Symptomatic Dengue Disease in Five Southeast Asian Countries: Epidemiological Evidence from a Dengue Vaccine Trial

Abstract

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.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: JN, AFT, TAW, SB, CF, AM, MS, TL, ML and AB are employees of Sanofi Pasteur, a company engaged in the development of a dengue vaccine. MRC, NHT, SRH and TC have been clinical trial investigators for and received associated payments from Sanofi Pasteur. CCK has no competing interests to declare.

Figures

Fig 1. CYD14 study flow chart and source of each case definition.

Control arm subjects were actively followed for 25 months to detect episodes of fever ≥38°C for ≥ 2 consecutive days. Febrile episodes were recorded and clinically diagnosed as dengue based on 1997 WHO guidelines, or an alternative etiology. Irrespective of clinical diagnosis, serum samples were taken for virological confirmation of dengue by detection of NS1 antigen by immunoassay and viral RNA by RT-PCR. A positive result for either laboratory test was considered confirmatory of dengue. Clinically diagnosed dengue (CDD): all episodes that were clinically diagnosed as dengue, irrespective of virological confirmation. VCD: all virologically confirmed dengue episodes, irrespective of clinical diagnosis. cVCD: all VCD episodes that were also clinically diagnosed as dengue. UF-VCD: all VCD episodes that were not clinically diagnosed as dengue.