Association of dengue severity with the serotype of infection: a systematic review and meta-analysis

Dengue is a mosquito-borne infection caused by one of four dengue virus serotypes (DENV1-4) that circulates endemically across the tropics and subtropics. To date, there is contrasting evidence on the relationship between the serotype of infection and disease severity.

We conducted a systematic review (PROSPERO, CRD42023443101) and meta-analysis to examine the association between the serotype of symptomatic infections with severe disease while accounting for both prior exposure status and geographic region, with severity defined by (i) the 1997 World Health Organization (WHO) guidelines, (ii) the 2009 WHO guidelines or (iii) hospitalisation. We searched the Global Health, Embase Classic + Embase, and Medline databases using Ovid for studies published up to 20 January 2025 and extracted case counts with matched serotype and severity information. We fitted generalised linear mixed models to estimate the proportions of severe cases, running independent analyses per severity definition, and stratifying by prior exposure-serotype combinations (e.g. primary DENV2) and geographic region (Asia versus Americas). Heterogeneity was assessed using the $\tau$ and $I^2$ metrics and risk of bias was assessed by adapting an established tool for risk of bias in prevalence studies.

Our search yielded 4621 unique records, with 71 studies included for the meta-analysis. We found that, on average, DENV3 in Asia resulted in the highest proportion of DHF/DSS (21·00% [95% CrI: 13·02-30·44%]) and hospitalised (22·00% [95% CrI: 0·88-75·31%]) cases among symptomatic primary infections, while also causing the highest proportion of DHF/DSS among secondary infections (37·61% [95% CrI: 24·19-52·32%]). However, conditional on the same prior exposure status (primary/secondary infections), we found no statistically significant differences between serotypes across the three severity definitions. For 1997-type severity, we found some evidence of secondary infections being more severe than primary infections and found that dengue was significantly less severe in the Americas when compared to Asia, though this disparity between regions was sensitive to the inclusion of cases with unknown prior exposure status. There was no significant difference between regions for 2009-type severity and hospitalisations. The paucity of published studies from Africa limited the extent to which we could investigate dengue severity in this region.

This study provides evidence that, according to the published literature, prior dengue exposure has a stronger association with the development of severe disease than the serotype of infection. Better characterising the local population-level immunity remains a current priority for outbreak response and healthcare demand planning.

UK Medical Research Council, UK Foreign, Commonwealth & Development Office, Wellcome Trust, European Union.