Higher plasma viremia in the febrile phase is associated with adverse dengue outcomes irrespective of infecting serotype or host immune status: an analysis of 5642 Vietnamese cases

Background: One of the generally accepted constructs of dengue pathogenesis is that clinical disease severity is at least partially dependent upon plasma viremia, yet data on plasma viremia in primary versus secondary infections and in relation to clinically relevant endpoints remain limited and contradictory. Methods: Using a large database comprising detailed clinical and laboratory characterization of Vietnamese participants enrolled in a series of research studies executed over a 15-year period, we explored relationships between plasma viremia measured by RT-PCR and three clinically relevant endpoints – severe dengue, plasma leakage, and hospitalization – in the dengue-confirmed cases. All four dengue serotypes and both primary and secondary infections were well represented. In our logistic regression models we allowed for a non-linear effect of viremia, and for associations between viremia and outcome to differ by age, serotype, host immune status, and illness day at study enrolment. Results: Among 5642 dengue-confirmed cases we identified 259 (4.6%) severe dengue cases, 701 (12.4%) patients with plasma leakage, and 1441/4008 (40.0%) patients recruited in outpatient settings who were subsequently hospitalized. From the early febrile phase onwards, higher viremia increased the risk of developing all three endpoints but effect sizes were modest (ORs ranging from 1.12-1.27 per 1-log increase) compared to the effects of a secondary immune response (ORs 1.67-7.76). The associations were consistent across age, serotype and immune status groups, and in the various sensitivity and subgroup analyses we undertook. Conclusions: Higher plasma viremia is associated with increased dengue severity, regardless of serotype or immune status.