AbstractThe simian parasite Plasmodium knowlesi is an emergent public health threat in southeast Asia, with human infections now increasingly reported where its macaque hosts and An. Leucosphyrus group vector are present. In Malaysia, P. knowlesi is now the most common cause of human malaria, and has been demonstrated to cause severe and fatal disease. This thesis aimed to provide further understanding of the epidemiology, clinical and laboratory features, and treatment of P.knowlesi malaria in both children and adults, with studies conducted in an area of northwest Sabah, Malaysia.
Firstly, the major epidemiological study in this thesis was a case-control analysis of factors associated with acquiring symptomatic P. knowlesi infection. Key findings demonstrated the highest risk in farmers, specific activities such as plantation work and clearing vegetation, sleeping outside, travel, and other environmental and household factors, particularly at the forest-edge, although peri-domestic transmission was also evident. Intrinsic factors such as G6PD deficiency in humans were shown to have a protective benefit, in addition to conventional malaria prevention activities such as insecticide spraying of household walls. The presence of spatio-temporal case-clustering through analysis of P. knowlesi dhfr sequences was demonstrated, however was not found to be related to drug selection pressure from human-to-human transmission.
Secondly, a large prospective study in three district hospitals detailed the clinical and laboratory features in children and adults with knowlesi malaria, highlighting the significant morbidity due to anaemia and acute kidney injury in children, despite an absence of severe complications in this group. A lower pyrogenic threshold was seen with lower parasitaemia compared to other Plasmodium species overall. The risk of severe disease was 6.4% in adults, with independent predictors of severe disease including age ≥45 years and parasitaemia >15,000/μL.
Finally, two major randomised controlled trials for the treatment of uncomplicated knowlesi and vivax malaria in Malaysia were conducted comparing an ACT, artesunate-mefloquine, against chloroquine in adults and children. Faster parasite and fever clearance, and decreased anaemia risk at day 28 was seen in the artesunate-mefloquine arm in both studies. There were no treatment failures in the P. knowlesi study. High-grade P. vivax chloroquine resistance was demonstrated in the P. vivax study, with a 61% risk of recurrence at day 28. These studies support the use of ACT as the first-line blood stage treatment for malaria due to all Plasmodium species in this co-endemic area, which is now reflected in national Malaysian treatment guidelines.
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|Date of Award||Aug 2016|
|Supervisor||Nicholas Anstey (Supervisor), Tsin Yeo (Supervisor) & Bridget Barber (Supervisor)|