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October
2007: VOLUME
1, NUMBER 4
Illness in the Returned Traveler
In this Issue...
As the number of travelers expands, clinicians are more likely to encounter the illnesses these travelers develop. Knowing the rates of diagnoses according to region visited, as well as the time since travel was completed, can help practitioners focus on the most likely diagnoses for a particular traveler.
To that end, in this issue we review data from a variety of international sources, presenting current information on illnesses endemic to specific travel destinations. In addition, we present updates on 3 prominent systemic febrile illnesses: non-falciparum malaria, dengue, and Chikungunya virus infection, which recently erupted in the Indian Ocean Islands and is spreading into India.
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Course
Directors
John
G. Bartlett, MD
Professor of Medicine
Department of Medicine
The Johns Hopkins University
School of Medicine
Baltimore, MD
Paul
G. Auwaerter, MD
Associate Professor of Medicine
Clinical Director
Division of Infectious Diseases
The Johns Hopkins University
School of Medicine
Baltimore, MD
Sara
E. Cosgrove, MD, MS
Assistant Professor of Medicine
Division of Infectious Diseases
Director
Antibiotic Management Program
Associate Hospital Epidemiologist
The Johns Hopkins University
School of Medicine
Baltimore, MD |
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GUEST
AUTHOR OF THE MONTH |
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Commentary
& Reviews: |
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Robin
McKenzie, MD
Assistant Professor of Medicine
The Johns Hopkins University
School of Medicine
Baltimore, MD |
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Guest
Faculty Disclosures
Robin
McKenzie, MD has disclosed no relationship
with any commercial supporters.
Unlabeled/Unapproved Uses
The author has indicated that there will be no
reference to unlabeled or unapproved uses of drugs
or products in this presentation.
Program
Directors' Disclosures |
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the conclusion of this activity, participants
should be able to: |
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Identify
the most common illnesses in travelers returning
from different regions of the world |
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Describe
the difficulties in diagnosing non-falciparum
malaria |
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Discuss
the clinical manifestations of dengue and Chikungunya
virus infections in travelers |
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COMPLETE
THE
POST-TEST
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Click on the appropriate link below. This will take
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If you have participated in a Johns Hopkins on-line
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Step
3.
Complete the post-test and course evaluation.
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Print out your certificate.
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eInfections
Review is proud to continue its accredited
PODCASTS for 2007. Listen
here. |
In
this audio interview, Robin McKenzie, MD, Assistant
Professor of Medicine at The Johns Hopkins University
School of Medicine in Baltimore, Maryland will discuss
additional topics related to illness in travelers.
Participants can now receive 0.5 credits per podcast after completing an online post-test via the links provided on this page.
To learn more about podcasting and how to access this
exciting new feature of eInfections Review,
please visit
this page. |
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Faced
with an ill traveler, a clinician may narrow the long
list of possible diagnoses by focusing on those that
are most common for the region visited. Since studies
from one center, or even one country, cannot adequately
represent the tremendous number of travelers worldwide,
networks have been established to collect data from
clinics around the globe. With information from over
20,000 ill travelers, the GeoSentinel network provides
data for two of the articles reviewed in this issue.
Dr. Freedman's NEJM paper provides diagnoses
by region visited for 17,000 travelers, while Dr. Wilson
discusses 7,000 travelers with fever as a chief complaint,
emphasizing region of exposure and length of incubation
as two important diagnostic clues. Malaria, found in
one-fifth of all febrile travelers, must be ruled out
in every febrile traveler who has visited an endemic
area; the disease is especially common in those who
have visited sub-Saharan Africa or the Pacific Islands.
On the other hand, dengue is more common than malaria
after travel to Southeast Asia, and enteric fever (typhoid
and paratyphoid fever) occurs frequently in travelers
from south-central Asia. Timing—in regard to onset
of symptoms—is also an important diagnostic clue.
For example: dengue has a short incubation of 5-10 days
and, therefore, does not develop more than 2 weeks after
return; 65% of falciparum malaria infections
present within 2 weeks of travel; but one-half of vivax
cases and one-third of hepatitis cases present more
than 6 weeks after return.
In the US, almost one-third of the 1500 malaria cases
diagnosed annually are caused by P. vivax or
ovale. While P. falciparum causes
about 85% of cases in travelers to Africa, P. vivax
is the most common species in travelers to Asia, the
Americas, and the Middle East. As the article by Bottieau
points out, hypnozoites (latent liver forms) of P.
vivax or ovale are not prevented by most
approved malaria prophylaxis regimens. In fact, these
medications may delay the presentation of malaria, making
diagnosis more difficult. In the US and Israel, more
than one-third of malaria cases present more than two
months after travel. Most of these late cases are P.
vivax or ovale infections in persons who
have taken standard prophylaxis.1
Therefore, all travelers should be educated about malaria
symptoms and reminded that these symptoms may develop
months after travel. For some travelers with expected
heavy vivax exposure, primaquine can be considered
for primary prophylaxis or for post-exposure treatment
prophylaxis to prevent relapses. Bottieau also describes
a high relapse rate after treatment for P. vivax
or ovale. Currently, the CDC recommends primaquine
30 mg of base per day for 14 days to overlap with standard
treatment with a schizonticide such as chloroquine.2
Since relapses often occur after poor adherence, clinicians
should stress the importance of compliance with the
full regimen.
Two additional articles give us a snapshot of illnesses
that are common and devastating in the countries where
they are endemic. Dengue virus causes 100 million cases
of dengue fever and 250,000 cases of dengue hemorrhagic
fever each year. Dengue has been the subject of intensified
surveillance over several years by TropNetEurop, a large
European network that studies illness in travelers.
The Wichmann article points out that for travelers,
as for children in endemic areas, severe illness is
more common after secondary infections. In the Makonde
(African) language, "Chikungunya" means "that which
bends", describing the posture of those infected by
this mosquito-borne virus which recently swept through
the Reunion Island, infecting one-third of its 770,000
people. Simon describes the fever, arthritis, and other
manifestations of this illness in travelers returning
from the Indian Ocean Islands.
References
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THE
SPECTRUM OF ILLNESS IN TRAVELERS FROM ALL REGIONS
OF THE WORLD |
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Wilson
ME, Weld LH, Boggild A. Fever in
returned travelers: results from the GeoSentinel
Surveillance network. Clin
Infect Dis 2007;44:1560-8.
(For non-journal subscribers, an additional
fee may apply for full text articles.)
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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;354:119-30.
(For non-journal subscribers, an additional
fee may apply for full text articles.)
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These
two articles describe illness in about 20,000
returned travelers who were seen at GeoSentinel
clinics. The GeoSentinel Surveillance Network
consists of 30 travel or tropical-medicine clinics
on six continents. Clinicians at these sites obtain
information from all ill travelers and enter it
into a large database. Illnesses are reported
by categories, such as systemic febrile illness,
diarrheal illness, respiratory illness, and, when
possible, by specific diagnosis.
In the first article, Wilson et al describe the
causes of fever in returned travelers. From March
1997 to March 2006, approximately 25,000 persons
were seen after travel for illnesses that were
confirmed or considered probable. Among these,
almost 7000 reported fever as a chief reason for
seeking care. Overall, systemic febrile illness
was the largest category, accounting for one-third
of all febrile illness; diarrheal disease and
respiratory illness together caused another third.
Malaria, the most common specific illness, was
diagnosed in 20% of all febrile travelers; dengue
was diagnosed in 6%. The most common vaccine-preventable
illnesses were typhoid fever, hepatitis A, and
influenza A. The researchers reported that more
than 70% of typhoid fever was acquired in south-central
and southeast Asia. Furthermore, as compared to
other groups of travelers, those visiting friends
and relatives were more likely to have vaccine-preventable
causes of fever and less likely to have received
pre-travel medical advice.
In the second article, Freedman et al compare
the frequency of all travel-related illnesses—febrile
and nonfebrile—by region of exposure in
17,000 travelers seen from 1996 to 2004, highlighting
the important regional differences in the categories
of illnesses and specific diagnoses. For travelers
to sub-Saharan Africa and Southeast Asia, systemic
febrile illness was the most common category.
For Africa, the most frequent illness in this
category by far was malaria, with tick-borne rickettsial
infection a distant second, and dengue a rare
diagnosis. For Southeast Asia, dengue was 2 to
3 times more common than malaria. Travelers returning
from south-central Asia, on the other hand, were
seen more often for acute diarrhea than for systemic
febrile illness. Of note, however, enteric fever
(typhoid and paratyphoid illness) was found much
more commonly in south-central Asia than in any
other region, and was diagnosed at the same rate
as dengue and malaria. In South America, Central
America and the Caribbean, skin conditions and
acute diarrhea were the most common categories.
Insect bites with or without infections, cutaneous
larva migrans, and allergic reactions occurred
frequently in all three regions. The researchers
also reported that travelers to South America,
and to a lesser extent to Central America, acquired
cutaneous leishmaniasis, and that travelers to
both regions developed myiasis, infestation with
larvae of certain flies (maggots). Overall, parasites,
especially giardiasis and amebiasis, were more
common than bacteria as causes of diarrhea - the
exception being Southeast Asia, where campylobacter
was the predominant cause. Other commonly diagnosed
gastrointestinal illnesses included strongyloidiasis,
ascariasis, gastritis, peptic ulcer disease, and
acute hepatitis.
Whereas previous articles have described much
smaller numbers of travelers often from fewer
regions, these articles describe the illnesses
of a large number of travelers visiting all regions.
Certain caveats, however, must be considered.
Many of the GeoSentinel sites are referral centers,
which often see travelers with illnesses that
are more difficult to diagnose or more severe
than those seen at primary care centers. Also,
infections with short incubations or those which
are self-treated may be under-represented. While
bacterial pathogens are a more common cause of
travelers' diarrhea than parasites, bacteria were
reported less frequently in this study probably
because they cause diarrhea that is brief or responsive
to self-treatment. Furthermore, infections with
a shorter incubation period, such as dengue and
rickettsial infections, may develop during travel
and resolve or improve before return home. It
should also be noted that a large number of cases,
as in many series, did not have specific diagnoses.
For about 40% of systemic febrile illnesses and
acute diarrhea, no specific etiology was identified. |
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PITFALLS
IN THE PROPHYLAXIS, DIAGNOSIS, AND TREATMENT OF NON-FALCIPARUM
MALARIA |
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Bottieau
E, Clerinx J, Van den Enden, E, et al. Imported
Non-Plasmodium falciparum malaria: a five-year
prospective study in a European referral center.
Am J Trop Med Hyg 2006;75:133-38.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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There
are 4 species of malaria that cause illness in humans.
Plasmodium falciparum is the deadliest, but
the non-falciparum species, P. vivax, ovale,
and malariae, are often more difficult to diagnose.
They infect a smaller percentage of erythrocytes and
are, therefore, harder to see on peripheral blood smears.
Also, they may present months, or even years, after
exposure. P. vivax and ovale are the
only species which develop a dormant hypnozoite phase
in the liver. P. malariae, on the other hand,
may produce a low-level, chronic parasitemia unrecognized
until recrudescence after a long latent period. In this
article, Bottieau et al describe 98 cases of non-falciparum
malaria diagnosed by blood smear from 2000 to 2005 at
a referral center for tropical diseases in Belgium.
Among these 98 cases, the median time from leaving the
endemic area to the onset of fever was two months; however,
18% of patients became symptomatic more than 6 months
after exposure, and 5% after more than a year. Eighty
episodes were first attacks of malaria, with 21 occurring
in persons who reported adherence to malaria prophylaxis.
These 21 had a longer time from exposure to onset of
fever (median 91 days vs. 40 days for those who didn't
take prophylaxis). Eighteen episodes (3 of the 34 P.
ovale cases and 15 of the 48 P. vivax
cases) were relapses following previous treatment of
malaria: 7 of these relapses were in patients who had
not taken primaquine, either because it was not prescribed
(5) or they were non-adherent (2), and 10 occurred after
treatment with low-dose primaquine (15 mg of base daily
for 14 days). These 10 were then successfully treated
with a higher dose of primaquine (0.5 mg/kg daily for
14 days). One patient infected with P. vivax
in Indonesia relapsed after 3 courses of primaquine,
the third course being at the higher dose.
This article demonstrates some of the pitfalls in diagnosing
and treating non-falciparum malaria. Since
primaquine is the only approved drug which prevents
or eradicates the dormant liver stage of P. vivax
and ovale, symptoms of infection with these
species may present in anyone who was exposed and did
not receive primaquine, including travelers who adhered
strictly to the commonly recommended prophylactic medications.
In fact, these prophylactic medications may actually
obscure the diagnosis by prolonging the time to development
of symptoms. For eradication of hypnozoites in the liver
and prevention of relapse, patients with P. vivax
and ovale infections should take primaquine.
The recommended dose is now 0.5 mg/kg (maximum dose
30 mg) per day for 14 days to all non-pregnant patients
who are not glucose-6-phosphate dehydrogenase (G6PD)
deficient. |
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MALARIA
DIAGNOSED IN THE US IN 2005 |
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Thwing
J, Skarbinski J, Newman RD, et al. Malaria
Surveillance - United States, 2005. MMWR
2007;56:23-38.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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In
2005, 1,528 cases of malaria were reported to the CDC.
All cases were confirmed by blood smear or PCR. To determine
rates for individual countries, the number of cases
acquired in a specific country was divided by the World
Tourism Organization estimate of the annual number of
U.S. travelers to that country.
Among these 1,528 cases, 1180 had a species identified:
63% were falciparum malaria, 29% were vivax,
5% malariae, and 3% ovale. About two-thirds
of all cases were acquired in Africa, and two-thirds
of African cases were acquired in West Africa. Most
of the remaining cases came from Asia (with India providing
the majority of Asian cases) and the Americas (predominantly
Central America and the Caribbean). Among individual
countries, Nigeria had the highest number of cases and
the highest rate. High rates were also seen in travelers
returning from other West and Central African countries,
Papua New Guinea, and Vanuatu. Honduras, India, and
Haiti had intermediate rates. The country with the lowest
rate was China; Mexico, the Philippines, Thailand, and
Costa Rica also had low rates. Eighty-three percent
of African cases were falciparum malaria; in
every other country except Haiti, vivax malaria
predominated. More than half of the malaria cases in
U.S. civilians occurred in persons who had visited friends
and relatives; among these civilian cases, only 20%
had taken recommended prophylaxis. All 7 deaths were
caused by P. falciparum; none of these 7 patients
had taken prophylaxis, and all had delays before diagnosis
was made and/or treatment was given. Two congenitally
acquired cases were reported, both vivax infections.
The mothers had emigrated from Honduras and India 10
months and 2 years earlier.
This article illustrates the critical importance of
taking a travel history from all febrile patients. As
the two congenital cases demonstrate, even a history
of remote travel may be important for diagnosing cases
of non-falciparum malaria. Furthermore, travelers
who visited friends or relatives accounted for the majority
of cases of malaria in the U.S. Those born in endemic
regions should be instructed that immunity to malaria
wanes quickly after leaving a malarious area, and prophylaxis
is needed for protection when returning to these areas.
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SEVERE
DENGUE IN TRAVELERS |
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Wichmann
O, Gascon J, Schunk M, et al. Severe dengue
virus infection in travelers: risk factors and
laboratory indicators. J Infect Dis
2007;195:1089-96.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Dengue
virus is a flavivirus spread by mosquitoes in most tropical
countries. Residents of these countries and travelers
to endemic areas may develop asymptomatic infection
or a systemic febrile illness. Four serotypes of dengue
virus cause infection. While infection with one of the
4 serotypes protects against subsequent infection with
that specific serotype, it predisposes to severe illness
from secondary infection (infection with a different
serotype). In endemic areas, children with secondary
infections may develop severe dengue illness, including
dengue hemorrhagic fever. In travelers, however, severe
infection has not been well characterized. Wichmann
and colleagues describe dengue illness in subjects seen
between 2003 and 2005 at 14 referral centers in the
European Network on Surveillance of Imported Infectious
Diseases. They determined how many met all 4 WHO criteria
for dengue hemorrhagic fever: fever, platelet count
<100,000 cells/mm3,
capillary leak (20% increase in the hematocrit, pleural
effusion, ascites, or hypoproteinemia), and hemorrhagic
tendency (spontaneous bleeding, petechiae, or a positive
tourniquet test). The authors also described other severe
manifestations and the risk factors for severe illness.
A total of 219 patients were reported. The median age
was 32 years (range, 11-70 years). Most patients were
European, but 17 were born in endemic areas and had
immigrated to or were visiting Europe. Sixty-five percent
of patients acquired the infection in Asia, with India
and Thailand topping the list of individual countries.
About 20% had traveled to Central America, and the remainder
to South America, the Caribbean, and Africa. Almost
two-thirds of patients had visited dengue-endemic countries
before. Dengue infection was confirmed in 133 patients:
115 had a rise in antibody titers in paired sera, and
18 had positive PCR results with or without an antibody
increase. The remaining 86 had a probable diagnosis
based on IgM antibodies in a single serum sample. One-fourth
of patients were considered to have secondary infections
diagnosed by a high IgG titer in the presence of IgM
antibodies. After 13 patients were excluded for potentially
confounding flavivirus vaccination (yellow fever, tick-borne
encephalitis, Japanese encephalitis), 27 cases (17%)
remained as the group of secondary infections. Overall,
93% of patients with dengue had fever and 69% had headache.
One-half of subjects reported rash, myalgia, and retroorbital
pain. Petechiae occurred in 13%, and spontaneous bleeding,
most often from the nose or gums, in 8%. Most patients
had leukopenia and thrombocytopenia, usually presenting
within the first 3 to 6 days. Elevated transaminases
and LDH were common but often occurred later. Forty-four
percent had a positive tourniquet test (≥20 petechiae
per square inch on the forearm after inflation of a
blood pressure cuff between the diastolic and systolic
pressures for 5 minutes). Only 2 (1%) fulfilled the
4 WHO criteria for dengue hemorrhagic fever. Twenty-three
patients (11%) had one or more of the following severe
manifestations: internal hemorrhage, plasma leak, shock,
and platelet count <50,000. Those with severe manifestations,
compared to those without, had lower nadir WBC and platelets
counts, higher ALT and AST increases, and a higher rate
of secondary immune responses (44% vs. 13%, p<0.05);
however, 8 of these patients with severe manifestations
had visited a dengue-endemic country for the first time.
A positive tourniquet test did not predict severe infection
or spontaneous bleeding. Overall, 51 patients (23%)
were hospitalized.
This report provides clinical and laboratory data for
a large number of travelers with dengue. While dengue
hemorrhagic fever diagnosed by WHO criteria was rare,
severe manifestations occurred in 11% of subjects. Severe
disease was more likely to occur in those with secondary
infection but also occurred in some travelers with primary
infection. For travelers to endemic areas, mosquito
precautions are important for prevention of dengue and
other infections. |
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CHIKUNGUNYA
INFECTION CAUSES FEVER AND ARTHRITIS IN TRAVELERS TO
THE INDIAN OCEAN ISLANDS |
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Simon
F, Parola P, Grandadam M. Chikungunya
infection, an emerging rheumatism among travelers
returned from Indian Ocean islands. Report of
47 cases. Medicine 2007;86:123-37.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Chikungunya,
a mosquito-transmitted infection, discovered in the
1950s in Africa, was little known until recently, when
an outbreak exploded in the Indian Ocean Islands. This
epidemic has already reached India and Malaysia, and
may continue to spread, producing fever and arthritis
in both the indigenous population and travelers. Simon
and colleagues provide a comprehensive description of
this dramatic illness in 47 travelers seen at two referral
centers for tropical and travel-related illness in Marseilles,
France. The diagnosis was suspected in persons with
fever and/or arthralgia who had traveled to the Indian
Ocean Islands - Reunion Island, the Comoros Archipelago,
the Seychelles, or Mauritius. The diagnosis was confirmed
by serology, PCR, or isolation of the virus from blood.
The 47 patients comprised 22 females and 25 males, with
a mean age of 45 (range 0.5-73 years). The majority
were tourists, although 17 were born in the islands
and had either migrated to or were visiting France.
Simon describes a biphasic illness with fever and arthralgia/arthritis
in the initial phase. Fever lasted a mean of 4 days
(range 2-9 days). One half of the patients had a transient
rash for 1-4 days in the early phase, consisting of
macules, papules, or erythema mainly on the face, trunk
and extremities. Arthritis was commonly symmetrical
and peripheral, involving distal fingers, wrists, toes,
and ankles, but arthralgia extended to knees, hips,
shoulders, and elbows. Edema of the face and pruritus
of the rash were common. Leukopenia occurred in 75%
of patients and thrombocytopenia and elevation of liver
and muscle enzymes in 50%. All patients improved in
7 to 10 days, but the majority (83%) had persistent
or recurrent joint pain, often debilitating, marking
the second phase of the illness. Common findings were
swelling of proximal finger joints, tenosynovitis, carpal/tarsal/cubital
tunnel syndrome, and Raynaud's phenomenon. At 1, 3,
and 6 months after disease onset, 88%, 86% and 48% of
patients were still symptomatic.
As often happens, travelers brought an epidemic illness
into the spotlight. Since this illness is spreading
rapidly, physicians in Western countries are likely
to see more patients with this previously little-known
illness. For any traveler to the Indian Ocean islands
or India presenting with fever and arthralgia/arthritis,
Chikungunya infection must be considered. Unfortunately,
there is no specific treatment, and the disabling joint
disease often persists for months. Prevention of mosquito
bites is the key to preventing infection. |
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At
the conclusion of this activity, participants
should be able to:
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Identify
the most common illnesses in travelers returning
from different regions of the world |
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Describe
the difficulties in diagnosing non-falciparum
malaria |
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Discuss
the clinical manifestations of dengue and
Chikungunya virus infections in travelers |
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Office of Continuing Medical Education (CME) at
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Continuing Medical Education at The Johns Hopkins
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policy of The Johns Hopkins University School
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relationship a faculty member or a provider has
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Program Directors reported the following:
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John
G. Bartlett, MD has disclosed that
he has served on the HIV Advisory Board
for GlaxoSmithKline, Abbott, Bristol-Myers
Squibb, Pfizer and Tibotec. He is also on
the Policy Board for Johnson & Johnson.
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Paul
G. Auwaerter, MD has disclosed
that he has served as a consultant for Novartis,
Pfizer, Ortho-McNeil, Schering-Plough, and
Genzyme. He is on the Speakers' Bureau for
Schering-Plough and has also disclosed that
he is a Stock Shareholder for Johnson &
Johnson. |
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Sara
E. Cosgrove, MD, MS has disclosed
that as a co-investigator, she has received
grants or research support from Merck and
served on the Advisory Boards for Ortho-McNeil
and Cadence Pharmaceuticals. |
Guest
Author Disclosures |
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©
2007 JHUSOM and eInfections Review
Created by
DKBmed. |
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COMPLETE
THE
POST-TEST
Step
1.
Click on the appropriate link below. This will take you to
the post-test.
Step
2.
If you have participated in a Johns Hopkins on-line course,
login. Otherwise, please register.
Step
3.
Complete the post-test and course evaluation.
Step
4.
Print out your certificate.
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