Identifying and targeting human parasite reservoirs of malaria in areas of high transmission Restricted; Files & ToC

Shah, Monica (Summer 2020)

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Despite several decades of global declines in malaria morbidity and mortality, progress has recently stagnated and new interventions are being considered to complement existing strategies. In particular, the design and implementation of interventions targeting the human parasite reservoir could be improved by a more nuanced understanding of areas or populations that disproportionately contribute to malaria transmission. In high transmission settings, where frequent malaria exposure leads to the development of partial immunity, >60% of all malaria infections occur asymptomatically and harbor parasite densities below the detection threshold of rapid diagnostic tests (RDTs) but can be identified using resource-intensive polymerase chain reaction ([PCR]; subpatent infections). These infections contribute substantially to the human infectious reservoir and can persist chronically in the absence of care-seeking behavior. The goal of this dissertation was to characterize asymptomatic and subpatent malaria infections in an area of high transmission, specifically to improve the identification and targeting of these infections.

The source population was derived from the intervention arm of a mass test and treat trial for malaria conducted in a high transmission area of western Kenya between 2013-2015. In Aim 1, I characterized the human parasite reservoir spatially and temporally by describing malaria hotspots in a large, representative dataset of >23,000 individuals at six time points over two years. I identified spatial hotspots of RDT positivity, asymptomatic, and symptomatic infections at each time point and determined that hotspots of asymptomatic infection may be more stable than hotspots of symptomatic infection over two years. Aim 2 explored whether the spatial clustering of malaria infections could be leveraged in a focal treatment strategy in which index case screening scenarios at the compound level (geographically distinct social units) could be used to identify subpatent infections. The compound-level scenarios of RDT screening, fever screening, or symptomatic RDT screening were each significantly associated with subpatent parasitemia. However, a majority of compounds met index case criteria, suggesting limited feasibility as a focal intervention. In Aim 3, I evaluated the accuracy and test characteristics of a one-step pooled PCR test for estimating the prevalence of subpatent parasitemia. Considering individual testing as the gold standard, pooling underestimated the prevalence of subpatent infection; however, the accuracy was improved with the inclusion of a validation subset and using an inverse-variance weighted estimator derived from a composite of internal and external validation data.

The findings of this dissertation provide spatial, temporal, and population contexts to improve the design and evaluation of malaria interventions targeting the human infectious reservoir in areas of high transmission.

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