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 vaccine. o 1996 Excerpta Medica, Inc. Am J Med. 1996;101:516-520.

D 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 (sad- dleback) pattern, chills, severe headache, mostly

From the Center of GeographIcal Medicine (ES), Chalm Sheba Medical Center, Tel Hashomer, and Travel Medicine Center, Misgav Ladach Hos- oital. 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, Depart- ment of Medicine C. Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.

Manuscript submitted May 10, 1996 and accepted in revised form Au- gust 27, 1996.

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 princi- pally by the Aedes aegypti mosquito (the yellow fe- ver 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 ac- quired infection is unknown. However, there has been a dramatic increase in the number of Israeli travelers to tropical areas in the past decade, open- ing 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 endoge- nous populations has been extensively reviewed, I-3 but a paucity of information exists regarding travel- ers or nonimmune populations.5-‘0 In this, report, we describe a series of 18 patients who tested serolog- ically positive to dengue fever.

PATIENTS AND METHODS During 1994 to 1995, 25 patients, who were either

admitted to the medical ward with symptoms sug- gesting 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 immu- nosorbant 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

516 01996byExcerpta Medica,Inc. All rights reserved.

0002-9343/96/$15.00 Pll SOOO2-9343196)00278-l

DENGUE FEVER AMONG TRAVELERS/SCHWARTZ ET AL

- TABLE I

Epidemiological Data No. Age (wars) Sex Country Month JE Vaccine Evacuation 1 22 M Thailand July + - 2 54 M India February - - 3 23 M Thailand April + - 4 22 M Thailand July + - 5 23 F Thailand July No data - 6 22 M Thailand September No data - 7 24 F India May + - 8 28 F India June - -

9 23 M Thailand MArch + + 10 28 M Thailand January + + 11 27 M Thailand January - - 12 28 F Thailand April - -

13 24 M Thailand April - + 14 23 M Thailand May No data - 15 23 F Thailand May No data -

16 26 M Thailand August + + 17 44 F Thailand August - -

18 56 F India October - +

- Mean: 28.9 + 11 11 M/7F 14Th/4ln 7+/7- 5+/13-

are those of tests done in local laboratories. For pa- tients who presented after the acute phase of the disease, no laboratory results are available.

Epidemiology and Clinical Description Epidemiology. All the patients were Israeli trav-

elers who visited endemic areas for the first time and were therefore nonimmune. The mean age was 28.9 ? 11 years (range 22 to 56). Twelve patients were hospitalized, and the rest received ambulatory care. Due to severe morbidity, 5 of the patients had to in- terrupt their trip and were flown home for treatment (Table I). Although thousands of Israelis travel to South America and Africa, all the patients in the se- ries contracted the disease in Southeast Asia. Of the 18 patients, 14 (77.8%) contracted dengue in Thai- land, mostly on the small island of Koh-Pangan in the south (57%). Four patients contracted the dis- ease in India. The time of year in which the disease was contracted was between January and October, the majority of the cases between April and July.

Clinical presentation. The clinical presentation is summarized in Table II. High fever and chills ap- peared in all patients. The duration of the fever was 5 to 7 days. Severe headache, mostly frontal or ret- roocular, was a major complaint (83%). Extreme weakness and fatigue were experienced by almost all the patients; however, myalgia and arthralgia, usually typical of dengue, were less frequent, occur- ring in 5 of 18 (28%). Nausea and vomiting occurred in 6 of 16 (38%) of the patients, 3 of whom also had diarrhea. Diarrhea, however, could be due to con- comitant gastrointestinal infection common in trav- elers to the tropics. Rash appeared in only 8 of 18

(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 count of under 100,000/mm~~, hemorrhagic manifes- tations, and leaky capillary syndrome (hemoconcen- tration, hypoalbuminemia, or pleural effusion). Den- gue shock syndrome (DSS) is diagnosed wlhen there is a decrease in blood pressure as well. The WHO definition listed above did not appear in any of the patients in the series described here. However, se- vere thrombocytopenia coupled with melena ap- peared in 1 patient and purpura in 2. One patient was admitted with a blood pressure of 75/45 mm Hg without evidence of hemorrhagic manifestations. The condition of this patient improved after 2 days of symptomatic treatment. No fatality occurred.

Laboratory results. The laboratory findings are summarized in Table III. Marked leukopenia oc- curred, with values well below the normal, the av- erage being 3,100 cells/mm”. In only 1 patient was a normal white blood cell count found at presentation. Leukopenia was usually accompanied by lympho- penia. Thrombocytopenia was found in all patients, and in 6 of 11 (54.5%) cases, the platelet count was even lower than 100,000. In contrast, he:moglobin levels were normal in all patients. Liver en.zyme ab- normality was found in all patients. However, only transaminase and LDH were elevated, whereas al- kaline phosphatase was within the normal range in all. Hyponatremia, with an average sodium level of 134 meq/L, was evident in 5 of 9 (56%) of the pa- tients at presentation. Hyponatremia is an outstand-

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DENGUE FEVER AMONG TRAVELERS/SCHWARTZ ET AL -~

TABLE II

Clinical Manifestations

Myalgia Organ Hemorrhagic No. Headache Weakness Arthralgia Rash Enlargement GI Symptoms Phenomena

1 + ++ Day 3 Spleen liver 2 - ++ - Day 5 Neck glands 3 + + - - - 4 - + - Day 4 5 + ++ - Day 2 6 + + - - Spleen 7 + + - - - Vomiting 8 + ++ - Day 4 -

9 - ++ - - - Purpura 10 - ++ - Day 4 Spleen, liver 11 + + + Day 5 - Vomiting, diarrhea 12 f ++ ++ Day 2 - Nausea, diarrhea 13 + ++ + - - Vomiting, diarrhea 14 + ++ + - Melena 15 - + - - - klelena 16 + ++ - - - Vomiting 17 + + + Day 5 - Purpura 18 + ++ - - Neck glands Vomiting --

Sum 13 18 5 9 5 6 4

TABLE Ill Laboratory Results

Test Number of Patients Mean ? SD Normal Values Range

Blood count: Leucocytes (. 10q/L) 12 3.1 2 1.4 5-10 1.3-6.9 Lymphocytes (. log/L) 9 0.747 5 0.350 1.800-4.800 0.085-1.200 Thrombocytes (. lO’/L) 11 87 2 39 150-300 15-125

Biochemistry GOT (U/L) 11 245 t 212 <40 46-630 LDH (U/L) 8 376 2 147 <220 213-643 Na (meq/L) 9 134 z 6 >136 128-142

ing symptom, not previously emphasized when de- scribing dengue.

DISCUSSION Dengue fever is a common disease in many parts

of the globe. In endemic areas the disease assumes epidemic proportions.‘1-“3 Moreover, the incidence of the acute forms of the disease, dengue hemor- rhagic fever (DHF) and dengue shock syndrome (DSS) , is increasing, and dengue is rapidly becom- ing the most important arthropod-borne disease in humans.’

The epidemiology and the clinical manifestation of the disease in endemic countries have been exten- sively described, but few reports exist of the clinical manifestation of dengue among the t,raveler popula- tion. Furthermore, the incidence of the disease among travelers from nonendemic areas is un- known, and the impact of the disease on this popu- lation is probably underestimated. In this paper we describe a series of 18 patients who tested IgM-pos-

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-pos- itive result for dengue fever in the serology tests.‘” However, from results of a preliminary study we con- ducted, it appears that there is no cross reactivity, and no case was found of a healthy person vacci- nated against JE who developed dengue IgM anti- bodies (unpublished data).

All the patients in the series cont.racted the disease in Asia-75% in Thailand and the remainder in India. In Thailand, the highest incidence was from the is- land of Koh-Pangan in the south. The clinical mani- festation in the series described was of severe mor- bidity with high fever, extreme fatigue, and headaches. Other symptoms usually considered characteristic of the disease such as arthralgia, my- algia, and rash were found in only a small fraction of the patients. Biphasic fever appeared in only 1 case.

518 November 1996 The American Journal of Medicine’” Volume 101

Outstanding laboratory results were marked leu- kopenia. The decrease in white blood cells may be used as an aid for differential diagnosis, distinguish- ing 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 pa- tients of endemic populations, in whom alkaline phosphatase was occasionally found to be ele- vated.‘”

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. Hypona- tremia was only referred to in severe cases of DHF, and is considered to be a possible mechanism of en- cephalopathy. “J Hyponatremia may be explained by increased capillary permeability, or by the syn- drome 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 enhance- ment by repeat exposure to dengue virus of a differ- ent serotype.“’ Despite this theory, there are reports of first exposure with hemorrhagic phenomena.“~‘0~21 In this series, all the travelers were exposed to den- gue 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 unavail- able. 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 dis- ease, 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 mos- quito-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 den- gue becoming established in the developed coun- tries, where the vector is present and there are suf- ficient travelers to form a viral pool. In southern United States, both Aedes aeggpti, the principal den- gue 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 re- cently 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 be- come established.

ACKNOWLEDGMENT We wish to thank Mr. Fernando Mileguir for hts technical assistance

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