Immune status alters the probability of apparent illness due to dengue virus infection: Evidence from a pooled analysis across multiple cohort and cluster studies

Dengue is an important vector-borne pathogen found across much of the world. Many factors complicate our understanding of the relationship between infection with one of the four dengue virus serotypes, and the observed incidence of disease. One of the factors is a large proportion of infections appear to result in no or few symptoms, while others result in severe infections. Estimates of the proportion of infections that result in no symptoms (inapparent) vary widely from 8% to 100%, depending on study and setting. To investigate the sources of variation of these estimates, we used a flexible framework to combine data from multiple cohort studies and cluster studies (follow-up around index cases). Building on previous observations that the immune status of individuals affects their probability of apparent disease, we estimated the probability of apparent disease among individuals with different exposure histories. In cohort studies mostly assessing infection in children, we estimated the proportion of infections that are apparent as 0.18 (95% Credible Interval, CI: 0.16, 0.20) for primary infections, 0.13 (95% CI: 0.05, 0.17) for individuals infected in the year following a first infection (cross-immune period), and 0.41 (95% CI: 0.36, 0.45) for those experiencing secondary infections after this first year. Estimates of the proportion of infections that are apparent from cluster studies were slightly higher than those from cohort studies for both primary and secondary infections, 0.22 (95% CI: 0.15, 0.29) and 0.57 (95% CI: 0.49, 0.68) respectively. We attempted to estimate the apparent proportion by serotype, but current published data were too limited to distinguish the presence or absence of serotype-specific differences. These estimates are critical for understanding dengue epidemiology. Most dengue data come from passive surveillance systems which not only miss most infections because they are asymptomatic and often underreported, but will also vary in sensitivity over time due to the interaction between previous incidence and the symptomatic proportion, as shown here. Nonetheless the underlying incidence of infection is critical to understanding susceptibility of the population and estimating the true burden of disease, key factors for effectively targeting interventions. The estimates shown here help clarify the link between past infection, observed disease, and current transmission intensity.Author summary: Dengue disease severity is known to vary widely from the very severe to asymptomatic. There is a wide range of estimates of how many infections result in each of these outcomes. It is known that after a first infection the outcome of a second infection with a different serotype varies over time, but this has not been taken into account in these previous estimates. In this paper, we use modelling methods, combined with information from published dengue research in which individuals are followed over time, to estimate the proportion of infections that result in symptoms at different times after infection. We estimated the proportion of infections that are symptomatic for first infections as 0.18 (95% Credible Interval, CI: 0.16, 0.20), 0.13 (95% CI: 0.05, 0.17) for individuals infected in the year following a first infection and 0.41 (95% CI: 0.36, 0.45) for those experiencing secondary infections after this first year. The estimates here will help understand how cases relate to underlying transmission, which is vital for understanding how much of the population are susceptible to infection and for effectively targeting interventions.