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BackgroundCommon causes of acute febrile illness in tropical countries have similar symptoms, which often mimic those of dengue. Accurate clinical diagnosis can be difficult without laboratory confirmation and disease burden is generally under-reported. Accurate, population-based, laboratory-confirmed incidence data on dengue and other causes of acute fever in dengue-endemic Asian countries are needed.Methods and principal findingsThis prospective, multicenter, active fever surveillance, cohort study was conducted in selected centers in Indonesia, Malaysia, Philippines, Thailand and Vietnam to determine the incidence density of acute febrile episodes (≥38°C for ≥2 days) in 1,500 healthy children aged 2–14 years, followed for a mean 237 days. Causes of fever were assessed by testing acute and convalescent sera from febrile participants for dengue, chikungunya, hepatitis A, influenza A, leptospirosis, rickettsia, and Salmonella Typhi. Overall, 289 participants had acute fever, an incidence density of 33.6 per 100 person-years (95% CI: 30.0; 37.8); 57% were IgM-positive for at least one of these diseases. The most common causes of fever by IgM ELISA were chikungunya (in 35.0% of in febrile participants) and S. Typhi (in 29.4%). The overall incidence density of dengue per 100 person-years was 3.4 by nonstructural protein 1 (NS1) antigen positivity (95% CI: 2.4; 4.8) and 7.3 (95% CI: 5.7; 9.2) by serology. Dengue was diagnosed in 11.4% (95% CI: 8.0; 15.7) and 23.9% (95% CI: 19.1; 29.2) of febrile participants by NS1 positivity and serology, respectively. Of the febrile episodes not clinically diagnosed as dengue, 5.3% were dengue-positive by NS1 antigen testing and 16.0% were dengue-positive by serology.ConclusionsDuring the study period, the most common identified causes of pediatric acute febrile illness among the seven tested for were chikungunya, S. Typhi and dengue. Not all dengue cases were clinically diagnosed; laboratory confirmation is essential to refine disease burden estimates.

The burdens of dengue were substantial in the two regions and in all age groups. Burdens varied widely according to country, but the rates were generally higher and the disease more frequently severe in Asian countries than in Latin American countries. (Funded by Sanofi Pasteur; CYD14 and CYD15 ClinicalTrials.gov numbers, NCT01373281 and NCT01374516.).

Dengue incidence has increased globally, but empirical burden estimates are scarce. Prospective methods are best-able to capture all severities of disease. CYD14 was an observer-blinded dengue vaccine study conducted in children 2–14 years of age in Indonesia, Malaysia, Thailand, the Philippines, and Vietnam. The control group received no vaccine and resembled a prospective, observational study. We calculated the rates of dengue according to different laboratory or clinical criteria to make inferences about dengue burden, and compared with rates reported in the passive surveillance systems to calculate expansion factors which describe under-reporting. Over 6,933 person-years of observation in the control group there were 319 virologically confirmed dengue cases, a crude attack rate of 4.6%/year. Of these, 92 cases (28.8%) were clinically diagnosed as dengue fever or dengue hemorrhagic fever by investigators and 227 were not, indicating that most symptomatic disease fails to satisfy existing case definitions. When examining different case definitions, there was an inverse relationship between clinical severity and observed incidence rates. CYD14’s active surveillance system captured a greater proportion of symptomatic dengue than national passive surveillance systems, giving rise to expansion factors ranging from 0.5 to 31.7. This analysis showed substantial, unpredictable and variable under-reporting of symptomatic dengue, even within a controlled clinical trial environment, and emphasizes that burden estimates are highly sensitive to case definitions. These data will assist in generating disease burden estimates and have important policy implications when considering the introduction and health economics of dengue prevention and control interventions.