Dengue In Travelers Research Articles

CHARACTERIZATION OF CLINICAL AND BIOLOGIC MANIFESTATIONS OF CHIKUNGUNYA AMONG CHILDREN IN AN URBAN AREA, THAILAND: A RETROSPECTIVE COHORT STUDY.

Chikungunya virus (CHIKV), transmitted by Aedes mosquitoes, has reemerged in Southeast Asia since 2019. A retrospective review of CHIKV cases was conducted. Children commonly presented with high-grade fever, rash, arthralgia, and lymphopenia. Neurological manifestations or shock occurred in 20% of hospitalized children. These findings indicate the need for increased vigilance for CHIKV alongside dengue in travelers from Southeast Asia with suspected mosquito-borne viral infections.

Clinical Characteristics and Outcomes Among Travelers With Severe Dengue : A GeoSentinel Analysis.

Dengue virus is a flavivirus transmitted by Aedes mosquitoes and is an important cause of illness worldwide. Data on the severity of travel-associated dengue illness are limited. To describe the epidemiology, clinical characteristics, and outcomes among international travelers with severe dengue or dengue with warning signs as defined by the 2009 World Health Organization classification (that is, complicated dengue). Retrospective chart review and analysis of travelers with complicated dengue reported to GeoSentinel from January 2007 through July 2022. 20 of 71 international GeoSentinel sites. Returning travelers with complicated dengue. Routinely collected surveillance data plus chart review with abstraction of clinical information using predefined grading criteria to characterize the manifestations of complicated dengue. Of 5958 patients with dengue, 95 (2%) had complicated dengue. Eighty-six (91%) patients had a supplemental questionnaire completed. Eighty-five of 86 (99%) patients had warning signs, and 27 (31%) were classified as severe. Median age was 34 years (range, 8 to 91 years); 48 (56%) were female. Patients acquired dengue most frequently in the Caribbean (n= 27 [31%]) and Southeast Asia (n= 21 [24%]). Frequent reasons for travel were tourism (46%) and visiting friends and relatives (32%). Twenty-one of 84 (25%) patients had comorbidities. Seventy-eight (91%) patients were hospitalized. One patient died of nondengue-related illnesses. Common laboratory findings and signs were thrombocytopenia (78%), elevated aminotransferase (62%), bleeding (52%), and plasma leakage (20%). Among severe cases, ophthalmologic pathology (n= 3), severe liver disease (n= 3), myocarditis (n= 2), and neurologic symptoms (n= 2) were reported. Of 44 patients with serologic data, 32 confirmed cases were classified as primary dengue (IgM+/IgG-) and 12 as secondary (IgM-/IgG+) dengue. Data for some variables could not be retrieved by chart review for some patients. The generalizability of our observations may be limited. Complicated dengue is relatively rare in travelers. Clinicians should monitor patients with dengue closely for warning signs that may indicate progression to severe disease. Risk factors for developing complications of dengue in travelers need further prospective study. Centers for Disease Control and Prevention, International Society of Travel Medicine, Public Health Agency of Canada, and GeoSentinel Foundation.

Fatal outcomes of imported dengue fever in adult travelers from non-endemic areas are associated with primary infections.

The case-fatality rate of dengue in travelers is low. Secondary dengue virus (DENV) infections are considered a risk factor for fatal outcome in endemic populations; however, the impact of secondary infections on mortality in travelers has not been studied systematically. We performed a descriptive analysis of case reports of dengue fatalities in travelers. We searched Medline for clinical case reports, using the free terms and MeSH headings: 'Dengue' OR 'Severe Dengue' AND 'Travel-Related Illness' OR 'travel' AND 'Mortality' OR 'Fatal Outcome'. We analyzed case reports of fatal dengue in returning travelers published from 1995 to 2020, with the objective to detail risk factors for dengue mortality in this population. We verified the authors' classifications of primary or secondary dengue infections; infections were considered as primary by absence of anti-DENV immunoglobulin (Ig)G or by IgM-to-IgG ratios greater than or equal to 1.8 in the first 7 days post symptom onset. We identified nine detailed reports of dengue with fatal outcome among travelers from non-endemic countries. Eight fatalities were female. The median age was 32years (range 21-63). Out of nine fatal cases, seven travelers had a primary DENV infection, one had a secondary infection and, in one, these data were not reported. The infecting DENV serotypes were DENV-1 (n = 2), DENV-2 (n = 2) and DENV-3 (n = 3); DENV-1 or 2 (n = 1) and in one case, the serotype could not be determined. Dengue-related deaths in travelers are rare. Most dengue cases in travelers are primary infections. Contrary to prevailing conceptions, we found that fatal outcomes of dengue in travelers from non-endemic countries were reported mainly with primary DENV infections. We alert health care providers that primary DENV infections are not always harmless and that in adult travelers from non-endemic countries, primary infections may contribute more to dengue-related mortality than secondary infections.

Optimising dengue pre-vaccination screening

Optimising dengue pre-vaccination screening

Severe dengue in travellers: pathogenesis, risk and clinical management.

Dengue is a frequent cause of febrile illness among travellers and has overtaken malaria as the leading cause of febrile illness for those traveling to Southeast Asia. The purpose is to review the risk of dengue and severe dengue in travellers with a particular focus on the pathogenesis and clinical management of severe dengue. The risk of travel-acquired dengue depends on destination, season and duration of travel and activities during travel. Seroconversion rates reported in travellers, therefore, vary between <1% and >20%. The most common life-threatening clinical response to dengue infection is the dengue vascular permeability syndrome, epidemiologically linked to secondary infection, but can also occur in primary infection. Tertiary and quaternary infections are usually associated with mild or no disease. Antibody-dependent enhancement, viral factors, age, host factors and clinical experience of the managing physician modulate the risk of progressing to severe dengue. The relative risk of severe dengue in secondary versus primary infection ranges from 2 to 7. The absolute risk of severe dengue in children in highly endemic areas is ~0.1% per year for primary infections and 0.4% for secondary infections. About 2-4% of secondary infections lead to severe dengue. Severe dengue and death are both relatively rare in general travellers but more frequently in those visiting friends and relatives. Clinical management of severe dengue depends on judicious use of fluid rehydration. Although dengue is a frequent cause of travel illness, severe dengue and deaths are rare. Nevertheless, dengue infections can interrupt travel and lead to evacuation and major out-of-pocket costs. Dengue is more frequent than many other travel-related vaccine preventable diseases, such as hepatitis A, hepatitis B, rabies, Japanese encephalitis and yellow fever, indicating a need for a dengue vaccine for travellers.

Dengue infection in international travellers visiting Bali, Indonesia.

BackgroundDengue, an acute febrile illness caused by infection with dengue virus (DENV), is endemic in Bali, Indonesia. As one of the world’s most popular tourist destinations, Bali is regularly visited by domestic and international travellers, who are prone to infection by endemic pathogens, including DENV. Currently, limited data are available on the characteristics of dengue in travellers visiting Bali. Information on the epidemiology and virological aspects of dengue in these tourists is important to gain a better understanding of the dengue disease in international travellers.MethodsWe performed a prospective cross-sectional dengue study involving foreign travellers visiting Bali, Indonesia in the period of 2015–17. Patients presenting at Kasih Ibu Hospital with fever and clinical symptoms of dengue were asked to participate in the study. Clinical and laboratory assessments were performed and sera were collected for molecular analysis, which included DENV serotyping, genome sequencing and phylogenetic analysis.ResultsAmong the 201 patients recruited, dengue was confirmed in 133 (66.2%) of them, based on detection of NS1 antigen and/or viral RNA. Of these, 115 (86.5%) manifested dengue fever (DF) and 18 (13.5%) dengue haemorrhagic fever (DHF). The temporal predominance of infecting DENV serotype was DENV-2 (48.7%), followed by DENV-3 (36.1%), DENV-1 (9.2%) and DENV-4 (3.4%). Phylogenetic analysis of DENV based on envelope gene sequences revealed that the source of DENVs was local endemic viruses.ConclusionOur study confirms that dengue is one of the causes of fever in travellers visiting Bali. Although it is a cause of significant morbidity, the majority of patients only experienced mild DF, with only a small proportion developing DHF. We revealed that DENVs isolated were autochthonous. Accurate diagnosis, preventive measures and continuous disease surveillance will be useful for better management of dengue infection in travellers.

Attack rates of dengue fever in Swedish travellers

Dengue is endemic in many countries visited by Swedish travellers. We aimed to determine the attack rate of dengue in Swedish travellers and analyse the trends over time and the geographical variation. We obtained the following data from the Swedish Institute for Communicable Disease Control for the y 1995-2010: number of Swedish residents with confirmed dengue, the country and year of infection. We also obtained registers on the Swedish annual air traveller arrivals to dengue endemic areas from the United Nations World Tourist Organization for the time period. We estimated attack rates with 95% confidence intervals (CI). In total, 925 Swedish travellers with confirmed dengue were reported. We found an increasing trend over time for most destinations. The majority of the dengue cases were acquired in Thailand (492 out of 925 travellers; 53%), with an attack rate of 13.6 (95% CI 12.7, 14.4) per 100,000 travellers. However, the 2 highest attack rates per 100,000 travellers were found for Sri Lanka (45.3, 95% CI 34.3, 56.4) and Bangladesh (42.6, 95% CI 23.8, 61.5). Information on attack rates in travellers is more helpful in guiding travel medicine practitioners than reports of absolute numbers, as the latter reflect travel preferences rather than the true risk. Although the majority of dengue infections in Swedish travellers were acquired in Thailand, the attack rates for dengue in travellers to Sri Lanka and Bangladesh were much higher. These data aid in refining information on the risk of dengue in travellers.

Dengue Fever and International Travel

Dengue is a leading public health problem with an expanding global burden. Dengue virus is also a significant cause of illness in international travelers with an increasing number of cases of dengue fever identified in travelers returning from dengue-endemic countries. This review focuses on the clinical illness of dengue infection in international travelers and provides a summary of the risk of infection for travelers, clinical features of infection, and an overview of dengue vaccines and their potential applicability to travelers. Four prospective studies of travelers to dengue-endemic destinations have shown that the dengue infection incidence ranges from 10.2 to 30 per 1,000 person-months. This varies according to travel destination and duration and season of travel. Dengue is also a common cause of fever in returned travelers, accounting for up to 16% of all febrile illnesses in returned travelers. Although the majority of infections are asymptomatic, a small proportion of travelers develop dengue hemorrhagic fever. The diagnosis of dengue in travelers requires a combination of serological testing for IgG and IgM together with either nucleic acid or NS1 antigen testing. Several vaccine candidates have now entered into clinical trials including ChimeriVax Dengue, which is currently in phase 3 trials, live-attenuated chimeric vaccines (DENV-DENV Chimera, Inviragen), live-attenuated viral vaccines, recombinant protein subunit vaccines, and DNA vaccines. Dengue infection in international travelers is not infrequent and may be associated with substantial morbidity. Furthermore, an accurate diagnosis of dengue in travelers requires the use of a combination of diagnostic tests. Although a vaccine is not yet available a number of promising candidates are under clinical evaluation. For now travelers should be provided with accurate advice regarding preventive measures when visiting dengue-endemic areas.

Response to Letters

We write in response to the letters of Sonder and van den Hoek1 and Lachish and Schwartz (above) to answer the questions they have raised in relation to our study “The incidence of HBV and HCV infection in Australian travelers to Asia.”2 Our original study was not designed solely for the purpose of determining the seroprevalence of dengue in travelers, as suggested by Sonder and van den Hoek. The cohort has also been used to study the risk of acquiring influenza, Japanese encephalitis, as well as dengue fever.3–5 However, it would have been ideal for us to collect additional serial blood samples and additional demographic and travel information from study participants after their return consultation, but this was not feasible owing to restrictions placed on us by our ethics committee, a limitation we acknowledged in our report. Both letters have raised concerns regarding the time frame from travel to testing in relation to the incubation periods of hepatitis B virus (HBV) and hepatitis C virus (HCV). The letters of Sonder and van den Hoek and Lachish and Schwartz are both incorrect in their interpretation of incubation periods. They have stated that both infections have relatively long incubation periods, making acquisition during study …

Dengue in Travelers: Kinetics of Viremia and NS1 Antigenemia and Their Associations with Clinical Parameters

Despite the increasing numbers of travel-acquired dengue, few studies have assessed virologic markers of the disease in non-endemic populations. We examined the kinetics of diagnostic markers and their associations with clinical parameters in 93 patients with travel-acquired dengue fever. Kinetics analyses suggested a longer average duration for viremia (9 days, CI95%: 8–10) and non-structural protein 1 (NS1) antigenemia (15 days, CI95%: 12–20) than reported in endemic populations. While none of the tests sufficed alone, the best diagnostic coverage was achieved by combining antibody detection with RNA or NS1 testing. Studied by regression models, early relative levels of viremia and NS1 antigenemia proved to be significantly associated with several clinical parameters: high viremia predicted greater likelihood and increased length of hospitalization, the degree of NS1 antigenemia correlated positively with hematocrit and liver transaminases, and both viremia and NS1 antigenemia levels negatively with platelet counts in follow-up. Levels of viremia and NS1 antigenemia may serve as predictors of the clinical manifestations in travel-acquired dengue.

Dengue in travellers: applicability of the 1975–1997 and the 2009 WHO classification system of dengue fever

The aim of this study was to assess the applicability and benefits of the new WHO dengue fever guidelines in clinical practice, for returning travellers. We compared differences in specificity and sensitivity between the old and the new guidelines for diagnosing dengue and assessed the usefulness in predicting the clinical course of the disease. Also, we investigated whether hypertension, diabetes or allergies, ethnicity or high age influenced the course of disease. In our setting, the old classification, compared with the new, had a marginally higher sensitivity for diagnosing dengue. The new classification had a slightly higher specificity and was less rigid. Patients with dengue who had warning signs as postulated in the new classification were admitted more often than those who had no warning signs (RR, 8.09 [1.80-35.48]). We did not find ethnicity, age, hypertension, diabetes mellitus or allergies to be predictive of the clinical course. In our cohort of returned travellers, the new classification system did not differ in sensitivity and specificity from the old system to a clinically relevant degree. The guidelines did not improve identification of severe disease.

Imported Dengue Virus Serotype 3, Yemen to Italy, 2010

Imported Dengue Virus Serotype 3, Yemen to Italy, 2010

Comparison of a novel real-time RT-PCR, NS1 antigen detection and serology in early diagnosis of dengue in travelers

Background The increased traveling to dengue endemic regions and the numerous epidemics have led to a rise in imported dengue. The laboratory diagnosis of acute dengue requires several types of tests and often paired samples are needed for obtaining reliable results. Although several diagnostic methods are available, comparative data on their performance are lacking. The aim of the study was to compare the performance of novel methods including a novel pan-DENV real-time RT-PCR and a commercially available NS1 capture-EIA in regard to IgM detection for optimizing the early diagnosis of DENV in travelers.

Early diagnosis of dengue in travelers: Comparison of a novel real-time RT-PCR, NS1 antigen detection and serology

Background The increased traveling to dengue endemic regions and the numerous epidemics have led to a rise in imported dengue. The laboratory diagnosis of acute dengue requires several types of tests and often paired samples are needed for obtaining reliable results. Although several diagnostic methods are available, proper comparative data on their performance are lacking. Objectives To compare the performance of novel methods including a novel pan-DENV real-time RT-PCR and a commercially available NS1 capture-EIA in regard to IgM detection for optimizing the early diagnosis of DENV in travelers. Study design A panel of 99 selected early phase serum samples of dengue patients was studied by real-time RT-PCR, NS1 antigen ELISA, IgM-EIA, IgG-IFA and cell culture virus isolation. Results The novel real-time RT-PCR was shown specific and sensitive for detection of DENV-1-4 RNA and suitable for diagnostic use. The diagnostic rate using combination of RNA and IgM detection was 99% and using NS1 and IgM detection 95.9%. The results of RNA and NS1 antigen detection disagreed in 15.5% of samples that had only RNA or NS1 antigen detected. Conclusions The diagnostic rates of early samples are higher when either RNA or NS1 antigen detection is combined with IgM detection. Besides the differences in the RNA and NS1 detection assays, the observed discrepancy of results could suggest individual variation or differences in timing of these markers in patient serum.

Dengue vaccines for travelers

Dengue is an arthropod-borne infection caused by a flavivirus and spread by the Aedes mosquitoes. Many of the countries where dengue is endemic are popular tourist destinations and the disease is an increasingly important problem encountered by international travelers. Personal protection against the day-feeding dengue vectors is problematic, indicating the urgent need for a dengue vaccine. This review discusses the challenges of vaccine development, current vaccine strategies and the prospects for the availability of a vaccine for travelers in the future. Cost–effectiveness studies will need to take into account many factors, including the attack rate of dengue in travelers, the proportion of travelers who will need hospitalization, the cost of altered travel itineraries, the cost of the vaccine, duration of travel, destination and season. To be licensed as a travelers’ vaccine, vaccine trials must address safety, immunogenicity, duration of protection, schedules and boosters in adults (in particular in immunologically naive adults), trials that may differ from those conducted in endemic countries. Vaccine schedules with long intervals would be a major obstacle to the uptake of the vaccine by travelers. Enhanced reactogenicity or interference with immunization must be effectively excluded for travelers with prior or concurrent vaccination against other flaviviruses, such as yellow fever or Japanese encephalitis. Licensing dengue as a travelers’ vaccine poses unique challenges beyond the development of a vaccine for the endemic population.

Clinical features and pitfalls in the laboratory diagnosis of dengue in travellers

BackgroundSeveral enzyme-linked immunosorbent assay (ELISA)-kits are commercially available for the rapid diagnosis of dengue infection, and have demonstrated good sensitivity and specificity in paired serum samples. In practice, however, often only one blood sample is available from febrile travellers returning from dengue endemic areas.MethodsTo evaluate the diagnostic value of positive dengue antibody-titres performed by a standard ELISA (PanBio IgM- and IgG-ELISA) in single serum samples (regarded as "probable infection"), 127 positive samples were further analyzed using envelope/membrane IgM-, and nonstructural protein 1 IgM- and IgG-ELISAs, immunofluorescence assays, and real-time reverse transcription polymerase chain reaction assays (RT-PCR). A combination of the test-results served as the diagnostic "gold standard". A total of 1,035 febrile travellers returning from dengue-endemic countries with negative dengue-serology and RT-PCR served as controls to compare clinical and haematological features.ResultsOverall, only 64 (positive predictive value = 50%) of the probable cases were confirmed by additional analysis and 54 (42.5%) were confirmed to be "false-positive". Rash was the only clinical feature significantly associated with confirmed dengue fever. The combination of thrombocytopenia and leucopenia was present in 40.4% of confirmed and in 6.1% of false-positive cases. Thus, the positive predictive value for the combination of positive PanBio-ELISA plus the two haematological features was 90.5%.ConclusionThe examination of paired serum samples is considered the most reliable serodiagnostic procedure for dengue. However, if only one blood sample is available, a single positive ELISA-result carries a high rate of false-positivity and should be confirmed using a second and more specific diagnostic technique. In the absence of further testing, platelet and white blood cell counts are helpful for the correct interpretation.

The timeliness of notification of clinically suspected cases of dengue imported into north Queensland

ObjectiveEvaluate the timeliness of notifications by medical practitioners of clinically suspected dengue importations into north Queensland (NQ). Describe the features the disease and determine the likely duration of viraemia prior to implementating public health measures. MethodSince December 1994, the Tropical Public Health Unit (TPHU) has maintained a register of all imported cases of dengue into NQ. Only confirmed viraemic cases were included in the study. Timeliness of notifications was defined as the interval between the first medical consultation in NQ and notification to TPHU. An Epi info database was developed and used to analyse data. ResultsThere were 31 confirmed dengue importations into NQ during the study period, including all four dengue serotypes. The largest source (39%) was Papua New Guinea. The median time for notifications was 5.5 days. Doctor notifications ranged from 0 to 21 days (median 2 days), remaining notifications range from 1 to 42 days (median 10 days) (p<0.05).The mean duration of viraemia of public health importance was 7 days (2-12 days). ConclusionsOf concern, doctors failed to notify >50% of suspected cases and only 26% of notifications were received within 48 hours. Notification delays led to prolonged viraemia of public health importance increasing the potential risk of secondary infections. ImplicationsGeneral practitioners need to promptly notify all clinically suspected cases of dengue in travellers recently arrived in NQ. The TPHU intends to reemphasise to general practitioner the importance of timely notifications and develop an orientation package for new doctors.