with intact membranes, indicating that in
tion of U. urealyticum with congenital pneumo- utero transmission occurs rather commonly, at
nia. Case reports also provide evidence that U. least in premature infants.
urealyticum is a cause of pneumonia in newborn In a study of 98 infants, respiratory distress
infants (22-23). The organism has been isolated syndrome, the need for assisted ventilation,
from affected lungs in the absence of chlamydiae, severe respiratory insufficiency, and death were

Vol. 4, No. 3, July–September 1998 477 Emerging Infectious Diseases

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significantly more common among those infants from mycoplasmal respiratory diseases of
<34 weeks gestation from whom U. urealyticum animals indicates that preexisting antibody is
was recovered from endotracheal aspirates at the protective, whereas antibody in the presence of
time of delivery than among uninfected infants an established infection is rarely effective in
(27). U. urealyticum was isolated from 34% of elimination of the organism (32).
blood cultures and also from four of six CSF
samples and in 6 of 11 postmortem brain and lung CLD in Premature Infants
biopsy pecimens. Eighty-two percent of the Some, but not all, studies (33-36) show an
ureaplasma isolates were present in pure culture, association between isolation of U. urealyticum
and 48% of infants born by cesarean section with from the respiratory tract of newborn infants and
intact membranes had ureaplasmas isolated the development of CLD (33). Differing results
from one or more sites. may be obtained because some studies do not
U. urealyticum can induce ciliostasis and limit culture isolation to the affected site (the
mucosal lesions in human fetal tracheal organ lower respiratory tract), do not limit their patient
cultures (20). Furthermore, we have shown that population to those at greatest risk (birth weight
ureaplasmas isolated from the lungs of human <1,000 g); or do not limit culture isolation to
infants with congenital and neonatal pneumonia within 12 hours of delivery, i.e., most likely
produce a histologically similar pneumonia in infected in utero. Several facts suggest that
newborn mice (28). Even in this mouse model, age infants who acquire U. urealyticum in utero may
is a critical determinant of disease. Newborn be at greatest risk for development of CLD. Dyke
mice are susceptible to colonization of the et al. (34) found U. urealyticum in the gastric
respiratory tract and development of pneumonia; aspirates of infants ≤1,000 g was associated with
14-day-old mice are resistant. a significantly increased risk of CLD in those
We have shown that endotracheal inocula- infants delivered by cesarean section but not in
tion of premature baboons (well-established those delivered vaginally. This could result from
models of premature human infants) with U. a longer exposure to U.urealyticum as a result of
urealyticum isolated from human infants results in utero exposure, or it may be a reflection of
in the development of pathologically recognizable differences in the virulence of those organisms
pulmonary lesions, including acute bronchiolitis found only in the cervix versus those that have
with epithelial ulceration and polymorpho- invasive potential and that can cause an
nuclear infiltration, which is distinguishable ascending infection from the vagina into the
from hyaline membrane disease (29). U. urealyticum uterus. Along these lines it is of interest that a
can be isolated from blood, endotracheal aspirates, recent study of 49 preterm infants which included
and pleural fluid and lung tissue from some of only three infants from whom U. urealyticum was
these animals 6 days after infection. recovered within 24 hours of birth found no
The available evidence provides a strong association with development of CLD (35). The
argument that U. urealyticum is a common cause remaining 11 infants were not culturally positive
of pneumonia in newborn infants, particularly until 48 to 72 hours after birth suggesting that
those born before 34 weeks of gestation. The only the three study infants were infected in
organism can be isolated from endotracheal utero. In another recent study reported by
aspirates in up to 34% of infants weighing <2,500 g; Valencia et al. (36) CLD was found in 26% of U.
radiographic evidence of pneumonia is twice as urealyticum infected infants compared to only
common in these infants as in U. urealyticum 4.7% of the noncolonized group. However, these
negative infants (30% vs. 16%, p = .03) (30). Many results were not statistically significant possibly
of these infections develop as a result of in utero because of the small number of patients studied
exposure. Cases of ureaplasmal pneumonia occur but also possibly because 22% of the patients
much less frequently in term infants. These included did not have cultures performed until
findings in infants are consistent with the fact between 2 days and 3 months postnatal life.
that U. urealyticum infection of the chorioamnion Isolation of U. urealyticum from endotra-
is also much more common before 34 weeks of cheal aspirates is not only a risk factor for
gestation. Lack of transplacental passage of development of pneumonia but also of precocious
immunoglobulin prior to 32 weeks gestation (31) dysplastic changes (30). Walsh et al. (38) isolated
may partially explain these findings. Experience U. urealyticum directly from pleural fluid and

Emerging Infectious Diseases 478 Vol. 4, No. 3, July–September 1998

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tissue collected by open lung biopsy in four of oxygen requirements of very low birth-weight
eight infants cultured who had CLD. We (19) infants might predispose them to lower respira-
continued to recover ureaplasmas from endotra- tory tract infection or, alternatively, that U.
cheal aspirates of infants with CLD for months urealyticum infection potentiates oxygen-induced
following initial recovery of the organism from injury (28,37). Exposure to oxidants is known to
endotracheal aspirates within 12 hours of birth. enhance respiratory disease and death due to M.
Available evidence creates a cohesive argu- pulmonis respiratory disease in mice (41).
ment that U. urealyticum infection of the lower That U. urealyticum is a cause of pneumonia
respiratory tract is a likely risk factor for, and not in newborns can no longer be questioned. Data
only associated with, CLD. Because U. urealyticum provide strong evidence that U. urealyticum can
has only recently been suggested as a cause of be a primary cause or a contributing cofactor in
pneumonia in newborns, it is not routinely sought development of CLD in humans, but the data are
by most hospital laboratories. Furthermore, the not definitive. Cohort studies allow follow-up of
organism is not susceptible to antibiotics used exposed persons and thus reduce bias, but the
prophylactically in very low birth-weight infants designs of these studies cannot rule out the
with evidence of respiratory distress. Conse- possibility that a third factor associated with
quently, the infection, i.e., pneumonia, goes U. urealyticum is actually the true cause of
undetected and untreated. Due to the difficulties CLD. However, a randomized trial of exposure to
in diagnosis, most hospital laboratories do not infection in humans is not ethical or practical.
culture for this organism. Although a randomized trial of antibiotic
The pathophysiology of CLD in premature treatment could provide critical information
infants suggests that U. urealyticum produces related to patient management, it would still not
undetected and untreated pneumonia and bring us closer to proving causality. Even if
results in an increased requirement for oxygen treatment is found to be efficacious, conclusions
and subsequent development of CLD as a result about causation will be limited by the fact that
of oxygen toxicity (33,37) or a synergistic effect the third factor might also be susceptible to the
between the ureaplasmas and hyperoxia. It has antibiotic chosen. If it is not found to be efficacious,
been proposed that hyperoxia-induced lung it may be because ureaplasma infection in utero or
injury contributes to development of CLD by soon after birth results in irreversible lung damage.
stimulating the proinflammatory cytokine Nevertheless, a treatment trial is urgently needed
interleukin (IL)-6 (38). U. urealyticum may also to determine whether appropriate therapy can
contribute to the development of CLD by reduce the incidence of illness and death
stimulation of proinflammatory cytokines. In- associated with CLD. First, studies are needed to
fants from whom ureaplasmas are isolated from determine dose and duration of antibiotic
endotracheal aspirates within the first 24 hours therapy and whether currently available antibi-
of life are more likely to have neutrophils in their otics will even eliminate the organism.
tracheal aspirates on day 2 than are those not
colonized (39). Aspirates from colonized infants Mycoplasma pneumoniae and C. pneumoniae
are also more likely to have class II cytology than as Causes of Chronic Asthma
those from uncolonized patients at day 2 of life. Asthma, a CLD characterized by airway
This may explain why ureaplasma-infected obstruction, inflammation, and bronchial
infants respond to dexamethasone therapy (39). hyperresponsiveness to a variety of stimuli,
These in vivo findings are consistent with the including infections, is a common illness in both
recent demonstration of U. urealyticum induc- pediatric and adult populations. In the United
tion of IL-6 and IL-8 in human neonatal States alone, approximately 12 million people
pulmonary fibroblasts even in the absence of have asthma, resulting in health-care costs of
hyperoxia (38). Interestingly, together approximately 4.6 billion dollars annually (42).
ureaplasmas and hyperoxia resulted in greater In children, asthma is the most common reason
stimulation of IL-6 and IL-8 than either alone. for hospital admissions and school absenteeism
This is consistent with the synergism previously (43). Yet the etiology and pathogenesis of this
demonstrated in vivo between ureaplasmal important disease remains poorly defined.
infection and hyperoxia (37). Historically, viruses that commonly infect the
Studies in mice also suggest that increased respiratory tract have been thought to play a role

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in both provoking asthma exacerbations and in M. pneumoniae was detected by PCR in 10 of

altering responses to other environmental agents 18 asthma patients and 1 of 11 controls (p = 0.02).
that might be involved (44). All patients were culture, EIA, and serologically
M. pneumoniae is a common cause of both negative for M. pneumoniae. All PCR and
upper and lower respiratory infection in humans; cultures were negative for C. pneumoniae and all
tracheobronchitis is the most common clinical EIAs for respiratory viruses were negative. Nine
manifestation (45). Previously thought to cause persons with asthma and one control exhibited
acute, self-limited disease primarily in persons positive serology for C. pneumoniae (p = 0.05). For
between 6 and 21 years of age (45), M. C. pneumoniae, the lack of correlation between
pneumoniae is now known to be the cause of serologic results and culture and PCR was not
pneumonia in 20% to 25% of all age groups and to unexpected. We have seen discordance between
persist in certain persons for weeks to months, culture and serologic results in patients with
resulting in prolonged reduced pulmonary community-acquired pneumonia (58,59), but in
clearance and airway hyperresponsiveness these cases more patients were culture positive
(46,47). Epidemiologic evidence links myco- than seropositive. Thus, the culture methods
plasma infection with asthma exacerbation and we used in the study have previously been
possibly with the pathogenesis of asthma (47-50). shown to be valid.
While M. pneumoniae has been associated with Our failure to culture M. pneumoniae might
exacerbations of asthma, its role in sustaining be explained by its extreme fastidiousness or its
chronic asthma or in initiating exacerbation is low numbers. Culture is the least sensitive of the
unknown. However, the proven role of mycoplas- methods used in this study for detection of M.
mas in similar chronic respiratory diseases of pneumoniae. However, the culture methods we
numerous animal species, including M. pulmonis in used in this study we also used to evaluate more
rodents, suggests that careful, systematic studies than 2,000 respiratory specimens during the
should be undertaken in humans (45). same period in patients with radiographically
C. pneumoniae, the most recently described confirmed, community-acquired pneumonia.
Chlamydia species, has been associated with a These methods have resulted in recovery of M.
wide range of respiratory tract illnesses, from pneumoniae by culture in up to 17% of patients
pharyngitis to pneumonia with empyema (51). C. (G. Cassell, et al., unpub. obs.; 58,59).
pneumoniae has been isolated from 15% to 20% of Recent studies indicate that some other
adults and children with community-acquired mycoplasma species of human origin may be able
pneumonia (51). On the basis of serologic results to survive intracellularly in chronic infections of
only, C. pneumoniae has been associated with cell cultures (60). Likewise, some strains of M.
acute exacerbations of asthma in adults (52); on hyorhinis, the etiologic agent of chronic respira-
the basis of nasopharyngeal cultures, it has been tory disease of swine, can become so adapted to
associated with asthma in children (53). In both growth in the presence of cells that it is no longer
children and adults, the organism persists for cultivable on artificial media (61). If this occurs in
months in the upper respiratory tract of patients vivo, organisms like M. pneumoniae could be
with wheezing (54). difficult if not impossible to recover by culture.
If M. pneumoniae, or for that matter any In the absence of other known respiratory
infectious agent, is a causal factor in initiating and pathogens in other patient populations, the
sustaining asthma in certain persons, the agent presence of M. pneumoniae can be detected
should be present and persistent in the lungs of longer by PCR than by either culture or serologic
some persons with stable, chronic asthma. We have test. Guinea pigs experimentally infected with M.
recently undertaken a study to determine if M. pneumoniae become chronically infected as
pneumoniae can be detected in the lungs of adults detected by PCR for up to 200 days but are culture
with stable, chronic asthma versus asymptomatic negative by 70 days. Also by 70 days, antibody
controls (55). To facilitate interpretation of results, levels become negative (62). Thus, patients with
we also evaluated the presence of other fastidious asthma appear chronically infected with M.
infectious agents that have previously been pneumoniae, despite negative culture results,
implicated in the pathogenesis of asthma, including because they are PCR positive. That positive PCR
the seven common respiratory viruses (44) and C. results truly reflect involvement of the lower
pneumoniae (56,57). respiratory tract by M. pneumoniae is supported

Emerging Infectious Diseases 480 Vol. 4, No. 3, July–September 1998

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by the fact that 9 of the 10 M. pneumoniae- persons with asthma than control subjects had
positive patients were positive in the serologic evidence of C. pneumonia infection.
bronchoalveolar lavage (BAL), bronchial biop- Further study is needed to determine if these
sies, or bronchial brush specimens. Furthermore, findings are an epiphenomenon or, as we expect,
the organism was detected in the nasopharynx or a pathogenic mechanism in asthma. If the latter
the throat of only five of the nine asthma-positive is correct, greater evaluation of the process
patients, thus indicating that detection in the involved is needed to further our understanding
lower tract was not merely due to contamination of the pathogenesis and treatment of asthma.
by organisms from the upper tract during sample
collection. More importantly, a significant Role of C. pneumoniae in Atherosclerosis
number of persons with asthma were positive in Infection was proposed as a cause of
the lower respiratory tract on repeat sampling (2 atherosclerosis by Sir William Osler and others at
to 4 months between samples), thus indicating the beginning of the century (65). However, it was
persistent colonization. By cloning and sequenc- not until the 1970s that experimental infection of
ing the PCR product in BAL from several germ-free chickens with an avian herpesvirus
representative patients, we demonstrated 100% was found to produce arterial disease that
sequence homology with M. pneumoniae. Use of resembled human atherosclerosis (66). Associa-
multiple primer pairs as well as confirmation of tions have since been reported of human coronary
PCR findings in two different laboratories also heart disease with certain gram-negative bacte-
attests to the validity of the PCR results. Our ria (i.e., Helicobacter pylori and C. pneumoniae)
failure to detect M. pneumoniae in specimens (67,68), with certain herpesviruses (especially
from age-matched control patients as well as in cytomegalovirus) (69), and with clinical markers
specimens from 100 asymptomatic children using of chronic dental infection (70). Rather than an
the same PCR methods further verifies the exhaustive evaluation of each of these purported
specificity of our PCR methods and argues that associations, it seems reasonable to focus on the
finding M. pneumoniae in persons with chronic respiratory pathogen, C. pneumoniae, for which
asthma does not merely reflect a carrier state. the evidence seems strongest.
We have previously noted the lack of antibody C. pneumoniae, like M. pneumoniae, is a
response to M. pneumoniae in both pediatric and common cause of community-acquired pneumo-
adult populations with community-acquired nia (70,71). C. pneumoniae infects more than 50%
pneumonia (G. Cassell et al, unpub. obs.; of people at some point in their lives (51,71). It
58,59,63). Study results indicate that a subset of can often go undiagnosed and improperly treated
infected persons do not mount an antibody because again it is fastidious and diagnostic
response, perhaps due to genetic differences. methods are not routinely available. Even in the
Lack of antibody may in fact contribute to the best reference laboratories, diagnosis can be a
organism’s persistence. The immunomodulatory challenge (71). It, like M. pneumoniae, is also
properties of M. pneumoniae (12) also could thought to play a role in acute asthma and chronic
facilitate the organism’s persistence. bronchitis (52) as well as to cause extrapulmonary
Recent studies indicate that M. pneumoniae manifestations (51,71). It, like M. pneumoniae, can
respiratory disease is often misdiagnosed and also result in persistent infection following acute
inappropriately treated, which would also respiratory disease (54).
contribute to persistence. Admitting physicians Eighteen seroepidemiologic studies evalu-
chose other pathogens as the most likely agents ated the association of C. pneumoniae infection
in 46% of the cases subsequently documented as and cardiovascular disease (67). Most found at
M. pneumoniae infections (64). Even upon correct least twofold or larger odds ratios; some reported
diagnosis, at least 10% of the patients did not increasing odds ratios with increasing antibody
receive appropriate antibiotics during their titers. The general consistency of their findings in
hospitalization. a total of 2,700 cases supports the existence of
In summary, we have demonstrated that some real association between C. pneumoniae
persons with chronic asthma, but not healthy and coronary heart disease because the studies
persons, exhibit evidence of M. pneumoniae were done in different populations, used different
colonization of the lower airways. Like several criteria for cases, adjusted for potential confound-
other investigators (56,57), we found more ers to differing degrees, and were, therefore, prone

Vol. 4, No. 3, July–September 1998 481 Emerging Infectious Diseases

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to different biases. While diagnosis by serology has bacteriocidal, some patients may remain infected
its limitations, C. pneumoniae has been demon- up to 11 months after treatment. Even if these
strated by a variety of laboratory techniques issues could be resolved, antibiotic treatment
(including culture, PCR, electron microscopy, trials will not prove causality, just as is the case
and immunocytochemistry) in the atherosclerotic with U. urealyticum and CLD of prematurity or
lesions of coronary arteries, carotid arteries, M. pneumoniae and chronic asthma. The
aorta, smaller cerebral vessels, and larger nonantimicrobial effects may also influence the
peripheral arteries (72-78). In the more than 13 outcome of such studies. For example, tetracyclines
published studies of C. pneumoniae in human can inhibit metalloproteinases, which may contrib-
pathology samples (67), chlamydiae were present ute to acute coronary syndromes (89). Some
in 257 (52%) of 495 atheromatous lesions but in macrolides have antiinflammatory effects (90-93).
only 6 (5%) of 118 control samples of arterial Moreover, antibiotics are not selective, thus making
tissue, yielding a weighted odds ratio of about 10 it impossible to determine the effects of treatment
(95% confidence interval 5-22). It seems unlikely upon C. pneumoniae versus other potential
that sampling biases can entirely account for this culprits, e.g., H. pylori, which is also susceptible to
extreme difference between case and control tissue. tetracyclines and macrolides. However, if antibiotic
C. pneumoniae, an obligatory intracellular treatment could reduce atherosclerotic events, the
bacterium capable of causing persistent infection public health implications could be enormous.
and multiplying in endothelial and smooth muscle
cells and macrophages (79), can also be dissemi- Causal Role of Viruses and Bacteria in
nated by macrophages (80). Hence, some have Cancer
argued that macrophages may ingest C. pneumoniae Early in this century, Peyton Rous (2)
in the lung or elsewhere before migrating to established beyond doubt that cancer can be
atheromatous lesions, in which case it may only caused by an infectious agent in chickens. Since
be a bystander. However, in two different rabbit then, evidence has accumulated that other
models, atherosclerotic changes develop only viruses cause cancer in a number of different
after infection with C. pneumoniae (81,82). The animal species (94). A growing body of research
organism by itself induces the production of suggests that a number of viruses, bacteria, and
cytokines (83) and adhesion molecules (84), and it parasites cause cancer in humans, thus providing
possesses an endotoxin (85) capable of modulat- new possibilities for treatment and prevention of
ing the host inflammatory response. Thus, the cancer (94). In 1997, the World Health Organiza-
biologic properties of C. pneumoniae make it a tion estimated that up to 84% of cases of some
logical candidate for triggering the chronic cancers are attributable to viruses, bacteria, and
inflammation found in atherosclerosis (82). parasites and that more than 1.5 million (15%) new
Finally, some studies have found rising or cases each year could be avoided by preventing the
elevated levels of antibodies to C. pneumoniae in infectious disease associated with them (95).
some males during the months just preceding a H. pylori, found in the stomachs of a third of
heart attack (86). Recent studies indicate that all adults in the United States, causes inflamma-
antibiotics given during or after a first heart attack tion of the mucous membrane of the stomach (96).
may decrease the risk of a second cardiac problem In 20% of infected persons, H. pylori induces
(86-88). This finding also raises the possibility that gastric ulcers (96). Peptic ulcer disease, a chronic
antibiotics may have a role in the treatment of inflammatory condition of the stomach and
cardiovascular illnesses; that could be especially duodenum, affects as many as 10% of people in
beneficial in developing countries where traditional the United States at some time in their lives. In
treatments like angioplasty are expensive. the early 20th century, pathogenesis was
Some have proposed additional large-scale believed related to stress and dietary factors.
antibiotic treatment trials in an attempt to Thus treatment focused on bed rest and bland
further prove causality. Several major issues food. Later, gastric ulcers were believed to be
need to be resolved first. Ideally, one should treat caused by the injurious effects of digestive
patients with documented C. pneumoniae secretions. Following the identification of the
infection; however, reliable diagnostic methods histamine receptor that appeared to be the
and treatment protocols are lacking (71). Because principal mediator of gastric acid secretion,
most available antibiotics are bacteriostatic, not antagonists of this receptor were used for therapy

Emerging Infectious Diseases 482 Vol. 4, No. 3, July–September 1998

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for peptic ulcer disease. In 1982, H. pylori was regression (96). This finding not only suggests a
first isolated from the human stomach, but it was causal role but that treatment of a bacterial
not until one decade later and after Marshall infection can actually result in regression of cancer.
ingested pure cultures of the organism that Another landmark study, published in June,
causality was accepted by the medical and 1997, shows that a 12-year nationwide vaccina-
scientific community (97). tion program against hepatitis B virus in Taiwan
In 1994, the International Agency for resulted in a significant reduction in the number
Research on Cancer concluded that infection of of cases of childhood liver cancer (102). The role of
humans with H. pylori is causally associated with chronic infection with hepatitis B virus in the
the risk of developing adenocarcinoma of the etiology of hepatocellular carcinoma is well
stomach (98), one of the most common established (103,104). Yet this is the first
malignancies in the world, although relatively evidence that prevention of a viral infection is
uncommon in the United States (24,000 new cases also effective against cancer. The implications
and 14,000 deaths per year). However, also in 1994, are profound. Hepatitis B infection causes some
a Consensus Panel of the National Institutes of 316,000 cases of liver cancer (60% of all liver
Health (NIH) concluded that available evidence cancer) a year worldwide (103,104). While
was insufficient to recommend eradication of H. hepatitis C causes a further 118,000 cases (22% of
pylori for the purpose of preventing gastric cancer all cases) a year (103,104), some cases result from
(99). The NIH conclusion was based upon the infections with both viruses (104).
existence of clear examples of disparity in the The infectious origin of carcinoma of the
epidemiology of the two diseases. Gastric cancer is cervix has long been suspected, because known
more common in males than in females, whereas risk factors for the disease are linked to sexual
the rates of H. pylori infection are not different for activity (105). Recent evidence indicates that
the two genders. Some populations are human papillomavirus (HPV) types 16 and 18 are
reported to have a high rate of H. pylori definitely carcinogenic in humans (94,105).
infection but low rates of gastric cancer. Types 31 and 33 are classified as probably
Gastric cancer occurs in some persons with carcinogenic (94,105). In the United States,
no evidence of H. pylori infection, and in the HPVs, are associated with 82% of the 15,000
United States, fewer than 1% of H. pylori– cases and 4,600 deaths due to cervical cancer
infected persons will ever develop gastric each year. They are also associated with more
cancer. The strongest evidence that H. pylori than a million precancerous lesions of varying
is associated with gastric cancer comes from severity. The combined direct medical costs due
three prospective studies that indicate that H. to HPV are approximately 1.3 billion dollars per
pylori–infected persons have a significantly year in the United States alone. Thus, effective
increased rate of gastric cancer (96,98). therapy and vaccines would have a major impact.
Only some retrospective serologic studies The pathogenic mechanisms by which
have shown an association. These disparities infectious agents cause cancer have not been
indicate that factors other than H. pylori resolved but they appear to be diverse. In cervical
infection are also important in gastric cancer cancer, there seems to be a clear role for HPV-
risk. It is possible that only some strains of H. encoded genes in tumor cell growth (106). In
pylori are involved in the carcinogenic process. addition to stimulation of cell proliferation,
For example, infection with H. pylori strains inactivation of tumor suppressor genes, such as
possessing the cagA virulence factor is associated p53 may be a common pathway leading to
with an increased risk of developing adenocarci- malignancy in HPV and hepatitis B virus (106,107).
noma of the stomach (100,101). In the case of other viruses and H. pylori, active
H. pylori is also associated with two less oxygen and nitrogenic species generated by
common forms of cancer, non-Hodgkin lym- inflammatory cells may cause DNA damage,
phoma and mucosa-associated lymphoid tissue induce apoptosis, and modulate enzyme activities
lymphomas of the stomach (96). These types of and gene expression (94,108).
lymphomas in the stomach only arise in the
setting of H. pylori inflammation. In 70% of Future Research Opportunities
H. pylori–infected patients with lymphoma, The basic biology of agents implicated in
treatment with appropriate antibiotics leads to chronic diseases and cancer, in contrast to many

Vol. 4, No. 3, July–September 1998 483 Emerging Infectious Diseases

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other infectious agents, is relatively unknown. therapies for chronic diseases, most of which are
With rare exception, the means by which likely to be complex, multifactorial illnesses in
pathogens suppress, subvert, or evade host which behavioral and lifestyle factors play an
defenses and establish chronic or latent infection important role. Some of the difficulties associated
have received little attention. Few areas of basic with this approach have already been discussed.
research compared with microbial latency hold Well-defined, relevant animal models will be
greater promise of substantially contributing to extremely important in elucidating the role of
our understanding of infectious diseases and the infectious agents in chronic inflammatory diseases.
eventual relief of human suffering (109). Given The animal studied should be the most genetically
that the diseases discussed are among the most susceptible to the infecting agent and chronic
common in the world, even if only some cases are infection. All too often inappropriate conclusions
proven to be of infectious origin and effective are based on use of a single strain of a single species.
therapies or vaccines can be developed, the The value of using a naturally occurring disease
impact on reducing health-care costs would be with features that closely parallel those of the
substantial. Thus, further research to clarify the human disease cannot be overestimated.
etiologic agents and pathogenic mechanisms As we attempt to prove the role of infection in
involved in chronic diseases and cancer should be chronic inflammatory diseases and cancer, the
given the highest priority. biggest challenge will be convincing peer review
To address the potential role of infectious groups who establish research priorities and who
agents in chronic diseases requires a new research facilitate funding decisions that these are not
paradigm compared to that which most investiga- “fishing expeditions.” Likewise, the challenge will
tors and funding agencies in infectious diseases are be to convince journal editors that the findings are
accustomed. Such an approach will require high not merely coincidental. To make rapid progress we
levels of sustained funding of networks of research must keep an open mind and accept the likely
groups (ideally at least for 10 years). The approach possibility that fulfillment of Koch’s postulates for
will require collaborative research groups that infectious agents involved in chronic inflammatory
follow a large number of well-defined patients over diseases and cancer may not be possible.
long periods. Success will depend on involvement
Dr. Cassell is a recent past president of the Ameri-
of researchers highly skilled in clinical and
can Society for Microbiology, a member of the National
epidemiologic investigation supported by labora- Institutes of Health Director’s Advisory Committee,
tory personnel with proven expertise in detection and a member of the Advisory Council of the National
of a wide spectrum of fastidious organisms. No Institute of Allergy and Infectious Diseases of NIH.
single agent is likely to be the cause of chronic She was named to the original Board of Scientific Coun-
obstructive lung disease, asthma, or cancer; cilors of the National Center for Infectious Diseases,
rather a number of infectious agents are likely to CDC, and is the immediate past chair of the board.
have this potential, hence the need for studies of
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Bioterrorism as a Public Health Threat

D.A. Henderson
The Johns Hopkins University, Baltimore, Maryland, USA

The threat of bioterrorism, long ignored and denied, has heightened over the past
few years. Recent events in Iraq, Japan, and Russia cast an ominous shadow. Two
candidate agents are of special concern—smallpox and anthrax. The magnitude of the
problems and the gravity of the scenarios associated with release of these organisms
have been vividly portrayed by two epidemics of smallpox in Europe during the 1970s
and by an accidental release of aerosolized anthrax from a Russian bioweapons facility
in 1979. Efforts in the United States to deal with possible incidents involving bioweapons
in the civilian sector have only recently begun and have made only limited progress. Only
with substantial additional resources at the federal, state, and local levels can a credible
and meaningful response be mounted. For longer-term solutions, the medical
community must educate both the public and policy makers about bioterrorism and build
a global consensus condemning its use.

Until recently, biological terrorism had been discovered to have a large biological weapons
little discussed or written about. Until recently, I program. In 1995, Iraq confirmed that it had
had doubts about publicizing the subject because produced, filled, and deployed bombs, rockets,
of concern that it might entice some to undertake and aircraft spray tanks containing Bacillus
dangerous, perhaps catastrophic experiments. anthracis and botulinum toxin (1,2); its work
However, events of the past 12 to 18 months have force and technologic infrastructure are still
made it clear that likely perpetrators already wholly intact. Also in 1995, the Japanese cult,
envisage every possible scenario. Aum Shinrikyo, released the nerve gas Sarin in
Four points of view prevalent among national the Tokyo subway. The cult also had plans for
policy circles and the academic community at biological terrorism (3); included in its arsenal
various times have served to dismiss biological were large quantities of nutrient media,
terrorism as nothing more than a theoretical botulinum toxin, anthrax cultures, and drone
possibility. l) Biological weapons have so seldom aircraft equipped with spray tanks. Members of
been deployed that precedent would suggest they this group had traveled to Zaire in 1992 to obtain
will not be used. 2) Their use is so morally samples of Ebola virus for weapons development.
repugnant that no one would deign to use them. Of more recent concern is the status of one of
3) The science of producing enough organisms Russia’s largest and most sophisticated former
and dispersing them is so difficult that it is within bioweapons facilities, called Vector, in Koltsovo,
the reach of only the most sophisticated Novosibirsk. Through the early 1990s, this was a
laboratories. 4) Like the concept of a “nuclear 4,000-person, 30-building facility with ample
winter,” the potential destructiveness of bioweapons biosafety level 4 laboratory facilities, used for the
is essentially unthinkable and so to be dismissed. isolation of both specimens and human cases.
Each of these arguments is without validity. Situated on an open plain surrounded by electric
Nations and dissident groups exist that have fences and protected by an elite guard, the facility
both the motivation and access to skills to housed the smallpox virus as well as work on
selectively cultivate some of the most dangerous Ebola, Marburg, and the hemorrhagic fever
pathogens and to deploy them as agents in acts of viruses (e.g., Machupo and Crimean-Congo). A
terrorism or war. After the Gulf War, Iraq was visit in the autumn of 1997 found a half-empty
facility protected by a handful of guards who had
Address for correspondence: D.A. Henderson, The Johns
not been paid for months (P. Jahrling, pers.
Hopkins University, The Johns Hopkins School of Medicine,
615 North Wolfe Street, Baltimore, MD 21205, USA; fax: 410- comm., 1998). No one can say where the scientists
955-6898; e-mail: have gone, nor is there confidence now that this is

Emerging Infectious Diseases 488 Vol. 4, No. 3, July–September 1998

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the only storage site for smallpox virus outside the list followed closely by anthrax and plague. None
Centers for Disease Control and Prevention. of these agents has so far effectively been
The number of countries engaged in deployed as a biological weapon, and thus no real
biological weapons experimentation has grown world events exist to provide likely scenarios.
from 4 in the 1960s to 11 in the 1990s (4). However, we have had several well-documented
Meanwhile, the bombing of the World Trade smallpox importations into Europe over recent
Center and the Oklahoma City Federal Building decades; two bear recounting.
have dramatized the serious problems even small Smallpox is caused by a virus spread from
dissident groups can cause. person to person; infected persons have a
A comprehensive review of the problems characteristic fever and rash. Virus infection
posed by biological terrorism and warfare has invariably results in symptomatic disease. There
been published (5). Four observations deserve are no mild, subclinical infections among
special note. First, biological terrorism is more unvaccinated persons. After an incubation period
likely than ever before and far more threatening of 10 to 12 days, the patient has high fever and
than either explosives or chemicals. Second, pain. Then a rash begins with small papules
official actions directed at the threat to the developing into pustules on day 7 to 8 and finally
civilian population (less than 2 years in the changing to scabs around day 12. Between 25%
making) have been only marginally funded and and 30% of all unvaccinated patients die of the
minimally supported (6). Third, preventing or disease. There was, and is, no specific treatment.
countering bioterrorism will be extremely Until 1980, essentially all countries con-
difficult. Recipes for making biological weapons ducted vaccination programs of some sort,
are now available on the Internet, and even whether or not they had endemic disease (9).
groups with modest finances and basic training in Until 1972, the United States mandated
biology and engineering could develop, should smallpox vaccination for all children at school
they wish, an effective weapon (7) at little cost. entry, although the last cases had occurred in
Fourth, detection or interdiction of those 1949, 23 years before. In the United Kingdom,
intending to use biological weapons is next to four standby hospitals were to be opened only if
impossible. Thus, the first evidence of such smallpox cases were imported, and in Germany,
weapons will almost certainly be cases in hospital two state-of-the-art isolation hospitals were
emergency rooms. Specialists in infectious constructed in the 1960s specifically for the
diseases thus constitute the front line of defense. isolation of smallpox cases should they occur.
The rapidity with which they and emergency In 1962, the initial response of U.S. officials
room personnel reach a proper diagnosis and the to the occurrence of a single case of smallpox
speed with which they apply preventive and illustrated extreme concern. That year, a young
therapeutic measures could spell the difference Canadian boy returned from Brazil, traveling by
between thousands and perhaps tens of air to New York and by train to Toronto by way of
thousands of casualties. Indeed, the survival of Albany and Buffalo (10). Shortly after arrival in
physicians and health-care staff caring for the Toronto, he developed a rash and was hospitalized.
patients may be at stake. However, today few In response to this single case, senior U.S.
have ever seen so much as a single case of government officials seriously considered a plan of
smallpox, plague, or anthrax, or, for that matter, action that called for the border with Canada to be
would recall the characteristics of such cases. closed, for mass vaccination campaigns to be
Few, if any, diagnostic laboratories are prepared conducted in all cities along the route from New
to confirm promptly such diagnoses. York through Albany, Syracuse, Rochester, and
Of a long list of potential pathogens, only a Buffalo, and for vaccination of all who had been in
handful are reasonably easy to prepare and Grand Central Station on the day the Canadian
disperse and can inflict sufficiently severe boy was there. Sensibly, this plan was soon
disease to paralyze a city and perhaps a nation. In scrapped for more modest measures, albeit not
April 1994, Anatoliy Vorobyov, a Russian without considerable debate.
bioweapons expert, presented to a working group The potential of aerosolized smallpox to
of the National Academy of Sciences the spread over a considerable distance and to
conclusions of Russian experts as to the agents infect at low doses was vividly demonstrated in
most likely to be used (8). Smallpox headed the an outbreak in Germany in 1970 (11). That year,

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a German electrician returning from Pakistan increasingly ill, he was transferred to a

became ill with high fever and diarrhea. On dermatology ward in a city hospital, then to a
January 11, he was admitted to a local hospital similar ward in the capital city, and finally to a
and was isolated in a separate room on the critical care unit because he was bleeding
ground floor because it was feared he might have profusely and in shock. He died before a definitive
typhoid fever. He had contact with only two diagnosis was made. He was buried 2 days before
nurses over the next 3 days. On January 14 a the first case of smallpox was recognized.
rash developed, and on January 16 the diagnosis The first cases were correctly diagnosed 4
of smallpox was confirmed. He was immediately weeks after the first patient became ill, but by
transported to one of Germany’s special then, 150 persons were already infected; of these,
isolation hospitals, and more than 100,000 38 (including two physicians, two nurses, and
persons were promptly vaccinated. The hospital four other hospital staff) were infected by the
had been closed to visitors because of an young teacher. The cases occurred in widely
influenza outbreak for several days before the separated areas of the country. By the time of
patient was admitted. After the diagnosis of diagnosis, the 150 secondary cases had already
smallpox, other hospital patients and staff were begun to expose yet another generation, and,
quarantined for 4 weeks and were vaccinated; inevitably, questions arose as to how many other
very ill patients received vaccinia-immune yet undetected cases there might be.
globulin first. However, the smallpox patient Health authorities launched a nationwide
had had a cough, a symptom seldom seen with vaccination campaign. Mass vaccination clinics
smallpox; coughing can produce a large-volume, were held, and checkpoints along roads were
small-particle aerosol like what might occur established to examine vaccination certificates.
after its use as a terrorist weapon. Subse- Twenty million persons were vaccinated. Hotels
quently, 19 cases occurred in the hospital, and residential apartments were taken over,
including four in other rooms on the patient’s cordoned off by the military, and all known contacts
floor, eight on the floor above, and nine on the of cases were forced into these centers under
third floor. Two were contact cases. One of the military guard. Some 10,000 persons spent 2 weeks
cases was in a visitor who had spent fewer than or more in isolation. Meanwhile, neighboring
15 minutes in the hospital and had only briefly countries closed their borders. Nine weeks after the
opened a corridor door, easily 30 feet from the first patient became ill, the outbreak stopped. In all,
patient’s room, to ask directions. Three of the 175 patients contracted smallpox, and 35 died.
patients were nurses, one of whom died. This What might happen if smallpox were
outbreak occurred in a well-vaccinated popula- released today in a U.S. city? First, routine
tion. vaccination stopped in the United States in 1972.
An outbreak in Yugoslavia in February 1972 Some travelers, many military recruits, and a
also illustrates the havoc created even by a small handful of laboratory workers were vaccinated
number of cases. Yugoslavia’s last case of smallpox over the following 8 years. Overall, however, it is
had occurred in 1927. Nevertheless, Yugoslavia, doubtful that more than 10% to 15% of the
like most countries, had continued populationwide population today has residual smallpox immunity.
vaccination to protect against imported cases. In If some modest volume of virus were to be
1972, a pilgrim returning from Mecca became ill released (perhaps by exploding a light bulb
with an undiagnosed febrile disease. Friends and containing virus in a Washington subway), the
relatives visited from a number of different areas; 2 event would almost certainly go unnoticed until
weeks later, 11 of them became ill with high fever the first cases with rash began to appear 9 or 10
and rash. The patients were not aware of each days later. With patients seen by different
other’s illness, and their physicians (few of physicians (who almost certainly had never
whom had ever seen a case of smallpox) failed before seen a smallpox case) in different clinics,
to make a correct diagnosis. several days would probably elapse before the
One of the 11 patients was a 30-year-old diagnosis of smallpox was confirmed and an
teacher who quickly became critically ill with the alarm was sounded.
hemorrhagic form, a form not readily diagnosed Even if only 100 persons were infected and
even by experts. The teacher was first given required hospitalization, a group of patients
penicillin at a local clinic, but as he became many times larger would become ill with fever

Emerging Infectious Diseases 490 Vol. 4, No. 3, July–September 1998

Special Issue

and rash and receive an uncertain diagnosis. was probably considerably more than 100. The
Some would be reported from other cities and persons affected lived or worked somewhere
other states. Where would all of these patients be within a narrow zone extending some 4 km south
admitted? In the Washington, D.C., metropolitan and east of a military bioweapons facility. An
area, no more than 100 hospital beds provide accidental airborne release of anthrax spores
adequate isolation. Who would care for the occurred during a single day and may well have
patients? Few hospital staff have any smallpox lasted no more than minutes. Further investiga-
immunity. Moreover, one or two patients with tions revealed anthrax deaths among sheep and
severe hemorrhagic cases (which typically have cows in six different villages up to 50 km
very short incubation periods), who would have southeast of the military compound along the
been hospitalized before smallpox was suspected, same axis as the human cases.
would have been cared for by a large, unprotected Of the 58 patients with known dates of disease
intensive care team. onset, only 9 had symptoms within a week after
What of contacts? In past outbreaks, contacts exposure; some became ill as late as 6 weeks after
of confirmed or suspected cases numbered in the exposure. Whether the onset of illness occurred
thousands, if not tens of thousands. What sooner or later, death almost always followed
measures should or could be taken to deal with within 1 to 4 days after onset. However, there
such numbers? Would patients be isolated as in appeared to be a somewhat higher proportion of
Yugoslavia, and if so, where? Logistics could be survivors after the fourth week. This almost
simplified if rapid, easily used laboratory tests certainly resulted from the widespread application
could confirm or rule out smallpox among suspected of penicillin prophylaxis and anthrax vaccine, both
cases. At present, however, such tests are known of which were distributed in mid-April throughout a
only to scientists in two government laboratories. population of 59,000.
An immediate clamor for mass vaccination Meselson and his colleagues, who docu-
(as in the outbreaks in Germany and Yugoslavia) mented this outbreak, calculate that the weight
can be predicted. U.S. stocks of smallpox vaccine of spores released as an aerosol could have been
are nominally listed at 15 million doses, but with as little as a few milligrams or as much as “nearly
packaging, the useful number of doses is perhaps a gram.” Iraq acknowledged producing at least
half that number. How widely and quickly should 8,000 L of solution with an anthrax spore and cell
this vaccine be used? Were vaccine to be limited count of 109/ml (1). The ramifications of even a
strictly to close contacts of confirmed cases, modest-sized release of anthrax spores in a city
comparatively few doses would be needed. are profound. Emergency rooms would begin
However, the realities of dealing with even a small seeing a few patients with high fever and some
epidemic would almost certainly preclude such a difficulty breathing perhaps 3 to 4 days after
cautious, measured vaccination effort. Vaccine exposure. By the time the patients were seen, it is
reserves would rapidly disappear, and there is, at almost certain that it would be too late for
present, no manufacturing capacity to produce antibiotic therapy. All patients would die within
additional vaccine. If an emergency effort were 24 to 48 hours. No emergency room physicians or
made to produce new stocks of smallpox vaccine, infectious disease specialists have ever seen a
many months to a year or more would be required. case of inhalation anthrax; medical laboratories
What of anthrax, which has been so have had virtually no experience in its diagnosis.
enthusiastically embraced by both Iraq and the Thus, at least 3 to 5 days would elapse before a
Aum Shinrikyo? The organism is easy to produce definitive diagnosis would be made.
in large quantity. In its dried form, it is extremely Once anthrax was diagnosed, one would be
stable. The effect of aerosolized anthrax on faced with the prospect of what to do over the
humans once had to be inferred from animal succeeding 6 to 8 weeks. Should vaccine be
experiments and the occasional human infection administered to those who might have been
among workers in factories processing sheep and exposed? At present, little vaccine is available,
goat hides (12). It was clear that inhalation of and no plan exists to produce any for civilian use.
anthrax is highly lethal. Just how lethal became Should antibiotics be administered prophylacti-
evident in the 1979 Sverdlovsk epidemic (13). cally? If so, which antibiotics, and what should be
In all, 77 cases were identified with certainty; the criteria for exposure? What quantity would be
66 patients died. The actual total number of cases required to treat an exposed population of

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perhaps 500,000 over a 6-week period? Should plans for coping with civilian bioterrorism. The
one be concerned about additional infections resulting needed stocking of vaccines and drugs as well as
from anthrax spores subsequently resuspended and the training and mobilization of health
inhaled by others? Should everyone who has been workers, both public and private, at state, city,
anywhere near the city report to a local physician and local levels will require time. Knowing well
for treatment at the first occurrence of fever or what little has been done, I can only say that a
cough, however mild? Undoubtedly, many would mammoth task lies before us.
have such symptoms, especially in the winter;
how can such symptoms be distinguished from D.A. Henderson is a distinguished service professor
the premonitory symptoms of anthrax that may at the Johns Hopkins University, with appointments in
proceed to death within 24 to 48 hours? the Departments of Health and Epidemiology, School of
Hygiene and Public Health. Dr. Henderson directed the
We are ill-prepared to deal with a terrorist
World Health Organization’s global smallpox eradica-
attack that employs biological weapons. In tion campaign (1966-1977) and helped initiate WHO’s
countering civilian terrorism, the focus (a modest global program of immunization in 1974. He also served
extension of existing protocols to deal with a hazard in the federal government as deputy assistant secretary
materials incident) has been almost wholly on and senior science advisor in the Department of Health
chemical and explosive weapons. A chemical and Human Services.
release or a major explosion is far more manageable
than the biological challenges posed by smallpox or References
anthrax. After an explosion or a chemical attack, 1. Ekeus R. Iraq’s biological weapons programme: UNSCOM’s
the worst effects are quickly over, the dimensions of experience. Memorandum report to the United Nations
Security Council; 1996 20 Nov; New York.
the catastrophe can be defined, the toll of injuries
2. Zalinskas RA. Iraq’s biological weapons: the past as
and deaths can be ascertained, and efforts can be future? JAMA 1997;278:418-24.
directed to stabilization and recovery. Not so 3. Daplan E, Marchell A. The cult at the end of the world.
following the use of smallpox or anthrax. Day New York: Crown Publishing Group; 1996.
after relentless day, additional cases could be 4. Roberts B. New challenges and new policy priorities for
the 1990s. In: Biologic weapons: weapons of the future.
expected, and in new areas.
Washington: Center for Strategic and International
The specter of biological weapons use is an Studies; 1993.
ugly one, every bit as grim and foreboding as that 5. Bioweapons and bioterrorism. JAMA 1997;278:351-70,
of a nuclear winter. As was done in response to 389-436.
the nuclear threat, the medical community 6. Tucker JB. National health and medical services
response to incidents of chemical and biological
should educate the public and policy makers
terrorism. JAMA 1997;285:362-8.
about the threat. We need to build on the 1972 7. Danzig R, Berkowsky PB. Why should we be concerned
Biological and Toxin Weapons Convention to about biological warfare? JAMA 1997;285:431-2.
strengthen measures prohibiting the develop- 8. Vorobyov A. Criterion rating as a measure of probable
ment and production of biological weapons and to use of bio agents as biological weapons. In: Papers
presented to the Working Group on Biological
ensure compliance with existing agreements. In a
Weapons Control of the Committee on International
broader sense, we need a strong moral consensus Security and Arms Control, National Academy of
condemning biological weapons. Sciences; 1994 Apr; Washington.
But this is not enough. In the longer term, we 9. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi I.
need to be as prepared to detect, diagnose, Smallpox and its eradication. Geneva: World Health
Organization; 1988.
characterize epidemiologically, and respond
10. Epidemiologic report. Smallpox, Canada. MMWR
appropriately to biological weapons use as to the Morb Mortal Wkly Rep 1962;11:258.
threat of new and reemerging infections. In fact, 11. Wehrle PF, Posch J, Richter KH, Henderson DA. An
the needs are convergent. We need at interna- airborne outbreak of smallpox in a German hospital
tional, state, and local levels a greater capacity and its significance with respect to other recent
outbreaks in Europe. Bull World Health Organ
for surveillance; a far better network of
laboratories and better diagnostic instruments; 12. Brachman PS, Friedlander AM. Anthrax. In: Plotkin
and a more adequate cadre of trained epidemiolo- SA, Mortimer EA, editors. Vaccines. Philadelphia: WB
gists, clinicians, and researchers. Saunders; 1994.
On the immediate horizon, we cannot delay 13. Meselson M, Guillemin V, Hugh-Jones M, Langmuir A,
Popova I, Shelokov A, et al. The Sverdlovsk anthrax
the development and implementation of strategic
outbreak of 1979. Science 1994;266:1202-8.

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Bioterrorism as a Public Health Threat

Joseph E. McDade* and David Franz‡
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA;
‡U.S. Army Medical Research Institute of Infectious Diseases,
Ft. Detrick, Maryland, USA

In addition to meeting the continuing threat several occasions before the election. A
of new and reemerging infectious diseases, public communitywide outbreak of salmonellosis re-
health officials must also prepare for the possible sulted; at least 751 cases were documented in a
use of infectious agents as weapons by terrorists county that typically reports fewer than five
to further personal or political agendas. These cases per year. Although bioterrorism was
were the conclusions of session panelists Scott considered a possibility when the outbreak was
Lillibridge, Centers for Disease Control and being investigated by public health officials, it
Prevention (CDC); Michael Skeels, Oregon State was considered unlikely. The source of the
Public Health Laboratory; Marcelle Layton, New outbreak became known only when FBI
York City Department of Public Health; David investigated the cult for other criminal viola-
Franz, U.S. Army Medical Research Institute of tions. A vial of S. Typhimurium identical to the
Infectious Diseases; and Randall Murch, Federal outbreak strain was found in a clinical laboratory
Bureau of Investigation (FBI). on the cult’s compound, and members of the cult
The potential spectrum of bioterrorism subsequently admitted to contaminating the
ranges from hoaxes and use of non–mass casualty salad bars and putting Salmonella into a city
devices and agents by individuals and small water supply tank. This incident, among other
groups to state-sponsored terrorism that employs recent events, underscores the importance of
classic biological warfare agents and can produce improving preparedness at all levels.
mass casualties. The agents of anthrax, plague, A bioterrorist attack may be difficult to
brucellosis, smallpox, viral encephalidites, and distinguish from a naturally occurring infectious
viral hemorrhagic fevers are of particular disease outbreak. Investigators must first
concern: they are relatively easy and inexpensive examine the etiology and epidemiology of an
to produce, cause death or disabling disease, and outbreak to identify its source, mode of
can be aerosolized and distributed over large transmission, and persons at risk. Certain clues
geographic areas. If released under ideal may indicate whether an outbreak is the result of
environmental circumstances, these agents can purposeful release of microorganisms. Naturally
infect hundreds of thousands of persons and occurring diseases are endemic to certain areas
cause many deaths. Such scenarios would and involve traditional cycles of transmission;
present serious challenges for patient manage- some diseases occur seasonally, and sentinel
ment and for prophylaxis of exposed persons; cases are not uncommon. In contrast, a disease
environmental contamination could provide a outbreak due to bioterrorism could occur in a
continuing threat to the population (especially nonendemic-disease area, at any time of year,
those exposed at the beginning of the crisis) and without warning, and depending on the etiologic
generate panic in the community. agent and mode of transmission, in large
Bioterrorist attacks could be covert or numbers—thousands of cases might occur
announced and could be caused by virtually any abruptly. Public health officials must be
pathogenic microorganism. The case of the appropriately sensitized to the possibility of
Rajneeshee religious cult in The Dalles, Oregon, bioterrorism when investigating disease out-
is an example (1). The cult planned to infect breaks. Suspected bioterrorism should be
residents with Salmonella on election day to reported promptly to FBI, which is responsible
influence the results of county elections. To for coordinating interagency investigations of
practice for the attack, they contaminated salad such episodes. FBI scientists are also well trained
bars at 10 restaurants with S. Typhimurium on in forensic methods for criminal investigations

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and are prepared to react quickly and effectively. against bioterrorist attacks. CDC is well
Maintaining effective disease surveillance is positioned to provide leadership in several areas.
an essential first step in preparedness and is In partnership with state health departments,
important in helping law enforcement officials to the agency maintains infectious disease surveil-
react swiftly. Ensuring adequate epidemiologic lance systems and provides reference laboratory
and laboratory capacity nationwide are prerequi- diagnosis and epidemiologic support, especially
sites to effective surveillance systems. Prepara- during outbreak investigations; disseminates
tions also must include plans for rapid public health recommendations and other
identification and characterization of agents information, issues quarantine measures, and
involved and for emergency distribution of large provides expert advice on worker health and safety;
quantities of medical supplies, especially antibi- and is the logical bridge between the public health
otics and vaccines. Coordination and communica- community and FBI’s scientific and response
tion links also need to be strengthened to capabilities. Enhancing the public health infra-
minimize response time, especially at first when structure will improve U.S. ability to respond to
exposed but asymptomatic persons may still be any infectious disease outbreak and provide
treated prophylactically. Also, when response added value in the event of a bioterrorist event.
time is shortened, the possibility of apprehending
perpetrators increases. Education and training References
in bioterrorism and its potential consequences 1. Torok TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow
must become national priorities. R, Mauvais S, et al. A large community outbreak of
salmonellosis caused by intentional contamination of
Many agencies and organizations must work
restaurant salad bars. JAMA 1997;278:389-95.
collaboratively to ensure national preparedness

Joseph McDade (L)

Centers for Disease Control
and Prevention, Atlanta,
Georgia, USA
Carlos Lopez;
Eli Lilly and Company,
Indianapolis, Indiana, USA
D.A. Henderson
The Johns Hopkins
University, Baltimore,
Maryland, USA

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Who Speaks for the Microbes?

Stanley Falkow
Stanford University School of Medicine, Stanford, California, USA

In discussing emerging infectious diseases, slowed and has been replaced by the encroach-
the focus is often on the clinical effects of the host- ment of human populations into the domain of
parasite relationship, i.e., the impact on the animal species all over the globe. It is little wonder
health and survival of humans and animals, that our deliberate destruction of predators and the
rather than the examination of the biology of the outgrowth of human populations into virgin land
pathogen. It seems fitting to take a moment to with its attendant destruction of habitat led to the
reflect on how pathogens “got that way in the first emergence of new diseases such as Lyme disease
place.” Thus, while we discuss emerging and murine typhus (spread now by opossums and
infections, it is worthwhile to consider that from cat fleas in our slums, instead of by the more classic
the beginning of recorded history—in books or rat and rat flea vector—“sic transit gloria mundi”).
the pictographs of ancient cultures—infectious
diseases have been the leading cause of illness The Enemy Is Us
and death. Even today, because of infectious The cartoon character Pogo, invented by Walt
diseases most of the world’s population does not Kelly, once announced to his companions that
have the luxury of living long enough to succumb “the enemy is us.” I believe that many of what
to the chronic diseases of aging. we refer to as emerging diseases are
What were and what remain the reasons that characterized better as “diseases of human
infectious diseases are still the leading cause of progress.” Thus, many major public health
death? I believe there are four answers. 1) The crises of the past 2 decades have been infectious
presence of human populations was and is large in origin. Many, like the outbreaks of Lyme
enough to sustain and amplify parasites. We have disease and murine typhus, are a natural
lived in communities large enough to perpetuate consequence of human meddling. Similarly, the
parasites for only about 10,000 years, barely a appearance of infections, like Legionnaires’
blink of the eye in the time frame of evolution, disease, can be traced to more subtle
which means that most of the well-known differences in human behavior and social
infectious diseases adapted to humans are very conventions that have an effect on the microbial
recent in the evolutionary sense. The black death world. Thus, the aerosolization of water, now so
of the 14th century, just 700 years ago, led to the prominent in the Western world from the
death of approximately one quarter to one third of widespread use of showers instead of baths to the
the human population of what was then the spraying of produce in large markets to air
Western world. We may never understand the conditioning, likely has played an important role
full implications of the plague outbreaks of the in the emergence of Legionnaires’ disease and also
Middle Ages. The resistance of some caucasian of Mycobacterium avium infection in both healthy
populations to the recent scourge of HIV actually and immunocompromised persons.
may reflect the genetic consequences of plague Legionella pneumophila, the Legionnaires’
survival 20 generations ago. 2) Poverty, with its bacillus, is found in nature as an infectious agent of
crowding, unsanitary conditions, and often predatory protozoa. Introduction of this organism,
malnutrition, has led to an increased susceptibil- often as part of an aerosol of potable water into the
ity to infection and disease. 3) War, famine, civil alveolus of the lung, results in the microorganism’s
unrest, and, indeed, epidemic disease have led to finding a new niche in the macrophage instead of in
a breakdown in public infrastructure and the its usual host Acanthamoeba or Hartmanella. More
increased incidence of infectious diseases. 4) The absorbent tampons helped select for a new disease,
domestication of animals, beginning about 12,000 toxic shock syndrome.
years ago, was another important factor. The While pathogenic traits of the disease-
actual large-scale domestication of animals has causing microbes are of consequence, humans

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and their technology and social behavior have The distinct difference between commensal,
played a major role in providing pathogenic opportunistic, and pathogenic microbes is that
microbes with new venues for their wares. Food pathogenic microbes have evolved the genetic
poisoning by Escherichia coli O157, Campy- ability to breach cellular and anatomic barriers
lobacter, and Salmonella emerged more from food that ordinarily restrict other microorganisms.
technology and food distribution networks than Thus, pathogens can inherently cause damage to
from any fundamental change in the virulence cells to forcefully gain access to a new, unique
properties of the bacteria. In a sense, we have niche that provides them with less competition
provided these bacteria with a moveable feast. from other microorganisms, as well as with a
ready new source of nutrients.
What Is a Pathogen, Anyway? For microorganisms that inhabit mammals
Medicine views pathogens as microorgan- as an essential component of their survival tactic,
isms capable of causing disease. The emphasis is success can be measured by their capacity to
on disease, not the microorganism. However, multiply sufficiently to be maintained or be
from the microbial standpoint, being pathogenic transmitted to a new susceptible host. This is true
is a strategy for survival and simply one more for commensal and pathogenic organisms alike.
remarkable example of the extraordinary However, if the pathogen gains a new niche free
diversity of the microbial world. Humans are a of competition and rich in nutrients, it also faces
home to a myriad of other living creatures. From a more hostile environment designed by
mouth to anus, from head to toes, every evolution to restrict microbial entry and, indeed,
millimeter of our cells exposed to the outside to destroy any intruders that enter these
world is inhabited by a rich biology. From the protected regions. Thus, pathogens have not only
mites that may inhabit the eyebrows to the acquired the capacity to breach cellular barriers
seething cauldron of more than 600 species of but also, by necessity, have learned to
bacteria that inhabit the large bowel, we are a circumvent, exploit, and subvert our normal
veritable garden of microorganisms. Most of cellular mechanisms for their own selfish need to
these microorganisms are not only innocuous but multiply at our expense.
play a useful, yet unseen, role in our lives. They
protect against the few harmful microorganisms How Did Pathogens Get That Way?
that we encounter each day; they provide vitamins Recent advances in bacterial genetics,
and nutrients and help digest food. We have molecular biology, and microbial genomics have
harbored them so long in our evolution that they are led to a better understanding of the evolution of
even a necessary part of the developmental bacterial pathogenicity. In genera that have both
pathways required for the maturation of intestinal pathogenic and nonpathogenic organisms, the
mucosa and the immune system. nonpathogenic bacteria frequently possess one
Most microbes are commensal; that is, they (or more) large genetic insert that contains genes
“eat from the same table.” Others are either exclusively associated with the pathogenic
commensal or transient microbes that are phenotype. Indeed, in gram-negative enteric
opportunistic; they can cause disease if one (or bacteria, pathogenic traits are commonly found
more) usual defense mechanism, evolved to as large inserts of DNA in the chromosome, as are
restrict microorganisms from normally sterile plasmids dedicated to the pathogenicity of the
inner organs and tissue, is breached by accident, host microbe. Certain qualities of these DNA
by intent (as in surgery and, increasingly, in inserts suggest that they were acquired by
gunshot wounds), or by an underlying metabolic horizontal gene transfer from one microbe to
or even infectious disorder. Nevertheless, a small another and that the ultimate origin of these
group of microorganisms often causes infection virulence genes was a microbe very different from
and overt disease in seemingly healthy persons. the organism in which these genes now reside.
Many of the microorganisms, for example, These “pathogenicity islands” have been the
the typhoid bacillus, gonococcus, tubercle subject of a number of recent articles. However,
bacillus, and treponema of syphilis, are adapted the evolution of pathogenicity is not the product
exclusively to humans; others, for example, of a slow, plodding process as much as it is the
Salmonella Typhimurium, can regularly cause product of a large single genetic event that had a
disease in humans, animals, birds, and reptiles. profound influence on the biology of the

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microorganism. Thus, the divergence of Salmo- debate after 50 years. Is it because we could see
nella from an ancestor that also gave rise to E. coli the effects of DDT in the pictures of fragile eagle
resulted when the organism received a large eggs but not in the unseen microscopic world? As
pathogenicity island that encoded a contact- Pasteur said, the microbe will endure. Perhaps
dependent secretory system, which gave the host the fate of the last human is to be consumed by
bacterium the ability to cross epithelial barriers. its own microorganisms.
Later on in evolution, some Salmonellae received
another pathogenicity island that provided the Suggested Bibliography
host bacterium with the ability to survive within 1. Bäumler AJ. The record of horizontal gene transfer in
phagocytic macrophages; finally, other Salmonel- Salmonella. Trends Microbiol 1997;5:318-22.
2. Falkow S. The evolution of pathogenicity in
lae that infect only warm-blooded animals
Escherichia, Shigella, and Salmonella. In: Neidhardt
eventually inherited a plasmid that appears to F, editor. Escherichia coli and Salmonella: cellular
permit systemic spread and, perhaps, some degree and molecular biology. Washington: American
of host animal preference. These genetic events Society for Microbiology; 1995. p. 2723-9.
occurred over millions of years of evolution and 3. Finlay BB, Cossart P. Exploitation of mammalian host
cell functions by bacterial pathogens. Science
were undoubtedly rare, perhaps occurring only
once in evolution. 4. Galán JE, Bliska JB. Cross-talk between bacterial
The success of these genetic changes also pathogens and their host cells. Ann Rev Cell Dev Biol
depended on subsequent selective pressures and 1996;12:221-55.
genetic fine-tuning by mutation and other 5. Groisman EA, Ochman H. How Salmonella became a
pathogen. Trends Microbiol 1997;5:343-9.
genetic mechanisms. Nevertheless, the molecu-
6. Hacker J, Blum-Oehler G, Muhildorfer I, Tachape H.
lar fossil record in the DNA of contemporary Pathogenicity islands of virulent bacteria: structure,
pathogens leads to the inevitable conclusion that function and impact on microbial evolution. Mol
microbial evolution is still dynamic and that Microbiol 1997;23:1089-97.
these periodic genetic upheavals in microbes
affecting their pathogenicity can occur at any
time. To underestimate the evolutionary poten-
tial of microorganisms and their ability to
survive, even in the face of enormous pressures to
eradicate them and their effects on humankind,
would be a mistake.
Infectious agents will emerge so long as there
are microorganisms. Humans help the evolution-
ary process sometimes unwittingly and some-
times by arrogance or ignorance. Antibiotic
resistance on a global scale in what seems such
a short time comes as no surprise. Does feeding
animals antibiotics to promote growth have any
effect on human microbes and the health of the
human population as a whole?
Rachel Carson’s book Silent Spring, which
documents the devastating effects of insecticides
(e.g., DDT) on the health of a number of living
creatures far removed from the insects that were
the target, was easily understood. Yet, applica-
Stanley Falkow and Lucy Tompkins
tion of a selective pressure on the microbes of the
Stanford University School of Medicine, Stanford,
planet with antibiotics, a pressure that dwarfs the California, USA
use of DDT in its scope, as well in the number of
species that are affected, still remains a subject of

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Emerging Diseases—What Now?

George A. O. Alleyne
Pan American Health Organization, Washington, D.C., USA

The Pan American Health Organization by normal intercity traffic.

(PAHO) was born in 1902 out of concern for the The spread of antibiotic resistance is another
spread of infectious diseases. The outbreak of reason for the emergence of disease; the
cholera in Hamburg in 1892 and the epidemics of indiscriminate use of antibiotics is to blame. In the
yellow fever in the Americas led to the decision to South, antibiotic abuse is facilitated by ready
establish the International Sanitary Bureau with availability without a prescription. In some
permanent headquarters in Washington. At the countries, local pharmacies stock and dispense
conference that made this historic decision in 1902, antibiotics with the same facility as they do cough
participating countries agreed to cooperate with syrups. In one study of private pharmacies, 42% of
each other and transmit to the bureau “all data of the antibiotics were dispensed without prescription
every character relative to the sanitary conditions (1); in another study, only 23% were given with a
of their ports and territories and furnish said physician’s prescription (2).
Bureau every opportunity and aid for a thorough The essential elements of a control strategy for
and careful study and investigation of any addressing emerging infections are a surveillance
outbreaks of pestilential disease.” All this was to be system, strengthening the public health infrastruc-
done to provide the “widest possible protection of ture (including enhancing laboratory capability),
the public health of each of the said republics and stimulation of research, and training of personnel.
that commerce between said republics may be This strategy is difficult. However, a review of past
facilitated.” surveillance activities provides specific lessons.
To a very large extent, we are still following the At the regional level, three disease surveillance
bureau’s recommendations, only the list of systems (for foot-and-mouth disease, poliomyelitis,
pestilential diseases is shorter by one. Smallpox is and measles) have worked and are working. An
no longer with us—and cholera, yellow fever, and essential common feature is that surveillance leads
bubonic plague are now among the emerging to definitive action. For example, detection of cases
diseases. Cholera is far from disappearing. There of poliomyelitis (before the disease was finally
were approximately 400,000 cases in the Americas eliminated from the Americas) automatically
in 1991. This number fell to 18,000 in 1997, but triggered a response. The report of a suspected
recent reports indicate that as a result of flooding case now causes resources to be mobilized to
caused by El Niño, the number of cases in Peru has establish the validity of the report.
increased dramatically this year. For the first 4 In addition, strong motivation undergirds
weeks of this year, 2,863 cases were reported surveillance. In the case of animal vesicular
compared with 174 for the same period last year disease, there is the intense commercial interest
and 3,500 for the whole of 1997. behind the maintenance of the system and the
Over the past 5 years, emerging diseases have possibility of eradication of foot-and-mouth disease.
caused intense concern and activity. The growth The commercial interest arises because elimina-
in international travel is a major factor. Statistics tion of the disease from the countries of the South
from the World Tourism Organization show that represents a possibility of exporting beef worth
some 1 million persons per day traveled from billions of dollars. Interest rests not only with the
their homes by air in 1995. International travel national authorities; small communities actually
has increased every one of the past 10 years with drive the system. An estimated 70% of the cattle are
an average increase of 5.5% per annum. owned by peasants, who each own 10 or fewer.
Approximately 1.6 million people cross or recross Systematic regular feedback is necessary to
the U.S.-Mexico border every day by land. maintain interest.
Cholera did not spread between the Peruvian The surveillance systems for these diseases are
towns of Chancay and Chimbote by air travel, but based on the use of geographic coordinates to

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divide the countries into grids that represent the American Regional Poliomyelitis Laboratory Net-
special unit in which the data are collected. work and have adopted “open regionalism”—
Reports are sent by the local veterinary service to establishing limited networks that may expand
the Pan American Foot-and-Mouth Disease eventually and cooperate among themselves.
Center in Brazil. In recent years, a system has PAHO is also creating a functional network of
been developed for childhood illnesses that is as laboratories in the greater Amazon Region to
sensitive as that which reports animal diseases. provide data on emerging infections. The partici-
The driving force behind the successful pating laboratories’ common objective will be the
development and maintenance of the surveillance provision of accurate results, prompt sharing of
system for these childhood illnesses is the information and research protocols, and a
possibility of a finite end—eradication and the mechanism for rapid transfer of technology.
emotional pride that national health workers and However, the laboratories will need external
politicians have in reaching this end. support to sustain the system.
Perhaps the most important aspect of A strong global system for the application of
successful surveillance systems is the presence of a strategies to control emerging diseases will not
credible coordinating international body. No occur if the agreement on global action exists only in
effective international surveillance system can be the sphere of surveillance. There is a fundamental
mounted by a single country, no matter how well it need for other health professionals, in addition to
is endowed. External energy, commitment, exper- microbiologists, to be convinced of the need for a
tise, and persistence are necessary for such systems global approach to some health issues.
to function. The fear of infectious disease has been a
The technology of communication should not powerful stimulus for global action. The successful
become the focus of our efforts. The surveillance global system for influenza is due partly to the
and containment systems for smallpox depended on coordinating efforts of the World Health Organiza-
telegrams, telexes, and, I suspect, talking drums. tion (WHO) and the work of the key collaborating
“In India, the largest of the endemic countries, laboratory centers. Involvement in these efforts
there were no fewer than 8,167 units reporting keeps laboratories abreast of the latest develop-
weekly to 397 district offices, which in turn reported ments in their special fields.
to 31 state program offices and those to the national The need for global health coordination has
program office in New Delhi” (3). All this and more been very much in the news; the appropriate body
was sent to Geneva to be analyzed and reported to perform that function is WHO. Most nations
back faithfully, without the benefit of electronic agree that they must assume responsibility for
mail. New information technology is not an what are called essential public goods, e.g.,
indispensable part of the solution. immunization, provision of clean water. But some
It is challenging to our sense of superiority as a goods are public beyond national considerations,
species to realize that diseases will always emerge. and no single nation can coordinate the availability
Changes in our social and physical ecology will of these international public goods.
almost certainly ensure the emergence of new or old International leadership goes beyond emerging
diseases, and we are now more vulnerable to these diseases; indeed the success of a global effort to
diseases than before. Thus, strategies and policies address the threat of these diseases depends largely
must be able to be adapted to confront the inevitable on the wider perception of responsibilities for global
new threats; the international community must coordination in health. Some believe that the global
avoid the peaks and valleys of action that effort must focus on problems more common in the
accompany public interest in the exotic. developing world and that global coordination is a
We have already begun to implement agreed- mechanism for channeling resources from the rich
upon strategies in one particular area. To establish to the less fortunate. However, all countries need to
a system for surveillance of antibiotic resistance to appreciate the benefits of global coordination of
enteric pathogens, we identified participating efforts such as those needed to address emerging
laboratories in 14 countries of the Americas. The diseases. Multilateralism is not antithetical to
next step was to standardize isolation techniques national interests or bilateral approaches. Success
and review methods for measuring antibiotic of this multilateral approach will require budgetary
sensitivity. We are applying an approach similar to support. The annual regular budget of WHO is
the one that proved successful with the Pan approximately US$420 million—14% of PAHO’s

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budget. As Joshua Lederberg said, “Our thinking has In conclusion, we must promote the individual
been impoverished in terms of budget allocation for study of the nature and local means of control of
dealing with health on an international basis.” emerging diseases. However, we also need a more
Some very successful efforts at global collective approach at the regional, or even better,
coordination in health have been disease or theme the global level—this approach is bound up with the
specific, and the “Special Program” approach has support for global action on other fronts in health.
given some very good results. However, we should The most powerful instrument we have is
go beyond that and have a global health forum or multipronged advocacy—advocacy is needed at the
council in which those agencies and institutions political and popular levels for this approach. The
active or becoming increasingly active in health join public must be engaged on a more regular basis to
with WHO in determining how to coordinate the consider the truism that public health must be a
various efforts. I would include in this forum concern of the public. This advocacy has to use some
representation from the multilateral financial specific examples of those matters that affect the
institutions, the private sector, and nongovernmen- public’s health so that emerging diseases are not
tal organizations. Different spheres of interest and seen as a threat only on television.
action would complement each other, which should
help correct the current ad hoc theme-driven References
approach that continues to draw criticism. 1. Brieva J, Danhier A, Villegas G, Yates T, Pérez H.
PAHO has emphasized the benefit of a Modalidades del uso de antibióticos en Concepción,
Chile. Boletín Oficina Sanitaria Panamericana
collective approach, and Panamericanism is one of
the major underlying principles of the organization’s 2. López R, Kroeger A. Morbilidad y medicamentos en
work. For example, “Health Technology Linking Perú y Bolivia. Universidad Peruana, Cayetano
the Americas,” a concept that promotes the Heredia, Lima, Perú. Acción para la salud, Chimbote,
availability of simple effective technologies through- Perú. Ministerio de Salud, La Paz, Bolivia.
Universidad de Heidelberg, Alemania, 1990.
out the Americas, is a current initiative. Vaccines
3. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID.
are one of the technologies emphasized. Smallpox and its eradication. Geneva: World Health
Organization; 1988. p. 497.

Emerging Infectious Diseases 500 Vol. 4, No. 3, July–September 1998

Special Issue

Plague Diagnostic Workshop1

May C. Chu
Centers for Disease Control and Prevention, Fort Collins, Colorado, USA

The Plague Diagnostic Workshop, cospon- electronic links between laboratories. During the
sored by the Centers for Disease Control and first session, representatives reported on their
Prevention (CDC) and the World Health countries’ plague activities and presented results
Organization (WHO), was held on March 8 and on improved and new tests for plague. During the
12, 1998. Participants represented major labora- second session, presenters discussed molecular
tories involved in plague diagnostic test methods used in typing Y. pestis and electronic
implementation and development, the WHO methods for linking laboratories through the
Collaborating Centers for Plague Research and Internet. Participants also met during the
Reference (Almaty, Kazakhstan; Stavropol, International Conference on Emerging Infectious
Russia; and Fort Collins, Colorado, USA), the Diseases to discuss issues ranging from plague
WHO Collaborating Center for Yersiniosis (Paris, diagnostic criteria to adoption of new test methods.
France), WHO headquarters, and the Pan Recommendations were made to broaden and
American Health Organization. Other participants refine the plague laboratory diagnostic criteria.
came from Brazil, China, Indonesia, Kazakhstan, Three working groups were created to evaluate
Madagascar, Myanmar, Peru, Russia, South and develop international standards of Y. pestis-
Africa, Taiwan, Tanzania, United Kingdom, specific F1 antigen, F1 antigen-sensitized sheep
United States, Venezuela, and Vietnam. From red blood cells, and specific bacteriophage stock.
the United States, state and local public health A fourth working group was charged with
laboratory specialists from California and New evaluating new diagnostic tests. Guidelines and
Mexico, Naval Medical Research Unit #2, and recommendations were made for molecular typing
private industry personnel also participated. of isolates using plasmid and protein profiling,
The goals of the workshop were to assess the pulsed-field gel electrophoresis, and ribotyping.
laboratories’ capabilities to perform plague The workshop participants also worked toward
diagnostic tests worldwide; discuss test methods; establishing an electronic bulletin board and
develop a program for molecular characterization soliciting support for another workshop in 2 years
of Yersinia pestis, with emphasis on monitoring to certify the results of the working groups.
drug resistance strains; and initiate worldwide

Summary of Satellite Session

Vol. 4, No. 3, July–September 1998 501 Emerging Infectious Diseases

Special Issue

The U.S.–EU Conference on Extension

of the Salm/Enter-net Surveillance
System for Human Salmonella and
Escherichia coli O157 Infections1
Alexandra Levitt
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

To help extend the European Union’s (EU) net’s objectives are to extend Salm-net monitoring
Enter-net system for the surveillance of to STEC, including E. coli O157:H7, as well as
Salmonella and Shiga toxin-producing Escheri- drug-resistant strains of Salmonella.
chia coli (STEC)2 to other countries, a conference Enter-net participants are working toward a
was held on March 12, 1998, under the auspices of common set of laboratory protocols, including
the U.S.–EU Task Force on Communicable procedures for serotyping, phage typing, and
Diseases. The conference was cochaired by James toxin typing. They report disease cases to the
LeDuc (Centers for Disease Control and international Enter-net database on a regular
Prevention [CDC], United States) and Christo- basis, through the Internet, by using standard-
pher Bartlett (Public Health Laboratory Service ized data fields. Every year, the participants from
[PHLS] Communicable Disease Surveillance each member country attend a workshop to
Center [CDSC], United Kingdom), who head the discuss technical issues and principles of
Task Force Working Group on Surveillance and collaboration. Potential conflicts addressed at
Response. Attendees from countries outside EU workshops include ownership of data; confidenti-
(South Africa, Hungary, Canada, Japan, Poland, ality; outbreak control measures; and liability
Australia, the Czech Republic, Latvia, and the concerns (e.g., what happens when a food product
United States) were invited to describe their is implicated by Enter-net as a vehicle of disease
countries’ procedures for monitoring Salmonella transmission). At the next workshop, which will
and E. coli O157:H7. take place in November 1998 in Denmark, Enter-
Enter-net, which has superseded the EU’s net members will review protocols for collabora-
Salmonella surveillance system (Salm-net), is an tive field investigations.
example of “globalization in action.” The network U.S. representatives described U.S. proce-
consists of the microbiologist in charge of the dures for surveillance of Salmonella and STEC,
member nation’s national reference laboratory and including procedures for antimicrobial resistance
the epidemiologist responsible for national surveil- monitoring. While Enter-net relies largely on
lance of foodborne diseases. A collaboration of phage typing to define E. coli O157:H7 subtypes,
epidemiologists and microbiologists working at the pulsed-field gel electrophoresis (PFGE) is the
technical level, the network is not a regulatory primary E. coli O157:H7 subtyping method in the
organization. It includes participants from all 15 United States. In 1996, CDC initiated PulseNet, a
EU countries plus Norway and Switzerland, with national molecular subtyping network for
a combined population of 380 million. Since 1994, tracking E. coli O157:H7. PulseNet is being
Enter/Salm-net has detected 10 international expanded to include Salmonella and other
outbreaks resulting from contaminated food or foodborne pathogens. PulseNet currently in-
water, including one that involved an Israeli snack cludes 26 state and large city health departments
food contaminated with S. Agona and one due to S. and laboratories from the U.S. Department of
Livingstone infection in visitors to Tunisia. Enter- Agriculture and the Food and Drug Administra-

1Summary presented at a satellite meeting, March 12, 1998.

2Previously known as verotoxin-producing Escherichia coli (VTEC).

Emerging Infectious Diseases 502 Vol. 4, No. 3, July–September 1998

Special Issue

tion. An electronic database at CDC will be monitoring in its member countries.

accessible to all participating PulseNet laborato- Enter-net’s goals for 1998 are to conduct an
ries and will include DNA patterns of foodborne inventory of national laboratory practices
pathogenic bacteria and epidemiologic informa- related to the diagnosis of STEC and to
tion associated with these isolates. Like Enter- antimicrobial resistance testing for STEC and
net, PulseNet requires that all reporting sites use Salmonella, perform a multicenter study in
harmonized laboratory methods and standard- participating reference laboratories on the
ized reporting specifications. detection of drug resistance, upgrade the
Each month, Enter-net’s coordinator, based Enter-net database to include STEC and
at the Communicable Disease Surveillance Center, antimicrobial resistance testing, agree on an
applies an automatic cluster-detection algorithm to outbreak investigation protocol, pilot weekly
detect international outbreaks. To make the best on-line reporting, and hold a scientific
use of the algorithm, each country must supply workshop in Denmark in November 1998.
Enter-net with retrospective data from at least 3 Formal invitations will be sent to non-EU
years. The United States has an analogous system, countries that have expressed interest in joining
the Salmonella Outbreak Detection Algorithm Enter-net. Pilot data exchanges will be initiated
(SODA), which analyzes data reported through in September 1998. If possible, new members will
CDC’s Public Health Laboratory Information begin routine data exchange by early October and
System (PHLIS). Some U.S. state health depart- will attend the November workshop in Denmark.
ments are beginning to use SODA to perform their For additional information on Enter-net,
own analyses for incident detection. contact Ian Fisher (e-mail:,
Over the past few months, Enter-net has begun PHLS Communicable Disease Surveillance Cen-
to define the data that will be collected on isolates of tre, 61 Colindale Avenue, London NW9 5EQ,
E. coli O157:H7; the data will be incorporated in an United Kingdom. For PulseNet, contact Bala
international database similar to the one used for Swaminathan, National Center for Infectious
Salmonella. The network has also begun a survey of Diseases, CDC, Mailstop C07, 1600 Clifton Road,
methods in use for antimicrobial resistance N.E., Atlanta, GA 30333, USA.

Vol. 4, No. 3, July–September 1998 503 Emerging Infectious Diseases

Special Issue

ASM/CDC/NIH Training in Emerging and

Reemerging Infectious Diseases1
Karl Western
National Institutes of Health, Bethesda, Maryland, USA

President Clinton’s directive on emerging and Webster, St. Jude Children’s Research Hospital,
reemerging infectious diseases calls for the who recounted lessons learned from research in
development of domestic and international Hong Kong during the recent avian influenza
training programs in this new and expanding outbreak. After questions and answers cochaired
field. A training workshop, which coincided with by John La Montagne and Joel Breman, Fogarty
the International Conference on Emerging International Center (FIC), D.A. Henderson,
Infectious Diseases, provided an opportunity to Johns Hopkins University, summed up the
exchange information on current training discussions and extracted recommendations.
activities; discuss future plans in clinical, public The workshop had the following conclusions.
health, and research training; and, more 1) A number of emerging infectious disease
importantly, generate discussion on unmet needs training initiatives either under way or under
and improvement of present activities. consideration at CDC, the Armed Forces, NIAID,
and FIC are modest (given the training needs)
NIH Academic Partnerships: Needs and and, without exception, underfunded. 2) There is
Future Directions considerable public, private, and Congressional
This part of the training workshop was interest in emerging infections, particularly in food
chaired by the National Institute of Allergy and safety and vector-borne diseases. 3) Recently, a new
Infectious Diseases (NIAID) Deputy Director, element, biological warfare and terrorism, has been
John R. La Montagne. Each participant was asked added to the equation. 4) Several CDC training
to address the following five questions: 1) What initiatives directed at local and state public health
is emerging infectious disease training? 2) What authorities are frustrated by lack of resources in the
are its most important priorities and needs? 3) What public health trenches. 5) Army and Navy overseas
are your recommendations for curriculum develop- laboratories represent an underappreciated and
ment? 4) What resources are needed to address underutilized resource for training of both U.S.
training and curriculum needs? and 5) How can the citizens and foreign nationals. 6) NIH training is
American Society for Microbiology (ASM), Centers limited to formal training; it sets ceilings on
for Disease Control and Prevention (CDC), National research training slots and its domestic mission.
Institutes of Health (NIH), and partners in As a result, most NIH research training is carried
academia, government, industry, and professional out through research awards. The expansion of
organizations promote and support the training? the NIAID International Collaboration in
Adel Mahmoud, Case Western Reserve Infectious Disease Research Program (with
University, spoke about the problem of incorpo- increased emphasis on training U.S. scientists)
rating emerging infections training into medical and the announcement of FIC international
school curricula. He was followed by David Actions for Building Capacity are welcome but are
Stephen, Emory University, who spoke on the still short of what is needed. 7) Industries’
integration of emerging disease training into contributions, such as Merck’s Mectizan and
infectious disease training; Mary E. Wilson, SmithKline Beecham’s Albendazole Donation
Harvard School of Medicine, who discussed Programs, are welcome. In addition, Lilly’s
continuing medical education; Gail Cassell, Eli decision, announced this week, to provide CDC
Lilly and Company, who brought in perspectives with funds for international participants in its
from industry and academia; and Robert training program is an innovative approach to

Summary of satellite session

Emerging Infectious Diseases 504 Vol. 4, No. 3, July–September 1998

Special Issue

promote intersectorial cooperation. 8) The recent serve as a model for the medical community. 4) An
Hong Kong avian influenza outbreak is a paradigm intersectorial emerging infectious diseases group
on how the research, clinical, public health, and composed of U.S. members from government
industrial communities can cooperate in an agencies (CDC, NIH) and state health depart-
emergency situation and prevent a recurrence of ments, universities, industry, schools of public
an influenza pandemic. Hong Kong may have been health, professional organizations (e.g., ASM,
a very close call; influenza is the only reemerging Infectious Disease Society of America, American
infectious disease for which a contingency plan Society of Tropical Medicine and Hygiene, and
involving all these players exists and is international organizations (USAID, WHO) should
operational. be organized to identify training needs. 5) ASM and
The workshop recommended the following. other professional organizations should work with
1) Current CDC, NIH, and Department of academic institutions to promote curriculum
Defense training programs should receive changes at the professional student, clinical
additional funding and be expanded through training, and research training levels to increase
increased U.S. government resources and through awareness of and capacity to recognize and treat or
innovative cooperative efforts with the private prevent emerging infections. 6) continuing medical
sector. 2) U.S. Agency for International Develop- education courses, audiovisual programs, and
ment (USAID), World Health Organization (WHO), interactive educational materials should be
and other international organizations should join developed to address these training needs and
forces with domestic agencies to provide for training should provide opportunities for cooperation with
of foreign nationals. 3) Increased communication industry and the private sector. 7) Intersectorial
and coordination between the clinical, public health, efforts should be undertaken to train personnel and
and research communities are needed. The support work plans for training and research that
veterinary educational model, which looks at will help anticipate and control emerging diseases
populations rather than individual patients, might other than influenza.

Vol. 4, No. 3, July–September 1998 505 Emerging Infectious Diseases


Outbreak of Suspected Clostridium Enrichment cultures of the sevu specimens in

butyricum Botulism in India enriched chopped meat–glucose–starch medium
contained toxin after 5 days of anaerobic
To the Editor: Foodborne botulism, particularly incubation at 30°C. This was shown by mouse
associated with Clostridium butyricum, is rare; toxicity test in which the enrichment broth of the
no cases had been reported in India before this specimen was injected intraperitoneally into
outbreak. A reported case of foodborne mice; botulinum toxin was detected by observing
botulism represents a public health emergency its lethal effect on mice. This effect was
because of the potential severity of the disease neutralized by specific polyvalent botulinum
and the possibility of mass exposure to the antitoxin types A, B, E (Biomed, Warsaw,
contaminated product. Poland). Cultures of other food items tested
In September 1996, the anaerobic section of negative for toxigenic organisms. Serum speci-
the All India Institute of Medical Sciences mens (obtained more than 1 week after the onset
received serum and food samples from the of illness) from eight patients with mildly
National Institute of Communicable Diseases, symptomatic illness were negative for toxin.
Delhi, India, for investigating a possible outbreak To test the presence of toxin gene in the
of foodborne botulism. isolated strain of C. butyricum, polymerase chain
In the early hours of September 18, 1996, 34 reaction (PCR) was performed. Degenerate
of 310 students of a residential school in rural primers BoNT 1 and BoNT 2 were used, which
Gujrat complained of abdominal pain, nausea, amplify a specific 1.1-kb fragment of neurotoxin
chest pain, and difficulty in breathing. One of the gene C. botulinum types (A, B, E, F, and G) as well
students, aged 14, died before he could be treated; as toxigenic strains of C. baratti and C. butyricum
two others, aged 13, died on their way to the (3). Five Escherichia coli strains containing
hospital. The remaining 31 students were clones encoding fragments of the C. botulinum
admitted to a rural hospital; eight were neurotoxin genes were used as positive controls
discharged 1 day later after being given in the PCR assay (kindly provided by Alison East,
symptomatic treatment, while the other 23 were Institute of Food Research, United Kingdom).
transported by ambulance to an urban emer- PCR profile used was as follows: 94°C for 2 min,
gency department in Ahemdabad, Gujrat. followed by 25 cycles of 92°C for 1 min, 42°C for 1
Findings on examination included ptosis, pupil- min, and 62°C for 5 min, then held at 4°C (Alison
lary mydriasis, extraocular palsies, and impair- East, pers. comm.). An amplified product of 1.1 kb
ment of conciousness. All students were given was detected from the culture isolate of sevu.
symptomatic treatment in the form of stomach The outbreak described in this report draws
lavage and intravenous administration of attention to the emergence of new foodborne
antibiotics and steroids. Over the subsequent 24 pathogens and to their association with unusual
hours, 21 improved clinically and were dis- foods. Human botulism is commonly caused by C.
charged; however, two (aged 14 and 17 years) had botulinum neurotoxin type A, B, and E (4). In the
respiratory distress and required mechanical present study, we showed that a neurotoxigenic
ventilation. Differential diagnosis included botu- C. butyricum was present in the food implicated
linum food poisoning, and both patients were in a clinically suspected outbreak of botulism in
administered trivalent (A,B,E) botulinum anti- Gujrat, India.
toxin. They responded well to the treatment and Laboratory studies could not confirm the
were discharged from the hospital 1 month later. diagnosis of botulism because clinical materials
Patients reported that 24 hours before onset (such as contents of the gastrointestinal tract,
of symptoms, they had eaten ladoo (a local sweet), feces) were not submitted for examination for the
curd, buttermilk, sevu (crisp made of gram flour), presence of the botulinum toxin or organisms. It
and pickle. Food samples were assayed for is not surprising that toxin could not be detected
botulinum toxin and were cultured anaerobically in the eight serum samples received by our
(1). Anaerobic culture of leftover sevu yielded an laboratory. Because of the delay in clinical
organism in pure culture whose cultural and diagnosis, early serum samples could not be
biochemical properties were consistent with obtained. Toxin is detected in only 13% of serum
those of C. butyricum; i.e., it was lipase-negative, samples collected more than 2 days after
fermentative, and did not liquefy gelatin (2). ingestion of botulinum toxin (5). However, the

Emerging Infectious Diseases 506 Vol. 4, No. 3, July–September 1998


botulinum—ecology and control in foods. New York:

clinical presentation of the patients, response to Marcel Dekker, Inc.; 1992. p. 3-20.
trivalent botulinum antitoxin, and isolation of 5. Woodruff BA, Griffin PM, McCroskey LM, Smart JF,
toxigenic C. butyricum from one of the consumed Wainwright RB, Bryant RG, et al. Clinical and
food articles strongly suggest that the outbreak laboratory comparison of botulism from toxin types A,
was caused by food contaminated with toxigenic B, and E in the United States, 1975-1988. J Infect Dis
C. butyricum. 6. Aureli PK, Fenicia L, Pasolini B, Gianfranceschi M,
Neurotoxigenic C. butyricum was first McCroskey LM, Hatheway CL. VII. Two cases of type E
reported in 1986 in two cases of infant botulism in infant botulism caused by neurotoxigenic Clostridium
Rome (6). Recently, neurotoxigenic C. butyricum butyricum in Italy. J Infect Dis 1986;154:207-11.
was isolated from the food implicated in an 7. Meng X, Karasawa T, Zou K, Kuang X, Wang X, Lu C.
et al. Characterization of a neurotoxigenic Clostridium
outbreak of clinically diagnosed type E botulism butyricum strain isolated from the food implicated in
in China (7). In this outbreak, it appears that an outbreak of food-borne type E botulism. J Clin
sevu, because of improper storage, was contami- Microbiol 1997;35:2160-2.
nated with the spores of C. butyricum, which
subsequently germinated and produced toxin. To
the best of our knowledge, this is the first report Molecular Analysis of Salmonella
of neurotoxigenic C. butyricum causing foodborne paratyphi A From an Outbreak in New
botulism in India. Delhi, India
The changing epidemiology of foodborne
disease as highlighted in this report calls for To the Editor: In the context of emerging
improved surveillance, including the develop- infectious diseases, enteric fever caused by
ment of new technology for identifying outbreaks. Salmonella paratyphi A deserves increased
attention and vigilance, although its severity is
We thank Alison East, Institute of Food Research, often milder than that of S. typhi disease.
Reading Laboratory, United Kingdom, for supplying E. coli
clones with BONT gene for PCR; Pradeep Seth, professor
Outbreaks associated with this organism are
and head, Department of Microbiology, All India Institute of exceedingly rare but have recently been reported
Medical Sciences for facilities provided; Biomed Warsaw, in India (1) and Thailand. In India, the first
Poland, for polyvalent botulinum antitoxin; and the medical reported outbreak of disease associated with S.
and paramedical staff of Civil Hospital, Ahemdabad.
paratyphi A (1) provided an opportunity to study
Rama Chaudhry,* Benu Dhawan,* Dinesh the molecular epidemiology of infection caused by
Kumar,* Rajesh Bhatia,† J.C Gandhi,‡ R.K. this organism.
Patel,§ and B.C. Purohit§ A total of 18 human blood isolates of S.
All India Institute of Medical Sciences, New Delhi, paratyphi A, 13 from the outbreak in New Delhi,
India; †National Institute of Communicable Diseases, India (from September to October 1996) (1) and 5
Delhi, India; ‡Health Medical Services and Medical sporadic isolates from cases unrelated to the
Education (H.S.), Gandhi Nagar, India; and §Civil outbreak, were used in this study. A total of 36
Hospital, Ahemdabad, Gujrat, India culture-positive cases were detected during the 6-
week outbreak. All strains were phage type 1 and
References were sensitive to all antibiotics tested. Isolates were
1. Hatheway CL. Botulism. In: Balows A, Hausler WJ, analyzed by ribotyping and pulsed-field gel
Lennette EH, editors. Laboratory diagnosis of electrophoresis (PFGE) (2,3). PFGE/ribotype pro-
infectious diseases: principles and practice. New York:
files were assigned arbitrary designations and
Springer-Verlag: 1988. p. 111-33.
2. McCroskey LM, Hatheway CL, Fenicia L, Pasolini B, analyzed by defining a similarity (Dice) coefficient,
Aureli P. Characterization of an organism that F (3), where F = 1.0 indicates complete pattern
produces type E botulinal toxin but which resembles identity and F = 0, complete dissimilarity.
Clostridium butyricum from the feces of an infant with The five sporadic isolates of S. paratyphi A
type E botulism. J Clin Microbiol 1986;23:201-2.
gave PFGE patterns following XbaI (5'-TCTAGA-
3. Campbell KD, Collins MD, East AK. Gene probes for
identification of the Botulinal Neurotoxin gene and 3') digestion that were unique and distinctly
specific identification of neurotoxin types B.E. and F.J. different, with differences of 8 to 12 bands (F =
Clin Microbiol 1993;31:2255-62. 0.63-0.70). In contrast, the 13 outbreak isolates
4. Hatheway CL. Clostridium botulinum and other shared only four closely related PFGE patterns
clostridia that produce botulinum neurotoxin. In:
differing only in 1 to 6 bands (F = 0.8-1.0). Among
Hauschild AHW, Dodds KL, editors. Clostridium
the outbreak strains, two distinct clones were

Vol. 4, No. 3, July–September 1998 507 Emerging Infectious Diseases


observed, X1 and X2, which differed by 5 to 6 among the S. paratyphi A isolates during the 2-
bands. Furthermore, outbreak isolates X3 and month outbreak. This observation agrees with
X4 were closely related to X1, differing by four the high mutation rates noted among pathogenic
and three DNA fragments, respectively. Similar Salmonella spp. (6) and the plasticity of the
results were obtained after digestion with a genome of salmonellae associated with enteric
second restriction endonuclease, SpeI (5'- fever (7). How these changes affected the biologic
ACTAGT-3'; pattern designation S). Although behavior of these isolates will be the subject of
fewer bands were seen compared to PFGE, further study. Our study reaffirms the usefulness
ribotyping of these isolates using SpeI-digested of PFGE and ribotyping in the molecular typing
genomic DNA largely confirmed the PFGE and discrimination of individual Salmonella
results in that the sporadic isolates gave unique isolates for epidemiologic investigations.
profiles and only three closely related ribotype
Kwai-Lin Thong,* Satheesh Nair,* Rama
profiles were detected among the outbreak
Chaudhry,† Pradeep Seth,† Arti Kapil,† Dinesh
isolates. Two Malaysian isolates of S. paratyphi A Kumar,† Hema Kapoor,‡ Savithri Puthucheary,*
included for comparison gave patterns very and Tikki Pang*
different from the Indian isolates by both PFGE *University of Malaya, Kuala Lumpur, Malaysia;
(F = 0.44-0.65) and ribotyping. Also, it was †All India Institute of Medical Sciences, New Delhi,
determined that isolates A-117 (X1/S1) and A-123 India; and ‡Safdarjang Hospital, New Delhi, India
(X2/S2) belonged to the index cases and that, as
the outbreak progressed, other patterns (X3/S3 References
and X4/S4), which differed from the original 1. Kapil A, Sood S, Reddaiah VP, Das B, Seth P.
patterns by one to four bands, appeared during Paratyphoid fever due to Salmonella enterica serotype
weeks 2 to 3 of the outbreak. Notably, patterns X1 paratyphi A. Emerg Infect Dis 1997;3:407.
and X2 reappeared at the end of the outbreak. 2. Pang T, Altwegg M, Martinetti G, Koh CL,
Although molecular analysis of S. typhi and Puthucheary SD. Genetic variation among Malaysian
isolates of Salmonella typhi as detected by ribosomal
S. paratyphi B by ribotyping (2,4) and PFGE (3) RNA gene restriction patterns. Microbiol Immunol
has been reported, to the best of our knowledge 1992;36:539-43.
the present study is the first performed with S. 3. Thong KL, Cheong YM, Puthucheary S, Koh CL, Pang
paratyphi A. The data obtained agree with those T. Epidemiologic analysis of sporadic and outbreak
observed for S. typhi (3) in that outbreak isolates Salmonella typhi isolates by pulsed field gel
electrophoresis. J Clin Microbiol 1994;32:1135-41.
are more clonal and limited in diversity, whereas 4. Ezquerra E, Burnens A, Jones C, Stanley J. Genotypic
sporadic isolates are more diverse genetically and typing and phylogenetic analysis of Salmonella
belong to unrelated clones. According to the paratyphi B and S. java with IS200. J Gen Microbiol
criteria of Tenover et al. (5), it seems likely that 1993;139:2409-14.
the present outbreak was associated with two 5. Tenover FC, Arbeit RD, Goering RV, Mickelson PA,
Murray BE, Persing DH, et al. Interpreting
distinct clones/strains of S. paratyphi A (X1/S1 chromosomal DNA restriction patterns produced by
and X2/S2) that are related (5) but have distinct pulsed field gel electrophoresis: criteria for bacterial
PFGE profiles. This observation is perhaps not strain typing. J Clin Microbiol 1995;33:2233-9.
surprising given the fact that both clones are 6. Leclerc JE, Li B, Payne WL, Cebula TA. High mutation
phage type 1 and that contaminated potable water frequencies among Escherichia coli and Salmonella
pathogens. Science 1996;274:1208-11.
was incriminated in the outbreak (1). The PFGE 7. Liu SL, Sanderson KE. Highly plastic chromosomal
results were largely confirmed by ribotyping, organization in Salmonella typhi. Proc Natl Acad Sci U
although this technique appears to be slightly less S A 1996;93;10303-8.
sensitive and discriminating in that fewer bands
were seen and the differences between outbreak
isolates were much less obvious. Unrecognized Ebola Hemorrhagic Fever at
We thus conclude that the outbreak in New Mosango Hospital during the 1995
Delhi, India, was caused by two related but Epidemic in Kikwit, Democratic Republic
distinct clones of S. paratyphi A. There also of the Congo
appears to be substantial genetic diversity among
S. paratyphi A strains as the Malaysian isolates To the Editor: We report here the clinical
were very different from those from India. The description of a hemorrhagic syndrome observed
data also suggested minor genetic changes

Emerging Infectious Diseases 508 Vol. 4, No. 3, July–September 1998


in Mosango General Hospital that, retrospec- watery vomits. An intractable hiccup developed.
tively, was one of the first cases of the Ebola The fever remained in plateau around 40°C with
hemorrhagic fever outbreak in the Bandundu spikes. Obnubilation occurred during episodes of
province of former Zaire in the spring of 1995 (1). high fever. Pulse and blood pressure remained
stable. ECG showed no modifications. Cutaneous
Case examination detected for the first time a
On April 20, 1995, a 70-year-old nun, working maculopapular rash and petechiae on flanks and
as a nurse in Kikwit General Hospital, was limbs, and the patient complained of gastric pain
admitted to Mosango General Hospital with a 5- for which the neurologic examination was
day history of fever, despite antimalarial normal. Urine was abundant and clear.
treatment. The day before hospitalization she On hospitalization day 3, high fever
had profuse diarrhea, vomiting, high fever, and continued, with some defervescence during
severe agitation with delirium. On arrival, quiet which the patient regained lucidity, although she
and apyretic, she complained of headache, loss of responded only with monosyllables because of the
appetite, and severe asthenia, but she walked to extreme asthenia and somnolence; diarrhea
her room without help. On examination, the only persisted but without hemorrhage. The patient
abnormalities recorded were severe dehydration had less vomiting. Laboratory data showed ESR
and oral thrush-like lesions, raising a suspicion of 35 mm/h; BT 10 min; CT 12 min; WBC 12.6x109/L
candidiasis. Pulse rate was 80/min and blood (70% neutrophils, 24% lymphocytes, 2% eosino-
pressure 120/80. Medical history included an phils, 1% basophils, 3% mastocytes). During the
amebiasis liver abscess 15 years ago and chronic night, the patient maintained a high tempera-
coronaritis since 1990. ture, still with temperature-pulse disparity. The
Electrocardiogram (ECG) abnormalities were diagnosis of typhoid fever was questioned, and
consistent with chronic diffuse ischemia. Labora- other diagnostic possibilities were reconsidered
tory investigations showed the following values: (shigellosis, mononucleosis); leukocytosis was
few trophozoites on a thick film; erythrocyte considered against the possibility of Ebola
sedimentation rate (ESR) 15 mm/h; bleeding time hemorrhagic fever. Chloramphenicol was switched
(BT) 7½ min; coagulation time (CT) 9 min; and to rifampicin (1,200 mg/24h).
white blood cells (WBC) 8.4x109/L (73% neutro- On April 23, the patient’s status was
phils, 23% lymphocytes, 2% eosinophils, 1% unchanged with fever, asthenia, and diarrhea.
basophils, 1% mastocytes). Urinalysis showed Later in the day, her condition deteriorated:
proteinuria (++), hyaline cylinders (+++), 50 petechiae could be seen on the entire body, and
white cells per field, and hematuria (+). The for the first time, bruises and bleeding at
patient was perfused with 4L/day of glucose and injection sites were observed and precluded
1.5 g of quinine. She was kept in a private room in intramuscular injections. The patient had
the nearby nuns’ convent. bleeding cracks on the lips and diffuse bleeding in
Later during the day, high fever (40°C) and the oral cavity (i.e., gums, tongue). The volume of
severe diarrhea with melena developed; the pulse urine was low, and antibiotic therapy was
rate was normal (80/min). Typhoid fever was changed to cephalosporin.
suspected despite the lack of hepatosplenom- On hospitalization day 5, hemorrhages in-
egaly; Widal test was not available for creased, and fever remained high until the end of
confirmation. Treatment was started with the day, when it started to normalize. Urine volume
intravenous (i.v.) amoxicillin (1g/6h during the was still low (verified by vesical catheter) despite
first 24 h and then 1g/4h) and i.v. chlorampheni- the i.v. rehydration of 4 L/day. Fresh blood
col (2g/24h). Subsequently, coagulation abnor- transfusion (300 ml) did not slow the hemorrhag-
malities developed in addition to the melena; ing; disseminated intravascular coagulation was
vitamin K and epsilon amino caproic acid were suspected, and heparin treatment was started.
added to i.v. therapy. Watery vomits remained The patient became comatose. The laboratory
frequent and abundant, and the patient’s results showed ESR 55mm/h and WBC 30.2x109/
condition was unresponsive to treatment. L with an unchanged formula. No coagulation
On hospitalization day 2, the clinical picture was observed on BT and CT. Blood pressure fell
remained the same, with severe asthenia, (80/50); the clinical status remained unchanged
anorexia, abundant blackish diarrhea, and until the patient’s death on April 25 at 10:00 a.m.

Vol. 4, No. 3, July–September 1998 509 Emerging Infectious Diseases


No special nursing precautions were taken References

either during the hospitalization or after the 1. Muyembe T, Kipasa M, the International Scientific and
death, and the body was transferred to Kikwit to Technical Committee, WHO Collaborating Centre for
Haemorrhagic Fevers. Ebola haemorrhagic fever in
be buried. On April 30, another nun who took care of
Kikwit, Zaire. Lancet 1995;345:1448.
the index patient during the night of April 23 2. Khan AS, Kweteminga TF, Heymann DL, LeGuenno
became ill with fever, headache, and myalgia. Over B, Nabeth P, Kerstiens B, et al. The reemergence of
the next few days, the second patient had a clinical Ebola hemorrhagic fever, Zaire, 1995. J Infect Dis. In
picture identical to that of the index patient, press 1998.
3. Piot P, Sureau P, Breman JG, Heymann D, Kintoki V,
including high fever, severe asthenia, vomiting,
Masamba M, et al. Clinical aspects of Ebola virus infection
hiccups, and diarrhea. On May 5, epistaxis and in Yambuku area, Zaire, 1976. In: Pattyn SR, editor. Ebola
coagulation abnormalities developed, followed by virus haemorrhagic fever. Amsterdam: Elsevier/North-
other clinical signs of the hemorrhagic syndrome. Holland Biomedical Press; 1977. p. 7-14.
The second patient was transferred to Kikwit 4. Sureau PH. Firsthand clinical observations of
hemorrhagic manifestations in Ebola hemorrhagic
General Hospital, where she died 6 days later. A
fever in Kitwit, Democratic Republic of the Congo
laboratory confirmation of Ebola hemorrhagic fever (former Zaire): clinical observations in 103 patients.
was made on a blood specimen collected on May 5 Review of Infectious Diseases 1989;11:S790-3.
and sent to Special Pathogens Branch (Centers for 5. Bwaka MA, Bonnet M-J, Calain P, Colebunders R, De
Disease Control and Prevention, Atlanta, GA). Roo A, Guimard Y, et al. Ebola hemorrhagic fever in
Kikwit, Democratic Republic of the Congo (former
These cases of unrecognized Ebola hemor-
Zaire): clinical observations in 103 patients. J Infect
rhagic fever were part of the hospital outbreak Dis. In press 1998.
that precipitated and mobilized international
community efforts (2). Retrospectively, the
clinical symptoms observed were typical of Ebola
hemorrhagic fever (3,4) and were described again
Classification of Reactive Arthritides
in subsequent patients during this outbreak (5).
To the Editor: We read with interest J.A.
In tropical Africa, the presence of hemorrhagic
Lindsay’s article on sequelae of foodborne
symptoms in the course of a febrile illness should
disease (1). However, we believe that there are
raise the possibility of one of the viral hemorrhagic
errors in the classification of the reactive
fever diseases. In viral hemorrhagic fevers,
arthritides. Lindsay states that ankylosing
maculopapular rash is constantly observed only in
spondylitis (AS) is a “rheumatoid inflammation
filovirus disease. Typically, the clinical laboratory
of synovial joints and entheses within and
findings include an early lymphopenia and marked
distal to the spine.” Although not the primary
thrombocytopenia. Containment and barrier nurs-
focus of the article, the classification and
ing procedures should be initiated until the
etiopathogeneses of rheumatoid arthritis (RA)
diagnosis of viral hemorrhagic fever can be ruled
and the seronegative spondyloarthropathies,
out. The index patient described here was the third
including AS, should be clarified. The term
patient transferred from Kikwit General Hospital
spondylitis, from the Greek spondylos, for
in less than 1 month to die of a hemorrhagic
vertebra, means inflammation of the vertebrae.
illness after a few days of an unexplained febrile
The term rheumatoid is generally taken to
syndrome. Two patients were health-care
apply to rheumatoid arthritis, while rheumatic
workers in Kikwit General Hospital. This cluster
is a more general term applying to all
of hemorrhagic illness and possible human-to-
connective tissue diseases.
human transmission, particularly among hospi-
AS is a chronic, systemic, inflammatory
tal staff, was (and should always be) sufficient to
disorder primarily affecting the axial skeleton,
suspect a viral hemorrhagic fever. The laboratory
with sacroiliac joint involvement as its hallmark.
confirmation of this presumptive diagnosis was
Back pain is the first clinical manifestation in
the clenching factor in the multinational effort in
approximately 75% of the patients (2). The
backache is usually insidious in onset, dull, and
Marie-Jo Bonnet, Philippe Akamituna, and difficult to localize. After several months, it
Anicet Mazaya generally becomes bilateral and persistent. The
Mosango General Hospital, Kikwit, République ache is often worse in the morning or after
Démocratique du Congo periods of inactivity and improves with move-

Emerging Infectious Diseases 510 Vol. 4, No. 3, July–September 1998


ment. The course is highly variable. Involvement found. The majority of patients have elevated
of peripheral joints other than hips and shoulders titers of serum rheumatoid factor, as opposed to
is uncommon. the seronegative spondyloarthropathies. Spinal
AS is strongly associated with human involvement in RA is seen but most often involves
leukocyte antigen (HLA) B27, a major histocom- the cervical spine. The pathogenesis of the spinal
patibility complex (MHC) class I allele, and may disease is that of synovitis of the odontoid-atlas
show familial aggregation. More than 90% of joints. The major HLA association is with HLA-
patients with AS have the HLA-B27 allele (3). DR4, an MHC class II allele.
HLA-B27 is believed to be directly involved in Reactive arthritis is so named because it is
disease pathogenesis. Transgenic rats expressing felt that the arthritis and other inflammatory
human HLA-B27 develop a broad spectrum of manifestations are an immune reaction to a
disease closely resembling human disease. These distant infection. There is an association with
rats have peripheral and axial arthritis, HLA-B27 but less so than that found in AS (60%
gastrointestinal inflammation, and diarrhea. to 80%, compared with more than 90% in AS).
Psoriatic-like skin changes and inflammation of While bacterial antigens can be found within the
the heart and male genitalia are also seen. joint, the offending infectious process most often
Histologically, the joint, gut, skin, and heart subsides before the onset of arthritis, and no
lesions resemble those seen in HLA-B27-related living organisms are found in the joint (2). In
disease in humans (4). many cases, no infectious trigger can be
The inflammatory process in AS involves the identified. Persistence of microbial antigens has
synovial and cartilaginous joints, as well as the been demonstrated and is likely to play a
osseous attachments of tendons and ligaments prominent role in the pathogenesis of acute and
(entheses). Much of the skeletal pathology of AS can chronic inflammation. Antigens to several
be explained by the changes that take place at the gastrointestinal pathogens have been isolated
entheses. After an initial inflammatory, erosive from the synovial fluid in patients with reactive
process involving the entheses, there is healing in arthritis. Salmonella, Shigella, Yersinia, Campy-
which new bone is formed. The final outcome of this lobacter, and Borrelia are the most common
process is an irregular bony prominence with pathogens capable of initiating reactive arthritis
sclerosis of the adjacent cancellous bone (5). This (2). The arthritis is generally an asymmetric
can be contrasted with the pathology of RA, in oligoarthritis predominantly affecting the lower
which there is a greater tendency to affect extremities and typically develops 6 to 14 days
cartilaginous joints such as the intervertebral after a bout of diarrhea. However, onset can occur
discs and symphysis pubis. The process in RA is up to 3 months later. Diarrhea can also be absent,
one of bony erosion rather than new bone and there is no relationship between the severity
formation. of the arthritis and the severity of the diarrhea.
The term ankylosing spondylitis, derived Reiter syndrome is in fact a reactive arthritis.
from the Greek for “bent spinal vertebrae,” by In 1916, Hans Reiter described a triad of arthritis,
definition requires exclusion of the other urethritis, and conjunctivitis in a soldier with
spondyloarthropathies, such as Reiter syndrome dysentery. However, the disease was actually first
and reactive arthritides due to enteric (or described by Sir Benjamin Brodie in the early 1800s
urogenital) organisms. Spondylitis may occur in (6). The complete triad is actually seen in only a
reactive arthritis, psoriatic arthritis, or the minority of patients. Arthritis develops 1 to 3 weeks
arthropathy associated with inflammatory bowel after the diarrhea or urethritis. It is generally
disease, but is less common in these diseases asymmetric, involving large joints, especially in the
(approximately 50% in reactive arthritis, 20% in lower extremities. The term Reiter syndrome
enteric arthritis or psoriatic arthritis). All of actually refers only to the triad of arthritis,
these diseases can be viewed as seronegative urethritis, and conjunctivitis. Reiter syndrome is
spondyloarthropathies in that, by definition, both clinically and historically more accurately
rheumatoid factor is not present. termed reactive arthritis. Nevertheless, the term
RA is a systemic autoimmune disorder of reactive arthritis does not reflect the systemic
unknown etiology. It is a chronic symmetric nature of the disease.
arthropathy of peripheral joints, associated with In summary, while both reactive arthritis
erosive synovitis. Enthesopathy is generally not and ankylosing spondylitis are seronegative

Vol. 4, No. 3, July–September 1998 511 Emerging Infectious Diseases


spondyloarthropathies, they are separate enti- test applied; in this case, both the information and
ties. Both are distinct from rheumatoid arthritis. the cost are greater than necessary.
Information on the prevalence of bloodborne
Darren R. Blumberg and Victor S. Sloan
infections among the general population or,
Robert Wood Johnson Medical School, New
Brunswick, New Jersey, USA
preferably, among potential donors (particularly
where professional donors are frequent) along
with information on the costs of the tests to be
References used can form the basis of a stepwise screening
1. Lindsay JA. Chronic sequelae of foodborne disease. scheme. Tests for infections with the highest
Emerg Infect Dis 1997;3:443-52.
2. Veys EM, Mielants H. Enteropathic arthropathies. In: prevalence would be applied first. For example,
Klippel JH, Dieppe PA, editors. Rheumatology. St. in many areas of Peru, using the Venereal
Louis: 1994; 3.35. Disease Research Laboratory (VDRL) test (for
3. Khan MA. Seronegative spondyloarthropathies. In: screening Treponema pallidum infection) first
Schumache HR, editor. Primer on rheumatic diseases. would reduce the number of samples to be
Atlanta (GA): Arthritis Foundation; 1993.
4. Hammer RE, Maika SD, Richardson JA, Tang J-P, subjected to other more expensive and often less
Taurog JD. Spontaneous inflammatory disease in available tests (e.g., HIV enzyme-linked
transgenic rats expressing HLA-B27 and human a2m: immunosorbent assay [ELISA] or hepatitis C
an animal model of HLA-B27-associated human virus [HCV] ELISA); in others areas, a test for
disorders. Cell 1990;63:1099-112. hepatitis B virus antigen (HBsAg) should be used
5. El-Khoury GY, Kathol MH, Brandser EA. Seronegative
spondyloarthropathies. Radiol Clin North Am before HIV ELISA. The reduction in cost
1996;34:343-57. provided by stepwise screening will depend on
6. Toivanen A. Reactive arthritis. In: Klippel JH, Dieppe the prevalences of the more frequent infections
PA, editors. Rheumatology. St. Louis: 1994: 4.9. and the frequency of concurrent infections.
The questionnaires applied to candidate
Reply to Drs. Blumberg and Sloan donors should be validated, and the benefit of
using them should be assessed. In most settings,
To the Editor: I concur with your comments. After candidate donors are either ignorant of their
reviewing the literature related to foodborne status as carriers of bloodborne infection or ready
disease, it appears that the original classification to deny it; therefore, the questionnaire is of little
of reactive arthritides has been in error for some use. In some cases candidate donors are turned
time. I certainly appreciate the correction. down because of “hepatitis history” when in fact
they have not had bloodborne hepatitis.
James A. Lindsay
Finally, screening tests seem to be quite more
University of Florida, Gainesville, Florida, USA
expensive than reported in Table 4 of the Schmunis
article. In Lima, at a ministry of health facility,
some prices are as follows: HIV ELISA US$12.50,
Cost of Blood Screening VDRL US$6.40, HBsAg US$13.90.

To the Editor: In reference to G.A. Schmunis’ O. Jaime Chang

article on the risk for transfusion-transmitted Instituto Nacional de Salud, Ministerio de Salud,
infections in Central and South America (1), I Lima, Peru
would like to comment on the cost of blood
screening. In a screening program, the objective Reference
is to have safe blood units, not to assess the 1. Schmunis GA, Zicker F, Pinheiro F, Brandling-Bennett
prevalence of different infections among poten- D. Risk for transfusion-transmitted infectious diseases
tial or actual donors. Thus, while acknowledging in Central and South America. Emerg Infect Dis
all infections present in a given donor or potential 1998;1:5-11.
donor is not required, detecting at least one of the
infections that would make a donor noneligible is. If
samples from every potential donor are subjected
(by default) to all the tests, information on every
infection present is provided, and the cost of
screening this donor is the sum of the cost of every

Emerging Infectious Diseases 512 Vol. 4, No. 3, July–September 1998

Book Review

Emerging Infections. R.M. Krause, Editor. Academic and the complexities of dengue hemorrhagic
Press, New York, 1998, 513 pages. fever and dengue shock syndrome are reviewed
by Holmes, Bartley, and Garnett of Oxford
Emerging Infections is the first volume in a University, with a strong emphasis on the
new series entitled Biomedical Research Reports, epidemiologic aspects. This discussion is followed
edited by John Gallin and Anthony Fauci. The by an authoritative review of the AIDS epidemic by
volume contains 17 chapters, all outstanding and Quinn and Fauci, who include sobering predictions
for the most part both timely and comprehensive, of future epidemics in Asia and Africa.
written by experts in the field. After an A short chapter on hantavirus by Nathanson
intellectually stimulating introductory chapter and Nichol is followed by a searching account of
by Richard Krause, we are treated to an analysis Ebola virus emergences, including fascinating
of epidemics by one of the supreme authorities, speculations on their possible origin, by Murphy
Roy Anderson of Oxford University. Included and Peters. The final chapter, related to virus
here is a valuable discussion on the transmission diseases, by Tabachnick, considers arthropod-
of microbial infections in populations as well as borne pathogens and is dedicated to George
the development of drug resistance. Craig, a leader in the field of vector biology.
Chapters on emerging bacterial diseases Two chapters are devoted to emerging
include a superb one on Persisting Problems in parasitic diseases. Adel Mahmoud reviews
Tuberculosis, by McKinney, Jacobs, and Bloom, Giardia, Cryptosporidium, Isospora, and
which is right up to date yet includes fascinating Cyclospora organisms, whose role in human
literary quotes, from Charles Dickens to Sir diseases has only recently been recognized.
Arthur Conan Doyle. The possible role of mobile Karen Day of Oxford University discusses
genetic elements in the emergence of new strains malarial infection and disease and the factors
of cholera is briefly discussed by Rubin, Waldor, that have led to the current world in which the
and Mekalanos. Escherichia coli O157:H7 and its effects of malaria in many regions are the same or
evolution as an emerging infectious disease are worse than at the turn of the century.
considered by Whittam, McGraw, and Reid. A Finally, a chapter on transmissible spongiform
useful overview of group A streptococcal diseases, encephalopathies by Hope brings us up to 1996
combined with an overview of staphylococcal toxic when new variant Creutzfeldt-Jakob disease
shock syndrome, is given by Musser and Krause (bovine spongiform encephalopathy agent in
and followed by a scholarly account of Lyme disease humans) was first recognized.
by Allen Steere. Finally, Davies and Webb devote Emerging Infections sets a high standard for
nearly 40 pages to a discussion of the emergence of future volumes in this series. Nicely produced, it
antibiotic resistance in bacteria. is recommended reading for everyone with an
There are six chapters on viral diseases, interest in infectious diseases and in strategies
beginning with Robert Webster on influenza, the for research, understanding, and control of the
classic pandemic disease threat. Webster’s complex factors that lead to infectious disease
review provides a remarkably current descrip- emergence and reemergence.
tion (up to mid-1997) of what we know about
influenza pandemics and their origins, including Brian W. J. Mahy
Centers for Disease Control and Prevention, Atlanta,
a discussion of the first H5N1 influenza case in a
Georgia, USA
human in Hong Kong. The emergence of dengue

Vol. 4, No. 3, July–September 1998 513 Emerging Infectious Diseases

News and Notes

CDC To Release Updated Emerging First Congress of the European Society

Infectious Disease Plan for Emerging Infections, September 13-16,
1998, Budapest, Hungary
Preventing Emerging Infectious Diseases: A
Strategy for the 21st Century outlines new Founded in 1997 by human and veterinary
measures toward achieving emerging infectious infectious disease specialists, the European
disease prevention and control. The updated plan Society for Emerging Infections (ESEI) forms a
signals the second phase of the campaign European network for the study of new or
launched in 1994 with the publication of emerging infectious diseases. This interdiscipli-
Addressing Emerging Infectious Disease Threats: nary forum was a necessity because most
A Prevention Strategy for the United States, a emerging infections are zoonoses or are linked
collaborative effort of the Centers for Disease with animal care or with animal product
Control and Prevention under the leadership of handling. ESEI is holding its first International
the National Center for Infectious Diseases and Congress in the Atrium Hyatt Conference
institutions and agencies throughout the United Centre, Budapest, Hungary, September 13–16,
States and abroad. 1998. The opening lecture, “Emerging infec-
The objectives and activities in the updated tions—an overview,” will be given by Prof. Luc
plan are organized under the same four goals Montagnier. The meeting will consist of invited
described in the 1994 publication: surveillance lectures, two free paper sessions, a roundtable
and response, applied research, infrastructure discussion, and daily poster presentations.
and training, and prevention and control. Nine Conference topics include risk factors for
specific priority program areas are outlined: emergence of pathogens, tick-borne diseases,
antimicrobial resistance; foodborne and water- hantavirus infections, transmissible spongiform
borne diseases; vector-borne and zoonotic encephalopathies, Borna disease, lyssavirus
diseases; diseases transmitted through blood infections, and foodborne diseases. A banquet
transfusions or blood products; chronic diseases cruise on the Danube will end the Congress on
caused by infectious agents; vaccine development Wednesday evening, September 16, 1998.
and use; diseases of people with impaired host Abstracts should address one of the above
defenses; diseases of pregnant women and topics and be submitted before the deadline of
newborns; and diseases of travelers, immigrants, May 31, 1998. For more information, please
and refugees. contact ESEI President Prof. M. Granström,
Achieving the goals outlined in the updated Microbiology, Karolinska Hospital, S-171 76
plan will continue to require sustained and Stockholm, Sweden; fax: 46-8-30-80-99; e-mail:
coordinated efforts of agencies and organizations, or the local organizer Dr. A.
state and local health departments (surveillance Lakos, Centre for Tick-borne Diseases, Visegradi
of infectious diseases), academic centers and 14, H-1132 Budapest, Hungary, fax: 36-1-349-49-
other federal agencies (research), health-care 26, e-mail:
providers and health-care networks (guideline
development and dissemination), international
organizations (outbreak responses overseas), and Foodborne Illness: A Disease for All
other partners. Seasons, October 27 and 28, 1998,
The executive summary of Preventing Newark, Delaware
Emerging Infectious Diseases: A Strategy for the
21st Century will be released as a special issue of Sponsored by the Public Health Laboratories of
the Morbidity and Mortality Weekly Report on Delaware, Maryland, New Jersey, and Pennsyl-
September 10, 1998. An electronic version of the vania and the National Laboratory Training
full document as well as information on how to Network, Eastern Office, this seminar will
order a print copy will be available shortly provide up-to-date information on changes in
afterwards at epidemiology in foodborne diseases, emerging
ncid.htm. infectious organisms, proper food and clinical
specimen collection and testing, and strategies to

Emerging Infectious Diseases 514 Vol. 4, No. 3, July–September 1998

News and Notes

decrease foodborne illness. Speakers will repre- based on selected abstracts and scientific poster
sent the Centers for Disease Control and sessions. Topics include drug design and
Prevention, the Food and Drug Administration, discovery, chemistry and preclinical develop-
Minnesota Department of Agriculture, Minne- ment, pharmacology, virology and drug resis-
sota Department of Public Health, and the tance, and clinical development (phase I/II/III
University of Maryland. and novel combination therapies).
For more information, contact Christine Ford, Registration is limited, and preference will be
National Laboratory Training Network, Eastern given to those delegates who submit an abstract.
Office, Delaware Public Health Laboratory; tel.: For further information, contact the Interna-
302-653-2841; fax: 302-653-2844; e-mail: tional Medical Press; tel: 404-233-6446; fax 404- 233-2827; e-mail:; or
Website: http//

December 1998 International Conference

on Antiretroviral Therapy, St. Thomas, Erratum
West Indies
Vol. 4, No. 2
The International Medical Press will sponsor
the International Conference on the Discovery In the article, “Accommodating Error Analysis in
and Clinical Development of Antiretroviral Comparison and Clustering of Molecular Finger-
Therapies from December 13-17, 1998. In prints, by H. Salamon, M.R. Segal, A. Ponce de Leon,
and P.M. Small, in Table 1 on page 162, mean
addition to plenary talks from invited speakers,
kilobases for H37Rv band 12 should be 0.936.
the conference will feature oral presentations

Vol. 4, No. 3, July–September 1998 515 Emerging Infectious Diseases

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 404-639-3967 (tel), 404-639-3075 (fax), or (e-mail).
Emerging Infectious Diseases is published in English and features three types of articles: Perspectives, Synopses, 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
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 Manuscript Submission
Follow “Uniform Requirements for Manuscripts Submitted to Include a cover letter verifying that the final manuscript has
Biomedical Journals” (Ann Int Med 1997:126[1]36-47) (http:// been seen and approved by all authors. Submit three copies of the original manuscript with three sets
Begin each of the following sections on a new page and in this of original figures and an electronic copy (on diskette or by e-mail) to
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Perspectives: Articles in this section should provide insightful
Abstract and key words. Avoid citing references in the abstract.
analysis and commentary about new and reemerging infectious
Include up to 10 key words; use terms listed in the Medical Subject
diseases or related issues. Perspectives may also address factors
Headings from Index Medicus (
known to influence the emergence of diseases, including microbial
adaptation and change; human demographics and behavior;
Text. Double-space everything, including the title page,
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