Title: 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.
Publication Year: 2015
Publication Date: 2015-10-09
Language: en
Type: dissertation
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Cited By Count: 1
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