EMERGING INFECTIOUS DISEASES

Editors

Editor 
Joseph E. McDade, Ph.D.
National Center for Infectious Diseases
Centers for Disease Control 
  and Prevention (CDC)
Atlanta, Georgia, USA

Perspectives Editor
Stephen S. Morse, Ph.D.
The Rockefeller University
New York, New York, USA

Synopses Editor
Phillip J. Baker, Ph.D.
Division of Microbiology and
  Infectious Diseases
National Institute of Allergy and
  Infectious Diseases
National Institutes of Health (NIH)
Bethesda, Maryland, USA

Dispatches Editor
Stephen Ostroff, M.D.
National Center for Infectious Diseases
Centers for Disease Control 
  and Prevention (CDC)
Atlanta, Georgia, USA

Managing Editor
Polyxeni Potter, M.A.
National Center for Infectious Diseases
Centers for Disease Control 
  and Prevention (CDC)
Atlanta, Georgia, USA


Liaison Representatives

Anthony I. Adams, M.D.
Chief Medical Adviser
Commonwealth Department of
  Human Services and Health
Canberra, Australia

David Brandling-Bennett, M.D.
Director, Division of Communicable
  Diseases
Pan American Health Organization
World Health Organization
Washington, D.C., USA

Richard A. Goodman, M.D., M.P.H.
Editor, MMWR
Centers for Disease Control 
  and Prevention (CDC)
Atlanta, Georgia, USA

William Hueston, D.V.M., Ph.D
Acting Leader, Center for Animal 
  Health Monitoring
Centers for Epidemiology and 
  Animal Health
Veterinary Services, Animal and Plant
  Health Inspection Service
U.S. Department of Agriculture
Fort Collins, Colorado, USA

James LeDuc, Ph.D.
Advisor for Arboviral Diseases
Division of Communicable Diseases
World Health Organization
Geneva, Switzerland

Joseph Losos, M.D.
Director General
Laboratory Center for Disease Control
Ontario, Canada

Gerald L. Mandell, M.D.
Liaison to Infectious Diseases Society
  of America
University of Virginia Medical Center
Charlottesville, Virginia, USA

Robert Shope, M.D.
Director, Yale Arbovirus Research Unit
Yale University School of Medicine
New Haven, Connecticut, USA

Bonnie Smoak, M.D.
Chief, Dept of Epidemiology
Division of Preventive Medicine
Walter Reed Army Institute of Research
Washington, D.C., USA

Robert Swanepoel, B.V.Sc., Ph.D.
Head, Special Pathogens Unit
National Institute for Virology
Sandrinham 2131, South Africa

Roberto Tapia, M.D.
Director General de Epidemiologa
Direccin General de Epidemiologa
Secretara de Salud
Mxico

Morag Timbury, M.D.
Director
Central Public Health Laboratory
London, United Kingdom



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Editorial Policy and Call for Articles

The goals of Emerging Infectious Diseases (EID) are to promote the
recognition of new and reemerging infectious diseases and to
improve the understanding of factors involved in disease emergence,
prevention, and elimination. EID 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 whose study elucidates the factors
influencing the emergence of infectious diseases.

EID will be published in English and will feature three types of
articles: Perspectives, Synopses, and Dispatches. The purpose and
requirements of each type of article are described in detail below.


Instructions to Authors

Editorial Material: Manuscripts should be prepared according to the
Uniform Requirements for Manuscripts Submitted to Biomedical
Journals (JAMA 1993:269[17]: 2282-6).

Begin each of the following sections on a new page and in this
order: title page, abstract, text, acknowledgments, references,
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for accepted journal abbreviations. Tables and figures should be
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except for vernacular names (viruses that have not really been
speciated, such as coxsackievirus and hepatitis B; bacterial
organisms, such as pseudomonads, salmonellae, and brucellae). 

Perspectives: Contributions to the Perspectives section are welcome
from scientists and professionals in all disciplines and should
address factors known to contribute to the emergence of infectious
diseases, including microbial adaption and change; human
demographics and behavior; technology and industry; economic
development and land use; international travel and commerce; and
the breakdown of public health measures. Articles should be
approximately 3,500 words and should include references, not to
exceed 40. The section should begin with an introduction outlining
the relationship of the issues discussed in the paper to the
emergence of infectious diseases. Use of additional subheadings in
the main body of the text is recommended. If detailed methods are
included, a separate section on experimental procedures should
immediately follow the body of the text. Photographs and
illustrations are optional. Provide a short abstract (150 words)
and a brief biographical sketch.

Synopses: Submit concise reviews of infectious diseases or closely
related topics. Preference will be given to reviews of new and
emerging diseases; however, timely updates of other diseases or
topics are also welcome. Synopses should be approximately 3,500
words and should include references, not to exceed 40. The section
should begin with an introduction outlining the relationship of the
issues discussed in the paper to the emergence of infectious
diseases. Use of additional subheadings in the main body of the
text is recommended. If detailed methods are included, a separate
section on experimental procedures should immediately follow the
body of the text. Selective use of illustrations is encouraged.
Provide a short abstract of no more than 150 words and a brief
biographical sketch.

Dispatches: Provide brief updates on trends in infectious diseases
or infectious disease research. Dispatches (1,000 to 1,500 words of
text) should be in a  letter to the editor  format and should not
be divided into sections. Dispatches should begin with a brief
introductory statement about the relationship of the topic to the
emergence of infectious diseases. Include methods development;
references, not to exceed five; and figures or illustrations, not
to exceed two.

All articles will be reviewed by independent reviewers. The Editor
reserves the right to edit articles for clarity and to modify the
format to fit the publication style of Emerging Infectious
Diseases.

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Send all manuscripts and correspondence to the Editor, Emerging
Infectious Diseases, National Center for Infectious Diseases,
Centers for Disease Control and Prevention, 1600 Clifton Road,
Mailstop C-12, Atlanta, GA  30333, USA, or by e-mail on the
Internet to eideditor@cidod1.em.cdc.gov.


CONTENTS, EMERGING INFECTIOUS DISEASES, VOL. 1, NO.1

Perspectives

Emerging Infections: Getting Ahead of the Curve, 1, David Satcher
Factors in the Emergence of Infectious Diseases, 7, Stephen S. 
Morse

Synopsis

Unraveling Mysteries Associated with Cat-Scratch Disease, Bacillary
Angiomatosis, and Related Syndromes, 16, Russell Regnery and      
Jordan Tappero

Dispatches

Emergence of Barmah Forest Virus in Western Australia, 22, Michael
D.A. Lindsay, Cheryl A. Johansen, Annette K. Broom, David W. Smith,
and John S. Mackenzie

An Outbreak of Shigella sonnei Infection Associated with
Consumption of Iceberg Lettuce, 26, J.A. Frost, M.B. McEvoy, C.A.
Bentley, Y. Andersson, and B. Rowe

?Lyme Disease in Australia--Still To Be Proven!, 29, Richard C.
Russell

A Novel Morbillivirus Pneumonia of Horses and its Transmission to
Humans, 31, Keith Murray, Russell Rogers, Linda Selvey, Paul
Selleck, Alex Hyatt, Allan Gould, Laurie Gleeson, Peter Hooper, and
Harvey Westbury



Commentary

Electronic Communication and the Future of International Public
Health Surveillance, 34, T. Demetri Vacalis, Christopher L. R.
Bartlett, and Cheryl G. Shapiro

News and Notes

Communicable Diseases Intelligence, 36, Helen Longbottom

DxMONITOR: Compiling Veterinary Diagnostic Laboratory Results, 36,
William Hueston

WHO Scientific Working Group on Monitoring and Management of
Bacterial Resistance to Antimicrobial Agents, 37, Fred C. Tenover
and James M. Hughes


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Perspectives

Emerging Infections: Getting Ahead of the Curve

David Satcher, M.D., Ph.D.
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Abstract
The early history of infectious diseases was characterized by
sudden, unpredictable outbreaks, frequently of epidemic proportion.
Scientific advances in the late 19th and early 20th centuries
resulted in the prevention and control of many infectious diseases,
particularly in industrialized nations. Despite these improvements
in health, outbreaks of infectious disease continue to occur, and
new infections emerge. Since 1987, the National Academy of
Science's Institute of Medicine (IOM) has published three reports
that have identified erosion of the public health infrastructure
among the factors contributing to new and reemerging infectious
diseases. In partnership with many public and private organizations
in the United States and abroad, the Centers for Disease Control
and Prevention (CDC) has developed a strategic plan that addresses
the priorities set forth in the IOM reports and serves as a guide
for CDC and its partners to combat emerging microbial threats to
health. Laboratory-based surveillance, better communication
networks, and improvements in the public health infrastructure are
the cornerstones of the strategy. Emerging Infectious Diseases, a
new periodical produced by CDC, will serve as a forum for exchange
of information about incipient trends in infectious diseases,
analysis of factors contributing to disease emergence, and
development and implementation of prevention measures.

"Nothing in the world of living things is permanently fixed."  
Hans Zinnser--Rats, Lice and History, 1935




Early History of Infectious Diseases

Infectious diseases have plagued humans since the dawn of
civilization (1-5). The history of these diseases provides a
valuable perspective for evaluating current trends. Humans are
presumed to have originated in tropical climates and to have been
affected by the same parasitic diseases as other primates in these
areas. As available supplies of game diminished, early hunters
migrated into temperate zones which were free of tropical
parasites. Historians speculate that humans were relatively safe
from infectious diseases during that period. Later, however, as
agriculture began to provide a substantial portion of the human
diet, populations stabilized and grew. Eventually, populations
reached a size that would support persistent person-to-person
spread of infectious microorganisms. With this newly established
mode of transmission, infectious diseases soon became widespread.
The exact origins of many infectious agents remain obscure, but
with the advent of large populations, humans eventually became the
established reservoir of many agents. Infected animals and
contaminated food and water were additional sources of infectious
microorganisms.

Dissemination of infectious diseases intensified as civilizations
progressed. Caravans of traders carried new pathogens to
unsuspecting and susceptible populations. Explorers and later
conquering armies brought infectious microorganisms to new
continents. Stowaway rats and other vermin in the holds of ships
traveled down the moorings when the ships docked, bringing fleas,
lice, and deadly pathogens to a new world. Sporadic epidemics of
plague, smallpox, typhus, and measles ravaged cities, decimated
armies, and altered the course of history.

19th Century Discoveries Lead to Infectious Disease Prevention and
Control

Control of many infectious diseases became possible with the
pioneering work of Robert Koch and Louis Pasteur and the
introduction of the germ theory of disease. With bacteriologic
cultivation techniques came the first isolation and identification
of etiologic agents; virus cultivation and identification became
available some decades later. Reservoirs of microorganisms and
their life cycles were identified; the epidemiology and natural
history of many infectious diseases were described, and successful
control measures were initiated. Water treatment, vector control,
and rodent reduction programs followed. By the beginning of the
20th century, the principles of vaccination, established
empirically by Edward Jenner more than 100 years earlier, began to
be realized in earnest. Antibiotics were discovered, and
disinfectants were developed. Collectively, these control measures
dramatically decreased the incidence and prevalence of many
infectious diseases and their fatality rates. The early part of
this century is appropriately regarded as a golden age in public
health.

New and Reemerging Infectious Diseases--A Contemporary Problem

Compared with earlier generations, we possess an enormous
scientific base, and the rate of acquisition of new information
about infectious diseases is at a historic high. Moreover, thanks
in large measure to effective childhood immunization programs,
including the President's Childhood Immunization Initiative, many
infectious diseases are under control, particularly in the
industrialized world. The elimination of smallpox in 1977 stands as
a towering achievement in the fight against infectious diseases.
However, many infectious diseases have persisted and have displayed
a remarkable ability to re-emerge after lengthy periods of
stability. Therefore, we must be ever mindful of the cyclical
nature of disease trends. 

A careful review of infectious disease trends shows a fragile
equilibrium between humans and infectious microorganisms.
Infectious diseases are still broadly endemic and maintain a large
reservoir of agents that have the potential for rapid and
widespread dissemination. Infectious diseases remain the leading
cause of death worldwide, even as the International Code of
Diseases places many infectious diseases in other categories. For
example, meningitis and cirrhosis are classified as diseases of the
nervous system and liver, respectively, and only 17% of deaths
attributable to infections are actually included in the codes for
parasitic and infectious diseases (6). In the United States, each
year, approximately 25% of physician visits are attributable to
infectious diseases, with direct and indirect costs, including
those for human immunodeficiency virus (HIV) infection and related
illnesses, estimated at more than $120 billion (7).

Persons living in tropical climates are still as vulnerable to
infectious diseases as their early ancestors were. Each year more
than one million children die of malaria in sub-Saharan Africa
alone (8); worldwide, approximately 200 million people have
schistosomiasis (9), and each year 35-60 million people contract
dengue (10). Moreover, infectious diseases and their attendant
problems are not confined to tropical climates. For example, an
estimated 600,000 cases of pneumonia occur in the United States
each year and cause 25,000 to 50,000 deaths (11). More than 10,000
cases of diphtheria have occurred in Russia since 1993 because of
inadequate levels of immunization (12). Despite a century of
scientific progress, infectious diseases still cause enormous human
suffering, deplete scarce resources, impede social and economic
development, and contribute to global instability. The potential
for even greater dissemination looms as a continuous threat.

Recent outbreaks underscore the potential for the sudden appearance
of infectious diseases in currently unaffected populations. In the
United States, contamination of the municipal water supply in
Milwaukee, Wisconsin, in 1993 resulted in an outbreak of
cryptosporidiosis that affected an estimated 400,000 people;
approximately 4,400 persons required hospitalization (13). In the
1990s, epidemic cholera reappeared in the Americas, after being
absent for nearly a century; from 1991 through June of 1994 more
than one million cases and nearly 10,000 deaths were reported (14).
During the 1980s, tuberculosis reemerged in the United States after
decades of decline, and drug-resistant strains have made its
control more difficult (15,16). The increasing prevalence of
antibiotic-resistant strains of gonococci, pneumococci,
enterococci, and staphylococci portend of other serious treatment
and control failures. Many other examples of emerging infections
could be given (17,18). 

New infectious diseases, often with unknown long-term public health
impact, continue to be identified. Table 1 lists major diseases or
etiologic agents identified just within the last 20 years (19-41).
New agents are regularly added to the list, particularly with the
availability of nucleic acid amplification techniques for detecting
and identifying otherwise noncultivable microorganisms (40, 42).

Table 1. Major Etiologic Agents, Infectious Diseases Identified
Since 1973*

Year  Agent             Disease                           Reference

1973 Rotavirus        Major cause of infantile diarrhea       19
                       worldwide
1975 Parvovirus       Fifth disease; Aplastic crisis          20
      B19              in chronic hemolytic anemia 
1976 Cryptosporidium  Acute enterocolitis                     21
      parvum
1977 Ebola virus      Ebola hemorrhagic fever                 22
1977 Legionella       Legionnaires' disease                   23
      pneumophila
1977 Hantaan virus    Hemorrhagic fever with renal            24
                       syndrome (HFRS)
1977 Campylobacter    Enteric pathogens distributed           25
      sp.              globally
1980 Human T-cell     T-cell lymphoma--leukemia                26
      lymphotropic 
      virus-I (HTLV I)
1981 Staphylococcus   Toxic shock syndrome associated         27
      toxin            with tampon use 
1982 Escherichia coli O157:H7, Hemorrhagic colitis;           28
                        hemolytic uremic syndrome 
1982 HTLV II          Hairy cell leukemia                     29
1982 Borrelia         Lyme disease                            30
      burgdorferi
1983 Human immuno-    Acquired immunodeficiency               31
      deficiency       syndrome (AIDS)
      virus (HIV)
1983 Helicobacter     Gastric ulcers                          32
      pylori
1988 Human            Roseola subitum                         33
      herpesvirus-6 
      (HHV-6)
1989 Ehrlichia        Human ehrlichiosis                      34
       chaffeensis
1989 Hepatitis C      Parenterally transmitted non-A,         35
                       non-B hepatitis
1991 Guanarito virus  Venezuelan hemorrhagic fever            36
1992 Vibrio cholerae  New strain associated with              37
      O139             epidemic cholera
1992 Bartonella        Cat-scratch disease; bacillary         38,39
      (= Rochalimaea)  angiomatosis 
      henselae 
1993 Hantavirus        pulmonary syndrome          40
      isolates
1994 Sabi virus       Brazilian hemorrhagic fever            41


* Compiled by CDC staff. Dates of discovery are assigned on the
basis of the year the isolation or identification of etiologic
agents was reported.


In some cases, etiologic agents have been identified as the causes
of known diseases or syndromes (e.g., rotavirus, parvovirus, human
T-cell lymphotropic viruses I and II (HTLV I/II), and human
herpesvirus type 6, (HHV-6); in other cases, diseases became better
recognized or defined (e.g., Legionnaires' disease, Lyme disease,
human ehrlichiosis). Still others are entirely new: with some
parallels to medieval times, a previously unknown and deadly
disease, acquired immunodeficiency syndrome (AIDS), originated from
uncertain sources in one part of the world and became globally
disseminated; this time the disease spread at a rate that would
have been unthinkable in medieval times. Clearly, the complete
history of infectious diseases remains to be written.

Getting Ahead of the Curve

Recent disquieting infectious disease trends have not gone
unrecognized, and their similarity to earlier disease trends with
immense global consequences has not gone unnoticed. Primary
responsibility for addressing new and reemerging infectious
diseases rests squarely with the custodians of public health.
Indeed, the fundamental maxim of public health must guide current
prevention programs: the health of the individual is best ensured
by maintaining or improving the health of the entire community.
Core functions necessary to ensure the health of the public were
defined in the National Academy of Science's Institute of Medicine
(IOM) report on The Future of Public Health (43):

Assessment of health status, risks, and services
Development of health policy
Assurance of quality health services

Surveillance (assessment) is the sine qua non of infectious disease
prevention programs; however, for surveillance to be effective it
must be specific. Consider, for example, surveillance of viral
hepatitis. Only after the various agents of viral hepatitis were
identified and specific laboratory testing became available was it
possible to explain trends in disease prevalence and establish the
epidemiologic principles underlying the different modes of
transmission. Specific laboratory testing is also the basis of
screening programs that ensure the safety of the blood supply
against hepatitis B and hepatitis C. Agent-specific surveillance is
a critical component of many immunization programs. Vaccines to
Haemophilus influenzae type b, (Hib), for example, were developed
in response to laboratory-based surveillance that identified Hib as
a major cause of invasive disease in children. The effectiveness of
the Hib vaccination campaign in the United States has been dramatic
(Figure 1).  (Figure cannot be viewed in ASCII.) Similar approaches
will ensure appropriate formulation of other developmental
vaccines. Monitoring antibiotic resistance is yet another important
example of the value of laboratory-based surveillance. Within this
context, current discoveries of etiologic agents and diseases
(Table 1) are reasons for optimism. The potential for improvements
in assessment and prevention of these and other newly discovered
diseases is reminiscent of the watershed years of Koch and Pasteur.

We cannot overstate the role of behavioral science in our effort to
"get ahead of the curve" with emerging infections. Having the
science or laboratory technology to control infectious diseases is
not enough, unless we can influence people to behave in ways that
minimize the transmission of infections and maximize the efforts of
medical interventions. For example, even though HIV/AIDS does not
have a vaccine or cure, it is almost entirely preventable. For many
people, however, reducing the risk for HIV infection and AIDS
requires important changes in lifestyle or behavior. We must use
our knowledge of human behavior to help people make lifestyle
changes and prevent disease.

Another illustration of the need to use behavior science is the
problem of antibiotic resistance. To a great extent, this problem
is related to the behavior of both physicians and patients.
Physicians continue to use antibiotics inappropriately, and
patients continue to demand antibiotic treatment when it is not
indicated, for example, for the common cold. As society changes and
institutions such as day care centers and prisons become more
crowded, the spread of infectious diseases is exacerbated. For
homeless and drug-dependent populations, completing a 6- to 9-month
course of therapy for tuberculosis is difficult, and the failure to
complete the therapy increases the risk for drug-resistant
tuberculosis in the community.

Microbiologists, infectious disease specialists, and other basic
and clinical scientists must collaborate with behavioral scientists
in an interdisciplinary effort to prevent and control emerging
infections.

The Future of Public Health emphasizes the relationship between a
sound public health infrastructure and infectious disease
prevention programs. Infrastructure improvements must become a
national priority: certainly they are among CDC's top priorities.
Improvements in infectious disease surveillance are particularly
needed (44). Enriching the capacity to respond to urgent threats to
health and developing nationwide prevention strategies are also CDC
priorities. To combat new and reemerging infectious diseases, CDC,
in collaboration with other federal agencies, state and local
health departments, academic institutions, professional societies,
international organizations, and experts in public health
infectious diseases and medical microbiology developed a
plan--Addressing Emerging Infectious Disease Threats: A Prevention
Strategy for the United States (7). The plan has four major goals:

Surveillance and response--detect, promptly investigate, and
monitor emerging pathogens, the diseases they cause, and the
factors influencing their emergence

Applied research--integrate laboratory science and epidemiology to
optimize public health practice

Prevention and control--enhance communication of public health
information about emerging diseases and ensure prompt
implementation of prevention strategies

Infrastructure--strengthen local, state, and federal public health
infrastructures to support surveillance and implement prevention
and control programs

CDC's plan provides a framework for the agency to work
collaboratively with its many partners to identify and reverse
worrisome trends in infectious diseases.

The need for implementing CDC's plan is urgent, given the extremely
dynamic nature of disease trends and the complexity of factors
contributing to disease emergence; these were outlined in detail in
the 1992 IOM report--Emerging Infections: Microbial Threats to
Health in the United States (45) and are discussed in a companion
article by Stephen S. Morse, Ph.D., in this issue. The IOM report
concludes that infectious diseases must be viewed as but one
component of a dynamic and complex global ecology, which is shaped
and buffeted by technologic, societal, economic, environmental, and
demographic changes, not to mention microbial change and
adaptation.

Clearly, broader coalitions are needed, and communication must
improve if we are to  get ahead of the curve.  This new periodical
is part of the overall strategy to draw worldwide attention to
emerging infections and improve communication. Given the
multiplicity of factors contributing to disease emergence, Emerging
Infectious Diseases (EID) will present relevant concepts from
professionals in multiple disciplines and disseminate information
about emerging infectious diseases in order to develop and apply
ecologically acceptable interventions that will benefit humankind.
Prevention and control of new and emerging infectious diseases
depend on the participation of scientists and other professionals
in the public and private sectors.

CDC will make EID available by print and electronically to
facilitate rapid communication. We hope that in the process EID
will promote the exchange of infectious disease information through
global electronic networks and bulletin boards.

Although there are many similarities between our vulnerability to
infectious diseases and that of our ancestors, there is one
distinct difference: we have the benefit of extensive scientific
knowledge. Ultimately, our success in combatting infectious
diseases will depend on how well we use available information. A
recent report by the Carnegie Commission  Science, Technology, and
Government for a Changing World,  provides valuable insight in this
regard (46). Commenting on the Earth Summit in Rio de Janeiro in
1992, the report emphasizes the need to shift from the
 manifestations of environmental changes in the air, land, water,
and plant and animal kingdoms to the causes of those changes. 
Indeed, the advice of that report challenges us all--"our capacity
to generate, integrate, disseminate, and apply knowledge will
determine the human prospect in the 21st century."

Dr. Satcher is director of the Centers for Disease Control and
Prevention, Atlanta, Georgia. He was president of Meharry Medical
College, Nashville, Tennessee, from 1982 to 1993 and is a former
faculty member of the King-Drew Medical Center and the UCLA School
of Medicine, Los Angeles, California.

Address for correspondence: David Satcher, Centers for Disease
Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, USA,
fax 404-639-3030, e-mail eideditor@cidod1.em.cdc.gov.

References
1. Zinsser H. Rats, lice and history. Boston: Little, Brown, and
Company, 1935.
2. Hopkins DR. Princes and peasants: smallpox in history. Chicago:
University of Chicago Press, 1983. 
3. Bollet AJ. Plagues and poxes. New York: Demos Publications,
1987.
4. Burnet M, White DO. Natural history of infectious disease.
London: Cambridge University Press, 1972.
5. McNeill WH. Plagues and peoples. Garden City, New York: Anchor
Press/Doubleday, 1976.
6. Bennett JV, Holmberg SD, Rogers MF, Solomon SL. Infectious and
parasitic diseases. In: Amler RW, Dull HB, editors. Closing the
gap: the burden of unnecessary illness. New York: Oxford University
Press, 1987.
7. Centers for Disease Control and Prevention. Addressing emerging
infectious disease threats: a prevention strategy for the United
States. Atlanta, Georgia: U.S. Department of Health and Human
Services, Public Health Service, 1994.
8. World Health Organization. Severe and complicated malaria. Trans
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                          Perspectives

Factors in the Emergence of Infectious Diseases
Stephen S. Morse, Ph.D.
The Rockefeller University, New York, NewYork, USA

Abstract
"Emerging" infectious diseases can be defined as infections that
have newly appeared in a population or have existed but are rapidly
increasing in incidence or geographic range. Among recent examples
are HIV/AIDS, hantavirus pulmonary syndrome, Lyme disease, and
hemolytic uremic syndrome (a foodborne infection caused by certain
strains of Escherichia coli). Specific factors precipitating
disease emergence can be identified in virtually all cases. These
include ecological, environmental, or demographic factors that
place people at increased contact with a previously unfamiliar
microbe or its natural host or promote dissemination. These factors
are increasing in prevalence; this increase, together with the
ongoing evolution of viral and microbial variants and selection for
drug resistance, suggests that infections will continue to emerge
and probably increase and emphasizes the urgent need for effective
surveillance and control. Dr. David Satcher's article and this
overview inaugurate "Perspectives," a regular section in this
journal intended to present and develop unifying concepts and
strategies for considering emerging infections and their underlying
factors. The editors welcome, as contributions to the Perspectives
section, overviews, syntheses, and case studies that shed light on
how and why infections emerge, and how they may be anticipated and
prevented.


Infectious diseases emerging throughout history have included some
of the most feared plagues of the past. New infections continue to
emerge today, while many of the old plagues are with us still.
These are global problems (William Foege, former CDC director now
at the Carter Center, terms them "global infectious disease
threats"). As demonstrated by influenza epidemics, under suitable
circumstances, a new infection first appearing anywhere in the
world could traverse entire continents within days or weeks.

We can define as "emerging" infections that have newly appeared in
the population, or have existed but are rapidly increasing in
incidence or geographic range (1,2). Recent examples of emerging
diseases in various parts of the world include HIV/AIDS; classic
cholera in South America and Africa; cholera due to Vibrio cholerae
O139; Rift Valley fever; hantavirus pulmonary syndrome; Lyme
disease; and hemolytic uremic syndrome, a foodborne infection
caused by certain strains of Escherichia coli (in the United
States, serotype O157:H7).

Although these occurrences may appear inexplicable, rarely if ever
do emerging infections appear without reason. Specific factors
responsible for disease emergence can be identified in virtually
all cases studied (2-4). Table 1 summarizes the known causes for a
number of infections that have emerged recently. I have suggested
that infectious disease emergence can be viewed operationally as a
two-step process: 1) Introduction of the agent into a new host
population (whether the pathogen originated in the environment,
possibly in another species, or as a variant of an existing human
infection), followed by 2) establishment and further dissemination
within the new host population ("adoption") (4). Whatever its
origin, the infection "emerges" when it reaches a new population.
Factors that promote one or both of these steps will, therefore,
tend to precipitate disease emergence. Most emerging infections,
and even antibiotic-resistant strains of common bacterial
pathogens, usually originate in one geographic location and then
disseminate to new places (5).


Table 1. Recent examples of emerging infections and probable
factors in their emergence

Infection or Agent          Factor(s) contributing to emergence

Viral 

Argentine, Bolivian      Changes in agriculture favoring rodent
 hemorrhagic fever        host
Bovine spongiform        Changes in rendering processes
 encephalopathy (cattle)
Dengue, dengue           Transportation, travel, and migration;
 hemorrhagic fever        urbanization
Ebola, Marburg           Unknown (in Europe and the United
                          States, importation of monkeys)
Hantaviruses             Ecological or environmental changes
                          increasing contact with rodent hosts
Hepatitis B, C           Transfusions, organ transplants,
                          contaminated hypodermic apparatus,
                          sexual transmission, vertical spread
                          from infected mother to child
HIV                      Migration to cities and travel; after
                          introduction, sexual transmission,
                          vertical spread from infected mother
                          to child, contaminated hypodermic
                          apparatus (including during intravenous
                          drug use), transfusions, organ 
                          transplants
HTLV                       Contaminated hypodermic apparatus, other
Influenza (pandemic)     Possibly pig-duck agriculture,
                          facilitating reassortment of avian and
                          mammalian influenza viruses*
Lassa fever              Urbanization favoring rodent host,
                          increasing exposure (usually in homes)
Rift Valley fever        Dam building, agriculture, irrigation; 
                          possibly change in virulence or
                          pathogenicity of virus
Yellow fever             Conditions favoring mosquito vector
 (in "new" areas)

Bacterial

Brazilian purpuric fever  Probably new strain
  (Haemophilus influenzae,
   biotype aegyptius) 
Cholera                   In recent epidemic in South America,
                             probably introduced from Asia by ship,
                           with spread facilitated by reduced
                           water chlorination; a new strain (type
                           O139) from Asia recently disseminated 
                           by travel (similarly to past
                           introductions of classic cholera)
Helicobacter pylori       Probably long widespread, now 
                           recognized(associated with gastric
                           ulcers, possibly other 
                           gastrointestinal disease)
Hemolytic uremic syndrome Mass food processing technology
 (Escherichia coli         allowing contamination of meat
   O157:H7)
Legionella (Legionnaires' Cooling and plumbing systems (organism
 disease)                  grows in biofilms that form on water
                           storage tanks and in stagnant
                           plumbing)
Lyme borreliosis          Reforestation around homes and other
 (Borrelia burgdorferi)    conditions favoring tick vector and
                           deer (a secondary reservoir host)
Streptococcus, group A    Uncertain
 (invasive; necrotizing)
Toxic shock syndrome      Ultra-absorbency tampons
 (Staphylococcus aureus)

Parasitic

Cryptosporidium, other    Contaminated surface water, faulty
 waterborne pathogens      water purification
Malaria (in "new" areas)  Travel or migration
Schistosomiasis           Dam building


* Reappearances of influenza are due to two distinct mechanisms:
Annual or biennial epidemics involving new variants due to
antigenic drift (point mutations, primarily in the gene for the
surface protein, hemagglutinin) and pandemic strains, arising from
antigenic shift (genetic reassortment, generally between avian and
mammalian influenza strains).



Regarding the introduction step, the numerous examples of
infections originating as zoonoses (7,8) suggest that the "zoonotic
pool"--introductions of infections from other species--is an
important and potentially rich source of emerging diseases;
periodic discoveries of  new  zoonoses suggest that the zoonotic
pool appears by no means exhausted. Once introduced, an infection
might then be disseminated through other factors, although rapid
course and high mortality combined with low transmissibility are
often limiting. However, even if a zoonotic agent is not able to
spread readily from person to person and establish itself, other
factors (e.g., nosocomial infection) might transmit the infection.
Additionally, if the reservoir host or vector becomes more widely
disseminated, the microbe can appear in new places. Bubonic plague
transmitted by rodent fleas and ratborne hantavirus infections are
examples.

Most emerging infections appear to be caused by pathogens already
present in the environment, brought out of obscurity or given a
selective advantage by changing conditions and afforded an
opportunity to infect new host populations (on rare occasions, a
new variant may also evolve and cause a new disease) (2,4). The
process by which infectious agents may transfer from animals to
humans or disseminate from isolated groups into new populations can
be called "microbial traffic" (3,4). A number of activities
increase microbial traffic and as a result promote emergence and
epidemics. In some cases, including many of the most novel
infections, the agents are zoonotic, crossing from their natural
hosts into the human population; because of the many similarities,
I include here vector-borne diseases. In other cases, pathogens
already present in geographically isolated populations are given an
opportunity to disseminate further. Surprisingly often, disease
emergence is caused by human actions, however inadvertently;
natural causes, such as changes in climate, can also at times be
responsible (6). Although this discussion is confined largely to
human disease, similar considerations apply to emerging pathogens
in other species.

Table 2 summarizes the underlying factors responsible for
emergence. Any categorization of the factors is, of course,
somewhat arbitrary but should be representative of the underlying
processes that cause emergence. I have essentially adopted the
categories developed in the Institute of Medicine report on
emerging infections (12), with additional definitions from the CDC
emerging infections plan (13). Responsible factors include
ecological changes, such as those due to agricultural or economic
development or to anomalies in climate; human demographic changes
and behavior; travel and commerce; technology and industry;
microbial adaptation and change; and breakdown of public health
measures. Each of these will be considered in turn.

Table 2. Factors in infectious disease emergence*

Factor             Examples of             Examples of diseases
                    specific factors

Ecological changes Agriculture; dams,     Schistosomiasis (dams);
 (including those   changes in water       Rift Valley fever 
 due to economic    ecosystems; deforesta-  (dams, irrigation);   
 development and    tion/reforestation;    Argentine hemorrhagic 
 land use)          flood/drought; famine; fever (agriculture);
                    climate changes        Hantaan (Korean
                                           hemorrhagic fever)
                                            (agriculture);        
                                           hantavirus pulmonary
                                           syndrome, south-
                                            western US, 1993      
                                           (weather anomalies)
Human demographics, Societal events:      Introduction of HIV;
behavior             Population growth     spread of dengue;
                     and migration         spread of HIV and
                     (movement from        other sexually
                     rural areas to        transmitted diseases 
                     cities); war or 
                     civil conflict; 
                     urban decay; sexual 
                     behavior; intravenous 
                     drug use; use of 
                     high-density 
                     facilities              
International       Worldwide movement of  "Airport" malaria;
 travel and          goods and people;       dissemination of 
 commerce            air travel              mosquito vectors;
                                              ratborne            
                                              hantaviruses;       
                                              introduction of     
                                              cholera into South  
                                              America;            
                                             dissemination of     
                                             O139 V. cholerae
Technology and      Globalization of food   Hemolytic uremic 
  industry           supplies; changes in    syndrome (E. coli
                     food processing and     contamination of
                     packaging; organ or     hamburger meat),
                     tissue transplantation; bovine spongiform
                     drugs causing           encephalopathy;
                     immunosuppression;      transfusion-
                     widespread use of       associated hepatitis
                     antibiotics             (hepatitis B, C),    
                                             opportunistic
                                             infections in
                                             immunosuppressed
                                              patients,           
                                              Creutzfeldt-        
                                             Jakob disease from
                                             contaminated batches
                                             of human growth
                                             hormone (medical
                                             technology)
Microbial           Microbial evolution,   Antibiotic-resistant
 adaptation and      response to selection  bacteria, "antigenic
 change              in environment         drift" in influenza 
                                             virus
Breakdown in        Curtailment or          Resurgence of
  public health      reduction in            tuberculosis in the
  measures           prevention programs;    United States;
                     inadequate sanitation   cholera in refugee
                     and vector control      camps in Africa;
                     measures                resurgence of
                                             diphtheria in the
                                             former Soviet Union

* Categories of factors (column 1) adapted from ref. 12, examples
of specific factors (column 2) adapted from ref. 13. Categories
are not mutually exclusive; several factors may contribute to
emergence of a disease (see Table 1 for additional information).



Ecological interactions can be complex, with several factors
often working together or in sequence. For example, population
movement from rural areas to cities can spread a once-localized
infection. The strain on infrastructure in the overcrowded and
rapidly growing cities may disrupt or slow public health
measures, perhaps allowing establishment of the newly introduced
infection. Finally, the city may also provide a gateway for
further dissemination of the infection. Most successful emerging
infections, including HIV, cholera, and dengue, have followed
this route.

Consider HIV as an example. Although the precise ancestry of
HIV-1 is still uncertain, it appears to have had a zoonotic
origin (9,10). Ecological factors that would have allowed human
exposure to a natural host carrying the virus that was the
precursor to HIV-1 were, therefore, instrumental in the
introduction of the virus into humans. This probably occurred in
a rural area. A plausible scenario is suggested by the
identification of an HIV-2-infected man in a rural area of
Liberia whose virus strain resembled viruses isolated from the
sooty mangabey monkey (an animal widely hunted for food in rural
areas and the putative source of HIV-2) more closely than it did
strains circulating in the city (11). Such findings suggest that
zoonotic introductions of this sort may occur on occasion in
isolated populations but may well go unnoticed so long as the
recipients remain isolated. But with increasing movement from
rural areas to cities, such isolation is increasingly rare. After
its likely first move from a rural area into a city, HIV-1 spread
regionally along highways, then by long distance routes,
including air travel, to more distant places. This last step was
critical for HIV and facilitated today's global pandemic. Social
changes that allowed the virus to reach a larger population and
to be transmitted despite its relatively low natural
transmissibility were instrumental in the success of the virus in
its newfound human host. For HIV, the long duration of
infectivity allowed this normally poorly transmissible virus many
opportunities to be transmitted and to take advantage of such
factors as human behavior (sexual transmission, intravenous drug
use) and changing technology (early spread through blood
transfusions and blood products) (Table 1).

Ecological Changes and Agricultural Development

Ecological changes, including those due to agricultural or
economic development, are among the most frequently identified
factors in emergence. They are especially frequent as factors in
outbreaks of previously unrecognized diseases with high
case-fatality rates, which often turn out to be zoonotic
introductions. Ecological factors usually precipitate emergence
by placing people in contact with a natural reservoir or host for
an infection hitherto unfamiliar but usually already present
(often a zoonotic or arthropod-borne infection), either by
increasing proximity or, often, also by changing conditions so as
to favor an increased population of the microbe or its natural
host (2,4). The emergence of Lyme disease in the United States
and Europe was probably due largely to reforestation (14), which
increased the population of deer and the deer tick, the vector of
Lyme disease. The movement of people into these areas placed a
larger population in close proximity to the vector.

Agricultural development, one of the most common ways in which
people alter and interpose themselves into the environment, is
often a factor (Table 2). Hantaan virus, the cause of Korean
hemorrhagic fever, causes over 100,000 cases a year in China and
has been known in Asia for centuries. The virus is a natural
infection of the field mouse Apodemus agrarius. The rodent
flourishes in rice fields; people usually contract the disease
during the rice harvest from contact with infected rodents. Junin
virus, the cause of Argentine hemorrhagic fever, is an unrelated
virus with a history remarkably similar to that of Hantaan virus.
Conversion of grassland to maize cultivation favored a rodent
that was the natural host for this virus, and human cases
increased in proportion with expansion of maize agriculture (15).
Other examples, in addition to those already known (2,15), are
likely to appear as new areas are placed under cultivation.

Perhaps most surprisingly, pandemic influenza appears to have an
agricultural origin, integrated pig-duck farming in China.
Strains causing the frequent annual or biennial epidemics
generally result from mutation ("antigenic drift"), but pandemic
influenza viruses do not generally arise by this process.
Instead, gene segments from two influenza strains reassort to
produce a new virus that can infect humans (16). Evidence amassed
by Webster, Scholtissek, and others, indicates that waterfowl,
such as ducks, are major reservoirs of influenza and that pigs
can serve as "mixing vessels" for new mammalian influenza strains
(16). Pandemic influenza viruses have generally come from China.
Scholtissek and Naylor suggested that integrated pig-duck
agriculture, an extremely efficient food production system
traditionally practiced in certain parts of China for several
centuries, puts these two species in contact and provides a
natural laboratory for making new influenza recombinants (17).
Webster has suggested that, with high-intensity agriculture and
movement of livestock across borders, suitable conditions may now
also be found in Europe (16).

Water is also frequently associated with disease emergence.
Infections transmitted by mosquitoes or other arthropods, which
include some of the most serious and widespread diseases (18,19),
are often stimulated by expansion of standing water, simply
because many of the mosquito vectors breed in water. There are
many cases of diseases transmitted by water-breeding vectors,
most involving dams, water for irrigation, or stored drinking
water in cities. (See "Changes in Human Demographics and
Behavior" for a discussion of dengue.) The incidence of Japanese
encephalitis, another mosquito-borne disease that accounts for
almost 30,000 human cases and approximately 7,000 deaths annually
in Asia, is closely associated with flooding of fields for rice
growing. Outbreaks of Rift Valley fever in some parts of Africa
have been associated with dam building as well as with periods of
heavy rainfall (19). In the outbreaks of Rift Valley fever in
Mauritania in 1987, the human cases occurred in villages near
dams on the Senegal River. The same effect has been documented
with other infections that have aquatic hosts, such as
schistosomiasis.

Because humans are important agents of ecological and
environmental change, many of these factors are anthropogenic. Of
course, this is not always the case, and natural environmental
changes, such as climate or weather anomalies, can have the same
effect. The outbreak of hantavirus pulmonary syndrome in the
southwestern United States in 1993 is an example. It is likely
that the virus has long been present in mouse populations but an
unusually mild and wet winter and spring in that area led to an
increased rodent population in the spring and summer and thus to
greater opportunities for people to come in contact with infected
rodents (and, hence, with the virus); it has been suggested that
the weather anomaly was due to large-scale climatic effects (20).
The same causes may have been responsible for outbreaks of
hantaviral disease in Europe at approximately the same time
(21,22). With cholera, it has been suggested that certain
organisms in marine environments are natural reservoirs for
cholera vibrios, and that large scale effects on ocean currents
may cause local increases in the reservoir organism with
consequent flare-ups of cholera (23).

Changes in Human Demographics and Behavior

Human population movements or upheavals, caused by migration or
war, are often important factors in disease emergence. In many
parts of the world, economic conditions are encouraging the mass
movement of workers from rural areas to cities. The United
Nations has estimated that, largely as a result of continuing
migration, by the year 2025, 65% of the world population (also
expected to be larger in absolute numbers), including 61% of the
population in developing regions, will live in cities (24). As
discussed above for HIV, rural urbanization allows infections
arising in isolated rural areas, which may once have remained
obscure and localized, to reach larger populations. Once in a
city, the newly introduced infection would have the opportunity
to spread locally among the population and could also spread
further along highways and interurban transport routes and by
airplane. HIV has been, and in Asia is becoming, the best known
beneficiary of this dynamic, but many other diseases, such as
dengue, stand to benefit. The frequency of the most severe form,
dengue hemorrhagic fever, which is thought to occur when a person
is sequentially infected by two types of dengue virus, is
increasing as different dengue viruses have extended their range
and now overlap (25). Dengue hemorrhagic fever is now common in
some cities in Asia, where the high prevalence of infection is
attributed to the proliferation of open containers needed for
water storage (which also provide breeding grounds for the
mosquito vector) as the population size exceeds the
infrastructure (19). In urban environments, rain-filled tires or
plastic bottles are often breeding grounds of choice for mosquito
vectors. The resulting mosquito population boom is complemented
by the high human population density in such situations,
increasing the chances of stable transmission cycles between
infected and susceptible persons. Even in industrialized
countries, e.g., the United States, infections such as
tuberculosis can spread through high-population density settings
(e.g., day care centers or prisons) (12,26-28).

Human behavior can have important effects on disease
dissemination. The best known examples are sexually transmitted
diseases, and the ways in which such human behavior as sex or
intravenous drug use have contributed to the emergence of HIV are
now well known. Other factors responsible for disease emergence
are influenced by a variety of human actions, so human behavior
in the broader sense is also very important. Motivating
appropriate individual behavior and constructive action, both
locally and in a larger scale, will be essential for controlling
emerging infections. Ironically, as AIDS prevention efforts have
demonstrated, human behavior remains one of the weakest links in
our scientific knowledge.

International Travel and Commerce

The dissemination of HIV through travel has already been
mentioned. In the past, an infection introduced into people in a
geographically isolated area might, on occasion, be brought to a
new place through travel, commerce, or war (8). Trade between
Asia and Europe, perhaps beginning with the silk route and
continuing with the Crusades, brought the rat and one of its
infections, the bubonic plague, to Europe. Beginning in the 16th
and 17th centuries, ships bringing slaves from West Africa to the
New World also brought yellow fever and its mosquito vector,
Aedes aegypti, to the new territories. Similarly, smallpox
escaped its Old World origins to wreak new havoc in the New
World. In the 19th century, cholera had similar opportunities to
spread from its probable origin in the Ganges plain to the Middle
East and, from there, to Europe and much of the remaining world.
Each of these infections had once been localized and took
advantage of opportunities to be carried to previously unfamiliar
parts of the world.

Similar histories are being repeated today, but opportunities in
recent years have become far richer and more numerous, reflecting
the increasing volume, scope, and speed of traffic in an
increasingly mobile world. Rats have carried hantaviruses
virtually worldwide (29). Aedes albopictus (the Asian tiger
mosquito) was introduced into the United States, Brazil, and
parts of Africa in shipments of used tires from Asia (30). Since
its introduction in 1982, this mosquito has established itself in
at least 18 states of the United States and has acquired local
viruses including Eastern equine encephalomyelitis (31), a cause
of serious disease. Another mosquito-borne disease, malaria, is
one of the most frequently imported diseases in
non-endemic-disease areas, and cases of "airport malaria" are
occasionally identified.

A classic bacterial disease, cholera, recently entered both South
America (for the first time this century) and Africa. Molecular
typing shows the South American isolates to be of the current
pandemic strain (32), supporting the suggestion that the organism
was introduced in contaminated bilge water from an Asian
freighter (33). Other evidence indicates that cholera was only
one of many organisms to travel in ballast water; dozens, perhaps
hundreds, of species have been exchanged between distant places
through this means of transport alone. New bacterial strains,
such as the recently identified Vibrio cholerae O139, or an
epidemic strain of Neisseria meningitidis (34,35) (also examples
of microbial adaptation and change) have disseminated rapidly
along routes of trade and travel, as have antibiotic-resistant
bacteria (5,36).

Technology and Industry

High-volume rapid movement characterizes not only travel, but
also other industries in modern society. In operations, including
food production, that process or use products of biological
origin, modern production methods yield increased efficiency and
reduced costs but can increase the chances of accidental
contamination and amplify the effects of such contamination. The
problem is further compounded by globalization, allowing the
opportunity to introduce agents from far away. A pathogen present
in some of the raw material may find its way into a large batch
of final product, as happened with the contamination of hamburger
meat by E. coli strains causing hemolytic uremic syndrome (37).
In the United States the implicated E. coli strains are serotype
O157:H7; additional serotypes have been identified in other
countries. Bovine spongiform encephalopathy (BSE), which emerged
in Britain within the last few years, was likely an interspecies
transfer of scrapie from sheep to cattle (38) that occurred when
changes in rendering processes led to incomplete inactivation of
scrapie agent in sheep byproducts fed to cattle (39).

The concentrating effects that occur with blood and tissue
products have inadvertently disseminated infections unrecognized
at the time, such as HIV and hepatitis B and C. Medical settings
are also at the front line of exposure to new diseases, and a
number of infections, including many emerging infections, have
spread nosocomially in health care settings (Table 2). Among the
numerous examples, in the outbreaks of Ebola fever in Africa many
of the secondary cases were hospital acquired, most transmitted
to other patients through contaminated hypodermic apparatus, and
some to the health care staff by contact. Transmission of Lassa
fever to health care workers has also been documented.

On the positive side, advances in diagnostic technology can also
lead to new recognition of agents that are already widespread.
When such agents are newly recognized, they may at first often be
labeled, in some cases incorrectly, as emerging infections. Human
herpesvirus 6 (HHV-6) was identified only a few years ago, but
the virus appears to be extremely widespread (40) and has
recently been implicated as the cause of roseola (exanthem
subitum), a very common childhood disease (41). Because roseola
has been known since at least 1910, HHV-6 is likely to have been
common for decades and probably much longer. Another recent
example is the bacterium Helicobacter pylori, a probable cause of
gastric ulcers (42) and some cancers (43,44). We have lived with
these diseases for a long time without knowing their cause.
Recognition of the agent is often advantageous, offering new
promise of controlling a previously intractable disease, such as
treating gastric ulcers with specific antimicrobial therapy.

Microbial Adaptation and Change

Microbes, like all other living things, are constantly evolving.
The emergence of antibiotic-resistant bacteria as a result of the
ubiquity of antimicrobials in the environment is an evolutionary
lesson on microbial adaptation, as well as a demonstration of the
power of natural selection. Selection for antibiotic-resistant
bacteria (5,36) and drug-resistant parasites has become frequent,
driven by the wide and sometimes inappropriate use of
antimicrobial drugs in a variety of applications (27,45,46).
Pathogens can also acquire new antibiotic resistance genes from
other, often nonpathogenic, species in the environment (36),
selected or perhaps even driven by the selection pressure of
antibiotics.

Many viruses show a high mutation rate and can rapidly evolve to
yield new variants (47). A classic example is influenza (48).
Regular annual epidemics are caused by "antigenic drift" in a
previously circulating influenza strain. A change in an antigenic
site of a surface protein, usually the hemagglutinin (H) protein,
allows the new variant to reinfect previously infected persons
because the altered antigen is not immediately recognized by the
immune system.

On rare occasions, perhaps more often with nonviral pathogens
than with viruses (49), the evolution of a new variant may result
in a new expression of disease. The epidemic of Brazilian
purpuric fever in 1990, associated with a newly emerged clonal
variant of Hemophilus influenzae, biogroup aegyptius, may fall
into this category. It is possible, but not yet clear, that some
recently described manifestations of disease by group A
Streptococcus, such as rapidly invasive infection or necrotizing
fasciitis, may also fall into this category.

Breakdown of Public Health Measures and Deficiencies in Public
Health Infrastructure

Classical public health and sanitation measures have long served
to minimize dissemination and human exposure to many pathogens
spread by traditional routes such as water or preventable by
immunization or vector control. The pathogens themselves often
still remain, albeit in reduced numbers, in reservoir hosts or in
the environment, or in small pockets of infection and, therefore,
are often able to take advantage of the opportunity to reemerge
if there are breakdowns in preventive measures.

Reemerging diseases are those, like cholera, that were once
decreasing but are now rapidly increasing again. These are often
conventionally understood and well recognized public health
threats for which (in most cases) previously active public health
measures had been allowed to lapse, a situation that
unfortunately now applies all too often in both developing
countries and the inner cities of the industrialized world. The
appearance of reemerging diseases may, therefore, often be a sign
of the breakdown of public health measures and should be a
warning against complacency in the war against infectious
diseases.

Cholera, for example, has recently been raging in South America
(for the first time in this century) (50) and Africa. The rapid
spread of cholera in South America may have been abetted by
recent reductions in chlorine levels used to treat water supplies
(34). The success of cholera and other enteric diseases is often
due to the lack of a reliable water supply. These problems are
more severe in developing countries, but are not confined to
these areas. The U.S. outbreak of waterborne Cryptosporidium
infection in Milwaukee, Wisconsin, in the spring of 1993, with
over 400,000 estimated cases, was in part due to a nonfunctioning
water filtration plant (51); similar deficiencies in water
purification have been found in other cities in the United States
(52).

For Our Future

In his accompanying article, Dr. David Satcher discusses the
history of infectious diseases and the many infections that, from
the dawn of history to the present, have traveled with the
caravans and followed the invading armies. The history of
infectious diseases has been a history of microbes on the march,
often in our wake, and of microbes that have taken advantage of
the rich opportunities offered them to thrive, prosper, and
spread. And yet the historical processes that have given rise to
the emergence of "new"  infections throughout history continue
today with unabated force; in fact, they are accelerating,
because the conditions of modern life ensure that the factors
responsible for disease emergence are more prevalent than ever
before. Speed of travel and global reach are further borne out by
studies modeling the spread of influenza epidemics (53) and HIV
(54,55).

Humans are not powerless, however, against this relentless march
of microbes. Knowledge of the factors underlying disease
emergence can help focus resources on the key situations and
areas worldwide (3,4) and develop more effective prevention
strategies. If we are to protect ourselves against emerging
diseases, the essential first step is effective global disease
surveillance to give early warning of emerging infections
(3,12,13,56). This must be tied to incentives, such as national
development, and eventually be backed by a system for an
appropriate rapid response. World surveillance capabilities are
critically deficient (12,56,57). Efforts, such as the CDC plan
(13), now under way in the United States and internationally to
remedy this situation are the essential first steps and deserve
strong support. Research, both basic and applied, will also be
vital.

This Journal and the "Perspectives"  Section

Early warning of emerging and reemerging infections depends on
the ability to identify the unusual as early as possible.
Information is, therefore, essential. Hence this journal, which
is intended as a peer-reviewed forum for the discussion of
concepts and examples relevant to emerging infectious diseases
and their causes, and to provide a channel for field reports and
observations on emerging infections. The "Perspectives" section
will provide general overviews dealing with factors in disease
emergence, conceptual syntheses of information, approaches for
studying or predicting emerging infections, and analyses that
shed light on how and why infections emerge, and how they may be
anticipated and prevented. Submissions for this section are
warmly invited. In coming issues, Perspectives will deal in
greater detail with many of the factors discussed in this
overview article, and with ways to dissect steps in the emergence
process. Discussion of technologies that are broadly applicable
to the identification or control of emerging diseases are also
appropriate for this section. Case studies are welcome if they
are used to develop broader lessons.

Acknowledgments

I thank Dr. John La Montagne, NIAID, for helpful discussions.
Supported by NIH grant RR 03121 (from CMP), US DHHS.

Dr. Morse, "Perspectives" section editor of this journal, is
assistant professor of virology at The Rockefeller University,
New York, N.Y. He chaired the NIH Conference on Emerging Viruses
(May 1989) and was a member of the committee on Emerging
Microbial Threats to Health (and chaired its Task Force on
Viruses), convened by the Institute of Medicine, National Academy
of Sciences (ref. 12).

Address for correspondence: Stephen S. Morse, The Rockefeller
University, 1230 York Avenue, Box 120, New York, NY 10021-6399,
USA; fax 212-327-7172; e-mail morse@rockvax.rockefeller.edu.

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                            Synopsis

Unraveling Mysteries Associated with Cat-Scratch Disease,
Bacillary Angiomatosis, and Related Syndromes

Russell Regnery, Ph.D., and Jordan Tappero, M.D.
National Center for Infectious Diseases, 
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Abstract
The search for the infectious agents responsible for cat-scratch
disease, bacillary angiomatosis, and related syndromes has a long
and often circuitous history. Recognition of the etiologic agents
and a new understanding of the fundamental features of the
epidemiology and natural history of modern day Bartonella
(formerly Rochalimaea)-associated diseases culminate a
multipartite story that combines clinical medicine, traditional
microbiology, and novel technological approaches to solve a
long-standing enigma.


The quest for the etiologic agent of cat-scratch disease (CSD)
has frequently been described as a mystery (1,2). Indeed, the
search has many qualities of a mystery novel; the pursuit has
spanned several decades and recently taken several unexpected
turns. During this period of important discovery, major microbial
suspects have undergone name changes, novel microbial culprits
have been introduced, new groups of affected patients have been
recognized, and yet significant questions remain to be answered.
Scientific and medical interest has been high; approximately 900
publications have dealt with CSD since the first good clinical
description of the disease in 1950 (3).

Clinical Features of CSD

Throughout the life of this evolving mystery, the clinical
descriptions of "classical" CSD have remained remarkably
consistent (Dalton MJ, et al. Rochalimaea antibody; a new era in
the diagnosis of cat-scratch disease, submitted for publication;
4-6). CSD is typically a benign and self-limited illness lasting
6 to 12 weeks in the absence of antibiotic therapy. Regional
lymphadenopathy (axillary, head and neck, inguinal) is the
predominant clinical feature of CSD; affected nodes are often
tender and occasionally suppurate (4-7). Between 25% and 60% of
patients report a primary cutaneous inoculation lesion (0.5- to
1-cm papule or pustule) at the site of a cat scratch or bite
(5,7). The skin lesions typically develop 3 to 10 days after
injury and precede the onset of lymphadenopathy by 1 to 2 weeks.
Low-grade fever and malaise accompany lymphadenopathy in up to
50% of patients; headache, anorexia, weight loss, nausea and
vomiting, sore throat, and splenomegaly may develop. In addition,
short-lived, non-specific maculopapular eruptions, erythema
nodosum, figurate erythemas, and thrombocytopenic purpura have
been observed (8).

Unusual manifestations of CSD, which occur in up to 14% of
patients, include Perinaud's oculoglandular syndrome (6%),
encephalopathy (2%), hepatic granulomas (0.3%), osteomyelitis
(0.3%), and pulmonary disease (0.2%) (4,5,8). In general, these
complications resolve without sequelae. Perinaud's oculoglandular
syndrome is manifested by conjunctival granuloma, periauricular
lymphadenopathy, and nonsuppurative conjunctivitis.
Encephalopathy, manifested as fever and coma that progress to
convulsions, may last for days to weeks; cerebrospinal fluid is
unremarkable. Optic neuritis with transient blindness may also
occur.

For many years, CSD has been clinically diagnosed when three of
the following four criteria are met in a patient: 1) history of
traumatic cat contact; 2) positive skin-test response to CSD
skin-test antigen; 3) characteristic lymph node lesions; and 4)
negative laboratory investigation for unexplained lymphadenopathy
(8). Although biopsy confirmation of CSD has been rarely required
(especially in lieu of a reliable serologic test--see below), a
constant pathologic hallmark of CSD-affected tissues has been
granuloma formation. With hematoxylin and eosin stains, the
primary inoculation lesion of CSD reveals small areas of frank
necrosis surrounded by concentric layers of histiocytes,
lymphocytes, and nucleated giant cells (9). Affected lymph nodes
are characterized by necrotizing granulomas ringed by lymphocytic
infiltrates and multinucleated giant cells.

Enter Afipia felis

During the past 44 years, a variety of microbial agents,
including herpes viruses and bacteria of the genera Chlamydia and
Pasteurella, have been suspected as the causes of CSD (3). A major
chapter of the CSD saga unfolded with the 1988 announcement by
the Armed Forces Institute of Pathology that a bacterial agent
had been visualized within CSD-involved lymph nodes by using the
Warthin-Starry silver stain (10), and a novel bacterial agent had
been isolated from a CSD patient's lymph node (11). By 1992, this
agent was characterized fully, given the name Afipia felis
(Afipia being a latinized acronym for the source of the original
isolate, the Armed Forces Institute of Pathology, and felis
referring to the presumed vertebrate vector of the human
infection), and proclaimed the agent of CSD (12).
Although A. felis was declared the putative CSD bacillus,
evidence of convincing patient humoral or cellular immune
responses to laboratory cultured A. felis antigen was not
forthcoming. Despite numerous attempts, other laboratories were
unable to recover additional isolates of A. felis from CSD
patients. In addition, although the majority of patients with CSD
reported exposure to a cat(s), no clear link between cats and A.
felis was demonstrated.

Enter New Syndromes

The story of CSD took a significantly divergent path with the
recognition that opportunistic infections were an important
consideration for patients infected with human immunodeficiency
virus (HIV). Bacillary angiomatosis (BA), a newly recognized
disease characterized by cutaneous and subcutaneous vascular
lesions containing bacillary organisms visualized by
Warthin-Starry silver staining, was described predominantly among
HIV-infected patients; however, bacterial isolates were not made
or identified (13-15). Over the ensuing decade, the clinical
spectrum of BA was expanded to include patients with single or
multiple vascular lesions affecting virtually every organ system,
including lymph node, bone, brain, liver (peliosis hepatis), and
spleen (14-17). Independently, an unidentified gram-negative
pathogen was isolated predominantly from HIV-infected patients
with fever and bacteremia, however, these patients lacked
cutaneous or parenchymal vascular lesions and were not recognized
as BA patients (18).

Because silver staining and electron microscopy of both BA and
CSD tissue sections revealed bacillary organisms
indistinguishable from one another, several authors suggested
that BA might represent disseminated CSD in the immunocompromised
host (17,19-21). In addition, several anecdotal reports of BA
described a history of cat contact preceding the onset of disease
(22).

Ultimately, the relationships between possible environmental
exposures and BA or CSD were systematically investigated. The
first case-control study conducted among patients with BA found
traumatic contact with a cat (bite or scratch) to be
significantly associated with BA disease (22). BA patients were
also more likely than controls to have a household kitten (a cat
<1 year of age). A subsequent case-control study of CSD patients
found that these patients were more likely than controls to have
traumatic contact with a cat, to own at least one kitten, and to
have kittens with fleas (7).

Despite the similarities in histochemical staining properties and
epidemiology, serious reservations remained concerning a possible
link between the causative agents of CSD and BA. The pathologic
features of classical CSD (granuloma) and BA (proliferative
vascular lesions without granuloma) were distinctly different,
and the two diseases seemed to respond differently to antibiotic
therapy. Although antimicrobial therapy for BA and CSD have not
been systematically evaluated, the majority of BA patients
evaluated responded quickly to single-agent therapy with either
erythromycin or doxycycline (14,23), whereas the symptoms and
signs of patients with CSD failed to show consistent rapid
resolution following antibiotic therapy (5). In addition,
clinicians' first choices of antibiotics for treating BA and CSD
vary (5,6,14,23).

Enter Rochalimaea henselae

A breakthrough occurred when a novel approach was used to
identify possible prokaryotic ribosomal DNA extracted from BA
skin lesions. When prokaryotic ribosomal gene DNA extracted from
BA lesions and amplified by polymerase chain reaction (PCR) was
compared with sequenced ribosomal genes from other organisms, it
become apparent that the agent associated with BA in this study
was related to, but not necessarily identical to, the agent of
trench fever, Rochalimaea quintana (24).

At nearly the same time in Oklahoma, Rochalimaea-like organisms
were being isolated on blood agar from bacteremic patients (18).
Independently in Houston, Texas, fastidious, slow-growing
Rochalimaea-like isolates were recovered on several occasions
from the blood of an HIV-infected patient with relapsing fever of
unknown origin; like the isolates from the Oklahoma patients, the
Houston isolate was recovered from a patient in the absence of BA
or CSD lesions (25). The Houston isolate (Houston-1) was
identified as the prototype isolate of a novel species of
Rochalimaea by using traditional as well as genotypic methods,
including ribosomal RNA gene analysis similar to that used to
identify the nucleic acid found in BA patients' lesions (25).
Almost simultaneously, the group from Oklahoma had come to a
similar conclusion by using DNA relatedness data (26); most of
their isolates also consisted of the novel species, R. henselae.
The new species designation, first officially used to describe
the Houston-1 isolate, was coined in recognition of the
contribution of Diane Hensel, a microbiologist who had isolated
several of the initial organisms in Oklahoma (18,25,26).
Subsequently, Koehler et al. isolated bacilli directly from
cutaneous lesions of persons with BA (27); surprisingly, either
R. henselae or R. quintana was isolated from BA lesions from
different HIV-infected patients.

At this juncture, R. henselae infections had been described
predominantly among immunocompromised patients with either BA or
fever with bacteremia. The availability of isolates made it
possible to develop a test for serologic evidence of Rochalimaea
infection and to refine PCR methods for identification of
Rochalimaea organisms in tissues and other samples. These
methods, together with new techniques for recovering Rochalimaea
species isolates, were crucial to obtaining a more detailed
account not only of BA but also of CSD.

The Cat-scratch Connection: A Synthesis
A Rochalimaea genus-specific, indirect fluorescence antibody
(IFA) test using irradiated whole cell antigen from the Houston-1
isolate of R. henselae was developed by the Centers for Disease
Control and Prevention (CDC) to help identify risk factors for
Rochalimaea-associated disease. Several blinded serum samples
from both HIV-infected BA patients and HIV-infected controls
residing in San Francisco were sent to CDC for serologic testing.
High-titered antibodies were identified in serum samples from
several of the BA patients (28). Similar high-titered antibodies
were not detected for any of non-BA control patients with one
exception; a serum sample from an HIV-infected patient with CSD
also demonstrated strong serologic reactivity to R. henselae
antigen.

Shortly thereafter, single sera collected from patients with
suspected CSD to look for A. felis antibodies were evaluated with
the new R. henselae serologic test; 36 (88%) of 41 sera were
positive (29). None of the sera had significantly elevated titers
to A. felis antigen. The same set of sera were coded and
resubmitted along with sera taken from other well-characterized
bacterial and viral diseases and tested again in a blinded
manner. The IFA test accurately identified sera of case-patients
with suspected CSD. In addition, 6 (6%) of 107 sera from
ostensibly healthy persons, obtained from a commercial vendor,
showed antibody by IFA testing (29). These serologic data were
the first laboratory evidence suggesting that R. henselae was
associated with CSD.

Data further substantiating the role of R. henselae in the
etiology of CSD soon followed. The newly developed serologic test
was used to help investigate a possible cluster of CSD cases in
Connecticut; 38 (84%) of 45 suspected CSD cases had elevated
Rochalimaea antibody titers, whereas 4 (3.6%) of 112 age-matched
controls had detectable antibody titers (7). In another
investigation, serum samples obtained from 600 prospectively
evaluated patients with well-characterized CSD (i.e., persons
with history of cat scratch, papule at site of inoculation, and
enlarged regional lymph node) had a 95% correlation with positive
Rochalimaea serology.

In 1993, R. henselae was isolated directly from the lymph nodes
of two CSD patients and was identified by genotypic means; both
patients had strong serologic responses to Rochalimaea antigen
(30). Evidence of R. henselae-specific nucleic acid sequences
were found in 21 (84%) of 25 CSD lymph node tissues submitted to
CDC for evaluation (31).

Additional supporting evidence for a Rochalimaea as the cause of
CSD came from archival sources. Skin-test antigen, used rather
extensively in the past to help diagnose examples of CSD (4,8),
consisted of pasteurized exudate collected from suppurative CSD
lymph nodes. Among a cohort of CSD patients who were skin-test
positive, 52 (93%) of 56 had positive IFA antibody titers to the
defined Rochalimaea reagents (32). Furthermore, various lots of
skin-test antigen were shown by PCR analysis to contain
Rochalimaea nucleic acid sequences (33), and R. henselae
sequences in particular (34). No A. felis DNA sequences could be
detected by PCR. These data strongly indicated that
microbiologically undefined skin-test reagents, which had been
used for many years for the diagnosis and clinical
characterization of CSD, were in fact R. henselae reagents.

Collectively, these data supported a Rochalimaea species etiology
for both CSD and BA. Despite numerous attempts, recent efforts to
implicate A. felis as a cause of either of these two clinical
entities have repeatedly failed.

Felis domesticus: A Reservoir for Rochalimaea henselae

In addition to epidemiologic data, serologic evidence also
implicated domestic cats with Rochalimaea-associated disease.
Rochalimaea-specific IFA antibodies were demonstrated in 6 (46%)
of 13 pet cats not associated with human disease and among 39
(81%) of 48 cats living in households reporting human CSD in
Connecticut (7). Microbiologic evidence for the domestic cat as a
reservoir for R. henselae soon followed. R. henselae was isolated
over a 3-week period from the blood of a single cat not linked to
human illness (35). Investigations by Koehler et al. established
the cat as a reservoir for R. henselae infection (36). R.
henselae was established as the cause of cutaneous BA in three or
four patients with the disease. R. henselae was isolated from the
blood of all seven asymptomatic pet cats with which these four BA
patients had prolonged contact. The prevalence of infection among
cats in the greater San Francisco Bay region was also studied; 25
(41%) of 61 pet or impounded cats had asymptomatic R. henselae
bacteremia (36). R. henselae was also detected by both direct
culture and PCR from several cat fleas combed from these
bacteremic cats (36).

The human body louse (Pediculus humanus) was established as a
vector for human-to-human trench fever R. quintana transmission
during the First World War (37). Likewise, B. bacilliformis, a
closely related organism (see below) found in the mountains of
South America, can be transmitted by another arthropod, the
Phlebotomus sand fly (38). The observation that related microbes
are vectored between humans by arthropods adds credence to the
proposed role of arthropod vectors of CSD. Despite several
suggestions that fleas or possibly ticks (7,36,39) are associated
with R. henselae disease, no experimental data exist to clearly
demonstrate that arthropods act as direct vectors.

Changes in Nomenclature: Rochalimaea becomes Bartonella

Genotypic evaluation of members of the genus Rochalimaea has led
to the conclusion that members of the genus are closely related
to Bartonella bacilliformis, the agent of Carrin disease, Oroya
fever, and verruga peruana (40). Because of historical
precedence, the genus designation Bartonella is now applied to
all species of the old genus Rochalimaea and replaces the
Rochalimaea designation (species names remain unchanged).

Physicians and researchers need to exercise care in using the
term "bartonellosis." This term has classically been used to
describe the frequently fatal syndromes caused by B.
bacilliformis. To date, B. bacilliformis and its associated
syndrome (bartonellosis) have been identified exclusively in
South America (38,41).

Remaining Questions for Ongoing and Future Research

Although B. henselae is now regarded as the etiologic agent of
CSD, as well as a cause of BA, endocarditis (42), and fever with
bacteremia, many questions remain unanswered. For example, why
did it take so long to isolate and identify B. henselae? Part of
the answer probably stems from the requirements necessary for
growth in vitro, including enriched, non-selective blood agar
incubated over a prolonged period in a CO2 atmosphere. Most
hospital laboratories discard their bacteriological plates before
primary isolates of B. henselae would be expected to appear (9-40
days). Extreme sensitivity to a wide variety of antibiotics, at
least in vitro, suggests that residual levels of antibiotics in
patients' blood or other tissues (such as lymph node biopsy)
might inhibit Bartonella growth during primary isolation attempts
in vitro. Selective medium has yet to be developed. Novel
genotypic methods were crucial for identification of B. henselae;
thus, isolates may well have been made in the past but remained
unidentified.

As mentioned above, it has become apparent that in addition to B.
henselae, B. quintana can also be another significant cause of BA
disease, at least among immunocompromised patients in San
Francisco (27). Another focus of B. quintana infections ("urban
trench fever") has been identified among homeless alcoholics in
Seattle (43,44). How common are B. quintana infections; are they
louseborne and vectored strictly between humans, as was believed
during World War I (37)? B. quintana-associated disease has no
known link with an alternative vertebrate vector (such as cats).
Bartonella elizabethae is known only from a single isolate from a
man surviving endocarditis following aortic valve-replacement
surgery (45). Is there further public health significance to this
organism? What additional Bartonella species have yet to be
identified and what diseases may they cause?

Members of the genus Bartonella are exquisitely sensitive to
antibiotics in vitro (30,46). Why then do CSD patients not
respond as rapidly and consistently to antibiotic therapy as BA
patients do? One hypothesis is that immunocompetent patients
somehow sequester infectious organisms beyond the reach of
antibiotics, whereas immunocompromised patients do not. An
alternative hypothesis regarding differential antibiotic
responsiveness recognizes that many of the signs of CSD are
immune mediated; antibiotics, even if effective in neutralizing
or killing bacteria, may not immediately alleviate long-duration
immunologic tissue manifestations of antigen stimulation.
Conversely, in the absence of the immunologic capability to react
to bacterial infection by forming granulomas, as in the case of
severely immunocompromised persons with BA, antibiotics are
generally effective in alleviating the symptoms and signs of
infection. Does this suggest that possible non-granulomatous
manifestations of CSD (for example, neuroretinitis and
encephalopathy) should respond well to the appropriate antibiotic
therapy?

Although BA has been described in immunocompetent patients (15),
the vast majority of BA patients are immunocompromised (14). What
are the factors explaining why B. henselae and B. quintana induce
vascular proliferative lesions, such as BA and parenchymal
bacillary peliosis, almost exclusively in severely
immunocompromised patients?

What percentage of the relatively large numbers of undiagnosed
febrile disease among HIV-infected persons is in fact due to
Bartonella species infections? The answer to this important
question may help alleviate significant morbidity among
HIV-infected patients. The potential for selection for
drug-resistance during long-term antimicrobial therapy deserves
scrutiny.

Does the 4%-6% of IFA antibody-positive, ostensibly healthy
"control" study populations suggest a relatively common
undercurrent of undiagnosed, subclinical Bartonella-associated
disease?

Is it possible to immunize cats and thereby interrupt B. henselae
transmission to humans? Preliminary data suggest that
asymptomatic bacteremia in cats can be successfully treated with
antimicrobial therapy (36). Once cleared of bacteremia, are these
cats routinely susceptible to reinfection?

Are the complications occasionally associated with CSD and BA
associated with different strains of Bartonella species or are
the variations in clinical presentation strictly functions of
dose, route of inoculation, and immune status?

And finally, in what role, if any, will A. felis reappear as an
agent of human disease? Is A. felis responsible for the
relatively small number of cases of CSD-like lymphadenopathy that
have no evidence of antibody to B. henselae? Or is there another
explanation for the originally proposed association between A.
felis and CSD that has not yet come to light?

The new recognition of the importance of Bartonella-associated
diseases will continue to spawn a host of unanswered related
questions. Whereas novel subplots will continue to unfold, the
new puzzles are no longer totally shapeless, and answers to
questions of natural history and epidemiology, enhanced diagnosis
and treatment, and methods for disease intervention should now
begin to unfold rapidly.

Address for correspondence: Russell Regnery, Centers for Disease
Control and Prevention, 1600 Clifton Road, MS G13, Atlanta, GA
30333, USA; fax 404-639-1058; e-mail rur1@ciddvd1.em.cdc.gov.

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                           Dispatches

Emergence of Barmah Forest Virus in Western Australia*

To the editor: Barmah Forest (BF) virus is a mosquito-borne
alphavirus, found only in Australia, which causes outbreaks of
polyarthritis in humans. The disease is very similar to epidemic
polyarthritis caused by infection with Ross River virus, another
Australian alphavirus. BF virus was first isolated from
mosquitoes in the State of Western Australia in 1989. After this,
small clusters of human cases were diagnosed in the arid northern
and central regions of Western Australia in 1992, and the first
substantial outbreak of human disease due to infection with BF
virus (BF virus disease) occurred in the southwestern region of
the state during the spring and summer (September-March) of
1993-94 (2). No evidence of BF virus activity had been found in
these regions before these events, which suggests that the virus
had only recently been introduced to Western Australia. This
report describes the timing and distribution of BF virus disease
in humans and the isolation of the virus from mosquitoes in
Western Australia, which corroborate the view that BF virus is an
emerging virus in this state.
_____
*This report is adapted from, and expands on, a previous bulletin
(1).

The ecology of Australian arboviruses that cause human disease,
including BF virus, has recently been reviewed (3). BF virus was
first isolated from Culex annulirostris mosquitoes collected at
the Barmah Forest in northern Victoria (southeastern Australia)
in 1974 (4). It was first shown to infect humans in New South
Wales (central-eastern and southeastern Australia) in 1986 (5)
and was reported as a cause of clinical disease in humans in 1988
(6). The most common clinical features include polyarthritis,
arthralgia, myalgia, fever, rash, and lethargy (7); in some
cases, symptoms may persist for more than 6 months (2). Although
the symptoms are similar to those caused by infection with Ross
River virus, there is little cross-reaction between the two
viruses in serologic tests (8), and differentiating between
infections caused by either is generally not difficult. The first
true outbreak of BF virus disease occurred concurrently with an
outbreak of Ross River virus infection at Nhulunbuy in the
Northern Territory in early 1992 (9).

The principal vectors of BF are believed to be mosquitoes, and
although the vertebrate hosts of BF virus are not known,
serologic surveys in eastern Australia have suggested that
marsupials are involved in the natural cycle.

BF virus was first detected in Western Australia in 1989. Since
then, 73 isolates of the virus have been obtained from mosquitoes
trapped in several different regions of Western Australia (Table
1). The first human cases of BF virus disease in Western
Australia were reported in 1992, and 67 serologically confirmed
cases have now been diagnosed. The locations of towns where human
cases have occurred or where mosquitoes that yielded BF virus
were collected are shown in Figure 1. (Figure cannot be viewed in
ASCII.)


Table 1. Mosquito species from which BF virus was isolated in
Western Australia by region and date, 1989 1993*

Region          Locality     Species            Date     Isolates

East Kimberley  Billiluna  Ae. bancroftianus    22 Apr 1989   1
East Kimberley  Billiluna  Ae. eidsvoldensis    22 Apr 1989   3
East Kimberley  Billiluna  Ae.                  22 Apr 1989   1
                            pseudonormanensis
East Kimberley  Billiluna  An. amictus          22 Apr 1989   2
East Kimberley  Billiluna  An. annulipes s.l.   22 Apr 1989   1
East Kimberley  Halls Creek Cx. annulirostris   11 Feb 1993   1


West Kimberley  Broome     Ae. vigilax       10-16 Feb 1993   9
West Kimberley  Fitzroy    Cx. annulirostris    13 Feb 1993   1
                 Crossing
West Kimberley  Willare    Ae. normanensis      16 Mar 1993   1

Pilbara         Onslow     Ae. EN Marks'      3-14 Jun 1992   3
  (Fortescue)                sp. #85
Pilbara         Onslow     Cx. annulirostris    13 Jun 1992   1
  (Fortescue)
Pilbara         Onslow     An. amictus       13-14 Jun 1992   2
  (Fortescue)
Pilbara         Exmouth     Ae. vigilax  16 Jun-11 Jul 1992   7
  (Fortescue)

        
Gascoyne (West) Minilya     Ae. eidsvoldensis    7 Jul 1992   5
Gascoyne (West) Minilya     Ae. eidsvoldensis    7 Jul 1992   1
                              (bloodfed)
Gascoyne (West)  Minilya    Ae. EN Marks'        7 Jul 1992   1
                              sp. #85
Gascoyne (West)  Carnarvon  Ae. eidsvoldensis   12 Jul 1992   3
Gascoyne (West)  Carnarvon  Ae. EN Marks'       12 Jul 1992   1
                               sp. #85
Gascoyne (West)  Carnarvon  Cx. quinquefasciatus 12 Jul 1992  1
Gascoyne (West)  Carnarvon  Unidentifiable      12 Jul 1992   1
                              mosquitoes

       
Central Coastal  Karnup     Cx. annulirostris     4 Jan 1993  1
Central Coastal  Karnup     Cq. species near      4 Jan 1993  4
                              linealis
Central Coastal  Perth      Cx. annulirostris     6 Jan 1993  1

        
South Coastal    Australind  Ae. camptorhynchus   6 Jul 1993  1
South Coastal    Mandurah    Ae.            5 Aug-5 Oct 1993 10 
                   (Peel)     camptorhynchus
South Coastal    Busselton   Ae.            1 Sep-15 Nov 1993  9
South Coastal    Busselton   Cx. globocoxitus      1 Nov 1993  1

                                                        Total 73
_____
* Numbers of mosquitoes trapped and processed and estimated
minimum field infection rates for each region will be published
in detail elsewhere.
  Refer to Figure 1 for location of regions and towns from which
isolates of BF virus were obtained.


Eight isolates of the virus were obtained from five different
mosquito species (Table 1) collected at Billiluna, a small,
remote aboriginal community in an arid area in the southeastern
Kimberley region in April 1989 (10). The infected mosquitoes were
collected 3 weeks after heavy local rains. Only moderate wet
season rains were recorded in the remainder of the Kimberley
region, and no cases of BF virus disease were reported from any
region in Western Australia that year. There have been no
subsequent isolations of BF virus from mosquitoes collected at
Billiluna, despite annual collections in the region. No human
cases have been reported from Billiluna.

The first cases of BF virus disease in Western Australian were
reported almost 3 years later, either individually or in small
clusters from towns in the arid East Kimberley, Pilbara,
Gascoyne, Murchison and Southeast (Goldfields) regions between
April and September (Autumn-Spring) 1992. Most activity was
reported from the towns of Exmouth (six cases) and Carnarvon
(four cases). All of these cases occurred during or just after
much larger outbreaks of disease caused by Ross River virus. This
suggested that BF and Ross River viruses may have similar
mosquito vectors and require similar environmental conditions for
successful transmission. The main environmental factor
contributing to the 1992 outbreaks of Ross River virus disease
was extremely heavy rain in these normally arid regions during
autumn and winter (11).

BF virus was isolated from five species of mosquito in the
Fortescue region of the Pilbara and from three species in the
West Gascoyne, just prior to, and during, these arid-region
outbreaks. In coastal regions of the Pilbara, the main vector of
BF virus appears to be Aedes vigilax, a salt marsh-breeding
species. Large numbers of this species develop after very high
tides or heavy rains on salt marshes. It is also the main vector
of Ross River virus in these regions (12). Several other
temporary freshwater ground pool-breeding species in the subgenus
Ochlerotatus, particularly Ae. eidsvoldensis and Ae. EN Marks'
species #85, were found to be infected with the virus in inland
areas or coastal areas where such pools develop. These
preliminary investigations also suggested that both BF and Ross
River virus can co-circulate. Both viruses were isolated from
different mosquitoes of the same species collected in the same
trap on several occasions.

A further six cases of BF virus disease were reported after
record wet season rains in the Kimberley region in early 1993.
The cases occurred just after mosquitoes in the Kimberley region
had been collected by personnel from this laboratory. These
collections yielded 12 isolates of BF virus. Eleven of these were
from Ae. vigilax and Cx. annulirostris mosquitoes trapped less
than 2 weeks after the first heavy wet season rains near the West
Kimberley towns of Broome and Fitzroy Crossing and the East
Kimberley town of Halls Creek (see Figure 1 for locations, Table
1 for isolation details). A twelfth isolate was obtained from Ae.
normanensis collected 5 weeks after the first rains at Willare in
the West Kimberley. The timing of the collections was such that
all three mosquito species could have transmitted BF virus to the
infected persons in the region. Vector competence studies are
required to determine if one or more species were likely to have
been the main vectors.

A single case was reported from the metropolitan area of Perth,
the state's capital, in August 1992. This was the first evidence
of BF virus activity in the temperate and populous southwestern
region of Western Australia. However, the travel history of the
patient was not obtained. Then, in early January 1993, this
laboratory isolated BF virus from Cx. annulirostris and
Coquillettidia species near linealis* mosquitoes collected at
Karnup, south of Perth (Table 1). A week later a single human
case was reported from an address near the site at which the
mosquitoes were trapped. BF virus was also isolated from Cx.
annulirostris mosquitoes trapped in the southern suburbs of Perth
in early January 1993, providing evidence that the virus may be
transmitted to humans in the metropolitan area. Two further cases
were reported from the Perth metropolitan area, one in February
and one in May 1993. Again, no travel histories were available
for these patients, but it appears that the virus remained and
was actively transmitted in the southwest during the autumn and
winter of 1993, as it was isolated from Ae. camptorhynchus
mosquitoes trapped in July and August (Table 1).
_____
*This species is similar to, but distinct from, Coquillettidia
linealis, according to E.N. Marks, the leading Culicid taxonomist
in Australia.

A larger outbreak of BF virus disease occurred in the southwest
region between September 1993 and March 1994. This has been
described in detail elsewhere (2). Twenty-eight serologically
confirmed cases were reported from the southwest region during
that period. Of these, more than half (17 cases) were in or near
the small coastal towns of Mandurah (Peel) and Busselton during
spring (September-November) of 1993. BF virus was isolated on 20
occasions from pools of Ae. camptorhynchus mosquitoes collected
in the Mandurah and Busselton regions before and during the
outbreak (Table 1), thereby implicating that species, along with
Cx. annulirostris and Cq. species near linealis, as an important
vector in the southwest. Ae. camptorhynchus breeds in salt
marshes and brackish wetlands during all but the hottest months
of the year in the southwest and is the main vector of Ross River
virus in the region (3, 11). The ratio of the carriage rate of BF
virus in Ae. camptorhynchus during the outbreak to the number of
human cases was very high compared with the rate observed for
Ross River virus in Ae. camptorhynchus in the same regions during
previous Ross River virus outbreaks (M.D. Lindsay, C.A. Johansen,
and J.S. Mackenzie, unpublished observations). This suggests that
the ratio of subclinical (therefore unreported) to clinical cases
may be much larger with BF virus than with Ross River virus or
that fewer humans were infected, possibly because Ae.
camptorhynchus may not transmit BF virus to humans as efficiently
as it does Ross River virus. Seven cases were reported between
November 1993 and March 1994 in small towns in the inland
southwest region in a later cycle of virus activity.
Unfortunately, no collections of mosquitoes were carried out in
the region during that time. Small clusters of cases or
individual cases were also reported from several other regions of
Western Australia during this time, including three additional
cases from Broome in the West Kimberley region, presumably
associated with the 1993-94 wet season.

BF virus disease was made a notifiable disease in Western
Australia in June 1994 as a direct result of the 1993-94
southwest outbreak (Health [Infectious Diseases] Amendment Order
1994, Government Gazette, Western Australia, 24 June 1994). The
outbreak was also the first report of a substantial number of
cases in the absence of Ross River virus activity anywhere in
Australia. Ross River virus is endemic in the Mandurah (Peel)
region but only one case of Ross River virus disease was reported
from the area during spring-summer (September-February) 1993-94.
This is the lowest recorded number of cases for that period in
the region since record keeping began in 1984. Environmental
conditions and vector mosquito populations in the southwest were
unfavorable for Ross River virus transmission during the BF
outbreak. In particular, populations of Ae. camptorhynchus from
October onwards were much smaller than in years when larger
numbers of cases of Ross River virus disease were reported (M.D.
Lindsay, C.A. Johansen, J.S. Mackenzie, unpublished
observations). It is not known whether the BF virus outbreak
occurred because BF virus can circulate under conditions that are
not suitable for Ross River virus activity or whether extremely
low levels of immunity in "virgin" vertebrate host and human
populations in the southwest may have enhanced transmission
cycles.

Surveillance and epidemiologic studies carried out by this
laboratory in the north of Western Australia since 1972 and in
the southwest since 1987 have found no convincing evidence of BF
virus activity in these regions prior to the events described in
this report. No BF virus was isolated from the north of Western
Australia before 1989, despite large-scale processing of
field-caught mosquitoes over a 17-year period that yielded
hundreds of isolates of other arboviruses. Similarly, no BF virus
isolate was obtained from more than 400,000 mosquitoes collected
throughout the southwest between 1987 and 1992 and processed for
virus isolation. Furthermore, an ongoing serosurvey has found no
evidence of infection with BF virus in more than 1,000
individuals of 18 vertebrate species collected in the southwest
before 1992 (C.A. Johansen, unpublished results). This suggests
that the virus responsible for the recent outbreaks was recently
introduced to Western Australia. The means of introduction,
initially to the northwest and more recently to the southwest of
Western Australia, is not known. In view of the activity at
Nhulunbuy in the Northern Territory, before the first Western
Australia cases in 1992, it is possible that the virus may have
been introduced from that region in a viremic human or in
livestock. However, little is known about the duration and height
of viremia in infected humans or other animals, and it is not
known whether person-to-person vector-mediated transmission of
Barmah Forest virus can occur. Our laboratory has begun a study
to investigate the molecular epidemiology of BF virus,
particularly whether the strain of virus responsible for the
Western Australia outbreaks was introduced from Eastern Australia
or was a local, hitherto undetected, strain.

Acknowledgments

The authors thank Tony Wright, (Health Department of Western
Australia) for assistance with collection of mosquitoes, Margaret
Wallace, Rosa Egerton-Warburton, Roger Clifton, and Dora Li for
assistance with laboratory processing of mosquito and virus
samples, and staff in the Virology Section, State Health
Laboratory Service, the Health Department of Western Australia,
for carrying out the serologic testing of human sera. This work
was funded by a grant from the Health Department of Western
Australia.

Michael D.A. Lindsay, Cheryl A. Johansen, Annette K. Broom, David
W. Smith,* and John S. Mackenzie 
Department of Microbiology, The University of Western Australia,
Queen Elizabeth II Medical Centre, Nedlands, WA
*State Health Laboratory Services, Queen Elizabeth II Medical
Centre, Nedlands, WA

References

1. Lindsay MD, Smith DW, Johansen C, Mackenzie JS. Barmah Forest
virus disease in Western Australia. Western Australian Notifiable
Diseases Bulletin 1994; 4: 1-4.
2. Lindsay MD, Johansen C, Smith DW, Wallace MJ, Mackenzie JS. An
outbreak of Barmah Forest virus disease in the south-west of
Western Australia. Med J Aust. In press.
3. Mackenzie JS, Lindsay MD, Coelen RJ, Hall RA, Broom AK, Smith
DW. Arboviruses causing human disease in the Australian
zoogeographic region. Arch Virol 1994;136:447-7.
4. Marshall ID, Woodroofe GM, Hirsch S. Viruses recovered from
mosquitoes and wildlife serum collected in the Murray Valley of
south-eastern Australia, February 1974, during an outbreak of
encephalitis. Aust J Exp Biol Med Sci 1982;60:457-70.
5. Vale TG, Carter IW, McPhie KA, James GS, Cloonan MJ. Human
arbovirus infections along the south coast of New South Wales.
Aust J Exp Biol Med Sci 1986;64:307-9.
6. Boughton CR, Hawkes RA, Naim HM. Illness caused by a Barmah
Forest-like virus in New South Wales. Med J Aust 1988;148:146-7.
7. Phillips DA, Murray JR, Aaskov JG, Weimers MA. Clinical and
subclinical Barmah Forest virus infection in Queensland. Med J
Aust 1990;152:463-6.
8. Hawkes RA, Boughton CR, Naim HM, Myrick BA, Ramsay LG. Barmah
Forest virus infections in humans in New South Wales. Med J Aust
1988;146:569-73.
9. Merianos A, Farland AM, Patel M, Currie B, Whelan P, Dentith
H, Smith D. A concurrent outbreak of Barmah Forest and Ross River
disease in Nhulunbuy, Northern Territory. Comm Dis Intell (Aust)
1992;16:110-1.
10. Broom AK, Mackenzie JS, Lindsay MD, Wright AE. Epidemiology
of Murray Valley encephalitis and Kunjin viruses in Western
Australia, 1980-89. Arbovirus Research in Australia 1989;5:14-8.
CSIRO and Queensland Institute of Medical Research.
11. Lindsay MD, Johansen C, Wright AE, Condon R, D'Ercole M,
Smith D, Mackenzie JS. The epidemiology of outbreaks of Ross
River virus infection in Western Australia in 1991-1992.
Arbovirus Research in Australia 1992;6:72-6. CSIRO and Queensland
Institute of Medical Research.
12. Lindsay MD, Broom AK, Wright AE, Johansen CA, Mackenzie JS.
Ross River virus isolations from mosquitoes in arid regions of
Western Australia: implication of vertical transmission as a
means of persistence of the virus. Am J Trop Med Hyg
1993;49:686-96.


An Outbreak of Shigella sonnei Infection Associated with
Consumption of Iceberg Lettuce

To the Editor: Shigella sonnei outbreaks in England and Wales are
typically associated with primary schools and nurseries. The mode
of transmission is usually from person to person by the
fecal-oral route (1). In a June 1994 outbreak of Sh. sonnei food
poisoning among adults in several countries in North West Europe,
the vehicle of infection appeared to be iceberg lettuce (2).

In early June, the Communicable Disease Surveillance Centre
(CDSC), Public Health Laboratory Service, received a report of an
increase in domestic cases of Sh. sonnei infections in Sweden
from the Salmnet network a European international laboratory-
based reporting system for human salmonella infections that
provides a timely on-line database. In this instance the network
was used for shigellosis. Of 100 reported cases of Sh. sonnei
infection in Sweden, 52 occurred in two outbreaks in mid- May.
Many cases seemed to be due to foodborne infection, and iceberg
lettuce and peeled frozen prawns were implicated as vehicles of
infection. Sh. sonnei phage types 2 and 3 alpha were associated
with the outbreaks, and phage types 2 and 65 had been isolated
from sporadic cases.

A message was sent throughout England and Wales on Epinet (a
system for rapid electronic data transfer to all Consultants in
Communicable Disease Control [CsCDC] in each District Health
Authority, Public Health Laboratories [PHLs] and other agencies
involved in infectious disease control) asking for information on
possible foodborne Sh. sonnei infection to be sent to CDSC and
for isolates to be referred to the Laboratory of Enteric
Pathogens (LEP) for phage typing.

Epidemiologic studies

Laboratory reports of Sh. sonnei infection received through the
routine reporting system at CDSC were scrutinized to determine
the age group and sex distributions during weeks 21 to 24.
After the Epinet message, CsCDC and laboratory directors who
reported clinical cases for which Sh. sonnei was isolated were
asked to administer trawling questionnaires to apparently
sporadic cases among adults with no recent history of overseas
travel. Personal details and history of illness and exposure to
particular foods were sought.

Several small outbreaks and clusters were reported during June.
CsCDC was asked for results of any analytical epidemiologic
studies to CDSC. The results of the national laboratory reporting
system are shown in Table 1. Although there were fewer reports in
the first 20 weeks of 1994 than in a similar period in 1993,
there were more reports in the weeks 21 to 24 and many more
reports among adults. The proportion of total reports constituted
by those from adults was 66% in weeks 21 to 24 of 1994 compared
with 44% with the same period in 1993. The proportion in women in
the 2 periods was 42% in 1994 compared with 26% in 1993.


Table 1. Shigella sonnei in England and Wales--Laboratory reports
to CDSC

Year                        Number of reports (%)

      Weeks 1-20   Weeks 21-24                         Weeks 1-24
        Total       Total         Adults     Women       Total

1993     3190      480 (100)     211 (44)   127 (26)      3670
1994     1557      505 (100)     333 (66)   214 (42)      2062



Forty trawling questionnaires were distributed. Almost all case-
patients (38/40) had eaten various salad items of which the
common food was iceberg lettuce. The lettuce had been consumed in
restaurants, pubs, and in the homes of the case-patients. The
lettuce was purchased from supermarkets, greengrocers' shops, and
street markets. In one outbreak in Northampton, 21 (52%) of
guests at a party became ill with diarrhea. Sh. sonnei was
isolated from fecal specimens. Illness was significantly
associated with consumption of iceberg lettuce (relative risk
3.68, confidence intervals 1.34 - 10.11, p = 0.0004).

The hypothesis that consumption of iceberg lettuce was associated
with apparently sporadic Sh. sonnei infection in adults was
tested by a case-control study. A case was defined as a person
aged 14 or more years who became ill after May 1, 1994, and had
microbiologic evidence (fecal isolation) of Sh. sonnei infection,
no recent history of overseas travel, and no identifiable contact
with other case-patients in the 3 days before onset. Controls
were nominated by case-patients and matched by sex, age (within a
10-year age band), and area of residence (within a 10-mile radius
of the case). For each case three matched controls were sought. A
questionnaire was administered by telephone by three interviewers
from CDSC. Clinical and demographic details and details of
exposure to food items, including iceberg lettuce, mentioned in
trawling questionnaires were sought.

Twenty-eight case-patients and 49 matched controls were
interviewed and, after excluding those who had recently traveled
abroad and controls who had been ill, results from 27 cases and
44 controls were analyzed. The median age of case-patients was 47
years, and the range was 19 to 79 years. Eight cases were among
men and 19 among women. All case-patients had diarrhea (i.e.,
three or more loose stools in a 24-hour period), although only
four of the 27 reported blood in the stools, 25 of the 27 had
abdominal pain, and 11 reported vomiting. The median duration of
symptoms was 9 days, and the range was 4 to 25 days. Taking into
account the matching inherent in the study design, a matched
analysis was performed. In any analysis 27 matched sets were
possible. For 13 sets there was one control per case, for 11 sets
there were 2 per case, and for 3 sets there were 3 controls per
case. Single variable analysis of the different foods consumed
revealed the possible risk factors (p <0.2) (Table 2). A
multivariable model was fitted with all those variables included.
This procedure was repeated, removing nonsignificant items at
each stage. In the third model, the only remaining significant
item was iceberg lettuce (p = 0.0172). The estimated odds ratio
for iceberg lettuce was 13.8 (95% confidence interval 1.26 to
150.5).

Table 2. Sh. sonnei case control study Single variable matched
analysis

               Case (n=27)      Control (n=44)

                  Did not           Did not       No. of 
Food           Ate  eat  % ate    Ate  eat  % ate  sets   p-value

Prawns          4    22     15     7    37     15  (26s)   0.9388
Shrimps         0    27      0     1    43      2  (27s)   0.3070
Steak           7    19     27     6    37     14  (26s)   0.0139
Burgers         5    22     19    12    32     27  (27s)   0.2045
Salad          25     2     93    34    10     77  (27s)   0.0081
Cold meats     15    10     60    29    13     69  (23s)   0.7708
Tomatoes       22     4     85    33    11     75  (26s)   0.1039
Spring onions   5    21     19     9    35     21  (26s)   0.7556
Celery          5    22     19     5    39     11  (27s)   0.2956
Cucumber       16    11     59    31    13     71  (27s)   0.3798
Other salads   16    10     62    26    18     59  (26s)   1.0000
Lettuce        25     2     93    31    13     71  (27s)   0.0007
Cos lettuce     2    20      9     3    25     11  (17s)   1.0000
Webb's lettuce  5    18     22     4    34     11  (21s)   0.2632
Lamb's lettuce  2    17     11     6    36     14  (19s)   0.1002
Raddicio 
  lettuce       4    20     17     7    34     17  (23s)   0.8720
Iceberg 
  lettuce      17     8     68    19     23    45  (25s)   0.0023
Frisee lettuce  5    18     22     4     37    10  (22s)   0.2582
Home           15     8     65    27     16    63  (23s)   0.8494
Restaurant      6    16     27     5     33    13  (21s)   0.1546
Pub             4    18     18     2     34     6  (20s)   0.0795
Other outlet   10    14     42     7     31    18  (22s)   0.0012



In sporadic cases associated with consumption of lettuce from
particular restaurants or public houses, it was possible to
compare the date of onset with the date of delivery of iceberg
lettuce by the wholesalers. The distribution chain was traced
back through importers supplying wholesale markets in England.
The wholesalers were supplied by packers in Spain. This was
consistent with the findings of the investigators in the
Norwegian outbreak. Iceberg lettuce investigated by the Public
Health Laboratory service during the second week of June 1994 did
not grow Sh. sonnei. However, the iceberg lettuce season in
Spain, which began in October, ended early in June, and the
source of lettuce available for testing could not be traced.

Laboratory studies

All Sh. sonnei isolates referred to LEP after the Epinet message
were phage typed by using the scheme described by Hammerstrom (3)
and Kallings and Sjoberg (4), according to a protocol supplied by
Dr. R. Wollin, Swedish Institute of Infectious Disease Control,
Sweden. Isolates were also tested for resistance to a range of
antibiotics by an agar dilution technique (5).

A total of 495 isolates were referred to LEP between June 14 and
July 31, from 51 laboratories in England and Wales. Most isolates
were from sporadic infections, but in a number of local
outbreaks, there was a strong epidemiologic association between
illness and consumption of iceberg lettuce. Two phage types
predominated among the 19 types identified during this period, PT
2 (42.6% of isolates) and a variant of PT65 provisionally
designated PT L (15.9%). In contrast, although a small number of
isolates of PT 65 and PT L were identified among strains of Sh.
sonnei isolated in England and Wales in 1991 and 1992, no
isolates of PT 2 were seen before May 1994. Towards the end of
the outbreak PT 3 and PT 6 were becoming reestablished in England
and Wales as the predominant types, as they had been in previous
years.

An exception to the recent pattern was an outbreak in North
Wales, involving several children and adults, in which infection
was associated either with eating ice cream at a particular
establishment or having contact with children who had done so.
All 73 of the isolates of PT 62 were associated with this
outbreak.

A total of 357 Sh. sonnei isolated during this period (72.1%)
were fully sensitive to all drugs tested. Phage types 2 (87%
fully sensitive) and PT L (99%) were predominantly sensitive, as
were all isolates of PT 62; usually one would expect more than
70% of Sh. sonnei isolates to be resistant to one or more drugs.
The use of the same phage-typing scheme across several European
countries has facilitated cross-referencing between the British,
German, and Swedish outbreaks. Phage types 2 and 65 (or the
closely related variant PT L) were identified in several
countries.

From the epidemiologic studies, it was concluded that the strong
statistical evidence (p = 0.0172) that consumption of iceberg
lettuce was associated with the risk of becoming ill together
with reports from other European countries, including Scotland,
Sweden, and Norway, and the temporal association of the outbreak
with the iceberg lettuce season in Spain implicated iceberg
lettuce as the vehicle of infection. This was corroborated by the
laboratory studies, which showed a change in predominant phage
types during the period of the outbreak. The predominance of the
same phage types in lettuce-associated Sh. sonnei infections in a
number of countries added further weight to this conclusion.

In England, there were several anecdotal accounts of dual
infection with salmonellae and viruses as well as Sh. sonnei.
This was also true of infections in Norway and Sweden (6). A
plausible explanation would be that fecally contaminated water
was used to irrigate the lettuce or to cool it after packing. If
iceberg lettuce is not washed thoroughly before consumption,
contamination could be retained in the leaves.

This study demonstrates both the importance of coordinating
laboratory results and epidemiologic investigations and the value
of rapid communications and common typing techniques in various
European countries.

J.A. Frost, M.B. McEvoy,* C.A. Bentley, Y. Andersson,** and B.
Rowe
Laboratory of Enteric Pathogens, Central Public Health
Laboratory, London, England
*Communicable Disease Surveillance Centre, London, England
**Swedish Institute for Infectious Diseases Control, Stockholm,
Sweden

References

1. Newman CPS. Surveillance and control of Shigella sonnei
infection.  Communicable Disease Report 1993; 3: R63-8.
2. Anonymous. A foodborne outbreak of Shigella sonnei infection
in Europe. Communicable Disease Report 1994; 4 No. 25.
3. Hammerstrom E. Phage typing of Shigella sonnei. Acta Med Scand
1949. 133 (Suppl 223).
4. Kallings LO, Lindberg AA, Sjoberg L. Phage typing of Shigella
sonnei. Arch Immun Ther Exp 1968; 16: 280-7.
5. Frost JA. Testing for resistance to antimicrobial drugs. In:
Chart H, ed. Methods in practical laboratory bacteriology. Boca
Raton Fla.: CRC Press; 1994.
6. Kapperud G, Rorvik LM, Hasseltvedt V, et al. Outbreak of
Shigella sonnei infection traced to imported iceberg lettuce. J
Clin Microbiol, in press.


?Lyme Disease in Australia--Still To Be Proven! 

To the Editor:  The first case of a syndrome consistent with Lyme
disease was reported from the Hunter Valley region of New South
Wales (NSW) in southeastern Australia in 1982, but there was no
confirming serology. More clinical cases, again without serologic
confirmation, were reported in 1986, two from the south coast and
one from the central coast of NSW. The Queensland State Health
Laboratories reported that 186 (14.9%) of 1,247 sera taken from
patients between 1986-1989 showed antibody response to Borrelia
burgdorferi of 64 by indirect fluorescence antibody test (IFAT),
but none of these results were confirmed by immunoblotting.

In 1988, a multidisciplinary investigation of putative Lyme
disease began, encompassing clinical, serologic, vector, and
reservoir host studies, and results from these studies have been
published (1). What follows herein is derived from the
accumulated published and unpublished data of the research team,
the members of which are credited in the acknowledgments.

Over the past 6 years, principally because of local publicity,
there has been an increase in serologic testing for Lyme disease
in Australia, particularly in southeastern Australia. Testing has
often been initiated by patients with undiagnosed health
problems. Thus, most Lyme disease patients seen by infectious
disease specialists are self-selected and are referred for
assessment on the basis of tick exposure and reported positive
serologic test results for Lyme disease.

Patients with positive serologic test results frequently have
long-standing symptoms for which no other diagnosis has been
established. The most common symptoms are musculoskeletal,
including myalgias and arthralgias without objective evidence of
joint swelling, and syndromes involving fatigue and loss of
energy resembling chronic fatigue syndrome. Some patients fulfill
diagnostic criteria for fibromyalgia. The next most common
symptoms are neurological, and include frequent headaches,
inability to concentrate, and memory loss. The most common
dermatologic manifestation of chronic Lyme disease,
acrodermatitis chronica atrophicans, seen occasionally in Europe
and rarely in the United States, has not been reported from
Australia.

A few cases of erythema migrans, the characteristic dermatologic
manifestation of acute Lyme disease, have been reported from
southeastern Australia, but clinical diagnosis can be confounded
by hypersensitivity reactions to tick bite; a spectacular
erythematous reaction is often associated with the bite of Ixodes
holocyclus, the most common tick biting humans in NSW. Only eight
specimens submitted to our laboratory included skin biopsies done
to isolate spirochetes. B. burgdorferi s.l. was isolated from one
patient returning from Europe, but no spirochetes were isolated
from local patients.

In our serologic diagnostic service, an enzyme-linked
immunosorbent assay (ELISA) for IgG and an IFAT for IgG and IgM
have been used with antigens derived from North American B.
burgdorferi strain B31 (2). From 1988 to April 1994, 78 (1.8%) of
4,372 local patients were positive for IgG by both methods. All
78 patients were tested by IgG Western blot for confirmation by
using the virulent North American B. burgdorferi strain 297 and a
German strain designated B7: with B. burgdorferi strain 297, 46
patient samples showed as many as four indicative bands; with the
European strain B7, 22 patient samples showed as many as three
indicative bands; bands used were 18, 21, 28, 30, 31, 34, 39, 41,
45, 58, 66, 83, and 93 kDa, modified from Dressler et al (3).
Twenty-four other patients with various bacterial, viral, or
autoimmune syndromes not relating to Lyme disease were tested as
controls: with strain 297, 11 control samples showed as many as
two indicative bands, and with strain B7, 10 control samples
showed as many as two indicative bands.

A high degree of cross-reactivity was demonstrated with the
controls, particularly with respect to the 31, 41, 58, and 66 Kda
bands for both the European and the American antigen. As none of
the 78 patients, including putative late-stage patients positive
by ELISA and IFAT, showed more than four specific bands to either
antigen, they would be considered negative by the criteria of
Dressler et al (3). Fewer than 1% of all referred patients
conformed with the national surveillance case definition used in
the United States by the Centers for Disease Control and
Prevention. Problems of specificity and sensitivity associated
with serologic testing for Lyme disease are well recognized,
particularly in Australia where no local spirochete has been
isolated for use as a reference antigen.

Seroprevalence rates for B. burgdorferi infection in humans have
been compared between 200 high (rural residents) and 200 low
(urban residents) tick exposure groups in coastal NSW, by using
the IgG ELISA. No significant difference was found between the
two groups, and the overall seropositivity rate was 2.2% (9/400).
A parallel survey of dogs in NSW has shown a similar result with
an overall seropositivity rate of 2.5% (6/239). These results
contrast with those reported from known endemic-disease areas
outside Australia that have rural populations with considerably
higher seropositive rates. The low rate found by our surveys is
similar to that found by other studies undertaken in areas where
Lyme disease is not endemic, and humans have 1%-3% positive
serologic results cause by cross-reacting antibodies (4).

From January 1990 to December 1992, ticks were collected in areas
associated with putative Lyme disease cases and were examined for
spirochetes to detect a possible causative agent in potential
vectors. Ticks were collected along the east coast of Australia,
from southern Queensland through NSW into northern Victoria, by
flagging in natural habitats, and from domestic and other native
animals. Detection of spirochetes was attempted by dark-field
microscopy and culturing of gut contents and by direct testing of
ticks using polymerase chain reaction (PCR) to detect the
Borrelia-specific flagellin gene (5).

In total, more than 12,000 (>1,000 by PCR) ticks were processed,
including 7,922 I. holocyclus (1). No spirochetes were detected
by dark-field microscopy or by PCR. Spirochete-like objects
(SLOs), were observed in 94 cultures from bloodfed ticks and only
in cultures with bacterial contaminants, presumably from the
bloodmeal. Some SLOs yielded positive fluorescence results when
tested with Borrelia-specific polyclonal antibodies, but tests
with monoclonal antibodies (anti-flagellin H9724, anti-OspA
H5332, anti-OspB H6831) were negative. Electron micrographs
showed that the SLOs were not typical of Borrelia, were composed
of fibers, and probably were not spirochetes. The electron
micrographs were similar to micrographs of SLOs recovered from
contaminated cultures from ticks in the United States and Europe
and thought to be composed of aggregations of bacterial flagella,
probably from the contaminants. Molecular characterization
indicated that the SLOs were not related to B. burgdorferi.

A small number of native vertebrate animals (13 native rats
Rattus fuscipes, 3 bandicoots Perameles nasuta, and 1 marsupial
mouse Antechinus stuartii) trapped on the south coast of NSW were
sampled by ear-punch biopsy (6) for culture and PCR
investigation, but no evidence of borreliae was found. The animal
sample was clearly inadequate, and the PCR primers used for the
tick and animal studies may have been inappropriate and unable to
identify native Australian spirochetes; however, the extensive
investigations of tick gut contents by culturing and dark field
microscopy were also negative for borreliae.

There are some major differences between Australia and the
Lyme-disease-endemic areas of the Northern Hemisphere with
respect to the natural history of borreliosis. No ticks of the
I. persulcatus complex, the principal vectors to humans in the
northern hemisphere, occur in Australia. In eastern Australia,
the logical candidate vector would be I. holocyclus, which has a
wide host range and is the most common tick biting humans.
I. holocyclus cannot transmit a North American strain of B.
burgdorferi (7) but the association with any possible Australian
spirochetes remains unresolved. Likewise, none of the mammal
species identified as reservoir hosts in the Northern Hemisphere
are present in Australia. There are reports of spirochetes in
Australian native animals, and a local mammal could be a
reservoir host for an indigenous spirochete that occasionally
infects humans through a tick vector and produces a clinical
syndrome similar to Lyme disease; however, no spirochete was
detected in the ticks or animals studied.

The diagnosis of Lyme disease outside known disease-endemic areas
should not be based solely on serology because unrelated
syndromes, such as autoimmune diseases and cross reactions with
other bacteria, can produce false-positive results. Likewise, a
definitive diagnosis on clinical grounds alone in a
nonendemic-disease area is difficult to justify without adequate
scientific support based on isolation of the causative agent from
the patient or from another patient or known vector from the
region. In Australia, disagreement as to what constitutes a
positive serologic result has additionally contributed to
overdiagnosis of Lyme disease. Until an organism is isolated from
a local patient and is characterized, the presence of Lyme
disease in Australia will remain controversial.

Acknowledgments

My colleagues Rosemary Munro (clinical microbiology), Department
of Microbiology, Liverpool Hospital, and Stephen Doggett
(entomology), David Dickeson (serology), Danielle Avery
(molecular biology), Cheryl Hunt (molecular biology), Joanne
Mercer (microbiology), and Nicole Trivett (electron microscopy),
CIDM at Westmead Hospital, and John Ellis (molecular biology),
Department of Microbiology, University of Technology Sydney,
contributed to the studies outlined in this paper. Richard
Lawrence, Clinical Superintendent of Medicine, Westmead Hospital,
provided valuable discussions on clinical aspects and case
presentation. Our investigations were supported by the National
Health and Medical Research Council and the Ramaciotti
Foundations.

Richard C. Russell
Department of Medical Entomology, Centre for Infectious Diseases
and Microbiology,
University of Sydney and Westmead Hospital, Westmead, Australia

References

1. Russell RC, Doggett SL, Munro R, Ellis J, Avery D, Hunt C,
Dickeson D. Lyme disease: a search for the causative agent in
ticks in southeastern Australia. Epidemiol Infect
1994;112:375-84.
2. Russell H, Sampson JS, Schmid GP, Wilkinson HW, Plikaytis B. 
Enzyme-linked immunosorbent assay and direct immunofluorescence
assay for Lyme disease. J Infect Dis 1984;149:465-70.
3. Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western
blotting in the serodiagnosis of Lyme disease. J Infect Dis
1993;167:392-400.
4. Barbour AG, Fish D. The biological and social phenomenon of
Lyme disease. Science 1993;260:1610-6.
5. Persing DH, Telford III SR, Rys PN, Dodge DE, White TJ,
Malawista SE, Spielman A. Detection of Borrelia burgdorferi DNA
in museum specimens of Ixodes dammini ticks. Science
1990;249:1420-3.
6. Sinsky RJ, Piesman J. Ear punch biopsy method for detection
and isolation of Borrelia burgdorferi from rodents. J Clin
Microbiol 1989;27:1723-7.
7. Piesman J, Stone BF. Vector competence of the Australian
paralysis tick, Ixodes holocyclus, for the Lyme disease
spirochaete Borrelia burgdorferi. Int J Parasitol 1991;21:109-11.


A Novel Morbillivirus Pneumonia of Horses and its Transmission to
Humans

To the editor: On September 22 and 23, 1994, veterinary
authorities in Queensland and at the CSIRO Australian Animal
Health Laboratory were advised of an outbreak of acute
respiratory disease in horses at a stable in the Brisbane suburb
of Hendra. The trainer of the horses had been hospitalized for a
respiratory disease and was in critical condition. At that time,
the cause of the horses' illness was unclear and any link between
equine and human disease was thought improbable. Poisoning,
bacterial, viral, and exotic disease causes were investigated.
The history of the horses on this property was considered
important (Figure 1) (Figure is not available in ASCII.) Two weeks
before the trainer's illness, on
September 7, two horses had been moved to the Hendra stable from
a spelling paddock in Cannon Hill (6 km). One of these, a
pregnant mare, was sick and died within 2 days. The other horse
was subsequently moved on and never became sick. By September 26,
13 horses had died: the mare; 10 other horses in the Hendra
stable; one horse, which had very close contact with horses in
the Hendra stable, on a neighboring property; and one which had
been transported from the stable to another site (150 km). Four
Hendra horses and three others (one in an adjacent stable, one
moved to Kenilworth, and one to Samford) were later considered to
have been exposed and recovered from the illness. Some of these
horses were asymptomatic. Nine Hendra horses have remained
unaffected. The sick horses were anorexic, depressed, usually
febrile (temperature up to 41 C), showed elevated respiratory
rates, and became ataxic. Head pressing was occasionally seen,
and commonly, a frothy nasal discharge occurred before death.

On September 14, a stablehand at the Hendra stable developed an
influenza-like illness characterized by fever and myalgia. The
next day, the horse trainer also became ill with similar
symptoms. Both had close contact with the dying mare,
particularly the trainer who was exposed to nasal discharge while
trying to feed her; he had abrasions on his hands and arms. The
stablehand, a 40-year-old man, remained ill for 6 weeks and
gradually recovered. Besides myalgia, he also had headaches,
lethargy, and vertigo. The trainer, a 49-year-old man, was a
heavy smoker and showed signs consistent with Legionella
infection. He ultimately required ventilation for respiratory
distress and died after 6 days (Selvey L, et al. A novel
morbillivirus infection causing severe respiratory illness in
humans and horses, submitted).

At the beginning of the diagnostic investigation in horses,
African horse sickness, equine influenza, and hyperacute equine
herpes virus were excluded as possible causes by antigen trapping
enzyme-linked immunosorbent assay (ELISA), polymerase chain
reaction (PCR), or electron microscopy. Tests for Pasteurella,
Bacillus anthracis, Yersinia, Legionella, Pseudomonas, and
Streptobacillus moniliformis were negative, and poisons
consistent with the clinical and gross pathology, such as
paraquat, were excluded by specific testing.

However, within 3 days, a syncytial forming virus was detected in
vero-cell cultures inoculated with diseased horse tissues and
shortly thereafter was seen to grow in a wide range of cells.
These included MDBK, BHK, and RK13 cells. Subsequently, a
syncytial forming virus also was isolated in LLK-MK2 cells that
had been inoculated with tissue from the deceased trainer's
kidney. The isolation of these viruses and their preliminary
characterization by electron microscopy, immunoelectromicroscopy,
serology, and genetic analyses are described elsewhere (Murray
PK, et al. A new morbillivirus which caused fatal disease in
horses and man, submitted).

In summary, ultrastructural analysis showed that the virus is a
member of the Paramyxoviridae family. It is enveloped,
pleomorphic (varies in size from 38 nm to more than 600 nm), and
is covered with 10 nm and 18 nm surface projections. It contains
herringbone nucleocapsids that are 18 nm wide with a 5 nm
periodicity. The presence of `double-fringed' surface projections
on this virus is considered unique. Immunoelectronmicroscopy
showed that both the horse and the human virus react with
convalescent-phase horse sera and with sera from the two human
cases.

PCR primers were synthesized from consensus Paramyxoviridae
matrix protein sequences and tested against the horse virus.
Those specific for paramyxoviruses and pneumoviruses did not
bind, but one pair of morbillivirus primers gave a 400 bp
product. Determination of the sequence of this product enabled
the synthesis of horse virus-specific primers. Phylogenetic
analyses of the matrix protein sequence indicates that the virus
is unique and distantly related to other known members of the
group. A comparison of translated M protein sequence shows that
it has a 50% homology with the morbillivirus group (80% if
conservative amino acid substitutions are used). This distant
relatedness is emphasized by our observations that neutralizing
antisera to measles virus, canine distemper, and rinperest virus
failed to neutralize the virus.

The viruses isolated from the horses and the trainer are
ultrastructurally identical. Serum from the horses and the two
human cases specifically cross-neutralize the virus, and the
horse virus-specific PCR primers provide a positive reaction with
the human virus isolate. Therefore, the horses and the trainer
were infected with the same virus.

At the beginning of the diagnostic investigation, tissues from
the lungs and spleens of diseased horses were injected into two
recipient horses. After 6 and 10 days, the recipient horses
became ill with high fever and severe respiratory signs,
demonstrating that the disease was transmissible. Two days later
the horses were destroyed. The equine morbillivirus was isolated
from tissues from both of these horses. To document that the
isolated horse virus was pathogenic, experimental transmission
tests were also conducted. Two additional horses received a total
of 2 x 107 TCID50 of tissue culture virus by intravenous
inoculation and by intranasal aerosol. Both horses became
seriously ill, and after a short, severe clinical episode, were
destroyed 4 and 5 days after exposure. At necropsy, they showed
gross and histopathologic lesions that were primarily respiratory
and consistent with the natural disease. Virus was reisolated
from their lungs, liver, spleen, kidney, lymph nodes, and blood.

The pathology of this infection is interesting. In horses, the
dominant gross pathology is lesions in the lungs. These are
congested and edematous with prominent lymphatic dilation in the
ventral margins. In natural cases, the airways were usually
filled with thick, fine, stable foam which was occasionally
blood-tinged; this was not seen in the experimental cases.
Histologically, in horses, there is interstitial pneumonia,
proteinaceous edema with pneumocyte, and capillary degeneration.
Virus can be located in endothelial cells by immunofluorescence
and syncitial cells also could be seen in blood vessel walls,
confirming the vascular of trophism of this virus (Murray PK, et
al, submitted). The trainer's post-mortem findings showed
similarities to those of the horses (Selvey L, et al, submitted).

No further clinical cases of disease have been seen in horses or
humans since this outbreak. Serologic surveillance of people who
had close contact with the sick horses, mostly stable workers,
veterinary pathologists, animal health field staff, or people who
lived in the vicinity of the affected stables, was negative
(Selvey L, et al, submitted).

Serologic testing of all horses on quarantined properties and
within 1 km of the Hendra stable, and a sample of horses from the
rest of Queensland was undertaken (Table 1). A total of 1,964
horses were tested from more than 630 premises. The negative
results from this testing also indicate that the infection has
not spread. In the entire horse survey, only seven horses, all
from the Hendra property and the adjoining stables, were
positive. Four of these animals had been clinically affected, but
three were asymptomatic. Because of the potential risk and the
difficulty in establishing freedom from infection, these seven
recovered horses were later destroyed.

Table 1. The premises and horses surveyed by serologic testing for
equine morbillivirus, after the disease outbreak

                                 Premises       Horses

Quarantine Premises*                13            107
1 (within 100 m of
  Hendra stables)                    7             54
2 (100 m to 200 m of
  Hendra stables)                   21            122
3 (200 m to 1 km of
  Hendra stables)                   93            730
4/5 (remainder of
  Queensland)                      500            963

Total                              630          1,964


* Quarantine premises included those with clinical cases, holding
properties associated with the Hendra stables, and other premises
where horses under investigation were kept.



Although persistent virus excretion or carrier states are not known
to occur in other morbillivirus infections, this equine virus is
unique and it cannot be presumed to behave similarly. Australian
veterinary authorities are now satisfied that the incident is over.

We have described a newly recorded disease of horses with an
obvious zoonotic potential; moreover, the causative agent was
previously unrecorded and is significantly different from other
members of its genus, morbillivirus. Infection seems to have spread
from the mare that first showed the now characteristic clinical
signs, to other horses in the same stables, to a horse in close
contact from an adjacent stable, and also to two human attendants.
Clearly, this outbreak was not highly contagious and it rapidly
resolved. However, the virus is highly pathogenic with 65% of
naturally infected horses and all four experimental horses dying. 

Further investigations of the virus and the disease are now
warranted since it could reemerge in Australia or elsewhere.
Investigations of its origin, its replication, its pathogenesis,
and its possible occurrence elsewhere in connection with equine
respiratory disease are merited.

Keith Murray, Russell Rogers,* Linda Selvey,** Paul Selleck, Alex
Hyatt, Allan Gould, Laurie Gleeson, Peter Hooper, and Harvey
Westbury
CSIRO Australian Animal Health Laboratory, Ryrie Street, East
Geelong, Victoria 3220, Australia
*Animal Health Bureau, Queensland Department of Primary Industries,
80 Ann Street, Brisbane, Australia
**Communicable Diseases, Queensland Health, 160 Mary Street,
Brisbane 4000, Queensland, Australia


                           Commentary

Electronic Communication and the Future of International Public
Health Surveillance

Recent developments in electronic communication have enhanced
national public health surveillance systems and facilitated
progress in  establishing surveillance that crosses national
boundaries. The international foodborne outbreak of Shigella sonnei
described by Frost and colleagues was first reported through
Salmnet (1), a laboratory-based surveillance system designed to
include an on-line network database. Salmnet was established in
1994 to improve the prevention and control of human salmonellosis
and other foodborne infections in the countries of the European
Union and the European Cooperation in Science and Technology.

Epidemiologists who have national surveillance responsibilities and
heads of reference laboratories in 13 countries currently
collaborate in the Salmnet project under the joint leadership of
the Directors of the Laboratory of Enteric Pathogens and the
Communicable Disease Surveillance Centre (CDSC) at the Public
Health Laboratory Service campus at Colindale, London. During the
course of two workshops, the collaborators agreed to a) develop and
apply standardized phage typing for the most common salmonella
serotypes within Europe, b) introduce an international quality
assurance scheme for laboratory performance of Salmonella phage
typing, c) establish a core set of data on each
laboratory-confirmed and typed human salmonella isolate for rapid
transfer into a shared nonaggregated dataset, and d) develop
statistical analysis programs to facilitate the early recognition
of international outbreaks. The collaborators also agreed to
rapidly report any clusters detected and to exchange information
concerning other infections, including those caused by Shigella,
Listeria, and vero-cytotoxin-producing strains of Escherichia coli.

Currently six countries share data through the Internet, while the
other seven countries rely on faxing material or sending diskettes
through the mail. All collaborating countries plan to join the
on-line network by the end of 1995. The opportunities offered by
electronic communication have encouraged a remarkable degree of
international cooperation in surveillance, as is evident in the far
reaching objectives agreed upon for Salmnet.
The Salmnet collaboration was already in place when the S. sonnei
outbreak in Sweden was reported to Colindale. CDSC responded by
sending an electronic message throughout England and Wales by
Epinet, an electronic system for the rapid transfer of vital public
health information developed by the CDSC Welsh Unit in Cardiff (2).
The message was sent to consultants in communicable disease control
in each district health authority, to the 53 public health
laboratories, and to other agencies in England and Wales involved
in infectious disease control. Further information from Norway,
Scotland, and Sweden reinforced and stimulated the ongoing
investigation in England and Wales. Since its inception, Salmnet
has also contributed information with potential international
implications concerning several Salmonella serotypes ( 3,4).

The signing of the Treaty of Maastricht (1992) was an important
milestone for international cooperation in public health
surveillance. The treaty established a basis for European Community
action in the field of public health and enjoined cooperation
between member states, third countries, and international public
health organizations to protect human health. Sufficient evidence
has accrued on the added value of international surveillance of
infectious diseases, and it is generally accepted that the
potential for major public health hazards is amplified as a
consequence of the increasing volume of international travel and
the global extension of food distribution networks (5).
Surveillance systems such as Salmnet and the European Surveillance
of Travel-Associated Legionnaires' Disease (6) will pave the way
for international surveillance by providing a communications
network that will facilitate the rapid collection and analysis of
data using standard case definitions, transmission of information
for the prevention of communicable diseases, and the promotion of
effective public health practice.

Parallel electronic surveillance systems in the United States offer
equal opportunity for international collaboration. For example,
since 1985, data on notifiable diseases have been transmitted
electronically each week to the Centers for Disease Control and
Prevention (CDC) from state health departments by the National
Electronic Telecommunications System for Surveillance (NETSS) (7).
NETSS was developed by CDC and the Council of State and Territorial
Epidemiologists for electronically collecting, transmitting,
analyzing, and publishing weekly reports of notifiable diseases and
injuries from 50 states, New York City, the District of Columbia,
Puerto Rico, the Virgin Islands, Guam, American Samoa, and the
Commonwealth of the Northern Mariana Islands (8). The operation of
NETSS is based on agreements on reporting conditions, standard case
definitions, and protocols for formatting and transmitting data,
rather than prescribed software or systems.

A second CDC electronic reporting system, the Public Health
Laboratory Information System (PHLIS), is used by public health
department laboratories in all states, New York City, the District
of Columbia, and Guam to report laboratory isolate-based
surveillance data to CDC. The PC-based system was developed jointly
by the National Center for Infectious Diseases, CDC, and the
Association of State and Territorial Public Health Laboratory
Directors to maintain a fast and direct link between public health
laboratories in the United States and CDC. PHLIS is used to gather,
analyze and transmit data (e.g., laboratory testing results,
epidemiologic information, findings from special studies and
surveys) among multiple sources of public health laboratory
information (e.g., hospitals, laboratories, or public health
departments), and it provides an automated program in its
longitudinal databases to detect outbreaks (9).

European and U.S. surveillance databases and information systems
should be linked to share public health information of
international concern. To that end, CDSC and CDC are developing a
cooperative communications information system that will use the
Internet to mirror vital public health documents (e.g., CDSC's
Communicable Disease Report [CDR], CDC's Morbidity and Mortality
Weekly Report [MMWR], and selected surveillance data sets). This
network is the beginning of a larger international network that
will share data, exchange information, and improve public health.
This larger network could link such systems as Salmnet, NETSS, and
PHLIS to create a virtual on-line library of international
surveillance data and information for public health.

With the diffusion of technology, internationally networked
electronic public health surveillance systems are gaining in
importance. Their existence clearly facilitates the rapid
collection, analysis, and dissemination of vital public health
information and promotes the establishment of effective
international public health policies.

T. Demetri Vacalis
Epidemiology Program Office
Centers for Disease Control and Prevention
Atlanta, Georgia, USA

Christopher L. R. Bartlett
PHLS Communicable Disease Surveillance Centre
London, England

Cheryl G. Shapiro
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, Georgia, USA

References

1. Fisher IST, Rowe B, Bartlett C, Gill O Nol."Salm-Net" 
laboratory-based surveillance of human salmonella infections in
Europe. PHLS Microbiology Digest 1994; 11:181-2.
2. Palmer S, Henry R. Epinet in Wales: PHLS Cadwyn Cymru
development of a public health information system. PHLS
Microbiology Digest 1992;9:107-9.
3. Communicable Disease Surveillance Centre. Salmonella mikawasima
update. Communicable Disease Report 1993;3:215.
4. Communicable Disease Surveillance Centre. Salmonella javiana in
Europe. Communicable Disease Report 1994;4:61.
5. Bartlett C, Gill N. International surveillance of
disease--communicable disease control after Maastricht: Germs and
subsidiarity. Lancet 1993; 341:997-8.
6. Communicable Disease Surveillance Centre. European surveillance
of Legionnaires' disease associated with travel. Communicable
Disease Report 1994;4:25.
7. Thacker SB, Stroup DF. Future directions for comprehensive
public health surveillance and health information systems in the
United States. Am J Epidemiol  1994;140:383-97.
8. Centers for Disease Control and Prevention. National Electronic
Telecommunications System for Surveillance--United States, MMWR
1990-1991;40:502-3.
9. Bean NH, Martin SM, Bradford H. PHLIS: An electronic system for
reporting public health data from remote sites. Am J Public Health
1992;82:1273-6.

                         News and Notes

Communicable Diseases Intelligence

Communicable Diseases Intelligence (CDI) is a fortnightly
publication of the Australian Department of Human Services and
Health and the Communicable Diseases Network of Australia and New
Zealand. The Network comprises representatives of the Australian
Department of Human Services and Health, the State and Territory
health authorities, and other organizations involved in
communicable disease surveillance and control from throughout the
country. In addition, there is a representative from New Zealand.
It has fortnightly teleconferences and other meetings to exchange
information on emerging communicable disease activity and to
coordinate surveillance and control activities.

Each issue of CDI incorporates reports from Australia's national
communicable diseases surveillance systems, including the National
Notifiable Diseases Surveillance System, the CDI Laboratory
Reporting Schemes, and the Australian Sentinel General Practitioner
Surveillance Network. Reports from the National Salmonella
Surveillance Scheme, the Australian Gonococcal Surveillance
Programme and the National HIV, AIDS, and Tuberculosis Reporting
Systems are also regularly included.

CDI also publishes timely reports of communicable disease outbreaks
and other articles dealing with a wide range of subjects relevant
to the surveillance and control of communicable diseases in
Australia. Recently published items have reported, for example, the
first identification of endemically acquired hepatitis E in the
Northern Territory of Australia, an outbreak of influenza in a
nursing home, the epidemiology of hepatitis A in South Australia,
the epidemiology of Barmah Forest virus disease in Western
Australia, and the outbreak of respiratory disease in humans and
horses due to a previously unrecognized paramyxovirus.

   CDI is available from
   The Editor
   Communicable Diseases Intelligence
   AIDS and Communicable Diseases Branch
   Department of Human Services and Health
   GPO Box 9848
   Canberra ACT 2601
   Australia

Helen Longbottom
Department of Human Services and Health
Canberra ACT Australia


DxMONITOR: Compiling Veterinary Diagnostic Laboratory Results

The DxMONITOR is a collaborative effort between the U.S. Department
of Agriculture, Animal and Plant Health Inspection Service's
Veterinary Services (USDA:APHIS:VS), the American Association of
Veterinary Laboratory Diagnosticians, and the United States Animal
Health Association. This quarterly animal health report presents
compiled data from national animal disease control and eradication
programs (bovine and porcine brucellosis, bovine tuberculosis,
porcine pseudorabies and equine infectious anemia); patterns of
selected diseases based on veterinary diagnostic laboratory data
(bovine leukosis; bovine bluetongue; bovine, ovine and caprine
paratuberculosis; equine arboviral encephalitis; equine viral
arteritis; porcine reproductive and respiratory syndrome); data on
selected etiologic agents associated with specific animal health
events such as bovine abortion; global disease distribution (bovine
spongiform encephalopathy); and notes from veterinary diagnostic
laboratories about unusual laboratory findings or new diagnostic
procedures.

The DxMONITOR has contributed to a greater awareness of animal
diseases in the United States. Global trade agreements, the
worldwide information explosion, and increasing public concern over
the safety and quality of food have focused attention on animal
health. Compilation of veterinary diagnostic laboratory data is one
component of the USDA: APHIS efforts to respond to these increased
demands for animal health information through an integrated and
coordinated monitoring and surveillance system. Animal-health
monitoring and disease surveillance concern not only animal health
per se, but also interactions with the environment, animal welfare,
production practices and product wholesomeness which impact animal
health. The DxMONITOR is mailed to all interested parties without
charge and is increasingly available through electronic
dissemination channels. For more information or subscription,
contact DxMonitor Animal Health Report, c/o Centers for
Epidemiology and Animal Health, USDA:APHIS:VS, 555 S. Howes, Suite
200, Ft. Collins, CO 80521-2586; telephone 303-490-7800; e-mail 
DXMONITOR@aphis.ag.gov.

William Hueston
Centers for Epidemiology and Animal Health
Veterinary Services
APHIS, U.S. Department of Agriculture
Fort Collins, Colorado, USA


WHO Scientific Working Group on Monitoring and Management of
Bacterial Resistance to Antimicrobial Agents

Antibacterial resistance is a global clinical and public health
problem that has emerged with alarming rapidity in recent years and
undoubtedly will increase in the near future. Resistant bacteria do
not respect national borders, and developments in the remote
locations can have an impact throughout the world. Resistance is a
problem in the community as well as in health care settings, where
transmission of bacteria is greatly amplified, in both developed
and developing countries. Because multiple drug resistance is a
growing problem, physicians are now confronted with infections for
which there is no effective therapy. The morbidity, mortality, and
financial costs of such infections pose an increasing burden for
health care systems worldwide, but especially in countries with
limited resources.

The Division of Communicable Diseases at the World Health
Organization, Geneva, Switzerland, recently convened a Scientific
Working Group to address the problem of drug-resistant bacterial
infections. From November 29 to December 2, 1994, participants from
23 countries reviewed and discussed scientific data on the nature
and costs of drug resistance; recent national and global trends;
approaches to limiting the emergence and spread of resistance in
community and institutional settings; and strategies to strengthen
local, national, and global surveillance. Participants included
representatives from clinical medicine, public health, the clinical
laboratory, and the biomedical research arenas and from the
pharmaceutical industry.

The Working Group formulated a series of recommendations to address
these issues at local, national, and international levels. The
recommendations placed emphasis on enhanced surveillance of drug
resistance through usage of WHONET software, increased monitoring
and improved usage of antimicrobial drugs in human, veterinary, and
animal husbandry settings, improved laboratory diagnostic capacity,
standardization and quality control of laboratory methodology,
professional and public education, development of new drugs and
assessment of alternative therapeutic modalities, assessment of
vaccine development and delivery priorities related to
antimicrobial resistance, better implementation of infection
control measures, and evaluation of prevention strategies. 

The Working Group plans to release its final report in the spring.

Fred C. Tenover
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, Georgia, USA

James M. Hughes
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, Georgia, USA