New and Emerging Infectious Diseases 2008, Vol.92, Issues 6

New and Emerging Infectious Diseases
Preface
Mary Elizabeth Wilson, MD, FACP, FIDSA

Guest Editor
Infectious diseases are changing in ways that are unprecedented in scope and scale.
The dynamic nature of infectious diseases has become increasingly evident in recent
years, because of the appearance of new infectious diseases, the recognition of pre-
viously unidentified pathogens, the resurgence and change in the distribution of well
characterized diseases, changes in resistance patterns (almost always involving in-
creased resistance) of microbes to antimicrobial agents, and, in some instances, the
appearance of more virulent forms of pathogens.1,2 These infections affect people,
plants, and animals; the pathogens come from all classes of organisms—bacteria, vi-
ruses, fungi, protozoa, and helminths. Changes are occurring in all regions of the world
and are not restricted to pathogens that are spread from person to person; they also
involve pathogens with other mechanisms of transmission.
Many broad factors are contributing to the global changes in infectious diseases.1,3
Multiple factors contribute to each emerging infection, which is described clearly in
many of the articles in this issue. Emergence of an infectious disease is typically com-
plex. For example, one cannot single out just one factor that led to the appearance and
rapid broad spread of West Nile virus infections in the United States and in the Amer-
icas. The complexity of the contributing factors also makes it difficult to anticipate and
predict where and when new microbial threats will emerge. A single simple intervention
usually will not suffice for prevention.
Socioeconomic, political, demographic, and environmental changes are among the
many factors involved in the emergence of new microbial threats.1,2 Many infectious
diseases (or their vectors or intermediate hosts) are sensitive to temperature, humidity,
and climatic factors, so they potentially can be influenced by global climate change.
Land use and alteration of the environment (including clearing forests, building roads,
dams, and other structures) can affect patterns of infectious diseases. The characteris-
tics of global populations today–size, density, mobility, and location–make the world es-
pecially vulnerable to new microbial threats.4 The size of the human population and that
of animals raised for food is larger than ever, providing unprecedented opportunities for
microbial replication, mutation, and adaptation. The size of many urban populations
now is sufficient to sustain the ongoing circulation of certain viruses, such as dengue.
Med Clin N Am 92 (2008) xiii–xviii

doi:10.1016/j.mcna.2008.08.002 medical.theclinics.com
0025-7125/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
xiv Preface
Mobility, as described in the article on travel, is unprecedented in volume, reach,

and speed. Movement involves people, plants, and animals and allows juxtaposition
of species that have never been in contact before and novel opportunities for trans-
mission across species, especially from animals to humans.5 The high density of pop-
ulations also facilitates the spread of microbes to large and interconnected
populations. For the first time in human history, more than half of the world’s people
live in urban areas. Urbanization in tropical and subtropical areas and global travel
have been key factors in the emergence of dengue virus infections in many tropical
areas.
The expansion of concentrated food animal operations in the United States, and
increasingly in other countries, means that large concentrations of genetically similar
animals are living together in close proximity, a milieu that could allow the rapid spread
of a pathogenic microbe.6 These sites also may be the setting for the emergence of
resistance genes and microbes that can infect humans.
The location of the most rapid population growth today and the location with the
most projected population growth in the coming decades is urban areas in low lat-
itudes—predominantly in developing countries and often in urban areas that lack ad-
equate infrastructure to provide clean water, sanitation, and adequate housing and
nutrition. Periurban slums at the periphery of these cities are inhabited by residents
who work in the city but remain connected to families in rural areas, and they provide
a conduit for movement of pathogenic microbes in both directions: from rural areas
into the city and from the city to rural areas.4 These tropical and subtropical locations
are also regions with greater species richness and presumably have a greater range
of pathogens that could potentially infect humans.7 Surveillance for infectious dis-
eases in humans and animals often is limited in developing countries because of in-
adequate laboratory facilities and a lack of resources. The presence of many
endemic infectious diseases, such as malaria and other infections that can cause fe-
ver, may mean that recognition and identification of a new or unusual infection in that
area may be delayed or that infection may go completely unrecognized. Serosurveys
of populations in tropical areas confirm the circulation of viruses and other pathogens
causing infections that have not been recognized in the health care systems in those
areas. Information about infections in some areas of the world becomes available
through surveillance networks that use returned travelers from those areas as senti-
nels.8 Careful evaluation of returned ill travelers in developed countries where spe-
cialized laboratory support is available may help distinguish pathogens (or
sequence specific strains or assess sensitivity patterns to antimicrobials) from other
parts of the world.9
Global changes in microbial threats are possible because of the abundance, vari-
ety, and the very nature of microbes.1 Microbes are old (existing before humans) and
diverse and occupy every part of earth, including areas that are extremely hot, cold, or
have other extreme environments. Humans have identified only a small fraction of mi-
crobial species that exist, and presumably, they have identified only a small portion of
those that are pathogenic for humans. The vast majority of microbes are not patho-
genic for humans. Many are essential for life. It is their capacity for rapid replication
and evolution through a variety of mechanisms that allow them to adapt to changing
environments, whether physical, chemical, immunologic, and so forth. The progres-
sive development of bacteria’s resistance to antibiotics (including Mycobacterium
tuberculosis to anti-tuberculosis drugs), the malaria parasite’s resistance to antimalar-
ials, and influenza’s resistance to antiviral agents over the past few decades are exam-
ples of microbes’ remarkable capacity to adapt to human-applied antimicrobial
interventions.
Preface xv
PEOPLE, PIGS, AND POULTRY: THE THREAT OF AVIAN INFLUENZA
Avian influenza is an emerging microbial threat that illustrates the complex factors
involved in an evolving disease and the dynamic nature of an infectious disease over
time. Although avian influenza brings to mind H5N1 (which was first identified in Hong
Kong as a cause of deaths in humans in 1997), multiple avian influenza viruses exist.10
The H5N1 virus is remarkable not only for the high mortality it causes when it infects
humans, but also the rapidity of its spread and its extreme lethality in poultry popula-
tions. Because of the potential threat that it poses to human populations, poultry pop-
ulations have been killed when they have been infected with H5N1 in an attempt to
eliminate the virus. Despite the slaughter of hundreds of millions of chickens over
the past decade, H5N1 persists in parts of the world and has continued to spread
in avian populations. Although chickens infected with H5N1 have high mortality, the
virus can infect ducks and other avian species without causing death, allowing the vi-
rus to persist and potentially spread. Mallard ducks, for example, can be infected with
H5N1 and excrete abundant virus without clinical or pathologic evidence of disease.11
Migratory bird species can be infected and can carry viruses into new areas, though
their precise contribution to the global spread of the virus is uncertain. Global move-
ment through trade (legal and illegal) of poultry, their parts, and materials contami-
nated with H5N1 virus also clearly plays an important role in the movement of the
virus. In one instance, two crested hawk-eagles smuggled by a traveler in hand lug-
gage from Thailand to Brussels via Vienna were placed in overhead compartments
on commercial airplane flights. The birds were seized in Brussels because they
were arriving from an area with H5N1 infection. Although the birds appeared healthy,
after necropsy and further testing, both were found to be infected with H5N1.12
Because the H5N1 virus is shed in feces, it can contaminate water, straw, feathers,
cages, and other materials that come into contact with infected poultry. Although in-
fection of poultry has been widespread and dramatic, the influenza virus also can in-
fect nonhuman mammalian species. Feline species in zoos were infected fatally when
they were fed carcasses of poultry infected with H5N1. The wide host range of H5N1
also includes dogs and cats, animals that potentially have close contact with humans.
Infection of humans with H5N1 has been infrequent but has produced disastrous out-
comes. As of June 19, 2008, 385 human infections had been confirmed from 15 coun-
tries; of these infections, 243 were fatal.13 Approximately 90% of confirmed infections
have been in persons 40 years of age and younger. Most of those infected were previ-
ously healthy individuals. The overall case fatality rate exceeds 60%. Serologic surveys
in areas with human cases suggest that asymptomatic and mild infection with H5N1 is
rare. Most deaths from H5N1 follow fulminant viral pneumonia, but evidence of dissem-
inated infection has been found by autopsy in some people who died from H5N1.10 The
virus also has been found in feces and the intestine, suggesting replication may occur in
the gastrointestinal tract. Tissue damage in infected individuals appears to be caused by
high levels of viral replication and severe inflammatory responses to infection. Treatment
with high doses of antiviral agents is recommended, but resistance to antiviral agents
has been documented.
Most human infections appear to be the result of close contact with live or dead poultry
or their products. Transmission might result from contact with contaminated fomites or
material containing poultry feces. Although a few instances of person-to-person spread
likely have occurred in settings where individuals had close contact, this virus has not
caused sustained person-to-person spread or airborne transmission to date.14 Given
the number of billions of replication events that have occurred with this virus in avian
and other hosts, it appears that changes (via mutation, recombination, or reassortment)
xvi Preface
that would allow the virus to become easily transmissible from person to person have not
occurred in a setting where the virus could sustain spread. Because the virus persists and
now is entrenched ecologically in many parts of Asia, it still could undergo such changes.
Some investigators are working on a methodology to use when interpreting surveillance
data in real time that would have predictive capacity to better allocate interventions.15
Many of the conditions that exist in southern Asia favor the evolution of new strains
of influenza viruses. Asia is home to a large, densely settled human population living in
close proximity to large populations of multiple avian species and swine. Many resi-
dents have chickens, ducks, and other avian species that live in and around their
houses. Close contact with avian species is common and widespread. Several studies
have found an association between the presence of H5N1 and the abundance of free-
ranging ducks and with rice farming intensity and human population.16 This provides
an ideal setting for the mixing of influenza viruses that infect humans, pigs, and avian
species. As the standard of living in China and other countries improves, the popula-
tion is able to afford more protein in the diet, which often comes in the form of poultry
and pork. Many animals are raised in backyards, and larger animal production facilities
are starting to appear in many developing countries. In China, for example, the human
population increased about twofold (790 million to 1.3 billion) between 1968 and 2005,
while the swine population increased almost 100-fold (5.2 million to 508 million), and
the poultry population increased more than 1000 fold (12.3 million to 13 billion).17
There is evidence that the viruses that cause the seasonal influenza outbreaks
globally originate in Asia. A recent study that carried out antigenic and genetic analysis
of the hemagglutinin of thousands of human influenza A (H3N2) viruses from six con-
tinents assessed the global circulation of these viruses. The results suggested that, at
least from 2002 to 2007, influenza H3N2 epidemics worldwide (including in temperate
areas) were seeded annually by viruses that had arisen in East and Southeast Asia.18
Most of the strains in Asia descended from other Asian strains and evolved during
temporally overlapping epidemics in East and Southeast Asia. In tropical areas, influ-
enza does not show the strong seasonality that is evident in temperate areas, and
transmission can occur throughout the year, presumably because transmission is
more efficient in cold, dry conditions, as has been shown in a guinea pig model.19
Transmission by contact is equally efficient at high and low temperatures, suggesting
that contact and short-range spread may be the predominant modes of transmission
in tropical areas.20
H5N1 continues to evolve, as do other influenza viruses. Another avian influenza vi-
rus, H7, has caused outbreaks in poultry since 2002 and has caused human infection
in poultry workers. Although H7 influenza virus can infect humans, most of the infec-
tions so far have been mild and self limited. One lineage of this virus appears to have
acquired cell binding characteristics that more closely resemble those of human influ-
enza viruses, which could favor transmissibility.21 This is a reminder that scientists and
surveillance systems must be alert to a broad range of influenza viruses that could
cause human disease.
It is uncertain if H5N1 will undergo the changes necessary for it to transmit effi-
ciently from person to person while maintaining its current capacity to cause severe
disease, killing more than half of those infected with it. It is much more certain that
we will have another influenza pandemic. Whether one will emerge with the destructive
force of the 1918-1919 pandemic is not certain, but it could. The current global cir-
cumstances with large, dense, extensively interconnected populations would result
in the rapid spread of influenza or another infection with efficient person-to-person
spread, like severe acute respiratory syndrome (SARS). In an analysis of factors that
make an infection more or less difficult to control, Fraser and colleagues22 note that
Preface xvii
the proportion of transmission that occurs before onset of symptoms or by those who
are asymptomatic is important in assessing the likelihood that the isolation and tracing
of contacts could be effective in halting the epidemic spread of a pathogen. SARS was
contained because almost all persons infected became symptomatic before they
could transmit the virus, which is in contrast to HIV/AIDS, which is transmitted mostly
by people who are asymptomatic or unaware that they are infected. Typical influenza
is difficult to control, because transmission can begin before the onset of symptoms.
Ongoing research and development focused on H5N1 vaccines potentially will pro-
vide knowledge that can be used to develop vaccines against other diseases as well.
Researchers are making progress, and investigators recently reported that a whole-
virus H5N1 vaccine derived from cell culture was immunogenic in a two-dose regimen
without adjuvant.23
The most important emerging infection of recent decades, HIV/AIDS, originated
from an animal reservoir (probably chimpanzees), and the best evidence suggests
that the virus entered the human population on several occasions.24 Traveling humans
have effectively spread HIV-1 genetic variants globally, leading to an ongoing devas-
tating pandemic.25 We can hope that the lessons learned from the global spread of
HIV and current work prompted by outbreaks of avian influenza and SARS viruses
can help to avert or limit the spread of other microbial threats in the future. Given
the remarkable capacity of microbes, humans should remain vigilant and anticipate
that the future will continue to bring new microbial threats. By better understanding
the multiple forces that lead to these events, we may be able to identify high risk geo-
graphic areas and populations, try to reduce their vulnerabilities, and develop early
interventions.
Mary Elizabeth Wilson, MD, FACP, FIDSA

1812 Kalorama Square NW
Washington, DC 20008-4022, USA
E-mail address:
mary_wilson@harvard.edu (M.E. Wilson)
REFERENCES
1. Smolinski MS, Hamburg MA, Lederberg J, editors. Microbial Threats to Health:

Emergence, Detection, and Response. National Academy of Sciences. Washing-
ton, DC: National Academies Press; 2003.
2. Wilson ME, Levins R, Spielman A, editors. Disease in evolution: global changes
and emergence of infectious diseases. New York: Ann NY Acad Sci; 1994.
3. Jones KJ, Patel NK, Levy MA, et al. Global trends in emerging infectious dis-
eases. Nature 2008;451:990–4.
4. Wilson ME. Infectious diseases: an ecological perspective. Bri Med J 1995;311:
1681–4.
5. Greger M. The human/animal interface: emergence and reemergence of zoonotic
infectious diseases. Crit Rev Microbiol 2007;33:243–99.
6. Pew Commission on Industrial Farm Animal Production. Putting Meat on the
Table: Industrial Farm Animal Production in America. Released 28 April 2008.
Available at: http://www.pcifap.org.
7. Guernier V, Hockberg ME, Guegan J-F. Ecology drives the worldwide distribution
of human diseases. PloS Biol 2004;2(6):740–6.
xviii Preface
8. Freedman DO, Kozarsky PE, Weld LH, et al. GeoSentinel: the global emerging in-
fections sentinel network of the International Society of Travel Medicine. J Travel
Med 1999;6:94–8.
9. Wilson ME. (2003a). The traveller and emerging infections: sentinel, courier, trans-
mitter. J Appl Microbiol 2003;94:1S–11S.
10. Writing Committee of the Second WHO Consultation on Clinical Aspects of Hu-
man Infection with Avian Influenza A (H5N1) A Virus. Update on avian influenza
A (H5N1) virus infection in humans. N Engl J Med 2008;358(3):261–73.
11. Keawcharoen J, van Riel D, van Amerongen G, et al. Wild ducks as long-distance
vectors of highly pathogenic avian influenza virus (H5N1). Emerg Infect Dis 2008;
14(4):600–7.
12. Van Borm S, Thomas I, Hanquet G, et al. Highly pathogenic H5N1 influenza virus
in smuggled Thai eagles. Belgium. Emerg Infect Dis 2005;11(5):702–5.
13. WHO. Avian influenza http://www.who.int/csr/disease/avian_influenza/country/
cases_table_2008_06_19/en/index.html
14. Wang H, Feng Z, Shu Y, et al. Probable limited person-to-person transmission of
highly pathogenic avian influenza A (H5N1) virus in China. Lancet 2008;371:
1427–34.
15. Bettencourt LMA, Ribeiro RM. Real time Bayesian estimation of the epidemic po-
tential of emerging infectious diseases. PloS One 2008;3(5):e2185.
16. Gilbert M, Xiao X, Pfeiffer DU, et al. Mapping H5N1 highly pathogenic avian influ-
enza risk in Southeast Asia. PNAS 2008;105(2):4769–74.
17. Osterholm M. Preparing for the next pandemic. N Engl J Med 2005;352:1839–42.
18. Russell CA, Jones TC, Barr IG, et al. The global circulation of seasonal influenza
A (H3N2) viruses. Science 2008;320:340–6.
19. Lowen AC, Mubareka S, Steel J, et al. Influenza virus transmission is dependent
on relative humidity and temperatures. PloS Path 2007;3:e151.
20. Lowen AC, Steel J, Mubareka S, Palese P. High temperature (30 C) blocks aero-
sol but not contact transmission of influenza virus. J Virol 2008;82(11):5650–2.
21. Belser JA, Blixt O, Chen L-M, et al. Contemporary North American influenza H7
viruses possess human receptor specificity: implications for virus transmissibility.
PNAS 2008;105:7558–63.
22. Fraser C, Riley S, Anderson RM, Ferguson NM. Factors than make an infectious
disease outbreak controllable. PNAS 2004;101(16):6146–51.
23. Ehrlich HF, Muller M, Oh HML, et al. A clinical trial of a whole-virus H5N1 vaccine
derived from cell culture. N Engl J Med 2008;358:2573–84.
24. Keele BF, van Heuverswyn F, Li Y, et al. Chimpanzee reservoirs of pandemic and
nonpandemic HIV-1. Science 2006;313:523–6.
25. Perrin L, Kaiser L, Yerly S. Travel and the spread of HIV-1 genetic variants. Lancet
Infect Dis 2003;3:22–7.
West Nile Virus
in the Americ as
Lyle R. Petersen, MD, MPHa,*, Edward B. Hayes, MDb
KEYWORDS
West Nile virus United States America
Epidemiology Arbovirus
In the summer of 1999, physicians at Flushing Hospital Medical Center in New York
City attended several patients with an acute neurologic illness of unknown etiology.1
On August 12, a 60-year-old man was admitted with a 3-day history of fever, weak-
ness, and nausea. He developed confusion, proximal muscle weakness, urinary reten-
tion, and respiratory insufficiency requiring mechanical ventilation. Three days later, an
80-year-old man was admitted with a 1-week history of fever, headache, weakness,
and diarrhea. He developed flaccid paralysis and died. From August 18 through Sep-
tember 2, four more patients with acute onset of encephalitis and two with meningitis
were admitted. Subsequent investigation revealed that these patients were infected
with the West Nile virus (WNV), documenting the first autochthonous WNV transmis-
sion in the Western Hemisphere and heralding its establishment as the principal cause
of arboviral disease in the United States and Canada.1,2
The 1999 New York City outbreak caused an estimated 8200 human infections,
resulting in approximately 1700 cases of West Nile fever (WNF).3 WNV infection was
diagnostically confirmed in 62 ill persons, 59 of whom were hospitalized with neuro-
logic disease and seven of whom died.2 Although human cases were documented
only in the New York City area, avian and equine mortality from WNV was noted
over a much wider area including Connecticut, New Jersey, New York, and Maryland
(Fig. 1).
ORIGIN OF WEST NILE VIRUS IN NORTH AMERICA
WNV was first isolated from the blood of a febrile woman in the West Nile district of
Uganda in 1937. The virus was recognized as the cause of usually self-resolving illness
a
Division of Vector-borne Infectious Diseases, National Center for Zoonotic, Vector-borne, and
Enteric Diseases, Centers for Disease Control and Prevention, 1350 Rampart Road, Fort Collins,
CO 80521, USA
b
Epidemiology Activity, Arboviral Diseases Branch, Division of Vector-borne Infectious Dis-
eases, National Center for Zoonotic, Vector-borne, and Enteric Diseases, Centers for Disease
Control and Prevention, 1350 Rampart Road, Fort Collins, CO 80521, USA
* Corresponding author.
E-mail address: lxp2@cdc.gov (L.R. Petersen).
Med Clin N Am 92 (2008) 1307–1322

0025-7125/08/$ – see front matter. Published by Elsevier Inc.
1308 Petersen & Hayes
Fig.1. WNV in the United States, 1999–2007. The incidence of human neuroinvasive disease
is indicated by county.
in humans and animals in Africa, Asia, Australia, Europe, and the Middle East.4 Spo-
radic cases of encephalitis and occasional small outbreaks were reported, but epi-
demics of neuroinvasive disease during the 1990s in Algeria, Romania, Tunisia, and
Russia suggested a new epidemiologic pattern of outbreaks of unusual severity.5 Viral
genetic analysis indicated that these outbreaks were caused by closely related new
genetic variants of apparently increased pathogenicity.6 A substantial human epi-
demic with concomitant avian mortality struck Israel in 2000.7 The Israel outbreak
was unusual in that avian mortality from WNV was previously rare. The virus strain
implicated in the Israel outbreak and avian epizootic was closely related to the recent
outbreak strains but contained an additional mutation in the NS3 helicase gene, which
greatly increased the virus’ avian mortality.8
The means of importation of WNV to the New York City area is unknown; however,
the virus was most likely introduced by an infected mosquito or bird, because humans
and horses develop insufficient viremia to efficiently infect mosquitoes. The genetic
sequences of WNV isolates obtained from ill patients and a dead flamingo in New
York were closely homologous to sequences from a patient who died from WNV in
Tel Aviv in 1999 and from a dead goose found in Israel following an epizootic in
1998, indicating that the New York strain probably originated from the Middle East
or Eastern Europe.4,9,10
GEOGRAPHIC SPREAD IN NORTH AMERICA
Following the New York City epidemic, the Centers for Disease Control and Prevention
(CDC) in conjunction with local and state health departments established an intensive
monitoring program (ArboNet) to document the virus’ geographic spread and focus
local prevention efforts.11–13 The unusual avian mortality produced by the North Amer-
ican WNV strain provided an unprecedented opportunity to monitor the spread of an
exotic arbovirus in its natural hosts.
West Nile Virus in the Americas 1309
Both bird migration and random bird dispersion are likely to have spread WNV
across North America.4,14 The clearest indication of the role of bird migration occurred
in 2000 when dead bird surveillance indicated northward viral spread to New Hamp-
shire and Vermont in the spring and southward spread to North Carolina in the
fall (Fig. 1); however, the virus’ rapid westward dispersion to Lake Erie in 2000 and
to California and Washington State by 2002 is more difficult to explain simply based
on bird migration.
Despite marked geographic expansion of WNV epizootic activity in 2000 and 2001,
human disease incidence remained low until 2002 when an epidemic concentrated in
the mid-West, Gulf region, and Great Plains caused over 2900 cases of neuroinvasive
disease resulting in at least 280 deaths (Fig. 1) (Table 1). A similarly large epidemic
occurred in the western plains and Rocky Mountain States the following year. From
2004 through 2007, continued intense transmission occurred in the western plains
and Rocky Mountain states, as well as in Arizona, California, Louisiana, and
Mississippi (Figs. 1 and 2).12,15 The higher incidence of WNV disease in the western
United States probably results from the prominence of Culex tarsalis as a highly effi-
cient WNV vector mosquito in these areas.12 Serological surveys in North America in-
dicate that fewer than 10% of residents of outbreak areas become infected, but in
some western regions, convenience samples have found prevalence of WNV-specific
antibody as high as 20%.3,16–22
Through 2007, more than 11,000 cases of WNV neuroinvasive disease (WNND) and
more than 1000 deaths from WNV had been reported in the United States (CDC, un-
published data) (Table 1). Based on an estimated ratio of 140 WNV infections for every
case of WNND and assuming that WNF develops in 20% of infected people, WNV has
infected more than 1.5 million people and caused more than 300,000 cases of WNF in
the United States from 1999 through 2007 (Fig. 3).3,12,13 Within the United States,
WNV transmission has been documented in all of the continental states and Puerto
Rico, and cases of human disease have been reported from all states except Maine,
Alaska, and Hawaii (see Fig. 1).12,23 The persistence of WNV transmission in eastern
states 9 years after it was first detected suggests that WNV will remain endemic in
most of the continental United States for the foreseeable future.
Analysis of WNV isolates in the United States indicates slowly evolving genetic di-
vergence in different geographic regions, suggesting the absence of strong selective
Table 1
Reported West Nile virus disease cases in humans by clinical syndrome, United States, 1999^2007
Year WNND Fever Othera Total Deaths

1999 59 3 0 62 7
2000 19 2 0 21 2
2001 64 2 0 66 9
2002 2946 1160 50 4156 284
2003 2866 6830 166 9862 264
2004 1148 1269 122 2539 100
2005 1309 1607 84 3000 119
2006 1495 2616 158 4269 177
2007 1227 2350 53 3630 124
Total 11,123 15,839 633 27,605 1086
Abbreviation: WNND, West Nile virus neuroinvasive disease.

a
Other clinical syndrome or syndrome unspecified.
Fig. 2. Cumulative incidence of WNND in humans by county, 2002–2007.
pressure.24–26 Nevertheless, a distinct genetic variant emerged in 2001 (WN02 strain),

which subsequently displaced the original New York 1999 strain by 2004. When com-
pared with the 1999 virus, this newly emergent genotype is transmitted earlier and
more efficiently in Culex mosquitoes.27,28 Genetic analysis suggests that all contem-
porary circulating viruses derive from the WN02 strain.
In Canada, WNV was first detected in southern Ontario in 2001, outbreaks of human
disease occurred in 2002 in Quebec and Ontario,29 and, in the following year, WNV
spread as far east as New Brunswick and as far west as Alberta (http://www.health.
gov.ab.ca/public/wnv.html, http://www1.gnb.ca/0600/west_nile_public/deadbirds-e.
asp, accessed April 16, 2008). From 2002 through 2007, more than 700 cases of
WNND were reported in Canada (http://www.phac-aspc.gc.ca/wnv-vwn/index-eng.
php, accessed April 16, 2008).
Fig. 3. Human infections with WNV in the United States, 1999–2007. The actual number of
reported infections represents a small fraction of the estimated number of infections
because national surveillance focuses on complete reporting of only neuroinvasive disease
cases. The estimated number of infections is based on a ratio of 1:140 for neuroinvasive
disease cases to total infections. Approximately 20% of infections results in WNF.
WEST NILE VIRUS IN LATIN AMERICA AND THE CARIBBEAN
By 2001, WNV had spread south to islands in the Caribbean Sea, probably carried by
migrating birds late in 2000.30 A Cayman Islands resident without recent international
travel developed WNND in summer 2001, and resident birds in Jamaica were probably
infected the same year.30 By 2002, WNV had infected horses and chickens on Guade-
loupe, birds in the Dominican Republic, and horses in Mexico.30 By 2003, WNV had
spread to El Salvador, Guatemala, Belize, Cuba, Puerto Rico, and the Bahamas,
and by 2004 to Haiti, Trinidad, Colombia, and Venezuela.30–32 By early 2005, WNV
had infected birds in Argentina.33
Surprisingly little human WNV disease has been reported in Latin America and the
Caribbean, with only isolated instances of human illness reported from Mexico,
Cuba, Haiti, the Bahamas, and Argentina.4,30,34 Several hypotheses may explain the
lack of epidemics south of the United States: (1) the spread of WNV through migrating
birds might select for attenuated viral strains if more virulent strains impair bird migra-
tion; (2) previous flavivirus infection such as dengue virus might provide some cross-
protection against severe WNV disease; (3) ecologic conditions in tropical regions
might select for less virulent virus strains; and (4) insensitive surveillance and nonspe-
cific laboratory tests could impair the detection of WNV disease.4 Another possibility is
that continuous avian host availability for ornithophilic mosquitoes in tropical areas
might decrease the likelihood that infected mosquitoes would feed on humans.
Whether any of these hypotheses, either singly or in combination, explains the
low incidence of reported WNV disease in Latin America awaits further research.
Epidemics of related flaviviruses, such as the Japanese encephalitis and St. Louis
encephalitis viruses (SLEV), also have been less common in the tropical reaches of
their distributions.4 Evidence of attenuation was found in a WNV isolate obtained
from a dead raven in Mexico, but eight other isolates from Mexico did not show the
attenuating feature, and an experiment with thrush and catbirds suggested that
WNV infection would not impair their migration.4,35–37 Although previous flavivirus
infection does not protect against heterotypic flavivirus infection, it might modulate
disease severity.4 The possibility that dengue virus infection, which is widespread in
the American tropics, or infection with yellow fever, SLEV, Ilheus, Roccio, or other
more rarely circulating flaviviruses might protect against severe WNV illness deserves
further investigation.4
Monitoring WNV transmission in the United States and Canada has required consid-
erable investment in sophisticated laboratory diagnostics and surveillance. Because
most Latin American and Caribbean nations do not have such systems, WNV disease
might not be detected or may be misdiagnosed as dengue or another infectious dis-
ease. Intensive WNV surveillance in Guatemala yielded evidence of WNV transmission
to birds and horses but conclusively has not yet detected WNND in humans (E. Dueger
and N. Komar, personal communication, CDC unpublished data, 2008).38 In Puerto
Rico, ecologic surveillance identified WNV transmission throughout the island, and
three viremic blood donors were identified through routine WNV screening.39 The
virus’ genetic sequence was identical to strains circulating in the continental United
States, yet an intensive effort failed to find WNND in humans.40
MOSQUITO-BORNE TRANSMISSION
WNV is transmitted to humans through the bite of infected mosquitoes that acquire the
virus after feeding on vertebrate amplifying hosts, usually birds. In the United States,
the principal mosquito vectors are Culex tarsalis, C quinquefasciatus, C pipiens,
C restuans, and C nigripalpus; other species may contribute to localized foci of
transmission. Birds, particularly corvids (crows, magpies, and jays), house sparrows,
house finches, and grackles, appear to be highly competent reservoirs for WNV.
Humans and horses generally develop insufficient WNV titers in the blood to infect
mosquitoes, but squirrels, chipmunks, and rabbits may develop sufficiently high vire-
mia to infect mosquitoes, raising the possibility that small mammals might contribute
to WNV transmission cycles.4,14,41,42 Alligators may also serve as competent reser-
voirs in the southeastern United States.43
In temperate climates, the virus overwinters in hibernating (diapause) adult female
Culex mosquitoes, probably in some birds and possibly in rodents.41,44,45 In spring-
time, overwintering mosquitoes emerge and bite birds, which initiates a mosquito-
bird-mosquito amplification cycle that persists until fall when female mosquitoes enter
diapause and stop biting. The intensity of WNV transmission to humans depends on
the abundance and feeding behavior of infected mosquitoes and on local ecologic
determinants of human exposure to mosquitoes. Departure of avian hosts at the
end of nesting season in temperate climates leads to shifts in mosquito feeding toward
mammals.46
Ambient temperature influences the abundance of vector mosquitoes, the extrinsic
incubation period of viral replication in mosquitoes (duration from virus acquisition to
when the mosquito is capable of transmitting the virus during subsequent blood
meals), the ability of an infected mosquito to transmit infection (vector competence),
and patterns of human behavior. Summer temperatures accelerate the enzootic
amplification cycle, which increases likelihood of human exposure to infected mosqui-
toes. WNV disease incidence in North America increases in early summer and peaks
during late summer or early fall (Fig. 4). In temperate areas of the United States,
regional increases in WNV transmission have been correlated with above average
temperatures, although this pattern is not as evident in southern latitudes.47,48 One
study along the Front Range of the Rocky Mountains in Colorado found that C tarsalis
Fig. 4. Number of neuroinvasive disease cases by week of symptom onset, 2002–2007.

abundance was variably correlated with the mean temperature, cooling degree days,
humidity, precipitation, and snowfall.49
In the United States and Canada, the WNV incidence is highest in rural and subur-
ban settings, presumably because of human proximity to enzootic transmission cycles
and infected vector mosquitoes. In New York City, the risk of WNV disease was cor-
related with areas of higher vegetation.50 In Chicago and Detroit, inner suburban urban
areas with moderate vegetation, housing built from 1940 to 1960, and moderate pop-
ulation density had higher WNV disease incidence.51 A nationwide study comparing
viremic with uninfected blood donors showed that residents of rural areas were 3.4
times more likely to be infected than residents of suburban or urban locations.52 In
Saskatchewan, Canada, residents of rural areas were approximately six times more
likely than urban dwellers to have WNV antibodies.20 In states experiencing outbreaks,
the county WNV incidence was correlated with farming activity as determined by total
crop sales.53 A calculated measure of the intensity of exposure to WNV-infected
mosquitoes in Illinois was highest in areas along two rivers, possibly related to the
presence of wetlands and forest preserves.54
A study in Ohio found that children were more likely to spend time outdoors and
were more likely to become infected with WNV, but, as reflected in national surveil-
lance data, they were less likely than adults to develop WNND.19,55 People of lower
socioeconomic status and particularly those who are homeless may be at higher
risk of WNV infection.56,57
NON-MOSQUITO TRANSMISSION
WNV can also be transmitted through blood transfusions, transplanted organs, and
from mother to fetus transplacentally.58–60 WNV transmission has also been reported
through percutaneous exposure and inhalation in laboratories, conjunctival exposure
while handling dead birds, in a dialysis center by unidentified means, and at a turkey
farm, possibly by aerosol.61–65 Transmission via breast milk has also been reported
but appears to be rare.66
Transfusion-associated WNV transmission was first detected during the 2002 WNV
epidemic in the United States when 23 transfusion recipients were infected through
receipt of platelets, red blood cells, or fresh frozen plasma from 16 viremic blood do-
nors.59 Mathematical models indicated that the risk of transfusion-associated WNV
transmission during the 2002 epidemic ranged from 2.1 to 4.7 cases per 10,000 do-
nors in high incidence states.67 Since 2003, the United States and Canadian blood
supplies have been screened using WNV nucleic acid amplification (NAT) tests. Blood
centers conduct NAT testing on minipools of 6 to 16 specimens depending on test kit
manufacturer. From 2003 through 2007, WNV NAT screening identified approximately
2000 NAT-positive blood donors, with as many as 1 in 150 donors being positive in
some outbreak areas;68 however, many NAT-positive donations also have WNV-
specific IgM antibody, which seems to confer a much lower transfusion transmission
risk, because all but 1 of 32 documented transfusion transmissions to date occurred
from donors lacking WNV IgM antibody.59,69 Universal pooled blood donation screen-
ing has not eliminated WNV transfusion transmission. Through 2007, nine ‘‘break-
through’’ transmissions have occurred from donations without WNV IgM antibody
and with virus levels below the limit of detection by minipool screening.69,70 To mini-
mize the risk of breakthrough transmissions, blood centers switch to individual dona-
tion testing in areas experiencing outbreaks.
In 2002, transmission via donated organs was first documented when WNV infection
developed in four recipients of organs from a common donor.60 Serum from the day of
organ harvest was positive for WNV by NAT and culture. A second transmission oc-
curred in 2005 in which WNV infection developed in three of four organ recipients.71
Serum from the day of organ harvest was positive for WNV-specific IgG and IgM
antibodies but was negative for WNV RNA, suggesting that transmission can occur
from virus sequestered in organs in the absence of detectable viremia in serum.
Intrauterine transmission of WNV was first documented in 2002 when a woman who
had WNV encephalitis (WNE) during the 27th week of pregnancy delivered a term
infant with chorioretinitis, cerebral lesions, and laboratory evidence of congenitally
acquired WNV infection.72 A follow-up study of 77 women infected with WNV during
pregnancy found that 71 women delivered 72 live infants, and most of these infants
were born healthy.58 Congenital WNV infection could not be proven in any of the
infants, but three infants had evidence of WNV infection that could have been congen-
itally acquired. One had WNV meningitis at 10 days of age, one had a neonatal rash
and was positive for anti-WNV IgM at 1 month of age, and one had WNE with under-
lying lissencephaly detected at 17 days of age.58 A study of 549 infants born at a com-
munity hospital in Colorado whose mothers were pregnant during a WNV outbreak in
the community found evidence of WNV infection in 4% of the mothers and none of the
infants.17 Birth outcomes of the infants born to mothers who had evidence of WNV
infection during pregnancy were similar to outcomes of infants whose mothers had
no evidence of WNV infection.17
CLINICAL MANIFESTATIONS
Data from serologic surveys in North America and Europe and from blood donor
screening in the United States indicate that about 70% to 80% of WNV infections
are asymptomatic, 20% to 30% result in WNF, and less than 1% result in
WNND.3,73 The incubation period for WNV disease ranges from 2 to 14 days but
can be longer in people who are immunocompromised. Older people are more likely
to develop WNND and appear less likely to develop WNF.11,73 The reported incidence
of WNND is higher in males than females. In an analysis of 880 patients with WNV dis-
ease reported to the California Department of Public Health, male sex, age greater
than 64 years, and a history of diabetes were risk factors for developing WNND.74 A
study of 172 patients with WNV disease in Houston found that those with WNE
were more likely to be older and have a history of hypertension or cardiovascular
disease than patients without WNE.75 A survey of 656 patients with WNV disease in
Colorado found that those with WNE were more likely to have histories of hyperten-
sion, diabetes, cancer, kidney disease, and chemotherapy.76 Patients who have
received solid organ transplants appear to be about 40 times more likely to develop
WNND than people who have not received transplants.77,78 In addition to apparently
increasing the risk of WNND, diabetes mellitus may be a risk factor for WNV chorior-
etinitis.79–81 Persons homozygous for a deletion in the CCR5 gene (CCR5D32) were
shown to be at increased risk for symptomatic infection and death from WNV.82
Symptoms and signs of WNF include fever, headache, malaise, fatigue, weakness,
muscle pain, difficulty concentrating, nausea, vomiting, diarrhea, abdominal pain, and
rash.83 WNND presents as WNE, meningitis, or flaccid paralysis, singly or in combina-
tion, sometimes with tremor, myoclonus, and parkinsonian features such as rigidity,
postural instability, and bradykinesia.84–86 Patients with WNV meningitis tend to
have nuchal rigidity, photophobia, phonophobia, and pleocytosis in the cerebrospinal
fluid.86,87 WNE is characterized by an altered mental status or lethargy with or without
focal neurologic signs or movement disorders.86,87 WNV paralysis often has an acute
onset and is typically asymmetrical in one or more limbs, sometimes without fever or
other manifestations of WNV disease.87 Chorioretinitis may be frequent in patients

with WNV infection, particularly those with underlying diabetes.79–81 Rare manifesta-
tions of WNV infection include hepatitis, pancreatitis, myocarditis, rhabdomyolysis,
orchitis, diabetes insipidus, stiff person syndrome, and hemorrhagic fever.88–92
Patients with WNF usually recover without severe sequelae, but many experience
fatigue, weakness, and aching that can last for weeks or months.76,83,87 WNF is rarely
fatal but can provoke hospitalization and has rarely been associated with cardiac
arrhythmias and respiratory failure.87,93 WNV meningitis frequently leads to hospitali-
zation, but the prognosis is similar to that of WNF. Severe sequelae are infrequent;
however, persistent fatigue, weakness, and difficulty with concentration and memory
for months after acute illness are common.87,94
Patients with WNE are usually hospitalized and have a higher risk of severe compli-
cations than patients with WNF or WNV meningitis.93 The case fatality rate for WNE
ranges from 12% to 20% and increases with age.11,87,93 Survivors often have persis-
tent neurologic sequelae such as parkinsonism, tremors, and ataxia, although some
recover completely.86,87 WNV paralysis may result in neuromuscular respiratory
failure, which carries a mortality above 50%.87 Most people who recover from WNV
paralysis have persistent weakness, but recovery of strength can occur during the first
8 months after the onset of paralysis, and even patients with severe quadriparesis can
completely recover.86,87 No proven specific treatment for WNV disease exists.
Patients with profound weakness following WNV paralysis may benefit from physical
or occupational therapy.86,87
PREVENTION
Prevention efforts have focused on encouraging personal protection such as wearing

repellent and on reducing the abundance of vector mosquitoes. A study in Ontario
found that people who practiced at least two personal protective strategies (wearing
repellent, wearing protective clothing, or avoiding outdoor exposure to mosquitoes)
were about half as likely to have been infected with WNV than people who did not
practice at least two protective strategies.22 A study comparing two adjacent commu-
nities in Colorado found that the incidence of WNV disease was better correlated eco-
logically with the practice of personal protection strategies than with the level of local
mosquito control efforts.57 A comparison of health risks from pesticides used to kill
adult mosquitoes with the health risks from WNV infection found that the health risks
of WNV infection outweighed the risks from pesticide use, suggesting that, depending
on its anticipated effectiveness, appropriately managed adult mosquito control is
a reasonable public health response to epidemics of WNV disease.95,96 Emergency
aerial pesticide spraying is highly effective in curtailing ongoing WNV epidemics.97
If WNV continues to cause epidemic disease in the Americas, a safe and effective
vaccine could be the optimal prevention tool. The introduction of a vaccine against
WNV for use in horses appears to have substantially reduced the incidence of equine
WNV disease in the United States.98 Although universal vaccination against WNV is
not likely to result in societal financial savings, vaccination could well be targeted to-
ward populations and individuals at highest risk for WNND.12,99 A live chimeric vaccine
using the widely used yellow fever 17-D vaccine as a backbone with insertion of the
premembrane and envelope proteins of WNV has been evaluated in a phase 1 safety
and immunogenicity trial in 45 humans.100 Adverse events were similar between
vaccine and placebo recipients, and the vaccine elicited neutralizing antibody against
WNV in 35 of 36 volunteers tested 12 months after vaccination. In a phase 1 safety and
immunogenicity trial, a single-plasmid DNA vaccine against WNV was administered to
15 human volunteers.101 The vaccine produced no serious adverse effects and elicited
neutralizing antibody to WNV in all 12 subjects who received three doses. Several
other WNV vaccines are in various stages of development.102
FUTURE OUTLOOK
The dramatic spread of WNV across the Western Hemisphere has produced a new
public health problem of substantial impact. Unlike in the Old World where outbreaks
are separated by years or decades of little or no WNV activity, epidemics continue to
arise each summer in North America. It remains unknown whether this pattern of
recurrent outbreaks will persist. The long-standing North American experience with
SLEV, a related flavivirus which uses the same vertebrate hosts and mosquito species
as WNV in its amplification cycle, may be foretelling. SLEV produces focal or regional
outbreaks spaced many years apart (Fig. 5); however, important biologic differences
exist between WNV and SLEV. WNV produces substantially higher viremia levels in
birds, which is a critical element in infecting vector mosquitoes and thereby promoting
enzootic WNV transmission cycles.103,104 House finches infected with WNV were pro-
tected against developing SLEV and WNV viremia; however, finches infected with
SLEV were protected against WNV mortality but still developed WNV viremia.104 Cur-
rently circulating WNV strains may be more likely than SLEV to be intensely transmit-
ted in enzootic cycles and may even be suppressing SLEV transmission.14
WNV outbreaks in temperate areas are more commonly reported during periods of
above average summertime temperatures, and improved models of the effects of
climate and weather on WNV transmission might be used to target prevention strate-
gies.47–49 Nevertheless, it remains unclear whether long-term global increases in
temperature will provoke an increased WNND incidence because of the multiple inter-
acting effects of increased temperature on vector survival, the distribution of vectors
and vertebrate amplifying hosts, and patterns of human behavior.
It also remains unknown whether the unexplained paucity of avian, equine, and
human morbidity and mortality in the Western Hemisphere south of the United States
Fig. 5. Reported number of SLEV (solid line) and WNV (dashed line) neuroinvasive disease
cases by year, 1932–2007.
will persist. The scarcity of large WNV outbreaks in the tropics of the Old World sug-
gests that seasonal temperature variations affecting bird and mosquito populations
may promote outbreaks, possibly by temporal and geographic alignment of the pres-
ence of highly susceptible nestling birds with springtime mosquito population
increases.105 Similarly, SLEV causes few outbreaks in tropical America. It is yet to
be determined whether WNV will produce large outbreaks as it becomes established
in temperate areas of South America.33,106
More than 100 arboviruses are known to cause human illness, many of which are not
extant in the New World. Two previously imported flaviviruses, dengue and yellow fever
viruses, remain important scourges in tropical America and at one time were consider-
able public health problems in the continental United States. After mosquito control
programs in the early twentieth century nearly eliminated these pathogens from most
countries in the Americas, public health priorities shifted and arbovirus surveillance,
prevention, and research programs withered.5 Meanwhile, dengue returned to most
of Latin America and the Caribbean with vengeance, partly due to importation of
more pathogenic strains from Asia.107 These experiences indicate that it is only a ques-
tion of time until globalization brings the next exotic arbovirus to the Americas. WNV
warns us of the unpredictable public health consequences of such an importation.
REFERENCES
1. Asnis DS, Conetta R, Teixeira AA, et al. The West Nile virus outbreak of 1999 in
New York: the Flushing Hospital experience. Clin Infect Dis 2000;30(3):413–8.
2. Nash D, Mostashari F, Fine A, et al. The outbreak of West Nile virus infection in
the New York City area in 1999. N Engl J Med 2001;344(24):1807–14.
3. Mostashari F, Bunning ML, Kitsutani PT, et al. Epidemic West Nile encephalitis,
New York, 1999: results of a household-based seroepidemiological survey.
Lancet 2001;358(9278):261–4.
4. Gubler DJ. The continuing spread of West Nile virus in the western hemisphere.
Clin Infect Dis 2007;45(8):1039–46.
5. Mackenzie JS, Gubler DJ, Petersen LR. Emerging flaviviruses: the spread and
resurgence of Japanese encephalitis, West Nile, and dengue viruses. Nat
Med 2004;10(12 Suppl):S98–109.
6. Lanciotti RS, Ebel GD, Deubel V, et al. Complete genome sequences and
phylogenetic analysis of West Nile virus strains isolated from the United States,
Europe, and the Middle East. Virology 2002;298(1):96–105.
7. Chowers MY, Lang R, Nassar F, et al. Clinical characteristics of the West Nile
fever outbreak, Israel, 2000. Emerg Infect Dis 2001;7(4):675–8.
8. Brault AC, Huang CY, Langevin SA, et al. A single positively selected West Nile
viral mutation confers increased virogenesis in American crows. Nat Genet 2007;
39(9):1162–6.
9. Giladi M, Metzkor-Cotter E, Martin DA, et al. West Nile encephalitis in Israel,
1999: the New York connection. Emerg Infect Dis 2001;7(4):659–61.
10. Lanciotti RS, Roehrig JT, Deubel V, et al. Origin of the West Nile virus responsible
for an outbreak of encephalitis in the northeastern United States. Science 1999;
286(5448):2333–7.
11. O’Leary DR, Marfin AA, Montgomery SP, et al. The epidemic of West Nile virus in
the United States, 2002. Vector Borne Zoonotic Dis Spring 2004;4(1):61–70.
12. Lindsey NP, Kuhn S, Campbell GL, et al. West Nile virus neuroinvasive disease
incidence in the United States, 2002–2006. Vector Borne Zoonotic Dis 2008;8(1):
35–40.
13. Petersen LR, Hayes EB. Westward ho? The spread of West Nile virus. N Engl
J Med 2004;351(22):2257–9.
14. Reisen W, Brault AC. West Nile virus in North America: perspectives on epide-
miology and intervention. Pest Manag Sci 2007;63(7):641–6.
15. Centers for Disease Control and Prevention. West Nile virus activity—United
States, 2007. MMWR Morb Mortal Wkly Rep 2008;57(26):720–3.
16. Hadler J, Nelson R, McCarthy T, et al. West Nile virus surveillance in Connecticut
in 2000: an intense epizootic without high risk for severe human disease. Emerg
Infect Dis 2001;7(4):636–42.
17. Paisley JE, Hinckley AF, O’Leary DR, et al. West Nile virus infection among preg-
nant women in a northern Colorado community, 2003 to 2004. Pediatrics 2006;
117(3):814–20.
18. Murphy TD, Grandpre J, Novick SL, et al. West Nile virus infection among health-
fair participants, Wyoming 2003: assessment of symptoms and risk factors.
Vector Borne Zoonotic Dis 2005;5(3):246–51.
19. Schweitzer BK, Kramer WL, Sambol AR, et al. Geographic factors contributing
to a high seroprevalence of West Nile virus–specific antibodies in humans
following an epidemic. Clin Vaccine Immunol 2006;13(3):314–8.
20. Mandalakas AM, Kippes C, Sedransk J, et al. West Nile virus epidemic, north-
east Ohio, 2002. Emerg Infect Dis 2005;11(11):1774–7.
21. Schellenberg TL, Anderson ME, Drebot MA, et al. Seroprevalence of West Nile
virus in Saskatchewan’s Five Hills Health Region, 2003. Can J Public Health
2006;97(5):369–73.
22. Loeb M, Elliott SJ, Gibson B, et al. Protective behavior and West Nile virus risk.
Emerg Infect Dis 2005;11(9):1433–6.
23. Centers for Disease Control and Prevention. West Nile virus activity–United
States, 2006. MMWR Morb Mortal Wkly Rep 2007;56(22):556–9.
24. Herring BL, Bernardin F, Caglioti S, et al. Phylogenetic analysis of WNV in North
American blood donors during the 2003–2004 epidemic seasons. Virology 2007;
363(1):220–8.
25. Davis CT, Ebel GD, Lanciotti RS, et al. Phylogenetic analysis of North American
West Nile virus isolates, 2001–2004: evidence for the emergence of a dominant
genotype. Virology 2005;342(2):252–65.
26. Grinev A, Daniel S, Stramer S, et al. Genetic variability of West Nile virus in US
blood donors, 2002–2005. Emerg Infect Dis 2008;14(3):436–44.
27. Moudy RM, Meola MA, Morin LL, et al. A newly emergent genotype of West Nile
virus is transmitted earlier and more efficiently by Culex mosquitoes. Am J Trop
Med Hyg 2007;77(2):365–70.
28. Kilpatrick AM, Meola MA, Moudy RM, Kramer LD, et al. Temperature, viral genet-
ics, and the transmission of West Nile virus by Culex pipiens mosquitoes. PLoS
Pathog 2008;27;4(6):e100092.
29. Drebot MA, Lindsay R, Barker IK, et al. West Nile virus surveillance and diagnos-
tics: a Canadian perspective. Can J Infect Dis 2003;14(2):105–14.
30. Komar N, Clark GG. West Nile virus activity in Latin America and the Caribbean.
Rev Panam Salud Publica 2006;19(2):112–7.
31. Beatty ME, Hunsperger E, Long E, et al. Mosquito-borne infections after Hurri-
cane Jeanne, Haiti, 2004. Emerg Infect Dis 2007;13(2):308–10.
32. Bosch I, Herrera F, Navarro JC, et al. West Nile virus, Venezuela. Emerg Infect
Dis 2007;13(4):651–3.
33. Diaz AL, Komar N, Visintin A, et al. West Nile virus in birds, Argentina. Emerg
Infect Dis 2008;14(4):689–91.
34. Pupo M, Guzman MG, Fernandez R, et al. West Nile Virus infection in humans
and horses, Cuba. Emerg Infect Dis 2006;12(6):1022–4.
35. Deardorff E, Estrada-Franco J, Brault AC, et al. Introductions of West Nile virus
strains to Mexico. Emerg Infect Dis 2006;12(2):314–8.
36. Beasley DW, Davis CT, Estrada-Franco J, et al. Genome sequence and attenu-
ating mutations in West Nile virus isolate from Mexico. Emerg Infect Dis 2004;
10(12):2221–4.
37. Owen J, Moore F, Panella N, et al. Migrating birds as dispersal vehicles for West
Nile virus. EcoHealth 2006;3(2):79–85.
38. Morales-Betoulle ME, Morales H, Blitvich BJ, et al. West Nile virus in horses,
Guatemala. Emerg Infect Dis 2006;12(6):1038–9.
39. Centers for Disease Control and Prevention. Detection of West Nile virus in blood
donations—Puerto Rico, 2007. MMWR Morb Mortal Wkly Rep 2008;57(21):
577–80.
40. Barrera R, Hunsperger E, Munoz-Jordan JL, et al. First isolation of West Nile
virus in the Caribbean. Am J Trop Med Hy 2008;78(4):666–8.
41. Platt KB, Tucker BJ, Halbur PG, et al. Fox squirrels (Sciurus niger) develop West
Nile virus viremias sufficient for infecting select mosquito species. Vector Borne
Zoonotic Dis 2008;8(2):225–33.
42. Platt KB, Tucker BJ, Halbur PG, et al. West Nile virus viremia in eastern chip-
munks (Tamias striatus) sufficient for infecting different mosquitoes. Emerg
Infect Dis 2007;13(6):831–7.
43. Klenk K, Snow J, Morgan K, et al. Alligators as West Nile virus amplifiers. Emerg
Infect Dis 2004;10(12):2150–5.
44. Nasci RS, Savage HM, White DJ, et al. West Nile virus in overwintering Culex
mosquitoes, New York City, 2000. Emerg Infect Dis 2001;7(4):742–4.
45. Reisen WK, Fang Y, Lothrop HD, et al. Overwintering of West Nile virus in South-
ern California. J Med Entomol 2006;43(2):344–55.
46. Kilpatrick AM, Kramer LD, Jones MJ, et al. West Nile virus epidemics in North
America are driven by shifts in mosquito feeding behavior. PLoS Biol 2006;
4(4):e82.
47. Reisen WK, Fang Y, Martinez VM. Effects of temperature on the transmission of
West Nile virus by Culex tarsalis (Diptera: Culicidae). J Med Entomol 2006;43(2):
309–17.
48. El Adlouni S, Beaulieu C, Ouarda TB, et al. Effects of climate on West Nile Virus
transmission risk used for public health decision-making in Quebec. Int J Health
Geogr 2007;6:40.
49. Winters AM, Bolling BG, Beaty BJ, et al. Combining mosquito vector and human
disease data for improved assessment of spatial West Nile virus disease risk.
Am J Trop Med Hyg 2008;78(4):654–65.
50. Brownstein JS, Rosen H, Purdy D, et al. Spatial analysis of West Nile virus: rapid
risk assessment of an introduced vector-borne zoonosis [erratum appears in
Vector Borne Zoonotic Dis 2003;3(3):155]. Vector Borne Zoonotic Dis 2002;
2(3):157–64.
51. Ruiz MO, Walker ED, Foster ES, et al. Association of West Nile virus illness and
urban landscapes in Chicago and Detroit. Int J Health Geogr 2007;6:10.
52. Orton SL, Stramer SL, Dodd RY. Self-reported symptoms associated with West
Nile virus infection in RNA-positive blood donors. Transfusion 2006;46(2):
272–7.
53. Miramontes R Jr, Lafferty WE, Lind BK, et al. Is agricultural activity linked to the
incidence of human West Nile virus? Am J Prev Med 2006;30(2):160–3.
54. Gu W, Lampman R, Krasavin N, et al. Spatio-temporal analyses of West Nile

virus transmission in Culex mosquitoes in northern Illinois, USA, 2004. Vector
Borne Zoonotic Dis 2006;6(1):91–8.
55. LaBeaud AD, Kile JR, Kippes C, et al. Exposure to West Nile virus during the
2002 epidemic in Cuyahoga County, Ohio: a comparison of pediatric and adult
behaviors. Public Health Rep 2007;122(3):356–61.
56. Meyer TE, Bull LM, Cain Holmes K, et al. West Nile virus infection among the
homeless, Houston, Texas. Emerg Infect Dis 2007;13(10):1500–3.
57. Gujral IB, Zielinski-Gutierrez EC, LeBailly A, et al. Behavioral risks for West Nile
virus disease, northern Colorado, 2003. Emerg Infect Dis 2007;13(3):419–25.
58. O’Leary DR, Kuhn S, Kniss KL, et al. Birth outcomes following West Nile Virus
infection of pregnant women in the United States: 2003–2004. Pediatrics
2006;117(3):e537–45.
59. Pealer LN, Marfin AA, Petersen LR, et al. Transmission of West Nile virus through
blood transfusion in the United States in 2002. N Engl J Med 2003;349(13):
1236–45.
60. Iwamoto M, Jernigan DB, Guasch A, et al. Transmission of West Nile virus from
an organ donor to four transplant recipients. N Engl J Med 2003;348(22):
2196–203.
61. Centers for Disease Control. Laboratory-acquired West Nile virus infections–
United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51(50):1133–5.
62. Nir Y, Beemer A, Goldwasser RA. West Nile virus infection in mice following
exposure to a viral aerosol. Br J Exp Pathol 1965;46(4):443–9.
63. Fonseca K, Prince GD, Bratvold J, et al. West Nile virus infection and conjunc-
tival exposure. Emerg Infect Dis 2005;11(10):1648–9.
64. Centers for Disease Control. Possible dialysis-related West Nile virus transmis-
sion–Georgia, 2003. MMWR Morb Mortal Wkly Rep 2004;53(32):738–9.
65. Centers for Disease Control. West Nile virus infection among turkey breeder
farm workers–Wisconsin, 2002. MMWR Morb Mortal Wkly Rep 2003;52(42):
1017–9.
66. Hinckley AF, OlLeary DR, Hayes EB. Transmission of West Nile virus through
human breast milk seems to be rare. Pediatrics 2007;119(3):e666–71.
67. Biggerstaff BJ, Petersen LR. Estimated risk of transmission of the West Nile virus
through blood transfusion in the US, 2002. Transfusion 2003;43(8):1007–17.
68. Busch MP, Caglioti S, Robertson EF, et al. Screening the blood supply for West
Nile virus RNA by nucleic acid amplification testing. N Engl J Med 2005;353(5):
460–7.
69. Centers for Disease Control. West Nile virus transmission through blood transfu-
sion–South Dakota, 2006. MMWR Morb Mortal Wkly Rep 2007;56(4):76–9.
70. Petersen LR, Epstein JS. Problem solved? West Nile virus and transfusion safety.
N Engl J Med 2005;353(5):516–7.
71. Centers for Disease Control. West Nile virus infections in organ transplant recipi-
ents–New York and Pennsylvania, August-September, 2005. MMWR Morb Mortal
Wkly Rep 2005;54(40):1021–3.
72. Alpert SG, Fergerson J, Noel LP. Intrauterine West Nile virus: ocular and systemic
findings. Am J Ophthalmol 2003;136(4):733–5.
73. Brown JA, Factor DL, Tkachenko N, et al. West Nile viremic blood donors and
risk factors for subsequent West Nile fever. Vector Borne Zoonotic Dis Winter
2007;7(4):479–88.
74. Jean CM, Honarmand S, Louie JK, et al. Risk factors for West Nile virus neuro-
invasive disease, California, 2005. Emerg Infect Dis 2007;13(12):1918–20.
75. Murray K, Baraniuk S, Resnick M, et al. Risk factors for encephalitis and death
from West Nile virus infection. Epidemiol Infect 2006;134(6):1325–32.
76. Patnaik JL, Harmon H, Vogt RL. Follow-up of 2003 human West Nile virus infec-
tions, Denver, Colorado. Emerg Infect Dis 2006;12(7):1129–31.
77. Kumar D, Drebot MA, Wong SJ, et al. A seroprevalence study of West Nile virus
infection in solid organ transplant recipients. Am J Transplant 2004;4(11):
1883–8.
78. Kumar D, Prasad GV, Zaltzman J, et al. Community-acquired West Nile virus
infection in solid-organ transplant recipients. Transplantation 2004;77(3):
399–402.
79. Chan CK, Limstrom SA, Tarasewicz DG, et al. Ocular features of West Nile virus
infection in North America: a study of 14 eyes. Ophthalmology 2006;113(9):
1539–46.
80. Khairallah M, Yahia SB, Letaief M, et al. A prospective evaluation of factors
associated with chorioretinitis in patients with West Nile virus infection. Ocul
Immunol Inflamm 2007;15(6):435–9.
81. Abroug F, Ouanes-Besbes L, Letaief M, et al. A cluster study of predictors of
severe West Nile virus infection. Mayo Clin Proc 2006;81(1):12–6.
82. Lim JK, Louie CY, Glaser C, et al. Genetic deficiency of chemokine receptor
CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-
analysis of 4 cohorts in the US epidemic. J Infect Dis 2008;197(2):262–5.
83. Watson JT, Pertel PE, Jones RC, et al. Clinical characteristics and functional
outcomes of West Nile fever. Ann Intern Med 2004;141(5):360–5.
84. Pepperell C, Rau N, Krajden S, et al. West Nile virus infection in 2002: morbidity
and mortality among patients admitted to hospital in south central Ontario.
CMAJ 2003;168(11):1399–405.
85. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and out-
come of West Nile virus infection. JAMA 2003;290(4):511–5.
86. Davis LE, DeBiasi R, Goade DE, et al. West Nile virus neuroinvasive disease.
Ann Neurol 2006;60(3):286–300.
87. Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect
Dis 2007;44(12):1617–24.
88. Hayes EB, Sejvar JJ, Zaki SR, et al. Virology, pathology, and clinical manifesta-
tions of West Nile virus disease. Emerg Infect Dis 2005;11(8):1174–9.
89. Montgomery SP, Chow CC, Smith SW, et al. Rhabdomyolysis in patients with
West Nile encephalitis and meningitis. Vector Borne Zoonotic Dis 2005;5(3):
252–7.
90. Paddock CD, Nicholson WL, Bhatnagar J, et al. Fatal hemorrhagic fever caused
by West Nile virus in the United States. Clin Infect Dis 2006;42(11):1527–35.
91. Hassin-Baer S, Kirson ED, Shulman L, et al. Stiff-person syndrome following
West Nile fever. Arch Neurol 2004;61(6):938–41.
92. Sherman-Weber S, Axelrod P. Central diabetes insipidus complicating West Nile
encephalitis. Clin Infect Dis 2004;38(7):1042–3.
93. Bode AV, Sejvar JJ, Pape WJ, et al. West Nile virus disease: a descriptive study
of 228 patients hospitalized in a 4-county region of Colorado in 2003. Clin Infect
Dis 2006;42(9):1234–40.
94. Klee AL, Maidin B, Edwin B, et al. Long-term prognosis for clinical West Nile
virus infection. Emerg Infect Dis 2004;10(8):1405–11.
95. Peterson RK, Macedo PA, Davis RS. A human-health risk assessment for West
Nile virus and insecticides used in mosquito management. Environ Health
Perspect 2006;114(3):366–72.
96. Schofield S, Tepper M, Lalonde J. Comparing risk of West Nile Virus against risk
of adulticiding. Environ Health Perspect 2006;114(9):A519 [author reply: A519].
97. Carney RM, Husted S, Jean C, et al. Efficacy of aerial spraying of mosquito adul-
ticide in reducing incidence of West Nile virus, California, 2005. Emerg Infect Dis
2008;14(5):747–54.
98. Petersen LR, Roehrig JT. Flavivirus DNA vaccines–good science, uncertain
future. J Infect Dis 2007;196(12):1721–3.
99. Zohrabian A, Hayes EB, Petersen LR. Cost-effectiveness of West Nile virus vac-
cination. Emerg Infect Dis 2006;12(3):375–80.
100. Monath TP, Liu J, Kanesa-Thasan N, et al. A live, attenuated recombinant West
Nile virus vaccine. Proc Natl Acad Sci U S A 2006;103(17):6694–9.
101. Martin JE, Pierson TC, Hubka S, et al. A West Nile virus DNA vaccine induces
neutralizing antibody in healthy adults during a phase 1 clinical trial. J Infect
Dis 2007;196(12):1732–40.
102. Dauphin G, Zientara S. West Nile virus: recent trends in diagnosis and vaccine
development. Vaccine 2007;25(30):5563–76.
103. Reisen WK, Fang Y, Martinez VM. Avian host and mosquito (Diptera: Culicidae)
vector competence determine the efficiency of West Nile and St. Louis enceph-
alitis virus transmission. J Med Entomol 2005;42(3):367–75.
104. Fang Y, Reisen WK. Previous infection with West Nile or St. Louis encephalitis
viruses provides cross protection during reinfection in house finches. Am
J Trop Med Hyg 2006;75(3):480–5.
105. Day JF. Predicting St. Louis encephalitis virus epidemics: lessons from recent,
and not so recent, outbreaks. Annu Rev Entomol 2001;46:111–38.
106. Morales MA, Barrandeguy M, Fabbri C, et al. West Nile virus isolation from equi-
nes in Argentina, 2006. Emerg Infect Dis 2006;12(10):1559–61.
107. Rico-Hesse R, Harrison LM, Salas RA, et al. Origins of dengue type 2 viruses
associated with increased pathogenicity in the Americas. Virology 1997;
230(2):244–51.
Chikung unya :
A Paradigm
of Emergence
a nd Globalization
of Ve c tor - Borne
Dis eas es
Fabrice Simon, MDa,b,*, Helene Savini, MDa, Philippe Parola, MD, PhDc,d
KEYWORDS
Chikungunya Aedes albopictus Arthritis Tenosynovitis
Travel Emerging disease Globalization
After a period of 50 years of silence, a disease with an unpronounceable name, ‘‘chi-

kungunya’’ (CHIK), has recently become a medical reality that has reached the public
throughout the world.1–3 Although the CHIK virus (CHIKV) is not a newcomer among
tropical viruses, it was unknown by most people in the world, including medical doc-
tors. However, during the second half of the twentieth century, CHIKV has been found
to be responsible for widespread outbreaks of a two-stage disease, consisting of an
intense, acute stage commonly followed by a long-lasting disabling polyarthritis.4
Before 2000, only a few benign, imported infections had been occasionally observed
in North American and European travelers.5–7 Therefore, until recently CHIKV had gen-
erated only minor interest in the global medical community and no fear in developed
countries, in contrast to other arboviruses, such as dengue and West Nile.8 However,
the recent large-scale outbreaks that successively swept through eastern Africa, the
western Indian Ocean islands, India, and the eastern Indian Ocean Islands demon-
strated the strength of this emerging human pathogen.3 With millions of people
a
Service de Pathologies Infectieuses et Tropicales, Hôspital d’Instruction des Armees Laveran,
BP 50, 13998 Marseille Arme es, France
b
Institut de Me decine Tropicale du Service de Sante des Arme es, Le Pharo, BP46, 13998 Mar-
seille Armees, France
c
Service des Maladies Infectieuses et Tropicales, Hôspital Nord, AP-HM, Chemin des Bourrelys,
13015 Marseille, France
d
Unite de Recherche en Maladies Infectieuses et Tropicales Emergentes, UMR CNRS-IRD 6236,
Faculte de Medecine, Marseille, France
* Corresponding author. Service de Pathologies Infectieuses et Tropicales, Hôspital d’Instruc-
tion des Arme es Laveran, BP 50, 13998 Marseille Arme es, France.
E-mail address: simon-f@wanadoo.fr (F. Simon).
Med Clin N Am 92 (2008) 1323–1343

1324 Simon et al
infected over the few past years,3,9 the classic clinical features of CHIK have been
rediscovered. Moreover, its dramatic emergence in developed countries such as
Reunion Island (a French island in the western Indian Ocean) and India rapidly led
to the identification of unexpected clinical presentations and enlarged our knowledge
of the epidemiology, virology, and pathophysiology of this fascinating arbovirus.10,11
Since 2006, CHIKV infection has also been identified in an unprecedented number
of travelers (more than 1000) after they returned home from epidemic areas.12 Among
CHIKV-infected travelers were some with high-grade viremia, who returned to
countries where competent vectors are present, raising serious concern for the glob-
alization of the disease.13 Indeed, Aedes albopictus, the Asian tiger mosquito (Fig. 1),
the main vector in Reunion, is also indigenous to Southeast Asia and the western
Pacific and Indian Oceans, and has recently spread to Africa, the Middle East, Europe,
and the Americas.14 The outbreak that developed in Italy in August 2007 demon-
strated the reality of this threat.15 Given its explosive spread, severe clinical burden,
and negative impacts on health, socioeconomic, and political systems in epidemic
countries, CHIKV is a major concern in most African and Asian areas. Because CHIKV
infection is an arboviral disease that all physicians should be prepared to encounter,
the authors review here the different aspects of this reemerging disease, focusing on
the lessons from recent and ongoing outbreaks.
WHAT WAS KNOWN ABOUT CHIKUNGUNYA VIRUS FROM THE PAST CENTURY
A Neglected Arboviral Infection in Africa and Asia
CHIKV infection was first described after outbreaks of febrile polyarthritis in Tanzania
in 1952 and 1953.16,17 The name ‘‘chikungunya’’ comes from Kimakonde, a vernacular
language in Tanzania and Mozambique. It means ‘‘that which contorts or bends up’’
and refers to the contorted posture of infected patients suffering with severe joint
pain and dramatic limited ability to ambulate in daily life.16,17 In Congo, people call
the disease ‘‘buka-buka,’’ which can be translated as ‘‘broken-broken.’’18
CHIKV was first isolated from the serum of a febrile human in Tanzania (formerly Tan-
ganyika) in 1953 during the epidemic investigation.17,19 Thereafter, given its ability to in-
capacitate those infected, military laboratories studied CHIKV as a natural threat and as
a putative biological weapon.20 CHIKV belongs tot he Alphavirus genus and Togaviridae
family. Like all alphaviruses, CHIKV has a genome consisting of a linear, positive-sense,
single-stranded RNA molecule.11 Other alphaviruses express antigenicity similar to
CHIKV. Most of them also share its tropism for joints and induce similar polyarthralgia/ar-
thritis (Table 1).21 Despite numerous experimental studies on other alphaviruses, the
pathophysiology of chronic rheumatism following alphaviral infections remains unclear.22
Fig.1. Aedes albopictus, the Asian tiger mosquito. (Adapted from Parola P, de L X, Jourdan J,
et al. Novel chikungunya virus variant in travelers returning from Indian Ocean islands.
Emerg Infect Dis 2006;12:1493–9.)
Chikungunya: A Paradigm of Emergence 1325
Table 1
Epidemiologic characteristics of arthritogenic alphaviruses
Virus MainVectors Main Areas of Endemicity

CHIKV Aedes aegypti, A albopictus Africa, India, Southeast Asia,
Indian Ocean
O’nyong-nyong virus Anopheles spp Africa
Ross River virus Aedes spp; rarely, Culex spp Australia, South Pacific
Barmah Forest virus Aedes spp Australia
Semliki Forest virus Aedes spp Africa
Sindbis group viruses Culex spp Africa, Asia, Australia, Northern
Europe
Mayaro virus Aedes spp; Haemagogus spp South America
Between the 1960s and 1990s, CHIKV was isolated repeatedly in numerous focal
outbreaks and clusters in numerous countries in central, southern, and western Africa
(Fig. 2).11 After spreading to Asia (the first documented outbreak was in 1958 in Thai-
land), frequent CHIKV outbreaks were reported in India, Pakistan, and Southeastern
Asian countries from the 1960s to the end of the last century.11,23
As CHIK struck focally in only a few tropical developing countries and was
anecdotally diagnosed in travelers,5–7 interest in CHIKV epidemiology was limited
before 2000. Most outbreaks had a rapid progression, affected hundreds to a few
thousand persons, and were followed by long, silent interepidemic periods.
Nevertheless, in Africa, CHIKV infection was endemic, with sporadic clusters of cases
and a tendency to cause small outbreaks.24–26
Fig. 2. Estimated global distribution of Aedes albopictus (areas enclosed in dotted lines) and
distribution of CHIKV (stars), including the Indian Ocean variant responsible for the 2006
outbreak (yellow stars). The color of the stars reflects the main evolutionary lineages of
the CHIKV. Arrows indicate the spread of the recent large-scale outbreak. (From Parola P,
de Lamballerie X, Jourdan J, et al. Novel chikungunya virus variant in travelers returning
from Indian Ocean islands. Emerg Infect Dis 2006;12:1493–9; with permission.)
1326 Simon et al
Two epidemiologic profiles of CHIKV infection were described. In Africa, CHIKV was
known to be zoonotic and maintained in a sylvatic cycle involving wild primates,
rodents, and forest-dwelling Aedes spp mosquitoes (particularly members of the
A furcifer-taylori group).11,27 The sylvatic mosquito densities that increase with periods
of heavy rainfall influenced the epidemiologic pattern of CHIV outbreaks in Africa.11
On the other hand, in Asian countries, CHIKV was known to be transmitted by the
urban Aedes aegypti mosquito (the urban, peridomestic, anthropophilic vector of
dengue), with an epidemiologic cycle resembling that of dengue: assumed absence
of animal reservoir, human-to-human transmission by mosquito bites, and potential
for major epidemics. Other abundant, common, peridomestic species, including
A albopictus, which colonizes artificial and natural containers in suburban and rural
areas, have been suspected in supplementing A aegypti in the transmission of
CHIKV.11,27
Febrile Polyarthralgia Followed by Long-Lasting Rheumatism

Since the first description of the disease in the 1950s, knowledge of its clinical features
has been based on the descriptions from South African teams after local epidemics in
the late 1970s.28–30 After a short incubation (2–6 days), two successive stages of the
disease have been identified. The acute stage is characterized by a sudden onset of
symptoms. Infection is frequently associated with high fever and, synchronous or not,
incapacitating polyarthritis and skin manifestations.29,30 In tropical areas, confusion
with dengue fever was common, although the two diseases present characteristic
clinical signs (Table 2). As early as 1955, Robinson proposed distinguishing CHIKV
infection from other epidemic illnesses with febrile diffuse pain, and identified lack
of pain when moving the eyes and extended duration of joint pain as more character-
istic of CHIKV infection.19 General manifestations of CHIK are not specific: high fever
that decreases only slightly with paracetamol (acetaminophen), intense asthenia, and
diffuse myalgia. Patients are often confined to bed because of coexisting multiple
inflammatory arthralgias or arthritides. This acute rheumatism is mostly bilateral, sym-
metric, and cumulative within few days, and it especially involves the peripheral joints:
hands, wrists, feet, and ankles. Nevertheless, all joints can be painful, and spinal pain
is also frequent. Skin manifestations can include maculopapular rash, diffuse hyper-
emia, and edema of the face and extremities. These manifestations usually start after
2 to 4 days and last for 3 days. Minor and transient mucosal bleeding is possible at this
Table 2
Main clinical differences between chikungunya and dengue infection
Chikungunya Dengue Fever

Fever, asthenia Common Common
Rash Days 1–4, important skin edema Days 3–7
Retro-orbital pain Rare Common
Myalgia Possible Very common
Polyarthritis Very common, edematous None
Tenosynovitis Yes None
Hypotension Possible Common, days 5–7
Minor bleeding Possible Common
Second stage Chronic polyarthritis up to 1 year Fatigue up to 3 months
Tenosynovitis at M2–M3
Raynaud’s syndrome at M2–M3
stage. Severe hemorrhage and deaths were described in 1960,31 but some cases may
have been confused with dengue.32 Two cases of acute CHIKV encephalitis were
reported in Cambodia.33 The second stage of CHIKV infection, also named the chronic
stage, was identified because of persisting polyarthralgia, which can severely inca-
pacitate the patient for weeks to more than 1 year. In Brighton’s experience, 88%
of 107 CHIKV-infected patients declared themselves cured 3 years after disease on-
set, whereas 12.1% mentioned persistent symptoms including occasional discomfort,
persistent joint stiffness, or stiffness, pain and effusion.30 Pain or stiffness was more
severe and more prolonged in the oldest patients and in those who had previous rheu-
matism. Only one case of late articular destruction was reported.34 The quality of
immunity after natural CHIK infection in humans has not been studied, but infecting
mice with a vaccinal strain protected them against various CHIKV strains.35
The therapy of infected patients was empiric because no well-conducted prospec-
tive study or guidelines were available. No antiviral drug with in vitro activity was cor-
rectly tested on infected patients. Patients were commonly treated with pain killers or
anti-inflammatory drugs, steroidal or not. Only Brighton empirically conducted an
open pilot study, which suggested chloroquine sulfate was effective against chronic
symptoms, but no clear conclusion could be obtained.36
THE LESSONS FROM 2000’S LARGE-SCALE OUTBREAKS

A Chikungunya Virus Outbreak from Africa to Indian Ocean Islands, Asia, and Europe
In addition to the historical outbreaks starting in the 1960s, an unexpected resurgence
of CHIKV outbreaks has been observed since the end of the twentieth century, notably
in Africa. In 1999 to 2000, a reemergence was documented in the Democratic Repub-
lic of the Congo, where an estimated 50,000 persons were infected during an urban
epidemic after 39 years without any isolation of the virus.18,37 Also in Asia, epidemic
reemergence was documented in 2001 to 2003 in Indonesia, after a nearly 20-year
hiatus of epidemic CHIKV activity.38
In 2004, the ongoing giant CHIKV outbreak started. We know now that it began in
Lamu Island, Kenya, in 2004, with an attack rate higher than 50% and an estimated
13,500 persons infected. At first, this disease outbreak was suspected to be due to
o’nyong-nyong fever virus, another member of the genus Alphavirus (ProMED archive
number 20,041,214.331; http://www.promedmail.org).39,40 Then the outbreak spread
to the Indian Ocean Islands. More than 5000 cases were reported in the Comoros Is-
lands,41 and thereafter the virus circulated to other islands including Reunion42 and
Mayotte43 (two French territories), Mauritius,44 the Seychelles,45 and Madagascar
(see Fig. 2) (Table 3).46
At the beginning of 2006, after a period of lower transmission during the winter and
with the arrival of the Southern Hemisphere summer, the rainy season gave rise to a re-
newed epidemic circulation of the virus. Reunion Island suffered an explosive out-
break. By September 18, 2006, an estimate of 266,000 residents (population
770,000) infected with CHIKV was reported.47–49 This CHIKV epidemic was the first
in a country with an occidental health care environment.50 It was first noticed in the
southern state of Andhra Pradesh in February 2006.51,52 By the end of 2006, it had
spread to 15 other states. Several million cases have been reported in India and cases
have been reported continuously up to December 2007.9,53,54 Continued expansion
was reported in Sri Lanka,55 Indonesia,56 and Malaysia.57 By 2007, the virus had
reached Europe.15
Furthermore, since 2004, CHIK fever has been identified in an unprecedented num-
ber of travelers (more than 1000) after they returned home from epidemic areas to
1328
Simon et al
Table 3
Epidemiologic data on chikungunya outbreaks in islands of the Western Indian Ocean, 2004 to 2006
Estimated Estimated
Island, Epidemic Attack Rate or Number
Country Years (Peak) Seroprevalence of Cases Mortality References
39
Lamu Island, 2004 (July) Seroprevalence: 75% 13,500 No available data
Kenya
Seychelles 2005 No available data No available No available data None
data
41
Grande Comore, 2005 (March) Seroprevalence: 63% 215,000 No available data
Comoros Union
43
Mayotte, 2005–2006 Attack rate: 39.6 cases 6,346 1 reported death
France (March–April) per 1000 inhabitants
44
Mauritius 2005–2006 No available data w15,500 743 excess deaths
(February–March) in the 3 months after
the epidemic peak
46
City of Toamasina, 2006 (January) No available data No available No available data
Madagascar data
42,112
Reunion Island, 2005–2006 Seroprevalence: 35% 244,000 213 deaths certificates;
France (February–March) 260 excess deaths;
case-fatality rate: 1/1000
European countries,10,58,59 the United States,60 Australia,61 and Asia.62 Imported

CHIKV infection in returned travelers paralleled the spread of the explosive outbreaks
in the Indian Ocean islands and then India.10,60 Most patients consulted at the chronic
stage. The acute stage developed after return in 14% to 45% of CHIKV-infected trav-
elers.10,63 CHIKV viremia was identified in some recently infected travelers, raising
concern about the potential globalization of the disease,13,60 focusing on the role of
travelers and migrants visiting friends and relatives in their country of origin as
unwitting sentinels, transport media, and potential transmitters of infectious
diseases.12,64,65
As a consequence, the accumulated data and published papers from CHIK
epidemic experiences have increased exponentially (Fig. 3). Unexpected changes in
epidemiology, new clinical complications, improved insights into pathophysiology,
and the evolution of the virus have been described. CHIKV is no longer neglected.
Harsh Public Health Consequences in Large Outbreaks

The first characteristics noticed from CHIKV outbreaks are the rapid spread, high at-
tack rates, and severe impact on public health, as demonstrated in Reunion Island42,66
and India.9 Regional contiguous extension of the epidemics is partially explained by
the intensity of human exchanges, lack of regional strategy to control arboviral infec-
tions, and absence of immunity against CHIKV in local populations. In most countries,
adequate measures to control CHIKV outbreaks are commonly delayed for weeks to
months for several reasons: (1) difficulty in identifying the first cases in a formerly
CHIK-free area, (2) underestimation of the epidemic threat, (3) underestimation of
the clinical impact, (4) political or economic (tourism) reticence. In this situation, the
global CHIKV load exponentially increases in infected patients and mosquitoes.
More than 95% of CHIKV-infected adults are symptomatic, and most working adults
become disabled, with loss of mobility, hand handicap, and depressive reaction,
which can each last for weeks to months.67 Thus, a CHIKV outbreak has the effect
of a brutal epidemic of acute febrile polyarthritis plus endemic chronic rheumatism.
Quantity of work and quality of life are commonly altered for a prolonged period.
For example, in Grande Comore in 2005, 79% of the CHIKV-seropositive persons
were hospitalized or stayed at home in bed for a mean of 6 days, and 52% missed
work or school for a mean of 7 days.41 CHIKV outbreaks generate mild-to-major crises
Fig. 3. Evolution of the number of publications on dengue and CHIK over time. (Search per-
formed with PubMed. Available at: www.ncbi.nlm.nih.gov. Accessed July 20, 2008.)
1330 Simon et al
in public health in terms of morbidity and mortality, overloading of medical structures,

loss of availability of health care workers, lack of preventive and curative means, loss
of patients’ confidence, and excessive media coverage. In parallel, social, economic,
and political balances are also severely disturbed by the epidemics. The main public
health actions consist of public relations exercises, realization of guidelines, commu-
nity surveillance for suspect or proved cases, hospital-based surveillance for potential
severe forms, mortality surveillance, prevention of nosocomial CHIKV-transmission,
and vector control measures. Beside the management of the emotional impact in
such severe outbreaks, health authorities must promptly disseminate updated medi-
cal information, guidelines for diagnosis, and therapy of suspect patients, and must
manage saturation of hospitals. Thus, one important challenge is that most patients
have to be managed by general practitioners as outpatients with two consequences
in an epidemic context: the risk for misdiagnosing serious, treatable diseases (eg,
malaria, leptospirosis) when serologic assays are not performed and the risk for intra-
familial spread if the patient is maintained at home without a bed net. Measures are
required to limit nosocomial transmission of CHIKV through occupational blood expo-
sure with needlestick, tissues grafts, and blood transfusion.13,68,69
No More a Benign Infection: Morbi-Mortality in the Acute Stage, Handicap

in the Chronic Stage
The outbreaks in the Indian Ocean, India, and Asia brought new data on clinical spec-
trum of CHIK infection: improved description of the two stages, unexpected compli-
cations and deaths during the exceptional outbreak in Reunion Island. Excess
deaths were reported during the Reunion Island and Mauritius outbreaks, mainly in
persons older than 75 years of age; the estimated case-fatality rates for CHIK disease
were 0.3 to 1/1000 and 47/1000, respectively.42,47,70 Underlying diseases and age are
the most important negative prognostic factors.42,71 CHIKV infection is more severe in
autochthonous than in imported cases, perhaps because travelers are younger and
previously healthier than patients who have to be hospitalized in an epidemic situa-
tion.71 All these new data on CHIK morbidity and mortality clearly alter the character-
ization of CHIK as a benign infection.
Clinical studies from recent outbreaks reported signs and symptoms in the acute
stage that appear to vary more than those previously described (Table 4).10,58,67,71,72
The description of the two main clinical components in the acute stage (ie, rash and
polyarthralgia) is now enriched with a finer definition of associated symptoms. Polyar-
thritis commonly involves more than 10 joint groups.10 It can be edematous, asymmet-
ric, or atypical (Baker’s cyst), and is frequently associated with disabling acute
tenosynovitis; intense pain provoked by pressure on the anterior part of the wrists is
highly evocative.10
Some unusual locations are possible (eg, sternoclavicular and temporomandibular),
whereas hips are relatively spared.10,71 Axial involvement is common at any level. Skin
involvement consists of patchy to diffuse and edematous exanthema (Fig. 4A) and,
less frequently, itching, peeling, or epidermolysis; all types can be followed by persist-
ing dyschromic patches on dark skin.10,58,73,74 Nonspecific gastrointestinal signs are
common.63,71 Borgherini and colleagues71 also mentioned neurologic signs in 12% of
their patients, mainly delirium in the older ones. Respiratory symptoms have been
reported in India only, in relation to respiratory syncytial virus, influenza, or adenovirus
coinfections.75 Thrombocytopenia was not prominent and rarely severe in the Reunion
experience.71
The Reunion hospital-based surveillance allowed description of 123 severe
features during the epidemic peak that affected about 244,000 persons.42 The
Table 4
Early clinical features in chikungunya virus infection during Reunion outbreak
71 72 67 58 10
Recruitment 157 cases with acute 20 imported cases 125 cases in 22 imported cases 47 imported cases from
of patients stage in Reunion from western Indian Reunion Island from western Indian western Indian Ocean
Island Ocean, India, Southeast Ocean to mainland to mainland France
Asia to Germany France
Epidemiologic data
Mean/median age 57.9 44.4 y (12–66) 40 y (19–55) 47 y (22–72) 45 y (0.5–73)
(range) 1.2 0.7 17.9 0.57 0.88
Sex ratio (M/F) 71% NR NR NR 64%
Underlying disease
Symptoms and signs
Fever (duration) 95.9% 100% (4.9 days) 86.5% (3 days) 100% (4 days) 96% (3.7 days)
Asthenia NR ND 100% 77% NR
Headache 47.1% ND 74% 59% NR
Myalgia NR ND ND 55% NR
Chikungunya: A Paradigm of Emergence

Nausea, vomiting ND 30% and 1.5%, respectively NR 14% NR
Skin manifestations 40.1% 75% 54.4% 77% 51%
Pruritis 54% 25% NR 14% 19%
Mucous bleeding 2% 4% 2.6% 0% 4%
Arthralgias/arthritis 96.1% 100% Most patients 100% 100%
Hands 49.6% ND 76% 73% ND
Wrists 29.1% ND 74% 81% ND
Feet 41% ND 68% NR ND
Ankles 66.2% ND 68% 77% ND
Symmetry of arthralgias 73.2% NR Mainly present Mainly present 64%
Periarticular edema 31.8% 95% 44.8% NR 41%
Axial involvement 34.4% NR Neck: 49%; back: NR 47%
42%; loins: 52%
Peripheral lymphadenopathy 8.9% NR NR 9/22 (41%) NR
Complication 5 deaths (mean age: NR NR NR 4% (acute myocarditis: 1;
79.4 y) (see reference pancytopenia: 1)
for more details)
Abbreviations: ND, not detailed; NR, not reported.
1331
1332 Simon et al
Fig. 4. Clinical manifestations of CHIK infection. (A) Edematous exanthema of the face
(acute stage). (B) Raynaud’s phenomenon at the third month after disease onset (chronic
stage). (C) Polyarthritis in hands and hypertrophic tenosynovitis in wrists at the third month
after disease onset (chronic stage). (D) Bursitis of dorsal side of the hand (chronic stage).
(E) Chronic swelling and stiffness of the fingers with loss of grip strength (chronic stage).
most commonly observed complications, in decreasing frequency, were respiratory

failure, cardiovascular decompensation, meningoencephalitis, severe acute hepati-
tis, severe cutaneous effects, other central nervous system problem, and kidney
failure. More than half of the severe cases involved patients older than 65 years
of age, and more than one third died. A causal relationship between CHIKV and
most complications cannot be ascertained. In fact, many patients who had severe
acute forms also had underlying diseases that worsened71 or iatrogenic complica-
tions, such as drug-induced hepatitis or Reye syndrome.4,64 A direct role of CHIKV
in severe features seems limited to rare acute central neurologic or cardiac compli-
cations, which is consistent with previous experimental studies in mice,76 but the
exact pathophysiologic mechanisms remain unknown. To date, no evidence exists
for increased virulence of the recent CHIKV strains. CHIKV-induced meningoen-
cephalitis is the main neurologic complication, especially in children.42,74 Polyradicu-
loneuritis and acute flaccid paralysis are exceptional.77,78 Miscellaneous ocular
complications have been recently described in India: episcleritis, granulomatous and

nongranulomatous anterior uveitis, optic neuritis, retrobulbar neuritis, dendritic le-
sions, and retinitis; recovery is common.79–81 Acute myocarditis has also been re-
ported in a few cases in adults and children,74,81–83 but the long-term cardiac
prognosis is uncertain.81 The direct impact of CHIKV infection on pregnancy has
also been evidenced: higher risk for abortion in the first trimester and mother-to-
child transmission in the last trimester.64,84 During the epidemic peak in Reunion Is-
land, the attack rate was as high as 8.3% in pregnant women.84 Vertical transmis-
sion was not observed in the intrapartum period (ie, more than 7 days before
delivery), but around one half of the mothers with ongoing CHIKV infection in the
setting of delivery transmitted the disease to their offspring. Mother-to-child CHIKV
virus transmission has been shown to be common in the context of intrapartum ma-
ternal viremia, and often leads to severe neonatal infection. Caesarean section did
not prevent transmission. Neonatal infection was associated with fever, poor feed-
ing, pain, distal edema, and various skin manifestations. Severe illnesses have
been observed and mainly consisted of encephalopathy, including pathologic MRI
findings (brain swelling; cerebral hemorrhages) and possible evolution toward per-
sistent disabilities.84
Knowledge of the clinical aspects and outcome of the second stage has progressed
recently. This stage is not constant, but seems affected by age and underlying
diseases, notably rheumatic or traumatic diseases. Its evolution can include early
exacerbation, relapses, and long-lasting rheumatism. The first months after disease
onset can be marked by a temporary increase of handicap, joint pain and stiffness,
and sometimes dysesthesia in the extremities.10 The authors recently described tran-
sitory peripheral vascular disorders, such as Raynaud’s syndrome, at this period in
about one sixth of CHIKV-infected travelers (Fig. 4B).10 Chronic hypertrophic tenosyn-
ovitis are also common and sometimes induce nerve tunnel syndromes in wrists or
ankles (Fig. 4C).85 CHIKV-induced chronic rheumatism consists of three clinical com-
ponents, isolated or associated: finger and toe polyarthritis with morning pain and
stiffness (see Fig. 4B), severe subacute tenosynovitis/bursitis in hands (Fig. 4D),
wrists, and ankles, and exacerbation of pain on movement in previously injured joints
and bones.10 The handicap in handling objects during daily life can be major, leading
to prolonged sick leave (Fig. 4E). A follow-up of cohorts from 2000/2006 outbreaks
progressively details the real impact of the chronic symptoms. Patients frequently
complain of unpredictable relapses that include sensation of fever, asthenia, and
exacerbation of joint pain and stiffness, and often require intensification of symptom-
atic treatment. Complications of anti-inflammatory treatments for the chronic stage,
such as gastrointestinal perforation, are being reported.86 The psychologic burden
and loss of quality of life cannot be neglected; the frequency and intensity of chronic
rheumatologic changes remain high after 6 months.67 The severity of the persisting
handicap and depression led some patients to attempt suicide (F. Simon, unpublished
data, 2007). An 18-month follow-up identified persistent polyarthralgias in 65.9% of 88
patients previously infected in Reunion (mean age: 58.3 years).87 Ongoing follow-up
will define the long-term handicap and sequelae.
Changing Patterns in Relationship Between the Chikungunya Virus and Mosquitoes

The phylogenetic analyses based on the E1 gene (encoding one of the two major
envelope surface glycoproteins) sequences grouped CHIKV isolated worldwide by
2004 into three genotypes: Asian, East/Central/South African, and West African.11,37
The CHIKV strains responsible for the massive outbreak in the western Indian Ocean
have been isolated from autochthonous patients88 and from travelers who have
1334 Simon et al
returned to France.13 Molecular characterization first revealed that the epidemic

CHIKV was related to Central/East African CHIKV isolates, from which new variants
may have evolved.13,88 Extensive genome analysis of epidemic isolates identified
unique molecular changes in the envelope glycoprotein E1 when compared with the
few previously available sequences from laboratory-adapted viruses.89
In the successive outbreaks in Kenya, Comoros, and Seychelles, CHIKV was trans-
mitted by A aegypti.90 CHIKV isolates from these islands and early isolates from other
islands in this region had an alanine residue at position 226 of the E1 gene.88 When
reaching Reunion and Mauritius Islands, CHIKV met different ecologic environments,
characterized by the absence or scarcity of A aegypti and the proliferation of A albo-
pictus around human habitations. Within 1 year, a new mutation (A226V [ie, a valine
residue at position 226]) appeared in CHIKV strains in Reunion. The A226V mutation
was identified in all sequenced 2006 Mayotte isolates and in a recent 2007 isolate
from Madagascar.90 This mutation is associated with improved adaptation of CHIV
to A albopictus, which was previously considered a secondary vector. Indeed, recent
entomologic studies91,92 demonstrated that E1-A226V mutation was directly respon-
sible for significant increase in CHIKV infectivity for A albopictus, boosted CHIKV dis-
semination in A albopictus, including into the salivary glands, and improved
transmission to vertebrate species, conferring a selective advantage over infection
in A aegypti. Finally, in all Indian Ocean islands where A albopictus was present, the
A226V adaptive mutation was observed 1 or 2 years after CHIKV introduction. Overall,
the recent efficiency of CHIKV extension can be explained by the combination of: (1)
probable first entry of CHIKV among the nonimmune and vulnerable population in
Reunion island, (2) the abundance of potential vectors involved in local transmission
(A albopictus), and (3) the appearance of a viral mutation leading to increased infectiv-
ity and faster dissemination of the CHIKV mutant in A albopictus. As emphasized by de
Lamballerie, it is not known if this mutation was acquired several times independently
or if an ‘‘A albopictus–adapted’’ strain evolved in one island and then dispersed to
neighboring islands.90 Considering robust phylogenetic analysis, the same
investigator suggests separate acquisitions of A226V mutation by CHIKV isolates in
India, Cameroon (2006), and Gabon (2007) (two African countries where A albopictus
has displaced A aegypti), independently from the same mutation in Indian Ocean iso-
lates.90 Therefore, three independent events of virus exposure to A albopictus, each
followed by the acquisition of a single adaptive mutation, have provided selective
advantage for transmission by this mosquito. This unique example of the so-called
‘‘evolutionary convergence’’ occurring in nature illustrates rapid pathogen adaptation
to ecologic perturbation.90
A Paradigm for the Globalization of Vector-Borne Diseases

In 2006, after having identified high CHIKV viremia in some patients returned from
Indian Ocean islands, the authors alerted the scientific community about the risk for
CHIKV globalization.13 Indeed, since the 1980s, A albopictus has spread worldwide,
having reached the United States in 1985, Brazil in 1986, Central America in 1988,
and Africa in 1992 (see Fig. 2). In Europe, it was identified in Albania in 1979 and in Italy
in 1991, where it has become established. It was reported in France for the first time in
1999 when larvae were discovered in recycled tires imported from the United States
and Japan.14,93 Since 2005, A albopictus has become a major pest in the southern
French departments of Alpes-Maritimes and Var, and in 2006 it was found in
Corsica.93,94 A albopictus probably came from Italy, where it is active from February
through December, with a peak in August and September. It is also present in several
other European countries, including Belgium, Bosnia and Herzegovina, Croatia,
Greece, Montenegro, Serbia, Slovenia, Switzerland, and The Netherlands, and has
recently been found in Spain.95
A albopictus can be introduced in a new place through different routes. The eggs
can withstand desiccation and survive in miscellaneous containers during long travels
around the world. The international trade in used tires, which are optimal breeding
sites, has played a major role in the mosquito spread, as has the importation of Dra-
caena sanderiana plants, also known as ‘‘lucky bamboo.’’ Furthermore, public or pri-
vate transport from infested areas by highway, ferry, or air can contribute to the
passive dispersion of A albopictus. After its introduction into a new area, the mosquito
will disperse actively to nearby areas if environmental conditions are favorable (mean
winter temperature higher than 0 C, annual rainfall of at least 500 mm, sufficient rainfall
in warm season, and summer temperature around 25 to 0 C).96 Thus, A albopictus is
active year round in tropical and subtropical latitudes and it overwinters in the egg
stage in the colder latitudes of the Northern Hemisphere. For these reasons, risk for
CHIKV implantation from any destination is probably low, if not nil, during the colder
months in northern Europe and northern parts of North America. Synchronicity of
the vector activity in the epidemic country and of A albopictus in the susceptible
area seems necessary to allow CHIKV to spread from a viremic traveler to a local res-
ident, which is probably why CHIKV did not spread between January and April 2006
from the epidemic peak in the west Indian Ocean (warm months) to South Europe
(cold months). On the contrary, countries in Southern Europe are more susceptible
to CHIKV implantation and spread with the arrival of travelers with high CHIKV viremia
in warmer months. Risk became reality in Italy, as demonstrated by the outbreak that
developed in the summer of 2007 from an infected visitor from India. The overlapping
of mosquito seasons in India and Europe permitted travelers returning from India to
fuel an epidemic by infecting native mosquito populations in Europe. This seasonal
synchronicity made the scenario come true in the province of Ravenna in northeastern
Italy, when 205 cases of CHIKV infection were identified between July 4 and Sept 27,
2007. The presumed index case was a man from India who developed symptoms
while visiting relatives in one of the villages. A albopictus, which is the major human
biting pest in this area, was found CHIKV positive by reverse transcription-polymerase
chain reaction (RT-PCR)97 and was considered the most likely vector for this outbreak.
The Italian strain ITA07-RA1 (GenBank_EU244823) had the A226V mutation.98
HOW TO DIAGNOSE CHIKUNGUNYA VIRUS INFECTION
In the current context of globalization of CHIKV, CHIK fever has to be suspected in

any place, whether A albopictus is present or not (see Fig. 2). Appropriate laboratory
tools are available, including serology,13,99,100 culture isolation,99 and molecular
tools.13,37,60,100,101 Time after disease onset determines the choice between viral
detection and serologic assays. In the acute stage, viremia can be detected on blood
sampled in an EDTA tube within the first week of illness onset with culture or molecular
tools, both performed in specialized laboratories in nonendemic/epidemic areas.
CHIKV isolation is conducted on mosquito cells (C6/36), mammalian cells (Vero), or
mice.4 The test has low sensitivity more than 5 days after disease onset but it remains
the gold standard for determining the viral strain. CHIKV can also be detected in the
same period with RT-PCR assay, which appears to be more feasible, faster, and
more sensitive than culture and is also specific.100 Serologic assays are performed
more often in routine clinical practice. Anti-CHIKV IgM antibodies are detected by di-
rect enzyme-linked immunosorbent assay (ELISA) from the fifth day after the first
symptoms.100 IgG are detected a few weeks later by ELISA, following immunocapture.
1336 Simon et al
These tests have a good sensitivity after the fifth day, but false-negative results have
been observed in some patients, for which specific methods should be used.102 The
interpretation of serologic results should consider a possibility of cross-reactions with
antigens of o’nyong-nyong, Mayaro, and Ross River viruses in nonepidemic
situations.103 Considering the risk for local spread, all cases detected in nonendemic
countries should be reported to health authorities. In France, as in many places in
Europe, the disease requires a mandatory declaration.
FUTURE CHALLENGES
To date, at least 12 countries in Europe are susceptible to CHIKV implantation

because of the presence of A albopictus. Some A albopictus specimens collected
in Camargue and ‘‘Côte d’Azur,’’ southern France, in 2006, experimentally exhibited
the same high susceptibility to CHIKV infection as specimens collected in March
2006 in Reunion Island.93 The presence of this potential vector in such a touristy
area as ‘‘Côte d’Azur’’ is now considered a threat for CHIKV introduction in France.93
Furthermore, it is not known whether infected A albopictus can transmit CHIKV to its
progeny, and thus persist into the following season, which would expose nonimmune
people in the area to the risk for infection and the potential for epidemic resurgence
with a strong threat for secondary regional spreading, in Italy as in any previously
epidemic country.
Furthermore, other countries are at risk, including the United States.102 Recently,
the potential for a CHIKV outbreak in Florida was examined by the determination of
A aegypti and A albopictus susceptibility to CHIKV; all mosquito strains were suscep-
tible to infection and dissemination, with some variation between strains. Therefore,
Florida and probably all the states where A albopictus are prevalent in urban and rural
areas, would be vulnerable to transmission of CHIKV during the warmer months.102 In
2006, two viremic CHIKV-infected travelers returned to regions in the United States
(South Carolina and Louisiana) known to have populations of A albopictus.60
Many questions remain unanswered about the pathophysiology of CHIKV and the
interactions between CHIKV and humans. What are the mechanisms for CHIKV-
induced chronic rheumatism and transient peripheral vascular disorders? Why do
anti-CHIKV IgM still persist in about 40% of symptomatic patients 18 months after dis-
ease onset?87,100 Can CHIKV infection become chronic and where could the viral
sanctuaries be? Important data are waiting on CHIKV cell tropism and in vivo behavior
and on immune disorders. First of all, various human adherent cells (epithelial and en-
dothelial cells, primary fibroblasts, and macrophages) appear susceptible to Reunion
CHIKV strains whose replication induces a cytopathic effect and apoptosis.89 Skeletal
muscle progenitor cells, also named muscle satellite cells, contained viral antigen in
a muscle biopsy from a patient who had a clinical relapse some weeks after disease
onset,104 which suggests the possibility of persistence of CHIKV in some patients long
after initial viremia. It could also explain the low clearance of anti-CHIKV IgM in symp-
tomatic patients. Also, the authors recently identified a high incidence of mixed cryo-
globulimia in CHIKV-infected symptomatic travelers in the first months after disease
onset, induction for false-negative serologic tests, and long persistence. The associ-
ation of mixed cryoglobulinemia and Raynaud’s phenomenon is under investigation
(F. Simon, unpublished data, 2007). A good animal model will probably bring progress
on pathophysiology, therapy, and prevention.105
Treatment of the acute and chronic stages in CHIKV-infected patients remains
empiric. No well-designed trial of therapeutic interventions was conducted during
the recent huge outbreaks. Current therapy is solely symptomatic with painkillers or
anti-inflammatory drugs, steroidal or not. Intensity of pain and handicap can require
systemic short-term low-dosed corticotherapy when nonsteroidal anti-inflammatory
drugs are contraindicated or local treatment fails, but the steady or dramatic improve-
ment can be followed by a painful relapse.10 However, corticosteroid therapy should
not be prolonged or repeated, especially in elderly patients, to limit the severe side ef-
fects (eg, hip osteonecrosis, osteoporosis). Rapid replacement with local treatments,
including physiotherapy, is recommended when possible. Unfortunately, no alterna-
tive systemic drug with evidence-based efficiency exists. Although the efficacy of
chloroquine in the acute stage of the disease was recently discussed, no conclusive
results have been obtained in clinical studies and it use is currently not justified.106
New approaches have been proposed for wide screening for curative antiviral drugs
against CHIKV.107,108
When working on CHIKV as a potential threat, the United States Army developed
a live vaccine. Results from a phase II trial on 59 healthy volunteers were consistent
with safety, good tolerance (8% with transient arthralgia), and high immunogenicity
(98% seroconversion).109 Unfortunately, funding for this project was discontinued
and to date, no vaccine is yet available. Since 2006, research on this topic has
been growing again in France (VacciChik project). Nevertheless, recent findings on
pathophysiology in CHIKV infection raise questions about a live vaccine: Does wide
use in the general population present any risk (chronic infection, viral reversion, mos-
quito transmission)? Could a vaccine strain induce long-lasting rheumatism? DNA
vaccine strategy is an interesting alternative, as suggested by Muthumani and
colleagues.110 However, vaccination policy should also be defined in terms of wide
or targeted use during outbreaks and prevention for travelers or military personnel.
SUMMARY
Vector-transmitted infections are evolutionary threats in the modern world, even in

temperate, industrialized countries. Their potential for spreading was clearly demon-
strated with the West Nile fever that emerged in 1999 in the United States, which
has since became the main vector-borne viral disease in this country.111 The current
large-scale CHIKV outbreak has revealed extraordinary adaptive capacity and clear
potential for global extension of this previously neglected arbovirus. Within a few
years, CHIKV switched from rural endemicity in Africa and focal outbreaks in urban
Asia to a worldwide public heath problem. A single adaptive mutation in CHIKV has
provided a significant advantage for its transmission to and by A albopictus, which
is strongly linked to two main human activities, urbanization and international trans-
port. As a consequence, the new epidemiologic profile of CHIK fever is one of global
dissemination, in which travelers play a key role. They can be sentinels, whose surveil-
lance helps to alert and define clinical features, and, most of all, transporters and
transmitters of the disease to naive populations in nonendemic areas, as demon-
strated by the recent Italy outbreak. Also, the potential impact of global warming on
mosquito-borne diseases, such as CHIKV infection, in temperate countries deserves
consideration.
To be clear, CHIK fever is no longer a disease embedded in tropical and poor
countries. It should definitely be considered as a threat to global public health and
thus, requires adequate international actions: research programs, surveillance,
prompt local alerts, rapid confirmation of outbreaks, diffusion of information on Inter-
net networks, good application of international health regulations, and support for
local public health measures. Physicians in CHIKV-free areas should be prepared to
suspect and confirm promptly possible cases with two aims, an individual benefit
1338 Simon et al
for the patient and medical intelligence for such a remarkably adaptable pathogen in
countries with A albopictus.
ACKNOWLEDGMENT
This work was supported by the French Ministry of Defense. We are grateful to
Dr. Mary Wilson for her helpful comments.
REFERENCES
1. Enserink M. Infectious diseases. Massive outbreak draws fresh attention to little-

known virus. Science 2006;311:1085.
2. Bodenmann P, Genton B. Chikungunya: an epidemic in real time. Lancet 2006;
368:258.
3. Charrel RN, de Lamballerie X, Raoult D. Chikungunya outbreaks–the globaliza-
tion of vectorborne diseases. N Engl J Med 2007;356:769–71.
4. Pialoux G, Gauzere BA, Jaureguiberry S, et al. Chikungunya, an epidemic arbo-
virosis. Lancet Infect Dis 2007;7:319–27.
5. Woodruff AW, Bowen ET, Platt GS. Viral infections in travellers from tropical
Africa. Br Med J 1978;1:956–8.
6. Pile JC, Henchal EA, Christopher GW, et al. Chikungunya in a North American
traveler. J Travel Med 1999;6:137–9.
7. Eisenhut M, Schwarz TF, Hegenscheid B. Seroprevalence of dengue, chikungu-
nya and Sindbis virus infections in German aid workers. Infection 1999;27:82–5.
8. Weaver SC, Barrett D. Transmission cycles, host range, evolution and emer-
gence of arboviral disease. Nat Rev Microbiol 2004;2:789–801.
9. Mavalankar D, Shastri P, Raman P. Chikungunya epidemic in India: a major pub-
lic-health disaster. Lancet Infect Dis 2007;7:306–7.
10. Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging
rheumatism among travelers returned from Indian Ocean islands. Report of 47
cases. Medicine (Baltimore) 2007;86:123–37.
11. Powers AM, Logue CH. Changing patterns of chikungunya virus: re-emergence
of a zoonotic arbovirus. J Gen Virol 2007;88:2363–77.
12. Wilson ME, Freedman DO. Etiology of travel-related fever. Curr Opin Infect Dis
2007;20:449–53.
13. Parola P, de Lamballerie X, Jourdan J, et al. Novel chikungunya virus variant in
travelers returning from Indian Ocean islands. Emerg Infect Dis 2006;12:1493–9.
14. Reiter P, Fontenille D, Paupy C. Aedes albopictus as an epidemic vector of chi-
kungunya virus: another emerging problem? Lancet Infect Dis 2006;6:463–4.
15. Rezza G, Nicoletti L, Angelini R, et al. Infection with chikungunya virus in Italy: an
outbreak in a temperate region. Lancet 2007;370:1840–6.
16. Lumsden WHR. An epidemic of virus disease in southern province, Tanganyika
territory, in 1952–1953. II. General description and epidemiology. Trans R Soc
Trop Med Hyg 1955;49:33–57.
17. Ross W. The Newala epidemic. III. The virus: isolation, pathogenic properties
and relationship to the epidemic. J Hyg (Lond) 1956;54:177–91.
18. Muyembe-Tamfum JJ, Peyrefitte CN, Yogolelo R, et al. [Epidemic of chikungu-
nya virus in 1999 and 2000 in the Democratic Republic of the Congo]. Med
Trop (Mars) 2003;63:637–8.
19. Robinson MC. An epidemic of virus disease in Southern Province, Tanganyika
Territory, in 1952-53. I. Clinical features. Trans R Soc Trop Med Hyg 1955;49:
28–32.
20. Rusnak JM, Kortepeter MG, Aldis J, et al. Experience in the medical manage-
ment of potential laboratory exposures to agents of bioterrorism on the basis
of risk assessment at the United States Army Medical Research Institute of
Infectious Diseases (USAMRIID). J Occup Environ Med 2004;46:801–11.
21. Laine M, Lukkainen R, Toivanen A. Sindbis viruses and other alphaviruses as
cause of human arthritic disease. J Intern Med 2004;256:457–71.
22. Rulli NE, Melton J, Wilmes A, et al. The molecular and cellular aspects of arthritis
due to alphavirus infections: lesson learned from Ross River virus. Ann N Y Acad
Sci 2007;1102:96–108.
23. Mackenzie JS, Chua KB, Daniels PW, et al. Emerging viral diseases of Southeast
Asia and the Western Pacific. Emerg Infect Dis 2001;7:497–504.
24. Saluzzo JF, Ivanoff B, Languillat G, et al. [Serological survey for arbovirus
antibodies in the human and simian populations of the South-East of Gabon
(author’s transl)]. Bull Soc Pathol Exot Filiales 1982;75:262–6.
25. Saluzzo JF, Cornet M, Digoutte JP. [Outbreak of a chikungunya virus epidemic in
western Senegal in 1982]. Dakar Med 1983;28:497–500.
26. Thonnon J, Spiegel A, Diallo M, et al. [Chikungunya virus outbreak in Senegal in
1996 and 1997]. Bull Soc Pathol Exot 1999;92:79–82.
27. Chevillon C, Briant L, Renaud F, et al. The chikungunya threat: an ecological and
evolutionary perspective. Trends Microbiol 2008;16:80–8.
28. Kennedy AC, Fleming J, Solomon L. Chikungunya viral arthropathy: a clinical
description. J Rheumatol 1980;7:231–6.
29. Brighton SW. Chikungunya virus infections. S Afr Med J 1981;59:552.
30. Brighton SW, Prozesky OW, de la Harpe AL. Chikungunya virus infection,
A retrospective study of 107 cases. S Afr Med J 1983;63:313–5.
31. Hammon WM, Rudnick A, Sather GE. Viruses associated with epidemic
hemorrhagic fevers of the Philippines and Thailand. Science 1960;131:
1102–3.
32. Chastel C. [Human infections in Cambodia by the chikungunya virus or a closelyre-
lated agent. 3. Epidemiology]. Bull Soc Pathol Exot Filiales 1964;57:65–82.
33. Mazaud R, Salaun JJ, Montabone H, et al. [Acute neurologic and sensorial
disorders in dengue and chikungunya fever]. Bull Soc Pathol Exot Filiales
1971;64:22–30.
34. Brighton SW, Simson IW. A destructive arthropathy following chikungunya virus
arthritis–a possible association. Clin Rheumatol 1984;3:253–8.
35. Harrison VR, Binn LN, Randall R. Comparative immunogenicities of chikungunya
vaccines prepared in avian and mammalian tissues. Am J Trop Med Hyg 1967;
16:786–91.
36. Brighton SW. Chloroquine phosphate treatment of chronic chikungunya arthritis.
An open pilot study. S Afr Med J 1984;66:217–8.
37. Pastorino B, Muyembe-Tamfum JJ, Bessaud M, et al. Epidemic resurgence of
chikungunya virus in democratic Republic of the Congo: identification of
a new central African strain. J Med Virol 2004;74:277–82.
38. Laras K, Sukri NC, Larasati RP, et al. Tracking the re-emergence of
epidemic chikungunya virus in Indonesia. Trans R Soc Trop Med Hyg
2005;99:128–41.
39. Sergon K, Njuguna C, Kalani R, et al. Seroprevalence of chikungunya virus
(CHIKV) infection on Lamu Island, Kenya, October 2004. Am J Trop Med Hyg
2008;78:333–7.
40. Chretien JP, Anyamba A, Bedno SA, et al. Drought-associated chikungunya
emergence along coastal East Africa. Am J Trop Med Hyg 2007;76:405–7.
1340 Simon et al
41. Sergon K, Yahaya AA, Brown J, et al. Seroprevalence of chikungunya virus infec-
tion on Grande Comore Island, Union of the Comoros, 2005. Am J Trop Med Hyg
2007;76:1189–93.
42. Renault P, Solet JL, Sissoko D, et al. A major epidemic of chikungunya virus infec-
tion on Reunion Island, France, 2005–2006. Am J Trop Med Hyg 2007;77:727–31.
43. Sissoko D, Malvy D, Giry C, et al. Outbreak of chikungunya fever in Mayotte,
Comoros archipelago, 2005–2006. Trans R Soc Trop Med Hyg 2008;102:780–6.
44. Beesoon S, Funkhouser E, Kotea N, et al. Chikungunya fever, Mauritius, 2006.
Emerg Infect Dis 2008;14:337–8.
45. Anonymous. Outbreak news. Chikungunya and dengue, South-West Indian
Ocean. Wkly Epidemiol Rec 2006;81:106–8.
46. Ratsitorahina M, Harisoa J, Ratovonjato J, et al. Outbreak of dengue and
chikungunya fevers, Toamasina, Madagascar, 2006. Emerg Infect Dis 2008;
14:1135–7.
47. Josseran L, Paquet C, Zehgnoun A, et al. Chikungunya disease outbreak,
Reunion Island. Emerg Infect Dis 2006;12:1994–5.
48. Paquet C, Quatresous I, Solet JL, et al. Chikungunya outbreak in Reunion:
epidemiology and surveillance, 2005 to early January 2006. Euro Surveill
2006;11:E060202.3.
49. Fontenille D. Arbovirus transmission cycles in Madagascar. Arch Inst Pasteur
Madagascar 1989;55:1–317.
50. Ledrans M, Quatresous I, Renault P, et al. Outbreak of chikungunya in the
French Territories, 2006: lessons learned. Euro Surveill 2007;12: E070906.3.
51. Kalantri SP, Joshi R, Riley LW. Chikungunya epidemic: an Indian perspective.
Natl Med J India 2006;19(6):315–22.
52. Anonymous. Outbreak news. Chikungunya, India. Wkly Epidemiol Rec 2006;81:
409–10.
53. Lahariya C, Pradhan SK. Emergence of chikungunya virus in Indian subconti-
nent after 32 years: a review. J Vector Borne Dis 2006;43:151–60.
54. Chhabra M, Mittal V, Bhattacharya D, et al. Chikungunya fever: a re-emerging
viral infection. Indian J Med Microbiol 2008;26:5–12.
55. Seneviratne SL, Perera J. Fever epidemic moves into Sri Lanka. BMJ 2006;333:
1220–1.
56. Hall J. Chikungunya outbreaks. N Engl J Med 2007;356:2650–2.
57. AbuBakar S, Sam IC, Wong PF, et al. Reemergence of endemic chikungunya,
Malaysia. Emerg Infect Dis 2007;13:147–9.
58. Hochedez P, Jaureguiberry S, Debruyne M, et al. Chikungunya infection in
travelers. Emerg Infect Dis 2006;12:1565–7.
59. Pfeffer M, Loscher T. Cases of chikungunya imported into Europe. Euro Surveill
2006;11:E060316.
60. Lanciotti RS, Kosoy OL, Laven JJ, et al. Chikungunya virus in US travelers return-
ing from India, 2006. Emerg Infect Dis 2007;13:764–7.
61. Johnson DF, Druce JD, Chapman S, et al. Chikungunya virus infection in travel-
lers to Australia. Med J Aust 2008;188:41–3.
62. Lee N, Wong CK, Lam WY, et al. Chikungunya fever, Hong Kong. Emerg Infect
Dis 2006;12:1790–2.
63. Hochedez P, Hausfater P, Jaureguiberry S, et al. Cases of chikungunya fever
imported from the islands of the South West Indian Ocean to Paris, France.
Euro Surveill 2007;12:42–3.
64. Simon F, Tolou H, Jeandel P. [The unexpected chikungunya outbreak]. Rev Med
Interne 2006;27:437–41.
65. Boutin JP, Simon F, Oliver M, et al. [Marseilles, the Indian Ocean and chikungu-
nya virus]. Bull Acad Natl Med 2007;191:785–7.
66. Boelle PY, Thomas G, Vergu E, et al. Investigating transmission in a two-wave
epidemic of chikungunya fever, Reunion Island. Vector Borne Zoonotic Dis
2008;8:207–17.
67. Queyriaux B, Simon F, Grandadam M, et al. Clinical burden of chikungunya virus
infection. Lancet Infect Dis 2008;8:2–3.
68. Boutin JP. [Chikungunya fever in La Reunion Island–2006]. Med Trop (Mars)
2006;66:221–5.
69. Brouard C, Bernillon P, Quatresous I, et al. Estimated risk of chikungunya viremic
blood donation during an epidemic on Reunion Island in the Indian Ocean, 2005
to 2007. Transfusion 2008;48(7):1333–41.
70. Bessaud M, Peyrefitte CN, Pastorino BA, et al. Chikungunya virus strains,
Reunion Island outbreak. Emerg Infect Dis 2006;12:1604–6.
71. Borgherini G, Poubeau P, Staikowsky F, et al. Outbreak of chikungunya on
Reunion Island: early clinical and laboratory features in 157 adult patients.
Clin Infect Dis 2007;44:1401–7.
72. Taubitz W, Cramer JP, Kapaun A, et al. Chikungunya fever in travelers: clinical
presentation and course. Clin Infect Dis 2007;45:e1–4.
73. Talarmin F, Staikowsky F, Schoenlaub P, et al. [Skin and mucosal manifestations
of chikungunya virus infection in adults in Reunion Island]. Med Trop (Mars)
2007;67:167–73.
74. Ernould S, Walters H, Alessandri JL, et al. [Chikungunya in paediatrics: epi-
demic of 2005–2006 in Saint-Denis, Reunion Island]. Arch Pediatr 2008;15:
253–62.
75. Sankari T, Hoti SL, Govindaraj V, et al. Chikungunya and respiratory viral infec-
tions. Lancet Infect Dis 2008;8:3–4.
76. Chastel C. [Human infections in Cambodia by the chikungunya virus or a closely
related agent. II. Experimental pathological anatomy]. Bull Soc Pathol Exot Fili-
ales 1963;56:915–24.
77. Wielanek AC, Monredon JD, Amrani ME, et al. Guillain-Barre syndrome compli-
cating a chikungunya virus infection. Neurology 2007;69:2105–7.
78. Singh SS, Manimunda SP, Sugunan AP, et al. Four cases of acute flaccid paral-
ysis associated with chikungunya virus infection. Epidemiol Infect 2008;136:
1277–80.
79. Lalitha P, Rathinam S, Banushree K, et al. Ocular involvement associated with an ep-
idemic outbreak of chikungunya virus infection. Am J Ophthalmol 2007;144:552–6.
80. Mahendradas P, Ranganna SK, Shetty R, et al. Ocular manifestations associated
with chikungunya. Ophthalmology 2008;115:287–91.
81. Simon F, Paule P, Oliver M. Chikungunya virus-induced myopericarditis: toward
an increase of dilated cardiomyopathy in countries with epidemics? Am J Trop
Med Hyg 2008;78:212–3.
82. Maiti CR, Mukherjee AK, Bose B, et al. Myopericarditis following chikungunya
virus infection. J Indian Med Assoc 1978;70:256–8.
83. Mirabel M, Vignaux O, Lebon P, et al. Acute myocarditis due to chikungunya
virus assessed by contrast-enhanced MRI. Int J Cardiol 2007;121:e7–8.
84. Gerardin P, Barau G, Michault A, et al. Multidisciplinary prospective study of
mother-to-child chikungunya virus infections on the island of La Reunion. PLoS
Med 2008;5:e60.
85. Parola P, Simon F, Oliver M. Tenosynovitis and vascular disorders associated
with chikungunya virus-related rheumatism. Clin Infect Dis 2007;45:801–2.
1342 Simon et al
86. Palanivelu C, Rangarajan M, Rajapandian S, et al. Perforation of jejunal divertic-

ula in steroids and nonsteroidal anti-inflammatory drug abusers: a case series.
World J Surg 2008;32:1420–4.
87. Borgherini G, Poubeau P, Jossaume A, et al. Persistent arthralgia associated
with chikungunya virus: a study of 88 adult patients on Reunion island. Clin
Infect Dis 2008;47:469–75.
88. Schuffenecker I, Iteman I, Michault A, et al. Genome microevolution of chikungu-
nya viruses causing the Indian Ocean outbreak. PLoS Med 2006;3:e263.
89. Sourisseau M, Schilte C, Casartelli N, et al. Characterization of reemerging chi-
kungunya virus. PLoS Pathog 2007;3:e89.
90. de Lamballerie X, Leroy E, Charrel RN, et al. Chikungunya virus adapts to tiger
mosquito via evolutionary convergence: a sign of things to come? Virol J 2008;
5:33.
91. Vazeille M, Moutailler S, Coudrier D, et al. Two chikungunya isolates from the out-
break of La Reunion (Indian Ocean) exhibit different patterns of infection in the
mosquito, Aedes albopictus. PLoS ONE 2007;2:e1168.
92. Tsetsarkin KA, Vanlandingham DL, McGee CE, et al. A single mutation in chikun-
gunya virus affects vector specificity and epidemic potential. PLoS Pathog 2007;
3:e201.
93. Vazeille M, Jeannin C, Martin E, et al. Chikungunya: a risk for Mediterranean
countries? Acta Trop 2008;105:200–2.
94. Queyriaux B, Armengaud A, Jeannin C, et al. Chikungunya in Europe. Lancet
2008;371:723–4.
95. Roiz D, Eritja R, Molina R, et al. Initial distribution assessment of Aedes albopic-
tus (Diptera: Culicidae) in the Barcelona, Spain area. J Med Entomol 2008;45:
347–52.
96. Straetemans M, on behalf of the ECDC consultation group on vector-related risk
for chikungunya virus transmission in Europe. Vector-related risk mapping of the
introduction and establishment of Aedes albopictus in Europe. Euro Surveill
2008;13(7):8040.
97. Bonilauri P, Bellini R, Calzolari M, et al. Chikungunya virus in Aedes albopictus,
Italy. Emerg Infect Dis 2008;14:852–4.
98. Bordi L, Carletti F, Castilletti C, et al. Presence of the A226V mutation in autochtho-
nous and imported Italian chikungunya virus strains. Clin Infect Dis 2008;47:428–9.
99. Powers AM, Brault AC, Tesh RB, et al. Re-emergence of chikungunya and
O’nyong-nyong viruses: evidence for distinct geographical lineages and distant
evolutionary relationships. J Gen Virol 2000;81:471–9.
100. Grivard P, Le RK, Laurent P, et al. Molecular and serological diagnosis of chikun-
gunya virus infection. Pathol Biol (Paris) 2007;55:490–4.
101. Pastorino B, Bessaud M, Grandadam M, et al. Development of a TaqMan RT-
PCR assay without RNA extraction step for the detection and quantification of
African chikungunya viruses. J Virol Methods 2005;124:65–71.
102. Oliver M, Grandadam M, Marimoutou C, et al. Persisting mixed cryoglobuline-
mia in Chikungunya infection. Plos Neglected Tropical Diseases, submitted.
103. Calisher CH, el-Kafrawi AO, Al-Deen Mahmud MI, et al. Complex-specific
immunoglobulin M antibody patterns in humans infected with alphaviruses.
J Clin Microbiol 1986;23:155–9.
104. Reiskind MH, Pesko K, Westbrook CJ, et al. Susceptibility of Florida mosquitoes
to infection with chikungunya virus. Am J Trop Med Hyg 2008;78:422–5.
105. Ozden S, Huerre M, Riviere JP, et al. Human muscle satellite cells as targets of
chikungunya virus infection. PLoS ONE 2007;2:e527.
106. Ziegler SA, Lu L, da Rosa AP, et al. An animal model for studying the pathogen-
esis of chikungunya virus infection. Am J Trop Med Hyg 2008;79:133–9.
107. Lamballerie XD, Boisson V, Reynier JC, et al. On chikungunya acute infection
and chloroquine treatment. Vector Borne Zoonotic Dis 2008, in press.
108. Ozden S, Lucas-Hourani M, Ceccaldi PE, et al. Inhibition of chikungunya virus
infection in cultured human muscle cells by furin inhibitors: impairment of the
maturation of the E2 surface glycoprotein. J Biol Chem 2008;283(32):
21899–908.
109. Pastorino BA, Peyrefitte CN, Almeras L, et al. Expression and biochemical char-
acterization of nsP2 cysteine protease of chikungunya virus. Virus Res 2008;
131:293–8.
110. Edelman R, Tacket CO, Wasserman SS, et al. Phase II safety and immunogenic-
ity study of live chikungunya virus vaccine TSI-GSD-218. Am J Trop Med Hyg
2000;62:681–5.
111. Muthumani K, Lankaraman KM, Laddy DJ, et al. Immunogenicity of novel con-
sensus-based DNA vaccines against chikungunya virus. Vaccine 2008;26(40):
5128–34.
112. Kilpatrick AM, Kramer LD, Jones MJ, et al. West Nile virus epidemics in
North America are driven by shifts in mosquito feeding behavior. PLoS Biol
2006;4:e82.
Emerging a nd
Re - emerging
Tick - Tra nsmit te d
Ricket tsial a nd
Ehrlichial I nfec tions
David H.Walker, MDa,*, Christopher D. Paddock, MDb,
J. Stephen Dumler, MDc
KEYWORDS
Rocky Mountain spotted fever
Human monocytotropic ehrlichiosis Rickettsia parkeri
Ehrlichia ewingii Human granulocytotropic anaplasmosis
Typhus
Recently in the field of rickettsiology, an explosion of new isolates of pathogens have

received species designation1–5 and new disease names, all of which have been
relatively neglected by primary care and infectious disease physicians.6,7
Rickettsial and ehrlichial diseases are remarkable for their uniform susceptibility to
doxycycline but are clinically difficult to distinguish from many viral infections and each
another, and therefore misdiagnosis and failure to treat have unfortunate and some-
times tragic outcomes. Rocky Mountain spotted fever (RMSF) and human monocyto-
tropic ehrlichiosis (HME) have substantial case-fatality rates. In North America, at least
five well-established tick-borne, obligately intracellular bacterial pathogens (Rickettsia
rickettsii, R parkeri, Ehrlichia chaffeensis, E ewingii, and Anaplasma phagocytophilum)
and four other pathogens exist (R massiliae, R prowazekii, R felis, and E canis) that
have been identified in ticks elsewhere in the world, but remain to be definitively iden-
tified as tick-transmitted infections in the United States. Finally, a broad group of other
tick-associated rickettsial and ehrlichial agents of unknown pathogenicity exist (eg,
R amblyommii) that may cause confusion in interpreting serologic surveys or a single
elevated antibody titer. Globally, many of these bacteria have been named (Table 1)
a
Department of Pathology, University of Texas Medical Branch, 301 University Boulevard,
Galveston, TX 77555-0609, USA
b
Centers for Disease Control and Prevention, Building CLFT Mailstop: G32, Atlanta, GA
30329-4018, USA
c
Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, The Johns Hop-
kins University, 720 Rutland Avenue, Ross Research Building, Room 624, Baltimore, MD 21205, USA
E-mail address: dwalker@utmb.edu (D.H. Walker).
Med Clin N Am 92 (2008) 1345–1361

1346 Walker et al
Table 1
Epidemology of tick-borne rickettsial infections
Geographic
Agent Disease Tick Vector Distribution
Rickettsia Rocky Mountain Dermacentor Eastern two thirds
rickettsii spotted fever variabilis of United States
and Pacific Coast
D andersoni Rocky Mountain
states
Rhipicephalus Arizona, northern
sanguineus Mexico
Amblyomma Central and South
cajennense, America
A aureolatum
Rickettsia Boutonneuse fever Rh sanguineus Southern Europe,
conorii Africa, western
and southern Asia
Rh pumilio Southern Russia
Rickettsia African tick bite A hebraeum Southern Africa
africae fever A variegatum Central, east,
and west Africa,
West Indies
Rickettsia North Asia tick D nuttallii, D Eurasia and Africa
sibirica typhus and silvarum,
lymphangitis- Haemaphysalis
associated concinna,
rickettsiosis Hyalomma
asiaticum,
other species
Rickettsia Queensland tick Ixodes holocyclus Eastern Australia
australis typhus
Rickettsia honei Flinders Island Bothrocroton Australia and
spotted fever hydrosauri, southeastern Asia
other species
Rickettsia Japanese spotted Vector status not Japan and Korea
japonica fever established for
ticks that are
hosts of the
agent (H flava,
H longicornis,
I ovatus, D
taiwanensis)
Rickettsia slovaca Tick-borne D marginatus, Europe
lymphadenopathy D. reticularis
Rickettsia parkeri R parkeri A maculatum United States,
rickettsiosis A triste, A Brazil, Uruguay,
dubitatum Argentina
Rickettsia Unnamed disease H marginatum Africa
aeschlimannii
Rickettsia Not characterized A imitator, H North America,
prowazekii truncatum Africa
Tick-Transmitted Rickettsial and Ehrlichial Infections 1347
but the genetic differences among them are often small, and many of their clinical
manifestations may not be distinguishable diagnostically (eg, R parkeri rickettsiosis,
African tick bite fever).
CYCLIC FLUCTUATIONS IN INCIDENCE OF ROCKY MOUNTAIN SPOTTED FEVER
The United States incidence of RMSF cases reported to the Centers for Disease
Control and Prevention8 has increased in recent years to 2288 cases in 2006 and
2106 cases in 2007, the highest recorded levels in more than 80 years of national sur-
veillance for this disease. RMSF also seems to be reemerging in several countries in
Latin America (Fig. 1).9–11 The reasons for this trend are multifactorial, and patterns
of dramatic cyclic waxing and waning have occurred previously over 30- to 40-year
intervals.12 An increase in the 1970s and early 1980s was followed by a decrease
during the late 1980s and early 1990s. Proposed causes for these cyclic changes in-
clude increased human contact with ticks because of recreational activities, extension
of homes into partially developed natural lands, and other variables that were subse-
quently ruled out because of lack of change during periods of decreased incidence.13
Finally, increasing reliance on serologic assays that are not specific for R rickettsii
infection may cause falsely elevated incidence rates of RMSF. In summary, the mech-
anism of reemergence of tick-borne rickettsioses is not known.
ECOLOGY OF SPOTTED FEVER GROUP RICKETTSIAE
Rickettsia rickettsii, the most pathogenic of all known rickettsial species, resulted in
the death of 23% of infected persons in the preantibiotic era. It is known to be trans-
mitted by three tick species in the United States, namely Dermacentor variabilis (Amer-
ican dog tick), D andersoni (Rocky Mountain wood tick), and recently in an outbreak
among Native Americans in Arizona Rhipicephalus sanguineus (brown dog tick).14
In South America, R rickettsii is transmitted by two other tick species, Amblyomma
cajennense (Cayenne tick) and A aureolatum (golden dog tick). Many United States
tick species that frequently bite humans, including the highly prevalent Ixodes scapu-
laris (blacklegged tick) and Amblyomma americanum (lone star tick), do not transmit
R rickettsii.
Fig. 1. Annual incidence and number of reported cases of Rocky Mountain spotted fever
(1920–1920). (Courtesy of J.S. Dumler, MD, Baltimore, MD.)
1348 Walker et al
The lifecycle of hard ticks such as Dermacentor, Rhipicephalus, and Amblyomma

species consists of three feeding stages: larvae that hatch from the eggs, nymphs
that develop from larvae, and adults that develop from nymphs and are differentiated
into males and females. Each of these stages takes one blood meal and remains at-
tached to the host for a few to several days, depending on the stage and other factors.
The life span of a tick can be completed in 1 year or may require as many as 5 years,
depending on success in obtaining the blood meals. Paradoxically, R rickettsii is path-
ogenic for the ticks that maintain the rickettsiae through transovarial transmission in
the infected eggs that infected female ticks lay.15 Ticks may maintain R rickettsii bac-
teria transovarially for several generations before these are killed by the rickettsial in-
fection.16 Thus, to survive in nature, R rickettsii must be periodically transmitted
horizontally to vertebrate hosts, such as cotton rats, which develop rickettsemia of
sufficient magnitude to infect cofeeding ticks.17,18 The newly infected larval or
nymphal ticks are the start of new lines of transovarially maintained rickettsiae. The
pathogenicity of R rickettsii for the tick hosts likely explains the low prevalence (gen-
erally <0.1%) in ticks carrying this pathogen.15,16,19
Another factor that affects the distribution of R rickettsii in ticks is rickettsial interfer-
ence, the phenomenon through which infection of a tick’s ovary with a nonpathogenic
rickettsia such as R peacockii prevents the establishment of transovarian infection by
R rickettsii in that tick.4,19,20 In most geographic locations, most ticks contain neither
pathogenic nor nonpathogenic rickettsiae.16 Currently, data are insufficient in the
United States regarding the size of the tick population, the changes and mechanisms
of the variation of R rickettsii prevalence in these ticks, and the incidence of human–
tick encounters to develop a model that explains the reemergence and cyclic fluctu-
ations of RMSF.
DIVERSITY OF SPOTTED FEVER GROUP RICKETTSIAE AND RICKETTSIOSES
The phylogeny of Rickettsia reveals four groups: the classic typhus and spotted fever
groups, an ancestral group (eg, R bellii, R canadensis), and a transitional group
(R akari, R australis, R felis). All rickettsiae of the redefined spotted fever group are
tick-associated. In North America, the named species of the spotted fever group
include the highly virulent R rickettsii, the moderately pathogenic R parkeri, many rick-
ettsiae of undetermined pathogenicity (R amblyommii, R rhipicephali, and R monta-
nensis), and nonpathogenic bacteria (eg, R peacockii).4,5 R massiliae, which has
been isolated recently from Rh sanguineus ticks collected in Arizona, is associated
with one report of human disease in Sicily.21,22 R massiliae and Rh sanguineus were
most likely introduced into the New World from the Eastern Hemisphere on domesti-
cated dogs. Many other nonspeciated isolates of spotted fever rickettsiae are also
obtained from North American ticks, including strain 364D from D occidentalis and
strain Tillamook from Ixodes pacificus, which are mildly pathogenic in experimentally
infected animals and require further genetic characterization to identify their unique-
ness.23 The geographic distribution of R rickettsii, R parkeri, and R amblyommii extend
through South America.24–26
No convincing evidence shows that R rickettsii infection can be asymptomatic.
Thrombocytopenia, petechial rash, noncardiogenic pulmonary edema, hypotension,
acute renal failure, meningoencephalitis, and death occur in many patients who
have RMSF who are not treated with doxycycline during the first 5 days of ill-
ness.27–29 In contrast, R parkeri seems to be a less virulent organism. Although the
agent was discovered in 1937, the first human infection was not documented until
2004, and the incidence of the disease and its spectrum of severity remain to be
determined.30,31 However, no infections ascribed to R parkeri have been fatal or life-

threatening. Other differences between A maculatum–transmitted R parkeri infection
and RMSF include the presence of an eschar at the site of Amblyomma tick bite,
tender regional lymphadenopathy, and a vesicular or pustular rash. In Uruguay,
many patients most likely infected with R parkeri do not have a rash.32 The eschar,
an approximately 1-cm focus of epidermal and dermal necrosis associated with
extensive vasculitis surrounded by an erythematous halo, is an important diagnostic
feature that should be sought during a complete skin examination, including the groin,
waist, axillae, and scalp (Fig. 2).
R amblyommii is found in a high portion of A americanum (lone star ticks), one of the
most prevalent and aggressive human-biting ticks in the southeastern and south
central United States33–35 and is maintained transovarially in its arthropod host. The
presence of R amblyommii and prevalence of A americanum tick bites are associated
with a substantial occurrence of persons who have antibodies to spotted fever group
rickettsiae.36–39 The organisms of the spotted fever group are closely related geneti-
cally and share antigens of the immunodominant rickettsial cell wall lipopolysaccha-
rides and outer membrane proteins A and B. R rickettsii antigens have detected the
presence of antibodies in many healthy persons who have no history of RMSF or
clinically compatible illness.40,41 These antibodies have sometimes been interpreted
erroneously as indicative of asymptomatic RMSF. In prospective studies of military
personnel who were heavily exposed to R amblyommii–infected A americanum ticks,
numerous seroconversions to antigens of spotted fever group rickettsiae oc-
curred.36,38,42 Although most persons who seroconverted did not report any illness,
some symptoms, including headache, myalgia, rash, joint pain, fever, chills, dyspnea,
and confusion, were reported more frequently (odds ratio, >2.0) in soldiers who had
antibodies to spotted fever group rickettsiae.38 Among 32 soldiers who had antibodies
to spotted fever group rickettsiae detected with enzyme immunoassay, 44% had an
illness (odds ratio, 3.5; P < .0001). Evidence shows that some soldiers developed
antibodies with specificity for an isolate of spotted fever group rickettsia from A amer-
icanum.43 One could tentatively conclude that R amblyommii is an organism of mild-
to-minimal virulence. R amblyommii has also been proposed to be a potential agent of
southern tick-associated rash illness, (STARI), which manifests as erythema migrans
and is confused clinically with Lyme disease.3 STARI had previously been associated
Fig. 2. Eschar associated with Rickettsia parkeri infection. (Courtesy of C.A. Ohl, MD,
Winston-Salem, NC.)
1350 Walker et al
with Borrelia lonestari, which is also found in A americanum ticks. However, subse-
quent studies have not supported a borrelia origin.44,45
A TICK-BORNE TYPHUS GROUP RICKETTSIOSIS
In 1955 Reiss-Gutfreund46 reported the discovery of R prowazekii in Hyalomma ticks in

Ethiopia. The identity of the organism was confirmed and is indistinguishable from
R prowazekii Addis Ababa strain. However, other investigators were unable to confirm
the presence of R prowazekii in ticks in Ethiopia.47
The detection of a high prevalence of antibodies to typhus group rickettsiae among
patients who had dengue-like illnesses in the state of Nuevo Leon in northern Mexico
led to field studies in which R prowazekii was detected in A imitator ticks and an isolate
was obtained48 (A. Medina-Sancheze, unpublished data, 2007).
This discovery may explain the occurrence of infection with R prowazekii in a 50-
year-old man from New Mexico who had vacationed in south Texas, where the range
of A imitator ticks extends.49 He developed headache, fever, photophobia, a stiff neck,
abdominal pain, and cerebrospinal fluid pleocytosis. DNA of R prowazekii was ampli-
fied from cerebrospinal fluid samples collected on two separate days, IgG indirect
fluorescent antibodies to typhus group rickettsiae rose to a titer of 512, and treatment
with doxycycline led to defervescence. The last recorded outbreak of louse-borne ty-
phus in the United States occurred on the San Juan Navajo Indian Reservation in the
Four Corners region of the southwestern United States during 1920 to 1921,50 making
the possibilities of louse-borne typhus, or Brill-Zinsser disease (recrudescent typhus),
seemingly remote because of the absence of human body lice on the patient or his
contacts and lack of history of previous epidemic typhus.49 The few contemporary
United States cases or R prowazekii infection have been consistently associated
with flying squirrels;51 however, the absence of flying squirrels in south Texas sug-
gests another source of infection. The most likely possibility is Amblyomma tick–trans-
mitted R prowazekii infection. The recognition of this epidemiologic situation may
provide insights to the true origin of typhus fever and a previously unrecognized res-
ervoir of the infection.
HUMAN EHRLICHIOSES AND ANAPLASMOSIS
Until 1987, ehrlichial infections were in the domain of veterinary medicine. Microcolo-
nies of small coccobacilli in Romanovsky-stained peripheral white blood cells of a tick-
exposed patient who had acute febrile illness were identified as Ehrlichia with electron
microscopy and the presence of antibodies reactive with E canis in the patient’s se-
rum.52 In 1991, the etiologic agent E chaffeensis was isolated and identified as a novel
pathogen.1,53 In 1994 and 1999, molecular methods determined that A phagocytophi-
lum and E ewingii, respectively, are also human pathogens.6,54,55 Investigators in Ven-
ezuela have identified E canis as a cause of human infections that in some cases
resemble human monocytotropic ehrlichiosis.56
E chaffeensis has been identified in several vertebrate animals, such as white-tailed
deer, dogs, coyotes, and goats, with A americanum the most important vector
(Table 2).57–60 These vertebrate hosts remain persistently infected and are bacteremic
for prolonged periods.60 Experimental studies have shown that A americanum ticks
can acquire E chaffeensis while feeding as larvae or nymphs on white-tailed deer.61
They maintain the ehrlichial infection transstadially (ie, during molting to the nymphal
or adult stage). These infected ticks can transmit E chaffeensis to other white-tailed
deer during the next blood meal. Ehrlichiae do not pass from one generation of ticks
to the next through transovarian transmission.62 E chaffeensis can overwinter in
Table 2
Epidemology of tick-borne ehrlichioses and anaplasmosis
Tick Geographic Vertebrate

Agent Disease Vector Distribution Hosts
Ehrlichia Human Amblyomma Southeastern and White-tailed
chaffeensis monocytotropic americanum, south-central deer, dogs,
ehrlichiosis Dermacentor United States, coyotes,
variabilis, California goats
Ixodes
pacificus
Ehrlichia Ehrlichiosis A americanum Southeastern and White-tailed
ewingii ewingii south-central deer, dogs
United States,
California
Ehrlichia Unnamed Rhipicephalus Worldwide Dogs, jackal,
canis disease sanguineus coyote, wild
African dog,
red and
gray fox
Anaplasma Human I scapularis Northern White-footed
phagocyto- granulocyto- United deer mouse,
philum tropic States white-tailed
anaplasmosis deer, dogs,
horses,
squirrels,
chipmunks,
red-backed
vole
I pacificus Pacific Squirrels,
coastal wood rats,
United elk, horses,
States llama,
black-tailed
deer, deer
mice
I ricinus Europe red deer, roe
deer, fallow
deer, horses,
dogs, cattle,
cats, sheep,
bank voles,
wood mice,
yellow-necked
mouse,
common
shrew
infected replete nymphs, unfed adult ticks, and deer. A high proportion (5%–15%) of
adult lone star ticks are infected with E chaffeensis.
The ecologic cycle of E ewingii is very similar, involving naturally infected white-tailed
deer, dogs, and A americanum ticks.63 E ewingii can be acquired by A americanum ticks
feeding on infected dogs, is maintained when the ticks molt to the next life stage, and is
transmitted to other dogs during the tick’s subsequent blood meal.64 E ewingii can also
be abundant in lone star ticks collected in nature, although it is generally found less
1352 Walker et al
frequently than E chaffeensis.63 A third Ehrlichia sp, designated provisionally as the Pan-
ola Mountain Ehrlichia, has been detected in A americanum ticks and white-tailed deer
from several southeastern states.65 This agent causes febrile disease in experimentally
infected animals, although its role as a human pathogen remains undetermined.
Classic canine monocytic ehrlichiosis was first described in Tunis in 1935. It is trans-
mitted by the brown dog tick, Rh sanguineus, which has been globally distributed by
domesticated dogs accompanying human migrations. E canis causes persistent
infection of dogs, from which brown dog ticks acquire the infection and maintain
the ehrlichiae transstadially but not transovarially.66 Rh sanguineus is not monophy-
letic. Strains of Rh sanguineus in the United States feed predominantly on dogs and
seldom bite humans. In contrast, European Rh sanguineus frequently feeds on rodents
and is the vector of R conorii (Mediterranean spotted fever or boutonneuse fever).
Human infections resembling HME caused by E canis have been documented in South
America, presumably transmitted by brown dog ticks.56 Because E canis is not main-
tained transovarially in ticks, the reservoir of ehrlichiae in nature is a cycle involving
persistently infected vertebrate hosts and infected tick hosts.
Veterinary diseases caused by what is now designated as A phagocytophilum were
identified in sheep in the United Kingdom in 1932, cattle in Scandinavia by the 1960s,
and horses in the United States in the 1970s. During the early 1990s, Johan Bakken
and colleagues,6 a physician in Duluth, Minnesota, recognized the similarity of cytoplas-
mic inclusions in peripheral blood neutrophils of his patients to those in monocytes of pa-
tients who had HME. Subsequently, Chen and colleagues55 used serology with antigens
of peripheral blood leukocytes of infected horses, electron microscopy, universal 16S
rRNA gene amplification and DNA sequencing, and immunohistochemistry to determine
that the etiologic agent was the organism currently classified as A phagocytophilum. In-
fections are transmitted by I ricinus complex ticks and involve many vertebrate hosts in
North America, Europe, and Asia (see Table 2). As for Ehrlichia spp A phagocytophilum is
not vertically transmitted to the tick progeny, and depends on persistent bacteremia
(deer, small rodents) and infection in high proportions of permissive mammalian and
tick reservoir populations. Ecologic changes that affect these factors directly impact nat-
ural transmission, and the proximity to and likelihood of human exposure permit periodic
infections in humans. Nonpermissive mammalian hosts, such as humans, horses, and
dogs, develop significant inflammatory disease that interrupts persistent bacteremia,
probably precluding a significant contribution to natural maintenance of anaplasmae.
APPROACH TO PATIENTS WHO HAVE UNDIFFERENTIATED FEBRILE ILLNESS

AND POTENTIAL TICK EXPOSURE
RMSF, R parkeri rickettsiosis, typhus fever, HME, E ewingii ehrlichiosis, human infec-
tions with E canis, and human granulocytic anaplasmosis (HGA) manifest similar
symptoms at onset and during the first few days of illness. These symptoms include
fever, headache, myalgia, and malaise.6,7,23,31,67–72 Nausea and vomiting also occur
with some infections. Thus, the diagnosis is difficult to distinguish from the syndrome
associated with many viral infections. Laboratory evaluation often shows similar
abnormalities, including thrombocytopenia, elevated hepatic transaminases, and
hyponatremia. Leukopenia (< 4000 white blood cells/mL) is observed more commonly
in HME and HGA but can occur in individual patients who have any of these infec-
tions.7,71,73–75
The severity of each illness reflects the relative virulence of the causative agent and
specific host factors that confer a greater risk for disease severity.12,76–78 The approx-
imate case fatality ratios range from 4% to 5% for RMSF and 3% for HME to 0.7% for
HGA. No deaths have been reported for human infections with R parkeri, E ewingii, and
E canis. E ewingii has been diagnosed mostly as an opportunistic infection in persons
who are immunocompromised.54,77
Presence of rash favors RMSF (90%), HME (31%), and R parkeri rickettsiosis (too
few cases have been described to assess frequency). Patients who have HGA seldom
manifest a rash unless coinfected with B burgdorferi associated with erythema
migrans.67,74 Detection of an eschar would strongly favor diagnosis of R parkeri
infection. Meningoencephalitis with coma and seizures is a frequent manifestation
of late-stage RMSF and typhus fever in untreated patients. Meningoencephalitis is
well documented in some patients who have HME but is rare in HGA.69 Respiratory
distress syndrome occurs more often in RMSF and HME than in HGA. Patients who
are immunocompromised and have HME often develop fatal overwhelming ehrlichial
infection.77 Severity of HGA and RMSF does not seem to be affected significantly by
a state of immunocompromise.
The most important diagnostic key is obtaining a history of an attached tick or tick
exposure by asking the patient the question, ‘‘Have you seen any ticks lately?’’ fol-
lowed by inquiry about recreational and occupational activities. High grass along
roadsides, trails, forest edges, stream banks, and weedy yards harbor questing ticks
that attach to passing walkers, hikers, fishermen, persons doing gardening and yard
work, and outdoor workers. Domestic pets such as dogs are frequent vehicles that
bring ticks into the house. Depending on the particular disease, as many as three dif-
ferent life stages of the same tick species are capable of transmitting the causative
agent to a human host when the tick obtains a blood meal, and larval and nymphal
stage ticks can be extremely small, sometimes smaller than the head of a pin. In
this context, as many as 40% of persons who have documented tick-transmitted
diseases are unaware of a tick bite, which is typically painless. Thus, probing the
activities of patients who have acute fever is worthwhile.
ROLE OF THE LABORATORY IN DIAGNOSIS OF RICKETTSIOSES, EHRLICHIOSES,

AND HUMAN GRANULOCYTIC ANAPLASMOSIS
The clinical laboratory offers little assistance in diagnosing rickettsial, ehrlichial, and
anaplasmal infections during the early stage of illness when therapeutic decisions
are required.7,68,71,78–80 The presence of thrombocytopenia, leukopenia, or elevated
serum concentrations of aspartate aminotransferase and alanine aminotransferase in-
crease the odds of one of these diagnoses. However, normal values do not exclude
the diagnoses, and abnormal values are observed in other medical conditions. Further
laboratory evaluation of the illness, such as clinical chemistries, blood gases, and
cerebrospinal fluid examination, helps define the pathophysiology and determine
supportive care, but will not define the etiologic agent.
Laboratory methods able to determine the diagnoses of these diseases are seldom
available in the clinic or hospital. During the acute stage of RMSF and R parkeri rick-
ettsiosis, immunohistochemical examination of biopsies of cutaneous lesions is the
most sensitive (70% sensitivity) approach.31,80 Appropriate tissue samples for the im-
munohistochemical diagnosis of HME are not readily accessible.81 This method is
available from only a few reference and research laboratories, requires a qualified
observer, and cannot be applied until the appearance of an exanthem or eschar. Con-
temporary improvements in nucleic acid amplification technology offer the opportunity
to develop techniques, such as real-time polymerase chain reaction (PCR), and apply
them to RMSF, HME, and HGA. Early reports of diagnostic PCR for RMSF were
disappointingly insensitive.82,83
1354 Walker et al
Few patients who have RMSF have detectable antibodies to R rickettsii in their serum
on day five of illness, after which the case fatality rate increases substantially. Most
rickettsial serologic tests are performed at reference laboratories, which use indirect
immunofluorescence and enzyme immunoassays. These tests do not distinguish
which particular organism among the spotted fever group or typhus group rickettsiae
stimulated the antibody response. Many patients’ antibodies reactive with R rickettsii
detected early in the illness may be actually stimulated at an earlier time by other spot-
ted fever group rickettsiae, such as A americanum–inoculated R amblyommii. A four-
fold rise in titer in a patient who has a clinically compatible illness is much stronger
evidence for RMSF. However, convalescent sera are seldom submitted, and patients
infected with R parkeri and clinical signs of rickettsiosis would develop a fourfold rise in
antibody titer cross-reactive with R rickettsii. Methods such as cross-absorption using
selected rickettsial antigens are impractical except in research laboratories. Even then
one cannot be sure that the antigens selected to be examined represent all of the
potential etiologic agents, because patients infected with R parkeri, and likely other
as-yet-undiscovered Rickettsia species, will also generate antibodies that react with
R rickettsii antigens in standard serologic assays.
Although rickettsiae can be cultivated in antibiotic-free cell culture, particularly with
centrifugation-enhanced shell vial techniques, this method does not yield rapid results
and requires Biosafety Level 3 laboratory facilities and procedures, which are available
mainly in research laboratories.
HME and HGA were discovered through detecting circulating monocytes and
neutrophils, respectively, with cytoplasmic vacuoles containing microcolonies of
bacteria.6,52 Although this diagnostic approach is available at clinical presentation, it
is insensitive (<10%) for diagnosing HME except in severely immunocompromised
patients who have overwhelming infection.69 In contrast, detecting inclusions in neu-
trophils from patients who have HGA is more diagnostically sensitive (25%–75%)
(Fig. 3). Because infected leukocytes are in the blood of patients who have HME
and HGA, diagnosis through PCR amplification of the organisms’ DNA is a relatively
sensitive (60%–90%) method.69 This diagnostic test is available only in reference
and research laboratories. Currently, diagnosis of HME and HGA through isolating
the etiologic agents is undertaken only in research laboratories.69,84
Fig. 3. Neutrophil in the peripheral blood of a patient who has HGA contains three morulae
(cytoplasmic vacuoles containing microcolonies of A phagocytophilum; Wright-Giemsa
stain, original magnification 780). (Courtesy of J.S. Dumler, MD, Baltimore, MD.)
The serologic diagnosis of HME and HGA is useful in the portion of patients
(22%–55%) who have developed antibodies when the sera are collected.69 Because
the clinical manifestations of HME and HGA generally progress slower than in RMSF,
patients tend to seek medical attention a few days later in the course, when they are
more likely to have already produced antibodies to ehrlichiae or anaplasma, than
those who have RMSF would for rickettsiae. Serologic diagnosis is sometimes con-
founded by cross-reactivity between E chaffeensis and A phagocytophilum and the
high prevalence of antibodies against A. hagocytophilum in some geographic areas,
underscoring the preference for testing acute and convalescent sera for a seroconver-
sion or fourfold increase in antibody titer. Patients infected with E ewingii are diag-
nosed specifically only with PCR because E ewingii antigens are not available and
E ewingii and E chaffeensis are serologically cross-reactive.54 One could easily hy-
pothesize that the presence of antibodies against E chaffeensis in healthy persons
in the range of A americanum ticks is caused by mild or asymptomatic infection
with mildly pathogenic E ewingii, or possibly other uncharacterized Ehrlichia spe-
cies.84 Ehrlichial inclusions, if present, are observed in neutrophils and eosinophils
of patients who have E ewingii ehrlichiosis, but could be confused with A phagocyto-
philum without other supportive laboratory data.
TREATMENT
Fortunately, the preferred drug for these tick-borne rickettsioses, ehrlichioses, and an-
aplasmoses is the same—doxycycline—even in children younger than 8 years.85–87
Chloramphenicol has long been used as a less-effective secondary drug for patients
who have infections caused by Rickettsia. Some data suggest that chloramphenicol
should no longer be used for RMSF, because patients treated with that drug alone
have a higher risk for death than those treated with a tetracycline antibiotic, and the
same risk for death as patients treated with neither.88 However, chloramphenicol
may still have a role when tetracyclines are contraindicated, such as in patients who
have hypersensitivity or during pregnancy. Ehrlichia and Anaplasma are resistant to
chloramphenicol. Rifampin inhibits the growth of ehrlichiae and anaplasma in vitro
and has been used to treat HGA in children and during pregnancy.89,90 Fluoroquino-
lones have not been proven effective in RMSF, HME, or HGA. Empiric oral treatment
with doxycycline (100 mg twice daily) should be initiated in patients with clinical or
epidemiologic evidence of rickettsial, ehrlichial, or anaplasmal infection, and contin-
ued until patients feel substantially improved and have been afebrile for at least
48 to 72 hours. Because some of these diseases are life-threatening and have little
time in which life-saving therapy can be administered effectively, treatment decisions
should never be delayed while awaiting laboratory confirmation of the diagnosis.91
REASONS FOR THE EMERGENCE OF TICK-BORNE HUMAN RICKETTSIOSES,

EHRLICHIOSES, AND ANAPLASMOSIS
Application of technologic advances led to the identification of novel agents (eg,

E chaffeensis) and the association of previously known organisms with human infec-
tions (eg, E ewingii, A phagocytophilum, R parkeri).1,2,31,54,55 Development of diagnos-
tic assays enabled the epidemiology of the infections and ecology of the agents to be
studied. Thus, to some extent, emergence was actually recognition of organisms that
had been present for eons. Increasing populations of severely and moderately immu-
nocompromised persons with conditions ranging from HIV-AIDS to advanced age led
to overwhelming infections in index patients with the visualization of organisms in the
blood (eg, E. chaffeensis and A. phagocytophilum).6,52
1356 Walker et al
However, ecologic changes were clearly responsible for dramatic increases in the
white-tailed deer population. The remarkable reforestation of the Eastern United States,
owing partly to growth of trees in expanding suburban areas, has been an important fac-
tor in providing habitat for the large deer population and A americanum and I scapularis
ticks.34 The population of white-tailed deer is a critical factor in determining the popu-
lation densities of A americanum and I scapularis ticks. Wild turkeys are also a determin-
ing factor in the size of the lone star tick population.92 White-tailed deer and wild turkeys
have rebounded from near extinction to populations beyond historic records. Coyote
populations and geographic range have also expanded remarkably. White-tailed
deer, coyotes, and lone star ticks are the major reservoir of E chaffeensis.59 The large
population of lone star ticks infected with E chaffeensis resulted in increased transmis-
sion to humans and the recognition of HME.92–95 White-tailed deer and lone star ticks
provide a significant reservoir of E ewingii, with similar opportunities for transmission
of E ewingii to humans. The emergence of HGA parallels the expansion of white-tailed
deer and small mammal populations that support adult and immature stages of Ixodes
spp ticks, as observed with B burgdorferi, which shares the same tick vector.96
The tremendous increase in reported cases of RMSF is confounded by the fact that
only 15% of these cases are laboratory confirmed using Centers for Disease Control
and Prevention criteria, and only approximately 5% are confirmed with diagnostic as-
says that specifically identify the causative agent, R rickettsii.97 Even the serologic and
immunohistochemical criteria would not distinguish infections with R rickettsii, R par-
keri, and R amblyommii.23 Many patients who have a single indirect immunofluorescent
antibody titer of 64 or higher may have antibodies stimulated by the ubiquitous R am-
blyommii. Failure to consider and investigate the potential diagnosis of ehrlichiosis by
physicians suggests that some, perhaps many, of these persons actually may have had
HME or HGA. The low case fatality rate in these patients implies that a large portion did
not have RMSF.97 Although something dramatic is occurring, inadequate longitudinal
diagnostic and epidemiologic investigation prevents knowledge of what the diseases
actually are. The high incidence of HME and HGA detected by active prospective stud-
ies strongly suggests that these diseases are underreported, perhaps by as much as
two orders of magnitude.7,70,98–100 For example, before the discovery of HME, only
12% of patients who had suspected RMSF could be confirmed with serologic tests. Af-
ter HME serology became available, an additional 12% of these patients received that
diagnosis, still leaving 76% of patients who had suspected rickettsial disease undiag-
nosed.101 The hope is that many patients who never had a confirmed diagnosis or ac-
curate public health reporting are being treated empirically early in the course with
doxycycline by primary care and emergency physicians. However, the recognition
that 50% of all deaths caused by RMSF in the United States are misdiagnosed shows
that a large gap between theory and practice still exists.28 Accurate and rapid labora-
tory confirmation of the diagnoses would assist public health strategic planning and
sharpen medical knowledge of these diseases. Until then, the best defense against
each of these tick-transmitted infections is increasing awareness among general prac-
titioners, pediatricians, emergency room physicians, and other primary care doctors of
the widespread occurrence, potentially severe manifestations, and rapid response to
doxycycline that characterize these diseases in the United States.
REFERENCES
1. Anderson BE, Dawson JE, Jones DC, et al. Ehrlichia chaffeensis, a new species
associated with human ehrlichiosis. J Clin Microbiol 1991;29:2838–42.
2. Anderson BE, Greene CE, Jones DC, et al. Ehrlichia ewingii sp. nov., the etiologic
agent of canine granulocytic ehrlichiosis. Int J Syst Bacteriol 1992;42(2):299–302.
3. Billeter SA, Blanton HL, Little SE, et al. Detection of ‘‘Rickettsia amblyommii’’
in association with a tick bite rash. Vector Borne Zoonotic Dis 2007;7:607–10.
4. Niebylski ML, Schrumpf ME, Burgdorfer W, et al. Rickettsia peacockii sp. nov.,
a new species infecting wood ticks, Dermacentor andersoni, in western Montana.
Int J Syst Bacteriol 1997;47:446–52.
5. Yu XJ, Walker DH. Family I. Rickettsiaceae. In: Brenner DF, Kreig NR, Staley JT,
editors, Bergey’s manual of systematic bacteriology. 2nd edition. vol. 2. New
York: Springer Science1Business Media, Inc.; 2005. p. 96–116.
6. Bakken JS, Dumler JS, Chen SM, et al. Human granulocytic ehrlichiosis in
the upper midwest United States. A new species emerging? JAMA 1994;272:
212–8.
7. Olano JP, Masters E, Hogrefe W, et al. Human monocytotropic ehrlichiosis, Mis-
souri. Emerg Infect Dis 2003;9:1579–86.
8. CDC. Morbidity and Mortality Weekly Report MMWR 2008;56(51&52):1353.
9. Hidalgo M, Orejuela L, Fuya P, et al. Rocky Mountain spotted fever, Colombia.
10. Zavala-Castro JE, Zavala-Velazquez JE, Walker DH, et al. Fatal human infection
with Rickettsia rickettsii, Yucatan, Mexico. Emerg Infect Dis 2006;12:672–4.
11. Paddock CD, Fernandez S, Echenique GA, et al. Rocky Mountain spotted fever
in Argentina. Am J Trop Med Hyg 2008;78:687–92.
12. Hattwick MAW, O’Brien RJ, Hanson BF. Rocky Mountain spotted fever: epidemi-
ology of an increasing problem. Ann Intern Med 1976;84:732–9.
13. Kaplan JE, Newhouse VF. Occurrence of Rocky Mountain spotted fever in rela-
tion to climatic, geophysical, and ecologic variables. Am J Trop Med Hyg 1984;
33:1281–2.
14. Demma LJ, Traeger MS, Nicholson WL, et al. Rocky Mountain spotted fever from
an unexpected tick vector in Arizona. N Engl J Med 2005;353:587–93.
15. Niebylski ML, Peacock MG, Schwan TG. Lethal effect of Rickettsia rickettsii on
its tick vector (Dermacentor andersoni). Appl Environ Microbiol 1999;65:773–8.
16. Burgdorfer W. Ecological and epidemiological considerations of Rocky Moun-
tain spotted fever and scrub typhus. In: Walker DH, editor. Biology of rickettsial
diseases. Boca Raton (FL): CRC Press; 1988. p. 33–50.
17. Gage KL, Burgdorfer W, Hopla CE. Hispid cotton rats (Sigmodon hispidus) as
a source for infecting immature Dermacentor variabilis (Acari: Ixodidae) with
Rickettsia rickettsii. J Med Entomol 1990;27:615–9.
18. McDade JE, Newhouse VF. Natural history of Rickettsia rickettsii. Annu Rev Mi-
crobiol 1986;40:287–309.
19. Walker DH, Fishbein DB. Epidemiology of rickettsial diseases. Eur J Epidemiol
1991;7:237–45.
20. Burgdorfer W, Hayes SF, Mavros AJ. Nonpathogenic rickettsiae in Dermacentor
andersoni: a limiting factor for the distribution of Rickettsia rickettsii. In: Burgdor-
der W, Anacker RL, editors. Rickettsiae and rickettsial diseases. New York:
Academic Press; 1981. p. 585–94.
21. Eremeeva ME, Bosserman EA, Demma LJ, et al. Isolation and identification of
Rickettsia massiliae from Rhipicephalus sanguineus ticks collected in Arizona.
Appl Environ Microbiol 2006;72:5569–77.
22. Vitale G, Mansueto S, Rolain J-M, et al. Rickettsia massiliae human isolation.
23. Paddock CD. Rickettsia parkeri as a paradigm for multiple causes of tick-
borne rickettsioses in the Western Hemisphere. Ann N Y Acad Sci 2006;
1063:315–26.
1358 Walker et al
24. Labruna MB, Pinter A, Szabo MPJ. Rickettsia parkeri infectando um carrapato
Amblyomma triste em pauliceia, estrado de São Paulo. Rev Bras Parasitol Vet
2004;13(1):359.
25. Pinter A, Labruna MB. Isolation of Rickettsia rickettsii and Rickettsia bellii in cell
culture from the tick Amblyomma aureolatum in Brazil. Ann NY Acad Sci 2006;
1078:523–9.
26. Labruna MB, Whitworth T, Bouyer DH, et al. Rickettsia bellii and Rickettsia
amblyommii in Amblyomma ticks from the state of Rondonia, Western Amazon,
Brazil. J Med Entomol 2004;41:1073–81.
27. Kaplowitz LG, Fischer JJ, Sparling PF. Rocky Mountain spotted fever: a clinical
dilemma. Curr Clin Top Infect Dis 1981;2:89–108.
28. Paddock CD, Greer PW, Ferebee TL, et al. Hidden mortality attributable to Rocky
Mountain spotted fever: immunohistochemical detection of fatal, serologically
unconfirmed disease. J Infect Dis 1999;179:1469–76.
29. Kirkland KB, Wilkinson WE, Sexton DJ. Therapeutic delay and mortality in cases
of Rocky Mountain spotted fever. Clin Infect Dis 1995;20:1118–21.
30. Parker RR, Kohls GM, Cox GW, et al. Observations on an infectious agent from
Amblyomma maculatum. Public Health Rep 1939;54:1482–4.
31. Paddock CD, Sumner JW, Comer JA, et al. Rickettsia parkeri: a newly recog-
nized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis
2004;38:805–11.
32. Conti Diaz IA. Rickettsiosis por Rickettsii conorii (fiebre botonosa de Mediterra-
neo o fiebre de Marsella). Estado actual en Uruguay. Revista Medica del Uru-
guay 2001;17:119–24.
33. Childs JE, Paddock CD. The ascendancy of Amblyomma americanum as a
vector of pathogens affecting humans in the United States. Annu Rev Entomol
2003;48:307–37.
34. Paddock CD, Yabsley MJ. Ecologic havoc, the rise of white-tailed deer, and the
emergence of Amblyomma americanum-associated zoonoses in the United
States. Curr Top Microbiol Immunol 2007;315:289–324.
35. Stromdahl EY, Vince MA, Billingsley PM, et al. Rickettsia amblyommii infecting
Amblyomma americanum larvae. Vector Borne Zoonotic Dis 2007;8:15–24.
36. Kardatzke JT, Neidhardt K, Dzuban DP, et al. Cluster of tick-borne infections at
Fort Chaffee, Arkansas: rickettsiae and Borrelia burgdorferi in ixodid ticks.
J Med Entomol 1992;29:669–72.
37. Marshall GS, Stout GG, Jacobs RF, et al. Antibodies reactive to Rickettsia rick-
ettsii among children living in the southeast and south central regions of the
United States. Arch Pediatr Adolesc Med 2003;157:443–8.
38. McCall CL, Curns AT, Rotz LD, et al. Fort Chaffee revisited: the epidemiology of
tick-borne rickettsial and ehrlichial diseases at a natural focus. Vector Borne
Zoonotic Dis 2001;1:119–27.
39. Yevich SJ, Sanchez JL, DeFraites RF, et al. Seroepidemiology of infections due
to spotted fever group rickettsiae and Ehrlichia species in military personnel ex-
posed to areas of the United States where such infections are endemic. J Infect
Dis 1995;171:1266–73.
40. Taylor JP, Tanner WB, Rawlings JA, et al. Serological evidence of subclinical
Rocky Mountain spotted fever infections in Texas. J Infect Dis 1985;151:
367–9.
41. Wilfert CM, MacCormack JN, Kleeman K, et al. Epidemiology of Rocky Mountain
spotted fever as determined by active surveillance. J Infect Dis 1984;150:
469–79.
42. Sanchez JL, Candler WH, Fishbein DB, et al. A cluster of tick-borne infections:
association with military training and asymptomatic infections due to Rickettsia
rickettsii. Trans R Soc Trop Med Hyg 1992;86:321–5.
43. Dasch GA, Kelly DJ, Richards Al, et al. Western blotting analysis of sera from military
personnel exhibiting serological reactivity to spotted fever group rickettsiae [ab-
stract]. Journal of the American Society of Tropical Medicine & Hygiene 1993;49:220.
44. Barbour AG, Maupin GO, Teltow GJ, et al. Identification of an uncultivable Bor-
relia species in the hard tick Amblyomma americanum: possible agent of a Lyme
disease-like illness. J Infect Dis 1996;173:403–9.
45. James AM, Liveris D, Wormser GP, et al. Borrelia lonestari infection after a bite
by an Amblyomma americanum tick. J Infect Dis 2001;183:1810–4.
46. Reiss-Gutfreund RJ. The isolation of Rickettsia prowazeki and mooseri from un-
usual sources. Am J Trop Med Hyg 1966;15:943–9.
47. Burgdorfer W, Ormsbee RA, Schmidt ML, et al. A search for the epidemic typhus
agent in Ethiopian ticks. Bull World Health Organ 1973;48:563–9.
48. Medina-Sanchez A, Bouyer DH, Alcantara-Rodriguez A, et al. Detection of a ty-
phus group Rickettsia in Amblyomma ticks in the State of Nuevo Leon, Mexico.
Ann N Y Acad Sci 2005;1063:1–6.
49. Massung RF, Davis LE, Slater K, et al. Epidemic typhus meningitis in the south-
western United States. Clin Infect Dis 2001;32:979–82.
50. Armstrong C. Typhus fever on the San Juan Indian reservation. 1920 and 1921.
Public Health Rep 1922;37:685–93.
51. McDade JE, Shepard CC, Redus MA, et al. Evidence of Rickettsia prowazekii
infections in the United States. Am J Trop Med Hyg 1980;29:277–84.
52. Maeda K, Markowitz N, Hawley RC, et al. Human infection with Ehrlichia canis,
a leukocytic rickettsia. N Engl J Med 1987;316:853–6.
53. Dawson JE, Anderson BE, Fishbein DB, et al. Isolation and characterization of
an Ehrlichia sp. from a patient diagnosed with human ehrlichiosis. J Clin Micro-
biol 1991;29:2741–5.
54. Buller RS, Arens M, Hmiel SP, et al. Ehrlichia ewingii, a newly recognized agent
of human ehrlichiosis. N Engl J Med 1999;341:148–55.
55. Chen S-M, Dumler JS, Bakken JS, et al. Identification of a granulocytotropic
Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol
1994;32:589–95.
56. Perez M, Bodor M, Zhang C, et al. Human infection with Ehrlichia canis accom-
panied by clinical signs in Venezuela. Ann NY Acad Sci 2006;1078:110–7.
57. Dugan VG, Little SE, Stallknecht DE, et al. Natural infection of domestic goats
with Ehrlichia chaffeensis. J Clin Microbiol 2000;38:448–9.
58. Kocan A, Levesque GC, Whitworth LC, et al. Naturally occurring Ehrlichia chaf-
feensis infection in coyotes from Oklahoma. Emerg Infect Dis 2000;6:477–80.
59. Paddock CD, Childs JE. Ehrlichia chaffeensis: a prototypical emerging patho-
gen. Clin Microbiol Rev 2003;16:37–64.
60. Davidson WR, Lockhart JM, Stallknecht DE, et al. Persistent Ehrlichia chaffeen-
sis infection in white-tailed deer. J Wildl Dis 2001;37(3):538–46.
61. Ewing SA, Dawson JE, Kocan AA, et al. Experimental transmission of Ehrlichia
chaffeensis (Rickettsiales: Ehrlichieae) among white-tailed deer by Amblyomma
americanum (Acari: Ixodidae). J Med Entomol 1995;32:368–74.
62. Long SW, Zhang X, Zhang J, et al. Evaluation of transovarial transmission
and transmissibility of Ehrlichia chaffeensis (Rickettsiales: Anaplasmataceae)
in Amblyomma americanum (Acari: Ixodidae). J Med Entomol 2003;40:
1000–4.
1360 Walker et al
63. Paddock CD, Liddell AM, Storch GA. Other causes of tick-borne ehrlichioses,
including Ehrlichia ewingii. In: Goodman JL, Dennis DT, Sonenshine DE, editors.
Tick-borne diseases of humans. Washington, DC: ASM Press; 2005. p. 258–67.
64. Anziani OS, Ewing SA, Barker RW. Experimental transmission of a granulocytic
form of the tribe Ehrlichieae by Dermacentor variabilis and Amblyomma ameri-
canum to dogs. Am J Vet Res 1990;51:929–31.
65. Loftis AD, Reeves WK, Spurlock JP, et al. Infection of a goat with a tick-transmitted
Ehrlichia from Georgia, U.S.A., that is closely related to Ehrlichia ruminantium.
J Vector Ecol 2006;31:213–23.
66. Groves MG, Dennis GL, Amyx HL, et al. Transmission of Ehrlichia canis to dogs
by ticks (Rhipicephalus sanguineus). Am J Vet Res 1975;36:937–40.
67. Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, et al. Human granulocytic
ehrlichiosis: a case series from a medical center in New York state. Ann Intern
Med 1996;125:904–8.
68. Chapman AS, Bakken JS, Bloch KC, et al. Diagnosis and management of tick-
borne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and
anaplasmosis - United States. MMWR 2006;55:1–29.
69. Dumler JS, Madigan JE, Pusteria N, et al. Ehrlichioses in humans: epidemiology, clin-
ical presentation, diagnosis, and treatment. Clin Infect Dis 2007;45(Suppl 1):S45–51.
70. Fishbein DB, Dawson JE, Robinson LE. Human ehrlichiosis in the United States,
1985 to 1990. Ann Intern Med 1994;120:736–43.
71. Olano JP, Hogrefe W, Cullman L, et al. Clinical manifestations, epidemiology,
and laboratory diagnosis of human monocytotropic ehrlichiosis in a commercial
laboratory setting. Clin Diagn Lab Immunol 2003;10:891–6.
72. Schutze GE, Buckingham SC, Marshall GS, et al. Human monocytic ehrlichiosis
in children. Pediatr Infect Dis J 2007;26:475–9.
73. Bakken JS, Aguero-Rosenfeld ME, Tilden RL, et al. Serial measurements of
hematologic counts during the active phase of human granulocytic ehrlichiosis.
Clin Infect Dis 2001;32:862–70.
74. Bakken US, Krueth J, Wilson-Nordskog C, et al. Clinical and laboratory charac-
teristics of human granulocytic ehrlichiosis. JAMA 1996;275:199–205.
75. Hamilton KS, Standaert SM, Kinney MC. Characteristic peripheral blood findings
in human ehrlichiosis. Mod Pathol 2004;17:512–7.
76. Eremeeva ME, Dasch GA, Silverman DJ. Quantitative analysis of variations in the
injury of endothelial cells elicited by 11 isolates of Rickettsia rickettsii. Clin Diagn
Lab Immunol 2001;8:788–96.
77. Paddock CD, Folk SM, Shore GM, et al. Infections with Ehrlichia chaffeensis and
Ehrlichia ewingii in persons coinfected with human immunodeficiency virus. Clin
Infect Dis 2001;33:1586–94.
78. Walker DH, Hawkins HK, Hudson P. Fulminant Rocky Mountain spotted fever: its
pathologic characteristics associated with glucose-6-phosphate dehydroge-
nase deficiency. Arch Pathol Lab Med 1983;107:121–5.
79. Aguero-Rosenfeld ME, Kalantarpour F, Baluch M, et al. Serology of culture-
confirmed cases of human granulocytic ehrlichiosis. J Clin Microbiol 2000;
38(2):635–8.
80. Walker DH, Burday MS, Folds JD. Laboratory diagnosis of Rocky Mountain spot-
ted fever. South Med J 1980;73:1443–7.
81. Dumler JS, Dawson JE, Walker DH. Human ehrlichiosis: hematopathology and
immunohistologic detection of Ehrlichia chaffeensis. Hum Pathol 1993;24:391–6.
82. Sexton DJ, Kanj SS, Wilson K, et al. The use of a polymerase chain reaction as a di-
agnostic test for Rocky Mountain spotted fever. Am J Trop Med Hyg 1994;50:59–63.
83. Tzianabos T, Anderson BE, McDade JE. Detection of Rickettsia rickettsii DNA in
clinical specimens by enzymatic amplification using polymerase chain reaction
technology. Ann NY Acad Sci 1990;590:553–6.
84. Standaert SM, Yu T, Scott MA, et al. Primary isolation of Ehrlichia chaffeensis
from patients with febrile illnesses: clinical and molecular characteristics.
J Infect Dis 2000;81:1082–8.
85. Marshal GS, Jacobs RF, Schutze GE, et al. Ehrlichia chaffeensis seroprevalence
among children in the southeast and south-central regions of the United States.
Arch Pediatr Adolesc Med 2002;156:166–70.
86. American Academy of Pediatrics. Ehrlichia infections (human ehrlichioses). In:
Pickering LK, Baker CJ, Overturf GD, et al, editors. 2003 Red book: report of
the Committee on Infectious Diseases. 26th edition. Elk Grove Village (IL): Amer-
ican Academy of Pediatrics, Committee on Infectious Diseases; 2003. p. 266–9.
87. American Academy of Pediatrics. Rocky Mountain spotted fever. In:
Pickering LK, Baker CJ, Overturf GD, et al, editors. 2003 Red book: report of
the Committee on Infectious Diseases. 26th edition. Elk Grove Village (IL): Amer-
ican Academy of Pediatrics; 2003. p. 532–4.
88. Holman RC, Paddock CD, Curns AT, et al. Analysis of risk factors for fatal Rocky
Mountain spotted fever: evidence for superiority of tetracyclines for therapy.
J Infect Dis 2001;184:1437–44.
89. Buitrago MI, Ijdo JW, Rinaudo P, et al. Human granulocytic ehrlichiosis during
pregnancy treated successfully with rifampin. Clin Infect Dis 1998;27:213–5.
90. Krause PJ, Corrow CL, Bakken JS. Successful treatment of human granulocytic
ehrlichiosis in children using rifampin. Pediatrics 2003;112:e252–3.
91. Hamburg BJ, Storch GA, Micek ST, et al. The importance of early treatment with
doxycycline in human ehrlichiosis. Medicine (Baltimore) 2008;87:53–60.
92. Lockhart JM, Davidson WR, Dawson JE, et al. Temporal association of Am-
blyomma americanum with the presence of Ehrlichia chaffeensis reactive
antibodies in white-tailed deer. J Wildlife Dis 1995;31:119–24.
93. Lockhart JM, Davidson WR, Stallknecht DE, et al. Site-specific geographic asso-
ciation between Amblyomma americanum (Acari: Ixodidae) infestations and Ehr-
lichia chaffeensis-reactive (Rickettsiales: Ehrlichieae) antibodies in white-tailed
deer. J Med Entomol 1996;33:153–8.
94. Lockhart JM, Davidson WR, Stallknecht DE, et al. Natural history of Ehrlichia
chaffeensis (Rickettsiales: Ehrlicieae) in the piedmont physiographic province
of Georgia. J Parasitol 1997;83:887–94.
95. Standaert SM, Dawson JE, Schaffner W, et al. Ehrlichiosis in a golf-oriented
retirement community. N Engl J Med 1995;333:420–5.
96. Belongia EA. Epidemiology and impact of coinfections acquired from Ixodes
ticks. Vector Borne Zoonotic Dis 2002;2:265–73.
97. Chapman AS, Murphy SM, Demma LJ, et al. Rocky Mountain spotted fever in the
United States, 1997–2002. Vector Borne Zoonotic Dis 2006;6:170–8.
98. Demma LJ, Holman RC, McQuiston JH, et al. Epidemiology of human ehrlichiosis and
anaplasmosis in the United States, 2001–2002. Am J Trop Med Hyg 2005;73:400–9.
99. Dumler JS, Dotevall L, Gustafson R, et al. A population-based seroepidemio-
logic study of human granulocytic ehrlichiosis and Lyme borreliosis on the
West coast of Sweden. J Infect Dis 1997;175:720–2.
100. Fishbein DB, Kemp A, Dawson JE, et al. Human ehrlichiosis: prospective active
surveillance in febrile hospitalized patients. J Infect Dis 1989;160:803–9.
101. Harkess JR, Ewing SA, Crutcher JM, et al. Human ehrlichiosis in Oklahoma.
J Infect Dis 1989;159:576–9.
The Soc ial Ecology
of HIV/AIDS
Kenneth Mayera,b,c,*, HF Pizerd, Kartik K Venkateshe
KEYWORDS
HIV AIDS Sexual activity Travel MSM Drug use
Although studying microbiology and immunology is essential to understanding the

pathogenesis of infections caused by fungi, parasites, bacteria, viruses, and other
microorganisms, the reasons that epidemics occur are largely a function of human
behaviors and responses to environmental changes. The study of microbial-host inter-
actions thus is the social ecology of infectious diseases, as it attempts to understand
and describe the ways in which human activities alter specific microenvironments and
thereby create favorable conditions for old and new microorganisms to develop and
spread. Although potential pathogens adapt to specific niches as a function of their
intrinsic properties, such as the ability to withstand heat, cold or drying, and their
microenvironment, it is changes in human behavior that potentiate their spread. So
although Yersinia pestis caused intermittent death in remote parts of Europe before
the fourteenth century, it was the development of increasingly globalized commerce
throughout the Mediterranean and Black Sea that enabled rats to carry the organism
onboard ships and produce the infamous Black Death, which killed 20 to 30 million
Europeans or approximately one third to two thirds of the population.1 The Spanish
influenza epidemic of 1918–1919 was greatly abetted by the social disruptions of
World War I, where large numbers of soldiers lived in densely crowded conditions
at the front and then traveled to and from the battlefield carrying infectious diseases.2
Meanwhile, malnutrition, the dislocation of millions of displaced persons, and unsan-
itary living conditions provided additional supports for spreading the virus. In just a few
years the flu virus spread around the world in three waves, killing an estimated
50 million people.
In the late 1960s, prominent medical scientists and public health officials were pre-
dicting the end of infectious diseases as a significant public health concern and were
a
Brown University, 164 Summit Avenue, Providence, RI 02906, USA
b
Miriam Hospital, Providence, RI, USA
c
The Fenway Institute, Fenway Community Health, Boston, MA, USA
d
Health Care Strategies, Inc., 213 Hamilton Street, Cambridge, MA 02139, USA
e
Department of Community Health, Alpert Medical School, Brown University, Box G8488,
Providence, RI 02912, USA
* Corresponding author. Infectious Disease Division, Miriam Hospital, 164 Summit Avenue,
Providence, RI 02906.
E-mail address: kenneth_mayer@brown.edu (K. Mayer).
Med Clin N Am 92 (2008) 1363–1375

1364 Mayer et al
advising policy makers to shift funding, research, and training priorities away from
infectious diseases to chronic medical conditions, such as cardiovascular disease
and cancer.3 Although wrong in hindsight, the optimism of the time was
understandable in light of the enormous strides being made in living standards and
longevity, public sanitation and public health, vaccines, antibiotics, and other new
medical technologies. These experts also predicted that the advances being attained
in combating infectious diseases in developed nations soon would be translated to the
developing ones. As events unfolded, the optimism was short-lived. Soon there was
a resurgence of old infectious diseases that had been well controlled, such as
tuberculosis,4–6 and an eruption of new ones, such as AIDS, legionnaires’ disease,
Lyme disease, and Ebola hemorrhagic fever. A sobering lesson was learned: microbial
pathogens have the extraordinary capacity to adapt to human lifestyles, including
advances in medical science and technology.
THE ADVENT OF THE AIDS PANDEMIC
In only approximately 25 years during the latter decades of the twentieth century, HIV-1,
the most common human immunodeficiency virus that causes AIDS, spread
throughout the world to infect more than 70 million people and cause approximately
35 million deaths.7 It is now the fourth leading cause of death worldwide and accounts
for approximately 25% of deaths in Africa.8 HIV-1 is part of a class of viruses known as
retroviruses discovered in the first decade of the twentieth century by Payton Rous,
when he observed a filterable agent capable of causing sarcoma, a type of cancer
that could be transmitted between chickens. Over subsequent decades researchers
were able to detect many retroviruses in a diverse array of vertebrate species. Once
genes were found to be comprised of DNA and the genetic code was deciphered,
investigators began to categorize the ways in which these viruses replicate through in-
fecting cells, integrating themselves into host cell genomes and then using the host
cell’s nucleus to direct the infected cell to make new viral copies. A major contribution
to the understanding of their pathogenesis was to characterize the enzyme, reverse
transcriptase, which allows retroviruses to infect cells through their RNA and then
integrate themselves into the host genome as a DNA provirus. In the late 1970s
researchers discovered that the human T- lymphotropic virus (HTLV), also a retrovirus,
could lie dormant in its host for decades. Like HIV-1, in a small subset of individuals
HTLV can cause hematologic malignancies and neurologic diseases, such as spastic
paraparesis.7,9
These discoveries were important for understanding AIDS when in 1980 and early
1981 clinicians in New York, Los Angeles, and San Francisco observed a new syn-
drome of opportunistic infections and atypical neoplasms, such as Kaposi’s sarcoma,
a rare hematologic malignancy, in a small group of homosexual men who had been
sexually active with multiple partners and injection drug users. Soon, a smaller group
of patients who had hemophilia were identified who apparently had acquired the new
disease from transfusions of contaminated blood products.10 For several years there
was speculation that this new disease, soon to be named the acquired immunodefi-
ciency syndrome (AIDS), was being caused by a retrovirus, because its pattern of
transmission seemed similar to that of animal retroviruses and HTLV.7,11,12 Even
before the AIDS virus was isolated in 1983, the clues to unraveling what was going
on were found through careful epidemiologic sleuthing and observing the sociobeha-
vioral factors associated with HIV transmission.
Because of the lack of specimen repositories in many underdeveloped parts of the
world, definitive conclusions about where and when epidemics originate often has
The Social Ecology of HIV/AIDS 1365
remained indecipherable. Recent developments in computer technology data storage

and evolutionary biology, however, have enabled molecular virologists to construct
schema to pinpoint patterns of microbial evolution that can be associated with
temporal sequences of viral transmission in different geographic areas. The collection
of multiple samples of HIV from around the world with subsequent genetic sequencing
have enabled molecular epidemiologists to estimate that HIV infection developed in
a remote part of sub-Saharan Africa, possibly the Democratic Republic of the
Congo.13 It is clear from more recent studies that viruses that are extremely similar
to HIV have been found in this region in several primate species, in particular chimpan-
zees whose immune systems are most homologous to humans compared with other
species. Additionally, anthropologic studies conducted in several regions of central
and contiguous areas of sub-Saharan Africa have demonstrated that monkey meat
is a major source of protein for indigenous peoples. Researchers have documented
that the preparation of monkey meat by traditional butchering methods involves sub-
stantial contact with blood and sharp objects.14 Thus, it is not difficult to imagine that
a simian retrovirus made the jump from primates to humans through the process of
preparing meat for local consumption.
Because it can take years before retroviruses, such as HIV, produce symptoms of
infection, it was likely that some significant time passed during which infected individ-
uals were freely passing the virus on to others. Whatever the actual start date and time
sequence for the leap from primate to human (recent studies suggest that there were
multiple introductions into the human population), by the 1970s there existed in rural
Africa a sufficiently large number of people infected with HIV to lay the foundation for
a much wider and long-lasting epidemic. It also is likely that the process developed as
concurrent and overlapping multiple microepidemics, each of which was fueled by
local social factors.
In sub-Saharan Africa of the 1960s and 1970s there were substantial population
migrations of men without their spouses and families that also served to propel the
transmission of HIV. These men were moving from the countryside to the city or to
mineral mines and labor camps looking for work. Throughout human history concen-
trations of young, mobile unattached men have set the stage for transactional sex and
homosexuality, both of which served at this time to spread HIV in an unsuspecting
population. Over time the men brought HIV and other sexually transmitted infections
(STIs), which enhance the infectiousness of HIV, back to their communities when
they returned home. HIV also spread along known truck routes where men engaged
in transactional sex and by soldiers involved in the many armed conflicts that engulfed
the region during those years. With extremely limited public health systems, no
government-sponsored prevention messages, and limited access to condoms, the
migrant populations and the sex workers that served them created an ideal social
ecology for the spread of HIV.
TRAVEL
How could an epidemic that was slowly brewing in sub-Saharan Africa become
a global pandemic in just a few decades, especially since transmission of HIV is neither
airborne, waterborne, nor rapid? The answers to that question are revealed in the
epidemiology of AIDS and the easy interconnectedness of people in the modern
era. One factor is the ready availability of fast and relatively inexpensive international
air travel that developed after World War II. Even poor and previously isolated
communities now are linked to the rest of the world by jet planes capable of transport-
ing a human pathogen around the world in less than a single day. From 1950 to 2005,
1366 Mayer et al
international tourist arrivals increased 32-fold worldwide. Approximately 2 million peo-

ple now cross international borders each day. In the United States, 18 airports receive
more than 500,000 international arrivals annually and 14 maritime ports provide entry
for an additional 150,000 passengers.15,16 People travel for work and play, and with
each trip are capable of spreading microbes in a variety of ways that range from casual
coughing and sneezing to sexual contact and drug use. The months or years it took to
spread an infectious agent in the era of the Black Death can now occur in days or
weeks. For example, on March 30, 2003, a 48-year-old businessman flew from
Hong Kong, China, to Frankfurt, Germany, and then over 5 days took 7 flights to dif-
ferent cities in Europe.17 At the time he left Hong Kong he felt well. But, on his return to
Hong Kong he was admitted to the hospital with SARS. There is no way to count the
number of people that single individual came into contact with in 1 week on plane
flights, in hotels and restaurants, at business meetings, and in public places generally.
Each one could have been exposed to SARS.15 One of the most sensationalized early
reports of HIV infection was an airline flight attendant, called patient zero, described in
the book And the Band Played On.18 Despite progressive signs and symptoms of AIDS,
during his travels he continued to engage in unprotected sex with other men. Over the
years when the AIDS epidemic was brewing there no doubt were other travelers, many
if not most of whom had no idea they were HIV positive, who engaged in unprotected
sex, thus unwittingly spreading the virus. Some even traveled for the specific purpose
of engaging in sexual activity, known as sex tourism, which included venues, such as
Thailand and Haiti, where explosive AIDS epidemics developed early on.
URBANIZATION
AIDS is primarily an urban disease in developing and developed countries. By the late
1970s and early 1980s there already was substantial seeding of HIV across major
metropolitan areas of Western Europe and the United States. The social ecology of
AIDS thus also is a product of the dramatic urbanization of the world’s population
that occurred after World War II. In 1800, Beijing was the only city with a population
of more than 1 million. Today there are more than 40 cites with a population of at least
5 million and 19 with more than 10 million. From 1950 to 2005, the world’s urban pop-
ulation grew from approximately 730 million to 3.2 billion, and demographers predict
that by 2030 it will be approximately 5 billion.19 Today’s city often is no longer a dis-
crete metropolitan area but a megacity that includes the original city plus other nearby
urban centers and a well-connected sprawl of suburbs and semirural areas. The pop-
ulation of Tokyo, Yokohama, Kawasaki, and Saitama is more than 34 million; Mexico
City, Nezahualcoyotl, Ecatepec, and Naucalpan contain more than 22 million. With the
efficiencies of modern travel and porous borders people now move readily within,
across, and between cities. The uncontrolled urbanization of the past 5 decades
has been the most challenging for the developing world, where sanitation, public
health, and medical infrastructures are weak or absent entirely. These settings offer
the potential to create a large single human reservoir for the eruption and propagation
of infectious diseases. Over the past 3 decades this included AIDS, which flourished in
urban centers across the globe. In Latin American approximately one third of people
who have HIV live in Brazil, where the first cases were noted in 1982; the highest con-
centration of cases continues to be in Rio de Janeiro and São Paulo. In the United
States, 85% of reported AIDS cases are in major metropolitan areas: approximately
200,000 in the New York metropolitan area at a rate of 29.2 per 100,000 population;
58,000 in Los Angeles at 13 per 100,000; 40,000 in San Francisco at 16.5 per
100,00; and 56,000 in Miami at 41.9 per 100,000. Although across the entire United
States the rate of infection in nonmetropolitan areas is 5.5 per 100,000 population, it is
15.9 in metropolitan areas of 500,000 or more. In 2006, the highest rates of new United
States AIDS diagnoses were in Miami (41.9 per 100,000 people), Baltimore (37.7), and
Washington, DC (31.8).20
CHANGING SEXUAL MORES AND GENDER ROLES
Although male homosexuality has existed since time immemorial, it was limited by
criminalization and social ostracism. And although it continues to be illegal in
approximately 70 countries, societal attitudes generally have become dramatically
more tolerant, especially in developed societies.21 In the United States, these changes
began in the late 1960s with a public and robust expression of gay liberation. A land-
mark event occurred on the evening of June 27, 1969, with resistance to a police raid
of the Stonewall Inn, a well-known gay bar in Greenwich Village New York. That unpro-
voked police action precipitated several days of rioting and within weeks the formation
of the Gay Liberation Front. Unfortunately, in the era of HIV the freedom to enjoy and
celebrate a gay lifestyle came with a tragic downside. In March 1983, the Centers for
Disease Control and Prevention shared the results of epidemiologic investigations,
which showed that homosexual men who had multiple sexual partners were at
increased risk for contracting AIDS and that the period between exposure and the
manifestation of symptoms could be as long as 2 years.22 These findings led to the
recommendation that individuals avoid sexual contact with ‘‘persons known or sus-
pected to have AIDS.’’ A New York Times article published in February 1983 explained
that the only protection against AIDS that clinicians could offer to homosexual patients
was behavior change. In particular, gay men were advised to practice monogamy and,
ideally, abstain from anal intercourse.23 Many gay men balked at these recommenda-
tions, feeling that they undermined their newly won sexual freedom to participate in
sexual relationships the way that heterosexuals do.18
As a result of these societal changes, there was a proliferation of bathhouses, bars,
and other venues where men could have anonymous homosexual sex with multiple
partners. By the 1970s there were clearly observed increases in STIs and hepatitis
B among men who have sex with men (MSM); and by the 1980s there was the
epidemic of HIV.24–26 Without effective antiretroviral therapy the 1980s produced
a mounting death toll in the gay community. The psychologic trauma was enormous.
The emotional devastation also catalyzed a tremendous outpouring of positive energy
in the gay community that included prevention outreach, volunteerism, support for
people living with AIDS, organizing for inclusion in public health planning, and advo-
cating for greater government funding for medical services, scientific research, and
public health programs. There were tangible results from these efforts, as individual
behavior change produced a demonstrable reduction in the number of new STIs
and HIV infections among MSM.27 The development and widespread availability of ef-
fective highly active antiretroviral therapy by 1996, however, made it seem like AIDS
could be managed. This, in turn encouraged some individuals to return to sexual
risk taking and with that there was an up-tick in HIV transmission, in particular in young
MSM.28 Meanwhile, the Internet became a new way for people to find sexual partners
and arrange for explicit sexual activities. Studies have shown that sexual activity
arranged on-line, especially among gay men, is associated with increased unsafe
sex, casual partnering, recreational drug use, and sex with HIV-positive persons,
including HIV-infected men having unsafe sex with HIV-uninfected men. These
encounters also are associated with transactional sex and STIs, including rectal
1368 Mayer et al
gonorrhea. Adding all these factors together, the Internet has the potential for accel-
erating the spread of HIV.29
Meanwhile, in North America and Europe there also was a sexual revolution for het-
erosexuals, in large part the result of advances in contraception for women that for the
first time in history allowed them to engage in sexual intercourse without fear of
unwanted pregnancy. This medical breakthrough was occurring at the same time
there were profound social changes for women, which offered them an unprece-
dented degree of independence and opportunity. More freely and equally than ever
before, women were able to participate in higher education and the workforce and
to live on their own without fear of social stigma. As part of the 1960s sexual revolution
it became acceptable and common for unmarried women and men to pursue sex for
its own pleasure, for women to seek and insist on their own sexual gratification, and for
men to become better lovers to accommodate them. Yet, despite the fact that young
women and men in developed nations commonly engage in premarital sex, there has
been relatively little HIV transmission in the group that enjoys higher education and so-
cioeconomic status. Here it seems that feminism played a protective role by giving
women the self-esteem and wherewithal to insist on safer sex. For example, between
1991 and 2003, condom use during last intercourse increased from 46% to 63%
among adolescents whereas the use of oral contraception declined.30 After 1990,
the prevalence of genital chlamydia declined among women entering job training
and by the late 1990s so had the number of new HIV infections among adoles-
cents.27,31 In the short run, at least, the impact of changing women’s roles may not
be as protective in recently traditional societies as it has been in the West. Women
across much of Asia are enjoying unprecedented opportunities in education, the work-
place, and their ability to socialize outside the home and family. In Thailand, for
instance, young women attend universities, communicate by cell phone and the Inter-
net, and in general enjoy a degree of personal freedom unheard of in their mothers’
generation. With these societal changes has come an increase in STIs among young
women and the possibility of an upsurge in HIV.
Meanwhile, the subordination of women in traditional societies continues to be
a potent factor in the social ecology of AIDS. In general it still is taboo in these cultures
to openly discuss sex even in marriage. In India, for example, being married and mo-
nogamous is the number one risk factor for a woman who becomes HIV infected, as
husbands frequent brothels and bring infection home.32,33 Using condoms is not
acceptable in marriage. A dutiful wife is expected to bear many children and to ignore
her husband’s infidelity. She has little personal or economic autonomy and few social
supports to help her negotiate sexual matters.
DRUG USE
Injecting recreational drugs had been present in developed societies for more than
a century by the time the AIDS epidemic surfaced. Today, approximately 10% of
HIV transmission worldwide can be attributed to injection drug use (IDU) through
the sharing of unsterile injection equipment. It is an important factor for HIV transmis-
sion virtually everywhere there is an epidemic and a principal driver in China, South-
east Asia, and Eastern Europe.34 It is likely that HIV was introduced into cohorts of
drug users via sexual contact and then amplified greatly by continuing IDU. Poverty,
social and income inequality, crime, and social norms play important roles. The HIV
epidemic in New York City probably began in the mid-1970s. It was illegal to purchase
and possess drugs and drug use paraphernalia, which contributed to the reuse
and sharing of syringes and equipment. Shooting galleries sprang up in poor
neighborhoods, where injection drug users got high together and sometimes engaged
in sex, including transactional sex. Although complex psychologic and social factors
play into drug addiction, the illegal status of recreational drugs increases their black
market prices, which in turn creates a continuing need to obtain ready cash to support
addiction and, thus, the frequent overlap between transactional sex and injecting drug
use. The need to maintain the high of the drug experience goes along with a desire to
be with other drug users and with sharing paraphernalia. Harm reduction and syringe
exchange programs were rarely available until the 1990s, by which time the HIV epi-
demic was already well established in the IDU community. Since then, programs to
facilitate drug users’ access to sterile injecting equipment and decriminalizing the pos-
session of sterile syringes have been associated with decreases in HIV.35,36 Although
drug users face many barriers to quitting, more needs to be done to provide access to
these programs.
Noninjection substance use is a factor in HIV transmission among MSM,
adolescents, the poor and homeless, and youth. Recreational drugs associated with
increased risk for HIV transmission include alcohol, which is consumed in most coun-
tries by a large portion of the youth and adult populations, amphetamines, cocaine,
nitrites (‘‘poppers’’), marijuana, and methylenedioxymethamphetamine (ecstasy).
Often, these drugs are used in combination as polydrug abuse. All are shown to
increase the risk for engaging in high-risk sex, including unprotected vaginal and
anal intercourse and sex with anonymous or multiple partners.
SPECIAL AT-RISK POPULATIONS
Although the number of new HIV infections in the United States has remained fairly
constant in recent years at approximately 40,000 annually, the impact continues to
be disproportionate in certain populations and the epidemiology of each risk group
points to the relevant social ecology.37 From 1985 to 2004, the proportion of new
AIDS cases among women increased from 18% to 27%, but as it is for STIs generally,
the risk is higher for African American women than other racial and ethnic groups,
including approximately 21 times more for African American women than white
women. Overall, in 2004, approximately half of all new cases of AIDS were among
African Americans who make up approximately 13% of the United States popula-
tion.38–40 Many prevention programs are being tried to combat these disparities,
including turning to African American churches to spread information and understand-
ing about the spread of HIV and The Balm in Gilead, which sponsors The Black Church
Week of Prayer for the Healing of AIDS.41
Of the approximately 1 million people living with HIV in the United States, approxi-
mately 60% are MSM. Young MSM have higher rates of HIV infection than older men,
and young African American MSM have higher rates than young white MSM. Studies
show that younger gay men engage in more risk taking, including drug use; have
higher rates of STIs, which facilitate HIV transmission; and are less likely to avail them-
selves of HIV testing than the general population.
Throughout the world, AIDS is primarily a disease among the young. Twenty-five
percent of HIV infections worldwide are in youth between the ages of 15 and 24,
and in 2005–2006 almost 50% of all new HIV infections worldwide were in this
group.8 This demographic group thus accounts for 5000 to 6000 new infections daily
and approximately 2.3 million new cases each year. In high-income countries, young
people account for approximately one third of new cases, most among young MSM.
In Asia most new infections in the younger population are the result of IDU. The risk
for youth is greatest in sub-Saharan Africa, which accounts for approximately two
1370 Mayer et al
thirds of all AIDS in young people worldwide and where HIV prevalence reaches 40%
in some communities.8,42 In these settings merely being an adolescent and entering
into a sexual relationship with one person, which many in the West consider normal
adolescent development, puts a young person at risk. Age of sexual debut, particu-
larly for young women, and partnering with older men also are risk factors.43 These
patterns reflect disparities in power and opportunity between men and younger
women. High rates of other STIs, the relative immaturity of the genital tract in young
women, and a lack of routine male circumcision also have an impact on risk. In South
Africa, approximately three quarters of HIV-positive individuals between the ages of
15 and 24 are women and more than 20% of pregnant women attending prenatal
clinics have HIV. More than 400,000 infants are HIV infected worldwide each year,
approximately 90% in Africa, and approximately half of new infections are transmit-
ted through breastfeeding.8 This is a tragedy that can be prevented with good pre-
natal care, antiretroviral therapy, HIV testing, and prevention of mother-to-child
transmission of HIV services, which can reduce mother-to-child transmission of
HIV to less than 2%.44–46
Sex workers are another group of people particularly affected by the worldwide
social ecology of AIDS. As early as 1985, the HIV infection rate among sex workers
was as high as 62% in Nairobi, Kenya, and by the late 1980s it was 89% in Abidjan,
Côte d’Ivoire.47,48 Sex workers face many risks: large number of sexual contacts
and low level of condom use, high prevalence of other STIs, and lack of access to
medical services. Sex work can be direct, which means it is open and formal, or indi-
rect, when it is hidden or informal. In many developing countries, it is a social norm for
men to purchase sex and 20% to 40% of men report having done so.49–51 The over-
whelming majority of women engaged in sex work are poor and poorly educated. Fre-
quently, they have been victims of childhood violence and sexual abuse and continue
sex work in an environment of exploitation, threat, and violence. Many are drug users
or have sexual contact with injection drug users. The fact that sex work is illegal and
socially ostracized means these women face obstacles to accessing medical services.
For example, although prostitution is lawful in the former Soviet Union, it is not legal to
live in Moscow without a special permit. Women from other parts of the country who
come to Moscow and engage in sex work thus are there illegally and report restrictions
in their access to health services. They are subject to exploitation and abuse generally,
including rape, and sexual exploitation by pimps, clients, and even the police.52 Al-
though efforts are being made to help sex workers worldwide, most programs have
been implemented on a small scale and most sex workers as yet have not had access
to them. To date there have been some notable programmatic successes, such as
high levels of condom use in Benin, Thailand, and Cambodia, which probably have
been effective in reducing the HIV rate among sex workers and by doing so probably
helped to slow the AIDS epidemic in the general population.51,53
Incarceration and institutionalization also are important factors in the transmission
of HIV throughout the world. In 2006 there were more than 2 million people in
United States prisons, and an estimated one fourth of people living with AIDS in
the United States had spent some time incarcerated. In this population the percent-
age of women (2.3%) who are HIV infected is higher than for men (1.7) and higher
for African American (2%) and Hispanic/Latino (1.8%) populations than for whites
(1%). China and the Russian Federation also have high incarceration rates, and it
is assumed they have or will have HIV/AIDS epidemics in their institutions. To
date, these governments have not provided what are believed reliable data on
HIV infection rates in their institutions. China did not publicly acknowledge the
existence of HIV/AIDS until 2001, but it is believed that approximately half of
China’s HIV-positive population contracted the virus through IDU. This likely puts
the incarcerated population at risk for an HIV epidemic, because intravenous
drug use often is associated with incarceration. The risk factors associated with
HIV transmission among institutionalized persons include addiction and IDU before
and during incarceration, mental illness, hepatitis C and other infectious diseases,
forced and consensual sex especially among MSM, and tattooing. In 1993 the
WHO recommended condom distribution in prisons, but this has yet to become
a widespread practice.54 It is not clear how effective condom distribution would
be because coercive sex is common and many inmates would not want to be
known publicly in the facility as participating in sex with other men.
In 1982 it was discovered that several hemophiliacs had developed AIDS, and even
though this was before the HIV had been isolated, it was presumed that the cause of
their infection was receipt of contaminated blood products. This finding further con-
firmed the already widespread conclusion that the new immune deficiency disorder
behaved in its transmission like hepatitis B and C viruses, cytomegalovirus, and other
agents that are spread by high-risk sexual activity and IDU. There were national
scandals in the United States, France, Japan, and Canada and a more recent scandal
in China among blood donors in which unscrupulous profit-making companies re-
used unsterile blood-collecting equipment. In developed nations, the blood banking
community responded quickly, based first and foremost on a system of voluntary
donation and careful screening of donors. Although there now are effective laboratory
tests to detect HIV contamination of donor units, blood bankers know that even with
advances in laboratory testing, the front-line prevention against blood contamination
is a voluntary system of blood donation coupled with careful questioning about rele-
vant donor behaviors, including health status, history of receiving a transfusion or
medical treatment in certain places, drug use, sexual activity, travel, and residency.
There is not now and probably never will be a laboratory test for every potential blood
pathogen. The result of these efforts is a success story in AIDS prevention in devel-
oped nations where HIV infection via blood transfusion is extremely rare; in the United
States, for HIV-1, it is as low as 1 in 676,000 units transfused. Unfortunately, this is not
the case in sub-Saharan Africa and parts of Asia, as a consequence of inadequate
resources and out dated technology in the health sector.10,55
LOOKING AHEAD
Although the global AIDS epidemic probably peaked in 2000–2001, there are an esti-
mated 4 million new cases annually and the downstream impacts of what has already
occurred will be felt for generations to come.37,39 In Africa it has reversed decades of
progress previously made in reducing mortality and increasing life expectancy.
Although a highly protective vaccine or effective oral or topical chemoprophylaxis
would greatly slow the spread of HIV to new individuals in endemic areas and new re-
gions, recent clinical trials suggest that a successful anti-HIV vaccine will take many
more years to develop. Even if chemoprophylaxis studies prove effective in decreas-
ing HIV transmission, the daily use of medications that comes with significant costs
and side effects is likely to be a holding action at best. One unavoidable conclusion
from the social ecology of HIV transmission is that it is difficult to impede the spread
of an infectious agent that is transmitted through pleasurable human activities—in this
case sexual activity and recreational drugs. Despite billions of dollars spent on
prevention programs, HIV continues to thrive in its various human niches and short
of a vaccine there is no magic bullet that can combat human nature.
1372 Mayer et al
So, more needs to be done with the tools currently available. The foundation for this
work is epidemiology that uncovers the hot spots of an epidemic and, thereby, directs
where to focus attention. There must be constant attention to prevention even among
low-risk populations, however, or facing the peril of seeing a low incidence pathogen
get out of hand. This is what occurred in Africa during the early days of AIDS, when
governments were slow to respond and the virus was free to spread to unsuspecting
people. Prevention efforts require a wide array of programs that involve mass public
health education, provider-patient communication, HIV testing, linkage to care,
enlisting the assistance of community leaders, and government and nongovernmental
allocation of resources to keep successful existing programs well funded and to
encourage new and creative ones.
For each risk group there needs to be targeted interventions that deal with the be-
haviors and underlying causes for HIV transmission. For instance, one clear example is
combating substance abuse, which is known to encourage high-risk sexual activity.
Interventions would include education, treatment, and harm reduction. There also
is, of course, the bigger picture that includes poverty, segregation of neighborhoods,
and the culture of drug use. Another example is in the education and empowerment of
women, especially in traditional societies, to provide them with the self-esteem and
social backing to insist on safe sex. Even if an effective microbicide is developed in
short order, it would be necessary to provide women in these settings the social tools
to use it. Interventions are needed with sex workers that include changing government
policies that make them vulnerable to abuse and exploitation and disease. Interven-
tions with MSM are needed that involve the entire community, particularly in societies
where gay men still are much in the closet. The lessons learned from the activism be-
gun in the 1980s in the United States can be applied elsewhere. And, there needs to be
continued focus on prevention research, including program evaluation, to understand
what works and how to implement successful pilot programs on a larger scale. Even
among populations studied as extensively as MSM substance users, few people are
accessing substance use treatment services. In the National HIV Behavioral Surveil-
lance System, for instance, only 16% of MSM substance users reported ever access-
ing treatment services.56 It is important to understand why people at risk do not
access services to overcome the barriers standing in their way. This basic theme
can be applied throughout.
Determined government action to combat AIDS is critical. Brazil is a success story in
this regard. With the end of military rule, Brazil’s democracy activists turned to public
health. New constitutional language declared universal health to be a basic human
right and with that efforts were made to greatly expand health services to underserved
groups and regions, including the goal of providing universal access to antiretroviral
drugs and ramping up HIV prevention programs. HIV prevention messages now are
widely disseminated in Brazil’s public spaces, often by well-known entertainers,
athletes, and models. Prevention programs, including harm reduction, reach out to
high-risk groups, such as MSM, sex workers, injection drug users, and incarcerated
persons. Public education helps destigmatize AIDS and encourages individuals to vol-
untarily partake of HIV testing and counseling. It is estimated that approximately one
third of Brazilians infected with HIV know their status as opposed to only approxi-
mately 10% of those infected elsewhere in the developing world. Although the AIDS
epidemic exploded in much of the developing world during the 1990s, because of
effective public effort it remained stabilized and contained in Brazil.57,58
Until there is a biologic tool to prevent HIV transmission, no single type of prevention
program is going to work for each at-risk population in the diverse geographic and cul-
tural settings where HIV has found its human niche.
REFERENCES
1. Cliff A, Haggett P. Time, travel and infection. Br Med Bull 2004;69:87–99.

2. Barry J. The great influenza. The epic story of the deadliest plague in history. New
York: Viking; 2004.
3. Garrett L. Betrayal of trust: the collapse of global public health. New York:
Hyperion; 2000.
4. Dye C, Scheele S, Dolin P, et al. Consensus statement. Global burden of tubercu-
losis: estimated incidence, prevalence, and mortality by country. WHO Global
Surveillance and Monitoring Project. J Am Med Assoc 1999;282(7):677–86.
5. Corbett E, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends
and interactions with the HIV epidemic. Arch Intern Med 2003;163(9):1009–21.
6. Dye C, Watt CJ, Bleed DM, et al. Evolution of tuberculosis control and prospects
for reducing tuberculosis incidence, prevalence, and deaths globally. J Am Med
Assoc 2005;293(22):2767–75.
7. Kanki P, Essex ME. Virology. In: Mayer K, Pizer HF, editors. The AIDS pandemic:
impact on science and society. New York: Academic Press; 2004. p. 13–35.
8. Unaids. UNAIDS/WHO AIDS epidemic update. Available at: http://www.unaids.
org/epidemic-update/. Accessed May 9, 2008.
9. Murphy E. The clinical epidemiology of human T-lymphotropic virus type II (HTLV-II).
J Acquir Immune Defic Syndr 1996;13(Suppl 1):S215–219.
10. Page P, Pizer HF. Protecting blood safety. In: Mayer KH, Pizer HP, editors. The
social ecology of infectious diseases. London: Elsevier; 2008. p. 187–214.
11. Gallo R, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of
cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS.
Science 1984;224(4648):500–3.
12. Essex M, McLane MF, Kanki PJ, et al. Retroviruses associated with leukemia and
ablative syndromes in animals and in human beings. Cancer Res 1985;45:
4534s–8s.
13. Hahn B, Shaw GM, DeCock KM, et al. AIDS as a zoonosis, scientific and public
health implications. Science 2000;287:607–14.
14. Wolfe N, Daszak P, Kilpatrick AM, et al. Bushmeat hunting and deforestation in
prediction of zoonoses emergence. Emerg Infect Dis 2005;11(12):1822–7.
15. Wilson M, Chen LH. Travel. In: Mayer KH, Pizer HP, editors. The Social ecology of
infectious diseases. London: Elsevier; 2008. p. 17–49.
16. Sivitz LB, Stratton K, Benjamin GC, editors. Quarantine stations at ports of entry:
protecting the public’s health. The National Academies Press; 2006.
17. Breugelmans J, Zucs P, Porten K, et al. SARS transmission and commercial
aircraft. Emerg Infect Dis 2004;10(8):1502–3.
18. Shilts R. And the band played on. New York: St. Martin’s Press; 1987.
19. United Nations Department of Economic and Social Affairs. World Urbanization
Prospects: the 2007 revision. Available at: http://www.un.org/esa/population/
publications/wup2007/2007WUP_ExecSum_web.pdf. Accessed June 22, 2008.
20. Avert. United States AIDS cases in major cities. Available at: http://www.avert.
org/usastatc.htm. Accessed May 25, 2008.
21. Timberlake S. Men having sex with men and human rights: the UNAIDS
perspective. Presented at the ILGA World Conference, Pre-Conference: MSM
and Gay Men’s Health Geneva, Switzerland; March 27–April 3, 2006.
22. Centers for Disease Control and Prevention. Current trends prevention of
acquired immune defi ciency syndrome (AIDS): report of inter-agency
recommendations. MMWR Morb Mortal Wkly Rep 1983;32:101–3.
1374 Mayer et al
23. Henig R. AIDS: a new disease’s deadly odyssey. The New York Times. February
6, 1983.
24. Fichtner R, Aral SO, Blount JH, et al. Syphilis in the United States: 1967–1979.
Sex Transm Dis 1983;10(2):77–80.
25. Ostrow D, Altman NL. Sexually transmitted diseases and homosexuality. Sex
Transm Dis 1983;10:208–15.
26. Rotello G. Sexual ecology: AIDS and the destiny of gay men. New York: Penguin
Books; 1997.
27. Celentano D, Sifakis F, Go V, et al. Changing sexual mores and disease transmis-
sion. HP. In: Mayer KH, Pizer HP, editors. The social ecology of infectious diseases.
London: Elsevier; 2008. p. 50–76.
28. Ekstrand M, Coates TJ. Maintenance of safer sexual behaviors and predictors of
risky sex: the San Francisco Men’s Health Study. Am J Public Health 1990;80:
973–7.
29. Bull S, McFarlane M. Soliciting sex on the Internet: what are the risks for sexually
transmitted diseases and HIV? Sex Transm Infect 2000;27:545–50.
30. Biddlecom A. Trends in sexual behaviours and infections among young people in
the United States. Sex Transm Infect 2004;80(Suppl 2):74–9.
31. Mertz K, Ransom RL, St Louis ME, et al. Prevalence of genital chlamydial infection in
young women entering a national job training program, 1990–1997. Am J Public
Health 2001;91:1287–90.
32. Newmann S, Sarin P, Kumarasamy N, et al. Marriage, monogamy and HIV: a pro-
file of HIV-infected women in south India. Int J STD AIDS 2000;11:250–3.
33. Gangakhedkar R, Bentley ME, Divekar AD, et al. Spread of HIV infection in
married monogamous women in India. J Am Med Assoc 1997;278(23):2090–2.
34. Hammett T, Wu Z, Duc TT, et al. ‘Social evils’ and harm reduction: the evolving
policy environment for human immunodeficiency virus prevention among injec-
tion drug users in China and Vietnam. Addiction 2008;103(1):137–45.
35. Watters J, Estilo MJ, Clark GL, et al. Syringe and needle exchange as HIV/AIDS
prevention for injection drug users. J Am Med Assoc 1994;271(2):115–20.
36. Ouellet L, Huo D, Bailey SL. HIV risk practices among needle exchange users
and nonusers in Chicago. J Acquir Immune Defic Syndr 2004;37(1):1187–96.
37. Centers for Disease Control and Prevention. Epidemiology of HIV/AIDS—United
States, 1981–2005. MMWR Morb Mortal Wkly Rep 2006;55:589–92.
38. U.S. Census Bureau. Infoplease. Available at: http://www.infoplease.com/spot/
bhmcensus1.html. Accessed May 30, 2008.
39. Centers for Disease Control and Prevention. Racial/ethnic disparities in diagno-
ses of HIV/AIDS—33 states, 2001–2004. MMWR Morb Mortal Wkly Rep 2006;
55:121–5.
40. Centers for Disease Control and Prevention. HIV/AIDS among African Americans.
Atlanta (GA): US Department of Health and Human Services; 2006.
41. Avery B, Bashir S. The road to advocacy—searching for the rainbow. Am J Public
Health 2003;93:1207–10.
42. Pettifor A, van der Straten A, Dunbar MS, et al. Early age of first sex: a risk factor
for HIV infection among women in Zimbabwe. AIDS 2004;18:1435–42.
43. Abdool Karim Q. Heterosexual transmission of HIV - the importance of a gendered
perspective in HIV prevention. In: Abdool Karim S, Abdool Karim Q, editors. HIV/
AIDS in South Africa. Cape Town (South Africa): Cambridge University Press;
2005. p. 243–61.
44. Newell M, Thorne C. Antiretroviral therapy and mother-to-child transmission of
HIV-1. Expert Rev Anti infect Ther 2004;2(5):717–32.
45. McIntyre J, Lallemaent M. The prevention of mother-to-child transmission of HIV:

are we translating scientific success into programmatic failure? Current Opinion
in HIV & AIDS 2008;3(2):139–45.
46. Fowler M, Lampe MA, Jamieson DJ, et al. Reducing the risk of mother-to-child
human immunodeficiency virus transmission: past successes, current progress
and challenges, and future directions. Am J Obstet Gynecol 2007;197:S3–9.
47. Hunt C. Migrant labor and sexually transmitted disease: AIDS in Africa. J Health
Soc Behav 1989;30(4):353–73.
48. Simonsen J, Plummer FA, Ngugi EN, et al. HIV infection among lower
socioeconomic strata prostitutes in Nairobi. AIDS 1990;4(2):139–44.
49. Wilson D, Dubley I, Msimanga S, et al. Psychosocial predictors of reported HIV-
preventive behaviour change among adults in Bulawayo, Zimbabwe. Cent Afr
J Med 1991;37(7):196–202.
50. Aklilu M, Messele T, Tsegaye A, et al. Factors associated with HIV-1 infection
among sex workers of Addis Ababa, Ethiopia. AIDS 2001;15(1):87–96.
51. Morison L, Weiss HA, Buve A, et al. Commercial sex and the spread of HIV in four
cities in sub-Saharan Africa. AIDS 2001;15(Suppl 4):S61–9.
52. Stachowiak J, Peryshkina A. Women’s health and women’s rights: selling sex in
Moscow. In: Beyrer C, Pizer HF, editors. Public Health and Human Rights: evi-
dence-based approaches. Baltimore (MD): Johns Hopkins University Press;
2007. p. 88–104.
53. Rojanapithayakorn W, Hanenberg R. The 100% condom program in Thailand.
AIDS 1996;10(1):1–7.
54. World Health Organization. Interventions to address HIV in prison: prevention of
sexual transmission. Available at: http://www.who.int/hiv/idu/oms_ea_sexual_
transmission_df.pdf. Accessed May 30, 2008.
55. Heyns A, Benjamin RT, Swanevelder JPR. Blood supply and demand. Lancet
2005;365(9478):2151.
56. Sanchez J, Finlayson T, Drake A, et al. Human Immunodeficiency Virus (HIV) risk,
prevention, and testing behaviors—United States, National HIV Behavioral
Surveillance System: men who have sex with men, November 2003–April 2005.
MMWR Morb Mortal Wkly Rep 2006;55(SS06):1–16.
57. Okie S. Fighting HIV–lessons from Brazil. N Engl J Med 2006;354(19):1977–81.
58. Gauri V, Beyrer C, Vaillancourt D. Human Rights principles to public health
practice. In: Beyrer C, Pizer HF, editors. Public health and human rights:
evidence-based approaches. Baltimore, (MD): Johns Hopkins University Press;
2007. p. 289–329.
Geo graphic Expansion
of Dengue : The Impac t
of I nternational Travel
AnneliesWilder-Smith, MD, PhD, MIH, DTM&H, FACTMa,b,*,
Duane J. Gubler, ScD, FIDSA, FAASb,c
KEYWORDS
Dengue International travel Geographic spread of dengue
Factors for resurgence of dengue
The dengue viruses are among the most widespread geographically of the arboviruses
and are found in tropical and subtropical areas where 2.5 to 3 billion people are at risk
of infection.1 Each year an estimated 50 to 100 million dengue infections occur, with
several hundred thousand cases of dengue hemorrhagic fever (DHF) and about
20 thousand deaths.1 Global deaths from DHF already rank with yellow fever in
exceeding combined deaths from all other viral hemorrhagic fevers, including Ebola,
Marburg, Lassa, and Crimean-Congo. The past 2 decades saw an unprecedented
geographic expansion of dengue.2 This article reviews factors responsible for the
worldwide spread of dengue, with a particular focus on the role of travel. International
travelers have the potential to acquire and spread dengue virus infection.3
BACKGROUND
Dengue viruses belong to the family of Flaviviridae (single-stranded, nonsegmented

RNA viruses); there are four serologically distinct dengue virus serotypes (DENV-1,
DENV-2, DENV-3, DENV-4).1 Infection with one serotype confers long-term immunity
to that serotype but not to the other types, and individuals may therefore be infected
up to four times.4 Cocirculation of various virus serotypes in a community (hyperende-
micity) is the single most common risk factor associated with the emergence of the
severe form of disease—DHF—in an area.5 Dengue virus infection of all four virus
serotypes causes a spectrum of illness ranging from asymptomatic or mild febrile
illness to classic dengue fever (DF) and to severe and fatal hemorrhagic disease.2
a
Department of Medicine, Travelers’ Screening and Vaccination Clinic, National University
Hospital of Singapore, National University of Singapore, 5, Lower Kent Ridge, Singapore 119074
b
Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Jalan Burkit
Merah 2, Singapore
c
Asia-Pacific Institute of Tropical Medicine and Infectious Diseases, Department of Tropical
Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, 651
Ilalo Street, BSB 3rd Floor, Honolulu, HI 96813, USA
E-mail address: epvws@pacific.net.sg (A. Wilder-Smith).
Med Clin N Am 92 (2008) 1377–1390

1378 Wilder-Smith & Gubler
Although the pathogenesis of severe dengue is not fully understood, the main risk
factors for developing DHF and dengue shock syndrome (DSS) are believed to be sec-
ondary infection with a heterologous serotype and infection with a more virulent strain
of virus.4–8 Cross-reactive but nonneutralizing anti-dengue antibodies from a previous
infectious bind to the new infecting virus serotype and enhance viral uptake by mono-
cytes and macrophages. This antibody-dependent enhancement is believed to result
in an amplified cascade of cytokines and complement activation causing endothelial
dysfunction, platelet destruction, and consumption of coagulation factors, which re-
sult in plasma leakage and hemorrhagic manifestations.4,9–11 T-cell activation accom-
panied by massive apoptosis has also been proposed as an explanation of the
activated cytokine production seen in secondary infection.12,13
Dengue viruses are transmitted by mosquitoes of the genus Aedes, subgenus
stegomyia (such as Aedes aegypti and albopticus).1 Ae aegypti is well established in
much of the tropical and subtropical world. It is the principal vector, and is an efficient
epidemic vector for several reasons: it is highly susceptible to dengue virus, feeds
preferentially on human blood, is a daytime feeder, has an almost imperceptible
bite, and is capable of biting several people in a short period for one blood meal.1,2
As a peri-domiciliary mosquito, it is well adapted to urban life because it typically
breeds in clean stagnant water in a wide variety of man-made containers, such as
tires, tin cans, pots, and buckets that collect rainwater. The alternative dengue vector,
Ae albopictus, is continuing its geographic expansion into tropical and temperate
climates, but this has had little impact on epidemic dengue transmission.14
HISTORY
Dengue virus has a relatively recent evolutionary history; it is estimated that the four
serotypes originated approximately 1000 years ago and have established endemic
transmission in humans only in the last few hundred years.15 The geographic origin
remains uncertain, however, as does the extent of genetic and phenotypic diversity
present in the sylvatic (primate) transmission cycle. Some suggest an African origin,
arguing that many of the flaviviruses circulate exclusively in Africa and often infect pri-
mates. On the other hand, the presence of all four serotypes in humans and monkeys
from Asia, and particularly the phylogenetic position of the Asian sylvatic strains, sug-
gests that the virus has an Asian rather than an African origin.5 The high prevalence of
dengue in this region also supports this hypothesis.16
Epidemics that were clinically compatible with DF occurred as early as 1635 and
1699 in the West Indies and Central America, respectively.17 In 1780, a major epidemic
occurred in Philadelphia in the United States and subsequent epidemics were
common in the United States into the 1930s, with the last outbreak occurring in
New Orleans in 1945.17
The epidemiology and transmission dynamics of dengue viruses were changed
dramatically in Southeast Asia during World War II. The disruption and change in
the ecology caused by the war effort expanded the geographic distribution of the
viruses and vectors, and increased the densities of Ae aegypti, making many countries
in this region highly permissive for epidemic transmission. The first recorded epidemic
of DHF occurred in Manila, Philippines in 1953 to 1954, followed by Bangkok, Thailand
in 1958 and Malaysia, Singapore, and Vietnam in the 1960s.17 With the economic
boom and associated urbanization in Southeast Asia in the postwar years, epidemic
DF/DHF spread to the whole region during the 1970s.17
In the American tropics, DHF was a rare disease before 1981.17 A characteristic of
dengue in the Americas during these years was that the disease presented as classical
Geographic Expansion of Dengue 1379
DF usually caused by a single virus serotype. Epidemics were self-limited and trans-
mission disappeared after several months.5,17 The 1980s and 1990s then saw a dra-
matic geographic expansion of epidemic DF and DHF from Southeast Asia to the
South Pacific Islands, the Caribbean, and the American tropics, with the regions
changing from nonendemic (no serotypes) to hypoendemic (one serotype present)
or hyperendemic (multiple serotypes present).17,18
More than 100 tropical countries now have endemic dengue virus infections, and
DHF has been documented in more than 60 of these countries.1 Global reports of
DHF have increased on average by fivefold in the past 20 years.1 Dengue epidemics
vary greatly in magnitude and severity. In 1998, the largest epidemics in history
occurred throughout Asia and the Americas, with more than 1.2 million cases of
DF/DHF reported to the World Health Organization (WHO). The factors responsible
for periodic epidemics in an area are not well understood. They are likely a combination
of the increased movement of viruses in people among countries and regions, the level
of herd immunity to specific virus serotypes in human populations, and genetic
changes in circulating or introduced viruses that give them greater epidemic potential.
At the beginning of the twenty-first century, dengue is the most important arboviral
disease of humans.19 Between 2000 and 2007 alone, at least eight previously dengue-
free areas experienced outbreaks, including Hong Kong, Macau, Nepal, Bhutan,
Madagascar, Hawaii, Galapagos, and Easter Island (Fig. 1).20 According to the Pan
American Health Organization (PAHO), 2007 was the worst year on record since
1985, with 918,495 cases of DF/DHF in the Americas.20
REASONS FOR THE GEOGRAPHIC SPREAD OF DENGUE IN THE PAST 30 YEARS

Climate
Global climate change is commonly blamed for the resurgence of dengue.21 There are
no good scientific data to support this conclusion, however.22 Dengue activity has
Fig. 1. Countries/areas at risk for dengue transmission, 2007. (Courtesy of DengueNet, World
Health Organization. Available at: www.who.int/ith (chapter 5). Accessed June 12, 2008; with
permission).
been reported to correlate with the El Nino Southern Oscillation (ENSO), in the South
Pacific region, where ENSO or southern oscillation indexes correlated with tempera-
ture or rainfall anomalies.23 The ENSO has not been shown to affect periodicity of den-
gue activity in Southeast Asia or the Americas independent of factors such as herd
immunity and infection enhancement.24 Warm temperature and high moisture may
contribute to increased adult survival, however.25 In addition, warmer temperatures
shorten the extrinsic incubation period.25 The minimum daily temperature, rather
than the average temperature, was reported to be the most important determinant
of dengue transmission seasonality in Bangkok.26 One study attempted to analyze
a potential association between dengue hemorrhagic fever (DHF) incidence and tem-
perature computed by satellite.27 Land surface temperature (LST) was chosen as an
indicator that combined radiated earth temperature and atmospheric water vapor
concentration. Positive association between LST and DHF incidence was significantly
correlated in 75% of the cases during nonepidemic months, whereas no correlation
was found during epidemic months. The authors concluded that nonclimatic factors
are supposed to be at the origin of this discrepancy between seasonality in climate
(LST) and DHF incidence during epidemics.27
A study in Puerto Rico showed that mosquito density was positively correlated with
rainfall.28 An increase in mosquito populations with the onset of the rainy season was
also shown in Bangkok.29 Dengue outbreaks on the Indian subcontinent frequently oc-
cur during the hot, dry season, however, because Ae aegypti breeds abundantly in the
reservoirs of desert coolers (also known as evaporative coolers).25 A study in Thailand
by the Aedes Research Unit showed no fluctuations in adult mosquito production and
densities in response to rainfall.26,30 Instead, there was a seasonal increase in adult
survival attributable to temperature and atmospheric moisture indicating that the
most likely reason for the association of dengue epidemics with rainfall can be ex-
plained by increased adult mosquito survival. In other words, adult abundance varies
not so much with temperature or rainfall but with increased humidity and the availabil-
ity and productivity of water-holding containers.25 This hypothesis is supported by the
fact that Ae aegypti–borne viral diseases were widespread in temperate latitudes dur-
ing the Little Ice Age (1600–1700 AD) because water for human consumption was
stored in rain barrels, which supported the populations of mosquitoes needed to
transmit viruses that were introduced during summer seasons.25,31 Dengue and yellow
fever caused multiple epidemics in the United States (mainly in the eastern and south-
ern parts) in the eighteenth, nineteenth, and early twentieth centuries, and their control
was not attributable to a change in climate but rather to changes in industrialization
and modernization that led to a reduction in open water-holding containers and breed-
ing sites and improved screening of houses. It is unlikely that these diseases will cause
major epidemics in the United States if the public health infrastructure is maintained
and improved.22 The spread of dengue between Pacific islands seems to be indepen-
dent of inter-annual climate variations, pointing to the importance of modulating fac-
tors in dengue transmission, such as population density and travel.32 In conclusion,
climate has rarely been the principal determinant of the prevalence or range; human
activities and their impact on local ecology have generally been much more signifi-
cant.31 In the future, models of the impact of climate change must attempt to account
for these factors.
Virus Evolution
The evolution of dengue viruses has had a major impact on their virulence for humans
and on the epidemiology of dengue disease around the world.33 Although antigenic and
genetic differences in virus strains have become evident, it is mainly the lack of animal
models for the disease that has made it difficult to detect differences in virulence among
dengue viruses. Phylogenetic studies of many different dengue virus samples have led
to the association between specific genotypes (within serotypes) and the presentation
of more or less severe disease. Currently, dengue viruses can be classified as being of
epidemiologically low, medium, or high impact; some viruses may remain in sylvatic
cycles of little or low transmissibility to humans, others produce DF only, and some
genotypes have been associated with the potential to cause the more severe DHF
and DSS in addition to DF.7,8,33 The American genotypes of DENV-2 and DENV-3, for
example, are less virulent with a reduced ability to grow in cell cultures and mosquitoes
compared with the Asian genotypes of DENV-2 and DENV-3.33,34 Phylogenetic studies
using envelope protein gene sequences of DENV-1, -2, and -4 suggested that the
endemic/epidemic lineages of these three DENV serotypes evolved independently
from sylvatic progenitors.16 Analysis of envelope protein amino acid changes predicted
to have accompanied endemic/epidemic emergence suggested a role for domain III in
adaptation to new mosquito or human hosts.16 Although the factors that contribute to
dengue virus epidemiology are complex, studies have suggested that specific viral
structures may contribute to increased replication in human target cells and to
increased transmission by the mosquito vector. Severity of disease also depends on
the strain and serotype of the infecting virus, age and genetic background of the
patient,4,5,8 and the degree of viremia.7,35 As to the question of whether dengue viruses
are evolving toward virulence as they continue to spread throughout the world, phylo-
genetic and epidemiologic analyses suggest that the more virulent genotypes are now
displacing those that have lower epidemiologic impact, but there is no evidence for the
transmission of antigenically aberrant new strains.5
Vector Control
Epidemic dengue was effectively controlled in most of tropical America in the 1950s
and 1960s as a side benefit of malaria and yellow fever control programs.1 Disruption
of vector control programs, be it for reasons of political and social unrest or scientific
reservations about the safety of DDT, has contributed to the resurgence of dengue
around the world. Lack of political will or complacency concerning vector-borne dis-
eases is another factor. Few new and effective mosquito-control methods have been
developed in the past 30 years.36 Vector control strategies are often limited to one ap-
proach, such as larvicidal or just adulticidal control. Vector control, however, should
be integrated and include source reduction and killing of adult mosquitoes, a com-
bined vertical and horizontal approach that depends on community participation,
and possibly the use of predacious copepods of the genus Mesocyclops as a biologic
control agent.37
Societal Factors
The dengue viruses are unique among the arboviruses as the only members of this
group that have evolved and fully adapted to the human host and the environment,
essentially eliminating the need for maintenance in the primitive enzootic forest cycle.1
Human population growth is highly correlated with dengue epidemics.38 Large popu-
lations in which viruses circulate may also allow more co-infection of mosquito and
human with more than one serotype of virus,39,40 potentially setting the stage for re-
combination events that could lead to the emergence of more virulent or transmissible
strains. Studies have documented that the number of dengue lineages has been
increasing roughly in parallel with the size of the human population over the last two
centuries.41 More urban areas in tropical and subtropical areas have reached the pop-
ulation size, estimated at perhaps 150,000 to 1 million, needed to sustain the ongoing
circulation of dengue virus.42 The unprecedented global population growth in the past
decades, in particular in the developing world, is also the main factor that has driven
many of the demographic and societal changes, such as urbanization, deforestation,
new dams and irrigation systems, poor housing, sewage and waste management sys-
tems, and lack of reliable water systems that make it necessary to collect and store
water.1 Poor garbage disposal associated with poorly controlled urbanization is com-
monly associated with dengue activity.43 Nonreturnable containers, such as cans,
plastic bottles, and tires, account for almost half of the container habitats found pos-
itive for the Ae aegypti mosquito in a study in Brazil.44 Urbanization associated with
poor infrastructure contributes to increased mosquito populations and closer contact
between humans and mosquito vectors. Population dynamics and viral evolution offer
the most parsimonious explanation for the observed epidemic cycles of the disease,
far more than climatic factors.22,27,45
The reasons for the resurgence of dengue are complex. It is impossible to determine
the extent that single factors, such as climate change, virus evolution, deteriorating
vector control, and societal changes, play in the expansion of dengue. Our opinion
is that population growth associated with rapid uncontrolled urbanization is likely
the main factor that has driven the rapid amplification of dengue in the past decades.
But the main factors responsible for the geographic spread are movements of popu-
lations or individuals by way of travel.1,5,22
SPREAD BY WAY OF TRAVEL
Mosquito vectors for dengue were historically spread by sailing ships.17 The mosquito
used the stored water on the ships as a breeding site and could maintain the transmis-
sion cycle, even on long journeys.17 Because of the slow mode of transportation,
epidemics were infrequent, with intervals of 10 to 40 years. When a new dengue virus
was introduced, however, it frequently resulted in major epidemics that affected
numerous countries in that region. Troop movements during WWII accelerated the
spread of viruses between population centers in the Asia-Pacific regions, causing
major epidemics. By the end of the war, most countries in Southeast Asia were hyper-
endemic, and a few years later epidemic DHF emerged in the region.17
Modern transportation provides an efficient mechanism to quickly move dengue
viruses and mosquitoes to new geographic regions around the globe. In recent
decades, used automobile and truck tires have been shown to be carriers for Ae
albopictus and other exotic species of mosquitoes.46 Ae albopictus, an Asian species,
was known outside of that region only in several Pacific islands before the 1980s. In
1979, it was introduced to Albania, most likely from China. In the mid-1980s, it was
independently introduced into the United States and Brazil from Japan in used tires.46
It subsequently spread throughout the Americas and to Italy and Africa. There are no
reports that dengue viruses have been introduced in mosquitoes, however. On the
other hand, it is well documented that the viruses are spread among countries by
way of infected humans incubating the virus.17
Viremic humans, whether troops, migrant workers, tourists, business travelers,
refugees, or others, carry the virus into new geographic areas, which can lead to out-
breaks if a competent vector inhabits the new area. Although a great deal of effort is
taken to prevent the spread of dengue viruses in infected mosquitoes by implementing
mosquito abatement programs at international airports and spraying adulticides in
passenger cabins of arriving aircraft, mosquitoes as agents of spread over long
distances (eg, between continents) are probably overrated, and viremic travelers are
the most likely source of the importation of dengue viruses.17,28
Individual and population movements can lead to epidemic waves. Dengue epi-
demic waves seem to originate from cities and then move to the rest of the country,
causing epidemics in smaller communities.47 Using the method of empiric mode
decomposition to show the existence of a spatial-temporal traveling wave, Cummings
and colleagues48 suggested that the dengue epidemics in Thailand emanated from
Bangkok, the largest city in Thailand, moving radially at a speed of 148 km/mo.
Molecular-epidemiologic studies are crucial in determining the transmission patterns
of dengue viruses and tracking the spread of dengue around the world.49 The following
section expands on the impact of travel as a mechanism for introducing dengue viruses
to new areas, thereby triggering outbreaks and further spread of the disease.
EXAMPLES OF IMPORTATION OF DENGUE

United States
Widespread epidemics of dengue in the continental United States are not likely,
despite claims to the contrary.50 Since its introduction into the United States in
1985, Ae albopictus has spread to 36 states, replacing Ae aegypti in many areas of
the Gulf Coast.51 Because it is such an inefficient epidemic vector, however, the
risk for dengue outbreaks is reduced.14 The public health infrastructure for vector-
borne diseases has deteriorated badly over the past 30 years and became virtually
nonexistent in many state and local health departments.1,50 After an absence of
56 years, dengue caused a small outbreak in Hawaii in 2001,52 and has appeared
with increasing frequency along the Texas-Mexico border from 1980 to the present,
usually associated with imported cases from Mexico, but limited local transmission
has also occurred.53 A DENV-2 epidemic causing dengue hemorrhagic fever (DHF)
occurred in the contiguous border cities of Matamoros, Tamaulipas (Mexico), and
Brownsville, Texas, in 2005.53 Discarded waste tires and buckets were the two largest
categories of Aedes-infested containers found in both cities.53 Dengue has also re-
emerged as a major problem in United States tropical territories and commonwealths,
such as Puerto Rico, which has experienced increasingly larger and more frequent
epidemics caused by all four virus serotypes since the mid-1970s. Because dengue
is a common problem in United States travelers,54,55 more frequent importation events
could potentially lead to more autochthonous transmission in the Southern parts of the
United States where Ae aegypti exists.
The Americas and the Caribbean

The American genotypes of DENV-2 and DENV-3 were present in the 1970s. Dengue
serotypes from Asia were introduced into the Americas, most likely by travelers, in
1977 (DENV-1), followed by DENV-2 and DENV-4 in 1981, and DENV-3 in 1994.17
The Asian genotypes of DENV-2 and DENV-3 were more virulent compared with the
American genotypes and resulted in increased epidemics.33,34 The introduction of
DENV-2 in 1981 from Vietnam to Cuba was associated with a major epidemic of
DHF and spread throughout the tropical Americas, effectively replacing the American
genotype in the region.4,5,56 The Asian genotype of DENV-3 also spread throughout
the Americas causing major epidemics of DHF.4
To determine rates or determinants of viral spread or their directions of movement,
a Bayesian method of a coalescent approach was used to assess patterns of strain
migration of DENV-2 and DENV-4 after their introduction in 1981.57 For both viruses
there was an initial invasion phase characterized by an exponential increase in the
number of DENV lineages, after which levels of genetic diversity remained constant
despite reported fluctuations in DENV-2 and DENV-4 activity. Viral lineage numbers
increased far more rapidly for DENV-4 than DENV-2, indicating a more rapid rate of
exponential population growth in DENV-4 or a higher rate of geographic dispersal,
allowing this virus to move more effectively among localities, most likely reflecting
underlying differences in patterns of host immunity.57 DENV-4 has never caused a ma-
jor epidemic in Brazil, however.
A total of 4,243,049 dengue cases have been reported in Brazil between 1981 and
2006, with the Northeast and Southeast regions most affected.58 DENV-1 and DENV-4
were isolated for the first time in the Amazon region of Brazil in 1981 and 1982. The
disease became a nationwide public health problem following outbreaks of DENV-1
and DENV-2 in the state of Rio de Janeiro in 1986 and 1990, respectively. The intro-
duction of DENV-3 in 2000, also in the state of Rio de Janeiro, led to a severe epidemic
with 288,245 reported dengue cases.59 Virus strains that were typed during the 2002
epidemic showed that DENV-3 has displaced other dengue virus serotypes and
entered new areas.59
Europe
Ae albopictus was detected in Albania in 1979 and in Italy in 1990 and has become
a threat to many other Mediterranean countries, particularly the southern part of
France (French Riviera and Corsica) where climatic conditions are suitable for its es-
tablishment.60 The origin of the infestation in Northern Italy was shown to be related to
the importation of used tires.61 The tolerance exhibited by some natural populations of
Ae albopictus for low temperatures allows this species to occupy an area much farther
north than Ae aegypti.60,62 Ae albopictus is now believed to be in at least 12 countries
in Europe.63 An outbreak of chikungunya virus disease affecting more than 200 inhab-
itants occurred in Northern Italy in 2007 following the importation by a viremic traveler
from India.64 Autochthonous spread was possible because of the susceptibility of Ae
albopictus for chikungunya virus. Dengue is much more frequently imported than chi-
kungunya,65 but no autochthonous transmission of dengue has been reported to date.
In the past, however, dengue did occur in Europe before the eradication of Ae
aegypti.17
Pacific Islands
Dengue continues to be a threat to Pacific Island countries and territories (PICTs). After
an absence of 25 years, all four serotypes were introduced in the 1970s, causing major
epidemics, some associated with DHF.17 The last DENV-1 epidemic affected 16 PICTs
and in some of them it affected as much as 20% of the population, having a major pub-
lic health impact and a massive impact on their fragile economies.25 The continuing
outbreak of dengue in the Pacific has been attributed to multiple, direct introductions
of dengue viruses from various locations in Asia followed by local transmission.66,67
Australia
Outbreaks of DF have repeatedly occurred in North Queensland following the impor-
tation of dengue virus in returned travelers.68 The successful prevention of widespread
local transmission in these circumstances was facilitated by early notification and
isolation of cases, and collaboration with local public health authorities in vector
control.68
DENGUE IN INTERNATIONAL TRAVELERS
The marked increase of dengue over the past 3 decades is in tandem with increasing
reports of international travelers suffering from dengue, including long-term
expatriates, aid/development workers, the military stationed in dengue-endemic

countries, and immigrants from endemic countries.3,65,69–89 In some case series, DF
now presents the second most frequent cause of hospitalization (after malaria) in
travelers returning from the tropics.71,80 GeoSentinel is a worldwide network of travel
medicine providers who see ill returning travelers.90 Dengue accounted for up to 2% of
all morbidity in returned ill travelers visiting GeoSentinel clinics.91 As part of a broad
comprehensive analysis of the spectrum of disease in travelers, the GeoSentinel
surveillance network has shown that over the past decade dengue has emerged as
a more frequent diagnosis than malaria in ill returned travelers from all tropical regions
outside of Africa.91 Prospective seroconversion studies have estimated the attack rate
of dengue virus infection in travelers to the tropics to be 2.9% in Dutch travelers
traveling for 1 month to Asia,76 whereas among Israelis traveling for an average of
5 months the seroconversion rate was 6.7%.92 The incidence of dengue is now con-
sidered to be higher than that of other typical travel-related diseases, such as hepatitis
A or typhoid fever.3 Risk factors for acquiring dengue depend on duration of travel,
season, and destination.76 Most dengue virus infections in travelers are acquired in
Asia, followed by the Americas, and only a small proportion in Africa.69,91
Classic DF in travelers, although mostly self-limiting and rarely fatal, can be incapa-
citating, may halt travel, and may require hospitalization and even evacuation and a re-
turn home.3 Severe dengue infections, such as DHF, seem to be less frequent in
travelers compared with the indigenous population, however.93 The low incidence
of DHF in these travelers may be attributable to most travelers not having pre-existing
antibodies to dengue, given their lack of previous exposure.94 Another factor that may
contribute to the lower incidence of DHF in travelers is that most travelers are adults,
and adults are reported to have a lower risk for DHF compared with children.95
TRAVELERS AS SENTINEL
As travelers return from any of the countries where dengue is currently endemic, they
potentially reflect the evolving epidemiology of dengue. The analysis of DENV isolated
from travelers contributes to the global picture of strain distribution and circulation.96
Properly annotated sequence data for flaviviruses can aid in tracking the spread of
dengue. Flavitrack was designed to help identify conserved sequence motifs, interpret
mutational and structural data, and track evolution of phenotypic properties, and now
contains more than 590 complete flavivirus genome/protein sequences and informa-
tion on known mutations and literature references.97 Flavitrack could potentially be
used to compare sequences of viruses found in returning travelers and those
described worldwide.
Data collected longitudinally over a decade by the GeoSentinel Surveillance
Network examined month-by-month morbidity from a sample of 522 cases of dengue
as a proportion of all diagnoses in 24,920 ill returned travelers seen at our 33 surveil-
lance sites.98 The data showed that travel-related dengue reflects defined seasonality
for some regions (Southeast Asia, South Central Asia, Caribbean, South America). The
natural, year-to-year oscillations of dengue cases in endemic populations were also
observed in travelers. In each of the epidemic years of 1998 and 2002 in Southeast
Asia, the usual pattern of seasonality changed with an excess of cases throughout
the whole year.98 The outbreak in 1998 in Thailand was reflected in travelers by an
excess in cases that preceded the usual increased seasonal activity. When the
1998 pattern in travelers reoccurred in early 2002, it led to the immediate hypothesis
that this early transmission would once again herald an epidemic year. In April 2002,
GeoSentinel alerted the international community when it posted online the increase in
travel-related dengue from Thailand. Official surveillance data from local populations
are often not immediately available to the international community. Data reported later
by Thai authorities to the WHO confirmed the observation. The increase in dengue
cases in returned travelers from South Central Asia in 2003 was also evident before
official surveillance data were available, reinforcing the increasing usefulness of sen-
tinel surveillance in travelers. Because the number of travelers to areas with epidemics
may be small and some epidemics may occur in parts of a country that are not visited
by travelers, sentinel surveillance in travelers cannot be a definitive and uniquely
sensitive tool for detection of all disease outbreaks, but preliminary experience with
GeoSentinel show that the traveling population can give additional timely and specific
information.98 Travelers may therefore serve as sentinels rapidly informing the interna-
tional community about the onset of epidemics in endemic areas. Sentinel surveillance
of travelers can provide an additional layer in the international surveillance effort.
SUMMARY
Because of the expanding geographic distribution of the virus and the mosquito vec-
tor, increased frequency of epidemics, cocirculation of multiple virus serotypes, and
the emergence of DHF in new areas, WHO classifies dengue as a major international
public health concern.1,2 The reasons for this resurgence are complex and include
unprecedented urbanization with substandard living conditions, lack of vector control,
virus evolution, and international travel.1,4,5 Of all these factors, urbanization in tropical
and subtropical regions has probably had the most impact on the amplification of den-
gue within a given country, and travel had the most impact for the spread of dengue
from country to country and continent to continent. Modern rapid intercontinental
transportation has had a major influence on the distribution and transmission dynam-
ics of dengue. Epidemics of dengue, their seasonality, and oscillations over time are
reflected by the epidemiology of dengue in travelers. Sentinel surveillance of travelers
could augment existing national public health surveillance systems.
REFERENCES
1. Gubler DJ. The global emergence/resurgence of arboviral diseases as public

health problems. Arch Med Res 2002;33(4):330–42.
2. Gibbons RV, Vaughn DW. Dengue: an escalating problem. BMJ 2002;324(7353):
1563–6.
3. Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005;353(9):
924–32.
4. Guzman MG, Kouri G. Dengue: an update. Lancet Infect Dis 2002;2(1):33–42.
5. Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998;
11(3):480–96.
6. Gubler DJ. The global pandemic of dengue/dengue haemorrhagic fever: current
status and prospects for the future. Ann Acad Med Singapore 1998;27(2):227–34.
7. Gubler DJ, Suharyono W, Lubis I, et al. Epidemic dengue 3 in central java, asso-
ciated with low viremia in man. Am J Trop Med Hyg 1981;30(5):1094–9.
8. Rosen L. The emperor’s new clothes revisited, or reflections on the pathogenesis
of dengue hemorrhagic fever. Am J Trop Med Hyg 1977;26(3):337–43.
9. Halstead SB, O’Rourke EJ. Dengue viruses and mononuclear phagocytes. I. Infec-
tion enhancement by non-neutralizing antibody. J Exp Med 1977;146(1):201–17.
10. Halstead SB. In vivo enhancement of dengue virus infection in rhesus monkeys
by passively transferred antibody. J Infect Dis 1979;140(4):527–33.
11. Halstead SB. Immune enhancement of viral infection. Prog Allergy 1982;31:
301–64.
12. Mongkolsapaya J, Dejnirattisai W, Xu XN, et al. Original antigenic sin and apopto-
sis in the pathogenesis of dengue hemorrhagic fever. Nat Med 2003;9(7):921–7.
13. Dong T, Moran E, Vinh Chau N, et al. High pro-inflammatory cytokine secretion
and loss of high avidity cross-reactive cytotoxic T-cells during the course of sec-
ondary dengue virus infection. PLoS ONE 2007;2(12):e1192.
14. Gubler DJ. Aedes albopictus in Africa. Lancet Infect Dis 2003;3(12):751–2.
15. Holmes EC, Twiddy SS. The origin, emergence and evolutionary genetics of den-
gue virus. Infect Genet Evol 2003;3(1):19–28.
16. Wang E, Ni H, Xu R, et al. Evolutionary relationships of endemic/epidemic and
sylvatic dengue viruses. J Virol 2000;74(7):3227–34.
17. Gubler D. Dengue and dengue hemorrhagic fever: its history and resurgence as
a global public health problem. In: Gubler DJ, Kuno G, editors. Dengue and den-
gue hemorrhagic fever. London: CAB International; 1997. p. 1–22.
18. Gubler DJ, Clark GG. Dengue/dengue hemorrhagic fever: the emergence of
a global health problem. Emerg Infect Dis 1995;1(2):55–7.
19. Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health, social
and economic problem in the 21st century. Trends Microbiol 2002;10(2):100–3.
20. World Health Organization. International travel and health. Available at: www.who.
int/ith; 2008; (chapter 5). Accessed February 15, 2008.
21. Barclay E. Is climate change affecting dengue in the Americas? Lancet 2008;
371(9617):973–4.
22. Gubler DJ, Reiter P, Ebi KL, et al. Climate variability and change in the United
States: potential impacts on vector- and rodent-borne diseases. Environ Health
Perspect 2001;109(Suppl 2):223–33.
23. Hales S, Weinstein P, Woodward A. Dengue fever epidemics in the South Pacific:
driven by El Nino Southern Oscillation? Lancet 1996;348(9042):1664–5.
24. Wearing HJ, Rohani P. Ecological and immunological determinants of dengue
epidemics. Proc Natl Acad Sci U S A 2006;103(31):11802–7.
25. Halstead SB. Dengue virus-mosquito interactions. Annu Rev Entomol 2008;53:
273–91.
26. Pant CP, Jatanasen S, Yasuno M. Prevalence of Aedes aegypti and Aedes albo-
pictus and observations on the ecology of dengue haemorrhagic fever in several
areas of Thailand. Southeast Asian J Trop Med Public Health 1973;4(1):113–21.
27. Nitatpattana N, Singhasivanon P, Kiyoshi H, et al. Potential association of dengue
hemorrhagic fever incidence and remote senses land surface temperature,
Thailand, 1998. Southeast Asian J Trop Med Public Health 2007;38(3):427–33.
28. Moore CG, Cline BL, Ruiz-Tiben E, et al. Aedes aegypti in Puerto Rico: environ-
mental determinants of larval abundance and relation to dengue virus transmis-
sion. Am J Trop Med Hyg 1978;27(6):1225–31.
29. Tonn RJ, Macdonald WW, Sheppard PM, et al. The magnitude of seasonal
changes in larval populations of Aedes aegypti in Bangkok, Thailand. Bull World
Health Organ 1970;42(6):943–50.
30. Sheppard PM, MacDonald WW, Tonn RJ, et al. The dynamics of an adult popu-
lation of Aedes aegypti in relation to dengue hemorrhagic fever in Bangkok. J
Anim Ecol 1969;38:661–702.
31. Reiter P. Climate change and mosquito-borne disease. Environ Health Perspect
2001;109(Suppl 1):141–61.
32. Hales S, Weinstein P, Souares Y, et al. El Nino and the dynamics of vectorborne
disease transmission. Environ Health Perspect 1999;107(2):99–102.
33. Rico-Hesse R. Microevolution and virulence of dengue viruses. Adv Virus Res
2003;59:315–41.
34. Gubler DJ, Rosen L. Quantitative aspects of replication of dengue viruses in
Aedes albopictus (Diptera: Culicidae) after oral and parenteral infection. J Med
Entomol 1977;13(4–5):469–72.
35. Vaughn DW, Green S, Kalayanarooj S, et al. Dengue viremia titer, antibody
response pattern, and virus serotype correlate with disease severity. J Infect
Dis 2000;181(1):2–9.
36. Gubler DJ. The changing epidemiology of yellow fever and dengue, 1900 to
2003: full circle? Comp Immunol Microbiol Infect Dis 2004;27(5):319–30.
37. Kay B, Vu SN. New strategy against Aedes aegypti in Vietnam. Lancet 2005;
365(9459):613–7.
38. Gubler DJ, Meltzer M. Impact of dengue/dengue hemorrhagic fever on the devel-
oping world. Adv Virus Res 1999;53:35–70.
39. Lorono-Pino MA, Cropp CB, Farfan JA, et al. Common occurrence of concurrent
infections by multiple dengue virus serotypes. Am J Trop Med Hyg 1999;61(5):
725–30.
40. Worobey M, Rambaut A, Holmes EC. Widespread intra-serotype recombination in
natural populations of dengue virus. Proc Natl Acad Sci U S A 1999;96(13):
7352–7.
41. Zanotto PM, Gould EA, Gao GF, et al. Population dynamics of flaviviruses re-
vealed by molecular phylogenies. Proc Natl Acad Sci U S A 1996;93(2):548–53.
42. Wilson ME. The traveller and emerging infections: sentinel, courier, transmitter.
J Appl Microbiol 2003;94(Suppl):S1–11.
43. Thammapalo S, Chongsuvivatwong V, Geater A, et al. Environmental factors and
incidence of dengue fever and dengue haemorrhagic fever in an urban area,
Southern Thailand. Epidemiol Infect 2008;136(1):135–43.
44. Mazine CA, Macoris ML, Andrighetti MT, et al. Disposable containers as larval
habitats for Aedes aegypti in a city with regular refuse collection: a study in
Marilia, Sao Paulo State, Brazil. Acta Trop 1996;62(1):1–13.
45. Hay SI, Myers MF, Burke DS, et al. Etiology of interepidemic periods of mosquito-
borne disease. Proc Natl Acad Sci U S A 2000;97(16):9335–9.
46. Moore CG, Francy DB, Eliason DA, et al. Aedes albopictus in the United States:
rapid spread of a potential disease vector. J Am Mosq Control Assoc 1988;4(3):
356–61.
47. Gubler DJ. Cities spawn epidemic dengue viruses. Nat Med 2004;10(2):129–30.
48. Cummings DA, Irizarry RA, Huang NE, et al. Travelling waves in the occurrence of
dengue haemorrhagic fever in Thailand. Nature 2004;427(6972):344–7.
49. Rico-Hesse R. Molecular evolution and distribution of dengue viruses type 1 and
2 in nature. Virology 1990;174(2):479–93.
50. Morens DM, Fauci AS. Dengue and hemorrhagic fever: a potential threat to public
health in the United States. JAMA 2008;299(2):214–6.
51. Benedict MQ, Levine RS, Hawley WA, et al. Spread of the tiger: global risk of
invasion by the mosquito Aedes albopictus. Vector Borne Zoonotic Dis 2007;
7(1):76–85.
52. Effler PV, Pang L, Kitsutani P, et al. Dengue fever, Hawaii, 2001–2002. Emerg
Infect Dis 2005;11(5):742–9.
53. Ramos MM, Mohammed H, Zielinski-Gutierrez E, et al. Epidemic dengue and
dengue hemorrhagic fever at the Texas-Mexico border: results of a household-
based seroepidemiologic survey, December 2005. Am J Trop Med Hyg 2008;
78(3):364–9.
54. Wilson ME, Freedman DO. Etiology of travel-related fever. Curr Opin Infect Dis
2007;20(5):449–53.
55. From the Centers for Disease Control and Prevention. Imported dengue—United
States, 1997 and 1998. Jama 2000;283(15):1953–4.
56. Foster JE, Bennett SN, Carrington CV, et al. Phylogeography and molecular
evolution of dengue 2 in the Caribbean basin, 1981–2000. Virology 2004;
324(1):48–59.
57. Carrington CV, Foster JE, Pybus OG, et al. Invasion and maintenance of dengue
virus type 2 and type 4 in the Americas. J Virol 2005;79(23):14680–7.
58. Nogueira RM, de Araujo JM, Schatzmayr HG. Dengue viruses in Brazil, 1986–
2006. Rev Panam Salud Publica 2007;22(5):358–63.
59. Nogueira RM, Schatzmayr HG, de Filippis AM, et al. Dengue virus type 3, Brazil,
2002. Emerg Infect Dis 2005;11(9):1376–81.
60. Rodhain F. Aedes albopictus: a potential problem in France. Parassitologia 1995;
37(2–3):115–9.
61. Romi R. History and updating on the spread of Aedes albopictus in Italy. Parassi-
tologia 1995;37(2–3):99–103.
62. Rodhain F. Aedes albopictus in Europe: a real threat. Bull Soc Pathol Exot 1993;
86(1):3.
63. Vazeille M, Jeannin C, Martin E, et al. Chikungunya: a risk for Mediterranean
countries? Acta Trop 2008;105(2):200–2.
outbreak in a temperate region. Lancet 2007;370(9602):1840–6.
65. Jelinek T, Muhlberger N, Harms G, et al. Epidemiology and clinical features of
imported dengue fever in Europe: sentinel surveillance data from TropNetEurop.
Clin Infect Dis 2002;35(9):1047–52.
66. Nuegoonpipat A, Berlioz-Arthaud A, Chow V, et al. Sustained transmission of den-
gue virus type 1 in the Pacific due to repeated introductions of different Asian
strains. Virology 2004;329(2):505–12.
67. Chungue E, Cassar O, Drouet MT, et al. Molecular epidemiology of dengue-1 and
dengue-4 viruses. J Gen Virol 1995;76(Pt 7):1877–84.
68. Kitchener S, Leggat PA, Brennan L, et al. Importation of dengue by soldiers
returning from East Timor to north Queensland, Australia. J Travel Med 2002;
9(4):180–3.
69. Jelinek T, Dobler G, Holscher M, et al. Prevalence of infection with dengue virus
among international travelers. Arch Intern Med 1997;157(20):2367–70.
70. Wichmann O, Muhlberger N, Jelinek T. Dengue—the underestimated risk in travel-
lers. Dengue Bull 2003;27:126–37.
71. Schwartz E, Mendelson E, Sidi Y. Dengue fever among travelers. Am J Med 1996;
101(5):516–20.
72. Schwarz TF, Jager G, Gilch S. Imported dengue virus infections in German
tourists. Zentralbl Bakteriol 1995;282(4):533–6.
73. Lopez-Velez R, Perez-Casas C, Vorndam AV, et al. Dengue in Spanish travelers
returning from the tropics. Eur J Clin Microbiol Infect Dis 1996;15(10):823–6.
74. Wittesjo B, Eitrem R, Niklasson B. Dengue fever among Swedish tourists. Scand
J Infect Dis 1993;25(6):699–704.
75. Yamada KI, Takasaki T, Nawa M, et al. The features of imported dengue fever
cases from 1996 to 1999. Jpn J Infect Dis 1999;52(6):257–9.
76. Cobelens FG, Groen J, Osterhaus AD, et al. Incidence and risk factors of probable
dengue virus infection among Dutch travellers to Asia. Trop Med Int Health 2002;
7(4):331–8.
77. Norwood CG, Larocco A, Laravia DA, et al. Dengue fever risk and prevention for short-
term group travelers to tropical regions. J La State Med Soc 1999;151(6):313–8.
78. Janisch T, Preiser W, Berger A, et al. Emerging viral pathogens in long-term
expatriates (II): dengue virus. Trop Med Int Health 1997;2(10):934–40.
79. Lindback H, Lindback J, Tegnell A, et al. Dengue fever in travelers to the tropics,
1998 and 1999. Emerg Infect Dis 2003;9(4):438–42.
80. O’Brien D, Tobin S, Brown GV, et al. Fever in returned travelers: review of hospital
admissions for a 3-year period. Clin Infect Dis 2001;33(5):603–9.
81. Potasman I, Srugo I, Schwartz E. Dengue seroconversion among Israeli travelers
to tropical countries. Emerg Infect Dis 1999;5(6):824–7.
82. O’Leary DR, Rigau-Perez JG, Hayes EB, et al. Assessment of dengue risk in relief
workers in Puerto Rico after Hurricane Georges, 1998. Am J Trop Med Hyg 2002;
66(1):35–9.
83. Sharp TW, DeFraites RF, Thornton SA, et al. Illness in journalists and relief workers
involved in international humanitarian assistance efforts in Somalia, 1992–1993.
J Travel Med 1995;2(2):70–6.
84. Sharp TW, Wallace MR, Hayes CG, et al. Dengue fever in U.S. troops during
Operation Restore Hope, Somalia, 1992–1993. Am J Trop Med Hyg 1995;53(1):
89–94.
85. Imported dengue—United States, 1993–1994. MMWR Morb Mortal Wkly Rep
1995;44(18):353–6.
86. Imported dengue—United States, 1995. MMWR Morb Mortal Wkly Rep 1996;
45(45):988–91.
87. Imported dengue—United States, 1996. Can Commun Dis Rep 1998;24(20):
164–5, 168.
88. Imported dengue—United States, 1997 and 1998. MMWR Morb Mortal Wkly Rep
2000;49(12):248–53.
89. Imported dengue—United States, 1999 and 2000. MMWR Morb Mortal Wkly Rep
2002;51(13):281–3.
90. Freedman D. The GeoSentinel group. GeoSentinel: the global emerging infec-
tions sentinel network of the international society of travel medicine. J of Travel
Medicine 1999;6:94–8.
91. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to
place of exposure among ill returned travelers. N Engl J Med 2006;354(2):
119–30.
92. Schwartz E, Moskovitz A, Potasman I, et al. Changing epidemiology of dengue
fever in travelers to Thailand. Eur J Clin Microbiol Infect Dis 2000;19(10):784–6.
93. Wichmann O, Gascon J, Schunk M, et al. Severe dengue virus infection in trav-
elers: risk factors and laboratory indicators. J Infect Dis 2007;195(8):1089–96.
94. Wilder-Smith A, Tambyah PA. Severe dengue virus infection in travelers. J Infect
Dis 2007;195(8):1081–3.
95. Hammond SN, Balmaseda A, Perez L, et al. Differences in dengue severity in
infants, children, and adults in a 3-year hospital-based study in Nicaragua. Am
J Trop Med Hyg 2005;73(6):1063–70.
96. Huhtamo E, Uzcategui NY, Siikamaki H, et al. Molecular epidemiology of dengue
virus strains from Finnish travelers. Emerg Infect Dis 2008;14(1):80–3.
97. Misra M, Schein CH. Flavitrack: an annotated database of flavivirus sequences.
Bioinformatics 2007;23(19):2645–7.
98. Schwartz E, Weld LH, Wilder-Smith A, et al. Seasonality, annual trends, and char-
acteristics of dengue in ill returned travelers (1997–2006). Emerg Infect Dis 2008;
14(7):1081–8.
One Res er voir :
Re defining the
Communit y Origins of
Antimicrobial - resista nt
I nfe c tions
Ellen K. Silbergeld, PhDa,*, Meghan Davis, DVMa,
Jessica H. Leibler, MSa, Amy E. Peterson, DVMb
KEYWORDS
Antimicrobial resistance MRSA Agriculture
Resistance reservoir
Extraordinary health benefits have accrued from the discovery of antimicrobials since
the mid-twentieth century.1 However, as T.S. Eliot wrote, ‘‘In my beginning is my
end.’’2 The use of antibiotics has driven the evolution and spread of antimicrobial re-
sistance from the beginning. Fleming3 himself noticed this in his laboratory studies
and, soon after, Starr and Reynolds4 warned of the public health risks of the novel ap-
plication of these drugs to feeds for farm animals. Antimicrobial-resistant bacteria now
constitute a significant proportion of the emerging infectious disease pathogens that
have been reported since 1940.5 This has led to the dystopian declaration that we
have entered the ‘‘postantibiotic era.’’6
From an evolutionary perspective, selection for antimicrobial resistance is an inev-
itable biological response to continued exposure to antimicrobial agents.7 Bacteria
have evolved in the presence of naturally occurring antimicrobial agents. Many of
the antimicrobials used in clinical medicine are analogs of compounds produced by
organisms such as Streptomyces, Bacillus, Penicillium and Cephalosporum.8 How-
ever, human exploitation of these agents has accelerated the global development of
resistance. This is often ascribed to clinical health care settings involving practitioners
and consumers, supporting the assumption that the increasing prevalence of drug-
resistant infections is nosocomial, or health care-associated, in origin; and the result
of overly broad treatment regimens, incomplete treatment, or patient non-
a
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns
Hopkins University, 615 N. Wolfe Street, E6644, Baltimore, MD 21205, USA
b
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University,
615 N. Wolfe Street, E6644, Baltimore, MD 21205, USA
E-mail address: esilberg@jhsph.edu (E.K. Silbergeld).
Med Clin N Am 92 (2008) 1391–1407

1392 Silbergeld et al
compliance.1 Health care settings are clearly important in the evolution and spread of
resistant bacteria, but the fact that most resistant infections are identified in a hospital
does not necessarily imply that resistance originates there. There is growing recogni-
tion of the importance of community origins as ‘‘feeders’’ of pathogens into the clinical
setting. Methicillin-resistant Staphylococcus aureus (MRSA) serves as a model for re-
focusing the lens of research on the origins of emerging infections. The rapidly evolv-
ing epidemic of community-acquired MRSA9,10 has directed new attention to the
importance of investigating nonhospital antecedents of antimicrobial resistance. An
exclusive focus on the hospital setting restricts the scope of action to late stages of
control. Moreover, interventions that target the development of antibiotic resistance
in the community offer greater potential for success in preventing disease before it
can enter and be transmitted in the hospital.
In this review, the authors focus on a major component of the drivers for antimicro-
bial resistance in the community: the use of antimicrobial drugs as feed additives for
animals grown for human consumption. Antimicrobial feed additives are now the ma-
jor use of antimicrobials in the United States and many countries.11 This fact is not
generally recognized in clinical medicine; for example, a recent analysis of the problem
of antimicrobial resistance devotes less than one page to the issue of antimicrobial use
in agriculture.1 The purposes of agricultural antimicrobial use lie in the transformation
of agricultural practices over the past 50 years, away from many small-scale family
farms across the United States to fewer intensive, large-scale operations (known as
CAFOs, or confined animal feeding operations) that are concentrated regionally. The
transformation of food animal agriculture – involving changes in methods of produc-
tion, ownership, and stewardship – promotes the development of antimicrobial resis-
tance.11 These changes also contribute to economic marginalization of workers and
socioeconomic decline in rural communities, factors that may increase the difficulty
in monitoring and early detection of resistant infections.
THE HOSPITAL IN THE COMMUNITY AND THE COMMUNITY IN THE HOSPITAL
Hospitals are a focal point for recognizing the health problems of the community. As
a result, antimicrobial-resistant infections are more likely to be accurately diagnosed in
patients in the hospital setting as compared with clinics or by individual practitioners.
But patients in hospital bring their community with them, carrying their individual mi-
crocommunities of pathogens and commensal bacteria. In the face of widespread
antimicrobial use in the hospital setting, these microcommunities can shift toward
a higher prevalence of resistant organisms, and resistance determinants may be
transferred from commensals to pathogens.12 The hospital setting also enhances
transmission from new entrants to nonexposed patients, some of whom may be espe-
cially susceptible to infection. As a result, hospitals are both a surveillance point and
a multiplier for resistant infections.
There are standard methods for classifying strains as hospital-acquired or commu-
nity-acquired (Box 1). This categorization may obscure rather than illuminate the inter-
relationships that exist between health care environments and the community
because identification of a health care-associated risk factor is often a disincentive
for further exploration of additional risk factors. The Centers for Disease Control
(CDC) classification for infections is neither definitive nor exclusive. Identifying health
care-associated risk factors does not address the potential for entrance of a pathogen
from the community into the health care system.13
There is evidence for the increasing prevalence of community sources of other
antimicrobial-resistant infections isolated from patients in the hospital setting. For
Origins of Antimicrobial-resistant Infections 1393
Box 1
Criteria for definition of hospital-acquired (HA) versus community-acquired (CA) risk factors
for infection: the example of MRSA
HA-MRSAa
Recent or current exposure to hospital or outpatient clinic or long term care
(eg, residence in a facility)
Infection detected more than 48 hrs after admission to hospital or other health care facility
CA-MRSA
No documented health care risk factors
Infection detected before or within 48 hrs after admission to hospital or other health care
facility
a
Patients with prior MRSA colonization are often classified HA-MRSA.
Data from Klevens, Monina R, Morrison, Melissa A. et al. Invasive methicillin-resistant Staph-
ylococcus aureus infections in the United States. JAMA 2007;298(15):1763–71.
example, in a study of incoming patients at a tertiary care hospital in Boston, from

1998 to 2003, the likelihood of multidrug resistance in Escherichia coli increased
from 2% to almost 20% (Fig. 1).14
COMMUNITY RESERVOIRS OF ANTIMICROBIAL RESISTANCE: THE AGRICULTURAL INCUBATOR
Antimicrobial resistance reflects dynamic interactions among pathogens, drugs, and

hosts (both animal and human) in shared environments.15,16 Human exposure to resis-
tant pathogens occurs in the context of microbial ecosystems in which three mecha-
nisms drive the development and, most importantly, the dissemination of resistance:
natural selection, the sharing of resistance genes, and the reservoir of resistance. In-
dustrial food animal production is in many ways the ideal setting for all of these events.
The use of antimicrobials as feed additives results in uncontrolled and subtherapeutic
doses over the lifetime of animals raised in grossly unhygienic surroundings. This pres-
ents the worst possible scenario for resistance selection and infection control. Cou-
pled with incomplete biosecurity and biocontainment, and mostly nonexistent waste
treatment,17 these conditions lead to dissemination into human hosts and the environ-
ment, with amplification of reservoirs of resistance.
Fig.1. Increasing prevalence of multidrug-resistant E coli isolated from incoming patients in

Boston. Temporal increases were highly significant (P<.001). (Data from Pop-Vicas AE,
D’Agata EM. The rising influx of multidrug-resistant gram-negative bacilli into a tertiary
care hospital. Clin Infect Dis 2005;40(12):1792–98.)
The reservoir of resistance or ‘‘resistome’’ represents the genetic resources avail-

able within a community of organisms.7 The availability and persistence of resistance
determinants within the microbial ecosystem fuels the development and proliferation
of resistance.18 The resistance reservoir must be taken to include both pathogenic and
nonpathogenic organisms because of the wide-ranging ability of bacteria to share re-
sistance genes through molecular mechanisms of horizontal gene transfer.7 The
reservoir concept more broadly underscores the contribution of all sources of antimi-
crobial pressure to drug resistance, and it provides the theoretic construct for empha-
sizing the contribution of the nontherapeutic use of antimicrobials in food animal
production to the resistance reservoir. This has been documented specifically for
poultry and swine production.19,20
The intensive use of antimicrobials as feed additives in food animal production
began in the United States in the 1950s and paralleled other changes in the orga-
nization and structure of the industry.21 Current food animal production—including
poultry, cattle, swine, and aquaculture—employs a wide variety of antimicrobial
agents from all the major classes of antimicrobials approved for human clinical
use (Table 1). Antimicrobials are administered to food animals for three main pur-
poses: therapeutic use for the treatment of sick animals, prophylaxis to prevent
the spread of disease among susceptible animals, and, nontherapeutically, for
growth promotion. The assumed benefit of antimicrobial feed additive use is to de-
crease the time and total feed consumption needed to grow an animal to market
weight. Production-based estimates suggest that drug use in animal feeds ac-
counts for between 60% and 80% of total antimicrobial production in the United
States and, until recently, in the European Union as well.11 It is unfortunate, how-
ever, that direct information about antimicrobial uses is not available. In the United
States, estimated antimicrobial use in animal feeds in North Carolina alone exceeds
total human clinical use for the entire United States population.22 With relatively few
exceptions, no data are available from the rest of the world,23 but the expansion of
the modern industrial model of food animal production, including antimicrobial use
in feeds, is particularly rapid in Asia and South America.17
The sheer mass of antimicrobial use in agriculture suggests that the quantitative
global impact of this use is likely to be significant. Practices common to modern
food animal production enhance selection for resistance and sharing of pathogenic
and commensal bacteria among animals. The overwhelming majority of animals
grown for human consumption are raised in CAFOs in the United States and in-
creasingly throughout the world,24 where thousands to tens of thousands of animals
are crowded together close to or on top of their wastes (Fig. 2A,B). Crowding,
stress, inappropriate feeds, ventilation practices, and waste management tech-
niques inherent to this system enhance release of microbes to the external
environment.11
Antimicrobial use in animal feeds has played a major role in the development
and spread of fluoroquinolone-resistant Campylobacter jejeuni,25 streptogramin-
or vancomycin-resistant Enterococci (VRE),26 and multidrug-resistant Salmonella.27
The large community reservoir of VRE in Europe has been ascribed to the wide-
spread use of avoparcin (a vancomycin-like glycopeptide) in food animal produc-
tion, in contrast to the situation in the United States where avoparcin never was
approved as an animal feed additive.26 At its peak, use of avoparcin in animals
in Denmark was 1000 times the total clinical use of vancomycin.28 After the Euro-
pean Union ban on avoparcin in 1997, surveillance programs demonstrated a rapid
decrease in the prevalence of vancomycin resistance in Enterococci in human iso-
lates as well as in animal isolates, animal waste, and consumer food products,29
reflecting the contribution of agricultural antibiotic use to resistance in the clinical

setting.
PATHWAYS OF HUMAN EXPOSURE TO ANTIMICROBIAL RESISTANCE FROM AGRICULTURE
Food is clearly a significant pathway through which agricultural antimicrobial use af-
fects human health.30 There are many reports worldwide on the presence of resistant
bacteria and resistance genes in consumer meat products, including poultry, beef,
and pork.31–36 The national market dissemination of commercial meat products pro-
motes the rapid spread of resistant pathogens from the farm environment to the hu-
man community.
OCCUPATIONAL AND COMMUNITY EXPOSURES
Farmers and farm workers bridge the food animal production environment and nearby
communities. Workers employed in CAFOs (particularly those who collect and trans-
port live animals) are exposed to pathogens carried by live animals and their wastes.
Typically, workers in CAFOs are provided little to no protective equipment and, as a re-
sult, have elevated odds of carrying drug-resistant bacteria when compared with com-
munity referents.37,38 They may also transmit these infections to their households.39
Because they lack adequate insurance and access to health care,40 hospital-based
surveillance systems may not detect resistant infections in farm workers or their com-
munity contacts.
MRSA exemplifies these issues. In recent years, information on occupational risks
for MRSA infection has emerged in the European Union and Canada. In central Eu-
rope, a community-acquired, nontypable-MRSA strain (NT-MRSA) was traced to
hog farms, which were determined to be the origin of these new clones.41 Screening
of a sample of pig farms showed that this strain of NT-MRSA colonized 40% of pigs
overall, impacting 80% of farms.41 In the Netherlands, a high prevalence of MRSA
was also identified in pigs.42 Also in the Netherlands, MRSA infections were identified
in seven individuals who worked or lived on a farm and the infection was typed to
a strain found among swine at the farm.43 In Canada, in a survey of pig farmers,
20% were colonized with the same strain of MRSA found in pigs,44 consistent with
other cross-sectional studies.45–47 Weese and colleagues48,49 found increased prev-
alence of MRSA carriage among horse personnel and, notably, they identified animal
density as a distinct risk factor for MRSA in both humans and horses.
Agricultural workers may transmit MRSA from the farm environment to the com-
munity at large. Using hospital surveillance data, van Loo and colleagues50 found
that occupational exposure to farm animals or proximity to farms was a risk factor
for MRSA infection. In a study with extraordinary implications, van Rijen and col-
leagues51 sampled patients arriving at a Dutch hospital for MRSA carriage. Risk
of MRSA was strongly associated with exposure to pigs and veal calves; 32% of
patients with these exposures were positive for MRSA. Taken together, these stud-
ies provide strong evidence that cattle, horse, and swine farms are significant sour-
ces for community-acquired MRSA and for the movement of this pathogen into the
hospital setting.
ENVIRONMENTAL RELEASES FROM CAFOS
CAFOs, by design and operation, do not restrict the release of pathogens. High-
throughput ventilation systems—essential for animal health when thousands of
chickens or hogs are raised in close confinement—permit the release of bacteria
1396
Silbergeld et al
Table 1
Antimicrobials registered for use as feed additives in Australia, Denmark, European Union, Canada and the United States
Country Group/Class Antimicrobial Usage

Australia Arsenicals 3-Nitro-arsonic acid Pigs, poultry
Glycopeptides Avoparcin Pigs, meat poultry, cattle
Macrolides Kitasamycin Pigs
Oleandomycin Cattle
Tylosin Pigs
Polyethers (ionophores) Lasalocid Cattle
Monensisn (data available)
Narasin Cattle
Salinomycin Pigs, cattle
Polypeptides Bacitracin Meat poultry
Quinoxalines Olaquindox (data available) Pigs
Streptogramins Virginiamycin Pigs, meat poultry
Others Flavophospholiphol or Bambermycin Pigs, poultry, cattle
European Union Glycopeptides Avoparcin Banned, 1997
Macrolides Tylosin Pigs
Spiramycin Turkeys, chickens, calves, lambs and pigs
Oligosaccharides Avilamycin Pigs, chickens, turkeys
Polyethers (ionophores) Monensin Cattle (growth promotion)
Salinomycin Pigs
Polypeptides Bacitracin Turkeys, laying hens, chickens (growth promotion), calves, lambs, pigs
Streptogramins Virginiamycin Turkeys, laying hens, cattle (growth promotion), calves, sows, pigs
Others Flavophospholiphol Turkeys, laying hens, other poultry, calves, pigs, rabbits, cattle
or Bambermycin (growth promotion)
Canada Aminoglycosides Neomycin Cattle
Lincosamides Lincomycin hydrochloride Breeder chickens
Macrolides Erythromycin Chicken (broiler, breeder)
Tylosin Sheep
Penicillins Penicillin G Chicken (broiler, breeder)
Potassium Turkey
Penicillin G procaine Chicken, turkey, sheep
Tetracyclines Chlortetracycline Chicken (layer, breeder)
Oxytetracycline Turkey, swine, cattle, sheep
Sulfonamides Sulfamethazine Pigs, cattle
Ionophores Lasolocid sodium Cattle
Monensin Cattle
Narasin Pigs
Origins of Antimicrobial-resistant Infections

Salinomycin sodium Pigs, cattle
Polypeptides Bacitracin Chicken, pigs, turkey
Glycolipids Bambermycin Turkey, breeder chickens
Quinoxalines Carbadox Pigs
Others Arsanilic acid Broiler, turkey, pigs
USA Arsenicals Arsenilic acid Poultry, pigs
Roxarsone, cabarsone Poultry, pigs
Polypeptides Bacitracin Cattle, pigs, poultry
Glycolipids Bambermycin Pigs, poultry
Tetracyclines Tetracycline Pigs
Chlortetracycline Cattle, pigs, poultry
Oxytetracycline Cattle, pigs
Elfamycine Efrotomycin Pigs
(continued on next page)
1397
1398
Silbergeld et al
Table 1
(continued)
Country Group/Class Antimicrobial Usage

Macrolides Erythromycin Cattle
Oleandomycin Chicken, turkey
Tylosin Cattle, pigs, chicken, pigs
Tiamulin Pigs
Lincosamides Lincomycin Pigs
Ionophores Monensin Cattle
Lasalocid Cattle
Penicillins Penicillin Poultry, pigs
Quinoxalines Carbadox Pigs
Streptogramins Virginiamycin Swine
Sulfonamides Sulfamethazine Cattle, pigs
Sulfathiazole Pigs
From Silbergeld, EK, Graham, J, Price LB. Industrial food animal production, antimicrobial resistance, and human health. Annu Rev Public Health 2008;29:151–69;
with permission.
Fig. 2. (A) Conditions in a broiler poultry CAFO, Maryland. (Courtesy of J. Graham, PhD,
Baltimore, MD.) (B) Conditions in a swine CAFO. (Courtesy of the U.S. Geological Survey.
From Sapkota AR, Curriero FC, Gibson KE, Schwab KJ. Antibiotic-resistant Enterococci and
fecal indicators in surface water and groundwater impacted by a concentrated swine feed-
ing operation. Environmental Health Perspectives 2007;115:7; with permission.)
into the surrounding environment. For example, resistant S aureus has been recovered
downwind of a large swine operation.52 Resistant strains and resistance genes as well
as antimicrobial parent compounds have been detected through air sampling in the
confinement house itself.52–56 Resistant bacteria and resistance genes have been de-
tected in groundwater and surface water surrounding large swine facilities,57–59 and
resistance genes isolated from ground water were identical to isolates from nearby
swine lagoons.60
A RIVER OF PATHOGENS: DISPOSAL OF FOOD ANIMAL WASTES
Waste disposal is the major source of antimicrobial-resistant pathogens entering the

environment.11 Unlike human biosolids, in the United States there are no requirements
for the treatment of animal wastes, which are typically applied to land, generally on-
site or within 10 miles of the farm, following storage in lagoons (for swine and cattle
manure) or in dry heaps (poultry manure). These practices contaminate air, water,
and soils in the vicinity of both storage and field application.61 Large-scale animal ag-
riculture problems are compounded because of the large amount of animal wastes
that are produced in small geographic areas by thousands of animals held in open
or closed confinement. According to the US Department of Agriculture (USDA), con-

fined food animals excrete approximately 335 million tons (dry weight) of waste per
year,62 more than 40 times the total mass of human biosolids produced annually.
These wastes are of concern for the emergence and spread of resistant bacteria for
the following reasons: (1) resistant pathogens at infectious levels are present in animal
wastes; (2) wastes contain active forms of antimicrobial agents; and (3) transfer of re-
sistance genes occurs within the waste environment. Infectious levels of enteric bac-
teria are recoverable from CAFO wastes.61 Staphylococcus and Enterococcus spp
with high levels of resistance to clarithromycin, erythromycin, clindamycin, and tetra-
cycline (along with multidrug phenotypes) have been isolated from poultry litter
collected from farms across Georgia.63 Antimicrobial-resistant Enterococci and resis-
tance genes in swine waste can persist in soil for more than five months.64
Wastes from CAFOs, which include spilled feeds, also contain antimicrobial
compounds and metabolites. Also, food animals excrete significant amounts of bio-
logically active forms of the antimicrobials administered in feeds.65 Many antimicro-
bials used in food animal production are poorly absorbed in the gut of the animal,
and as much as 90% of the parent compound can be excreted in urine and up to
75% in feces.66 Antimicrobials in wastes may select for resistance in soil environ-
ments after land disposal of animal wastes, inferring from macrocosm experiments
conducted on chlortetracycline and selection for resistance in aerobic bacteria.67
The geographic concentration of large-scale agricultural operations in the United
States results in the frequent application of high levels of animal wastes to geograph-
ically confined regions, which increases the risks of environmental contamination in
these regions. This factor has been related to contamination of soils and irrigation
water for food crops and with the presence of antimicrobial-resistant bacteria in
vegetables.68–70
INTERVENTION POINTS: LOOKING DOWNSTREAM, ACTING UPSTREAM
As shown in Fig. 3, there are several pathways by which animal antimicrobial use con-
tributes to community exposures and reservoirs of resistance: contact with and
consumption of food products, occupational exposures, and environmental contam-
ination. The authors consider this schematic in the context of two philosophies rele-
vant to preventing human exposures to pathogens originating in food animal
production: Hazard Analysis and Critical Control Point (HACCP), a set of guidelines
and regulations promulgated by the US Food and Drug Administration (FDA) and
USDA;71 and the hierarchy of controls, a strategy used in occupational and environ-
mental health to prevent chemical exposures and injury.72 HACCP focuses on pre-
venting consumer exposure to foodborne pathogens by regulating points along the
path of food ‘‘from farm to fork.’’ Preventing contamination of meat products and
worker infection at slaughter and processing, as well as at the stages of food handling
and consumption, is important independent of concerns over transmission of resistant
pathogens. However, these strategies rely heavily on practices at the slaughter house,
on proper storage and handling of food products, and on behavioral changes among
consumers. Recent outbreaks in the United States suggest that these strategies do
not completely prevent transmission of microbial pathogens on food and that assur-
ance is ultimately based on a monitoring program that may be infeasible for a global-
ized food supply.
Mostly importantly, HACCP does not address the pathways of community exposure
by way of occupational or environmental routes. For this purpose, the hierarchy of
controls model, adapted from the industrial hygiene literature, is a useful way to
Fig. 3. Spread of antimicrobial-resistant pathogens (X) from agriculture to the community

and hospital. Pathogens from CAFOs (pig-farm house) spread through food products, ma-
nure lagoons, air, wildlife (birds), animal transport trucks, and deposit of manure on crop-
land. (Courtesy of Salvador Saenz, El Paso, TX. Copyright ª2008, Salvador Saenz.)
identify and evaluate interventions in terms of effective risk reduction (Fig. 4). In this
model, the most effective type of intervention is elimination of the hazard; followed
in decreasing order by engineering controls, administrative controls, and personal
protective equipment or behavior. This analysis demonstrates that eliminating the
use of antimicrobial agents in food animal production – particularly for functions unre-
lated to disease treatment – emerges as the most effective means of preventing further
contributions to the resistance reservoir. Controls further down the hierarchy are valu-
able tools in mitigating human health hazards in industrial food animal production and
as such are critically important. However, applying controls at these stages is complex
and resource intensive. Reducing environmental contamination requires substantial
investments at the CAFO level, including advanced waste treatment and changes in
ventilation. Reducing worker exposure requires improved improved hygiene and
protective equipment. Biosecurity between farm and community requires improved
hygiene and pathogen control, as well as improvements in animal transport and waste
management.
This analysis supports the conclusions of the World Health Organization (WHO), the
World Organization for Animal Health, and the Food and Agriculture Organization of
the United Nations. These organizations have specifically recommended ending the
practice of adding antimicrobials to feed. The European Union recently legislated
restrictions on antimicrobial feed additives. However, in the United States only the
use of ciprofloxacin analogs has been banned, and in much of the rest of the world
these uses have not been restricted. Thus, the majority of antimicrobial production
continues to be used for this purpose.11
Prohibiting the first use of new antimicrobials in animal feeds is critically important.
The practice of registering new antimicrobials for use in animal feeds before registra-
tion for human medicine is encouraged by the high barriers to approval for new agents
for clinical use. This can be predicted to impair the clinical life span of the same drug.73
For example, quinupristin/dalfopristin was first approved for use in animal feeds and
Fig. 4. The hierarchy of controls model applied to CAFOs.
only years later for treatment of otherwise resistant infections in clinical medicine. Be-
cause of prior use in feeds, clinicians quickly found resistance in human isolates.74
Further, the long-term implications of antimicrobial use in agriculture underscore the
importance of prudent drug registration and usage policies. Evidence suggests that
a ban on antimicrobial usage in feeds may not result in complete eradication of resis-
tance in bacteria isolated from the agricultural setting or the food supply. In the Euro-
pean Union, the introduction and subsequent removal of avoparcin from use in pig
farming demonstrates a trend of concern. While hospital prevalence rates of VRE
fell after the ban,29 VRE continued to be found in broiler chicken flocks in Denmark.75
In the United States, fluoroquinolone-resistant Campylobacter were still isolated in
2006 from poultry products from two companies that voluntarily stopped using enro-
floxacin in 2002.76
SUMMARY
The growing appreciation of the role of the community as a source of the increasing
prevalence of antimicrobial-resistant infections supports the importance of under-
standing nonnosocomial drivers of resistance. The emergence of community-
acquired MRSA highlights the relevance of reservoirs of antimicrobial resistance in
humans and animals in the community environment. Although hospital use of antimi-
crobials has been assumed to generate the highest risk of resistance and transmission
of resistant infections, the greater load of antimicrobial use in food animal production
makes a larger contribution to the reservoir of resistance.16 Multiple routes of expo-
sure connect human populations with this reservoir: food consumption, animal-to-hu-
man and human-to-human contacts, and environmental contamination. Agricultural
use of antimicrobial feed additives is a major driver for these reservoirs. Evidence
points to agriculture as a source of community MRSA and other drug-resistant infec-
tions – such as fluoroquinolone-resistant campylobacteriosis in the United States and
VRE in Europe. Based on this evidence, it is imperative to implement policies that pre-
vent increases in community reservoirs of antibiotic resistance. Such policies have
been repeatedly urged for health care providers and consumers.1 These policies are
important. However, there has been little or no attention by medical practitioners or
the general population to current practices in agricultural use of antimicrobials.
Adopting a public health perspective of the hierarchy of controls provides a policy
framework for regulation of antimicrobials in food animal production. Just as agricul-
tural antimicrobial use dwarfs clinical use, agricultural drivers of resistance likely ex-
ceed the impact of hospital-based factors to promote and maintain reservoirs of
resistance. The authors conclude that three steps are critical to reducing transmis-
sion from agriculture to these reservoirs: eliminating antimicrobial use in animal
feeds, reducing animal-to-human spread of resistant organisms, and preventing
microbial contamination of both the environment and the food supply. Banning
antimicrobial use in animal feeds is the responsibility of the FDA, while reducing
contamination of the environment—by both antibiotics and resistant microorgan-
isms—involves the Environmental Protection Agency, as well as the USDA. More
accurate assessment of the complex interactions between hospital and community
will improve characterization of community risk factors and will enhance the under-
standing of the linkages between human populations in and out of health care set-
tings as well as improve surveillance for resistance of community origin, including
agriculture. It is time to acknowledge and act upon the warning words of Starr
and Reynolds in 1951, ‘‘It would be unfortunate if a large reservoir of drug-fast
[sic] enteric pathogens were to accumulate in the [food animal] population. The au-
thors hope that those charged with the protection of public health will objectively
evaluate this situation.’’4 This evaluation is long overdue.
REFERENCES
1. Laxminarayan R. Extending the cure: policy responses to the growing threat of

antibiotic resistance. Washington, DC: Resources for the Future; 2007.
2. Eliot TS. Four quartets. San Diego (CA): Harcourt Brace and Company; 1988.
3. Fleming A. Nobel lectures, physiology or medicine 1942–1962. Amsterdam:
Elsevier Publishing Company; 1964.
4. Starr MP, Reynolds DM. Streptomycin resistance of coliform bacteria from turkeys
fed streptomycin. Am J Public Health Nations Health 1951;41(11 Pt 1):1375–80.
5. Jones KE, Patel NG, Levy MA, et al. Global trends in emerging infectious dis-
eases. Nature 2008;451(7181):990–3.
6. Falagas ME, Bliziotis IA. Pandrug-resistant Gram-negative bacteria: the dawn of
the post-antibiotic era? Int J Antimicrob Agents 2007;29(6):630–6.
7. Wright GD. The antibiotic resistome: the nexus of chemical and genetic diversity.
Nat Rev Microbiol 2007;5(3):175–86.
8. Schwarz S, Cloeckaert A, Roberts MC. Mechanism and spread of bacterial resis-

tance to antimicrobial agents. In: Aarestrup FM, editor. Antimicrobial resistance in
bacteria of animal origin. Washington, DC: ASM Press; 2006. p. 73–98.
9. Klein E, Smith DL, Laxminarayan R. Hospitalizations and deaths caused by meth-
icillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg Infect
Dis 2007;13(12):1840–6.
10. Okuma K, Iwakawa K, Turnidge JD, et al. Dissemination of new methicillin-resis-
tant Staphylococcus aureus clones in the community. J Clin Microbiol 2002;
40(11):4289–94.
11. Silbergeld EK, Graham J, Price LB. Industrial food animal production, antimicro-
bial resistance, and human health. Annu Rev Public Health 2008;29:151–69.
12. Salyers AA, Gupta A, Wang Y. Human intestinal bacteria as reservoirs for antibi-
otic resistance genes. Trends Microbiol 2004;12(9):412–6.
13. Patel M, Waites KB, Hoesley JB, et al. Emergence of USA300 MRSA in a tertiary
medical centre: implications for epidemiological studies. J Hosp Infect 2008;
68(3):208–13.
14. Pop-Vicas AE, D’Agata EM. The rising influx of multidrug-resistant gram-negative
bacilli into a tertiary care hospital. Clin Infect Dis 2005;40(12):1792–8.
15. Singer RS, Hofacre CL. Potential impacts of antibiotic use in poultry production.
Avian Dis 2006;50(2):161–72.
16. Smith DL, Dushoff J, Morris JG. Agricultural antibiotics and human health. PLoS
Med 2005;2(8):232–5.
17. Otte J, Roland-Holst D, Pfeiffer D, et al. Industrial livestock production and global
health risks. Rome (Italy): Food and Agriculture Organization; 2007.
18. Salyers A, Shoemaker NB. Reservoirs of antibiotic resistance genes. Anim Bio-
technol 2006;17(2):137–46.
19. Nandi S, Maurer JJ, Hofacre C, et al. Gram-positive bacteria are a major reservoir
of Class 1 antibiotic resistance integrons in poultry litter. Proc Natl Acad Sci U S A
2004;101(18):7118–22.
20. Jensen VF, Jakobsen L, Emborg HD, et al. Correlation between apramycin and
gentamicin use in pigs and an increasing reservoir of gentamicin-resistant
Escherichia coli. J Antimicrob Chemother 2006;58(1):101–7.
21. Graham JP, Boland JJ, Silbergeld E. Growth promoting antibiotics in food animal
production: an economic analysis. Public Health Rep 2007;122(1):79–87.
22. Florini K, et al. Resistant bugs and antibiotic drugs: state and county estimates of
antibiotics in agricultural feed and animal waste. Washington, DC: Environmental
Defense; 2005.
23. Sarmah AK, Meyer MT, Boxall AB. A global perspective on the use, sales, expo-
sure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the
environment. Chemosphere 2006;65(5):725–59.
24. World Bank. Managing the livestock revolution: policy and technology to address
the negative impacts of a fast-growing sector. Washington, DC: World Bank;
2005. Available at: ftp://ftp.fao.org/docrep/nonfao/lead/x6159e/x6159e00.pdf.
Accessed April 13, 2008.
25. Gupta A, Nelson JM, Barrett TJ, et al. Antimicrobial resistance among Campylo-
bacter strains, United States, 1997–2001. Emerg Infect Dis 2004;10(6):1102–9.
26. Bonten MJ, Willems R, Weinstein RA. Vancomycin-resistant Enterococci: why are
they here, and where do they come from? Lancet Infect Dis 2001;1(5):314–25.
27. Perron GG, Bell G, Quessy S. Parallel evolution of multidrug-resistance in Salmo-
nella enterica isolated from swine. FEMS Microbiol Lett 2008;281(1):17–22.
28. Wegener HC. Historical yearly usage of glycopeptides for animals and humans:
the American-European paradox revisited. Antimicrobial Agents Chemother
1998;42(11):3049.
29. Klare I, Badstueber D, Konstabel C, et al. Decreased incidence of VanA-type
vancomycin-resistant Enterococci isolated from poultry meat and from fecal sam-
ples of humans in the community after discontinuation of avoparcin usage in an-
imal husbandry. Microb Drug Resist 1999;5(1):45–52.
30. Mathew AG, Cissell R, Liamthong S. Antibiotic resistance in bacteria associated
with food animals: a United States perspective of livestock production. Food-
borne Pathog Dis 2007;4(2):115–33.
31. Simjee S, White DJ, Meng J, et al. Prevalence of streptogramin resistance genes
among Enterococcus isolates recovered from retail meats in the Greater Wash-
ington DC area. J Antimicrob Chemother 2002;50(6):877–82.
32. Emborg HD, Anderssen JS, Seyfarth AM, et al. Relations between the occur-
rence of resistance to antimicrobial growth promoters among Enterococcus fae-
cium isolated from broilers and broiler meat. Int J Food Microbiol 2003;84(3):
273–84.
33. Johnson JR, Kuskowski MA, Smith K, et al. Antimicrobial-resistant and extraintes-
tinal pathogenic Escherichia coli in retail foods. J Infect Dis 2005;191(7):1040–9.
34. Price LB, Johnson E, Vailes R, et al. Fluoroquinolone-resistant Campylobacter
isolates from conventional and antibiotic-free chicken products. Environ Health
Perspect 2005;113(5):557–60.
35. Garofalo C, Vignaroli C, Zandri G, et al. Direct detection of antibiotic resistance
genes in specimens of chicken and pork meat. Int J Food Microbiol 2007;
113(1):75–83.
36. Van TT, Moutafis G, Istivan T, et al. Detection of Salmonella spp. in retail raw food
samples from Vietnam and characterization of their antibiotic resistance. Appl
Environ Microbiol 2007;73(21):6885–90.
37. Price LB, Graham J, Lackey L, et al. Elevated risks of carrying gentamycin-resis-
tant E coli among US poultry workers. Environmental Health Perspectives 2007;
115(12):1738–42.
38. van den Bogaard AE, Stobberingh EE. Antibiotic usage in animals: impact on
bacterial resistance and public health. Drugs 1999;58(4):589–607.
39. Hannah EL, Angulo FJ, Johnson JR, et al. Drug-resistant Escherichia coli, rural
Idaho. Emerg Infect Dis 2005;11(10):1614–7.
40. Larson SL, Hill SC. Rural-urban differences in employment-related health insur-
ance. J Rural Health 2005;21(1):21–30.
41. Witte W, Strommenger B, Stanek C, et al. Methicillin-resistant Staphylococcus
aureus ST398 in humans and animals, Central Europe. Emerg Infect Dis 2007;
13(2):255–8.
42. de Neeling AJ, can den Broek MJ, Spalburg EC, et al. High prevalence of meth-
icillin-resistant Staphylococcus aureus in pigs. Vet Microbiol 2007;122(3-4):
366–72.
43. Huijsdens XW, van Dijke BJ, Spalburg EC, et al. Community-acquired MRSA and
pig-farming. Ann Clin Microbiol Antimicrob 2006;5:26.
44. Khanna T, Friendship R, Dewey C, et al. Methicillin-resistant Staphylococcus au-
reus colonization in pigs and pig farmers. Vet Microbiol 2008;128(3-4):298–303.
45. Hanselman BA, Kruth SA, Rousseau J, et al. Methicillin-resistant Staphylococcus
aureus colonization in veterinary personnel. Emerg Infect Dis 2006;12(12):
1933–8.
46. Armand-Lefevre L, Ruimy R, Andremont A. Clonal comparison of Staphylococcus

aureus isolates from healthy pig farmers, human controls, and pigs. Emerg Infect
Dis 2005;11(5):711–4.
47. Voss A, Loeffen F, Bakker J, et al. Methicillin-resistant Staphylococcus aureus in
pig farming. Emerg Infect Dis 2005;11(12):1965–6.
48. Weese JS, Rousseau J, Traub-Dargatz JL, et al. Community-associated methicil-
lin-resistant Staphylococcus aureus in horses and humans who work with horses.
J Am Vet Med Assoc 2005;226(4):580–3.
49. Weese JS, Dick H, Willey BM, et al. Suspected transmission of methicillin-resis-
tant Staphylococcus aureus between domestic pets and humans in veterinary
clinics and in the household. Vet Microbiol 2006;115(1-3):148–55.
50. van Loo I, Huijsdens XW, Tiemersma E, et al. Emergence of methicillin-resistant
Staphylococcus aureus of animal origin in humans. Emerg Infect Dis 2007;
13(12):1834–9.
51. van Rijen MM, Van Keulen PH, Kluytmans JA. Increase in a Dutch hospital of
methicillin-resistant Staphylococcus aureus related to animal farming. Clin Infect
Dis 2008;46(2):261–3.
52. Gibbs SG, Green CF, Tarwater PM, et al. Isolation of antibiotic-resistant bacteria
from the air plume downwind of a swine confined or concentrated animal feeding
operation. Environ Health Perspect 2006;114(7):1032–7.
53. Predicala BZ, Urban JE, Maghirang RG, et al. Assessment of bioaerosols in swine
barns by filtration and impaction. Curr Microbiol 2002;44(2):136–40.
54. Sapkota AR, Ojo KK, Roberts MC, et al. Antibiotic resistance genes in multidrug-
resistant Enterococcus spp. and Streptococcus spp. recovered from the indoor
air of a large-scale swine-feeding operation. Lett Appl Microbiol 2006;43(5):
534–40.
55. Chapin A, Rule A, Gibson K, et al. Airborne multidrug-resistant bacteria isolated
from a concentrated swine feeding operation. Environ Health Perspect 2005;
113(2):137–42.
56. Hamscher G, Pawelzick HT, Sczesny S, et al. Antibiotics in dust originating from
a pig-fattening farm: a new source of health hazard for farmers? Environ Health
Perspect 2003;111(13):1590–4.
57. Anderson ME, Sobsey MD. Detection and occurrence of antimicrobially resistant
E. coli in groundwater on or near swine farms in eastern North Carolina. Water Sci
Technol 2006;54(3):211–8.
58. Stine OC, Johnson JA, Keefer-Norris A, et al. Widespread distribution of tetracy-
cline resistance genes in a confined animal feeding facility. Int J Antimicrob
Agents 2007;29(3):348–52.
59. Sapkota AR, Curriero FC, Gibson KE, et al. Antibiotic-resistant Enterococci and
fecal indicators in surface water and groundwater impacted by a concentrated
swine feeding operation. Environ Health Perspect 2007;115(7):1040–5.
60. Chee-Sanford JC, Aminov RI, Krapac JJ, et al. Occurrence and diversity of tetra-
cycline resistance genes in lagoons and groundwater underlying two swine pro-
duction facilities. Appl Environ Microbiol 2001;67(4):1494–502.
61. Gerba CP, Smith JE Jr. Sources of pathogenic microorganisms and their fate dur-
ing land application of wastes. J Environ Qual 2005;34(1):42–8.
62. USDA. FY-2005 annual report manure and byproduct utilization national program
206. Washington, DC: Agricultural Research Service, United States Department
of Agriculture; 2007.
63. Simjee S, McDermott P, White DG, et al. Antimicrobial susceptibility and
distribution of antimicrobial-resistance genes among Enterococcus and
coagulase-negative Staphylococcus isolates recovered from poultry litter. Avian

Dis 2007;51(4):884–92.
64. Agerso Y, Wulff G, Vaclavik E, et al. Effect of tetracycline residues in pig manure
slurry on tetracycline-resistant bacteria and resistance gene tet(M) in soil micro-
cosms. Environ Int 2006;32(7):876–82.
65. Berger K, Petersen B, Buening-Pfaue H. Persistence of drugs occurring in liquid
manure in the food chain. Arch Lebensmittelhyg 1986;37(4):99–102.
66. Halling-Sorensen B, Nors Nielsen S, Lanzky PF, et al. Occurrence, fate and
effects of pharmaceutical substances in the environment—a review. Chemo-
sphere 1998;36(2):357–93.
67. Munoz-Aguayo J, Lang KS, LaPara TM, et al. Evaluating the effects of chlortetra-
cycline on the proliferation of antibiotic-resistant bacteria in a simulated river
water ecosystem. Appl Environ Microbiol 2007;73(17):5421–5.
68. Islam M, Morgan J, Doyle MP, et al. Persistence of enterohemorrhagic Escheri-
chia coli O157:H7 in soil and on leaf lettuce and parsley grown in fields treated
with contaminated manure composts or irrigation water. J Food Prot 2004;
67(7):1365–70.
69. Sivapalasingam S, Friedman CR, Cohen L, et al. Fresh produce: a growing cause
of outbreaks of foodborne illness in the United States, 1973 through 1997. J Food
Prot 2004;67(10):2342–53.
70. Tauxe RV. Emerging foodborne pathogens. Int J Food Microbiol 2002;78(1-2):
31–41.
71. Billy TJ, Wachsmuth IK. Hazard analysis and critical control point systems in the
United States Department of Agriculture regulatory policy. Rev Sci Tech 1997;
16(2):342–8.
72. Smith TJ, Schneider T. Occupational hygiene. In: Levy B, Wegman D, editors.
Occupational health. Philadelphia: LWW; 2000. p. 161–80.
73. Smith DL, Harris AD, Johnson JA, et al. Animal antibiotic use has an early but im-
portant impact on the emergence of antibiotic resistance in human commensal
bacteria. Proc Natl Acad Sci U S A 2002;99(9):6434–9.
74. Kieke AL, Borchardt MA, Kieke BA, et al. Use of streptogramin growth promoters
in poultry and isolation of streptogramin-resistant Enterococcus faecium from
humans. J Infect Dis 2006;194(9):1200–8.
75. Heuer OE, Pedersen K, Lensen LB, et al. Persistence of vancomycin-resistant
Enterococci (VRE) in broiler houses after the avoparcin ban. Microb Drug Resist
2002;8(4):355–61.
76. Price LB, Lackey L, Vailes R, et al. The persistence of fluoroquinolone-resistant
Campylobacter in poultry production. Environ Health Perspect 2007;115(7):
1035–9.
The Role of the Traveler
in Emerging I nfe c tions
a nd Magnitude
of Travel
Lin H. Chen, MD, FACPa,*, Mary Elizabeth Wilson, MD, FACP, FIDSAb
KEYWORDS
Travelers Travel volume Emerging infections
Travel-associated illnesses Disease surveillance
Global travel has evolved dramatically during the past 2 centuries, with ever escalating
speed, distance, and volume. Because the geographic distribution of diseases is
dynamic and influenced by ecologic, genetic, and human factors, travel allows
humans to interact with microbes and introduce pathogens into new locations and
populations. The increased numbers of travelers and their spatial mobility have
reduced geographic barriers for microbes and heightened the potential for spread
of infectious diseases.
MAGNITUDE OF TRAVEL AND TRADE

Population Growth
Between 1950 and 2007, world population grew from 2.5 to more than 6.6 billion.1 The
population growth favored centers of commerce, usually urban or periurban areas,
which brought more humans into close contact with larger groups of people. Concur-
rently, progress in transportation led to speedier movement of humans and goods and
microbial organisms.
Number of Travelers
The volume of travel has grown exponentially. International tourist arrivals increased
from 25.3 million in 1950 to 898 million in 2007, an astounding 35-fold increase
(Table 1).2 In recent years, the World Tourism Organization has estimated growth in
travel at approximately 6% per year, and anticipates similar growths in upcoming
decades.2
a
Travel Medicine Center, Mount Auburn Hospital, 330 Mount Auburn Street, Cambridge, MA
02238, USA
b
Harvard Medical School and Harvard School of Public Health, Boston, MA, USA
E-mail address: lchen@hms.harvard.edu (L.H. Chen).
Med Clin N Am 92 (2008) 1409–1432

1410 Chen & Elizabeth Wilson
Table 1
Growth in world population and international tourist arrivals
World Population International Tourist

Year (Millions) Arrivals (Millions)
1950 2557 25.3
1985 4852 329
1995 5694 550
2007 6600 898
Change from 1950 to 2007 2.6 35
Data from US Census Bureau and World Tourism Organization. Available at: http://www.census.
gov/ipc/www/idb and http://www.world-tourism.org/facts/menu.html, respectively.
Human migration data provide another indicator of population mobility.

Approximately 2% of the world’s population (>200 million people), including
immigrants, migrant workers, refugees, asylum seekers, and expatriates, now reside
outside their country of birth.3 The United States Census Bureau4 estimated that in
2003, 33.5 million people residing in the United States were foreign-born, comprising
11.7% of the population. Most figures of foreign-born populations only reflect legal
entrants, but provide some estimate of travel, because migration to foreign lands is
associated with long-distance travel to visit families.
Reason for Travel

People travel voluntarily for numerous and varied reasons, including planned trips for
pleasure, work, research, study, humanitarian aid, religious purposes, or missionary
activities. They may travel to visit friends and families or for economic opportunities.
However, people also migrate involuntarily because of catastrophic events, including
environmental disasters and sociopolitical upheaval.
Between 1990 and 2006, the proportion of international tourist arrivals that traveled
to visit friends and relatives, seek health care, or for religious reasons increased from
19.6% to 27%. Business and professional travel also increased (Table 2).5,6 Although
the total number of leisure travelers increased, the proportion traveling for leisure
declined from 55.6% to 51%.5,6
HOW POPULATIONS ARE MOVING
Over the decades, the modes of transportation have also shifted from horses and
sailing vessels to steamships, railways, automobiles, and aircrafts. In 1788, when
long-distance travel primarily occurred on sailing vessels, a trip from England to Aus-
tralia spanned 1 year.7 Clippers shortened travel time to 100 days by 1840; steamers
reduced it to 50 days by 1910; and in the 21st century, aircraft can reach almost any
major city on the globe in 24 hours.7 As a result of the augmented speed, sphere, and
range of modern transportation, the spatial mobility of the average person grew 1000-
fold over past 2 centuries.7
Air travel has accounted for the greatest gains in international travel. In 2006, air
travel accounted for 46% of transport, followed by road at 43%, water at 7%, and
rail at 4%.5 These figures indicate continued growth of long-haul travel, typically asso-
ciated with the use of large aircraft, and connections between different ecosystems
and their resident species.
The Role of the Traveler in Emerging Infections 1411
Table 2
Comparison of arrivals by purpose of visit, 1990 and 2006
Total International Arrivals (%)
1990 (International 2006 (International

Reason forTravel Tourist Arrivals 5 438 Million) Tourist Arrivals 5 846 Million)
Leisure, holiday 55.6 51
Business, professional 13.8 16
Visit friends and relatives, 19.6 27
health, religion
Not specified 11.0 6
Data from World Tourism Organization. Available at: http://www.unwto.org.
Conveyances
Although conveyances have become faster, they have also become larger. Jumbo jets
now carry several hundred passengers each. The risk for a traveler to acquire a com-
municable disease is estimated to increase fourfold when the aircraft size is doubled.7
The United States has 19,500 airports, of which 18 receive more than 500,000 inter-
national arrivals annually.8 Up to 5000 planes may be in United States airspace at
one time. The global civilian aviation network connects most areas of the world, allow-
ing rapid transit and mix of multiples species.
Ballast water from ships can transport pathogenic microbes (such as Vibrio
cholerae) over long distances, and disperse to habitats where the species can per-
sist.9 Cruises have become a popular leisure activity. Cruise ships can now carry
more than 3000 passengers and crew. During 2003, 184 ships served the United
States cruise industry, with an estimated 7.4 million passengers.8 Currently, 14 United
States ports receive more than 150,000 maritime passengers annually.8 Worldwide,
11.5 million passengers traveled on cruise ships in 2005, each for an average of
7 days.10 Passengers converge from different countries; a cruise may involve multiple
stops, where passengers may be dropped off or picked up. Passengers may also have
brief visits at multiple ports. These patterns expand the potential pool of exposures.
Cruise ships have served as sites of outbreaks, with passengers then dispersing
infections elsewhere. Many travelers on cruise ships are older and have chronic med-
ical conditions, and therefore may be susceptible to more severe consequences of
infections. The confined and crowded environs on cruise ships allow easy transmis-
sion of pathogens. The short durations of most cruises can allow an infected passen-
ger to reach another location before onset of symptoms. The most commonly
identified pathogens in cruise ship outbreaks have been norovirus and influenza,
but Salmonella, Shigella, Staphylococcus, V cholerae and other vibrios, Legionella,
Corynebacterium diphtheriae, and rubella have also been implicated.10,11 Sources
of gastrointestinal disease on cruise ships include water (eg, contaminated by sew-
age, inadequate disinfection, improper storage), food (poor handling, preparation,
cooking), and use of sea water in the galley.10
During 2006, an unusually high number of norovirus outbreaks occurred on cruise
ships. By July 5, 2006, 13 cruise ships traveling around Europe had reported 35 out-
breaks of gastrointestinal infection.12 In all, investigators confirmed 43 outbreaks on
13 cruise ships.13 The norovirus from stool or environmental samples were of two dis-
tinct lineages of the GGII.4 genotype, which emerged separately in Europe and Pacific
and caused concurrent outbreaks in the community.13 The cruise ship outbreaks were
an early indicator of increased activity in the region and revealed strains that originated
in distant locations.
Legionella is another pathogen associated with cruise ships, with more than 200
cases reported.10 A single cruise ship from New York to Bermuda was associated
with 50 cases during nine separate voyages in 1994, with the whirlpool spa as the
source.14 On another cruise ship, eight German passengers contracted legionellosis
(attack rate, 4%), also linked to the spa pool.15
Transmission of pathogens also occurs on aircraft. Infections spread by the airborne
or large droplet route are of greatest concern in aircraft transmission, and include
influenza, meningococcal infections, measles, tuberculosis, and severe acute respira-
tory syndrome (SARS). However, the most commonly documented infections trans-
mitted on aircraft have spread through contaminated food: Salmonella,
Staphylococcus, norovirus, and cholera.16 Most foodborne transmissions on aircraft
result from food contaminated before the flight. Only those with a short incubation
manifest during the flight; most often toxin-related (eg, staphylococcal) or, rarely,
infections such as V cholerae on a long flight.
Norovirus is exceptional in that it is a gastrointestinal pathogen that can be easily
transmitted in a crowded environment. For example, probable transmission of norovi-
rus occurred in 2002 among a flight crew, with limited transmission to passengers.17
Acute illness was reported on an 8-hour flight from London to Philadelphia, Pennsyl-
vania. A survey found 8 of the 14 crew members had symptom onset during flight.
Stool specimens from two hospitalized crew members had noroviruses with identical
sequences using polymerase chain reaction. Among 93 passengers who returned the
survey, 5 had probable norovirus gastroenteritis (5.4%).17
In-flight transmission of Mycobacterium tuberculosis is also possible. M tuberculosis
is transmissible through large droplets and droplet nuclei with productive cough, and
a single organism can cause infection.18 In 1994, a patient who had multidrug-resis-
tant tuberculosis (MDR TB) traveled on commercial flights from Honolulu to Chicago,
Chicago to Baltimore, and returned a month later.19 Contact tracing, questionnaire,
and skin testing found up to 6% skin test conversions, with greatest risk in passengers
seated within two rows of the case patient (31% conversion).19 Another traveler with
MDR TB flew on a commercial airline from Delhi, India, to Chicago, Illinois, in Decem-
ber 2007.20 The incident required coordinated efforts among the Centers for Disease
Control and Prevention (CDC) and multiple organizations (the airline, U.S. Customs
and Border Protection, U.S. state and local health departments, and the Indian Minis-
try of Family Welfare) to notify and follow up on passengers and crew that may have
been exposed.
MOST COMMON ORIGINS AND DESTINATIONS
The sphere of travel has enlarged over the years and travel patterns have become ever
more complex. The trend of average daily distance traveled in France increased 10-
fold with each generation, or more than 1000 times between 1800 and 2000.7 The
bacillus causing plague, carried by rats, took 3 years to reach Britain from Italy during
the 14th century.21 Today, aircraft can travel thousands of miles in less than a day,
allowing infected passengers to carry their microbial baggage to distant destinations
where susceptible populations may reside.
In recent years, the growth in travel to Africa, Asia and Pacific, and Middle East has
exceeded that in other regions (Fig. 1). For example, the average annual growth from
1995 to 2004 was 3.9% for the world, but these three regions (Africa, Asia and Pacific,
and Middle East) grew at higher rates: 5.7%, 6.5%, and 10.9%, respectively.6 These
2000
World
1500
Africa
1000
500 Americas
East
0
Asia/Pacific
00
90
10
20
Europe
20
19
20
20
Year
Fig.1. International tourist arrivals by region (millions) with forecast. (Data from WTO Tour-
ism Highlights 2007 and World Tourism Barometer 2008;6(1). Available at http://www.
world-tourism.org/facts/menu.html.)
areas of rapid growth include many developing countries in tropical/subtropical

regions, places characterized by greater species richness.22 Other attributes of these
areas, including poor infrastructure, lack of clean water and sanitation, and poor
vector control, may increase the risk that travelers will be exposed to local infections.
Although Europe is expected to remain the most popular destination, its overall share
in the market is projected to decline. Europe and America’s combined share in world
tourist arrivals was more than 95% in 1950, but declined to 82% in 1990 and 76% in
2000, and is predicted to fall to 64% by 2020.6 The shift of international tourist arrivals
to less-developed regions predicts increased exposure to diseases endemic in those
regions.
Implication of Travel Pattern on Disease Outbreaks

Travel pattern influences disease outbreaks. Frequent travelers accelerate
international spread if they are infected early and the outbreak does not otherwise
expand rapidly.23 The travel routes, aviation network, number of flights departing
from and arriving at airport, number of passengers carried, and size of aircraft are
important considerations in estimating the spread of modern epidemics.24 For some
types of infections, simulations illustrate that travel restrictions, particularly isolation
of largest cities, will be a necessary component in epidemic control strategies.24
The present pattern of air travel could expedite the spread of an influenza pandemic
compared with past pandemics. In 1968 to 1969, 160 million persons traveled interna-
tionally on commercial flights.25 The Hong Kong influenza strain of 1968 to 1969
spread globally through the network of cities by air travel: first to northern latitudes,
then southern latitudes.25 Modeling of the epidemic with air transportation data in
2000 for 52 cities showed that influenza would spread concurrently to cities in both
hemispheres, resulting in minimal seasonal swing and little time for public health inter-
vention.26 Disease would reach nearby cities first, but also distant cities with high air
travel volumes; a pandemic initiating in Hong Kong can now spread speedily to north-
ern hemisphere cities 111 days earlier than in 1968.26 Understanding the local ecology
and linkages through travel can provide projection of disease spread.
INTERACTIONS OF TRAVELERS, MICROBES, AND LOCATIONS
Travelers have dynamic interactions with microbes and places. Travelers can carry
microbes and their genetic material, and can play many roles with respect to
microbes. Travelers can be victims, sentinels, couriers, processors, and transmitters
of microbial pathogens.27 Conversely, arrival of travelers can affect host populations
through contact with diverse groups of people and microbes throughout their trip
and sharing environments sequentially. Travel should be considered a loop and not
just an origin and destination.27
Travel can be associated with behavior that leads to transmission of pathogens
through blood and body fluid exposure. Travelers may engage in sexual activities or
pursue extreme sports or other injury-prone activities that they would not risk at
home. A survey assessing possible exposures to hepatitis B among more than 9000
European travelers found that most had potential risk (60.8%–75.8%), including holi-
day romance (12.5% of all travelers), with 6.6%–11.2% at high risk.28 A Canadian
study found that 15% of travelers had potential exposure to blood and body fluids
through vehicles such as new sexual partner (9%); sharing instruments, such as razor
or toothbrush (5%); receiving injection for medical treatment (3.2%); having acupunc-
ture or other percutaneous nontraditional treatment (1%); tattooing or body piercing
(0.5%); and abrasive injury (0.5%).29
Other investigators found that 5.6% of tourists departing from Cuzco engaged in
sexual activity with a new partner during their stay.30 Although most reported having
sex with other travelers (54.3%), some had sex with local partners (40.7%) or commer-
cial sex workers (2.15%).30 Sexually transmitted infections (including hepatitis B, HIV,
and HTLV-1) acquired during travel can further spread during the journey and after re-
turn home.
Recent Illustrations
Many examples from the past decade show the range of infections in travelers and the
role that travelers can play in sparking outbreaks (Table 3). Some infections, such as
legionellosis, can affect travelers but also have a wide geographic distribution. Diag-
nosis is important to allow appropriate treatment (and identification of a risky place, in
some instances), but infected travelers do not pose a risk to others. Other infections,
such as Lassa fever, can present a risk to close contacts but are not likely to lead to an
outbreak in a new region where modern medical facilities are available.
Most relevant to emerging infections are agents that can be introduced by a traveler
that lead to multiple generations of spread or even establishment of a pathogen in
a new region. Infections in the latter category include those spread from person to per-
son, some with fecal–oral transmission, and some vector-borne infections, such as
SARS, chikungunya, dengue, hepatitis A, influenza, measles, meningococcal disease,
mumps, norovirus, pertussis, polio, and tuberculosis, including multidrug-resistant
(MDR) and extensively drug-resistant (XDR). Populations may be partially or com-
pletely protected if vaccinated, as in the case of hepatitis A, influenza, measles,
mumps, and polio.
The spread of some infections into new regions may lead to multiple generations in
any population (tuberculosis). Other infections may spread only if the appropriate en-
vironmental conditions (eg, temperature, humidity) and vector or intermediate hosts
are present (dengue, chikungunya). Yet others spread only if the community has sus-
ceptible/nonimmune individuals (measles, hepatitis A).
Severe Acute Respiratory Syndrome

The outbreak of SARS in 2003 exemplifies the impact of spatial mobility and the
dynamic role of travelers. In 2002, a previously unrecognized coronavirus caused an
outbreak of respiratory infections in the Guangdong Province of China. The virus
apparently jumped species from civet cats to humans, although subsequent research
suggests that the reservoir host is the fruit bat.31 The outbreak became visible to the
world community when an infected physician from Guangdong, who stayed for a day
in Hotel Metropole in Hong Kong, was the source of infection for multiple hotel guests,
who then disseminated the virus to numerous other countries. By May, more than
8000 SARS infections had been reported.32 By July, 29 countries and territories across
five continents reported outbreaks and attributed 774 fatalities to SARS.32 Transmis-
sion of SARS on aircraft occurred at rates of 0% to 18.3%, and occurred as far as
seven rows from the source passenger.33
One particular SARS case showed the potential for rapid international dispersion of
a pathogen that is spread from person to person.34 A businessman flew from Hong
Kong to Frankfurt, Germany, on March 30, 2003. He traveled on seven flights through-
out Europe during a 5-day period, including stops in Barcelona, London, Munich, and
Hong Kong. He was hospitalized in Hong Kong on April 8 for suspected SARS, sub-
sequently confirmed on April 10.34 Responding to SARS outbreak, the CDC issued
advisories to avoid travel to the SARS-affected countries. Most countries in Asia
instituted strict quarantine measures and restricted travel to reduce cross-border
spread and as intracountry spread. The CDC temporarily suspended international
adoption from China because of concern for dissemination.
SARS and the associated travel advisories led to a decline in international tourist ar-
rivals in 2003; the World Trade Organization (WTO) reported that arrivals to some af-
fected countries in Asia plunged to less than 50% of their usual levels.35 Although the
region rebounded quickly, SARS was responsible for a 9% overall loss in travel volume
for Asia in 2003 and had substantial economic impact.35
Chikungunya
Chikungunya virus, an alphavirus first isolated in Africa in 1952, is a mosquito-trans-
mitted virus that was recently carried by travelers to geographically disparate regions
on different continents. Recent outbreaks of chikungunya virus infection originated in
Kenya in 2004, and major outbreaks followed in the Indian Ocean Island countries (Re-
union, Mauritius, Comoros, Seychelles, Madagascar) in 2005 to 2006.36 Outbreaks en-
sued in India and Indonesia, and the virus was carried by travelers to Europe,37–41 the
United States42,43 Australia,44 and Hong Kong.45 A viremic traveler from India visiting
the Ravenna province of Italy became the index case of an outbreak that infected 205
local residents, which was transmitted through local Aedes albopictus, a mosquito
species introduced into Italy by ship in 1990.46
Dengue
Dengue virus, a flavivirus, is endemic in Southeast Asia, South Asia, the Pacific, Carib-
bean, and Central and South America, and its history illustrates the intricate interac-
tions of travel, movement of goods, and translocation of infectious disease.47 Most
cases of dengue virus infection diagnosed in the United States have been imported
in travelers, although limited local transmission in Texas has also occurred recently.
Less well-known is the fact that a competent vector, A albopictus, or Asian tiger mos-
quito, was introduced into the United States in 1980s by ships that carried used tires.
Since then, the mosquito has established itself in many states, and could potentiate
autochthonous dengue outbreaks.
In 2001 Hawaii experienced dengue outbreaks, the likely source being viremic trav-
elers returning from French Polynesia. Dengue had been present in Hawaii until the
1940s (after World War II), when autochthonous transmission ceased. However, A al-
bopictus became established in Hawaii, and in 2001was the primary vector in a local
outbreak involving more than 100 cases.48
1416
Chen & Elizabeth Wilson
Table 3
Examples of recent infectious disease transmission associated with travel
Location Where Countries Where

Pathogen Illnesses Originated Illnesses Occurred Comment Reference
Infections with a wide geographic distribution that can affect travelers but pose no risk to others
Legionella Worldwide Cruise ships >200 cases have occurred in outbreaks associated WHO 200710
with cruise ships CDC 200596
Kura et al.97
Cruise ship New York New York One single cruise ship was implicated in 50 cases of Jernigan e al.14
to Bermuda legionellosis during nine separate voyages in
1994; the source was the whirlpool spa
Cruise ship to Germany Eight German passengers developed infection after Beyrer et al.15
Nordic Sea a cruise to the Nordic SeaLegionella pneumophila
serogroup 1, subgroup ‘‘Knoxville’’ was
isolatedThe attack rate was 4%, and disease was
associated with prolonged exposure to the spa
pool
Infections with risk to immediate contacts but unlikely to lead to an outbreak in a new region with good health care infrastructure
Lassa fever Liberia or Sierra Leone New Jersey A businessman born in Liberia but residing in CDC 200498
United States returned from West Africa with
a febrile illness; lassa fever was confirmed
Infections that can be introduced by a traveler and may lead to multiple generations of spread or establishment in a new region
Chikungunya Reunion, Comoros, Europe, Travelers acquired chikungunya in Indian Ocean Panning et al.37
Mauritius, United States, Island countries and presented with illnesses Beltrame et al.38
Madagascar, Australia, when they returned home Parola et al.39
Seychelles, India Hong Kong Simon et al.40
Hochedez et al.41
Lanciotti et al.42
Druce et al.44
Lee et al.45
India Italy Traveler was infected in India, visited Italy, became Rezza et al.46
index case in an outbreak that occurred in Italy
Dengue Tahiti Hawaii In 2001–2002, a returning traveler from Pacific Effler et al.48
Islands was the index case in the first
autochthonous outbreak in Hawaii since 1944,
with 122 laboratory-confirmed cases
Meningococcal Saudi Arabia Worldwide Hajj pilgrims and contacts have transmitted disease Moore et al.69
disease to many areas CDC 200070
CDC 200171
Dull et al.72
WHO 200173
Wilder-Smith et al.86
Norovirus Worldwide Cruise ships The Vessel Sanitation Program at the CDC identified Widdowson et al.99
>12 outbreaks on cruise ships in 2002
Europe Cruise ships Increased outbreaks in Europe were associated with Lopman et al.100
cruise ships
Aircraft An outbreak occurred among the crew of a flight Widdowson et al.17
The Role of the Traveler in Emerging Infections

with limited transmission to passengers
Europe Cruise ships Outbreaks occurred in 2006 on cruise ships from the Koopmans et al.12
Netherlands, Scotland, England, most operating Bull et al.101
in the Baltic Sea
Severe acute Hong Kong, Worldwide Between November 1, 2002, and July 31, 2003, SARS WHO 200332
respiratory Singapore spread globally to >25 countries and caused 8096 CDC 2003102
syndrome reported infections and 774 deaths
Tuberculosis Worldwide, Saudi Worldwide, The 2005 tuberculosis rate in foreign-born persons CDC 2006103
Arabia air travel in the United States was 8.7 times that of United CDC 2006104
States–born persons; the incidence of multidrug-
resistant tuberculosis is higher in low- and middle-
income countries
Saudi Arabia Singapore Comparison of tuberculosis tests using a Wilder-Smith et al.87
whole-blood assay (QuantiFERON-TB assay)
before and after return from the Hajj showed
10% conversion consistent with exposure during
the pilgrimage
(continued on next page)
1417
1418
Table 3
(continued)
LocationWhere Countries Where

Pathogen Illnesses Originated Illnesses Occurred Comment Reference
Multidrug-resistant Honolulu, Chicago, United States Passengers on flights with an infectious patient had Kenyon et al.19
Mycobacterium and Baltimore up to 6% skin test conversions; passengers seated
tuberculosis within two rows of the case patient had the
highest risk for skin test conversion at 31%
Multidrug- Delhi, India United States A passenger with MDR TB traveled from Delhi to CDC20
resistant United States, and could potentially spread to
tuberculosis others on flight
Infections that can be spread by a traveler, but vaccine-induced immunity of the population can limit spread
Hepatitis A Ethiopia, Russia, United States International adoptees have transmitted hepatitis A CDC 2007105
Philippines to their families and contacts
Influenza Cruise ships Cruise ships, Multiple outbreaks occurred among cruise ship CDC 199751
widespread passengers between New York and Montreal, Tahiti Uyeki et al.50
and Hawaii, and Alaska and the Yukon Territory Brotherton et al.106
Measles China Many states in the International adoptees, their family, and other CDC 2000–200457–60
United States, contacts have acquired measles during travel
Denmark, Spain, and and after arriving home
likely other countries
United Kingdom, Many states in the Unvaccinated travelers have acquired measles CDC 200865,66
Switzerland, United States and during travel (to United Kingdom,
Israel Europe Switzerland, Israel, and other countries),
and led to outbreaks after return home
Israel, Switzerland, Many states in the Visitors and travelers from other countries have CDC 200765,66
India, Japan United States presented in the United States with measles
and led to outbreaks
Europe (Italy, Australia Traveler was diagnosed with measles in Australia Riddell et al.64
Germany, after a 3-week holiday in Europe; molecular
Switzerland, studies identified it to be a strain identified in
Austria, France) United Kingdom
Mumps United Kingdom Multiple states in the Multistate outbreaks began in Iowa in December CDC 2006107,108
United States 2005, and 2597 cases were reported from 11
states between January 1and May 2, 2006; some
cases were possibly infectious during air travel
United Kingdom United States Summer camp outbreak in New York involved 31 CDC 2006109
cases and was associated with a counselor from
the United Kingdom; attack rate was 5.7%
Polio Somalia Kenya Two children, aged 3 and 12 years and born in CDC 2008110
a camp in Kenya, developed paralytic polio
with WPV1, which was consistent with
isolates from Somalia
Nigeria, India, Angola, Burma, Chad, Wild poliovirus spread from endemic countries CDC 200875
Afghanistan, Democratic Republic to numerous previously polio-free countries;
Pakistan of the Congo, Nepal, introduction has led to sustained
Niger, Somalia, Sudan transmission in some countries

1419
Influenza: Seasonal and Pandemic

Influenza remains an ongoing global challenge, given the large pool of influenza vi-
ruses in avian and other species and the capacity of the virus to recombine, reassort,
and mutate. Spread through aerosol or direct contact, the aircraft provides an ideal
enclosed space for transmission of influenza virus. In one well-characterized outbreak,
a passenger who had influenza on an airplane with a nonfunctioning ventilation system
for 3 hours probably transmitted the infection to 72% of 54 passengers.49 Movement
of troops contributed to the spread of influenza in 1918 to 1919. Nowadays the ex-
panded range and speed of travel can rapidly disseminate a pandemic strain of
influenza.
Influenza has caused multiple outbreaks on cruise ships. A large outbreak of influ-
enza A (estimated >33,000) cases during the summer of 1998 in Alaska and the Yukon
Territory, Canada affected primarily tourists and workers in the tourism industry.50
Outbreaks also occurred on two cruise ships, affecting passengers between New
York and Montreal, and Tahiti and Hawaii.51 A major outbreak on a cruise ship can af-
fect thousands of individuals, and passengers can carry infection to their next
destination.
In a study of Swiss travelers that included a questionnaire and paired serologic test-
ing before and after travel (N 5 1450), 2.8% of travelers tested positive for influenza
and 1.2% had more than a fourfold increase in antibody titers. Investigators estimated
the incidence for influenza-associated events to be 1.0 per 100 person-months
abroad.52 These results indicate that influenza has become the most common vac-
cine-preventable disease in Swiss travelers to the tropics, and highlight the risk for
spread through travel.
An analysis of the CDC’s influenza and pneumonia mortality data from 1996 to 2005
found that international air travel influences the timing of influenza introduction, and
that domestic airline travel volume in November correlates with the rate of spread in
the United States.53 A study of the hemagglutinin of 13,000 human influenza A
(H3N2) viruses during 2002 through 2007 indicated that most new strains emerge in
East and Southeast Asia.54 The new strains circulate continuously in this region and
cause epidemics, leading to epidemics in temperate regions. The new strains initially
spread to Oceania, North America, and Europe, later reaching South America.54 The
new influenza strains most likely reach other parts of the world through travelers.
Measles
Measles has exemplified the travel-related spread of an infectious pathogen for cen-
turies. European explorers brought measles to the New World along with smallpox and
other pathogens, decimating local populations and contributing to the collapse of
civilizations in the New World. In the 1990s, as countries in the Americas attempted
measles eradication and cases declined, numerous importations were clearly docu-
mented. The countries of origin included developed countries in Asia and Europe,
and developing countries in these continents and Africa.55 The CDC reported 14 mea-
sles outbreaks in the United States between 2001 and 2004, with 7 originating from an
American traveler.56
Measles outbreaks have recently resulted from travel for international adoption, in-
cluding cases that were infectious during flights.57–60 Clusters of internationally adop-
ted children from China, their family members, and contacts contracted measles in
2000 and almost every year thereafter. Transmission was identified in the orphanages
in China, causing the CDC to suspend adoption temporarily from the affected
orphanages.
Measles outbreaks have also occurred in unvaccinated students returning from

community service in developing countries, with subsequent spread to their commu-
nities.61,62 During the Little League championships in 2007 in Pennsylvania, a player
from Japan became infected and transmitted measles to other players and contacts.63
Measles was also acquired by a traveler on a 3-week holiday in Europe (Italy, Ger-
many, Switzerland, Austria, France) and diagnosed after his return to Australia.64
Molecular analysis determined the genotype B3 strain to be one from the United King-
dom, where he had not visited, indicating unrecognized transmission of the strain in
continental Europe.64
In February, 2008, an adult visitor from Switzerland was hospitalized in Arizona for
measles and pneumonia.65 The individual acquired measles in Switzerland, where an
outbreak was occurring. In the several weeks that followed, nine confirmed cases
were linked, and additional cases were suspected to be associated.
Similarly, an unvaccinated child became infected with measles during travel to Swit-
zerland, which led to an outbreak of 11 cases in San Diego, and another patient who
became ill in Hawaii.66 Both outbreaks involved genotype D5, which was circulating in
Switzerland. Confirmed measles cases have also been reported in New York and Vir-
ginia, involving genotype D4, which has been causing large outbreaks in Israel
(Fig. 2).65
In Europe, 70% to 86% of measles cases have been associated with importation.67
Cases were noted in Spanish travelers returning from Thailand and Mozambique.67,68
Because of its high reproductive rate, as long as the measles virus persists anywhere,
it will remain a threat to the global population.
Meningococcal Disease
Meningococcal disease represents an infectious disease that impacts travel health
requirements. After the meningococcal outbreaks associated with the Hajj pilgrimage
in 1987, Saudi Arabia required meningococcal immunization for all pilgrims and local
populations in pilgrimage sites.69 Despite this immunization requirement, outbreaks of
serogroup W-135 associated with the Hajj occurred in 2000 and 2001.70–72 A study in
the United States found that 1.3% of pilgrims returning from the Hajj were carrying se-
rogroup W-135 N meningitidis,72 despite vaccination with a quadrivalent vaccine that
included W-135.
Because of these meningococcal outbreaks associated with the Hajj, Saudi Arabia
revised the meningococcal vaccination requirement to specifically use the
quadrivalent vaccine for pilgrims and all local population at risk.73 The widely used
meningococcal vaccines can reduce the risk for meningococcal disease but do not
prevent nasopharyngeal carriage with Neisseria meningitidis.
Polio
In 1988, the World Health Assembly resolved to eradicate polio globally by 2000. Al-
though eradication has not been achieved, global incidence has declined.74 However,
in the past several years, travel and migration have reintroduced poliovirus into many
countries that had previously achieved polio-free status. From 2002 to 2005, wild po-
liovirus resurged and spread from 6 endemic countries to 21 countries (Fig. 3).74
Among 13 countries with sustained transmission for more than 6 months, polio vac-
cine coverage was 52%, whereas those without sustained transmission had coverage
of 82%, clearly illustrating that higher immunization coverage is necessary to eradicate
polio.74 As of April 2008, only 4 countries (Afghanistan, India, Nigeria, Pakistan) remain
endemic for polio, but at least 13 have identified polio importation, including 4 that had
1422
Fig. 2. Measles outbreaks in the United States from January 1 through April 25, 2008. (From CDC. Measles—United States, January 1–April 25, 2008.
MMWR Morb Mortal Wkly Rep 2008;57(18):494–8. http://www.cdc.gov/mmwr/PDF/wk/mm5718.pdf; with permission.)
Fig. 3. Wild poliovirus (WPV) cases in 2005 and importation routes during 2002–2005 worldwide. (From CDC. Resurgence of wild poliovirus type 1 trans-
mission and consequences of importation—21 countries, 2002–2005. Morbidity Mortality Weekly Report 2006;55(6):145–50; with permission.)
1423
been polio-free for at least 4 years (Bangladesh, Burma, the Democratic Republic of
the Congo, Namibia) and 1 that had been polio-free for 10 years (Kenya).75
In addition to wild poliovirus circulation, vaccine-derived poliovirus has reverted to
virulent forms and has circulated in several countries (including Nepal, Myanmar,
Philippines, Madagascar, Haiti, and Dominican Republic), associated with paralytic
polio.75 A 22-year-old woman from the United States contracted paralytic polio
from vaccine-strain poliovirus in 2005 while studying abroad in South and Central
America.76 The source was probably an infant who had recently received the live polio
vaccine.76
Also in 2005, an immunocompromised Amish infant (unvaccinated) in Minnesota
was found to be infected with vaccine-derived poliovirus, although without paralysis.77
This finding led to the identification of four more children who had asymptomatic
infection. Molecular analysis of the virus suggested that it probably had replicated
for 2 years, and most likely originated in someone visiting the United States from
a country that used the live oral polio vaccine.77
Animal and Vector Movement and Travel

Animals are a common source of human pathogens recently and remotely, with
HIV/AIDS the most dramatic recent example of a pathogen of animal origin that en-
tered and spread in the human population.78 Although humans travel widely, they
also orchestrate the movement of many species of domestic and wild animals,
legally and illegally.79 Wild-caught African animals imported into the United States
were the source of a monkeypox outbreak in the Midwest. The African animals,
which had unrecognized monkeypox infection, were housed with prairie dogs
that were sold as pets.80 Dogs brought in from rabies-endemic areas have been
an occasional source of rabies in Europe. Movement of avian species, including
exotic birds sold to falconers, can be a potential route for introduction of H5N1
or other microbes potentially pathogenic for humans (Fig. 4).81 Some of these
infections have the potential for persistence and dissemination in a new geographic
region.
Conveyances of travel and trade have also transported mosquito vectors and
introduced them into new areas, where they have become established and have
been important in disease outbreaks. With chikungunya virus infection, A albopictus
mosquitoes were imported into Italy, probably by way of shipped used tires. Subse-
quently, a viremic travel carried the virus that was responsible for the outbreak in Italy
in the summer of 2007.46 A albopictus was introduced through used tires into the
United States in 1986 and spread broadly, and was the main vector identified in the
dengue outbreak in Hawaii in 2001 to 2002. Regions that have a competent vector
can be potentially vulnerable to outbreaks of new vector-borne infections, if the appro-
priate bioclimatic conditions exist.
Tatem and colleagues82 collected data on the volume of shipping and air traffic and
the climate and used it to identify shipping routes with the highest risk for A albopictus
invasion. Among 47 ports outside the original distribution of A albopictus, it invaded
just more than half. Those invaded had similar climate and high sea traffic volumes.
The authors concluded that ‘‘when climatic suitabilities are similar, shipping volume
alone appears to determine invasion probability.’’82 These studies may be useful in try-
ing to identify areas at highest risk so that strict surveillance and control activities can
be instituted. With increasing travel and trade, introductions of animals and insects are
expected to continue.
Investigators also tried to quantify which airports have the greatest risk for local
Plasmodium falciparum transmission through importation of infective mosquitoes
Fig. 4. Crested Hawk-Eagles confiscated at Brussels International Airport in the hand

luggage of a Thai passenger. The birds were wrapped in a cotton cloth, with the heads
free, and each of them inserted in a wicker tube w60 cm in length, with one end open.
(Courtesy of Paul Meuleneire, custom investigations officer, antidrug group. From Van
Borm S, Thomas I, Hanquey G, et al. Highly pathogenic H5N1 influenza virus in smuggled
Thai eagles, Belgium. Emerg Infect Dis 2005;11(5):702–5. Available from http://www.cdc.
gov/ncidod/EID/vol11no05/05-0211.htm.)
from sub-Saharan Africa.83 They used global climate and air traffic data and analyzed
risk according to season. They also estimated areas of greatest potential risk because
of development of new routes. These quantitative risk assessments can be used to
assess likely pathways of introductions into new regions.84
Mass Gatherings
When masses of people from different regions of the world congregate, great potential
arises for the translocation of microorganisms. Religious pilgrimages are typical of
these mass meetings of humans. Major sporting events where spectators and athletes
from distant lands are also possible venues for microbial mixing.
HAJJ PILGRIMAGE
The Hajj is a gathering of approximately 2 million Muslim pilgrims, which takes place
annually in Saudi Arabia. The Umra is a pilgrimage of a smaller scale, although pilgrims
also gather in Saudi Arabia from all parts of the globe. The WHO has issued health rec-
ommendations for the Hajj, with specific directives for yellow fever, meningococcal
disease, influenza, and poliomyelitis.85 Meningococcal disease in particular has dem-
onstrated transmission during Hajj and its spread after pilgrims return to their home
countries, despite vaccination.69–73,86
Tuberculosis also poses a threat. A study of possible exposure to tuberculosis using
whole-blood assay (QuantiFERON-TB) before travel and after return from the Hajj pil-
grimage found that 10% of pilgrims had a rise in immune response to tuberculosis an-
tigens.87 Influenza, measles, and pertussis also have potential for creating outbreaks
associated with crowded events such as the Hajj pilgrimage.
OLYMPICS
The Olympic Games are held every 4 years and attract approximately 10,500 athletes
worldwide. For the Beijing Olympics in 2008, several hundred thousand spectators are
expected at any one time, in addition to 20,000 media personnel.88 Although the
events will be held in 37 venues and involve several cities, the athletes and visitors
are expected to concentrate in densely populated cities of Beijing, Hong Kong, and
Shanghai. Communicable diseases can potentially spread among athletes and spec-
tators, and then into their home countries. Enterovirus 71 emerged in numerous Chi-
nese provinces in the spring of 2008. With SARS as a reminder, health authorities are
working to contain the enteroviral outbreaks before the Olympic Games.
During the Commonwealth Games in 2006, the case of measles in a returning trav-
eler to Australia generated concern about the possibility of spread through the event.64
A measles outbreak occurring in Germany just preceding the Football World Cup in
2006 caused concern about transmission to spectators and further dispersal when
they returned home. Fortunately, no major outbreaks occurred. However, the Little
League Tournament in Pennsylvania in 2007 led to outbreak of measles, and
strengthens the notion that mass gatherings facilitate dispersal of pathogens.63
Travel Medicine
Travel medicine is a specialty that coordinates various disciplines, including infectious
diseases, tropical medicine, public health, migrant health, wilderness medicine, and
psychiatry. In 1991, the International Society of Travel Medicine, was established
with the goal of providing health promotion and disease prevention for travelers.89
This specialty integrates an understanding of global health issues into the health
care of travelers,90 and many specialists in the field have led the research and teaching
that have provided insight into the impact of travel on infectious diseases.91
Programs on Outbreak Reporting and Disease Surveillance

Several programs have been established to report on outbreaks or survey infectious
diseases in travelers. ProMED, a program of the International Society of Infectious Dis-
eases (www.isid.org), disseminates news on humans, animals, and plant diseases
globally. GeoSentinel is a network of travel medicine clinics developed through a col-
laborative agreement between the International Society of Travel Medicine and the
CDC. Participants collect information on travel-related illnesses and report on unusual
illnesses in travelers.92 The GeoSentinel network now has 40 sites located in six con-
tinents. GeoSentinel analyses of illnesses in travelers help define geographic areas as-
sociated with risk for specific diseases, and thereby improve the health preparation of
travelers.93
A recent GeoSentinel report on schistosomiasis in travelers returning from Tanzania
alerted clinicians to exposure associated with swimming in an artificial pond. An anal-
ysis of dengue cases in the GeoSentinel database showed periodic increases, and the
cyclic pattern corresponded to epidemics in Southeast Asia, illustrating usefulness of
travelers as a sentinel population.94 GeoSentinel has notably reported on leptospirosis
associated with Eco-Challenge in Borneo, SARS in Canadian travelers returning to
from Asia, and malaria from resort holidays in Punta Cana, Dominican Republic.
Additional cases were identified in travelers after the initial alerts, and public health
responses followed.
TropNet Europe is another surveillance network of travel medicine providers that
also focuses exclusively on travelers returning to Europe.95 These networks show use-
ful information-sharing between clinicians and public health authorities.
SUMMARY
Travel influences the emergence of infectious diseases. Travelers have contact and in-
teractions with diverse microbes and people during their journeys, share environments
with other people, and can have in-transit transmission. Travelers can carry microor-
ganisms to new environments or allow mingling of organisms from different regions,
resulting in mixing of genetic material or resistance characteristics. Travelers can
become infected and then infect others. In some instances, this can lead to multiple
generations of spread or sustained transmission in a new area. Finally, diagnoses of
travelers in resource-rich regions can yield knowledge about infectious disease agents
acquired in resource-poor areas. This knowledge can be used to alert the global
community to the presence or susceptibility patterns of pathogens in different regions;
inform strategies that can be used to control infections in developing countries; and
prepare travelers to those areas and guide the care of those returning. Travelers
should be considered an integral part of the global surveillance network for emerging
infections.
REFERENCES
1. United States Census Bureau. International database. Available at: http://www.

census.gov/ipc/www/idb. Accessed March 1, 2008.
2. World Tourism Organization. UNWTO World Tourism Barometer January
2008;6(1). Available at: http://www.world-tourism.org/facts/menu.html. Accessed
February 8, 2008.
3. Gushulak BD, MacPherson DW. Globalization of infectious diseases: the impact
of migration. Clin Infect Dis 2004;38:1742–8.
4. United States Census Bureau. The Foreign-Born Population in the United

States—2003. Available at: http://www.census.gov/prod/2004pubs/p20-551.
pdf. Accessed February 8, 2008.
5. World Tourism Organization. Tourism highlights, edition 2007. Available at: http://
www.world-tourism.org/facts/menu.html. Accessed February 8, 2008.
6. World Tourism Organization. Tourism indicators. Available at: http://www.
world-tourism.org/facts/menu.html. Accessed February 8, 2008.
7. Cliff A, Haggett P. Time, travel and infection. Br Med Bull 2004;69:87–99.
8. Sivitz LB, Stratton K, Benjamin GC, editors. Quarantine stations at ports of entry:
protecting the public’s health. Committee on measures to enhance the effective-
ness of the CDC quarantine station expansion plan for U.S. ports of entry. Insti-
tute of Medicine of the National Academies. Washington, DC: The National
Academies Press; 2006.
9. Ruiz GM, Rawlings TK, Dobbs FC, et al. Global spread of microorganisms by
ships. Nature 2000;408:49–50.
10. WHO. Travel by sea: health considerations. Wkly Epidemiol Rec 2007;82(34):
305–8.
11. Minooee A, Rickman LS. Infectious diseases on cruise ships. Clin Infect Dis
1999;29:737–44.
12. Koopmans M, Harris J, Verhoef L, et al. European investigation into recent norovi-
rus outbreaks on cruise ships: update. Available at: http://www.eurosurveillance.
org/ViewArticle.aspx?ArticleId52997. Accessed March 1, 2008.
13. Verhoef L, Depoortere E, Boxman I, et al. Emergence of new norovirus variants
on spring cruise ships and prediction of winter epidemics. Emerging Infect Dis
2008;14(2):238–43.
14. Jernigan DB, Hofmann J, Cetron MS, et al. Outbreak of Legionnaires’ disease
among cruise ship passengers exposed to a contaminated whirlpool spa. Lan-
cet 1996;347(9000):494–9.
15. Beyrer K, Lai S, Dreesman J, et al. Legionnaires’ disease outbreak associated
with a cruise liner, August 2003: epidemiological and microbiological findings.
Epidemiol Infect 2007;135(5):802–10.
16. Mangili A, Gendreau MA. Transmission of infectious diseases during commercial
air travel. Lancet 2005;365:989–96.
17. Widdowson M-A, Glass R, Monroe S, et al. Probable transmission of norovirus on
an airplane. JAMA 2005;293:1859–60.
18. Musher DM. How contagious are common respiratory tract infections? N Engl
J Med 2003;348(13):1256–66.
19. Kenyon TA, Valway SE, Ihle WW, et al. Transmission of multidrug-resistant Mycobac-
terium tuberculosis during a long airplane flight. N Engl J Med 1996;334(15):933–8.
20. CDC. CDC investigation of traveler with multidrug resistant tuberculosis (MDR
TB). Available at: http://www.cdc.gov/tb/flightQA.htm. Accessed May 1, 2008.
21. Ozonoff D, Pepper L. Ticket to ride: spreading germs a mile high. Lancet 2005;
365(9463):917–9.
22. Guernier V, Hockberg ME, Guegan JE. Ecology drives the worldwide distribution
of human diseases. PLoS Biol 2004;2(6):740–6.
23. Hollingsworth TD, Ferguson NM, Anderson RM. Frequent travelers and rate of
spread of epidemics. Emerging Infect Dis 2007;13(9):1288–94.
24. Hufnagel L, Brockmann D, Geisel T. Forecast and control of epidemics in a glob-
alized world. Proc Natl Acad Sci USA 2004;101(42):15124–9.
25. Rvachev L, Longini I. A mathematical model for the global spread of influenza.
Math Biosci 1985;75:3–22.
26. Grais RF, Ellis JH, Glass GE. Assessing the impact of airline travel on the geo-
graphic spread of pandemic influenza. Eur J Epidemiol 2003;18:1065–72.
27. Wilson ME. The traveller and emerging infections: sentinel, courier, transmitter.
J Appl Microbiol 2003;94:1S–11S.
28. Zuckerman JN, Steffen R. Risks of hepatitis B in travelers as compared to immu-
nization status. J Travel Med 2000;7:170–4.
29. Correia JD, Shafer RT, Patel V, et al. Blood and body fluid exposure as a health
risk for international travel. J Travel Med 2001;8:263–6.
30. Cabada MM, Montoya M, Echevarria JI, et al. Sexual behavior in travelers visit-
ing Cuzco. J Travel Med 2003;10(4):214–8.
31. Li W, Shi Z, Yu M, et al. Bats are natural reservoirs of SARS-like coronaviruses.
Science 2005;310:676–9.
32. World Health Organization. Summary of probable SARS cases with onset of ill-
ness from 1 November 2002 to 31 July 2003. Available at: http://www.who.int/
csr/sars/country/table2004_04_21/en/. Accessed March 1, 2006.
33. Olsen SJ, Chang H-L, Cheung TY-Y, et al. Transmission of the severe acute
respiratory syndrome on aircraft. N Engl J Med 2003;349:2416–22.
34. Breugelmans JG, Zucs P, Porten K, et al. SARS transmission and commercial air-
craft. J Am Med Assoc 2004;10(8):1502–3.
35. World Tourism Organization. Tourism highlights, edition 2004. Available at: http://
www.unwto.org. Accessed October 27, 2005.
36. Charrel RN, de Lamballerie X, Raoult D. Chikungunya outbreaks–the globaliza-
37. Panning M, Grywna K, van Esbroeck M, et al. Chikungunya fever in travelers
returning to Europe from the Indian Ocean region, 2006. Emerging Infect Dis
2007;14(3):416–22.
38. Beltrame A, Angheben A, Bisoffi Z, et al. Imported chikungunya infection, Italy.
Emerging Infect Dis 2007;13(8):1264–6.
39. Parola P, de Lamballerie X, Jourdan J, et al. Novel chikungunya virus variant in
travellers returning from Indian Ocean Islands. Emerging Infect Dis 2006;12:
1493–9.
40. Simon F, Parola P, Grandalam M, et al. Chikungunya infection: an emerging
rheumatism among travellers returned from Indian Ocean Islands. A report of
47 patients. Medicine;86(3):123–37.
41. Hochedez P, Jaureguiberry S, Debruyne M, et al. Chikungunya infection in trav-
elers. Emerging Infect Dis 2006;12:1565–7.
42. Lanciotti RS, Kosoy OL, Laven JJ, et al. Chikungunya virus in US travelers return-
ing from India, 2006. Emerging Infect Dis 2007;13(5):764–7.
43. CDC. Update: chikungunya fever diagnosed among international travellers,
United States. MMWR Morb Mortal Wkly Rep 2007;56(12):276–7.
44. Druce JD, Johnson DF, Tran T, et al. Chikungunya virus infection in traveler to
Australia. Emerging Infect Dis 2007;13(3):509–10.
45. Lee N, Wong CK, Lam WY, et al. Chikungunya fever, Hong Kong. Emerging
Infect Dis 2006;12(11):1790–2.
46. Rezza G, Nicolleti L, Angelleti R, et al. Infection with chikungunya virus in Italy:
an outbreak in a temperate region. Lancet 2007;370:1840–6.
47. Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health,
social and economic problem in the 21st century. Trends Microbiol 2002;
10(2):100–2.
48. Effler PV, Pang L, Kitsutani P, et al. Dengue fever, Hawaii, 2001–2002. Emerging
Infect Dis 2005;11(5):742–9.
49. Moser MR, Bender TR, Margolis HS, et al. An outbreak of influenza aboard
a commercial airliner. Am J Epidemiol 1979;110:1–6.
50. Uyeki TM, Zane SB, Bodnar UR, et al. Large summertime influenza A outbreak
among tourists in Alaska and the Yukon territory. Clin Infect Dis 2003;36(9):
1095–102.
51. CDC. Update: influenza activity—United States, 1997–1998 season. MMWR
Morb Mortal Wkly Rep 1997;46:1094–8.
52. Mutsch M, Tavernini M, Marx A, et al. Influenza virus infection in travelers to trop-
ical and subtropical countries. Clin Infect Dis 2005;40(9):1282–7.
53. Brownstein JS, Wolfe CJ, Mandl KD. Empirical evidence for the effect of airline
travel on inter-regional influenza spread in the United States. PLoS Med 2006;
3(10):e401.
54. Russell CA, Jones TC, Barr IG, et al. The global circulation of influenza A (H3N2)
viruses. Science 2008;320(5874):340–6.
55. de Quadros C, Izurieta H, Venczel L, et al. Measles eradication in the Americas:
progress to date. J Infect Dis 2004;189(Suppl 1):S227–35.
56. CDC. Preventable measles among U.S. residents, 2001-2004. MMWR Morb
Mortal Wkly Rep 2005;54(33):817–20.
57. CDC. Update: multistate investigation of measles among adoptees from
China—April 16, 2004. MMWR Morb Mortal Wkly Rep 2004;53:323–4.
58. Centers for Disease Control and Prevention (CDC). Measles outbreak associ-
ated with an imported case in an infant—Alabama, 2002. MMWR Morb Mortal
Wkly Rep 2004;53(2):30–3.
59. CDC. Measles outbreak in adults associated with adoption of children in
China—California, Missouri, Washington, July-August 2006. MMWR Morb Mortal
Wkly Rep 2007;56(7):144–6.
60. CDC. Measles among adults associated with adoption of children in China—
California, Missouri, Washington, July-August 2006. MMWR Morb Mortal Wkly
Rep 2007;56(07):144–6.
61. Centers for Disease Control and Prevention (CDC). Import-associated measles
outbreak—Indiana, May-June 2005. MMWR Morb Mortal Wkly Rep 2005;54:
1073–5.
62. Parker AA, Staggs W, Dayan GH, et al. Implications of a 2005 measles outbreak
in Indiana for sustained elimination of measles in the United States. N Engl
J Med 2006;355(5):447–55.
63. CDC. Multistate measles outbreak associated with an international youth sport-
ing event—Pennsylvania, Texas, Michigan, August-September, 2007. MMWR
Morb Mortal Wkly Rep 2008;57(7):169–73.
64. Riddell MA, Lynch P, Jin L, et al. Measles case imported from Europe to Victoria,
Australia, March 2006. Euro Surveill 2006;11(20):2959. Available at: http://www.
eurosurveillance.org/ViewArticle.aspx?ArticleId52959. Accessed May 20, 2006.
65. CDC. Measles—United States, January 1-April 25, 2008. MMWR Morb Mortal
Wkly Rep 2008;57(18):494–8.
66. CDC. Outbreak of measles—San Diego, California, January-February, 2008.
MMWR Morb Mortal Wkly Rep 2008;57(8):203–6.
67. Muscat M, Glismann S, Bang H. Measles in Europe in 2001–2002. Euro Surveill
2003;8:123–9.
68. Munoz J, Alonso D, Vilella A, et al. Measles in travelers: are we aware enough?
J Travel Med 2008;15:124–5.
69. Moore PS, Harrison LH, Telzak EE, et al. Group A meningococcal carriage in
travelers returning from Saudi Arabia. JAMA 1988;260(18):2686–9.
70. CDC. Serogroup meningococcal disease among travelers returning from Saudi
Arabia: United States, 2000. MMWR Morb Mortal Wkly Rep 2000;49:345–6.
71. CDC. Public health dispatch: update: assessment of risk for meningococcal dis-
ease associated with the Hajj 2001. MMWR Morb Mortal Wkly Rep 2001;50(12):
221–2.
72. Dull PM, Abdelwahab J, Sacchi CT. Neisseria meningitidis serogroup W-135 car-
riage among US travelers to the 2001 Hajj. J Infect Dis 2005;191:33–9.
73. World Health Organization. 2001-Meningococcal disease, serogroup W135, dis-
ease outbreak news April 27, 2001. Available at: http://www.who.int/csr/don/
2001_04_27/en/index.html. Accessed April 4, 2008.
74. Centers for Disease Control and Prevention (CDC). Resurgence of wild
poliovirus type 1 transmission and consequences of importation—21 countries,
2002–2005. MMWR Morb Mortal Wkly Rep 2006;55(6):145–50.
75. CDC. Progress toward interruption of wild poliomyelitis transmission—World-
wide, January 2007–April 2008. MMWR Morb Mortal Wkly Rep 2008;57(18):
489–94.
76. CDC. Imported vaccine-associated paralytic poliomyelitis—United States, 2005.
MMWR Morb Mortal Wkly Rep 2006;55(4):97–9.
77. CDC. Poliovirus infections in four unvaccinated children—Minnesota, August-
October 2005. MMWR Morb Mortal Wkly Rep 2005;54:1053–5.
78. Hahn B, Shaw GM, De Cock KM, et al. AIDS as a zoonosis: scientific and public
health implications. Science 2000;287:607–14.
79. Karesh WB, Cook RA, Gilbert M, et al. Implications of wildlife trade on the move-
ment of avian influenza and other infectious diseases. J Wildl Dis 2007;43(3):
S55–9.
80. Reed KD, Melski JW, Braham MB, et al. The detection of monkeypox in humans
in the Western Hemisphere. N Engl J Med 2004;350:342–50.
81. Van Borm S, Thomas I, Hanquet G, et al. Highly pathogenic H1N1 influenza virus
in smuggled Thai eagles, Belgium. Emerging Infect Dis 2005;11(5):702–5.
82. Tatem AJ, Hay SI, Rogers DJ. Global traffic and disease vector dispersal. Proc
Natl Acad Sci USA 2006;103:6242–7.
83. Tatem AJ, Rogers DJ, Hay SI. Estimating the malaria risk of African mosquito
movement by air travel. Malar J 2006;5:57.
84. Kilpatrick AM, Gluzberg Y, Burgett J, et al. Quantitative risk assessment of the
pathways by which West Nile virus could reach Hawaii. Ecohealth 2004;1:205–9.
85. WHO. Health conditions for travellers to Saudi Arabia for the pilgrimage to
Mecca (Hajj). Wkly Epidemiol Rec 2007;82(44):385–8.
86. Wilder-Smith A, Barkham TM, Earnest A, et al. Acquisition of W135
meningococcal carriage in Hajj pilgrims and transmission to household con-
tacts: prospective study. Br Med J 2002;325:365–6.
87. Wilder-Smith A, Foo W, Earnest A, et al. High risk of Mycobacterium tuberculosis
infection during the Hajj pilgrimage. Trop Med Int Health 2005;10(4):336–9.
88. Shaw MT, Leggat PA, Borwein S. Travelling to China for the Beijing 2008 Olympic
and Paralympic games. Travel Med Infect Dis 2007;5,365–73.
89. Kozarsky PE, Keystone JS. Introduction to travel medicine. In: Keystone JE,
Kozarsky PE, Freedman DO, et al, editors. Travel medicine. Edinburgh (UK):
Mosby; 2004. p. 1–3.
90. Steffen R. Travel medicine—prevention based on epidemiological data. Trans R
Soc Trop Med Hyg 1991;85:156–62.
91. Wilson ME. Travel and the emergence of infectious diseases. Emerging Infect
Dis 1995;1:39–46.
92. Freedman DO, Kozarsky PE, Weld LH, et al. GeoSentinel: the global emerging
infections sentinel network of the International Society of Travel Medicine.
J Travel Med 1999;6(2):94–8.
93. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to
place of exposure among ill returned travelers. N Engl J Med 2006;354(2):
119–30.
94. Schwartz E, Weld LH, Wilder-Smith A, et al. Seasonality, annual trends, and char-
acteristics of dengue in ill returned travelers, 1997–2006. Emerg Infect Dis 2008;
14(7):1081–8.
95. Ross K. Tracking the spread of infectious diseases. EMBO Rep 2006;7(9):
855–8.
96. Centers for Disease Control and Prevention (CDC). Cruise-ship associated
Legionnaires disease, November 2003-May 2004. MMWR Morb Mortal Wkly
Rep 2005;54:1153–5.
97. Kura F, Amemura-Maekawa J, Yagita K, et al. Outbreak of Legionnaires’ disease
on a cruise ship linked to spa-bath filter stones contaminated with Legionella
pneumophila serogroup 5. Epidemiol Infect 2006;134:385–91.
98. CDC. Imported Lassa fever—New Jersey, 2004. MMWR Morb Mortal Wkly Rep
2004;53(38):894–7.
99. Widdowson M-A, Cramer EH, Hadley L, et al. Outbreaks of acute gastroenteritis
on cruise ships and on land: identification of a predominant circulating strain of
norovirus—United States 2002. J Infect Dis 2004;90:27–36.
100. Lopman B, Vennema H, Kohli E, et al. Increase in viral gastroenteritis outbreaks
in Europe and epidemic spread of new norovirus variant. Lancet 2004;363:
682–8.
101. Bull RA, Tu ET, McIver CJ, et al. Emergence of a new norovirus genotype II.4
variant associated with global outbreaks of gastroenteritis. J Clin Microbiol
2006;44(2):327–33.
102. CDC. Severe acute respiratory syndrome—Singapore, 2003. MMWR Morb Mor-
tal Wkly Rep 2003;52(18):405–11.
103. CDC. Trends in tuberculosis—United States, 2005. MMWR Morb Mortal Wkly
Rep 2006;55(11):305–8.
104. CDC. Emergence of mycobacterium tuberculosis with extensive resistance to
second-line drugs—worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep
2006;55(11):301–5.
105. CDC. Health advisory—Hepatitis A infections linked to children adopted from
Ethiopia and their family contacts. July 18, 2007. Available at: http://www.cdc.
gov/ncidod/diseases/hepatitis/a/HAHealthAdvisory.pdf. Accessed March 1,
2008.
106. Brotherton JM, Delpech VC, Gilbert GL, et al. A large outbreak of influenza A
and B on a cruise ship causing widespread morbidity. Epidemiol Infect 2003;
130:263–71.
107. CDC. Exposure to mumps during air travel—United States, April 2006. MMWR
Morb Mortal Wkly Rep 2006;55(14):401–2.
108. CDC. Update: multistate outbreak of mumps—United States, January 1–May 2,
2006. MMWR Morb Mortal Wkly Rep 2006;55(20):559–63.
109. Centers for Disease Control and Prevention (CDC). Mumps outbreak at a sum-
mer camp in New York, 2005. MMWR Morb Mortal Wkly Rep 2006;55(7):175–7.
110. CDC. US-incurred costs of wild poliovirus infections in a camp with US-bound
refugees—Kenya, 2006. MMWR Morb Mortal Wkly Rep 2008;57(9):232–5.
Me dic al Tourism
Christie M. Reed, MD, MPH, FAAP
KEYWORDS
Travel Health seeking traveler Medical tourism
Transplant tourism Reproductive tourism
Searches of the literature or Internet using the term ‘‘medical tourism’’ produce two
sets of articles: travel for the purpose of delivering health care or travel for the purpose
of seeking health care. The first usage primarily appears in the medical literature.1,2
Articles addressing the latter definition are beginning to appear in the medical litera-
ture but have become a common topic in the business sector,3 on the Internet,4,5
and in the lay media.6–8 A full discussion of both aspects of medical tourism is beyond
the scope of this article, which focuses on travel to seek health care, but there are
some aspects in common: both are affected by ease and speed of international travel
and communication associated with globalization, and both raise questions about
continuity of care as well as issues related to cultural, language, and legal differences;
both also raise questions about ethics.
Travel for the purpose of seeking health care is not new. There is a long history of
travel to be near friends or family who can provide support during care and convales-
cence, or to seek more sophisticated or specialized care not available locally, often in
a more developed area. ‘‘Medical tourism’’ refers primarily to a new phenomenon of
travelers leaving family and friends to seek care abroad, often in less developed coun-
tries, along with the organizations that support or offer incentives for such travel. This
article describes some of the motivating factors, contributing elements, and chal-
lenges in elucidating trends, as well as implications for clinicians who provide pretravel
advice and those who care for ill returning travelers.
GLOBALIZATION
International Travel
Exact measures of numbers of travelers involved in medical tourism are difficult to
obtain. Data from the US Department of Commerce in-flight survey between 2003
and 2006 shows an overall increase in the number of trips taken, for which at least
one purpose was health care (Fig. 1). In 2006 there were approximately half a million
international trips in which health treatment was one purpose of the trip.9–12
The opinions expressed by the author do not necessarily reflect the opinions of the Centers for
Disease Control and Prevention, 1600 Clifton Road, MS E-04, Atlanta, GA 30333, USA.
Medical Transmission Team, HIV Prevention Branch, Division of Global AIDS Centers for Disease
Control and Prevention, 1600 Clifton Road NE, MS E-04, Atlanta, GA 30333.
E-mail address: creed@cdc.gov
Med Clin N Am 92 (2008) 1433–1446

0025-7125/08/$ – see front matter. Published by Elsevier Inc.
1434 Reed
480000
470000
Travelers (in 1000s)

460000
450000
440000
430000
420000
410000
400000
390000
380000
2003 2004 2005 2006
Year
Fig.1. United States airline travelers to overseas and Mexico who report health treatment as
one purpose of the trip, 2003–2006.
India has a specific category of nonimmigrant medical visa for visitors seeking
health care;13,14 however, figures for entrants in this category are not readily available
and it is thought that medical tourists do not routinely use it, nor is it required. This visa
category is available via the High Commission of India, London Web site15 but not from
the Embassy of India in Washington D.C.16 The Confederation of Indian Industry (CII),
in collaboration with international marketing consultants McKinsey and Company,
produced a study on the country’s medical tourism sector in 2002. Based on data
from organization member hospitals, CII estimates that 150,000 medical tourists
came to India in 2005, accounting for $22.2 billion in United States funds (USD) or
5.2% of the gross domestic product of India. This sector is anticipated to account
for between $40 billion USD and $60 billion USD for India by 2012.5,13 On its Web
site homepage, Bumrumgrad Hospital in Bangkok, Thailand, reports treating
400,000 international patients annually.17
In 2004, United States citizens born in the United States made up 56% of all over-
seas air travelers outbound from the United States, but contributed a much smaller
proportion (17%) of travelers who listed health treatment as the main purpose of the
trip. The majority of health-seeking travelers that year were current United States cit-
izens born outside the United States (46%), followed by non-United States citizens
(36%).10 Residents born outside the United States have stated that health care needs,
such as dentistry, are often included in visits home because of familiarity with care in
the country of origin, the high cost of health care in the United States, and lack of in-
surance coverage.3,18
Official estimates of the number of United States patients receiving care abroad are
not available, as this type of care until recently has been paid for by the person. The
introduction of insurance coverage may provide some data in the future. Media re-
ports quote sources at individual facilities as opposed to official records and use dif-
ferent formats to report number of US patients. Estimates of the number of Americans
seen at Bumrungrad in Bangkok range from 55,000 to 64,000 in 2006,8,19 an 11% to
30% increase over 2005, and 83% of visits were for noncosmetic treatments.19 Ap-
proximately 850 United States patients were reportedly operated on in 2007 at two
Wockhardt hospitals in Bangalore and Bombay, twice as many as in 2006.6 Another
source estimates that 50,000 Americans travel each year for major noncosmetic sur-
gery, such as joint replacement, coronary artery bypass, new or repaired heart valves,
and back repair.20 As these are nonemergent, elective procedures it is not yet possible
to determine if the recent fluctuations noted here and in Fig. 1 reflect true trends or
events in the airline and travel industries. For example, following the severe acute re-
spiratory syndrome (SARS) epidemic, travel to Asia was reduced in 2004 and travel
Medical Tourism 1435
may have been postponed, with a subsequent rebound of the accumulated number of
trips in 2005 and 2006.
Role of the Internet

The Internet plays a major role in the growth of medical tourism as an industry, as it is
the portal for exchange of information across continents between the prospective
patients and providers.21 Enter a procedure name in a search engine and international
options appear among local options. Enter a procedure name with the addition of the
term ‘‘abroad’’ and 100,000 or more citations appear, offering direct connections to
services in individual countries from Europe to Asia or entities that will offer assistance
with every detail of travel.5,22
Healthcare Trip (www.healthcaretrip.org), a United States-based 501 (c) (3) non-
profit service of health care Tourism International, reports it has assumed accredita-
tion responsibility for all the major groups involved in the health tourism industry
from hotels to recovery facilities, medical tourism booking agencies, and other re-
sources, for nonclinical aspects of health tourism, such as language issues, business
practices, and advertising. However, this site differs from other accrediting agency
Web sites listed below in that advertisements for medical tourism providers appear
in a box driven by the search engine. Registration is required to review the specific
criteria and materials used.
Marketplace Issues
Outsourcing of medical treatment has been seen as an option by patients to bypass
or reduce waiting time in Canada, Britain, and other countries in the European
Union.5,23–25 However, in the United States, cost is the primary motivating factor.5
The cost of individual procedures have been estimated to be 20% to 80% lower in
less developed countries than in a private hospital in the United States; a hip replace-
ment might be less than $10,000, compared with $40,000 to $50,000 in the United
States.6–8 Patients with limited or no health insurance are attracted by the opportunity
to conserve limited financial resources and protect the equity in their homes.19 In
2006, 47 million people, representing 15.6 % of the United States population, did
not have health insurance. The proportion without insurance is even higher among
the working population aged 18 to 64 at 20.2%, and also varies by nativity: 13.2%
for native born citizens, 16.4% for naturalized citizens, and 45% for foreign-born non-
citizens.18 Only 50% of Americans have dental insurance.26
Employers, particularly those that are self-insured, unions that manage their own
health care resources, insurers, and even governments have also taken note and
begun to investigate or provide outsourced medical care.7,19 Their actions may take
the form of including international facilities as preferred providers on low-premium
mini-medical plans, which are increasingly popular with contract and hourly workers
who are often uninsured, to traditional plans that will make all arrangements, allow
a companion to accompany the patient, and include a recuperative stay in a hotel
along with a rebate of the savings.7 The West Virginia legislature considered a bill
that would offer similar incentives for public employees, and the United States Senate
held hearings in June 2006 to examine whether medical tourism can reduce health
care costs.7,19,27,28 Some insurers have reportedly begun selling policies that include
overseas care5 or are actively forming alliances with facilities in Thailand, Singapore,
Ireland, Turkey, and Costa Rica, all accredited by the Joint Commission International
(see below).29 Other carriers report cautious investigation, such as tailoring plans to
include overseas options at the specific request of an employer.30,31 The field is rapidly
changing. The employer-based rebate plan,7 which formed the basis of the West
1436 Reed
Virginia proposal, was reportedly discontinued by the next year because of displea-
sure voiced by the employee union.30 The Internal Revenue Service has also taken
note: amounts paid by a group health plan for medical procedures are not taxable
to employees, but the issues are less clear around provision of lodging, transportation,
and even the cash rebates in self-insured or fully-insured situations.30
Few consumers in a recent poll would elect surgery abroad for incentives below
$1,000. Above that, 45% of persons without insurance or who are underinsured and
19% of persons with insurance and an ill family member would travel; those numbers
jump to 61% and 40%, respectively, above $5,000.7 It has been suggested that, to
balance patient safety and cost savings, nonurgent, short-duration procedures cost-
ing more than $15,000 to $20,000, for conditions that are not exacerbated by air travel,
be the threshold for outsourcing. This would primarily include major cardiac and ortho-
pedic conditions, which currently account for only about 2% of United States noncos-
metic health care (excluding those who live on the United States-Mexico border).19
Types of Care
Distinctions are frequently made between reproductive care, dental care, cosmetic
versus noncosmetic surgery, and transplantation.19,32 Executive check-ups are also
becoming popular.8
Reproductive tourism encompasses travel for pregnancy termination and fertility
treatment.21 Both are heavily regulated globally, but the lack of regulation in some as-
pects of infertility treatments (ie, they are generally not covered by public or private
health plans) may allow the costs to vary so widely.33,34 It is a constantly changing
arena, and when airfares to and from the United States were lower, ‘‘medical cartog-
raphers’’ set out to map which places were ‘‘best’’ (in terms of cost, effectiveness and
timeliness), for what procedures and for whom.35 The desperation of many infertile
couples and the developing market for donated eggs raise issues similar to that of
transplantation tourism on safety for the recipient, in terms of infections, and protec-
tion of donors or surrogates from exploitation.36 Adverse events associated with med-
ical tourism for any purpose are primarily anecdotal media accounts; for infertility
treatment, these reports concern lack of viable pregnancy, exhaustion of resources,
and speculation regarding the health of the donor or surrogate.37
Poland, Hungary, other countries in Eastern Europe, and the Caribbean, Central and
South America are mentioned in regard to dental procedures. Costs in developed
areas may range from $1,000 for a root canal to 50 times that for multiple crowns.8,26
As this type of dental care is usually not emergent, it can be bundled into a vacation or
a trip home for many immigrants.3,38,39 Advertising for care, particularly dental and
cosmetic, in immigrant communities reportedly appears in the local native language
media, such as newspapers and radio, to a greater extent than the Internet
(M. Vega, personal communication, March 8, 2004).40
Dentistry also crosses over into the area of cosmetic procedures and provides a use-
ful example of the two main categories of outsourced care and how they differ. Root ca-
nals, just as joint replacements and cardiac by-passes, are therapeutic procedures
recommended by clinicians to treat a specific problem based on a diagnostic evaluation
that must either be shared with the treating clinician or repeated at the destination.
Esthetic procedures are primarily patient driven. For patients who travel abroad for ther-
apeutic procedures, quality is an equal concern with cost. There are issues related to
whether a local physician at the patient’s home will be comfortable or not providing im-
mediate postprocedure follow-up, but that would also be true if a the patient traveled to
another part of the United States. Patients seek cosmetic procedures for issues with
appearance; results are subjective and may not be final until healing is complete.41–45 It
is in the cosmetic surgery literature that the majority of adverse events have been noted.
QUALITY OF CARE
The American Medical Association developed guiding principles for employers, insur-
ance companies, and other entities that facilitate or offer incentives for care outside the
United States. These principles that were recently adopted at the June 17, 2008, an-
nual session. The principles stipulate that international care must be voluntary and pro-
vided by accredited institutions; financial incentives should not inappropriately limit or
restrict patient options; there should be continuity of care, including coverage of costs
upon return; patients should be informed of their rights and legal recourse before
travel; patients should have access to licensing, outcome, and accrediting information
when seeking care; medical record transfers should comply with Health Insurance Por-
tability and Accountability Act guidelines; and patients should be informed of potential
risks of combining surgical procedures with long flights and vacation activities.4,46
On, June 18, 2008, the American College of Surgeons (ACS), which already had
a public section of its Web site devoted to information for patients about choosing
a surgeon, qualifications, and second opinions, also took note of the phenomenon.
A 14-bullet report summarizing available information and Internet resources was
posted on its new Nora Institute for Surgical Patient Safety Web site, supplemented
with a list of the 17 country Web sites that promote and the 20 United States-based
companies that specialize in medical tourism, along with a cost comparison.32
The American Society for Plastic Surgery Web site has posted information on medical
tourism since early April 2005, with a briefing paper that emphasizes plastic surgery is
‘‘real’’ surgery and outlines the issues every patient undergoing surgery should con-
sider, whether at home or abroad, particularly when combined with travel.47 The Inter-
national Society of Plastic Surgery also certifies approximately 1,500 surgeons in 73
countries who meet United States standards (www.isaps.org). The American Dental
Association covers travel, dental care, and ‘‘dental tourism’’ on its Web site and pro-
vides a link to ‘‘A traveler’s guide to dental care,’’ which is available through the Global
Dental Safety Organization for Safety and Asepsis Procedures (www.osap.org).48
Accreditation
In October 2004, the World Health Organization (WHO) launched the World Alliance for
Patient Safety in response to a World Health Assembly Resolution (2002) urging WHO
and Member States to pay the closest possible attention to the problem of patient
safety (who.int/patientsafety/en). Countries have or are in the process of developing
national programs to survey facilities for performance on a range of quality-of-care
indicators. In India, 35 hospitals had applied for accreditation to the Ministry of Health
by March 2007, and 30 of 120 had been certified under the CII system, which has an
ethical code but self-regulates by establishing a system for its own members. As of
July 2008, nine Indian facilities and facilities in 31 other countries have also voluntarily
applied for and been accredited by an external organization, the Joint Commission
International (JCI) (www.jointcommissioninternational.org), the international arm of
the Joint Commission that accredits United States facilities. The International Society
for Quality in Health Care (www.isqua.org) is an umbrella organization that accredits
JCI and similar organizations that have also developed international components in
the last few years in response to increasing global interest, such as the Trent Interna-
tional Accreditation Scheme (www.trentaccreditationscheme.org), which recently
expanded from the United Kingdom to include private hospitals in Hong Kong; the
1438 Reed
Australian Council for Healthcare Standards International (www.achs.org.au/ACHSI/);

and the Canadian Council on Health Services (www.cchsa.ca). The Society for Inter-
national Healthcare Accreditation (www.sofiha.co.uk/index.htm), ‘‘devoted towards
the development and promulgation of high-quality accreditation of hospitals and
healthcare facilities across international borders,’’ was also formed recently in re-
sponse to the increase in medical tourism, and is open to both the public and health
care providers interested in international accreditation.
Individuals researching accreditation status should note that, although facilities may
be part of a chain, they are surveyed and accredited individually. They should also
check the duration of the accreditation and validate that the information is current
by consulting the public portion of the appropriate accrediting agency Web site.
Facilities and Staff

The first private hospital opened in India in 1983. As of 2008 it was part of a chain with
41 hospitals in two countries and claimed 10 million patients from 55 countries.49 Such
facilities may have allowed local physicians to return home and practice medicine, as
they had been trained in developed areas such as North America and Europe. For
India it has been postulated that the quality of the local medical schools, a low cost
of living, family preferences, and the barriers to foreign accreditation may mean that
Indian doctors may prefer to work in India rather than elsewhere, allowing this growth
in patient-care capacity.3 The fact that English is commonly spoken and that many of
the clinicians trained in institutions familiar to their North American patients are both
factors in site selection by United States-born patients, who may have never traveled
internationally before.3,7,8
ETHICS
The lower costs in developing countries are thought to be the result of a lower cost of
living, lower wages paid to physicians and other health care workers, low administra-
tive costs and medico-legal expenses, and cheaper prices offered by global suppliers
of medical devices.5,19 The Indian government has offered financial incentives by
defining medical care for tourists as an ‘‘export,’’ giving it special tax status along
with other related projects, such as building airports and promoting health infrastruc-
ture.23 However, World Bank support for building a private hospital in India recently
raised concerns that it was diverting resources from government run health services
in a country where, according to the 2005 Reproductive and Child Health Facility
Survey, fewer than 50% of the primary health centers have a labor room or a labora-
tory, only one in five have a telephone connection, and fewer than one in three stock
essential drugs.13 There is concern that privatization is diverting resources away from
the local poor.23 Widening access, improving quality across all strata, and ensuring
nonexploitive prices have been identified as measures to ensure that citizens of devel-
oping countries will also benefit from developments of a private health care structure
beyond the 10% in pro bono care such institutions may provide; whether the public
sectors are sufficient to the task is currently a subject of debate. The short waiting
time for procedures in these densely populated countries implies that the costs of
the services, though correlated with the nations per capita gross domestic product,
may still be above the means of the majority of the local population.5,50
Organ Transplantation
In the United States, there is a single system for organ procurement and transplantation
coordinated under congressional mandate by the United Network for Organ Sharing,
a nonprofit, scientific, and educational organization. As of July 18, 2008, there were
9,029 transplants between January and April from 4,578 donors with 99,393 candi-
dates on the waiting list (www.optn.org). The need for transplantable organs far
exceeds the available supply and travel to a country with less rigorous methods of
distribution has been termed ‘‘transplant tourism’’ or ‘‘organ trafficking.’’51 The 2007
United States Annual Report includes a study by Marion and colleagues, that has
been published separately,52 on transplant tourism. It examines transplants in foreign
countries among patients removed from the United States waiting list from 1986 to
2006. Patients are removed from the US waiting list when they receive a transplant
in the United States, die before receiving a transplant, or they can self-elect to remove
their name from the list to seek care outside the United States. The majority (89.3%) of
the 373 foreign transplants were kidney. Between 2001 and 2006 the annual number of
waiting-list removals increased. Recipients of foreign transplants were significantly
more likely to be male, college educated, nonresident or resident alien, and 10 times
more likely to be Asian and self-funded. Forty-two percent of the transplants occurred
in East Asia and the Pacific, with three countries accounting for one half of all foreign
transplants: China (26%), Philippines (12%), and India (10%). The report states ‘‘.it
is possible and indeed probable that instances of organ buying, selling, and/or traffick-
ing outside the U.S. occurred. On the other hand, bona fide emotionally and/or biolog-
ically related living donor transplants were likely done. For example, U.S. citizens as
well as resident and non-resident aliens may have friends or relatives in their country
of origin who are unable to come to the U.S. to donate because of restrictive policies
governing the issuance of travel visas.’’ Conversely, an analysis of kidney and liver
transplants to nonresident aliens in the United States, although small in number, shows
that these liver candidates had shorter times to transplant and the self paying had the
shortest time.53 In an accompanying commentary entitled ‘‘‘Transplant Tourism’ in the
United States?’’ the author makes the point that foreign nationals are paying for access
to organs, which should cause inward reflection on condemnation of other transplant
enterprises. It also demonstrates that the developed world has the opportunity to mea-
sure and report on the extent of the behavior and provide outcome results. The author
also notes that the National Task Force on Transplantation that developed the United
States system in 1986 stated that deceased donor organs were a ‘‘national resource,’’
but did not envision the globalization that has transpired in the interim. Shortages are
a universal problem and reliance on deceased organs, even in a well-developed pro-
gram such as Spain’s, can only meet 50% of the demand. Thus, other models involving
living donors, which could be regulated, prevent organ vending, and protect the donor,
have been proposed for discussion in a series of recent articles.54–56 Transparency,
where there is so much potential to exploit, is key.56–58
ADVERSE EVENTS
Little is known about the outcomes of medical care abroad.
Infectious Complications
The coordination of the United States transplant network lends itself to identification of
patients who undergo transplantation outside the system, as noted above. One United
States center identified 10 patients who underwent transplantation outside the United
States during the period September 16, 2002 to June 30, 2006, and returned to the
same center for care. Three patients had indicated they intended to seek transplanta-
tion abroad. Two patients were seen in the emergency room on the day of arrival in the
United States. Complications were primarily infectious, with six infections in four
1440 Reed
patients: severe wound infection with acinetobacter (one); sepsis (three); cytomegalo-
virus (CMV) (one); and central nervous system aspergillus (one). Nine of the 10 grafts
survived, as did 9 of the 10 patients, which is consistent with results obtained for pa-
tients transplanted in the United States and from a much larger series of patients, who
had also traveled for the purpose of transplantation, reported on from Malaysia (n 5
515) at about the same time.59,60 However, an Australian series of 16 patients who
had traveled overseas for commercial transplantation had survival rates at 1 and 5
years that were lower when compared with Australian living-donor transplants.61
Two of the 16 contracted Hepatitis B virus (HBV) abroad, three were hospitalized for
acute CMV infection shortly after return home, and one had aspergillus infection of
the graft and multiresistant Pseudomona aeruginosa of the surgical wounds. In the
Malaysian study there were significant rates of infection, but they did not differ be-
tween the living related donor (n 5 258) transplanted in Malaysia, the commercial living
donor (n 5 389), or commercial cadaveric donor (n 5 126) transplanted abroad. The
infection rates were: bacterial <535%; viral <526%; HCV <517%; HBV <512%; fun-
gal <57%; Mycobacterium tuberculosis, CMV and malaria <5%. There were no HIV
infections. Case reports such as this are affected by survivorship bias related to those
patients who did not return for unknown reasons, and differences of endemic rates of
infection in the population with such agents as HBV. One must be careful to examine
the year of study when comparing rates of infection with HIV, as prior studies may in-
clude patients transplanted in early time periods.61
There are also individual reports of HBV acquired during elective procedures per-
formed overseas; denominator data are difficult to derive and the ability to identify
the precise source of infection is also limited. However, Harling and colleagues62 re-
ported an outbreak of HBV in the United Kingdom linked to a patient who had acquired
his infection during a renal transplant in India. During the investigation, two additional
hospitals identified three other sporadic cases of HBV that had also apparently been
acquired during hemodialysis in South Asia. The prevalence of chronic HBV infection
in India is less than 2% to 7% and in Malaysia, China, and most of Asia it is greater
than 8%.63
Recognition of an outbreak or common source exposure is difficult as patients are
seen in a variety of localities upon return. However, posting of unusual cases or ques-
tions via electronic listserves has resulted in recognition of links between cases of
non-tuberculosis wound infections in 20 United States patients undergoing cosmetic
surgery procedures, ranging from abdominoplasty, liposuction, breast lift, and breast
reduction to breast implant in the Dominican Republic.64–67 In a 2005 electronic survey
of infectious disease specialists in North America, 6% of the 425 respondents indi-
cated that they or their colleagues encountered infectious complications of cosmetic
surgery performed outside the United States in the previous year.68 Systematic data
on the rates of infection after cosmetic surgery with M. abscessus in the United States
are not available for comparison with other countries. Outbreaks of fast growing my-
cobacterial species have been reported in the United States;69,70 however, a review of
the records at New York Presbyterian Hospital Columbia University Medical Center for
the period 2000 to 2005 found only eight infections with M. abscessus, all in patients
who had undergone cosmetic surgery in the Dominican Republic. For the same time
period, there were no other postsurgical wound infections at two of the sites where
patients were seen among the more than 230,000 surgical procedures at Columbia
or the fewer than 60,000 at Baystate Medical Center. Possible sources of infection,
stated in the report, would be environmental contamination of water sources, surgical
instruments, Gentian violet, injectable medications, and antiseptic solutions. At least
one patient in this series had been instructed to use tap water for irrigation.
The risk of nosocomial infections in intensive care is estimated to be 25% in devel-

oped areas but twice that, between 25% and 40%, in developing countries. In a study
by the WHO reported in 2008, it was estimated that 37% to 70% of injections world-
wide were given with reused syringes without sterilization, putting patients at risk for
blood-borne infections, 70% of medications in developing countries did not meet
standards, and 22% of blood donations were not screened for HIV infection. Counter-
feit medications accounted for 10% of the global medicines market worldwide and up
to 30% of medicines consumed in developing countries.71
Noninfectious Complications
The Australian Society of Plastic Surgeons conducted a national survey in April 2007
regarding women returning from Asia after holiday and requiring treatment for medical
complications from surgery, during the previous three years. Of the 68 surgeons
surveyed, 40 (59%) reported seeing patients with complications or poor results and
15 (22%) reported treating more than one patient. Most women seeking treatment
had undergone breast enlargements or reductions or facelifts. The majority of proce-
dures were reportedly performed in Thailand (66), followed by Malaysia (17).72
The issue of who should bear the costs of complications was raised in a report from
Australia of Mycobacterium fortuitum infection of a total knee arthroplasty, performed
in India.73 The patient had been advised to pursue a course of symptomatic treatment
for osteoarthritis but elected to pay $8,600 for the surgical option over concerns of
waiting time in the public sector, cost in the private sector, and desire for early return
to work. Treatment for the septic joint, with an organism not commonly encountered in
Australia, involved four separate surgeries and antimycobacterial therapy, resulting in
a cost of $140,000. The procedure had been done in a hospital accredited by the JCI,
rates of infection in the procedure worldwide are known to be 1% to 2%, and it was
acknowledged that even if 1 patient in 20 develops an infection, having the operation
overseas is an economically viable option. However, the case illustrates many of the
issues in medical tourism: exposure to infections of different types or
higher prevalence than at home, the lack of ability to address the root source of
adverse events and effect change, the wisdom of undertaking major surgery away
from one’s home environment (especially when long-haul air travel before major
surgery significantly increases the risk of perioperative venous thromboembolism74),
and in the event a complication does occur, the fairness of using resources that could
fund procedures for multiple patients to treat one who had disregarded medical
advice. Patients in this situation have little legal recourse75 and may also encounter
a radically different cultural framework of reference, based in part on the local percep-
tion of an individual’s decision to seek care away from home. The president of the
Society of Plastic and Reconstructive Surgeons of Thailand is quoted as saying that
all plastic surgery is ‘‘improvement not perfection,’’ and patients must realize there
are drawbacks to traveling to another country for medical care. ‘‘How can a doctor
look after patients if they go back to their country? You have to accept there are
disadvantages if something goes wrong.’’76
SUMMARY
This rapidly evolving area is full of nuances, contradictions and contrasts; few general
statements can be made and there is a general dearth of data. For example, many of
the same countries profiled as top destinations for medical tourists seeking care are
also profiled on the American College of Surgeons Web site link (www.operationgiving
back.facs.org), where health care professionals at all stages of their surgical career can
1442 Reed
search for opportunities to volunteer as the other type of medical tourist, the health
care worker who travels to provide medical care. New Orleans is also on the list of des-
tinations, and as the Web site is open source, international surgeons could consider
volunteer opportunities in the United States best suited to their expertise and interests
here. However, regardless of their level of skill, physicians and surgeons interested in
providing medical care in other countries may face legal barriers regarding licensing,
structures that have been put in place to establish standards with the goal of protecting
patients. Health care that involves invasive procedures is not without risk even in de-
veloped countries. The recent investigation of hepatitis C at an endoscopy clinic in
Las Vegas has demonstrated how standards are necessary but not sufficient, even
in developed areas.77 Recognition of the common source and subsequent gaps in ba-
sic infection-control practices were possible because, as a result of vaccination, rates
of hepatitis in the United States have declined to the point where individual cases can
be investigated.78 These public health and legal checks and balances provide valuable
insight but also add to health care costs,79 and although outbreaks receive wide atten-
tion, the majority of cases of hepatitis in the United States are now imported by trav-
elers from developing parts of the world.78
It has been said we live in a global village. Medical tourism demonstrates how
dynamic the boundaries of the village seem to be and how transit between countries,
particularly between country of birth and country of residence, affects health in both
areas. The patient having a check-up before visiting a child studying abroad may
also plan to have major dental procedures and be of an age to have missed both
natural exposure and vaccination programs for hepatitis A or B, be unaware of prev-
alence rate and vaccination practices at the destination, and be convinced that he or
she can tell whether the facility is safe just ‘‘by looking,’’ particularly when significant
cost savings are at stake. The field is changing constantly; some international sites
now describe care not just for adults but children, particularly for what are perceived
as cosmetic procedures, such as orthodontics.22 Physicians should either be familiar
with up-to-date sources of information (eg, www.cdc.gov/travel) or referral options,
and inquire whether or what role travel plays in their patient’s life.
ACKNOWLEDGMENTS
The author is indebted to Harvey Lipman for statistical support with the analysis of
the US Department of Commerce data.
REFERENCES
1. Bishop R, Litch JA. Medical tourism can do harm. BMJ 2000;320(7240):1017.

2. Morgan MA. Another view of ‘‘humanitarian ventures’’ and ‘‘fistula tourism’’. Int
Urogynecol J Pelvic Floor Dysfunct 2007;18(6):705–7.
3. Lagace M. The rise of medical tourism Harvard Business School Working Knowl-
edge. Available at: http://hbswk.hbs.edu/item/5814.html. Accessed July 14,
2008.
4. American Medical Association. AMA provides first ever guidance on medical
tourism. Available at: http://www.ama-assn.org/ama/pub/category/18678.html.
Accessed July 15, 2008.
5. Horowitz MD, Rosensweig JA, Jones CA. Medical tourism: globalization of the
healthcare marketplace. MedGenMed 2007;9(4):33.
6. Comarow A. Under the knife in Bangalore. US News World Rep 2008;144(13):
42,45,47–50.
7. Kher U. Outsourcing your heart. Time 2006;167(22):44–7.
8. Mecir A, Greider K. Traveling for treatment. AARP Bulletin 2007;48(8):12–6.

9. US Department of Commerce. Office of Travel and Tourism Industries survey of
international air travelers US to overseas and Mexico 2006 report, 2006
January–December. 2007.
international air travelers US to overseas and Mexico by birth and citizenship
2004 report, 2004 January–December. 2005.
international air travelers US to overseas and Mexico 2005 report, 2005 January–
December. 2006.
international air travelers US to overseas and Mexico by birth and citizenship.
2003 report, 2003 January–December. 2005.
13. Chinai R, Goswami R. Medical visas mark growth of Indian medical tourism. Bull
World Health Organ 2007;85(3):164–5.
14. Travel India Company. Medical tourism in India. Available at: http://www.indian-
medical-tourism.com/medical-visa-india-tourism.html. 2006. Accessed July 6, 2008.
15. High Commission of India L. Visa application center in the United Kingdom. Avail-
able at: http://in.vfsglobal.co.uk/visacategory.aspx. 2008. Accessed July 22, 2008.
16. Embassy of India WDC. India Visa Center. Available at: https://indiavisa.
travisaoutsourcing.com/requirements/gather?apply5bymail. 2008. Accessed July
22, 2008.
17. Bumrungrad International Hospital. Overseas Medical Care. Available at: http://
www.bumrungrad.com/Overseas-Medical-Care/Bumrungrad-International.aspx.
2008. Accessed July 15, 2008.
18. US Census Bureau. Income, Poverty, and Health Insurance Coverage in the
United States: 2006. In: DeNavas-Walt C, Proctor B, Smith J, editors. Current
Population Reports. Available at: http://www.census.gov/prod/2007pubs/
p60-233.pdfP60-233. Accessed July 22, 2008.
19. Milstein A, Smith M. America’s new refugees—seeking affordable surgery off-
shore. N Engl J Med 2006;355(16):1637–40.
20. Woodman J. Patients without borders. Available at: http://www.patientsbeyondborders.
com/. Accessed July 22, 2008.
21. Reed CM. The Health-Seeking Traveler. In: Keystone JS, Kozarsky P, Conner B, et al,
editors. Travel Medicine. 2nd edition. Philadelphia: Elsevier Ltd.; 2008. p. 343–50.
22. Health Travel Guides. Available at: http://www.healthtravelguides.com/_Content/
HTG/Default.aspx. 2007. Accessed July 22, 2008.
23. Oxford Analytica. North America: ‘Medical tourism’ industry grows rapidly. Avail-
able at: http://www.oxan.com/display.aspx?ItemID5DB129920. 2006. Accessed
February 15, 2008.
24. Stargardt T. Health service costs in Europe: cost and reimbursement of primary
hip replacement in nine countries. Health Econ 2008;17(1 Suppl):S9–20.
25. Beecham L. British patients willing to travel abroad for treatment. BMJ 2002;
325(7354):10.
26. Colliver C. Dental work too expensive? Go overseas. Available at: http://www.
sfgate.com/cgi-bin/article.cgi?file5/c/a/2006/04/05/MNGHSI3N671.DTL. 2006.
San Francisco Chronicle. Accessed July 22, 2008.
27. US Senate 109th Congress. The globalization of health care: can medical tourism
reduce health care costs? Available at: http://www.gpoaccess.gov/chearings/
109scat1.html. 109–26. 2006. Special Committee on Aging. Accessed July 22,
2008.
1444 Reed
28. Schadler E, Martin T, Ellem C, et al. West Virginia Public Employees Insur-
ance Act. Available at: http://www.legis.state.wv.us/Bill_Text_HTML/2007_
SESSIONS/RS/BILLS/hb2841%20intr.htm. 2007. HB 2841. Accessed July 22,
2008.
29. Einhorn B. Medical travel is going to be part of the solution. Business Week
2008; Available at: http://www.businessweek.com/globalbiz/content/mar2008/
gb20080312_835774.htm. Accessed March 13, 2008.
30. Higgins LA. Medical tourism takes off, but not without debate. Manag Care 2007;
16(4):45–7.
31. Carroll J. Aetna and Hannaford make a Singapore connection. Manag Care 2008;
17(3):44–7.
32. Unti J. Medical Tourism Report to the American College of Surgeons Patient
Safety and Quality Improvement Committee. Nora Institute for Surgical Patient
Safety, editor. 2008. Available at: http://www.surgicalpatientsafety.facs.org/
news/medicaltourism.html. Accessed July 22, 2008.
33. Spar D. Reproductive tourism and the regulatory map. N Engl J Med 2005;
352(6):531–3.
34. Spar DL. Where babies come from: supply and demand in an infant marketplace.
Harv Bus Rev 2006;84(2):133–140, 142–3, 166.
35. Jones CA, Keith LG. Medical tourism and reproductive outsourcing: the dawn-
ing of a new paradigm for healthcare. Int J Fertil Womens Med 2006;51(6):
251–5.
36. Reuters. Experts say reproductive tourism a growing worry. Available at: http://uk.
reuters.com/article/UKNews1/idUKL2492408820080724. 2008. Accessed July
24, 2008.
37. Leigh S. Reproductive ‘tourism’. Available at: http://www.usatoday.com/news/
health/2005-05-02-reproductive-tourism_x.htm. Accessed July 22, 2008.
38. Marklein M. The inciDENTAL tourist. Available at: http://www.usatoday.com/travel/
news/2005-07-28-dental-tourism_x.htm. 2005. USA Today. Accessed July 22,
2008.
39. Schlecht N. Face lift, luxury safari—bargain price. Available at: http://www.cnn.
com/2008/LIVING/wayoflife/01/03/lipo.tourism/index.html?iref5newssearch;
2008. Accessed July 22, 2008.
40. Bienvenidos Ortho Oral. Available at: http://www.orthooral.com/. 2007. Accessed
July 22, 2008.
41. Goddard JC, Vickery RM, Terry TR. Development of feminizing genitoplasty for
gender dysphoria. J Sex Med 2007;4(4 Pt 1):981–9.
42. Grossbart TA, Sarwer DB. Psychosocial issues and their relevance to the cos-
metic surgery patient. Semin Cutan Med Surg 2003;22(2):136–47.
43. Liao LM, Creighton SM. Requests for cosmetic genitoplasty: how should health-
care providers respond? BMJ 2007;334(7603):1090–2.
44. Most SP, Alsarraf R, Larrabee WF Jr. Outcomes of facial cosmetic procedures.
Facial Plast Surg 2002;18(2):119–24.
45. Sarwer DB. The psychological aspects of cosmetic breast augmentation. Plast
Reconstr Surg 2007;120(7 Suppl 1):110S–7S.
46. Wapner J. American Medical Association provides guidance on medical tour-
ism. Available at: http://elib2.cdc.gov:2138/cgi/content/full/337/jun30_1/a575.
Accessed October 16, 2008.
47. American Society of Plastic Surgeons. Medical Tourism. Available at: http://www.
plasticsurgery.org/patients_consumers/patient_safety/Medical-Tourism.cfm. 2005.
48. American Dental Association. Dental care away from home. Available at: http://
www.ada.org/public/manage/care/index.asp. 2008. Accessed July 27, 2008.
49. Apollo Hospitals home page. Available at: http://www.apollohospitals.com/. 2008.
50. Zwi AB, Brugha R, Smith E. Private health care in developing countries. BMJ
2001;323(7311):463–4.
51. Health Resources and Services Administration. 2007 Annual Report of the U.S.
Organ Procurement and Transplantation Network and the Scientific Registry of
Transplant Recipients: Transplant Data 1997–2006. 2007. Rockville, MD, Health-
care Systems Bureau, Division of Transplantation. Available at: http://www.optn.
org. Accessed July 22, 2008.
52. Merion RM, Barnes AD, Lin M, et al. Transplants in foreign countries among
patients removed from the US Transplant Waiting List. Am J Transplant 2008;
8(4 Pt 2):988–96.
53. Schold JD, Meier-Kriesche HU, Duncan RP, et al. Deceased donor kidney and
liver transplantation to nonresident aliens in the United States. Transplantation
2007;84(12):1548–56.
54. Barsoum RS. Trends in unrelated-donor kidney transplantation in the developing
world. Pediatr Nephrol 2008;23(11):1925–9.
55. Ghods AJ, Nasrollahzadeh D. Transplant tourism and the Iranian model of renal
transplantation program: ethical considerations. Exp Clin Transplant 2005;3(2):
351–4.
56. Oleksyn V. Top transplant surgeons involved in organ trafficking, expert says.
Available at: http://www.bookrags.com/news/top-transplant-surgeons-involved-
in-moc/. Accessed July 22, 2008.
57. Freeman RB. ‘‘Transplant tourism’’ in the United States? Transplantation 2007;
84(12):1559–60.
58. Shimazono Y. The state of the international organ trade: a provisional picture
based on integration of available information. Bull World Health Organ 2007;
85(12):901–80.
59. Canales MT, Kasiske BL, Rosenberg ME. Transplant tourism: outcomes of United
States residents who undergo kidney transplantation overseas. Transplantation
2006;82(12):1658–61.
60. Morad Z, Lim TO. Outcome of overseas kidney transplantation in Malaysia. Trans-
plant Proc 2000;32(7):1485–6.
61. Kennedy SE, Shen Y, Charlesworth JA, et al. Outcome of overseas commercial
kidney transplantation: an Australian perspective. Med J Aust 2005;182(5):224–7.
62. Harling R, Turbitt D, Millar M, et al. Passage from India: an outbreak of hepatitis B
linked to a patient who acquired infection from health care overseas. Public
Health 2007;121(10):734–41.
63. Fiore A, Bell B. Hepatitis, viral, type B. In: Arguin P, Kozarsky P, Reed C, editors.
Health information for international travel 2008. Atlanta (GA): US Department of
Health and Human Services, Public Health Services; 2007. p. 165.
64. CDC. Nontuberculous mycobacterial infections after cosmetic surgery—Santo
Domingo, Dominican Republic, 2003–2004. MMWR Morb Mortal Wkly Rep 2004;
53(23):509.
65. Newman MI, Camberos AE, Ascherman J. Mycobacteria abscessus outbreak in
US patients linked to offshore surgicenter. Ann Plast Surg 2005;55(1):107–10.
66. Newman MI, Camberos AE, Clynes ND, et al. Outbreak of atypical mycobacteria
infections in U.S. Patients traveling abroad for cosmetic surgery. Plast Reconstr
Surg 2005;115(3):964–5.
1446 Reed
67. Furuya EY, Paez A, Srinivasan A, et al. Outbreak of Mycobacterium abscessus

wound infections among ‘‘lipotourists’’ from the United States who underwent
abdominoplasty in the Dominican Republic. Clin Infect Dis 2008;46(8):1181–8.
68. Sunenshine RH. Complications of lipotourism: infectious complications of cos-
metic procedures and lipotourism—experience of infectious disease consultants
[abstract 145]. In: Program and abstracts of the 16th Annual Scientific Meeting of
The Society for Healthcare Epidemiology of America (Chicago). Arlington, VA:
The Society for Healthcare Epidemiology of America, 2006:106. 2008.
69. Meyers H, Brown-Elliott BA, Moore D, et al. An outbreak of Mycobacterium
chelonae infection following liposuction. Clin Infect Dis 2002;34(11):1500–7.
70. Safranek TJ, Jarvis WR, Carson LA, et al. Mycobacterium chelonae wound infec-
tions after plastic surgery employing contaminated gentian violet skin-marking
solution. N Engl J Med 1987;317(4):197–201.
71. WHO. Summary of the evidence on patient safety: implications for research.
Available at: http://www.who.int/patientsafety/information_centre/20080523_Sum
mary_of_the_evidence_on_patient_safety.pdf. Accessed July 22, 2008.
72. Metlikovec J. Warning on cheap ‘‘holiday’’ surgeries. Available at: http://www.
news.com.au/travel/story/0,00.html, 26058. 2007. Accessed July 22, 2008.
73. Cheung IK, Wilson A. Arthroplasty tourism. Med J Aust 2007;187(11–12):666–7.
74. Gajic O, Warner DO, Decker PA, et al. Long-haul air travel before major surgery:
a prescription for thromboembolism? Mayo Clin Proc 2005;80(6):728–31.
75. Turner L. Medical tourism: family medicine and international health-related travel.
Can Fam Physician 2007;53(10). 1639–41, 1646–8.
76. Duff E, Hall L. The ugly facts behind beauty tourism:Available at: http://www.
theage.com.au/news/beauty/the-ugly-facts-behind-beauty-tourism/2007/09/29/
1191090984137.html. 2007:Accessed July 22, 2008.
77. Labus B, Sands L, Rowley P, et al. Acute Hepatitis C Virus infections attributed to
unsafe injection practices at an endoscopy clinic—Nevada, 2007. MMWR Morb
Mortal Wkly Rep 2008;57(19):513–7.
78. Wasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitis—United
States, 2006. MMWR Surveill Summ 2008;57(2):1–24.
79. Dayan GH, Ortega-Sanchez IR, Lebaron CW, et al. The cost of containing one
case of measles: the economic impact on the public health infrastructure—
Iowa, 2004. Pediatrics 2005;116(1):e1–4.
Role of I mmigra nts a nd
Migra nts in Emerging
I nfec tious Diseases
Elizabeth D. Barnett, MDa,*, Patricia F.Walker, MD, DTM&Hb,c
KEYWORDS
Immigrant Migrant Emerging infectious diseases
Migrant populations have had a critical role in the spread of infectious diseases since
ancient times. Examples range from biblical plagues, the importation of smallpox into
Mexico, the 1918 influenza pandemic, and the AIDS pandemic, to severe acute respi-
ratory syndrome (SARS), outbreaks of meningococcal meningitis associated with the
Hajj, and diseases spread by population movement due to political conflict.1,2 In the
debut issue of the journal Emerging Infectious Diseases, Stephen S. Morse3 defined
emerging infectious diseases as ‘‘infections that have newly appeared in a population
or have existed but are rapidly increasing in incidence or geographic range.’’ Migrant
populations have played roles in introducing infections into naı̈ve populations (small-
pox and measles into Pacific island nations, the global spread of HIV), in changing the
incidence of infections in a population, and in increasing the potential for local trans-
mission (hepatitis A, tuberculosis [TB]). Migrants may also carry infections that pose
little risk to the local population but increase the geographic range at which these in-
fectious diseases might be encountered by health professionals unfamiliar with them
(leishmaniasis, Chagas disease, and malaria in North America). Such infections pres-
ent diagnostic dilemmas and over time also change the face of chronic disease in
a population (seizures and neurocysticercosis, heart disease and Chagas infection,
hepatocellular carcinoma and hepatitis B infection). Finally, population mobility may
increase the potential for establishing transmission of new infections in North America
(dengue and chikungunya fever in areas where vector mosquitoes exist). Immigrants
have ongoing links with populations in their countries of origin that may provide a chan-
nel through which infectious diseases potentially can be introduced to new areas. This
article focuses on the recent demographic changes in North America that have
a
Maxwell Finland Laboratory for Infectious Diseases, Room 625, Boston Medical Center, 670
Albany Street, Boston, MA 02118, USA
b
Center for International Health and Travel Medicine Program, HealthPartners Medical Group,
St. Paul, MN, USA
c
Department of Internal Medicine, Division of Infectious Diseases and International Medicine,
University of Minnesota, St. Paul, MN, USA
E-mail address: ebarnett@bu.edu (E.D. Barnett).
Med Clin N Am 92 (2008) 1447–1458

1448 Barnett & Walker
facilitated the introduction and spread of new microbial threats, the role migrant pop-
ulations play in changing the demographics of specific infectious diseases, and the
potential responses of clinicians and public health officials in addressing the
challenges posed by these infections. The emphasis of the article is on immigrant
and migrant populations entering North America; the role of travelers in emerging
infectious diseases is addressed in another article in this issue.
MIGRATION PATTERNS AND EMERGING INFECTIOUS DISEASES
More than 200 million people (roughly 2% of the world’s population) currently live
outside their country of birth.4 The largest number, more than 38 million, live in the
United States. Canada is the country with the sixth largest number of migrants,
with just over 6 million.5 The proportion of the United States population who were
foreign born was higher in the late nineteenth and early twentieth centuries, when
it reached almost 14%, but then it declined to less than 5% in the 1970s; it has
been increasing steadily for the past 3 decades and is now more than 12% and
growing. Almost 20% of the population of Canada is foreign born.6 More than half
(54%) of the migrants living in the United States are from the Americas, with an
additional 26% from Asia, 16% from Europe, and 3% from Africa. In contrast,
migrants living in Canada are mostly from Europe (41%) and Asia (37%), with 16%
from the Americas and 5% from Africa.7
International travel is also increasing at a record pace. More than 30 million trips out-
side the United States were made in 2006, an increase of more than 10 million in the
decade since 1996.8 Outbound travel from Canada is also increasing rapidly, with an
almost 8% increase from 2004 to 2005, and a record number of more than 21 million
trips made.9 A larger proportion of trips are made by those, usually immigrants and
their families, who identify visiting friends and relatives as the primary purpose of their
trip.10 The profile of travel destinations is linked to the changing demographics of the
North American population.
Population migration has been associated with the spread of diseases ranging from
plague, smallpox, measles, and syphilis to, more recently, HIV and TB. Travel and
trade are also associated with the spread of disease vectors, such as the mosquito
vectors for yellow fever and dengue fever.11 The rapidity of air travel has facilitated
the spread even of diseases with short incubation periods such as influenza and
measles.12,13 A 2003 Institute of Medicine report identified 13 factors affecting the
appearance of new and emerging infectious diseases, many of which were related
to migrating populations.14 Migrant populations can, however, have other roles in
changing the pattern of diseases present in a population. Some chronic conditions
are associated with remote acquisition of infections, such as American trypanosomi-
asis or Chagas disease (heart and esophageal disease), the parasitic infection cysti-
cercosis (seizure disorders), and hepatitis B and C infection (hepatic cirrhosis). The
incidence of some cancers (hepatocellular carcinoma, cervical cancer) in the future
may also be affected by the prevalence of infections such as hepatitis B and C and
human papillomavirus (HPV) in mobile populations resettling in areas where these
infections are less common.
MIGRANT POPULATIONS AND ACUTE AND CLINICALLY APPARENT INFECTIOUS DISEASES
Immigrants may have a direct role in transmitting acute infectious diseases from one
geographic location to another. This concern is especially great when large groups,
such as refugees, are resettled to locations around the world. Since 2004, the reset-
tlement of refugee populations has been disrupted in Kenya, Tanzania, Thailand,
Emerging Infectious Diseases 1449
Ethiopia, and Ivory Coast by outbreaks of vaccine-preventable diseases including

measles, mumps, rubella, polio, pertussis, hepatitis A, and typhoid fever. The planned
movement of 8000 Liberian refugees scheduled to begin in June 2003 and conclude in
April 2004 was interrupted several times by outbreaks of varicella, measles, o’nyong-
nyong fever, and rubella.15 During this period, 16 cases of varicella were imported into
four states and an infant who had congenital rubella infection was born to a mother
who had asymptomatic infection.16 Experts in refugee resettlement have proposed
immunization of large mobile populations before resettlement to reduce the spread
of infectious diseases and to realize a cost-savings compared with administering all
vaccines in the destination country.17
The United States and Canada, through successful routine immunization pro-
grams, have reduced the rates of vaccine-preventable diseases to extremely low
levels in the general population.18 Disease due to Haemophilus influenzae type
b has decreased by more than 99%, and most cases of measles and rubella in
the United States are now imported or associated with imported cases.19–21 Health
care professionals have become less familiar with the typical clinical manifestations
of some of these infections, leading to potential delays in diagnosis, as illustrated
by several recent outbreaks of measles associated with children adopted interna-
tionally.22 Other diseases, including varicella, pneumococcal disease, and
pertussis, have been reduced significantly by routine childhood immunization, al-
though clinicians continue with some regularity to see patients who have these
diseases.23–25 The major role of clinicians when evaluating newly arrived
immigrants is to maintain a high index of suspicion for diseases that have become
rare in the United States. Immigrants may not have received in their country of
origin vaccines given routinely in North America, or may have had exposures
that would be rare in North America.
Hepatitis A poses an additional challenge, in that individuals, usually children, who
have anicteric or asymptomatic infection may still shed virus and transmit disease to
others. Hepatitis A disease and disease mortality has decreased in the United States
since implementation of immunization at age 2 in high-incidence communities, and is
expected to decline further with routine immunization of all children at age 1.26,27
Cases have been linked, however, to internationally adopted children and to
immigrants and their families who live along the United States–Mexico border and
travel back and forth frequently.28–31 Clinicians must have a high index of suspicion
for situations that would place individuals at increased risk for hepatitis A, and provide
these individuals with hepatitis A vaccine.
Children adopted internationally are a special group who deserve additional
mention. Because they are not required to receive immunizations before leaving their
birth country, they may be susceptible to, or already infected with, vaccine-prevent-
able diseases at the time of arrival in North America. Transmission of measles, hepa-
titis A, hepatitis B, TB, and other infectious diseases has been documented from
internationally adopted children. Pertussis, rubella, and varicella have been diagnosed
in adoptees soon after arrival.32,33 Children adopted internationally, because they join
families that have not shared similar exposures, may pose a unique potential for trans-
mitting infectious diseases in their adoptive country. Recent reports of measles and
hepatitis A outbreaks in association with internationally adopted children illustrate
this phenomenon.22,28 The potential risk for transmission of diseases from the migrant
population of internationally adopted children has led to recommendations for
enhanced protection of families traveling to adopt children and of family members
and others who will have close contact with these children on arrival in North
America.32,34–36
MIGRANT POPULATIONS AND LATENT AND CHRONIC INFECTIOUS DISEASES

LESS FAMILIAR TO NORTH AMERICAN HEALTH PROFESSIONALS
The health characteristics of migrant populations depend on the conditions to which

migrants are exposed in their countries of origin, during migration, and in their reset-
tlement environment.4 Understanding a person’s journey from his/her country of origin
to his/her country of current residence is especially important when assessing risk for
diseases of long latency, such as TB, HIV, leprosy, and Chagas disease, and diseases
that occur when an individual’s immune status changes, such as strongyloides and
latent TB. Few of these diseases, with the notable exception of TB, pose significant
risk to the local population.
In many developed countries, TB occurs disproportionately in the foreign-born
population. In the United States, more than 50% of TB cases have occurred in non–
United States-born individuals since 2002, and most of these become apparent within
5 years of entering the United States.37 Although the total number of cases of TB re-
ported in the United States declined in 2007, 58.5% were in foreign-born individuals,
and the TB rates in the foreign-born were 9.7 times higher than in individuals born in
the United States. Multidrug-resistant TB also occurs more commonly in foreign-born
individuals; 84.5% of cases occurred in such individuals in the United States in 2006.38
Since the early 1990s, more than half the cases of TB in Canada have been reported in
foreign-born individuals.39 Patterns of TB seen in North America today and those pre-
dicted for the future are therefore driven by the trends in immigration now and in the
recent past. Currently, more than half of all TB cases in the United States occur in
individuals from four countries: Mexico, the Philippines, India, and Vietnam.38 In
Canada, most cases are seen in individuals from the Western Pacific region, although
increased numbers of cases from Southeast Asia and Africa are being reported.39 TB
control programs must take into account the needs of the foreign-born population and
make TB diagnosis and prevention programs accessible and acceptable to foreign-
born populations.40
The global burden of HIV falls disproportionately on individuals from certain parts of
the world, especially Africa. In North America, an increasing proportion of individuals
living with HIV are foreign born. In Massachusetts, as of November 2007, 19% of those
living with AIDS were foreign born, compared with a foreign-born population of about
12%.41 Less than 1% of Minnesota’s population was born in Africa, yet in 2004, 19%
of new HIV diagnoses were among those born in Africa.42 MacPherson and
colleagues43 contrast the prevalence of HIV in Canadian immigration applicant chil-
dren (14/100,000) with the rate of domestically reported pediatric HIV cases (0.02/
100,000). They conclude that population migration and immigration could more than
double the number of children who have HIV/AIDS in Canada, requiring a refocusing
of efforts to provide culturally and linguistically appropriate programs of HIV care and
prevention for immigrant families. Health care professionals and HIV program direc-
tors face significant challenges in accommodating the needs of diverse immigrant
populations. Overcoming language and cultural barriers to care, addressing differing
beliefs about HIV/AIDS, providing care in the context of competing priorities such as
housing, jobs, and family stress, and addressing the psychiatric needs of immigrants
living with HIV are all critical to the success of programs caring for immigrant
populations, yet are stretching the resources of these programs in unprecedented
ways.44
Immigrants may present with conditions unfamiliar to American-trained health care
professionals, resulting in delays in diagnosis. Dermatologic conditions are especially
challenging. Chronic conditions such as leprosy, leishmaniasis, and filarial disease
can provide diagnostic dilemmas and may not be recognized easily. Keystone45 pro-
vides an excellent overview of skin conditions of immigrants, and contrasts these with
those likely to be seen in travelers. Arriving at the correct diagnosis often requires de-
tailed information from the patient about migration history, access to specialized
laboratories that can assist in making a diagnosis, and, for some diseases, access
to specialized medications with limited availability. Once a diagnosis is made, addi-
tional challenges include addressing the stigma associated with diseases such as
Hansen’s disease (leprosy), the long period of treatment required (sometimes with
specialized medications), and, with conditions such as visceral leishmaniasis, ad-
dressing the possibility of HIV coinfection.
Parasitic diseases contracted outside North America may present after migration,
possibly because of long latency periods or because relapse or recrudescence is
characteristic of the infection. Relapses of malaria may present long after migration
and the diagnosis may seem elusive unless the migration history is known. Lymphatic
filariasis may present as intermittent leg swelling, and patients may undergo multiple
evaluations for cellulitis or deep venous thrombosis or other conditions unless resi-
dence in an area where lymphatic filariasis exists is ascertained. Neurocysticercosis
is one of the most common causes of seizures in some immigrant populations;
seizures may occur years after leaving the country of exposure. Granulomas formed
by Schistosoma may result in long-term complications such as hepatic fibrosis, hydro-
nephrosis, and infertility in women many years after initial exposure. Heart block,
cardiomyopathy, or esophageal dilatation may be late manifestations of Chagas’ dis-
ease. The clinician’s challenge for all these diseases is to link these clinical manifesta-
tions with a remote exposure occurring outside North America. With the multiple
pressures on clinicians today, including decreased time to spend with each patient,
increased requirements to complete specific tasks during a visit, and the challenges
of caring for patients with limited English/French proficiency and limited health liter-
acy, it is easy to understand how taking a migration history would be missed. Even
when migration histories are requested, additional barriers may exist, such as fear
of deportation, which may hinder obtaining an accurate history of exposure. This
situation was illustrated poignantly by Matteelli and colleagues,46 who described
a group of illegal Chinese immigrants to Italy diagnosed with malaria. The circuitous
route by which they traveled was obtained only with extreme difficulty partly because
of the clandestine status of these immigrants.
Chagas’ disease (American trypanosomiasis) deserves special mention for its
impact on health care policy. It is estimated that more than 100,000 individuals in-
fected with Trypanosoma cruzi may be living in the United States; most are asymptom-
atic and are unaware that they are infected. These individuals, however, are able to
transmit infection to others through donated blood or organs; such cases have
occurred in the United States. In addition, an infected pregnant woman can transmit
the infection to her fetus.47 During a 5-month period in 2006/2007, almost 150,000
blood donations were tested for antibodies to T cruzi; approximately 1 in 2365 dona-
tions was positive. In January 2007, the American Red Cross and Blood Systems, Inc.,
organizations that supply about 65% of the United States blood supply, adopted
routine screening of all blood donations for T cruzi.48
MIGRANT POPULATIONS AND CHANGING PATTERNS OF ONCOLOGIC DISEASES
Human migration patterns may have far-reaching implications for patterns of cancer
that will manifest in North America over the next few decades. The period of latency
between being infected with viruses such as hepatitis B or C, or HPV, and bacteria
such as Helicobacter pylori, and development of malignancy may be decades. Diag-

noses of hepatocellular carcinoma, cervical and other HPV-related cancers, and
gastric cancer made in the next 20 years are likely to be made in the populations of
immigrants who arrive already infected with these organisms. Individuals from many
regions outside the United States that are the origin of many immigrants are more
likely to be infected with hepatitis viruses, HPV, and H pylori than individuals born
and raised in the United States. The Centers for Disease Control and Prevention
(CDC) estimates that between 1994 and 2003, approximately 40,000 immigrants
who had chronic hepatitis B were admitted to the United States annually.49 Thus,
these infection-related cancers will be emerging diseases in immigrant populations
in the future. Efforts toward prevention of transmission of these infections and early
diagnosis and treatment of resulting diseases must be made with the populations
most at risk in mind. An example of the challenges presented by such a need is the
situation with respect to cervical cancer in Vietnamese women in California. Although
Vietnamese-American women have the highest rates of cervical cancer of any group in
the United States, and are diagnosed later than women in other groups, one report
noted that only 50% of them have ever had a Pap smear, compared with almost
98% of women in the general United States population.50 Another example is that
of hepatitis B infection and hepatocellular carcinoma in the Chinese-American
population. Approximately 10% of Chinese immigrants are infected with hepatitis B,
compared with about 1% of the American-born population. Several reports indicate,
however, that fewer than 40% of immigrants from China have been tested for hepatitis
B infection. Coronado and colleagues,51 in a study of Chinese immigrants in Seattle,
found that factors associated with having been tested included knowledge that
Chinese immigrants are more likely than whites to get hepatitis B, being told by
a doctor that they needed to be tested or requesting of a health care professional
that they be tested, and not needing an interpreter for the visit. The CDC currently
recommends screening for hepatitis B all immigrants from Africa, Asia, the Pacific is-
lands, and other areas where high rates of infection with hepatitis B occur, regardless
of vaccination status.49 Finally, H pylori, associated with gastric cancer, is more
common in individuals born in developing countries than it is in those born in
industrialized countries. The implications of this colonization over the long term is
unknown.52
IMMIGRANTS AND RISK FOR EXPOSURE TO INFECTIOUS DISEASES
As immigrants enter the workforce in their countries of resettlement, they may be

exposed to risks for infectious diseases for which they are unprepared. Jenks and Tra-
passo53 describe a cohort of migrant workers in New York who lacked familiarity with
Lyme disease, although their working conditions placed them at increased risk for ex-
posure to this disease. Pollock and colleagues54 report a high proportion of immigrant
workers involved in an outbreak of Q fever in Scotland in 2006. An outbreak of Plas-
modium vivax malaria involving migrant workers from Mexico was reported from
San Diego County, California, in 1986. These workers were not only at greatest risk
for disease (likely from sleeping outside near a marshy area where Anopheles hermsi
mosquitoes were breeding) but they also probably played a role in sustaining local
transmission through several generations.55 These situations highlight the challenges
of diagnosis and prevention of infectious diseases related to occupational exposures
in workplace situations where multiple languages and cultures complicate access to
health care, obtaining complete medical and migration histories, and the ability to
provide information about preventing infection.
Table 1
Emerging infectious diseases and role of migrants, public health officials, and clinicians
Type of Infection Role of Migrants Public Health/Policy Role Role of Clinicians

Acute infectious diseases with risk May arrive ill or incubating Immunization policy (provide Recognition of infections uncommon
for local transmission: measles, infection (measles, hepatitis A) vaccines before arrival for in the local population
rubella, varicella, pertussis, May be more susceptible than refugees, adoptees) Identification of need for and
hepatitis A local population (varicella) Financing of and access to provision of immunizations to
immunizations for immigrants immigrants
Infectious diseases with latency or May arrive ill or may reactivate Culturally appropriate TB Identification of at-risk individuals
asymptomatic states with some disease many years later (TB) programs and family members and provision
risk for local transmission Family/community members may Financing and provision of access of appropriate preventive measures
need immunization to immunizations Diagnosis of infection in
asymptomatic individual (LTBI,
hepatitis B infection)
Infectious diseases with low Bear a disproportionate burden Culturally appropriate treatment Recognition of infections rare in local
potential for local transmission of disease in some programs and prevention population (Chagas)
communities (HIV) initiatives (HIV)
Blood screening policies (HIV,
Chagas)
Infectious diseases with oncologic Bear an increased burden of Educational initiatives about Screening for infectious diseases
potential disease (Hepatitis B, C; HPV; diseases Regular monitoring of those infected
H pylori) Provision and financing for development of sequelae
Emerging Infectious Diseases

Have less access to, or less of screening and Education about transmission,
acceptance of, screening immunizations reduction of risk for disease and
procedures (HPV) sequelae
Routine cancer screening (Pap smears,
colonoscopy, and so forth)
Vector-borne diseases May arrive infected; may be more Monitoring/reduction of vector Recognition of diseases rare in the
likely to visit tropical/subtropical populations local population
areas with these infections Surveillance
when visiting relatives
Intermediate hosts
1453
Immigrant groups may also have food-borne exposures that differ from the indige-
nous population, resulting in infectious diseases that are unfamiliar to local health care
professionals. A recent report describes the differing rates of brucellosis in the local
German population and the Turkish immigrant population; this association has also
been reported in the Hispanic population in the United States.56,57 Childhood brucel-
losis in the United States is seen almost exclusively in immigrants with a history of
travel to Mexico or ingestion of unpasteurized mild products from Mexico.58 Mycobac-
terium bovis, spread through consumption of raw dairy products or contact with
infected cattle, rather than from person to person, accounted for 8% of all TB cases
and 45% of cases in children from 1994 through 2005 in San Diego County, Califor-
nia.59 Thirty-five cases of TB due to M bovis were identified in New York City between
2001 and 2004 and were linked in preliminary investigations to fresh cheese brought
from Mexico; no cases of human-to-human transmission were found.60 Reducing the
risk for M bovis infection will require multiple approaches, including education of
affected communities about unpasteurized dairy products, collaboration with Mexico,
where M bovis continues to be prevalent in cattle, and high index of suspicion of this
unusual form of TB by clinicians, because treatment may involve different drug
regimens or longer courses of treatment than disease caused by Mycobacterium
tuberculosis.
MIGRANTS AND VECTOR-BORNE DISEASES
West Nile virus has spread rapidly across North America since its introduction in 1999.
The virus is transmitted to humans, horses, and other mammals by mosquitoes, and
domestic and wild birds play a critical role in the spread of this disease. The rapid
emergence of West Nile virus in the United States and Canada is a wake-up call for
the public health community, highlighting that emergence of other mosquito-borne ill-
nesses is a real possibility. The presence in the United States of mosquito populations
that are competent to transmit several arboviruses means that viremic individuals
entering the United States could potentially spark local transmission.61 It is worth
remembering that outbreaks of yellow fever once occurred as far north as Boston,
and that malaria occurred throughout much of the United States. Changes in relation-
ships among vectors and intermediate hosts of parasitic diseases and humans as res-
ervoirs of infection are occurring and will continue to occur. On the west coast of the
United States, two intermediate hosts of the human lung fluke have appeared since
1990: the Chinese mitten crab in 1990 and the estuarine snail in 2007. These arrivals
set the stage for completion of the lung fluke life cycle should sanitary conditions allow
the lung fluke, carried by infected Asian immigrants, to enter bodies of water contain-
ing both intermediate hosts. At this time, the habitats of the two intermediate hosts do
not overlap, but it is likely that they will in the future (James T. Carlton, personal
communication, 2008). Human activity is constantly changing the balance among
vectors, hosts, and reservoirs of infection; migration of human populations contributes
to, and is affected by, changes in this balance.
SUMMARY
Population migration plays a critical role in the spread of disease by initiating out-
breaks of acute diseases, changing the prevalence of infectious diseases at a given
location, and changing the face of chronic disease resulting from previous infection.
Roles of migrants, public health officials, and clinicians are summarized in Table 1.
Human populations also interact with the environment and disease vectors in ways
that may contribute to the emergence of infectious diseases. Public health officials are
challenged by the extent of activities required to monitor the spread of such diseases
and implement measures to limit or prevent them. Clinicians are challenged by the
need to be familiar with new and emerging infections and by the need to consider
migration history for a growing number of individuals. Addressing the emergence
and reemergence of infectious diseases related to migration will require increased
surveillance of infectious disease patterns worldwide, increased knowledge by health
care professionals of a wider variety of infectious diseases and attention to migration
patterns of their patients, and a high index of suspicion on the part of clinicians when
faced with unfamiliar illnesses.
REFERENCES
1. Morens DM, Folkers GK, Fauci AS. The challenge of emerging and re-emerging
infectious diseases. Nature 2004;430:242–9.
2. Gayer M, Legros D, Formenty P, et al. Conflict and emerging infectious diseases.
3. Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis
1995;1:7–15.
4. Gushulak BD, MacPherson DW. Globalization of infectious diseases: the impact
of migration. Clin Infect Dis 2004;38:1742–8.
5. United Nations. Trends in total migrant stock: the 2005 revision. Available at:
http://esa.un.org/migration/index.asp?panel51. Also Available at: http://www.
migrationinformation.org/datahub/charts/6.1.shtml. Accessed April 9, 2008.
6. MPI. MPI data hub. Available at: http://www.migrationinformation.org/datahub/
charts/1.1.shtml. Accessed April 9, 2008.
7. US census 2000, census of Canada, 2001. Available at: http://www.migrationin
formation.org/datahub/migrant_stock_region.cfm. Accessed April 8, 2008.
8. ITA. Office of travel & tourism industries. Office of Travel and Tourism Industries.
Available at: http://tinet.ita.doc.gov/view/f-101/index.html. Accessed April 9, 2008.
9. Canada Tourism Commission 2007. Available at: http://www.corporate.canada.
travel/en/ca/research_statistics/statsFigures/tourism_performance/annual_tourism_
performance/2005.html. Accessed April 9, 2008.
10. Office of Travel and Tourism Industries Data. Available at: http://tinet.ita.doc.gov/
cat/f-2006-101-001.html. Accessed April 9, 2008.
11. Sellman J, Pederson P. Emerging infectious diseases of immigrant patients. In:
Walker PF, Barnett ED, editors. Immigrant medicine. Philadelphia: Elsevier, Inc.;
2007. p. 245–53.
12. Brownstein JS, Wolfe CJ, Mandl KD. Empirical evidence for the effect of airline
travel on inter-regional influenza spread in the United States. PLoS Med 2006;
3:e401.
13. Centers for Disease Control and Prevention. Measles—United States January 1–
April 25, 2008. MMWR Morb Mortal Wkly Rep 2008;57:494–8.
14. Smollinski MS, Hamburg MA, Lederberg J, editors. Microbial threats to health:
emergence, detection, and response. Washington, DC: Institute of Medicine Na-
tional Academiy Press; 2003.
15. Cetron M. Vaccine preventable diseases and mobile populations. Presented at
the 2008 International Conference on Emerging Infectious Diseases. Atlanta,
GA, March 17, 2008.
16. Centers for Disease Control and Prevention. Brief report: imported case of con-
genital rubella syndrome—New Hampshire, 2005. MMWR Morb Mortal Wkly
Rep 2005;54:1160–1.
17. Centers for Disease Control and Prevention. Cost of vaccinating refugees over-
seas versus after arrival in the United States, 2005. MMWR Morb Mortal Wkly
Rep 2008;57:229–32.
18. Roush SW, Murphy TV. Historical comparisons of morbidity and mortality for vac-
cine-preventable diseases in the United States. JAMA 2007;298:2155–63.
19. Centers for Disease Control and Prevention. Progress toward elimination of Hae-
mophilus influenzae type b invasive disease among infants and children—United
States, 1998–2000. MMWR Morb Mortal Wkly Rep 2002;51:234–7.
20. Centers for Disease Control and Prevention. Measles—United States, 2005.
MMWR Morb Mortal Wkly Rep 2006;55:1348–51.
21. Centers for Disease Control and Prevention. Elimination of rubella and congenital
rubella syndrome—United States, 1969–2004. MMWR Morb Mortal Wkly Rep
2005;54:279–82.
22. Centers for Disease Control and Prevention. Measles among adults associated
with adoption of children in China—California, Missouri, and Washington, July–
August 2006. MMWR Morb Mortal Wkly Rep 2007;56:144–6.
23. Zhou F, Harpaz R, Jumaan AO, et al. Impact of varicella vaccination on health-
care utilization. JAMA 2005;294:797–802.
24. Centers for Disease Control and Prevention. Direct and indirect effects of routine
vaccination of children with 7-valent pneumococcal conjugate vaccine on inci-
dence of invasive pneumococcal diseases—United States, 1998–2003. MMWR
Morb Mortal Wkly Rep 2005;54:893–7.
25. Centers for Disease Control and Prevention. Pertussis—United States 2001–
2003. MMWR Morb Mortal Wkly Rep 2005;54:1283–6.
26. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United States in
the era of vaccination. JAMA 2005;294:194–201.
27. Vogt TM, Wise ME, Bell BP, et al. Declining hepatitis A mortality in the United
States during the era of hepatitis A vaccination. J Infect Dis 2008;197:1282–8.
28. Health advisory—Hepatitis A infection linked to children adopted from Ethiopia
and their family contacts. Available at: http://www.cdc.gov/ncidod/diseases/hep
atitis/a/HAHealthAdvisory.pdf. Accessed April 22, 2008.
29. Wilson ME, Kimble J. Posttravel hepatitis A: probably acquisition from an asymp-
tomatic adopted child. Clin Infect Dis 2001;33:1083–5.
30. Jong EC. United States epidemiology of hepatitis A: influenced by immigrants
visiting friends and relatives in Mexico? Am J Med 2005;118:50S–7S.
31. Weinberg M, Hopkins J, Farrington L, et al. Hepatitis A in Hispanic children who
live along the United States-Mexico border: the role of international travel and
food-borne exposures. Pediatrics 2004;114:e68–73. Available at: http://pediat
rics.aappublications.org/cgi/content/abstract/114/1/e68. Accessed April 22,
2008.
32. Barnett ED, Chen LH. Prevention of travel-related infectious diseases in families
of internationally adopted children. Pediatr Clin North Am 2005;52:1271–86.
33. Barnett ED. Immunizations and infectious disease screening for internationally
adopted children. Pediatr Clin North Am 2005;52:1287–309.
34. Chen LH, Barnett ED, Wilson ME. Preventing infectious diseases during and after
international adoption. Ann Intern Med 2003;139:371–8.
35. Centers for Disease Control and Prevention. Health information for international
travel 2008. Available at: http://wwwn.cdc.gov/travel/yellowBookCh8-Adoptions.
aspx. Accessed April 27, 2008.
36. Barnett ED. Immunizations for immigrants. In: Walker PF, Barnett ED, editors. Im-
migrant medicine. Philadelphia: Elsevier, Inc.; 2007. p. 151–70.
37. Centers for Disease Control and Prevention. Trends in tuberculosis—United

States, 2005. MMWR Morb Mortal Wkly Rep 2006;55:305–8.
38. Centers for Disease Control and Prevention. Trends in tuberculosis—United
States, 2007. MMWR Morb Mortal Wkly Rep 2008;57:281–5.
39. Canada Health. Tuberculosis among the foreign-born in Canada. 15 January
2003. Available at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/03vol29/
dr2902eb.html. Accessed April 25, 2008.
40. Bernardo J. Tuberculosis. In: Walker PF, Barnett ED, editors. Immigrant medicine.
Philadelphia: Elsevier, Inc.; 2007. p. 255–71.
41. Massachusetts HIV/AIDS data fact sheet: who is currently living with HIV/AIDS?.
Available at: http://www.mass.gov/Eeohhs2/docs/dph/aids/2008_profiles/living_
with_hiv.pdf. Accessed April 26, 2008.
42. A growing crisis: a funder’s response to HIV/AIDS in the African community in
Minnesota. Available at: http://www.phillipsfnd.org/documents/FinalHIVAfrican
Report.pdf. Accessed April 26, 2008.
43. MacPherson DW, Zencovich M, Gushulak BD. Emerging pediatric HIV epidemic
related to migration. Emerg Infect Dis 2006;12:612–7.
44. Crosby SS, Piwowarczyk LA, Cooper ER. HIV infection. In: Walker PF, Barnett ED,
editors. Immigrant medicine. Philadelphia: Elsevier, Inc.; 2007. p. 361–73.
45. Keystone JS. Skin problems. In: Walker PF, Barnett ED, editors. Immigrant med-
icine. Philadelphia: Elsevier, Inc.; 2007. p. 375–91.
46. Matteelli A, Volontario A, Gulletta M, et al. Malaria in illegal Chinese immigrants,
Italy. Emerg Infect Dis 2001;7:1055–8.
47. Maguire JH. Chagas’ disease (American trypanosomiasis). In: Walker PF,
Barnett ED, editors. Immigrant medicine. Philadelphia: Elsevier, Inc.; 2007.
p. 393–8.
48. Centers for Disease Control and Prevention. Blood donor screening for Chagas’
disease—United States 2006–2007. MMWR Morb Mortal Wkly Rep 2007;56:
141–3.
49. Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy
to eliminate transmission of hepatitis B virus infection in the United States: recom-
mendations of the Advisory Committee on Immunization Practices (ACIP) Part II:
immunization of adults. MMWR Morb Mortal Wkly Rep 2006;55(RR-16):1–25.
50. Tram K, Lam BS, McPhee SJ, et al. Encouraging Vietnamese-American women to
obtain Pap tests through lay health worker outreach and media education. J Gen
Intern Med 2003;18:516–24.
51. Coronado GD, Taylor VM, Tu S-P, et al. Correlates of hepatitis B testing among
Chinese Americans. J Community Health 2007;32:379–90.
52. Gebhard RL, Gebhard KH. Helicobacter pylori. In: Walker PF, Barnett ED, editors.
Immigrant medicine. Philadelphia: Elsevier, Inc.; 2007. p. 393–8.
53. Jenks NP, Trapasso J. Lyme risk for immigrants to the United States: the role of an
educational tool. J Travel Med 2005;12:157–60.
54. Pollock KGJ, Mellor DJ, Browning LM, et al. Q fever in migrant workers, Scotland.
55. Maldonado YA, Nahlen BL, Roberto RR, et al. Transmission of Plasmodium vivax
malaria in San Diego County, California, 1986. Am J Trop Med Hyg 1990;42:3–9.
56. Dahouk SA, Neubauer H, Hensel A, et al. Changing epidemiology of human bru-
cellosis, Germany, 1962–2005. Emerg Infect Dis 2007;13:1895–900.
57. White AC Jr, Atmar RL. Infections in Hispanic immigrants. Clin Infect Dis 2002;34:
1627–32.
58. Shen MW. Diagnostic and therapeutic challenges of childhood brucellosis in

a nonendemic country. Pediatrics 2008;121:e1178–83.
59. Rodwell TC, Moore M, Moser KS, et al. Tuberculosis from Mycobacterium bovis in
binational communities, United States. Emerg Infect Dis 2008. Available at: http://
www.cdc.gov/eid/content/14/6/jpdfs/07-1485.pdf. Accessed August 18, 2008.
60. Centers for Disease Control and Prevention. Human tuberculosis caused by
Mycobacterium bovis—New York City, 2001–2004. MMWR Morb Mortal Wkly
Rep 2005;54:605–8.
61. Charrel RN, de Lamballerie X, Raoult D. Chikungunya outbreaks—the globaliza-
Re gional Infe c tious Dis ease
Sur veillance Networks and
their Potential to Fac ilitate
the I mplement ation
of the International
Health Re gulations
Ann Marie Kimball, MD, MPHa,b,*, Melinda Moore, MD, MPHc,
Howard Matthew French, MPHd,Yuzo Arima, MPHa,
Kumnuan Ungchusak, MD, MPHe, Suwit Wibulpolprasert, MDf,
TerenceTaylor, BAg, Sok Touch, MDh, Alex Leventhal, MD, MPH, MPAi
KEYWORDS
Surveillance International health regulations
Infectious disease Global health Health security
Work described in this paper is supported by the Governments of Thailand, Laos, Cambodia, Myanmar,
China, the Palestinian Authority, Jordan, and Israel. Asia-Pacific Economic Cooperation Emerging Infec-
tions Network (APEC EINet) is supported by the APEC Secretariat and the United States Centers for Dis-
ease Control (CDC); AMK is Director of APEC EINet; HMF and YA are employed by this project. Project
support for Mekong Basin Disease Surveillance and Middle East Consortium on Infectious Disease Sur-
veillance is provided by Global Health and Security Initiative (GHSI). TT is GHSI Director; MM is employed
by RAND Corporation, which carried out regional tabletop activities funded by GHSI and the CDC.
a
Department of Epidemiology, School of Public Health and Community Medicine, University of
Washington, BOX 357236, Seattle, Washington 98195, USA
b
Department of Health Services, School of Public Health and Community Medicine, University of
Washington, BOX 357236, Seattle, Washington 98195, USA
c
RAND Corporation, 1200 South Hayes Street, Arlington, VA 22201-5050, USA
d
Community-Oriented Public Health Practice, School of Public Health and Community Medicine,
University of Washington, BOX 357236, Seattle, Washington 98195, USA
e
Bureau of Epidemiology and International Health Regulation Focal Point, Department of Diseases
Control, Ministry of Public Health, Tivanonda Road, Nonthaburi 11000, Thailand
f
Office of Permanent Secretary, Ministry of Public Health, Tiwanond Road, Nonthaburi 11000,
Thailand
g
Global Health and Security Initiative, NTI, 1747 Pennsylvania Avenue NW, 7th Floor, Washington, DC
20006, USA
h
Ministry of Health, No 151-153 Kampuchea Krom Boulevard, Phnom Penh, Cambodia
i
Ministry of Health and Braun School of Public Health, Hebrew University-Hadassah Medical School,
POB 12272, Jerusalem 91120, Israel
* Corresponding author. University of Washington, School of Public Health and Community Medicine,
Departments of Epidemiology and Health Services, BOX 357236, Seattle, WA 98195.
E-mail address: akimball@u.washington.edu (A.M. Kimball).
Med Clin N Am 92 (2008) 1459–1471

1460 Kimball et al
The implementation of the new International Health Regulations (IHR) requires the
proactive establishment of competence within all World Health Organization (WHO)
member countries to control infectious diseases within their territories. Some investi-
gators have contended that the establishment of regional networks for disease surveil-
lance actually may diminish the ability of low resource settings to establish such
competence.1 This article examines this theoretic possibility by closely describing
the experience of regional networks, focusing on two such networks, the Middle
East Consortium on Infectious Disease Surveillance (MECIDS) and the Mekong Basin
Disease Surveillance (MBDS) networks. These two cases clarify the contribution of
such networks to the successful implementation of the IHR.
The past 2 decades have witnessed increasing globalization of commerce, travel,
financial flows, production chains, and services. The market forces behind this glob-
alization do not always apply to public safety and protection; thus, the public health
sector has been slow to globalize and too few within the economic and trade sec-
tors embrace the urgency of supporting the transnationalization of public health.
While globalization of the health sector inches along, extension of production chains
and intensification of agriculture stress public health security at the point of origin
(commonly in resource poor settings).2 High-profile pandemics (eg, HIV/AIDS and
severe acute respiratory syndrome [SARS]) point to the lack of an effective global
public health safety net. Fig. 1 illustrates the challenge of transnational infection
and the need for transnational response. Resource poor settings continue to strug-
gle with high levels of preventable and treatable endemic and epidemic diseases.
Given the lack of economic incentive to globalize public health protection, the
task of realizing this global public good rests with national governments, interna-
tional agencies, and philanthropic interests.3 As travel and commerce so thoroughly
interconnect the globe that an outbreak in Asia today may be an outbreak in North
America tomorrow, or vice versa, the rhetoric of global disease security has become
more urgent.
Fig. 1. Transnationalization of infection through trade and travel.

Regional Surveillance Networks 1461
Although there are potentially several drivers for the rise of regional networks for sur-
veillance, at least two are in play. First, as markets globalize, consolidation and scale of
activity gain importance. Increasingly active trading economies have come together in
larger economic groups (eg, the European Union and the Asia-Pacific Economic
Cooperation [APEC]). As blocs of trading economies have emerged, new common con-
cerns about health security also have come to the fore. Second, in postconflict areas di-
vided by war, common geographic zones of activity come together for mutual economic
benefit during recovery. As commerce and travel increase economic integration, popu-
lation health security becomes an important issue. This article provides a brief review of
the rise of regional groupings of countries that have created networks for disease surveil-
lance and examines theoretically and through the experiences of these regional net-
works how they may facilitate the implementation of the revised IHR (2005). Although
this article offers a catalog of several of these systems (Table 1), the universe of networks
described is not exhaustive. Discussion focuses on the regional networks of MECIDS
and MBDS, which illustrate the challenges and opportunities these networks afford.
The emergence of novel infectious disease threats has increased in the modern era,
raising the need for new surveillance capabilities. Zoonotic origin accounts for the
majority of these events,4 and the increasing need to coordinate human and animal
health is an additional challenge for nascent surveillance systems. With the renewed
appreciation for the speed of transmission of agents given modern travel volumes
and rates, speed and accuracy of information become more important. Additionally,
with the broad geographic dispersal of pathogens in products and people, the ability
to sensitively, specifically, and promptly identify particular strains or subtypes of
organisms using modern diagnostic techniques becomes important. Such identifica-
tion is critical for (1) effective disease investigation to detect the source, (2) vaccine
development, and (3) tailoring treatment regimens for individual patients affected.
THE REVISED INTERNATIONAL HEALTH REGULATIONS
In the early 1990s the return of old epidemics, such as cholera in South America, and
the emergence of new infectious agents, such as Ebola hemorrhagic fever, sparked
a landmark study by the United States Institute of Medicine.5 The study, chaired by
the late Dr. Joshua Lederberg, identified new pathogen emergence as a cross-cutting
theme in global infectious disease and began to identify the anthropogenic factors
behind such emergence. The ongoing occurrence of emergent infections provoked
a resolution calling for the revision of the IHR (1969) at the 1995 World Health Assem-
bly. In 2001, the World Health Assembly adopted a resolution on global health security
epidemic alert and response in which WHO was to support its member states in
identifying, verifying, and responding to public health emergencies of international
concern. In 2002, the World Health Assembly reiterated the need to revise the IHR
to reflect the changes in its resolution, global public health response to natural occur-
rences, and accidental release or deliberate use of biologic, chemical, or nuclear
agents that affect health. The outbreak of SARS, however, prompted the World Health
Assembly, in 2003, to decide on establishing the Intergovernmental Working Group on
the Revision of the IHR to accelerate the process.
The revised IHR (2005) were adopted, by consensus and after 18 months of nego-
tiation, in May 2005 by the 58th World Health Assembly.1 They focus on strengthening
global surveillance, improving communication between WHO and member states, and
ensuring that each country has the laboratory capacity to identify outbreaks rapidly.6
The revised regulations encourage governments to participate in an international net-
work of surveillance networks through reviewing their current surveillance strategies
1462
Kimball et al
Table 1
Select examples of regional surveillance networks
Network Name Date Founded Legal Basis Membership

Early regional networks
OCCGE: Organisation de Coordination 1960 (now merged Multilateral agreement Benin, Burkina Faso, Côte d’Ivoire, Mali, Mauritania,
et de Cooperation pour la lutte contre into WAHO) Niger, Senegal, and Togo
les Grandes Endemies
WAHO: West African Health Organisation 1987 (merger of Multilateral agreement Burkina Faso, Cape Verde, Côte d’Ivoire, Gambia,
OCCGE and WAHC) Ghana, Guinea, Guinea Bissau, Liberia, Mali,
Niger, Nigeria, Senegal, Sierra Leone, and Togo
CAREC: Caribbean Epidemiology Centre 1975 Multilateral agreement American Samoa, Cook Islands, Federated States of
Micronesia, Fiji, French Polynesia, Guam, Kirbati,
Marshall Islands, Nauru, New Caledonia, Niue,
Commonwealth of the Northern Mariana Islands,
Palau, Papua New Guinea, Pitcairn Islands, Samoa,
Solomon Islands, Tokelau, Tonga, Tuvalu,
Vanuatu, and Wallis and Futuna
OCEAC: Organisation de Coordination 1963 Multilateral agreement Cameroun, Republic of Congo, Gabon, Equatorial
mies
pour la lutte contre les Ende Guinea, Central African Republic, and Chad
en Afrique Centrale
Trade cooperation based networks
APEC EINet: Asia-Pacific Economic 1996 Informal Australia, Brunei Darussalam, Canada, Chile,
Cooperation Emerging People’s Republic of China, Hong Kong (China),
Infections Network Indonesia, Japan, Republic of Korea, Malaysia,
Mexico, New Zealand, Papua New Guinea, Peru,
Philippines, Russia, Singapore, Chinese Taipei,
Thailand, United States, Vietnam
ECDC: European Centre for Disease 2005 Treaty Members of the European Union
Prevention and Control
Alert networks
GOARN: Global Outbreak Alert and 2000 Informal Scientific organizations in WHO member states,
Response Network United Nations organizations, international
humanitarian nongovernmental organizations,
surveillance and medical initiatives, and regional
technical networks
ProMED 1994 Informal More than 20,000 in 160 countries
Regional networks
SEEHN: South-eastern Europe 2001 Cooperation (initiative of Albainia, Bosnia and Herzegovina, Bulgaria,
Health Network the Stability Pact Social Croatia, Moldova, Romania, Serbia and
Cohesion Initiative) Montenegro, and Macedonia
PPHSN: Pacific Public Health 1996 Voluntary American Samoa, Cook Islands, Federated States of
Surveillance Network (coordinating body) Micronesia, Fiji, French Polynesia, Guam, Kirbati,
Marshall Islands, Nauru, New Caldonia, Niue,
Commonwealth of the Northern Mariana Islands,
Palau, Papua New Guinea, Pitcairn Islands, Samoa,
Solomon Islands, Tokelau, Tonga, Tuvalu,
Vanuatu, and Wallis and Futuna
MECIDS: Middle East Consortium 2003 Informal Palestinian Authority, Israel, Jordan
on Infectious Disease Surveillance
MBDS: Mekong Basin Disease 1999 Memorandum of Cambodia, China (Yunnan and Guangsi Provinces),
Regional Surveillance Networks

Surveillance understanding Lao PDR, Myanmar, Thailand, Vietnam
EAIDSNet: East Africa Integrated 2000 Treaty (Treaty for the Kenya, Tanzania, Uganda
Disease Surveillance Network Establishment of the
East African Community)
1463
1464 Kimball et al
and implementing programs capable of contributing to global outbreak intelligence.1

Member states are required to notify WHO and neighboring countries of all events po-
tentially constituting a public health emergency of international concern and to main-
tain a national focal point, available at all times, to mediate communication between
WHO and the government.6 The revised regulations, a broader binding pact than be-
fore, thus call for actions by member states and the WHO.
The passage of the IHR puts the world on a fast track to implementation. Networks,
such as MECIDS and MBDS, have reinforced national compliance efforts. The regu-
lations dictate minimum requirements for surveillance and response, although their
explicit agenda is to upgrade these systems on national levels and provide specific
measures to prevent disease spread at airports and other entry points.6 WHO main-
tains that surveillance is the cornerstone of efficient disease control and the key to
mounting an effective response,6 and the revised regulations provide some mecha-
nism for WHO to collaborate with member states after notification.7 In an era of glob-
alized infectious diseases, all countries are believed to have a stake in the success or
failure of surveillance and response capacity development in any one country.
Although global surveillance programs often are based on existing disease-specific
cooperation of regional networks (eg, WHO Global Influenza Surveillance Networks),
the revised IHR provide a framework for mandating countries to coordinate their action
through a universal network of surveillance networks (ie, a network of national and
regional networks).8 The regulations also provide a binding legal structure and raison
d’être umbrella to regional networks for solving practical issues near and within
national borders. Thus, regional surveillance networks, such as MBDS and MECIDS,
can facilitate the IHR and play an important role in their implementation. For example,
in 2007, MECIDS members convened a workshop on implementing the IHR in the
event of an influenza pandemic. This event was held in cooperation with WHO head-
quarters and WHO offices in the Eastern Mediterranean and European regions. As
pathogens do not respect national borders, regional outbreaks require collective
regional surveillance, response, accountability, and responsibility.
The perception is that if the revised IHR facilitate early detection and rapid imple-
mentation of effective control measures,7 most health emergencies will be dealt
with at a regional or national level and never become a global threat; hence, a regional
approach to surveillance may further strengthen the goals of MECIDS and MBDS and
help realize the greater goal of global health security. Lastly, as WHO is to be notified
only of public health events of international concern,7 discussions by regional mem-
bers may be useful in determining the notification threshold or procedures.
CORE CAPACITIES OF SURVEILLANCE AND RESPONSE
To build, maintain, or improve regional surveillance networks, it is important to have

a defined set of core capacities. Core capacities include the establishment of common
laboratory standards, an effective surveillance system (based on disease, syndromic,
or rumor reporting), and effective response capabilities (eg, contact tracing and mon-
itoring through field epidemiology). For example, each member state has to ensure
that it has the laboratory capacity to rapidly identify outbreaks;1,6 to do so, provisions
for technical support and extra resources for less-developed countries also are written
into the revised IHR (2005).1 The core response capacity requirements apply at all
public health response levels—from local to intermediate to national.9 Strengthening
national public health capacities contributes to improving national and international
readiness to detect, verify, investigate, and control disease outbreaks that have the
potential to spread internationally.7 Importantly, the revised IHR specify measures to

prevent disease spread at designated points of entry.6,9
Operational and technologic communications and trust across countries are central
tenets of regional surveillance networks. Moreover, each country’s particular
strengths can be leveraged across regional network partner nations. MECIDS and
MBDS have acted as catalysts for the introduction and spread of new communica-
tions and laboratory technologies. For example, MBDS members are working with
several international funding and technical partners to increase technical capacity
for surveillance and disease control through computing; high-speed Internet access
recently has been enhanced by the Trans-Eurasia Information Network 2 effort in
Vietnam. When Vietnam lacked such Internet capacity in 2006, Thailand facilitated
Vietnam’s participation in the multinational videoconference on pandemic prepared-
ness (organized by APEC Emerging Infections Network) by hosting the Vietnamese
representatives at their videoconference center. As another example, tabletop exer-
cises in individual MBDS countries and a regional MBDS exercise suggest that
each country has unique strengths that can be considered for application across
the region, such as electronic surveillance reporting in China; epidemiology training
in Thailand; laboratory capacity in Thailand, China, and Vietnam; community surveil-
lance in Cambodia; and government organization for national influenza preparedness
in Lao People’s Democratic Republic (PDR) (Dr. Moe Ko Oo, MBDS Coordinator, per-
sonal communication, 2008).
Given the focus on food safety in the Eastern Mediterranean,10 MECIDS has elected
to share food-borne disease information. Laboratory capacity has been reinforced
with the introduction of pulsed-field gel electrophoresis technology for pathogen
identification (eg, PulseNet). This effort has been facilitated through the MECIDS col-
laboration with donors, coordinated by GHSI (the World Bank, the government of the
United Kingdom, the Bill and Melinda Gates Foundation, the Nuclear Threat Initiative,
IBM, and Becton Dickenson). Financial and other forms of support were carefully used
to enhance capabilities, particularly in early detection and identification, and to bring
the partners’ differing capabilities to a level at which they can operate efficiently
together in sharing data and other cooperative activities. Thus, the regional network
provides a forum for sharing lessons learned and, over time, harmonizing such efforts
to assure systems (and operator) interoperability.
CORE COMPETENCIES OF SURVEILLANCE AND RESPONSE
Of equal importance to core capacities are core competencies, which entail appropri-
ate training of qualified workers and maintenance of necessary human resources.
Training in applied epidemiology, informatics, and laboratory methods for key surveil-
lance personnel is essential, and such training needs to be conducted at the frontline
level (eg, routine surveillance with regular reporting)11 and at the supervisory, senior
level (eg, field epidemiology training program [FETP] trainers and trainees). It is impor-
tant that the local frontline workers be included in surveillance, disease investigation,
and response training. Doing so empowers the community,1 evidenced by success
stories of local volunteer workers and disease control officers participating in surveil-
lance and response activities (eg, Thai avian influenza preparedness and response
system in response to human case from across the border in Lao PDR in early 2007).
The key to a strong surveillance and response system is effective training and
development of core competencies. More than 30 national FETPs around the world
are patterned after the United States Centers for Disease Control and Prevention
Epidemic Intelligence Service;12 a similar program, European Programme for
1466 Kimball et al
Intervention Epidemiology Training, is conducted in Europe.9,13 MECIDS partners are

establishing the Middle East Program for Interventional Epidemiology Training, follow-
ing the European model. Thailand has a mature FETP, which benefits its neighbors in
regional outbreak control. Surveillance competencies are central to these programs,
similar to competencies developed for applied epidemiologists in the United States.9
Given the rapidly evolving nature of modern surveillance approaches with links to
public health informatics, additional efforts are underway to include training in
technologic aspects of surveillance systems.9 These informatics skills are critical
emerging competencies for surveillance workers.9 At a practical level, imported
models must be tailored for local use and new solutions may be found by local
innovators as informatics skill levels increase. Thailand, for example, has taken the
lead in MBDS to create a Center of Excellence in Public Health Informatics in collab-
oration with the University of Washington.
MIDDLE EAST CONSORTIUM ON INFECTIOUS DISEASE SURVEILLANCE

AND MEKONG BASIN DISEASE SURVEILLANCE
MECIDS and MBDS illustrate that effective regional surveillance can be realized even
in difficult and disparate political environments. Both groups provide a forum to share
information, develop relationships, and build capacity, and they have proved effective
during recent regional outbreaks. These two networks have similar goals and focus on
many of the same threats to public health, yet their structures and the political climates
in which they exist are different.
The capitals of Jordan, Israel, and the Palestinian Authority are located within 80 km
of each other. The constant flow of goods, family ties among Palestinians residing in
the three countries, and human travelers that pass over their borders each day has led
Tulchinsky to refer to these inexorably related countries as one ‘‘epidemiologic fam-
ily’’.14 Before the Palestinian uprising (intifada), which began in 2000, a young but
healthy cooperation existed on health matters between Israel and the Palestinian
Authority. With the conflict, communication and collaboration came to be low profile
as far as public health issues were concerned.15,16 In this political climate, two inter-
national nongovernmental organizations, Search for Common Ground and the Global
Health and Security Initiative (GHSI), which operates within the Nuclear Threat Initia-
tive, facilitated the establishment of MECIDS in 2003. MECIDS is considered a unique
model of trilateral sustainable activity. This intergovernmental partnership among the
Ministries of Health in Jordan, Israel, and the Palestinian Authority has been effective
on many levels, including harmonizing diagnostic and reporting methodologies; com-
mon training; data sharing and analysis; improving detection and control of infectious
diseases; facilitating cross-border communication; dealing with avian influenza
outbreaks in the three countries;15 and, finally, creating the potential for the trust
and cooperation fostered through this collaboration to translate into cooperation on
other issues.17
Using the layered structure of the public health services in each of its member
countries, MECIDS currently gathers data on food-borne illnesses caused by two
pathogens, salmonella and shigella, at the district, national, and international levels.
At the district level, a network of clinical laboratories covers the many districts of
each country; the national level includes a national center for disease control and a na-
tional laboratory; and the international level consists of one regional health information
center—the Cooperative Monitoring Center in Amman, Jordan. National centers for
disease control collect data from their district laboratories and report important infor-
mation to the regional center in Amman. This hierarchic architecture allows for
systematic disease reporting that helps identify potentially dangerous situations be-
fore they become serious epidemics.18
The second example of regional surveillance is MBDS, a collaboration between
Cambodia, China (Yunnan and Guangsi provinces), Lao PDR, Myanmar, Thailand,
and Vietnam. Southeast Asia experienced intense conflict during the Cold War era
but has since made enormous strides toward peace and economic development.
Implementation of trade liberalization policies, such as the Association of Southeast
Asian Nations Free Trade Area, the Ayeyawady-Chao Phraya-Mekong Economic Co-
operation Strategy, and the entry of Vietnam and Thailand into APEC, have greatly in-
creased the ease with which goods, services, and capital flow throughout the
region.19 With support from the Rockefeller Foundation, WHO, and other organizations,
MBDS was established in 1999 to deal with the public health challenges of high-volume
regional trade and travel. Its activities include epidemiologic training, cross-border ex-
change of information, joint epidemic response and investigation, and joint tabletop ex-
ercises on pandemic influenza preparedness.20 Because some MBDS member
countries belong to WHO’s Western Pacific region (Cambodia, China, Lao PDR, and
Vietnam) whereas others belong to the Southeast Asian region (Myanmar and Thailand),
coordination under the WHO umbrella adds some bureaucratic burden. Based on trust
and close friendships, built through many years of interactive learning and collective ac-
tion, MBDS has played an important role in filling this bureaucratic gap.
MBDS uses a reporting structure that links countries at the national, provincial, dis-
trict, community, and village levels. Members have established communication links at
parallel levels and rely on a system of periodic reports and cross-border meetings to
facilitate information exchange and build trust between parties.21,22 Dr. Suwit Wibul-
polprasert, active member and former MBDS Executive Board Chair, commented,
‘‘This network is an excellent example of effective implementation of the International
Health Regulations, with rapid formal and informal reporting of diseases of public
health emergencies across borders’’.20
The stability of the Southeast Asian region allows for a formal partnership between
countries of the Mekong Basin; the legal basis of MBDS is two memoranda of under-
standing signed by the ministers of health from the six countries. This organizational
architecture creates a strong and durable partnership that has well-defined responsi-
bilities and expectations. In contrast to MBDS, the volatile political situation among
MECIDS countries has led to an informal memorandum of understanding agreement
among partners. It is not bound by a formal decision-making process and, therefore,
has the freedom and flexibility to respond quickly to changing priorities in infectious
disease control.
MECIDS and MBDS have been tested by disease outbreaks. MECIDS, originally
established to monitor food-borne infections, has provided a robust platform to
broaden surveillance activities to include other serious emerging infections, such as
avian influenza H5N1.17 Avian influenza among poultry hit the region in March 2006,
and although MECIDS had been active for only 3 years, the reporting system, open
lines of communication, and cooperative control measures proved essential in mitigat-
ing the impact of the outbreak. The revised IHR, although initial implementation was
not required until June 15, 2007, were put into practice by a joint decision among
MECIDS partners and shown to be effective.15 In 2007, MECIDS partners conducted
a workshop on the implications of the revised IHR in pandemic influenza
preparedness.
The year 2007 saw a large increase in the number of cholera cases in Northern Thai-
land and Southeastern Myanmar, with 877 cases resulting in seven deaths. From June
to August 2007, an outbreak of cholera El Tor Inaba (344 confirmed cases) occurred in
1468 Kimball et al
Tak province, one of Thailand’s northern provinces that borders Myanmar. As one fifth
of the cases were found in migrant workers from Myanmar, the Thai MBDS country
coordinator, who acts as the IHR focal point, informed his Myanmar counterpart.
The source of the illnesses was not identified in this outbreak and officials of both
countries in the border area responded by encouraging citizens to follow proper
hand-washing procedures and boil their water. From mid-September to October of
the same year, an outbreak of cholera El Tor Ogawa (235 confirmed cases) occurred
in 12 provinces of the northeastern region of Thailand and crossed the border into
Vientiane, Lao PDR. The disease control officer of Lao PDR notified WHO and the
Thai MBDS counterpart. In this instance, with an increased disease surveillance and
response effort, the Thai FETP and the surveillance rapid response team of several
affected provinces, in collaboration with the Laotian authorities, were able to trace
the infection to uncooked blood cockles. Identifying the source of the outbreak was
a major factor in reducing illness and protecting public health.
The successful ongoing collaboration within MECIDS and MBDS provide two
examples of effective regional surveillance systems implemented in areas historically,
and even currently, embroiled in conflict. As Leventhal and colleagues15 argue, ‘‘Irre-
spective of political circumstances, the common threat of an emerging infectious
disease serves as an opportunity to bridge disputes and focus on humanitarian and
health matters for the common good of all bordering countries.’’ WHO23 maintains
that international partnerships are essential in implementing the revised IHR; there-
fore, finding common ground in regions of conflict is especially important as it pro-
motes health cooperation in areas where it is most lacking.
SUSTAINING EFFECTIVE REGIONAL SURVEILLANCE NETWORKS
To maintain surveillance core capacities and competencies, collaborative partner-

ships are critical and long-term investment strategies are needed. Supporting regional
surveillance programs can be an efficient way for external partners to help resource-
poor countries develop their own national surveillance infrastructure.1 And, regional
initiatives investing in surveillance programs on emerging infectious diseases may
directly help developing countries meet the revised IHR’s new core requirements.1
These networks have the potential to enhance the transnational capacity for disease
response (shown in Fig. 2).
Today, an increasing number of private sector foundations with a public health
focus are funding disease surveillance programs in limited resource settings.9 Such
enhanced support can greatly assist in sustaining the core capacities and competen-
cies necessary for successful regional surveillance networks. Public-private partner-
ships for infectious disease surveillance are becoming increasingly common. An
encouraging effort has begun, with support from the Rockefeller Foundation and
GHSI, to develop a process for the various operating and nascent regional infectious
disease surveillance systems to share best practices on issues, such as governance
and the technical aspects of cross-border surveillance.22 This effort should have the
effect of bringing more government and private sector resources into infectious
disease surveillance capabilities, which, if sustained, will bring about an increase in
overall global surveillance capacity. This complements the essential and more top-
down efforts of the WHO’s strategy for epidemic alert and response that also relies
on collaborative partners, including WHO Collaborating Centres, nongovernmental
organizations, and industry.7 Countries, therefore, will benefit from the renewed
impetus to strengthen national capacity in surveillance and response and from the
Fig. 2. Implementation of transnational disease response.
enhanced access to international investors interested in improving health in countries

across the world, in the interest of global health and security.7
SUMMARY
The revised IHR (2005) encourage a new paradigm of global public health intelligence.
With mandatory reporting procedures and requirements for building surveillance and
response capacity, the revised IHR are a move toward more effective global health se-
curity. The revised regulations have broadened and diversified the effort for global in-
fectious disease control. This article has addressed the rise of regional networks and
focused on how two such networks have contributed to the implementation of the IHR.
Specifically, through hosting regional workshops for IHR implementation, introducing
and implementing communications and laboratory technologies in member countries,
responding to regional outbreak events, and linking field investigation efforts to
response, the networks have moved their member groups closer to the implementa-
tion goal. Far from diminishing the abilities of fragile public health systems, these
networks have reinforced operational competence.
In resource-poor settings and regions of political instability, the need for coopera-
tion is even more urgent. The examples of MBDS and MECIDS illustrate the benefits
of regional cooperation, communication, and trust building. They demonstrate that
historical conflict, and even current political strife, can be overcome by focusing on
common interests. The trust and communication MECIDS and MBDS partners built
were a foundation for upgrading the infectious disease surveillance systems in each
country, in terms of training personnel and purchasing laboratory and information
technology equipment. Through successful communication and capacity building,
these networks have effectively responded to disease outbreaks (eg, MECIDS’s re-
sponse to the 2006 outbreak of avian influenza and MBDS’s response to the cholera
outbreaks of 2007) and increased their ability to address future emerging infectious
1470 Kimball et al
disease threats. As is true with MBDS and MECIDS, regional networks have greater
access to international investors whose objectives are to strengthen the health of
recipient countries while also improving overall global health security. Investment is
a key concept in the new paradigm; it is an idea that the return on an investment in
surveillance capacity and cross-border cooperation is the improved health of all
nations and all global citizens. The revised IHR (2005) provide the impetus for change,
and regional networks are one important way of achieving that change.
ACKNOWLEDGMENTS
The authors would like to thank Ms. Alicia Silva-Santisteban for her administrative
support.
REFERENCES
1. Calain P. From the field side of the binoculars: a different view on global public
health surveillance. Health Policy Plan 2007;22(1):13–20.
2. Faye B, Lancelot R. Ecopathological approach in tropical countries: a challenge
in intensified production systems. Ann N Y Acad Sci 2006;1081:137–46.
3. Daulaire N. Beyond trade: taking globalization to the health sector. New Solut
2003;13(1):67–71.
4. Jones KE, Patel NG, Levy MA, et al. Global trends in emerging infectious dis-
eases. Nature 2008;451(7181):990–3.
5. Lederberg J, Shope R, Oaks SJ, editors. Emerging infections: microbial threats to
health in the United States. Washington, DC: National Academy Press; 1992.
6. Public-health preparedness requires more than surveillance. Lancet 2004;
364(9446):1639–40.
7. Hardiman M. The revised International Health Regulations: a framework for global
health security. Int J Antimicrob Agents 2003;21(2):207–11.
8. Calain P. Exploring the international arena of global public health surveillance.
Health Policy Plan 2007;22(1):2–12.
9. Mikanatha N, Lynfield R, Van Beneden C, et al. Infectious disease surveillance.
Malden (MA): Blackwell Publishing Ltd; 2007.
10. Elmi M. Food safety: current situation, unaddressed issues and the emerging pri-
orities. East Mediterr Health J 2004;10(6):794–800.
11. Durrheim DN, Speare R. Communicable disease surveillance and management
in a globalised world. Lancet 2004;363(9418):1339–40.
12. Thacker SB, Dannenberg AL, Hamilton DH. Epidemic intelligence service of the
Centers for Disease Control and Prevention: 50 years of training and service in
applied epidemiology. Am J Epidemiol 2001;154(11):985–92.
13. White ME, McDonnell SM, Werker DH, et al. Partnerships in international applied
epidemiology training and service, 1975–2001. Am J Epidemiol 2001;154(11):
993–9.
14. Tulchinsky T. One epidemiologic family changing disease patterns and the health
status of the Palestinian population of the west bank and gaza. In: Barnea T,
Husseini R, editors. Separate and cooperate, cooperate and separate. Ports-
mouth (UK): Greenwood Publishing Group; 2002.
15. Leventhal A, Ramlawi A, Belbiesi A, et al. Regional collaboration in the Middle
East to deal with H5N1 avian flu. BMJ 2006;333(7573):856–8.
16. Leventhal A, Melville L, Berry EM. Public health education in a conflict area:
a report from Israel. Lancet 2003;361(9364):1222.
17. Global Health and Security Initiative. Middle east consortium on infectious dis-
ease surveillance (MECIDS). Available at: http://www.ghsi.org/projects/mecids.
html. Accessed March 12, 2008.
18. Leventhal A, Cohen D, Bassal R, et al. Public health affinity domain (PHAD)—
regional cooperation in the middle east: Israel, Jordan and the Palestinians.
Healthcare and life sciences seminar 2007. Israel: Haifa; 2007.
19. Severino R. Building the peace in southeast Asia. The fourth high-level meeting
between the united nations and regional organizations on cooperation for
peace-building. New York: United Nations; 2001.
20. Mekong Basin Disease Surveillance Network Signs New Memorandum Of Agree-
ment At The World Health Assembly. Maximnews. May 28, 2007.
21. Oo M. Strengthening national capacities for epidemic preparedness and
response in support to national implementation of IHR (2005). WHO Meeting.
Lyon, France; May 2–5, 2006.
22. Oo M, Touch S. Public Health Surveillance: learning from regional network
diplomacy, science and technology. Bellagio call for action. Bellagio (Italy):
Global Health and Security Initiative; 2007.
23. WHO. The World Health Report 2007—a safer future: global public health
security in the 21st century. Geneva (Switzerland): WHO; 2007.
Dis eas e Emergence
from Global Climate
a nd L a nd Us e Cha nge
Jonathan A. Patz, MD, MPHa,b,*, Sarah H. Olson, BSa,b,
Christopher K. Uejio, MSa, Holly K. Gibbs, PhDa
KEYWORDS
Climate change Global warming Emerging diseases
Deforestation Malaria Urbanization
From the years 1906 to 2005, global average temperature has warmed by 0.74 C, and
since 1961, sea level has risen on average by approximately 2 mm per year.1 Arctic
sea ice extent has declined by 7.4% per decade and snow cover and glaciers have
diminished in both hemispheres. The rate of change in climate is faster now than in
any period in the last 1000 years. According to the United Nations Intergovernmental
Panel on Climate Change, in 90 years, average global temperatures will increase
between 1.8 C and 4.0 C and sea level will rise between 18 and 59 cm (Fig. 1).
Extremes of the hydrologic cycle (eg, floods and droughts) are also expected to
accompany global warming trends.
The global rate of tropical deforestation continues at staggering levels, with nearly
2% to 3% of global forests lost each year. Land use change for agriculture represents
the largest driver of land cover change across the earth. Together, croplands and pas-
tures have become one of the largest terrestrial biomes on the planet, rivaling forest
cover in extent, and occupying w40% of the land surface.2,3
Emergence or resurgence of numerous infectious diseases are strongly influenced
by environmental factors such as climate or land use change. The most sensitive dis-
eases are those that are indirectly transmitted, that is, those requiring either a vehicle
for transfer from host to host (eg, water- and food-borne disease) or an intermediate
host or vector as part of its life cycle. Most vector-borne diseases involve arthropod
vectors, such as mosquitoes, flies, ticks, or fleas. Because insects are cold blooded,
a marginal change in temperature can have a potentially large biologic effect on
a
Global Environmental Health, Center for Sustainability and the Global Environment (SAGE)
Nelson Institute for Environmental Studies, University of Wisconsin (at Madison), 1710
University Avenue, Madison, WI 53726, USA
b
Department of Population Health Sciences, University of Wisconsin (at Madison) 1710
University Avenue, Madison, WI 53726, USA
* Corresponding author. Global Environmental Health, Center for Sustainability and the Global
Environment (SAGE) Nelson Institute for Environmental Studies, University of Wisconsin (at
Madison), 1710 University Avenue, Madison, WI 53726.
E-mail address: patz@wisc.edu (J.A. Patz).
Med Clin N Am 92 (2008) 1473–1491

1474 Patz et al
Fig.1. Observed trends in global temperature, sea level, and extent of Northern Hemisphere
snow cover. (From IPCC. Climate change 2007: impacts, adaptation and vulnerability: contri-
bution of Working Group II to the Fourth Assessment Report of the IPCC. Cambridge (UK):
Cambridge University Press; 2007; with permission.)
disease transmission. Therefore, climate change can alter the incidence, seasonal
transmission, and geographic range of diseases such as malaria, dengue and yellow
fever (mosquitoes), leishmaniasis (sand flies), Lyme disease (ticks), and
onchocerciasis or ‘‘river blindness’’ (black flies). Schistosomiasis (involving water
snails as the intermediate hosts) is also influenced by water temperature.4
CLIMATE EFFECTS ON WATER- AND FOOD-BORNE DISEASES

Waterborne Diseases
Heavy rainfall events can increase risk for waterborne disease outbreaks. Existing
seasonal contamination of surface water in early spring in North America and Europe
may explain some of the seasonality of many waterborne diseases. According to the
North American chapter of the most recent Intergovernmental Panel on Climate
Change (IPCC)1 report, heavy precipitation events are expected to increase under cli-
mate change scenarios.
Preliminary analysis from the authors’ research shows that overall, climate
models project that these extremely heavy precipitation events will become 10%
Disease Emergence from Global Climate and Land Use 1475
to 40% stronger in southern Wisconsin, resulting in greater potential for the flooding
and waterborne diseases that often accompany high discharge into Lake
Michigan.5
Community water systems are already overwhelmed by extreme rainfall events.
Runoff can exceed the capacity of the sewer system or treatment plants, and these
systems are designed to discharge the excess wastewater directly into surface water
bodies.6,7 Urban watersheds experience more than 60% of the annual loads of all con-
taminants during storm events.8 Turbidity also increases during storm events, and
studies have linked turbidity and illness in many communities.9,10
Waterborne disease outbreaks from all causes in the United States are distinctly
seasonal, clustered in key watersheds, and associated with heavy precipitation.11 In
Walkerton, Ontario, in May 2000, heavy precipitation combined with failing infrastruc-
ture contaminated drinking water with Escherichia coli 0157:H7 and Campylobacter
jejuni, resulting in an estimated 2300 illnesses and seven deaths.12
Intense rainfall can also contaminate recreational waters and increase the risk for
human illness13 through higher bacterial counts. This association is strongest at the
beaches closest to rivers.14 Involvement of the respiratory tract, ears, nose, and throat
and gastrointestinal illnesses are commonly associated with recreational swimming in
fresh and salt waters. High-risk groups for exposure to pathogens include frequent
water users such as lifeguards or water sport enthusiasts, whereas young children,
the elderly, pregnant women, and the immunocompromised have the greatest risk
for suffering serious complications.15,16 Population trends in the United States toward
an older and more immunocompromised population suggest that the United States’
vulnerability to waterborne pathogens will continue to increase.
Pathogens tend to co-occur with indicator bacteria but indicators are prone to false-
positive readings. Indicator bacteria may survive in soil sediments or beach sand,
resuspended during a precipitation event, and confound waterborne disease risk
estimates.17–19 E coli indicator bacteria are influenced by precipitation events up to
a week before sample collection, although recent precipitation (0–3 days) tends to
exhibit the strongest relationships with their numbers.11 The spacing of rainfall events
can also increase pollutant accumulation and subsequent loading into water bod-
ies.20,21 Longer interval processes such as the El Niño Southern Oscillation (ENSO)
strongly influence interannual precipitation and therefore must be taken into account.
During periods of heavy precipitation, Cryptosporidium parvum, a protozoan asso-
ciated with domestic livestock, can readily contaminate drinking water. The 1993
cryptosporidiosis outbreak in Milwaukee killed more than 50 people and potentially
exposed more than 400,000; this epidemic coincided with unusually heavy spring
rains and runoff from melting snow.22 The authors’ review of all-cause waterborne dis-
ease outbreaks in the United States over a 50-year period demonstrated a distinct
seasonality, a spatial clustering in key watersheds, and a strong association with
heavy precipitation.11
Marine organisms
In warm marine waters, Vibrio species proliferate. Copepods (or zooplankton), which
feed on algae, can serve as reservoirs for Vibrio cholerae and other enteric pathogens.
In Bangladesh, for example, cholera follows seasonal warming of sea surface
temperature that can enhance plankton blooms.23 After including intrinsic host immu-
nity factors, interannual variability of cholera is strongly correlated to (1) sea surface
temperatures in the Bay of Bengal; (2) ENSO; (3) the extent of flooding in Bangladesh
across short time periods (<7 years), and (4) monsoon rains and Brahmaputra river dis-
charge, for longer-period climate patterns (>7 years).24 ENSO has had an increasing
1476 Patz et al
role in explaining cholera outbreaks in recent years, perhaps because of concurrent

climate change.25
Similarly, during the 1997 to 1998 El Niño event, winter temperatures in Lima
increased more than 5 C above normal, and the number of daily admissions for diar-
rhea increased by more than 200% compared with expected levels based on the prior
5 years.26 For every degree centigrade rise in air temperature above normal, an 8%
increase in hospital admissions for childhood diarrhea was observed (Fig. 2).
Food-Borne Diseases
Some food-borne diseases are impacted by fluctuations in temperature. An estimated
30% of reported cases of salmonellosis across much of continental Europe have been
attributed to warm temperatures, especially when they exceed a threshold of 6 C
above average.27 Monthly incidence of food poisoning in Britain is most strongly
associated with temperatures of the previous 2 to 5 weeks.28 Other food-borne
agents, such as campylobacter, are also seasonal but are not as strongly linked to
temperature fluctuations.
MALNUTRITION RISKS
Global climate change is expected to cause extremes of the hydrologic cycle (more
floods and droughts). Droughts will exacerbate malnutrition, still one of the world’s
largest health challenges, with 800 million undernourished.29 Climate extremes have
direct impacts on food crops and can indirectly influence food supply by altering
the ecology of plant pathogens, and higher soil temperatures can promote fungal
growth that kills seedlings. According to the IPCC, reduced yields will occur
throughout the tropics because of heat stress, and crops can be damaged from flood-
ing, erosion, and wildfires.1 Malnutrition increases the risk for death from infectious
diseases, especially diarrhea, and micronutrient deficiencies are related to drought.
Fig. 2. Daily hospitalizations for diarrhea, by daily temperature, Lima, Peru. Top graph shows
hospital admission over time for childhood diarrhea in Lima, Peru. Bottom graph is ambient
temperature for Lima. Note the marked seasonality of disease incidence, and that during
the winter of 1997–98, a strong El Niño (shaded region) made winter temperatures 5 C
above normal, associated with a higher than expected incidence of diarrheal disease. For
every 1 C rise in ambient temperature, admissions increased by 8%. (From Checkley W, Ep-
stein LD, Gilman RH, et al. Effect of El Nino and ambient temperature on hospital admissions
for diarrhoeal diseases in Peruvian children. Lancet 2000;355:442–50; with permission.)
Although malnutrition is complex in cause, one study has estimated that by the 2050s,
climate change will increase the percentage at risk for hunger from a current 34% to
a level of 64% to 72%, unadjusted for potential adaptive interventions.30
Droughts also can increase diarrhea and diseases such as scabies, conjunctivitis,
and trachoma that are associated with poor hygiene and result from a breakdown in
sanitation if water resources become depleted.31
Biofuels and Malnutrition?

The global biofuel industry is growing rapidly as rising oil prices and government
mandates encourage increased production of these alternative fuels. Global biofuel
production may quadruple within the next 15 to 20 years32–34 and it has already
been implicated in changing world food supplies and price.35 Rising prices for food
staples resulting from an unregulated biofuels boom could place undue burden on
poor or malnourished populations in a potential scenario. According to one estimate,
for every percentage increase in the real prices of staple foods, 16 million more
people could become food insecure.36 Further, the amount of humanitarian food aid
available for extremely impoverished countries will be affected in the short term
because food aid shipments from the United States are inversely correlated to
commodity prices.37
Demand for crop-derived ethanol or biodiesel also could have devastating effects
on the fate of the world’s tropical forests. Expansion of the leading biofuel crops is
already evident in South America and insular Southeast Asia as large-scale fields of
soybean and oil palm, respectively, expand in these regions, leading to forest clearing,
expulsion of subsistence farmers, and large emissions of carbon dioxide to the atmo-
sphere.38–41 The authors’ center has found that most recently expanding oil palm
fields have replaced forests in parts of Malaysia and Indonesia and that increases in
soybean production in Brazil coincide with more forest conversion (Gibbs, unpub-
lished data, 2008).
CLIMATE VARIABILITY AND CHANGE EFFECTS ON VECTOR-BORNE DISEASES
The transmission dynamics and geographic distribution of most insect- or rodent-

borne (vector-borne) diseases are highly climate sensitive. Vector-borne pathogens
spend part of their life cycle in cold-blooded arthropods that are subject to many
environmental factors. Changes in weather and climate that can affect transmission
of vector-borne diseases include temperature, rainfall, wind, extreme flooding or
drought, and sea level rise. Rodent-borne pathogens can be affected indirectly by
ecologic determinants of food sources affecting rodent population size, and floods
can displace and lead them to seek food and refuge. See Box 1. The extrinsic incuba-
tion time of an infective agent within its vector organism is typically sensitive to
changes in temperature and humidity.42 Some examples of temperature thresholds
are included in Table 1.
Malaria
Malaria kills between 700,000 and 2.7 million persons each year, mostly children in
sub-Saharan Africa.43 Although malaria’s resurgence involves multiple factors,
from climate and land use change to drug resistance, variable disease-control ef-
forts, and other sociodemographic factors, malaria is an extremely climate-sensitive
tropical disease, and one of the most important climate change/health questions to
resolve.44
1478 Patz et al
Box 1
Effects of weather and climate on vector- and rodent-borne diseasesa
Examples of temperature effects on selected vectors and vector-borne pathogens

Vector
Survival can decrease or increase, depending on the species.
Some vectors have higher survival at higher latitudes and altitudes with higher temperatures.
Changes are possible in the susceptibility of vectors to some pathogens (eg, higher
temperatures reduce the size of some vectors but reduce the activity of others).
Changes occur in the rate of vector population growth.
Changes occur in feeding rate and host contact (which may alter the survival rate).
Changes occur in the seasonality of populations.
Pathogen
Extrinsic incubation period of pathogen is decreased in vector at higher temperatures,
Changes occur in the transmission season.
Changes occur in distribution.
Viral replication is decreased.
Examples of effects of changes in precipitation on selected vector-borne pathogens
Vector
Increased rain may increase larval habitat and vector population size by creating a new habitat.
Excess rain or snow pack can eliminate habitat by flooding, thus decreasing the vector
population size.
Low rainfall can create habitat by causing rivers to dry into pools (dry season malaria).
Decreased rain can increase container-breeding mosquitoes by forcing increased water
storage.
Epic rainfall events can synchronize vector host seeking and virus transmission.
Increased humidity increases vector survival; decreased humidity decreases vector survival.
Pathogen
Few direct effects are evident but some data indicate humidity effects on malarial parasite
development in the anopheline mosquito host.
Vertebrate host
Increased rain can increase vegetation, food availability, and population size.
Increased rain can also cause flooding and decrease population size but increase contact with
humans.
Decreased rain can eliminate food and force rodents into housing areas, increasing human
contact, but it can also decrease population size.
Increased sea level
Increased levels alter estuary flow and change existing salt marshes and associated mosquito
species, decreasing or eliminating selected mosquito breeding sites (eg, reduced habitat for
Culiseta melanura).
a
The relationship between ambient weather conditions and vector ecology is complicated by
the natural tendency for insect vectors to seek out the most suitable ‘‘microclimates’’ for their
survival (eg, resting under vegetation or pit latrines during dry or hot conditions or in culverts
during cold conditions).
From Gubler DJ, Reiter P, Ebi KL, Yap W, Nasci R, Patz JA. Climate variability and change in the
United States: potential impacts on vector- and rodent-borne diseases. Environ Health Perspect
2001;109:223–33; with permission.
Table 1
Temperature thresholds of pathogens and vectors
Tmin for
Disease Pathogen Tmin Tmax Vector Vector
Malaria Plasmodium 16–19 33–39 Anopheles 8–10 biologic
falciparum activity
Malaria Plasmodium 14.5–15 33–39 Anopheles 8–10 biologic
vivax activity
Chagas Trypanosoma 18 38 Triatomine 2–6 survival
disease cruzi bugs 20 biologic
activity
Schistosomiasis Cercaria 14.2 >37 Snails (Bulinus 5 biologic activity
and others) 252 optimum
range
Dengue Dengue 11.9 Not Aedes 6–10
fever virus known
Lyme Borrelia No yet determined Ixodes ticks 5–8
disease burgdorferi
Tmin is the minimum temperature required for disease transmission. Tmax for the pathogen is the
upper threshold beyond which temperatures are lethal. Tmax for vectors are not provided. Temper-
atures in C. Note: temperatures assume optimum humidity, vector survival decreases rapidly as
dryness increases. Considerable variation exists in these thresholds within and among species.
Sources: Purnell, 1966; Pfluger, 1980; Molineaux, 1988; Curto de Casas and Carcavallo, 1984; Rue-
da et al, 1990.
Reprinted from IPCC. Climate change 2007: impacts, adaptation and vulnerability: contribution
of Working Group II to the Fourth Assessment Report of the IPCC. Cambridge (UK): Cambridge Uni-
versity Press; 2007; with permission.
Malaria incidence varies seasonally in highly endemic areas, and malaria transmis-
sion has been associated with temperature anomalies in some African highland
areas.45 In the Punjab region of India, excessive monsoon rainfall and resultant high
humidity have been recognized for years as major factors in the occurrence of malaria
epidemics. Malaria epidemics have increased approximately fivefold during the year
following an El Niño event46 and recently, indices of El Niño–related climate variability
predicted malaria incidence in Botswana.47
Special case of malaria in the African highlands

For every 1000-meter gain in elevation, temperatures decrease by 6 C. Minimum tem-
perature for parasite development of Plasmodium falciparum and Plasmodium vivax
approximates 18 C and 15 C, respectively, limiting the spread of malaria at higher al-
titudes. Increasing altitude also results in decreasing mosquito abundance in African
highlands.48
A warming trend from 1950 to 2002 was documented in the East African highlands,
coinciding with increases in malaria incidence.49 Well-recognized nonlinear and
threshold responses of malaria (a biologic system) are established for regional temper-
ature fluctuations. As a biologic system, the response of mosquito populations to
warming can be more than an order of magnitude larger than the measured change
in temperature; just half a degree centigrade increase in temperature trend can trans-
late into a 30% to 100% increase in mosquito abundance, demonstrating a ‘‘biologic
amplification’’ of temperature effects. In the African highlands, where mosquito pop-
ulations are small compared with lowland areas,50 such biologic responses may be
especially significant in determining the risk for malaria.
1480 Patz et al
Arboviruses
Dengue fever
The peridomestic urban mosquito, Aedes aegypti, is also strongly influenced by
climate, including variability in temperature, moisture, and solar radiation. Similar to
the extrinsic incubation period of the malaria parasite, the rate of dengue virus
replication in A aegypti mosquitoes increases directly with temperature in the labora-
tory. When linked to future climate change projections, biologic models of dengue
transmission suggest that small increases in temperature, given viral introduction
into a susceptible human population, could increase the potential for epidemics.51
For small countries with presumably some climate uniformity, a climate-based Aedes
mosquito population model strongly correlates climate conditions with the variability in
dengue cases reported at the national level.52
West Nile virus

Climate variability has an effect on West Nile virus (WNV), a disease that rapidly spread
across the Western hemisphere. Reisen and colleagues53 found that the strain of WNV
that entered New York (during the record hot July of 1999) differed from the South
African strain in that it required warmer temperatures for efficient transmission. The
investigators concluded that during the epidemic summers of 2002 and 2004 in the
United States, epicenters of WNV were linked to above-average temperatures. Tem-
perature influences other important components of the WNV transmission cycle, such
as the development rate and fitness of immature mosquitoes and the biting rate and
survival of adult female mosquitoes.54–58 Anomalously hot summer temperatures
are also linked to international WNV outbreaks in South Africa and Russia.59–61
Variability of precipitation may affect WNV transmission by (1) inducing a large
increase in disease-transmitting mosquito abundance or (2) killing mosquito predators
and competitors (3) vector–avian host contact. Multiple North American WNV vector
mosquito population sizes tend to mirror the total amount of summer season precip-
itation.62–65 Above-average summer precipitation likely activates new larval breeding
habitats and temporarily increases the number of disease vectors, which may increase
the level of WNV transmission. This mechanism appears to be behind the 1974 South
African WNV epidemic, which infected more than 18,000 people.60 In the United
States, below-average rainfall the previous year tended to increase WNV transmission
the following year.66 Drought over multiple time periods has inconsistently been
reported as a potential driver of multiple individual WNV outbreaks.61,67,68 Disease-
transmitting mosquito populations recover more rapidly than mosquito competitors
and predators from a disturbance like drought, which may increase disease transmis-
sion.69 In humid Florida, spring drought increases vector and avian host contact and
WNV transmission, and wet summer conditions foster mosquito dispersal and subse-
quent disease transmission.70
Similar to WNV, Saint Louis encephalitis virus (SLEV) is also associated with climatic
factors. In Florida, SLEV appearance in sentinel chicken flocks is preceded by a wet
period followed by drought.
Chikungunya
During July 2004, amidst a severe drought in East Africa, an epidemic of chikungunya
virus erupted in Lamu, Kenya, where an estimated 13,500 people (75% of the popu-
lation) were infected.71 Climate analysis showed that unseasonably warm and dry
conditions, especially over coastal Kenya, occurred during May 2004.72 Such condi-
tions may have (1) led to unsafe domestic water storage practices and infrequent
changing of water storage and (2) hastened viral development in the Aedes mosquito.
The virus spread to islands of the western Indian Ocean, then to India, and most
recently to Italy during the summer of 2007. Although the role of climatic conditions
in Italy is not clear, southern Europe was experiencing an unusually warm and dry
summer.73
Rift valley fever

All known Rift Valley fever virus outbreaks in East Africa from 1950 to May 1998, and
probably earlier, followed periods of abnormally high rainfall. Analysis of this record
and Pacific and Indian Ocean sea surface temperature anomalies, coupled with satel-
lite normalized difference vegetation index data, shows that prediction of Rift Valley
fever outbreaks may be made up to 5 months in advance of outbreaks in East Africa.
Concurrent near–real-time monitoring with satellite normalized difference vegetation
data may identify actual affected areas.74
Dams and irrigation can increase breeding sites, exacerbating the effect of extreme
rainfall. Extensive human disease outbreaks were not reported until 1951, when an
estimated 20,000 persons were infected during an epidemic in cattle and sheep in
South Africa. Outbreaks were reported exclusively from sub-Saharan Africa until
1977–78, when 18,000 persons were infected and 598 deaths were reported in
Egypt.75
Lyme Disease
Lyme disease is a prevalent, tick-borne disease in North America that new evidence
suggests has an association with temperature76 and precipitation.77 In the field, tem-
perature and vapor pressure contribute to maintaining populations of the tick Ixodes
scapularis which, in the United States, is the microorganism’s secondary host.
A monthly average minimum temperature above 7 C is required for tick survival.78
The northern boundary of tick-borne Lyme disease is limited by cold temperature
effects on the tick, I scapularis. The northern range limit for this tick could shift north
by 200 km by the 2020s, and 1000 km by the 2080s (based on projections from the
CGCM2 and HadCM3 atmosphere-ocean global circulation models under the Special
Report on Emissions Scenarios A2 emissions scenario).79
Rodent-Borne Diseases
For hantavirus pulmonary syndrome, which newly emerged in the Southwest in 1993,
weather conditions led to a growth in rodent populations and subsequent disease
transmission, all following unusually heavy El Niño–driven rainfall.80 Hantavirus infec-
tions are transmitted largely by exposure to infectious excreta, and may cause serious
disease in humans and a high fatality rate.
Extreme flooding or hurricanes can lead to outbreaks of leptospirosis. In Nicaragua,
for example, an epidemic of leptospirosis followed heavy flooding in 1995. From
a case-control study, a 15-fold risk for disease was associated with walking through
flooded waters.81
Plague is another climate-sensitive disease that is carried by fleas, and it is associ-
ated with populations of rodents, the primary reservoir hosts of the Yersinia pestis bac-
terium. In the desert southwestern United States, plague bacterial levels in rodents
have been found to increase in the wake of wet climate conditions following El Niño
and Pacific Decadal Oscillation–driven wet weather conditions.82 Historically, accord-
ing to tree-ring proxy climate data, during the major plague epidemics of the Black
Death period (1280–1350), climate conditions were becoming warmer and wetter.83
1482 Patz et al
Other Vector-Borne Diseases and Climate

Bluetongue
Bluetongue disease, a viral illness that is fatal to sheep and other ruminants, is spread
by Culicoides spp (midges) and historically, only rarely reached north into Europe. But
since 1998, several strains of bluetongue virus have advanced 800 km further into
Europe than previously reported. Warming temperatures in the region have allowed
enhanced survival of viruses through winter and a northern expansion of the insect
vector of the disease.84 Warmer winter temperatures projected for the future may fur-
ther the geographic range of this serious livestock disease; the warm temperatures of
2007 already have allowed establishment of bluetongue in Northern Europe (Fig. 3).85
LAND USE CHANGE AND DISEASE EMERGENCE
Disturbance of habitats due to land cover change is likely the largest environmental
cause of altered risk for infectious diseases. Habitat change, in turn, may affect the
breeding sites of disease vectors or the biodiversity of vectors or reservoir hosts.
Major drivers of land use change include agricultural development or water projects,
urbanization and sprawl, and deforestation. These changes, in turn, cause a cascade
of factors that exacerbate infectious disease emergence, such as forest fragmenta-
tion, pathogen introduction, pollution, poverty, and human migration. These issues
are important but complex and are only understood for a few diseases. For example,
recent research has shown that forest fragmentation, urban sprawl, and loss of biodi-
versity are linked to increased Lyme disease risk in the northeastern United States.86
Fig. 3. Map of bluetongue virus (BTV) across the European Union. The molecular epidemiology
of BTV since 1998: routes of introduction of different serotypes and individual virus strains. The
presence of BTV-specific neutralizing antibodies in animals in Bulgaria is shown, but the
presence of BTV serotype 8 cannot yet be confirmed. (From Saegerman C, Berkvens D, Mellor
PS. Bluetongue epidemiology in the European Union. Emerg Infect Dis 2008;14:539–44; with
permission.)
Agricultural Development
Land use change for agricultural expansion represents the largest driver of land cover
change across the earth, and has continued to be the dominant cause of tropical
deforestation well into this decade.87 Together, croplands and pastures have become
one of the largest terrestrial biomes on the planet, rivaling forest cover in extent, and
occupying w40% of the land surface.2,3 The area of cultivated land is expected to in-
crease dramatically across the tropics because of unprecedented increases in global
demand for food, feed, and fuel. Indeed, estimates suggest that agricultural land area
in developing countries may increase considerably (25%) to meet this demand.88 Al-
ready, agriculture uses over two thirds of the world’s fresh water.89 Agricultural devel-
opment in many parts of the world has resulted in an increased requirement for crop
irrigation, which reduces water availability for other uses and increases breeding sites
for disease vectors. An increase in soil moisture associated with irrigation develop-
ment in the southern Nile Delta following the construction of the Aswan High Dam
has caused a rapid rise in the mosquito, Culex pipiens, and a consequential increase
in the arthropod-borne disease, Bancroftian filariasis.90,91 Onchocerciasis and try-
panosomiasis are further examples of vector-borne parasitic diseases that may be
triggered by changing land-use and water-management patterns. In addition, large-
scale use of pesticides has had deleterious effects on farm workers, including hor-
mone disruption and immune suppression.92
Urbanization and Urban Sprawl

On a global basis, the proportion of people living in urban centers will increase to an
unprecedented 65% by the year 2030.93 The 2000 census shows that 80% of the
American population now lives in metropolitan areas, with 30% in cities of 5 million
or more. The environmental issues posed by such large population centers have pro-
found impacts on public health beyond the city limits.94
Alterations of ecosystems and natural resources contribute to the emergence and
spread of infectious disease agents. Human encroachment of wildlife habitats has
broadened the interface between wildlife and humans, resulting in increased opportu-
nities for the emergence of novel infectious diseases in wildlife and their transmission
to people. Rabies is an example of a zoonotic pathogen carried by animals that has
become habituated to urban environments. Bats colonize buildings, skunks and rac-
coons scavenge human refuse, and in many countries, feral dogs in the streets are
common and the major source of human infection.95
Periurban slums provide the ideal conditions for major epidemics, combining dense
housing, poor sanitation and shelter, and open breeding sites for vectors that can
transmit pathogens. Peridomestic dengue fever, infecting an estimated 50 million peo-
ple each year, is one ramification of such poor urban conditions.
Deforestation
Rates of deforestation have grown explosively since the beginning of the twentieth
century. Driven by local to global demand for agricultural and forest products and
expanding human population centers, large swaths of species-rich tropical and
temperate forests, and prairies, grasslands, and wetlands, have been converted to
species-poor agricultural and ranching areas. The global rate of tropical deforestation
is continuing at staggering levels well into this decade, with more than 2.3% of humid
tropical forests cleared between 2000 and 2005 alone.87 Parallel to this habitat
destruction is an exponential growth in human–wildlife interaction and conflict, which
has resulted in exposure to new pathogens for humans, livestock, and wildlife.96
1484 Patz et al
Case study: malaria and deforestation

Land cover change can significantly affect local climate more acutely than long-term
global warming. Surface change can influence microclimatic conditions including tem-
perature, evapotranspiration, and runoff,97 all potentially important determinants of
mosquito abundance and survivorship. In Kenya, open, treeless habitats average
warmer midday temperatures than forested habitats, and also affect indoor hut tem-
peratures.98 Subsequently, the gonadotropic cycle of female Anopheles gambiae was
shortened by 2.6 days (52%) and 2.9 days (21%) during the dry and rainy seasons,
respectively, compared with that of forested sites. In Uganda, similarly higher temper-
atures have been measured in communities bordering cultivated fields compared with
those adjacent to natural wetlands, and the number of A gambiae s.l. per house
increased along with minimum temperatures after adjustment for potential confound-
ing variables.99
In aquatic breeding sites found in farmlands, higher maximum and mean tempera-
tures also hasten larval development and pupation rates.100 In western Kenya, heavier
canopy cover decreases the abundance of A gambiae complex and Anopheles
funestus larvae in natural aquatic habitats.50 In artificial pools, survivorship of
A gambiae larvae in sunlit open areas was 50 times the survivorship in forested areas
and also related to assemblages of predatory species.101 In short, deforestation and
cultivation of natural swamps in the African highlands create conditions favorable
for the survival of A gambiae larvae, making analysis of land use change on local cli-
mate, habitat, and biodiversity key to malaria risk assessments.
In the Amazon Basin, deforestation has also altered the risk for malaria. Vittor and
colleagues102 have found a strong association between the biting rates of Anopheles
darlingi and the extent of deforestation in the Amazon. Controlling for human
population density, the biting rates of A darlingi were more than 200-fold higher in sites
experiencing greater than 80% deforestation versus those with less than 30% defor-
ested landscape (Fig. 4).
Fig. 4. Deforestation and A darlingi biting rates, Peruvian Amazon. Average human biting
rates of the Anopheles darlingi mosquito according to the percentage of forest within
a 1 1 km pixel. Biting rates rise dramatically with deforestation, even after controlling
for human population density. Mean human-biting rate if determined per 6 hours per per-
son; 15 or 16 collection nights per site during 1 year (total: 888 6-hour nights). (Data from
Vittor AY, Gilman RH, Tielsch J, et al. The effect of deforestation on the human-biting
rate of Anopheles Darlingi, the primary vector of falciparum malaria in the Peruvian Ama-
zon. Am J Trop Med Hyg 2006;74:3–11.)
Host immunity against malaria can be affected indirectly by another form of land use
change. Gold mining is an extractive industry that damages local and regional environ-
ments and has adverse human health effects because mercury is used to extract gold
from riverbeds in the tropical forests. Not only does mercury accumulate in local fish
populations, making them toxic to eat,103,104 but mercury also suppresses the human
immune system. In gold-mining areas, more mosquito-breeding sites and increased
malaria risk result from digging gem pits in the forest and the craters resulting from log-
ging; broader disease spread occurs as populations disperse throughout the
region.105
SUMMARY
Climate change and land use change can affect multiple infectious diseases of
humans, acting either independently or synergistically. Although in isolated cases, dis-
ease resurgence has been attributed to recent warming trends, some of the long-term
and complex problems posed by climate change may not be readily discernible from
other causal factors. Expanded efforts, therefore, in empiric and future scenario-
based risk assessment are required to anticipate these problems. Moreover, the
many health impacts of climate and land use change must be examined in the context
of the myriad other environmental and behavioral determinants of disease.
Health risks are but one of many sectors expected to be affected by climate and
ecologic change and represent the interconnected context in which decision makers
must implement strategies. To optimize prevention capabilities, upstream environ-
mental approaches must be part of any intervention, rather than assaults on single
agents of disease. Clinicians must develop stronger ties, not only to public health
officials and scientists, but also to earth and environmental scientists and policy
makers. Without such efforts, we risk practicing medicine in an unsustainable manner
and will inevitably benefit our current generation at the cost of generations to come.
FURTHER READINGS
Aron JL, Patz JA, editors. Ecosystem change and public health: a global perspective.
Johns Hopkins University Press; 2001.
Foley JA, DeFries R, Asner GP, et al. Global consequences of land use. Science 2005;
309:570–4.
Haines A, Patz JA. Health effects of climate change. JAMA 2004;291(1):99–103.
Patz JA. Climate change. In: Frumkin H, editor. Environmental health: from global to
local. San Francisco (CA): John Wiley & Sons Inc.; 2005.
Patz JA, Daszak P, Tabor GM, et al. Unhealthy landscapes: policy recommendations
on land use change and infectious disease emergence. Environ Health Perspect
2004;101:1092–8.
REFERENCES
1. IPCC. Climate change 2007: impacts, adaptation and vulnerability: contribution

of working group II to the fourth assessment report of the IPCC. Cambridge (UK):
Cambridge University Press; 2007.
2. Asner GP, Elmore AJ, Olander LP, et al. Grazing systems, ecosystem responses,
and global change. Ann Rev Environ Resour 2004;29:261–99.
3. Ramankutty N, Foley JA. Estimating historical changes in global land cover:
croplands from 1700 to 1992. Global Bioeochemical Cycles 1999;13:
997–1027.
1486 Patz et al
4. McMichael A, Campbell-Lendrum D, Ebi K, et al. Climate change and human

health: risks and responses. Geneva (Switzerland): WHO; 2003.
5. McLellan SL, Hollis EJ, Depas MM, et al. Distribution and fate of Escherichia coli
in Lake Michigan following contamination with urban stormwater and combined
sewer overflows. J Great Lakes Res 2007;33(3):566–80.
6. Perciasepe R. Combined sewer overflows: where are we four years after adop-
tion of the CSO control policy? Report of the Environmental Protection Agency,
1998.
7. Rose JB, Simonds J. King County water quality assessment: assessment of public
health impacts associated with pathogens and combined sewer overflows. Wash-
ington State Department of Natural Resources, 1998.
8. Fisher GT, Katz BG. Urban stormwater runoff: selected background information
and techniques for problem assessment with a Baltimore, Maryland, case study.
1988.
9. Morris RD, Naumova EN, Levin R, et al. Temporal variation in drinking water tur-
bidity and diagnosed gastroenteritis in Milwaukee. Am J Public Health 1996;
86(2):237–9.
10. Schwartz J, Levin R, Hodge K. Drinking water turbidity and pediatric hospital
use for gastrointestinal illness in Philadelphia. Epidemiology 1997;8(6):
615–20.
11. Curriero FC, Patz JA, Rose JB, et al. The association between extreme precip-
itation and waterborne disease outbreaks in the United States, 1948–1994.
Am J Public Health 2001;91(8):1194–9.
12. Hrudey SE, Payment P, Huck PM, et al. A fatal waterborne disease epidemic in
Walkerton, Ontario: comparison with other waterborne outbreaks in the devel-
oped world. Water Sci Technol 2003;47(3):7–14.
13. Schuster CJ, Ellis AG, Robertson WJ, et al. Infectious disease outbreaks related
to drinking water in Canada, 1974–2001. Can J Public Health 2005;96(4):254–8.
14. Dwight RH, Semenza JC, Baker DB, et al. Association of urban runoff with
coastal water quality in Orange County, California. Water Environ Res 2002;
74(1):82–90.
15. Gerba C, Rose J, Haas C, et al. Waterborne rotavirus: a risk assessment. Water
Res 1996;30(12):2929–40.
16. Wade TJ, Pai N, Eisenberg JN, et al. Do U.S. Environmental Protection Agency
water quality guidelines for recreational waters prevent gastrointestinal illness? A
systematic review and meta-analysis. Environ Health Perspect 2003;111(8):
1102–9.
17. Colford JM Jr, Wade TJ, Schiff KC, et al. Water quality indicators and the risk of
illness at beaches with nonpoint sources of fecal contamination. Epidemiology
2007;18(1):27–35.
18. McLellan SL, Salmore AK. Evidence for localized bacterial loading as the cause
of chronic beach closings in a freshwater marina. Water Res 2003;37(11):
2700–8.
19. Whitman RL, Nevers MB. Foreshore sand as a source of Escherichia coli in near-
shore water of a Lake Michigan beach. Appl Environ Microbiol 2003;69(9):
5555–62.
20. Ackerman D, Weisberg SB. Relationship between rainfall and beach bacterial
concentrations on Santa Monica bay beaches. J Water Health 2003;1(2):85–9.
21. Olyphant GA, Whitman RL. Elements of a predictive model for determining
beach closures on a real time basis: the case of 63rd Street Beach Chicago.
Environ Monit Assess 2004;98(1–3):175–90.
22. Mac Kenzie WR, Hoxie NJ, Proctor ME, et al. A massive outbreak in Milwaukee
of Cryptosporidium infection transmitted through the public water supply. N Engl
J Med 1994;331(3):161–7.
23. Colwell RR. Global climate and infectious disease: the cholera paradigm.
Science 1996;274:2025–31.
24. Koelle K, Rodo X, Pascual M, et al. Refractory periods and climate forcing in
cholera dynamics. Nature 2005;436:696–700.
25. Rodo X, Pascual M, Fuchs G, Faruque AS, et al. ENSO and cholera: a non-sta-
tionary link related to climate change? Proc Natl Acad Sci USA 2002;99(20):
12901–6.
26. Checkley W, Epstein LD, Gilman RH, et al. Effect of El Nino and ambient temper-
ature on hospital admissions for diarrhoeal diseases in Peruvian children. Lancet
2000;355(9202):442–50.
27. Kovats RS, Edwards SJ, Hajat S, et al. The effect of temperature on food poison-
ing: a time-series analysis of salmonellosis in ten European countries. Epidemiol
Infect 2004;132(3):443–53.
28. Bentham G, Langford IH. Climate change and the incidence of food poisoning in
England and Wales. Int J Biometeorol 1995;39(2):81–6.
29. WHO. The World Health Report 2002. Geneva (Switzerland): WHO; 2002.
30. Butt TA, McCarl BA, Angerer J, et al. The economic and food security implica-
tions of climate change in Mali. Clim Change 2005;68(3):355–78.
31. Patz JA, Kovats RS. Hotspots in climate change and human health. BMJ 2002;
325(7372):1094–8.
32. International Energy Agency. Biofuels for transport 2004.
33. Himmel ME, Ding SY, Johnson DK, et al. Biomass recalcitrance: engineering
plants and enzymes for biofuels production. Science 2007;315(5813):804–7.
34. Fairless D. Biofuel: the little shrub that could—maybe. Nature 2007;449(7163):
652–5.
35. United Nations-Energy. Sustainable bioenergy: a framework for decision
makers. 2007.
36. Boddiger D. Boosting biofluel crops could threaten food security. Lancet 2007;
370(9591):923–4.
37. Naylor RL, Liska AJ, Burke MB, et al. The ripple effect: biofuels, food security,
and the environment. Environment 2007;49(9):30–43.
38. Fearnside PM. Soybean cultivation as a threat to the environment in Brazil.
Environ Conserv 2001;28(1):23–38.
39. Morton DC, DeFries RS, Shimabukuro YE, et al. Cropland expansion changes
deforestation dynamics in the southern Brazilian Amazon. Proc Natl Acad Sci
U S A 2006;103(39):14637–41.
40. Koh LP, Wilcove DS. Is oil palm agriculture really destroying tropical biodiver-
sity? Conserv Letts 2008;2(1):1–5.
41. Gibbs HK, Johnston M, Foley JA, et al. Carbon payback times for crop-based biofuel
expansion in the tropics: the effects of changing yield and technology. Environmental
Research Letters 3, in press.
42. Gubler DJ, Reiter P, Ebi KL, et al. Climate variability and change in the United
States: potential impacts on vector- and rodent-borne diseases. Environ Health
Perspect 2001;109:223–33.
43. CDC. Malaria: topic home. Available at: http://www.cdc.gov/malaria/. Accessed
September 18, 2008.
44. Patz JA, Campbell-Lendrum D, Holloway T, et al. Impact of regional climate
change on human health. Nature 2005;438(7066):310–7.
1488 Patz et al
45. Zhou G, Minakawa N, Githeko AK, et al. Climate variability and malaria epi-
demics in the highlands of East Africa. Trends Parasitol 2005;21(2):54–6.
46. Bouma MJ, van der Kaay HJ. The El Nino Southern Oscillation and the historic
malaria epidemics on the Indian subcontinent and Sri Lanka: an early warning
system for future epidemics? Trop Med Int Health 1996;1(1):86–96.
47. Thomson MC, Doblas-Reyes FJ, Mason SJ, et al. Malaria early warnings based
on seasonal climate forecasts from multi-model ensembles. Nature 2006;
439(7076):576–9.
48. Bodker R, Akida J, Shayo D, et al. Relationship between altitude and intensity of
malaria transmission in the Usambara Mountains, Tanzania. J Med Entomol
2003;40(5):706–17.
49. Pascual M, Ahumada JA, Chaves LF, et al. Malaria resurgence in East African
highlands: temperature trends revisited. Proc Natl Acad Sci USA 2006;
103(15):5829–34.
50. Minakawa N, Sonye G, Mogi M, et al. The effects of climatic factors on the dis-
tribution and abundance of malaria vectors in Kenya. J Med Entomol 2002;39(6):
833–41.
51. Patz JA, Martens WJM, Focks DA, et al. Dengue fever epidemic potential as pro-
jected by general circulation models of global climate change. Environ Health
Perspect 1998;106(3):147–53.
52. Hopp MJ, Foley JA. Worldwide fluctuations in dengue fever cases related to
climate variability. Clim Res 2003;25(1):85–94.
53. Reisen WK, Fang Y, Martinez V. Effects of temperature on the transmission of
West Nile virus by Culex tarsalis (Diptera: Culicidae). J Med Entomol
2006;43(2), in press.
54. Madder DJ, Surgeoner GA, Helson BV. Number of generations, egg production,
and developmental time of Culex pipiens and Culex restauns (Diptera: Culici-
dae) in southern Ontario. J Med Entomol 1983;20(3):275–87.
55. Buth JL, Brust RA, Ellis RA. Development time, oviposition activity and onset of
diapause in Culex tarsalis, Culex restuans and Culiseta inornata in southern
Manitoba. J Am Mosq Control Assoc 1990;6(1):55–63.
56. Rueda LM, Patel KJ, Axtell RC, et al. Temperature-dependent development and
survival rates of Culex quinquefasciatus and Aedes aegypti (Diptera: Culicidae).
J Med Entomol 1990;27(5):892–8.
57. Turell MJ, O’Guinn ML, Dohm DJ, et al. Vector competence of North American
mosquitoes (Diptera: Culicidae) for West Nile virus. J Med Entomol 2001;
38(2):130–4.
58. Dohm DJ, O’Guinn ML, Turell MJ. Effect of environmental temperature on the
ability of Culex pipiens (Diptera: Culicidae) to transmit West Nile virus. J Med
Entomol 2002;39(1):221–5.
59. McIntosh BM, Jupp PG, Dos Santos I, et al. Epidemics of West Nile and Sindbis
viruses in South Africa with Culex (Culex) univittatus Theobald as vector. S Afr
J Sci 1976;72:295–300.
60. Jupp PG, McIntosh BM, Blackburn NK. Experimental assessment of the vector
competence of Culex (Culex) neavei Theobald with West Nile and Sindbis
viruses in South Africa. Trans R Soc Trop Med Hyg 1986;80(2):226–30.
61. Platonov AE, Shipulin GA, Shipulina OY, et al. Outbreak of West Nile virus
infection, Volgograd Region, Russia, 1999. Emerg Infect Dis 2001;7(1):128–32.
62. Raddatz RL. A biometeorological model of an encephalitis vector. Boundary
Layer Meteorology 1986;34:185–99.
63. Day JF, Curtis GA. Influence of rainfall on Culex nigripalpus (Diptera: Culicidae)
blood-feeding behavior in Indian River County, Florida. Ann Entomol Soc Am
1989;82(1):32–7.
64. Andreadis TG, Anderson JF, Vossbrinck CR, et al. Epidemiology of West Nile
virus in Connecticut: a five-year analysis of mosquito data 1999–2003. Vector
Borne Zoonotic Dis Winter 2004;4(4):360–78.
65. Degaetano AT. Meteorological effects on adult mosquito (Culex) populations in
metropolitan New Jersey. Int J Biometeorol 2005;49(5):345–53.
66. Landesman WJ, Allan BF, Langerhans RB, et al. Inter-annual associations
between precipitation and human incidence of West Nile virus in the United
States. Vector Borne Zoonotic Dis Fall 2007;7(3):337–43.
67. Han LL, Popovici F, Alexander JP Jr, et al. Risk factors for West Nile virus
infection and meningoencephalitis, Romania, 1996. J Infect Dis 1999;179(1):
230–3.
68. Despommier DD. West Nile story. New York: Apple Trees Productions LLC; 2001.
69. Chase JM, Knight TM. Drought-induced mosquito outbreaks in wetlands. Ecol
Lett 2003;6(11):1017–24.
70. Shaman J, Day JF, Stieglitz M. Drought-induced amplification and epidemic trans-
mission of West Nile virus in southern Florida. J Med Entomol 2005;42(2):134–41.
71. Sergon K, Njuguna C, Kalani R, et al. Seroprevalence of chikungunya virus
(CHIKV) infection on Lamu Island, Kenya, October. Am J Trop Med Hyg 2008;
78(2):333–7.
72. Chretien JP, Anyamba A, Bedno SA, et al. Drought-associated Chikungunya
emergence along coastal East Africa. Am J Trop Med Hyg 2007;76(3):405–7.
outbreak in a temperate region. Lancet 2007;370(9602):1840–6.
74. Linthicum KJ, Anyamba A, Tucker CJ, et al. Climate and satellite indicators to
forecast Rift valley fever epidemics in Kenya. Science 1999;285(5426):397–400.
75. Patz JA, Confalonieri UEC, Amerasinghe F, et al. Health: ecosystem regulation of
infectious diseases. In: Reid W, editor. Millennium ecosystem assessment
series. ecosystems and human well-being: current state and trends. findings
of the condition and trends working group. Washington, DC: Island Press; 2005.
76. Ogden NH, Lindsay LR, Beauchamp G, et al. Investigation of relationships
between temperature and developmental rates of tick Ixodes scapularis (Acari:
Ixodidae) in the laboratory and field. J Med Entomol 2004;41(4):622–33.
77. Mccabe GJ, Bunnell JE. Precipitation and the occurrence of Lyme disease in the
northeastern United States. SUM. Vector Borne Zoonotic Dis 2004;4(2):143–8.
78. Brownstein JS, Holford TR, Fish D. A climate-based model predicts the spatial
distribution of Lyme disease vector Ixodes scapularis in the United States. Envi-
ron Health Perspect 2003;111:1152–7.
79. Ogden NH, Maarouf A, Barker IK, et al. Climate change and the potential for
range expansion of the Lyme disease vector Ixodes scapularis in Canada. Int
J Parasit 2006;36(1):63–70.
80. Glass GE, Cheek JE, Patz JA, et al. Using remotely sensed data to identify areas
at risk for hantavirus pulmonary syndrome. Emerg Infect Dis 2000;6(3):238–47.
81. Trevejo RT, Rigau-Perez JG, Ashford DA, et al. Epidemic leptospirosis associated with
pulmonary hemorrhage—Nicaragua, 1995. J Infect Dis 1998;178(5):1457–63.
82. Parmenter RR, Yadav EP, Parmenter CA, et al. Incidence of plague associated
with increased winter-spring precipitation in New Mexico. Am J Trop Med Hyg
1999;61(5):814–21.
1490 Patz et al
83. Stenseth NC, Samia NI, Viljugrein H, et al. Plague dynamics are driven by
climate variation. Proc Natl Acad Sci U S A 2006;103(35):13110–5.
84. Purse BV, Mellor PS, Rogers DJ, et al. Climate change and the recent emer-
gence of bluetongue in Europe. Nat Rev Microbiol 2005;3(2):171–81.
85. Saegerman C, Berkvens D, Mellor PS. Bluetongue epidemiology in the Euro-
pean Union. Emerg Infect Dis 2008;14(4):539–44.
86. Schmid KA, Ostfeld RS. Biodiversity and the dilution effect in disease ecology.
Ecology 2001;82(3):609–19.
87. Hansen MC, Stehman SV, Potapov PV, et al. Humid tropical forest clearing from
2000 to 2005 quantified using multi-temporal and multi-resolution remotely
sensed data. PNAS, in press.
88. Balmford A, Green RE, Scharlemann JPW. Sparing land for nature: exploring the
potential impact of changes in agricultural yield on the area needed for crop pro-
duction. Global Change Biol 2005;11(10):1594–605.
89. Horrigan L, Lawrence RS, Walker P. How sustainable agriculture can address
the environmental and human health harms of industrial agriculture. Environ
Health Perspect 2002;110(5):445–56.
90. Harb M, Faris R, Gad AM, et al. The resurgence of lymphatic filariasis in the Nile
delta. Bull World Health Organ 1993;71(1):49–54.
91. Thompson DF, Malone JB, Harb M, et al. Bancroftian filariasis distribution and
diurnal temperature differences in the southern Nile delta. Emerg Infect Dis
1996;2(3):234–5.
92. Straube E, Straube W, Kruger E, et al. Disruption of male sex hormones with
regard to pesticides: pathophysiological and regulatory aspects. Toxicol Lett
1999;107(1–3):225–31.
93. Population Reference Bureau. World population data sheet, 1998. Available at:
http://www.prb.org/Publications/Datasheets/2008/2008wpds.aspx. Accessed
September 18, 2008.
94. Knowlton K. Urban history, urban health. Am J Public Health 2001;91(12):
1944–6.
95. Singh J, Jain D, Bhatia R, et al. Epidemiological characteristics of rabies in Delhi
and surrounding areas, 1998. Indian Pediatr 2001;38(12):1354–60.
96. Wolfe ND, Switzer WM, Carr JK, et al. Naturally acquired simian retrovirus infec-
tions in central African hunters. Lancet 2004;363(9413):932–7.
97. Foley JA, DeFries R, Asner GP, et al. Global consequences of land use. Science
2005;309(5734):570–4.
98. Afrane YA, Lawson BW, Githeko AK, et al. Effects of microclimatic changes
caused by land use and land cover on duration of gonotrophic cycles of Anoph-
eles gambiae (Diptera: Culicidae) in western Kenya highlands. J Med Entomol
2005;42(6):974–80.
99. Lindblade KA, Walker ED, Onapa AW, et al. Land use change alters malaria trans-
mission parameters by modifying temperature in a highland area of Uganda.
Trop Med Int Health 2000;5(4):263–74.
100. Munga S, Minakawa N, Zhou G, et al. Association between land cover and hab-
itat productivity of malaria vectors in western Kenyan highlands. Am J Trop Med
Hyg 2006;74(1):69–75.
101. Tuno N, Okeka W, Minakawa N, et al. Survivorship of Anopheles gambiae sensu
stricto (Diptera: Culicidae) larvae in western Kenya highland forest. J Med
Entomol 2005;42(3):270–7.
102. Vittor AY, Gilman RH, Tielsch J, et al. The effect of deforestation on the human-
biting rate of Anopheles Darlingi, the primary vector of Falciparum malaria in the
Peruvian Amazon. Am J Trop Med Hyg 2006;74(1):3–11.
103. Lebel J, Mergler D, Lucotte M, et al. Evidence of early nervous system
dysfunction in Amazonian populations exposed to low-levels of methylmercury.
Spring. Neurotoxicology 1996;17(1):157–67.
104. Lebel J, Mergler D, Branches F, et al. Neurotoxic effects of low-level methylmer-
cury contamination in the Amazonian Basin. Environ Res 1998;79(1):20–32.
105. Silbergeld EK, Nash D, Trevant C, et al. Mercury exposure and malaria
prevalence among gold miners in Para, Brazil. Rev Soc Bras Med Trop 2002;
35(5):421–9.

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New and Emerging Infectious Diseases 2008, Vol.92, Issues 6

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New and Emerging Infectious Diseases

Mary Elizabeth Wilson, MD, FACP, FIDSA

Med Clin N Am 92 (2008) xiii–xviii

Mobility, as described in the article on travel, is unprecedented in volume, reach,

PEOPLE, PIGS, AND POULTRY: THE THREAT OF AVIAN INFLUENZA

Mary Elizabeth Wilson, MD, FACP, FIDSA

1. Smolinski MS, Hamburg MA, Lederberg J, editors. Microbial Threats to Health:

ORIGIN OF WEST NILE VIRUS IN NORTH AMERICA

Med Clin N Am 92 (2008) 1307–1322

GEOGRAPHIC SPREAD IN NORTH AMERICA

Year WNND Fever Othera Total Deaths

Abbreviation: WNND, West Nile virus neuroinvasive disease.

Fig. 2. Cumulative incidence of WNND in humans by county, 2002–2007.

pressure.24–26 Nevertheless, a distinct genetic variant emerged in 2001 (WN02 strain),

WEST NILE VIRUS IN LATIN AMERICA AND THE CARIBBEAN

Fig. 4. Number of neuroinvasive disease cases by week of symptom onset, 2002–2007.

other manifestations of WNV disease.87 Chorioretinitis may be frequent in patients

Prevention efforts have focused on encouraging personal protection such as wearing

54. Gu W, Lampman R, Krasavin N, et al. Spatio-temporal analyses of West Nile

After a period of 50 years of silence, a disease with an unpronounceable name, ‘‘chi-

Med Clin N Am 92 (2008) 1323–1343

Virus MainVectors Main Areas of Endemicity

Febrile Polyarthralgia Followed by Long-Lasting Rheumatism

Chikungunya Dengue Fever

THE LESSONS FROM 2000’S LARGE-SCALE OUTBREAKS

European countries,10,58,59 the United States,60 Australia,61 and Asia.62 Imported

Harsh Public Health Consequences in Large Outbreaks

in public health in terms of morbidity and mortality, overloading of medical structures,

No More a Benign Infection: Morbi-Mortality in the Acute Stage, Handicap

Chikungunya: A Paradigm of Emergence

Abbreviations: ND, not detailed; NR, not reported.

most commonly observed complications, in decreasing frequency, were respiratory

complications have been recently described in India: episcleritis, granulomatous and

Changing Patterns in Relationship Between the Chikungunya Virus and Mosquitoes

returned to France.13 Molecular characterization first revealed that the epidemic

A Paradigm for the Globalization of Vector-Borne Diseases

HOW TO DIAGNOSE CHIKUNGUNYA VIRUS INFECTION

In the current context of globalization of CHIKV, CHIK fever has to be suspected in

To date, at least 12 countries in Europe are susceptible to CHIKV implantation

Vector-transmitted infections are evolutionary threats in the modern world, even in

1. Enserink M. Infectious diseases. Massive outbreak draws fresh attention to little-

86. Palanivelu C, Rangarajan M, Rajapandian S, et al. Perforation of jejunal divertic-

Recently in the field of rickettsiology, an explosion of new isolates of pathogens have

Med Clin N Am 92 (2008) 1345–1361

CYCLIC FLUCTUATIONS IN INCIDENCE OF ROCKY MOUNTAIN SPOTTED FEVER

ECOLOGY OF SPOTTED FEVER GROUP RICKETTSIAE

The lifecycle of hard ticks such as Dermacentor, Rhipicephalus, and Amblyomma

DIVERSITY OF SPOTTED FEVER GROUP RICKETTSIAE AND RICKETTSIOSES

determined.30,31 However, no infections ascribed to R parkeri have been fatal or life-

A TICK-BORNE TYPHUS GROUP RICKETTSIOSIS

In 1955 Reiss-Gutfreund46 reported the discovery of R prowazekii in Hyalomma ticks in

HUMAN EHRLICHIOSES AND ANAPLASMOSIS

Tick Geographic Vertebrate

APPROACH TO PATIENTS WHO HAVE UNDIFFERENTIATED FEBRILE ILLNESS

ROLE OF THE LABORATORY IN DIAGNOSIS OF RICKETTSIOSES, EHRLICHIOSES,

REASONS FOR THE EMERGENCE OF TICK-BORNE HUMAN RICKETTSIOSES,

Application of technologic advances led to the identification of novel agents (eg,

Although studying microbiology and immunology is essential to understanding the