Symptomatic versus inapparent outcome in repeat dengue virus infections is influenced by the time interval between infections and study year

Abstract

Four dengue virus serotypes (DENV1-4) circulate globally, causing more human illness than any other arthropod-borne virus. Dengue can present as a range of clinical manifestations from undifferentiated fever to Dengue Fever to severe, life-threatening syndromes. However, most DENV infections are inapparent. Yet, little is known about determinants of inapparent versus symptomatic DENV infection outcome. Here, we analyzed over 2,000 DENV infections from 2004 to 2011 in a prospective pediatric cohort study in Managua, Nicaragua. Symptomatic cases were captured at the study health center, and paired healthy annual samples were examined on a yearly basis using serological methods to identify inapparent DENV infections. Overall, inapparent and symptomatic DENV infections were equally distributed by sex. The mean age of infection was 1.2 years higher for symptomatic DENV infections as compared to inapparent infections. Although inapparent versus symptomatic outcome did not differ by infection number (first, second or third/post-second DENV infections), substantial variation in the proportion of symptomatic DENV infections among all DENV infections was observed across study years. In participants with repeat DENV infections, the time interval between a first inapparent DENV infection and a second inapparent infection was significantly shorter than the interval between a first inapparent and a second symptomatic infection. This difference was not observed in subsequent infections. This result was confirmed using two different serological techniques that measure total anti-DENV antibodies and serotype-specific neutralizing antibodies, respectively. Taken together, these findings show that, in this study, age, study year and time interval between consecutive DENV infections influence inapparent versus symptomatic infection outcome, while sex and infection number had no significant effect. Moreover, these results suggest that the window of cross-protection induced by a first infection with DENV against a second symptomatic infection is approximately 2 years. These findings are important for modeling dengue epidemics and development of vaccines.

Figure 1. Proportion of symptomatic infections by year and infection number.

(A–G) Proportion of symptomatic infections in all, first, second, third and post-second infections by study year (2004–05 to 2010–11). * The proportion of symptomatic infections was not calculated when the total number of infections per group was ≤5.

Figure 2. Interval between consecutive DENV infections according to inapparent or symptomatic outcome as determined by total antibody titer.

The mean interval was calculated for all consecutive DENV infections (A) and stratified considering infection number into first-to-second sequences (B) and other (not first-to-second) infection (C). The inapparent-to-inapparent interval is shorter than inapparent-to-symptomatic (A) but only for first-to-second sequences (B). Error bars represent the standard error of the mean. * Mann–Whitney U test, p<0.05.

Figure 3. Longitudinal analysis of neutralizing antibody titers in selected cohort participants.

NT₅₀ for annual samples of two participants are shown as well as the interpretation of the results and the corresponding total DENV-specific antibody titer determined by Inhibition ELISA. Seroconversion or a ≥4-fold rise in antibody titer in paired annual samples was considered as indicative of a DENV infection during the study year. If the participant experienced a documented symptomatic infection, the serotype from RT-PCR/virus isolation is indicated.

Figure 4. Interval between DENV infections according to inapparent or symptomatic outcome as determined by neutralizing antibody titer.

The mean interval was calculated for all consecutive infections (A) and stratified considering infection number into first-to-second (B) and second-to-third (C) sequences. The inapparent-to-inapparent interval is shorter than inapparent-to-symptomatic (A) but only for first-to-second sequences (B). Error bars represent the standard error of the mean. * Mann–Whitney U test, p<0.05.