The Pathogenesis and Clinical Management of Dengue

Abstract

Dengue is an arboviral disease that exerts a significant public health burden on the tropical world. Currently there is no available vaccine or specific therapeutic. My reviews show that our understanding of dengue pathogenesis, transmission dynamics and optimal case management is incomplete. The work presented in this thesis is a compilation of expert reviews/perspectives and primary research that addresses some of these knowledge gaps. Understanding dengue pathogenesis and in particular, risk factors for progression to severe dengue, is an important priority to reduce morbidity and mortality, especially in young children. Genetic variants of the MICB and PLCE genes have been shown to be associated with severe dengue. I tested the hypothesis that these variants are also associated with less severe dengue infection and with higher early viraemia levels in two studies involving the genotyping of 3961 and 2742 dengue cases respectively. My studies showed that these genetic variants are associated with less severe but clinically apparent dengue infection but showed no evidence of an association with higher viraemia levels. The functional basis of these susceptibility mutations remains unclear. Dengue transmission dynamics are shaped by the prevalence of the permissive vectors, Aedes aegypti and Aedes albopictus. My research hypothesis was that susceptibility and transmission of dengue might differ between the two species. I conducted a clinical study that compared the susceptibility of Ae. aegypti and Ae. albopictus to both initial and disseminated dengue after direct blood feeding experiments on viraemic patients. This work showed that both mosquito types were equally susceptible to initial infection with dengue but that Ae. albopictus was less likely to develop salivary infection, and, thus, an infectious phenotype. These results have important implications for the development of dengue transmission models, especially in areas of dengue emergence where the influence of Ae. albopictus is thought to be greatest. In addition, the results confirm the central importance of patient plasma viraemia in causing successful DENV transmission, suggesting that reducing this through the use of antivirals could potentially reduce transmission. Clinical management of dengue patients remains an enormous challenge. Statins are rational candidate drugs for dengue because of their previously identified positive influence on vascular endothelial function. I conducted a clinical trial of lovastatin therapy in adult dengue patients. The trial showed that lovastatin was safe and well tolerated in dengue patients but it did not show any positive effects on the kinetics of viraemia or on any of the pre-specified clinical or laboratory features. I conducted a survey of platelet management in 20 countries and found a wide variety of approaches to the use of platelets in dengue underscoring the need for prospective clinical trials to inform evidence in this area. To reduce the large sample size normally required for the development of dengue therapeutics, I considered the use of a human dengue infection model in dengue drug development. This model has the potential to a game-changer in drug development and in the design of future trials.