Dengue Fever in Travelers Returning from Southeast Asia

Transcription

1 ORIGINAL ARTICLES Dengue Fever in Travelers Returning from Southeast Asia Valerie Sung, Daniel P. O Brien, Elizabeth Matchett, Graham V. Brown, and Joseph Torresi Background: Dengue fever is an important illness facing travelers from nonendemic to endemic countries. Methods: We reviewed 696 consecutive returned travelers managed at an Australian tertiary-care hospital for an illness acquired overseas. Patients with dengue fever were compared to those with a dengue-like illness, malaria, typhoid fever and rickettsial infections. Results: In total, 19 cases of dengue fever and 20 cases of dengue-like illness were diagnosed, with 85% of cases acquired in Asia. The most common presenting features of dengue were fever (100%), myalgia (79%), rash (74%), headache (68%), nausea (37%), and diarrhea (37%). Compared to those with malaria, typhoid fever and rickettsial infections, patients with dengue were significantly more likely to have myalgia and a temperature 39 C. Compared to all other illnesses in our returned travelers, dengue fever was 18 times more likely if fever and leukopenia were present, 71 times if fever and rash were present, and 230 times if fever, rash and leukopenia were present. All patients with dengue recovered completely. Conclusions: Dengue fever is an important health problem for travelers not only to Southeast Asia but to all endemic countries. The prevalence appears to be increasing in travelers, and health care professionals need to be familiar with its presentation in travelers. The clinical presenting features provide important guides to establishing the diagnosis. Dengue fever is an arthropod-borne infection caused by a Flavivirus spread by the Aedes aegypti and Aedes albopictus mosquitoes. Both vectors are widespread throughout Southeast Asia, South America, Africa and Central Asia, and have adapted to cohabiting with humans in urban as well as rural environments. 1 The disease is now endemic in over 100 countries,many of which have Valerie Sung, MBBS; Daniel P. O Brien, MBBS, FRACP; and Elizabeth Matchett, B. Nursing: Victorian Infectious Disease Service, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia; Graham V. Brown, MBBS, MPH, FRACP, PhD, and Joseph Torresi, MBBS, B.Med.Sci., FRACP, PhD: Victorian Infectious Disease Service, Department of Medicine, and Clinical Center Research Excellence, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia. The authors had no financial or other conflicts of interest to disclose. Correspondence: Dr Joseph Torresi, Department of Medicine and Victorian Infectious Diseases Service, Royal Melbourne Hospital, The University of Melbourne, Grattan Street, Parkville, VIC 3050, Australia. J Travel Med 2003; 10: poor mosquito control programs and a high prevalence of infection. 2 Infection is caused by one of four serotypes (DEN-1, DEN-2, DEN-3 and DEN-4) and is often a mild illness or subclinical. 3,4 Up to 500,000 cases are reported annually in Southeast Asia and South America, 2, with case-fatality rates ranging from 1% to 5% for dengue hemorrhagic fever (DHF), and from 12% to 44% for dengue shock syndrome (DSS). 1,4 The incidence of dengue fever in travelers has not been well documented, despite numerous reports describing it as a cause of fever in returned travelers. 5 9 Similarly,the clinical presentation of dengue fever in shortterm travelers who may be exposed for the first time is also not well described, although it is presumed to be similar to that in patients resident in endemic countries. In travelers returning from developing countries, dengue fever may be confused with other infections, such as chickungunya virus infection, which may cause an illness that is almost indistinguishable from dengue fever. DSS has also been infrequently reported following primary infection in travelers. 10,11 In this paper, we describe the frequency, epidemiology and clinical and laboratory features of dengue fever in a population of returned travelers from the Asia-Pacific region presenting to a specialist infectious diseases unit in a nonendemic country. 208

2 Sung et al., Dengue Fever in Travelers Returning from Southeast Asia 209 Methods Our study included all returned travelers who were managed by the Victorian Infectious Diseases Service (VIDS) at the Royal Melbourne Hospital over a 4-year period. Data were collected prospectively between 1 July 1998 and 31 December 2001, and retrospectively from 1 January 1997 to 30 June Patient details, including epidemiologic features, travel itinerary, clinical features, laboratory investigations, management and outcome, were collected on data collection forms and entered into TravMed, an Access (Microsoft) database created and operated by the VIDS. 8. Data were analyzed using Epi- Info 6 (Centers for Disease Control and Prevention, Atlanta, GA, USA) to calculate odds ratios with 95% confidence intervals and chi-squared ( 2 ) tests for 2 2 tables to test the significance of the relationship between two variables. The following definitions 8 were used. Patient Classification 1. Traveler: an Australian resident whose illness was acquired during recent overseas travel but not as an expatriate 2. Expatriate: an Australian resident whose illness was acquired while living outside Australia in a single country for the purpose of work or education for a period longer than 1 month 3. Visitor: a non-australian resident traveling to Australia whose illness was acquired prior to arrival and who had been in a dengue-endemic region in the 14 days prior to arrival Regions Countries were classified according to broad regions as follows: 1. Asia: Southeast Asia and the Indian subcontinent 2. The Pacific: in the Pacific Ocean east of Australia, including New Zealand and Papua New Guinea, but excluding Hawaii Diagnosis A diagnosis of dengue fever was established by the authors of this study, or by the specialist infectious diseases physicians of VIDS, on the basis of: 1. Consistent epidemiology, clinical features and supporting nonserologic laboratory investigations, or 2. Serology IgG or IgM positive using an ELISA (PanBio Pty Ltd, Brisbane, Queensland, Australia). Patients who did not have a history of travel to an endemic country prior to the recent journey were considered to have dengue if the first blood sample collected had a serum IgG titer of 1:10, or if a 4- fold rise in IgG antibody titer could be demonstrated in two serum samples collected 14 days apart. A diagnosis of a dengue-like illness was established on the basis of consistent epidemiology, clinical features and supporting nonserologic laboratory investigations but with negative, equivocal or incomplete serologic testing. DHF and DSS were defined according to the World Health Organization (WHO) diagnostic criteria. 12 In brief, DHF included:(1) fever;(2) hemorrhagic manifestations, including at least a positive tourniquet test or either a major or minor bleeding phenomenon; (3) thrombocytopenia (platelet count 100,000 cells/mm 3 ); and (4) plasma leakage as evidenced by a rise in hematocrit (hematocrit increased by 20% relative to baseline values) or clinical signs, such as pleural effusions or ascites. DSS included all of the above plus evidence of circulatory failure. Thick and thin blood films confirmed all cases of Plasmodium vivax and Plasmodium falciparum malaria.typhoid fever was confirmed by isolation of Salmonella typhi in either blood or fecal cultures. Blood cultures were collected from all febrile returned travelers. Rickettsial infections included only patients in whom the diagnosis was confirmed serologically. Leukopenia was defined as a white cell count (WCC) of cells/mm 3, neutropenia as a neutrophil count of cells/mm 3, and thrombocytopenia as a platelet count of cells/mm 3. Results Epidemiology Sixty-nine returned travelers were included in our study. Dengue fever and dengue-like illness were diagnosed in 39 (5.6%) of all patients,and in 10.6% (39/368) of those returning from Asia alone. Dengue fever was diagnosed in 2.7% (19/696) of all patients, and in 5.2% (19/368) of travelers returning from Asia. Of the patients with dengue fever,9 (47%) were men, and 10 (53%) were women. Patients ages ranged from 15 to 54 years, with a median age of years for men, and years for women (p 0.02). Three of 19 (15.8%) with confirmed dengue fever and 5 of 20 with a dengue-like illness were managed as outpatients. All patients had uncomplicated dengue fever. Thirty-five (89.7%) patients acquired infection in Asia, 3 (7.7%) in the Pacific region, and one in Africa (Kenya) (2.6%). The period of travel could be ascertained for 32 travelers, and of these 11 (34.4%) had traveled between the months of June and September inclusive. Thailand was the country most frequently visited (15 patients; 38.5%) (Fig.). Twelve of these travelers had not

3 210 Journal of Travel Medicine, Volume 10, Number 4 traveled to other destinations in Southeast Asia. The duration of travel was determined for 34 travelers and was relatively short,with a median of 19 days (range 5 to 180 days). In 21 patients (62%), the total duration of travel was 3 weeks. Of the travelers with confirmed dengue fever, 18 (95%) acquired their infection in Asia (of whom 9 included Thailand as travel destination) and 1 in the Pacific region (Fiji). Clinical Presentation of Dengue Fever The time to presentation to hospital after returning home was short, with a median of 3 days (range 1 to 28 days). Seventy-one percent of travelers had presented by 6 days. Fever was the most commonly reported symptom, affecting all patients with dengue fever, followed by myalgia (79%), rash (74%), headache (68%), nausea (37%) and diarrhea (37%) (Table 1). Fever and headache were also commonly encountered in patients with malaria, typhoid fever and rickettsial infections (Table 1). In hospital, 15 (74%) patients with dengue fever and 9 (45%) patients with dengue-like illness had a documented fever. The temperatures of patients with confirmed dengue fever were 39 C for 5 (26%), 38 C to 38.9 C for 5 (26%), and 37 C to 37.9 C for 4 (21%). The temperatures of patients with dengue-like illness were 39 C for 3 (15%), 38 C to 38.9 C for 3 (15%), and 37 C to 37.9 C for 3 (15%). A temperature of 39 C was reported in only 2 (1.8%) patients with rickettsial infections. Fourteen (74%) patients with dengue fever had a rash detected; 7 (50%) were described as maculopapular or macular, 4 (29%) as diffusely erythematous, 2 (14%) as nonspecific, and 1 (7%) as petechial. Splenomegaly was clinically detectable in 1 patient, but hepatomegaly was absent in all patients (Table 2). Table 1 Spectrum and Frequency of Symptoms in Patients with Dengue Fever Patients with Patients with Patients with Patients with Patients with Symptoms and Confirmed Dengue-like Malaria Typhoid Fever Rickettsial Infection signs Dengue Fever (n 19) Illness (n 20) (n=121) (n=10) (n=11) Fever 19 (100%) 17 (85%) 118 (98%) 10 (100%) 9 (82%) Rash 14 (74%) 11 (55%) 2 (2%) 1 (10%) 2 (2%) Headache 13 (68%) 13 (65%) 75 (62%) 8 (80%) 7 (67%) Myalgia 15 (79%) 14 (70%) 33 (27%) 2 (20%) 8 (73%) Arthralgia 8 (42%) 3 (15%) 21 (17%) 0 3 (27%) Nausea 7 (37%) 7 (35%) 28 (23%) 6 (60%) 1 (9%) Diarrhea 7 (37%) 6 (30%) 20 (17%) 3 (30%) 3 (27%) Cough 5 (26%) 2 (10%) 14 (12%) 6 (60%) 2 (18%) Vomiting 4 (21%) 4 (20%) 18 (15%) 6 (60%) 2 (18%) Abdominal pain 1 (5%) 3 (15%) 14 (12%) 4 (40%) 1 (9%) Splenomegaly (21%) 2 (20%) 0 Hepatomegaly (12%) 1 (10%) 0 Table 2 Comparison of Clinical and Laboratory Features of Patients with Serologically Confirmed Dengue Fever and Patients with Presumptive Dengue Fever Serologically Confirmed Dengue Fever (n 19) Dengue-like Illness (n 20) Symptoms: n (%) Fever 19 (100%) 17 (85%) Rash 14 (74%) 11 (55%) Examination: n (%) Elevated temperature 15 (74%) 9 (45%) Rash 12 (63%) 7 (35%) Maculopapular 5 (42%) 2 (29%) Macular 2 (17%) 3 (43%) Erythematous 4 (33%) 2 (29%) Petechial 1 (8%) 1 (14%) Laboratory findings (median SE) Serum ALT (IU/L) p.1 WCC ( 10 9 cells/mm 3 ) p.01 Lymphocyte ( 10 9 cells/mm 3 ) p.02 Neutrophil ( 10 9 cells/mm 3 ) p.03 Platelet ( 10 9 cells/mm 3 ) p.01 WCC white blood cell count.

4 Sung et al., Dengue Fever in Travelers Returning from Southeast Asia 211 Sri Lanka Western Samoa Country visited Fiji East Timor Indonesia Singapore Laos Philippines / Indonesia Philippines / Malaysia Thailand / Nepal Thailand / Laos / Malaysia Thailand / Laos Thailand / Vietnam Thailand Number of patients Figure Countries recently visited by patients with confirmed dengue fever. Table 3 Laboratory Results (median SE) for Patients with Dengue Fever, Typhoid Fever and Malaria Confirmed Dengue fever Typhoid Malaria Rickettsia Normal range White blood cell count ( 10 9 cells/mm 3 ) * * * Neutrophil count ( 10 9 cells/mm 3 ) * * * Platelet count ( 10 9 cells/mm 3 ) Serum ALT (IU/L) *p for the comparison with dengue; p 0.01 for the comparison with dengue fever; p NS for the comparison with dengue fever. In contrast to patients with confirmed dengue fever, those with a dengue-like illness were less likely to have fever and rash, and a smaller proportion of these patients had a fever with temperature above 38 C (Tables 1 and 2). Laboratory Investigations Serologic testing for dengue fever revealed that 19 (45%) patients were positive, 9 (45%) were not tested or had equivocal results, and 11 (55%) had negative first-bleed serology and failed to have follow-up testing performed. Several important differences in laboratory investigations were noted between patients with confirmed dengue fever and those with a dengue-like illness. Leukopenia was detected in 17 (89.5%) patients, and thrombocytopenia in 16 (84.2%) patients. The median WCC was cells/mm 3, and the median platelet count was cells/mm 3.Lymphopenia was detected in 15 of 17 patients (88%), with a median count of cells/mm 3. Neutropenia was detected in 17 of 17 patients, with a median count of cells/mm 3. Comparing patients with serologically confirmed dengue and those with a dengue-like illness, the latter had significantly less leukopenia (median cells/mm 3 ),thrombocytopenia ( cells/mm 3 ) and lymphopenia ( cells/mm 3 ) (Table 2). A platelet count of cells/mm 3 was detected in 10 patients with confirmed dengue (52.6%) compared to 4 of 18 patients (who had complete data) with a dengue-like illness (22%) (p NS).In comparison,patients with typhoid fever and rickettsial infections had significantly higher mean total WCCs, neutrophil counts and platelet counts. For malaria patients, leukopenia and neutropenia were not observed, but thrombocytopenia was similarly common (Table 3). Alanine transaminase (ALT) serum levels were elevated in 8 of 17 (47%) patients with dengue fever,with a median of IU/L.Abnormalities of liver function tests were more severe in patients with typhoid fever whose median serum ALT was IU/L (Table 3).

5 212 Journal of Travel Medicine, Volume 10, Number 4 We examined combinations of clinical features and laboratory abnormalities on admission to determine the usefulness of these combinations in predicting the likelihood of a diagnosis of dengue fever compared to other illnesses in returned travelers. Patients with serologically confirmed dengue fever were significantly more likely to present with the combination of fever and rash (OR 71,95% CI %) or fever and leukopenia (OR 18.3, 95% CI %) than other returned travelers. Returned travelers with dengue fever were significantly more likely to present fever, rash and leukopenia than any other diagnosis (OR 230, 95% CI %). Blood cultures were negative in all patients. Outcome Apart from 3 patients who were initially started on parenteral antibiotics for presumed bacterial sepsis, all patients received supportive management alone. All recovered without complications, and there were no readmissions or deaths. Discussion Dengue fever remains an important disease in developing countries, where over 10 million cases of dengue fever and 250,000 cases of DHF are reported annually. 13 International travel to dengue-endemic countries places many at risk of acquiring this infection. 9 Despite this, the reported incidence of dengue fever among travelers is variable and dependent on several factors, including the destination, season, and duration of travel. The incidence of severe and complicated dengue fever in travelers returning from endemic countries is also poorly documented. In this paper, we have described the clinical presentation of dengue fever in travelers returning to Australia, mainly from Southeast Asia. This was compared to other common causes of fever in returned travelers, including those with a dengue-like illness but in whom a serologic diagnosis could not be confirmed. Serologic evidence of dengue fever has been reported in over 6% of travelers with fever after returning from endemic areas. 5,8,14 16 In expatriates who have spent several years in endemic areas, serologic evidence of dengue fever is present in over 7% of individuals. 17,18 The majority of infections in our patients were acquired in Thailand. This is similar to other reports of the occurrence of dengue fever in travelers. 5,7,10,15,19 In a recent report of dengue fever in European travelers, over 35% of infections were acquired in Southeast Asia, compared to 22% from India and 16.2% from the Americas. 19 Our findings support those of previous reports that have similarly shown that prolonged travel is not required for the development of symptomatic dengue fever. Many of our patients had stayed in an endemic country for as little as 1 week [10]. The incidence of dengue virus infection may also vary depending on the season of travel. 17,18 In a study of Israelis traveling to Thailand, the overall attack rate for dengue fever was found to be 3.4/1,000 people. However, in the dry season (December to June),the attack rate was substantially higher (5/1,000 people) than in the wet season (July to November; 1.7/1,000 people). 7 A substantial proportion (14 87%) of patients infected with dengue virus develop few or atypical symptoms. 3,20,21 This may be important in returned travelers, in whom the diagnosis may be overlooked. Rash is reported to occur in approximately half of returned travelers with dengue fever, 5,10,22 although a recent study reported rash in only 29% of travelers with dengue fever. 9 In contrast, in our study rash was present in 74% of patients with dengue fever and was more common than in other febrile returned travelers and those with a dengue-like illness. When present with fever, rash in a returned traveler is an important clinical sign that is useful in predicting a diagnosis of dengue fever. Diarrhea was also not infrequent in our study, occurring in 37% of patients. This is not unusual, as diarrhea is a feature of dengue fever and is a common finding in travelers with dengue fever. 9. Differentiating dengue fever from other viral infections associated with fever and rash may be difficult on clinical grounds alone. A full blood analysis together with the clinical symptoms and signs may provide important clues that will help to separate returned travelers with dengue fever from those with a dengue-like illness. A high proportion of our returned travelers with dengue fever were found to have leukopenia, neutropenia and thrombocytopenia. This was not the case for patients with a dengue-like illness. Furthermore, thrombocytopenia was not useful in differentiating patients with dengue fever from those with malaria, but in patients with typhoid fever the platelet count was normal or only mildly decreased. These abnormalities are commonly reported in returned travelers with dengue fever, 5,10,16 and thrombocytopenia may be severe even in the absence of hemorrhagic manifestations. 5,10 It should also be noted that although rash, leukopenia and neutropenia in a febrile returned traveler are suggestive of dengue fever, these abnormalities may also be present in patients with severe bacterial sepsis and leptospirosis, and a high index of suspicion must be maintained to ensure appropriate management of potentially septicemic patients. A more useful assessment can be made if combinations of clinical features and laboratory abnormalities are considered. We found that in returned travelers, the combinations of fever and rash, fever and leukopenia, and

6 Sung et al., Dengue Fever in Travelers Returning from Southeast Asia 213 fever, rash and leukopenia were all strongly predictive of a diagnosis of dengue fever. The majority of the travelers who acquire dengue fever are likely to recover completely; however, the concern regarding potentially fatal DHF/DSS remains. Although DHF and DSS are more often the result of recurrent infection, DSS has been reported following primary infection in a traveler. 10,11 Severe dengue fever and DHF have also been reported in immigrants from endemic areas who have returned to dengue-endemic areas. 19 In a large European study,dhf developed in 2.4% of travelers. 9 The risk of developing this serious complication is therefore very real for travelers who travel to dengue-endemic countries. However, for long-term travelers, expatriates and their families, and immigrants returning to endemic areas, the concern regarding DHF and DSS may be of greater significance. Returned travelers with a dengue-like illness may well have had a milder form of dengue fever. However, several important differences in the clinical illness and laboratory findings were noted between patients with dengue fever and a dengue-like illness. This raises the possibility that these patients may have been infected with another virus that produced a clinical illness not unlike dengue fever. Chikungunya virus, which is endemic in Southeast Asia and not infrequently causes an illness which is characterized by fever, rash, arthralgia and myalgia, is one potential etiologic agent. We were unable to test for infection with chikungunya virus, as serologic testing is not routinely available in Australia. In conclusion, we have described the clinical presentation and epidemiology of returned travelers presenting with dengue fever to a specialist Australian infectious diseases unit. An initial assessment combining clinical and laboratory features in the patient will help the travel health practitioner to predict a diagnosis of dengue fever in febrile returned travelers and avoid unnecessary therapeutic interventions. Acknowledgments The Clinical Center Research Excellence, Royal Melbourne Hospital, is funded by the National Health and Medical Research Council of Australia. We wish to acknowledge Leisa Weld, CDC, Atlanta, GA, United States, for her critical review of the manuscript and the analyses performed in this study. References 1. Rigau-Perez J, Gubler DJ, Vorndam AV, Clark GG. Dengue surveillance: United States, MMWR 1994; 43: Kay B. Dengue vector surveillance and control. Curr Opin Infect Dis 1999; 12: Waterman S,Novak R,Sather GE,Rios I,Gubler DJ.Dengue transmission in two Puerto Rican communities in Am J Trop Med Hyg 1985; 34: Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998; 11: Schwartz E, Mendelson E, Sidi Y. 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