Dengue Fever among Travelers Eli Schwartz, MD, DTMH, Ella Mendelson, PhD, Yehezkel Sidi, MD, Tel Hashomer, Israel
PURPOSE: The present paper describes the epidemiology and clinical manifestations of dengue fever in a nonendemic population of travelers. PATtENTs AND MErtioos: Clinical manifestations, epidemiologic information, and laboratory findings are described for a series of 18 Israeli travelers who tested serologically positive for dengue. RESULTS: All the patients in the series contracted the disease in Southeast Asia, mostly in Thailand; 30% had to be evacuated due to severe morbidity. The clinical symptoms in travelers somewhat differ from the classical description among endogenous populations. High fever, chills, extreme fatigue, and severe headaches were prevalent. Other symptoms considered to be typical of dengue fever, such as myalgia, arthralgia, rash, biphasic fever, were uncommon. Laboratory findings were marked leukopenia, usually accompanied by lymphopenia, thrombocytopenia, liver function impairment, and hyponatremia. Some hemorrhagic phenomena were manifest despite it being the first exposure, without mortality. CONCLUSIONS: Dengue fever among the nonimmune has a somewhat different manifestation from that reported for the Southeast Asian population. Although it is a significant cause for morbidity and hospitalization, it is underestimated as a factor affecting traveler’s health. More efforts should be expended in developing an effective o 1996 Excerpta Medica, Inc. Am J vaccine. Med. 1996;101:516-520.
engue fever is an acute febrile illness caused by a Flaviviridae virus. The disease is characterized by sudden onset of high fever with a biphasic (saddleback) pattern, chills, severe headache, mostly
From the Center of GeographIcal Medicine (ES), Chalm Sheba Medical Center, Tel Hashomer, and Travel Medicine Center, Misgav Ladach Hosoital. Jerusalem. Israel: and the Central Virology Laboratory (EM) and the bepertment of Medicine C (ES, YS), Chaim Sheba Medical Center, Tel Hashomer. and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Requests for reprints should be address to EII Schwartz, MD, Department of Medicine C. Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. Manuscript submitted May 10, 1996 and accepted in revised form August 27, 1996.
01996byExcerpta Medica,Inc. All rights reserved.
frontal or retroocular, skin rash, and general malaise. Typically severe muscle and joint pains gave it the name “breakbone disease.” Four serotypes of the virus are known, designated dengue types 1 through 4.l Transmission is principally by the Aedes aegypti mosquito (the yellow fever vector), which breeds in storage tanks of clear drinking water. The mosquito is active da,y and night, making it difficult to protect against its bite. There is no effective method of prevention, and a vaccine does not yet exist.” Dengue fever is endemic in most tropical areas of the world, including the Caribbean, Central and South America, Africa, and Southeast Asia.” Israel has never been an endemic area, and locally acquired infection is unknown. However, there has been a dramatic increase in the number of Israeli travelers to tropical areas in the past decade, opening the way for the importation of tropical diseases. About 40,000 Israelis set out annually, more than 25,000 of whom are backpackers traveling for 3 to 9 months off the beaten track.4 The clinical syndrome of dengue fever in endogenous populations has been extensively reviewed, I-3 but a paucity of information exists regarding travelers or nonimmune populations.5-‘0 In this, report, we describe a series of 18 patients who tested serologically positive to dengue fever.
PATIENTS AND METHODS During 1994 to 1995, 25 patients, who were either admitted to the medical ward with symptoms suggesting dengue fever or who presented to the travel clinics after developing symptoms typical of dengue fever, were tested serologically. The sera were tested using the dengue IgM capture enzyme lin.ked immunosorbant assay (ELISA) kit (Pn-Bio Pty Ltd., Queensland, Australia). Of the present series of 18 patients whose sera tested positive for dengue IgM, 8 were hospitalized in Israel, 6 were treated in outpatient travel clinics in Israel, and 4 had been hospitalized abroad before we saw them. All the sera were sent to the Center for Disease Control and Prevention (CDC, Atlanta, Georgia), for confirmation. All were IgM positive, and in 1, acute-phase serum dengue virus type 1 was isolated. Complete blood count and biochemistry tests were conducted for patients hospitalized in Israel. Results for patients who were hospitalized abroad 0002-9343/96/$15.00 Pll SOOO2-9343196)00278-l
DENGUE FEVER AMONG TRAVELERS/SCHWARTZ
1 2 3 4 5
6 7 8 9 10
11 12 13 14
15 16 17 18 Mean:
I Age (wars) 22 54 23 22 23 22 24 28 23 28 27 28 24 23 23 26 44 56 28.9 + 11
Sex M M M M F M
Thailand India Thailand Thailand Thailand Thailand India India
July February April July July September May June
M M M F
Thailand Thailand Thailand Thailand
MArch January January April
M M F
Thailand Thailand Thailand
April May May
+ + +
No data No data + + + -
No data No data
are those of tests done in local laboratories. For patients who presented after the acute phase of the disease, no laboratory results are available.
(44%) on the 2nd to 5th day of the disease, and was usually maculopapular, involving also the palms of the hands. Biphasic fever appeared in only 1 patient. Hemorrhagic phenomena. Dengue hemorrhagic fever (DHF) is characterized by fever, a platelet Epidemiology and Clinical Description count of under 100,000/mm~~,hemorrhagic manifesEpidemiology. All the patients were Israeli travtations, and leaky capillary syndrome (hemoconcenelers who visited endemic areas for the first time and tration, hypoalbuminemia, or pleural effusion). Denwere therefore nonimmune. The mean age was 28.9 gue shock syndrome (DSS) is diagnosed wlhen there ? 11 years (range 22 to 56). Twelve patients were is a decrease in blood pressure as well. The WHO hospitalized, and the rest received ambulatory care. definition listed above did not appear in any of the Due to severe morbidity, 5 of the patients had to inpatients in the series described here. However, seterrupt their trip and were flown home for treatment vere thrombocytopenia coupled with melena ap(Table I). Although thousands of Israelis travel to peared in 1 patient and purpura in 2. One patient was South America and Africa, all the patients in the seadmitted with a blood pressure of 75/45 mm Hg ries contracted the disease in Southeast Asia. Of the without evidence of hemorrhagic manifestations. 18 patients, 14 (77.8%) contracted dengue in Thailand, mostly on the small island of Koh-Pangan in The condition of this patient improved after 2 days the south (57%). Four patients contracted the dis- of symptomatic treatment. No fatality occurred. Laboratory results. The laboratory findings are ease in India. The time of year in which the disease summarized in Table III. Marked leukopenia ocwas contracted was between January and October, curred, with values well below the normal, the avthe majority of the cases between April and July. erage being 3,100 cells/mm”. In only 1 patient was a Clinical presentation. The clinical presentation normal white blood cell count found at presentation. is summarized in Table II. High fever and chills apLeukopenia was usually accompanied by lymphopeared in all patients. The duration of the fever was 5 to 7 days. Severe headache, mostly frontal or ret- penia. Thrombocytopenia was found in all patients, and in 6 of 11 (54.5%) cases, the platelet count was roocular, was a major complaint (83%). Extreme weakness and fatigue were experienced by almost even lower than 100,000. In contrast, he:moglobin levels were normal in all patients. Liver en.zyme aball the patients; however, myalgia and arthralgia, usually typical of dengue, were less frequent, occur- normality was found in all patients. However, only transaminase and LDH were elevated, whereas alring in 5 of 18 (28%). Nausea and vomiting occurred in 6 of 16 (38%) of the patients, 3 of whom also had kaline phosphatase was within the normal range in diarrhea. Diarrhea, however, could be due to con- all. Hyponatremia, with an average sodium level of comitant gastrointestinal infection common in trav- 134 meq/L, was evident in 5 of 9 (56%) of the paelers to the tropics. Rash appeared in only 8 of 18 tients at presentation. Hyponatremia is an outstandNovember
DENGUE FEVER AMONG TRAVELERS/SCHWARTZ
II Clinical Manifestations
2 3 4 5 6
+ + +
++ + + ++ +
Day 4 -
12 13 14
f + +
++ ++ ++
++ + +
16 17 18 Sum
Day 3 Day 5
Spleen liver Neck glands
Day 4 Day 2
Day 4 Day 5 Day 2 -
+ + +
++ + ++
Vomiting Purpura liver
Day 5 -
Vomiting, diarrhea Nausea, diarrhea Vomiting, diarrhea Melena klelena Vomiting Purpura
Ill Laboratory Results Number of Patients Mean ? SD
Test Blood count: Leucocytes (. 10q/L) Lymphocytes (. log/L) Thrombocytes (. lO’/L) Biochemistry GOT (U/L) LDH (U/L) Na (meq/L)
0.747 5 0.350 87 2 39
1.3-6.9 0.085-1.200 15-125
245 t 212 376 2 147
134 z 6
3.1 2 1.4
itive for dengue fever. Since some 40% od the group were vaccinated against Japanese encephalitis (JE) , also caused by a Flaviviridae virus, there might have been a possibility that the vaccine gave a false-posDISCUSSION Dengue fever is a common disease in many parts itive result for dengue fever in the serology tests.‘” of the globe. In endemic areas the disease assumes However, from results of a preliminary study we conepidemic proportions.‘1-“3 Moreover, the incidence ducted, it appears that there is no cross reactivity, of the acute forms of the disease, dengue hemor- and no case was found of a healthy person vaccirhagic fever (DHF) and dengue shock syndrome nated against JE who developed dengue IgM anti(DSS) , is increasing, and dengue is rapidly becom- bodies (unpublished data). All the patients in the series cont.racted the disease ing the most important arthropod-borne disease in in Asia-75% in Thailand and the remainder in India. humans.’ In Thailand, the highest incidence was from the isThe epidemiology and the clinical manifestation of land of Koh-Pangan in the south. The clinical manithe disease in endemic countries have been extenfestation in the series described was of severe morsively described, but few reports exist of the clinical bidity with high fever, extreme fatigue, and manifestation of dengue among the t,raveler populaheadaches. Other symptoms usually considered tion. Furthermore, the incidence of the disease characteristic of the disease such as arthralgia, myamong travelers from nonendemic areas is unalgia, and rash were found in only a small fraction known, and the impact of the disease on this popuof the patients. Biphasic fever appeared in only 1 lation is probably underestimated. In this paper we describe a series of 18 patients who tested IgM-pos- case.
ing symptom, not previously emphasized when describing dengue.
DENGUE FEVER AMONG TRAVELERS/SCHWARTZ
Outstanding laboratory results were marked leukopenia. The decrease in white blood cells may be used as an aid for differential diagnosis, distinguishing dengue from other infectious tropical diseases in which white blood cell counts remain near normal, such as malaria and typhoid fever.15 Platelet counts were low as well, with not a single case of normal count. The hemoglobin levels remained normal in all patients. Another consistent laboratory tiding was of liver function abnormality found in all patients, manifested by an increase in transaminase and lactic dehydrogenase. Alkaline phosphatase was normal in all cases. This differs from findings in dengue patients of endemic populations, in whom alkaline phosphatase was occasionally found to be elevated.‘” Hyponatremia is an unusual laboratory finding found in almost 60% of the patients described here. We found only one other report in the literature of this condition among travelers, lo and it was rarely described among endogenous populations. Hyponatremia was only referred to in severe cases of DHF, and is considered to be a possible mechanism of encephalopathy. “J Hyponatremia may be explained by increased capillary permeability, or by the syndrome of inappropriate anti-diuretic hormone (SIADH) secretion. Both these mechanisms have been described in conditions such as rickettsiosis.‘g Capillary leakage is part of the pathologic process in DHF and DSS. These severe forms of dengue fever are usually described in children in endogenous countries. The current theory is that the acute form of the disease is caused through immune enhancement by repeat exposure to dengue virus of a different serotype.“’ Despite this theory, there are reports of first exposure with hemorrhagic phenomena.“~‘0~21 In this series, all the travelers were exposed to dengue for the first time, and some had hemorrhagic manifestations such as purpura with a low platelet count. A couple who traveled together and became ill together reported having melena, suggesting that it may be due to a virulent strain of the virus. This observation does not support the common theory of enhanced antibody mechanism. Since in Israel there is no requirement to report dengue fever to the health authorities, the actual number of people affected by the disease is unavailable. However, at two major travel medicine centers, our experience has been that dengue is the second most frequent cause of hospitalization of returning travelers, malaria being first. In the same period of time there were 32 cases of malaria, but only 7 of them were of travelers returning from Asia. Because of the short 5 to 10 day incubation time of the disease, most infected travelers may have experienced the fever while still abroad. The patients described
here were either in such poor condition th#at they had to break their trip and be flown home for (care or the disease appeared close to their return date. Unlike malaria, where the number of patients reported is close to the number of patients affected, tlhis dengue series is only the tip of the iceberg representing the true incidence. Dengue is probably the greatest mosquito-borne disease risk to travelers. The need for a dengue vaccine is increasingly becoming important for the traveler population as well as for ertdogenous populations. A real risk exists of new endogenous cycles of dengue becoming established in the developed countries, where the vector is present and there are sufficient travelers to form a viral pool. In southern United States, both Aedes aeggpti, the principal dengue virus vector, and A albopictus, which also serves as a dengue vector, range year round from Florida to Texas. In fact, three outbreaks have been reported in the United States, in 1980, in 1986, ’ and more recently in 1995 (unpublished data). Aedes aegypti was at one time prevalent in the Mediterranean region, including Israel.“’ In Israel, with the introduction of central water systems and the disappearance of water jars, the mosquito has disappeared almost completely. Dengue fever may not as yet be a danger to public health in Israel, but is a serious health risks for its travelers.“” However, there have recently been reports of the appearance of the other dengue vector, A albopictus, in southern Europe and the Mediterranean area, “‘z and in these areas new autochtonus cycles of infection may become established.
ACKNOWLEDGMENT We wish to thank
for hts technical
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