Dengue fever in travelers to the tropics, 1998 and 1999. (Research).Dengue dengue /den·gue/ (den´ge) an infectious, eruptive, febrile, viral disease of tropical areas, transmitted by Aedes mosquitoes, and marked by severe pains in the head, eyes, muscles, and joints, sore throat, catarrhal symptoms, and sometimes a skin eruption and painful swellings of parts. fever (DF DF - Damage Free DF - Danske Folkedanseres (Denmark) DF - Dark Falz (Phantasy Star Online boss, gaming) DF - Dark Forces (LucasArts game) DF - Dark Friend DF - Dark Future (role playing game) DF - Darkfall (game) DF - Darkness Falls (Dark Age of Camelot online game) DF - Data Field DF - Data Formatter DF - Data Frame DF - Data Fusion DF - Dead Files DF - Dead Freight DF - Dean of the Faculty DF - Decimation Factor) has become common in western travelers to the tropics. To improve the basis for travel advice, risk factors and dengue manifestations were assessed in 107 Swedish patients for whom DF was diagnosed after return from travel in 1998 and 1999. Patient data were compared with data on a sample of all Swedish travelers to dengue-endemic countries in the same years. Only three of the patients had received pretravel advice concerning DF from their physicians. Hemorrhagic manifestations were common (21 of 74 patients) but caused no deaths. Risk factors for a DF diagnosis were travel to the Malay Peninsula (odds ratio [OR] 4.95; confidence interval [CI] 2.92 to 8.46), age 15-29 years (OR 3.03; CI 1.87 to 4.92), and travel duration >25 days (OR 8.75; CI 4.79 to 16.06). Pretravel advice should be given to all travelers to DF-endemic areas, but young persons traveling to southern and Southeast Asia for >3 weeks (who constituted 31% of the patients in our study) may be more likely to benefit by adhering to it. ********** Dengue fever Dengue hemorrhagic fever hemorrhagic fever n. , a severe form of the disease, can cause hemorrhage, shock, and encephalitis. It occurs when a person who has acquired immunity to one of the viruses that cause dengue fever is infected by a different dengue virus. It is a leading cause of death among children in Southeast Asia and in recent years has become increasingly prevalent in tropical America. There is no specific treatment for dengue fever except good nursing care. (DF) is an acute, self-limiting febrile viral disease
of 2-7 days' duration, characterized by a sudden onset of fever and
a variety of other symptoms such as severe headache, joint and muscular
pain, retroorbital pain, and rash. Occasionally, hemorrhagic
manifestations, such as skin hemorrhages, gum bleeding, epistaxis,
menorrhagia, and gastrointestinal hemorrhage, occur. Dengue hemorrhagic
fever (DHF) is a more severe disease with fever, hemorrhagic phenomena,
thrombocytopenia, and plasma leakage caused by increased vascular
permeability. In patients with DHF, a sometimes-fatal circulatory
failure with hypovolemic shock, called dengue shock syndrome, can
develop (1,2). A syndrome that occurs in perhaps 20 percent to 40 percent of infections by certain arboviruses and is marked by high fever, scattered petechiae, bleeding from the gastrointestinal tract and other organs, hypotension, and shock. The dengue virus (formal name: Dengue virus [DENV]) belongs to the family Flaviviridae Flaviviridae /Fla·vi·vi·ri·dae/ (fla?vi-vir´i-de) the group B arboviruses: a family of RNA viruses with a single-stranded positive-sense RNA genome; there is a single genus, Flavivirus., which also includes yellow fever virus and Japanese encephalitis virus (2). Dengue virus has four serotypes, DENV-1 to DENV-4. Infection with one of these serotypes conveys life-long immunity but not cross-protective immunity to the other serotypes (2). Serologic analysis is difficult because of cross-reactivity between the viruses. However, together with clinical symptoms and travel history, dengue serology can yield a diagnosis (3). Humans are infected with dengue virus by the bite of infective Aedes mosquitoes. The most important vector is Aedes aegypti (1), which prefers to feed on humans during daylight hours. The incubation time is 3-14 days, most often 4-7 days (2). DF is endemic in most countries in the tropical areas of southern and Southeast Asia, the Western Pacific regions, Central and South America, the Caribbean, and Africa (1,4). Transmission of DF increases during the rainy season (1,5). With an increased travel to tropical countries (6), and an increased incidence of DF in these countries (1,7), DF has become the most common imported arbovirus disease in Sweden (8). In the absence of an effective vaccine, pretravel advice, mainly on protection against mosquito bites, is important to prevent the disease (2,7,9). Such advice should be focused on individual risk assessments, based on available epidemiologic data. The aim of this study was, in the light of changing travel patterns, to give an update on risk factors for DF in order to form the basis for pretravel advice. Patients and Methods Cases The Department of Virology at the Swedish Institute for Infectious Diseases is the only laboratory in Sweden that performs dengue serology. Indirect immunofluorescence immunofluorescence /im·mu·no·flu·o·res·cence/ (-fldbobr-res´ens) a method of determining the location of antigen (or antibody) in a tissue section or smear by the pattern of fluorescence resulting when the specimen is exposed to the specific antibody (or antigen) labeled with a fluorochrome. is used for the diagnosis. Antibody detection by indirect immunofluorescence has proved to be at least as reliable as hemagglutination he inhibition for diagnosis of DF in Swedish
patients (3,10). All cases with a positive dengue serologic test
diagnosed at the Swedish Institute for Infectious Diseases in 1998 and
1999 were considered for inclusion in the study. Thus, 114 patients, 92
from 1998 and 22 from 1999, were identified. Seven patients were
excluded from the study because of incorrect or missing data that
prevented us from confirming age and sex. From the laboratory records,
data for the remaining patients were obtained on age, sex, name of
physician, country of infection, and the date when the patient became
ill. A detailed questionnaire on the journey, symptoms, preventive
measures, and pretravel advice was sent to the 107 case-patients through
their physicians. mag·glu ti·nate v.Control Group A control population consisting of travelers to dengue-endemic countries was used (Are Marknadsfakta AB, Are, Sweden). The Are dataset is a commercial database, based on a randomized selection of 2,000 members of the Swedish population every month. These persons are interviewed by telephone with questions on recent overnight travel outside Sweden. Data are then extrapolated to estimate the total number of Swedish travelers abroad. No data on any illness are available from this dataset. The data are presented as journeys per principal country or geographic area, categorized by age, sex, length of journey, and purpose for travel (business or leisure). A total of 4,217 persons with overnight travel abroad were recorded in the Are database for 1998 and 1999; 292 had traveled to dengue-endemic countries or regions, defined as those reporting one or more dengue cases to the World Health Organization (WHO) in 1998 (11). These 292 persons were included as controls. Statistics Odds ratios (ORs) with the corresponding 95% confidence interval (CI) were calculated as relative risk measures to assess the risk factors for being diagnosed with DF. These ORs should be interpreted as the odds of being exposed to a risk factor among the cases divided by the odds of being exposed to that risk factor among the controls, given that only traveling to areas with risk of DF is under consideration. To study whether risk factors were confounded, stratified analyses were performed and Mantel-Haenszel ORs calculated. We performed all analyses with Epi Info 6.04 software (Centers for Disease Control and Prevention, Atlanta, GA). Results Cases Most cases (95 of 107) were investigated at departments of infectious diseases throughout Sweden. Of the original 107 patients who received a questionnaire, 74 (69%) responded. DF was diagnosed in 59 responders and 29 nonresponders in 1998 and in 15 responders and 4 nonresponders in 1999. Of the 74 responders, 40 (54%) were women and 34 men, compared with 13 (39%) women and 20 men among the nonresponders (p=0.16). The responders were of similar age (median 28 years; range 19-60 years), as the nonresponders (median age 28 years; range 8-52 years). Age distribution did not differ between the different countries of infection. Country of Infection The country where the person was staying 3-14 days before becoming ill with DF was considered the country of infection. Data on country of infection were available for 105 of the 107 patients. Most patients (75 of 105; 71%) were infected in Thailand. The remaining patients were infected in 15 different countries (Table 1). The DF risk per 1,000 travelers is shown in Table 2, in comparison with the number of cases reported to WHO in 1998 (11). In the Figure, month of disease onset (combined for 1998 and 1999) is shown for the 75 travelers to Thailand. For comparison, the mean seasonal variation for indigenous cases in Thailand in the years 1987-1991 (5) is also shown. [FIGURE OMITTED] Length of Stay The median length of time spent abroad for the 74 case-patients was 30 days (range 11-496 days). The length of stay in the country of infection was less in some cases, since one person could have traveled to more than one country. The mean length of stay did not differ between the different countries of infection. Risk Factors for DF With the Are sample used as controls, ORs for a diagnosis of DF were calculated for the risk factors of age, country of infection, and length of stay (Table 3). Risk factors for DF were travel to the Malay Peninsula (OR 4.95; 95% CI 2.92 to 8.46), age 15-29 years (OR 3.03; CI 1.87 to 4.92), and travel duration >25 days (OR 8.75; CI 4.79 to 16.06). OR for travel to the Malay Peninsula was basically unchanged after stratification by age group (OR 4.48) or length of stay (OR 4.41). When stratified for travel versus no travel to the Malay Peninsula, the results for length of stay remained unchanged, as did the results for age group. The Are database did not provide us with cross-classified information about age group and length of stay so those factors could not be studied together. Unadjusted ORs are shown in Table 3. Prophylaxis against Mosquito Bites Bed nets as prophylaxis against mosquito bites were used regularly by 17 of the DF patients, irregularly by 14 patients, and never by 42 patients. Mosquito repellents were used regularly by 13 patients, irregularly by 37 patients, and never by 23 patients. One person did not answer the questions on prophylaxis. Information on DF Fourteen of 74 patients stated that they had been informed about DF before the journey, 5 could not remember, and the remaining 55 patients stated they had not received any information. Three of the 14 informed patients had received the information from their doctor; the rest had received it from friends, the Internet, or travel literature. Of the 74 patients, 23 were aware that DF occurred at the country of infection. Clinical Data Thirty patients visited a physician in the country where they became ill, as well as after returning to Sweden. All patients had fever, and 58 patients (78%) had headache. The other nonhemorrhagic symptoms noted were retroorbital pain (n=23; 31%), musculoskeletal and joint pain (n=54; 73%), conjunctivitis (n=17; 23%), rash (n=46; 62%), gastrointestinal complaints (n=12; 16%), neurologic complaints (n=8; 11%), psychologic complaints (n=3; 4%), alopecia (n=2; 3%), and respiratory complaints (n= 1; 1%). One or more hemorrhagic manifestations consistent with DHF (12) were observed in 21 patients, including petechiae (n=12; 16%), epistaxis (n=9; 12%), hematuria endemic hematuria urinary schistosomiasis. essential hematuria that for which no cause has been determined. false hematuria pseudohematuria. renal hematuria that in which the blood comes from the kidney. (n=2;
3%), hematemesis hematemesis /he·ma·tem·e·sis/ (he?mah-tem´e-sis) the vomiting of blood.he·ma·tem·e·sis (h  m (n=2; 3%), melena (n=2; 3%), menorrhagia (n=2; 3%), gum
bleeding (n=2; 3%), and internal bleeding (n=1; 1%). The one patient
with internal bleeding stated that he was treated for DHF at a hospital
in Bangkok. He had lived in Laos earlier in his life but had no
knowledge of previous DF.Discussion The number of Swedes and other westerners traveling to DF-endemic areas has steadily increased. The patients in our study only included those Swedish patients with DF who, after returning from their travels, visited a physician in Sweden who made a diagnosis on the basis of a positive dengue serologic test. Questionnaires were sent out with the help of the patients' physicians. Whether the questionnaires ever reached the nonresponders is not known. Responders were mostly women, and nonresponders were mostly men. Age and country of infection were similar between the groups, except for in travelers to India and its neighboring countries (Afghanistan, Bangladesh, Bhutan, Nepal, Pakistan, and Sri Lanka) and to Central America, where fewer cases occurred in nonresponders than in responders. We do not think that these differences significantly affect the results and conclusions from this study. Since not all persons with symptoms visited a physician, or only did so abroad, our case-patients probably represent a small fraction of the Swedish travelers ill with DF in the 2 study years. In 1998, DF was diagnosed in considerably more patients in Sweden (92 patients) than during the previous years, 1991-1997 (median 24; range 0-45) (8). Similarly, in 1998 more than twice as many cases were reported to WHO than the average for the 3 preceding years. For the diagnosis, we used antibody detection by indirect immunofluorescence. As with other antibody assays, such as the hemagglutination inhibition method, serologic cross-reactions with other flaviviruses cannot be ruled out. However, in addition to their positive serologic results, all patients had a history of signs and symptoms compatible with DF. The data presented in this study only represent Swedish travelers. The travel patterns of persons from other western countries may differ. However, since we have adjusted for age, sex, and length of travel, and the risk estimates are related to the number of Swedes traveling to different countries, the main conclusions should also be valid for travelers from other countries to those areas for which we have enough power to detect elevated risks. No data on travel-related illnesses in the controls were available from the Are database. Therefore we cannot exclude the possibility that the control group could have included persons who actually had DF during their travel. However, all calculations are based on the odds of DF's being diagnosed in Sweden after the traveler returned home, not on the odds of becoming ill with DF (for which we do not have any data). If we consider the small number of diagnosed cases and controls in relation to the estimated total number of travelers (circa 1:2,000), any single person being included both as a patient and as a control would be unlikely. Large discrepancies exist between the calculated risks for the Swedish travelers to become ill with DF in different regions and the incidence rates of cases reported to WHO. Several factors might explain these variations, including the small number of Swedish DF patients, different sensitivity of the surveillance and reporting systems in different countries, and the classification of regions in the Are database, which sometimes includes both dengue-endemic and nonendemic countries in a region. Some of the non-DH-endemic countries thus included do not have many tourists (e.g., Afghanistan, North Korea, Liberia), but the inclusion of non-DH-endemic countries such as South Korea, New Zealand, Chile, Argentina, and Uruguay may have diluted the denominator sufficiently to give falsely low ORs for the rest of Asia, South America, and Australia and Pacific Islands. Furthermore, DF is endemic in only limited areas of China and Australia. The risk of contracting DF in the disease-endemic parts of these countries is therefore substantially higher than reflected by the low ORs in this study. The main risk factors for DF were travel to the Malay Peninsula (mainly Thailand), age 15-29 years, and travel duration >25 days. The Are database is based on a relatively small sample of travelers from each country; the results for other single-risk countries is therefore more uncertain. In 1998, many countries in Asia had unusually high levels of DF and DHF (13). That year, Thailand reported >126,000 cases of DF and DHF to WHO, compared with 99,000 cases in 1997, and 38,000 cases in 1996 (11). The DF epidemic in Asia in 1998 has probably also affected the odds for our case-patients' being infected in these countries. The results might have been different if the study had been performed in a nonepidemic year. Most Swedish travelers to Thailand were infected during May to August, with a peak in July, a pattern that agrees with that of indigenous cases in Thailand in 1987 to 1991. The Swedish cases also peaked in December and January, a finding that does not agree with the indigenous Thai cases. Most likely, this second peak among the Swedes reflects the travel pattern of many tourists who traveled to Thailand during the Christmas and New Year's holiday. A similar two-peak seasonal pattern was also observed among Israeli DF patients returning from Thailand in 1998 (14). The general symptoms in the travelers with DF agreed with symptoms previously described (1,2). Many patients had clinical hemorrhagic manifestations, consistent with DHF (21/74). WHO's case definition for DHF includes thrombocytopenia as well as plasma leakage. Since we did not have access to laboratory test results, we cannot say how many of the patients fulfilled WHO's DHF case criteria. Patients with hemorrhagic manifestations may be more inclined to seek medical care than other DF patients, which would explain our findings. In conclusion, DF is an important infection threatening travelers to disease-endemic areas. In the absence of available vaccines, pretravel advice on mosquito protection is important when attempting to reduce the number of DF cases in travelers. Only 3 of 74 case-patients in our study had received pretravel advice on DF from their doctor. Such advice should be given to all travelers to DF-endemic areas, but young person traveleing to south, em and Southeast Asia for >3 weeks (31% of the patients in our study) may be more likely to benefit by adhering to it. This advice should also be given to travelers going to areas where DF is endemic, even when the disease is not in season.
Table 1. Country of infection for dengue fever cases
Country of infection All cases Responders Nonresponders
Thailand 75 50 25
Philippines 5 5 0
India 4 3 1
Caribbean Islands
(unspecified) 4 3 1
Malaysia 3 3 0
Sri Lanka 2 2 0
Central America
(unspecified) 2 2 0
Indonesia 2 0 2
Nepal 1 1 0
Singapore 1 1 0
Cambodia 1 0 1
Laos 1 1 0
Viemam 1 0 1
Nicaragua 1 1 0
Colombia 1 1 0
Tanzania 1 1 0
Unknown 2 0 2
Total 107 74 33
(a) Divided by responders and nonresponders to travel questionnaires.
Table 2. Geographic area of DF infection, Swedish travelers to these
countries, DF risk, and number of cases and incidence of DF/DHF per
100,000 inhabitants (a,b)
Estimate of DF risk/100,000
Geographic area of Dengue all Swedish travelers
infection (c) patients travelers
India with its 7 12,000 58
neighboring
countries (a)
Malay Peninsula (c) 79 264,000 30
China 0 32,000 0
The rest of Asia, 3 33,000 9
excluding Japan (f)
Australia and Pacific 7 103,000 7
Islands (g)
Caribbean Islands 4 165,000 2
Central America 3 55,000 5
South America 1 54,000 2
West Africa (h) 0 16,000 0
East Africa (i) 1 17,000 6
South Africa (j) 0 38,000 0
Total 105 789,000 13
DF/DHF cases reported to DF/DHF incidence
Geographic area of WHO in 1998 rate/100,000/y
infection (c)
India with its 707 <1
neighboring
countries (a)
Malay Peninsula (c) 158,901 180
China 15 <1
The rest of Asia, 181,847 130
excluding Japan (f)
Australia and Pacific 132,126 40
Islands (g)
Caribbean Islands 24,545 121
Central America 67,403 49
South America 641,299 217
West Africa (h) No data No data
East Africa (i) No data No data
South Africa (j) No data No data
Total 1,203,831 37
(a) DF, dengue fever; DHF, dengue hemorrhagic fever; WHO, World Health
Organization.
(b) As reported to WHO. Data are combined figures for 1998 and 1999,
except for information from the WHO report, which covers 1998 (11).
The DF/DHF incidence calculations are based only on those countries in
the regions reporting DF/DHF cases to WHO.
(c) Categorized according to the Are database.
(d) India, Afghanistan, Bangladesh, Bhutan, Nepal, Pakistan, Sri Lanka.
(e) Malaysia, Singapore, Thailand.
(f) Brunei, Cambodia, Lao People's Democratic Republic, Maldives,
Myanmar (Burma), North Korea, South Korea, Taiwan, Viet Nam.
(g) Australia, Indonesia, New Zealand, Papua New Guinea, Philippines,
and other Pacific islands.
(h) Benin, Burkina Faso, Ivory Coast, The Gambias, Ghana, Guinea,
Guinea-Bissau, Cape Verde, Liberia, Mali, Mauretania.
(i) Ethiopia, Kenya, Somalia, Tanzania.
(j) Angola, Lesotho, Madagascar, Malawi, Mocambique, Namibia, South
Africa, Zambia, Zimbabwe.
Table 3. Odds ratios for diagnosis of dengue fever, calculated for
possible risk factors
Ratio in Ratio in Odds
Risk factor cases controls ratio 95% CI (a)
Geographic area
India with neighbors 7/105 7/292 2.91 0.89 to 9.50
Malay Peninsula 79/105 111/292 4.95 2.92 to 8.46
China 0/105 17/292 0.00 0.00 to 0.65
The rest of Asia 3/105 15/292 0.54 0.10 to 1.98
Carribean 4/105 40/292 0.25 0.06 to 0.72
Central America 3/105 17/292 0.48 0.11 to 1,77
South America 1/105 21/292 0.12 0.00 to 0.79
West Africa 0/105 6/292 0.00 0.00 to 2.60
East Africa 1/105 4/292 0.69 0.01 to 7.11
South Africa 0/105 11/292 0.00 0.00 to 1.09
Australia and
Pacific Islands 7/105 43/292 0.41 0.15 to 0.97
Age groups (y)
0-14 2/107 14/292 0.38 0.04 to 1.69
15-29 58/107 82/292 3.03 1.87 to 4.92
30-44 33/107 79/292 1.20 0.72 to 2.01
[greater than or
equal to] 45 14/107 117/292 0.23 0.12 to 0.43
Sex
Male 54/107 154/292 0.91 0.57 to 1.46
Length of travel
(nights)
0-10 0/74 68/292 0.00 0.00 to 0.17
11-17 16/74 149/292 0.26 0.14 to 0.50
18-24 13/74 31/292 1.79 0.83 to 3.82
[greater than or
equal to] 25 45/74 44/292 8.75 4.79 to 16.06
(a) CI, cofifidence interval.
The opinions expressed by authors contributing to this journal do not necessarily reflect the opinions of the Centers for Disease Control and Prevention or the institutions with which the authors are affiliated. References (1.) World Health Organization. Dengue hemorrhagic fever: diagnosis, treatment, prevention and control. Geneva: The Organization; 1997. (2.) Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 1998;11:480-96. (3.) Vene S, Mangiafico, Niklasson B. Indirect immunofluorescence for serological diagnosis of dengue virus infections in Swedish patients. Clinical and Diagnostic Virology 1995;4:43-50. (4.) Schwartz E, Mendelson E, Sidi Y. Dengue fever among travelers. Am J Med 1996;101:516-20. (5.) Chareonsook O, Foy HM, Teeraratkul A, Silarug N. Changing epidemiology of dengue hemorrhagic fever in Thailand. Epidemiol Infect 1999;122:161-6. (6.) Passengers in international traffic by first destination. Stockholm: The Swedish Civil Aviation Administration; 1999. (7.) Rigau Perez J, Clark GG, Gubler DJ, Reiter P, Sanders E J, Vorndam AV. Dengue and dengue hemorrhagic fever. Lancet 1998;352:971-7. (8.) Ekdahl K, editor. Communicable diseases 2000-the yearly report of the Department of Epidemiology. Solna, Sweden: Swedish Institute for Infectious Disease Control; 2001. (9.) Wittesjo B, Eitrem R, Niklasson B. Dengue fever among Swedish tourists. Scand J Infect Dis 1993;25:699-704. (10.) Hokenberg I, Vene S. Dengue fever: important differential diagnosis from malaria and typhoid fever [in Swedish]. Lakartidningen 1994;91:3692-4. (11.) WHO report on global surveillance of epidemic-prone infectious diseases: dengue and dengue haemorrhagic fever. Geneva: World Health Organization; 2000. Available from: URL: http://www.who.int/emc-documents/surveillance/docs /whocdscsrisr2001.html/dengue/dengue.htm (12.) WHO recommended surveillance standards, 2nd edition. Dengue fever including dengue haemorrhagic fever and dengue shock syndrome. Geneva: the World Health Organization; 1999. Available from: URL: http://www.who.int/emc-documents/surveillance/docs /whocdscsrisr992.html/06Dengue%20fever.htm (13.) Dengue in the WHO Western Pacific Region. Wkly Epidemiol Rec 1998;73:273-7. (14.) Schwartz E, Moskovitz A, Potasman I, Peri G, Grossman Z, Alkan ML. Changing epidemiology of dengue fever in travelers to Thailand. Eur J Clin Microbiol Infect Dis 2000; 19:784-6. Address for correspondence: Karl Ekdahl, Department of Epidemiology, Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden; fax: +46-8 300 626; email: karl.ekdahl@smi.ki.se Heidi Lindback, * ([dagger]) Johan Lindback, ([dagger]) Anders Tegnell, ([dagger]) Ragnhild Janzon, ([dagger]) Sirkka Vene, ([dagger]) and Karl Ekdahl ([dagger]) * Uppsala University, Uppsala, Sweden; and ([dagger]) Swedish Institute for Infectious Disease Control, Solna, Sweden Dr. Lindback is a physician with a keen interest in epidemiology and travel medicine. This analysis was conducted during her graduate studies. |
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