Emerging Infectious Diseases
[Volume 5 No.6 / November - December 1999]
  Dispatches
   Dengue Seroconversion among Israeli Travelers to
   Tropical Countries
   Israel Potasman,* Isaac Srugo,* Eli Schwartz
   *Bnai Zion Medical Center, Haifa, Israel; Bruce
   Rappaport Faculty of Medicine Technion-Israel Institute
   of Technology, Haifa, Israel; Center for Geographical
   Medicine, Sheba Medical Center, Tel Hashomer, Israel
    We tested for dengue seroconversion among
    104 Israeli young adults who traveled to
    tropical countries for at least 3 months.
    Seven (6.7%) seroconverted during travel;
    four (3.8%) had immunoglobulin (Ig) M
    antibodies; one was symptomatic with
    borderline IgM and a rise in IgG; two
    others (1.9%) had a rise in IgG titers,
    without detectable IgM. All four
    IgM-positive patients had traveled to
    Southeast Asia.
   Dengue fever is a rapidly spreading mosquito-borne
   viral disease. Some 40% of the world's population lives
   in disease-endemic areas, and dengue outbreaks occur in
   more than 100 countries (1). Infected persons usually
   have high fever, chills, frontal headache, rash, severe
   myalgia, and malaise. Sometimes, the disease goes
   unrecognized (2).
   According to surveillance data, nearly 200,000 cases of
   dengue fever occur in 31 countries in Central and South
   America (3); the attack rate among disease-endemic
   populations may be as high as 6,400 per 100,000 persons
   exposed. In contrast to data regarding the rate of
   dengue among populations in disease-endemic areas, data
   on the attack rate among travelers are scarce.
   The rate of dengue fever has been examined in selected
   Japanese, Spanish, Swiss, and German travelers and in
   U.S. troops deployed in Somalia (4-8). The rate of
   dengue in these febrile patients was 6.9% to 65%. To
   the best of our knowledge, the rate of dengue fever has
   never been examined prospectively in a cohort of
   healthy, long-term travelers to disease-endemic areas.
   The Study
   The study was approved by the Helsinki Committee of the
   Bnai Zion Medical Center, which provides service to
   approximately 1,500 travelers per year. Each traveler
   is requested to fill out a questionnaire including
   demographic, itinerary, and vaccination data, which are
   stored in a computerized database. The purpose of the
   study was explained to the travelers, and informed
   consent was obtained upon enrollment. Serum was drawn
   from random volunteers before starting the recommended
   vaccinations. Eligibility for inclusion was based on a
   minimum length of travel of at least 3 months and
   donation of a serum sample before and after travel. One
   hundred and four travelers fulfilled the inclusion
   criteria. The second serum sample was taken 1 to 4
   months after returning home. Travelers who had positive
   dengue immunoglobulin (Ig) G serologic results were
   sent a questionnaire. In addition to demographics, the
   patients were asked to indicate their destination,
   season and length of stay, mosquito bites, use of
   repellents, fever, chills, nausea or vomiting, muscle
   aches, headache, cough, rash, or arthralgia. A case of
   dengue fever was defined according to Centers for
   Disease Control and Prevention (CDC) criteria (9). An
   asymptomatic dengue infection was one that met the
   laboratory criteria for diagnosis without clinical
   signs. Confidence intervals (CIs) were calculated with
   Statmate (GraphPad Software, San Diego, CA).
   After thawing, 104 posttravel serum samples were tested
   for antibodies to dengue by an IgG enzyme-linked
   immunosorbent assay (ELISA) (Pan-Bio Pty, Ltd.,
   Queensland, Australia). All positive sera were then
   tested in parallel with pretravel sera to confirm
   seroconversion. Seroconverting pairs were sent to the
   CDC laboratories in San Juan, Puerto Rico, for
   confirmation and dengue IgM and IgG antibody
   determination.
   IgM antibody was measured as a qualitative ELISA. An
   optical density of 0.2 or greater compared with a
   negative control was considered positive. The test may
   show some cross-reactivity to other flaviviruses (10).
   IgG antibody was measured as a quantitative ELISA using
   mixed dengue antigens. This test may also show
   cross-reactivity with other flaviviruses (11).
   The mean age of the 104 study participants was 22.4 
   2.2 years. The average length of stay abroad was 6.1
   months (3 to 16 months), and the total time abroad for
   all 104 travelers was 53 person-years. The average time
   between serum samples was 11.1 months (4 to 22 months).
   The destinations were Southeast Asia (70%), South
   America (24%), Africa (4%), and both Southeast Asia and
   South America (2%).
   Seven travelers (6.7%; 95% CI = 2.7-13.3%) had either
   an IgM antibody or a fourfold (or greater) rise in IgG
   titers after the trip. The median age of this group was
   22 years, and four travelers were women. All seven
   stayed at their destinations (Table) during the summer
   months (some also spent the spring or autumn there).
   Their mean length of stay abroad was 5.3 months. The
   rates of conversion per month of exposure by continent
   were as follows: Southeast Asia, 5 (1.1%) of 451 (95%
   CI = 0.36-2.6%); South America, 1 (0.6%) of 159 (95% CI
   = 0.02-3.5%); and Africa, 1 (4%) of 25 (95% CI =
   0.1-20.3%).
   Four patients (3.8%) tested positive for dengue IgM
   after travel. All four had negative IgM dengue
   serologic test results before travel, and all but one
   had negative IgG titers. All four (two of them male)
   visited Southeast Asia, with Thailand being the only
   common destination. Two of these patients, who had
   traveled separately, indicated that they became ill on
   the island of Ko-Pangan. All four were engaged in
   extensive outdoor activities and consequently had
   mosquito exposure. All four used mosquito repellents
   (containing 20% to 25% DEET), but only three recalled
   being bitten by mosquitoes. Three travelers had fever,
   which in two (both female) was also accompanied by
   chills, headache, and protracted fatigue. One patient
   had an apparently asymptomatic infection.
Table. Dengue serologic results in seroconverting Israeli travelers to tropical countries
Only two of the four IgM-positive patients had received Japanese B encephalitis vaccine after the initial blood collection, which could have interfered with after-travel testing. Of the three travelers who had a fourfold IgG rise, two were asymptomatic, and one had a clinical picture compatible with dengue fever 1 month after arriving in
Thailand. This traveler also had a marginal IgM test. Among these three travelers, two had received yellow fever vaccine and one Japanese B encephalitis vaccine, which could have interfered with after-travel testing.
Conclusions
Researchers have found that the younger the age, the higher the rate of illness among travelers, but dengue fever has not been thoroughly investigated (12,13). Dengue fever has not been reported in Israel over the last 50 years, which made our group of young travelers particularly
suitable for this study. In addition, there has been a dramatic increase in the number of Israeli travelers to tropical areas during the past decade. Approximately 40,000 Israelis travel to the tropics each year, more than 25,000 of whom are backpackers who travel for 3 to 12 months off the beaten track (14) and are exposed to the same diseases as travelers from other countries. Dengue fever has not been
mentioned as a real hazard to Israeli travelers, despite an incidence in our study that may be as high as the rate of malaria without prophylaxis, and higher than the rates of hepatitis A, giardiasis, or typhoid fever (15). Nevertheless, it would be premature to extrapolate
from our group of youngsters traveling on prolonged journeys, to groups with other travel characteristics. Older and perhaps short-term travelers may, for example, choose other tracks or adhere more closely to recommendations regarding insect repellents (16).
Four travelers (3.8%) of our group had IgM antibodies, indicating acute infection. Another traveler had symptoms of dengue fever with borderline IgM and a rising titer of IgG, which most probably reflected a recent infection. This traveler could have been infected earlier during her 6-month trip, and by the time the serum was taken, the IgM
level might have dropped. Two additional travelers had a rise in IgG titers without detectable IgM.
Our results are tentative, as the serologic tests for dengue are not devoid of cross-reactivity (11). Both IgM and IgG may cross-react with other flaviviruses, such as Japanese B encephalitis, West Nile encephalitis, or yellow fever. The rate of IgG cross-reactivity between dengue infection and Japanese B encephalitis or yellow fever vaccine may be 17% to 40%; however, IgM cross-reactivity was not found after
vaccination (E. Schwartz, pers. comm.). As none of our travelers had signs of encephalitis and yellow fever does not exist in Southeast Asia, the five travelers with IgM antibodies (including the one with a borderline case) contracted dengue fever. Indeed, four of them had
clinical symptoms compatible with dengue fever. The diagnosis in the two travelers who had a fourfold rise in IgG titers was uncertain, since both were asymptomatic and had received yellow fever vaccines, which may have caused a cross-reaction in IgG assays. Dengue infection may be asymptomatic. Only three of the four IgM-positive patients were febrile; two of these also had chills. Asymptomatic dengue, which was found in three of our patients, has been described in populations of disease-endemic areas but never in travelers (2,17).
Two additional points in our study deserve comment. First, all four IgM-positive cases and the borderline IgM case occurred in travelers to Southeast Asia. A higher density of the vector and virus in Southeast Asia or visits by many of our travelers to Thai destinationsknown for their high rate of dengue (18-20) may have played a major role in this
trend (our data are insufficient to permit conclusions regarding travel to Africa and South America). Secondly, all seven cases occurred during the summer, a season known for its high rate of mosquito activity and dengue transmission. The rate of dengue fever among travelers has been
studied by four groups of researchers (4-7); an additional group described dengue in U.S. troops deployed in Somalia (8). The rate of dengue in their cohorts was 6.9% to 65%. However, all of these researchers focused on febrile patients with either fever of unknown origin, suspected dengue, or malaria. Hence, it is impossible to
extrapolate from their data the actual risk of acquiring dengue during travel to the tropics.
 
Other travel clinics in Israel also have indicated that (after malaria) dengue is the second most frequent cause of hospitalization of returning travelers (20). Based on a minimum figure of the four IgM-positive patients, the calculated risk for dengue during a 1-month trip is thus 630 out of 100,000 travelers, which puts dengue high on
the list of diseases contracted in the tropics. This statement holds true at least for Israeli travelers to the Far East. As patients may be evacuated because of dengue fever or may become sick after returning home, physicians need to be all the more vigilant in the face of this
diagnostic possibility.
We conclude that dengue fever is perhaps the most common mosquito-borne disease of long-term young travelers, particularly those visiting Southeast Asia. The present results should serve as a further impetus toward the development of a vaccine for dengue fever.
Acknowledgments
The authors thank Gary Clark and Vance Vorndam for performing the serologic tests and for their comments, and to R. Singer for excellent secretarial assistance.
This work was supported by the Research and Infrastructure Foundation, Israel Ministry of Health.
Dr. Potasman is head of Infectious Diseases at the Bnai Zion Medical Center, which is part of the Faculty of Medicine, Technion, Haifa. His area of expertise is travel medicine, with special interest in diseases among travelers, antimalarial drugs, vaccines, and Helicobacter pylori.
Address for correspondence: Israel Potasman, Infectious Disease Unit, Bnai Zion Medical Center, P.O. Box 4940, 31048 Haifa, Israel; fax: 972-4-835-9755; e-mail: ipotasma@netvision.net.il.
References
1. World Health Organization/CTD. Dengue and DHF prevention and control. Geneva: The Organization; 1998.
2. Burke DS, Nisalak A, Johnson DE, Scott RM. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg 1988;38:172-80.
3. Lifson AR. Mosquitoes, models, and dengue [commentary]. Lancet 1996;347:1201-2.
4. Yabe S, Nakayama M, Yamada K, Kitano T, Arai Y, Horimoto T, et al. Laboratory virological diagnosis of imported dengue cases. Kansenshogaku Zasshi 1996;70:1160-9 (In Japanese).
5. Lopez-Velez R, Perez-Casa C, Vorndam A, Rigau J. Dengue in Spanish travelers returning from the tropics. Eur J Clin Microbiol Infect Dis 1996;15:823-6.
6. Settah SG, Vernazza PL, Morant R, Schultze D. Imported dengue fever in Switzerlandserological evidence for a hitherto unexpectedly high prevalence. Schweiz Med Wochenschr 1995;125:1673-8 (In German).
7. Jelinek T, Dobler G, Holscher M, Loscher T, Nothdurft H-D. Prevalence of infection with dengue virus among international travelers. Arch Intern Med 1997;157:2367-70.
8. Sharp TW, Wallace MR, Hayes CG, Sanchez JL, DeFraites RF, Arthur RR, et al. Dengue fever in U.S. troops during Operation Restore Hope, Somalia, 1992-1993. Am J Trop Med Hyg 1995;53:89-94.
9. Centers for Disease Control. Dengue fever. MMWR Morb Mortal Wkly Rep 1990;39:10-1.
10. Burke DS, Nisalak A, Ussery MA. Antibody capture  immunoassay detection of Japanese encephalitis virus immunoglobulin M and G antibodies in cerebrospinal fluid. J Clin Microbiol 1982;16:1034-42.
11. Makino Y, Tadano M, Saito M, Maneekam N, Sittisombut N,
Sirisanthana V, et al. Studies on serological cross-reaction in sequential flavivirus infections. Microbiol Immunol 1994;38:951-5.
12. Steffen R, Rickenbach M, Wilhelm U, Helminger A, Schar M. Health problems after travel to developing countries. J Infect Dis 1987;156:84-91.
13. Reid D, Grist NR, Najera R. Illness associated with "package tours": a combined Spanish-Scottish study. Bull World Health Organ 1978;56:117-22.
14. Berger SA, Giladi M, Shapira I. Health concerns of Israelis traveling to third world countriesexperience of a travel advisory clinic. Harefuah 1994;126:410-2 (In Hebrew).
15. Reid D, Keystone J. Health risks abroad: general considerations. In: DuPont H, Steffen R, editors. Textbook of travel medicine and health. Vol 1. Hamilton, Canada: BC Decker; 1997. p. 3-9.
16. Fradin MS. Mosquitoes and mosquito repellents: a clinician's guide. Ann Intern Med 1998;128:931-40.
17. da Cunha RV, Dias M, Nogueira RM, Chagas N, Miagostovich MP, Schatzmayr HG. Secondary dengue infection in schoolchildren in a dengue endemic area in the state of Rio de Janeiro, Brazil. Rev Ins Med Trop Sao Paulo 1995;37:517-21.
18. Pick N, Potasman I. Dengue fever. Harefuah 1995;129:30-2 (In Hebrew).
19. Thavara U, Tawatsin A, Phan-Urai P, Ngamsuk W, Chansang C, Liu M, et al. Dengue vector mosquitos at a tourist attraction, Ko Samui, in 1995. Southeast Asian J Trop Med Public Health 1996;27:160-3.
20. Schwartz E, Mendelson E, Sidi Y. Dengue fever among travelers. Am J Med 1996;101:516-20.
Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA
URL: http://www.cdc.gov/ncidod/eid/vol5no6/ascii/potasman.txt
Please note that figures, equations, and most tables are not available in ASCII format; their placement within the text is noted by [fig] and [eq], respectively.  Greek symbols are spelled out. >/= is used for greater than or equal to.