Individual-level factors associated with the risk of acquiring human <i>Plasmodium knowlesi</i> malaria in Malaysia: a case-control study.

Abstract

The emergence of human malaria due to the monkey parasite <i>Plasmodium knowlesi</i> threatens elimination efforts in southeast Asia. Changes in land use are thought to be driving the rise in reported <i>P knowlesi</i> cases, but the role of individual-level factors is unclear. To address this knowledge gap we assessed human and environmental factors associated with zoonotic knowlesi malaria risk. We did this population-based case-control study over a 2 year period in the state of Sabah in Malaysia. We enrolled cases with microscopy-positive, PCR-confirmed malaria who presented to two primary referral hospitals serving the adjacent districts of Kudat and Kota Marudu. We randomly selected three malaria-negative community controls per case, who were matched by village within 2 weeks of case detection. We obtained questionnaire data on demographics, behaviour, and residential malaria risk factors, and we also assessed glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. We used conditional logistic regression models to evaluate exposure risk between <i>P knowlesi</i> cases and controls, and between <i>P knowlesi</i> and human-only <i>Plasmodium</i> spp malaria cases. From Dec 5, 2012, to Jan 30, 2015, we screened 414 patients and subsequently enrolled 229 cases with <i>P knowlesi</i> malaria mono-infection and 91 cases with other <i>Plasmodium</i> spp infection. We enrolled 953 matched controls, including 683 matched to <i>P knowlesi</i> cases and 270 matched to non-<i>P knowlesi</i> cases. Age 15 years or older (adjusted odds ratio [aOR] 4·16, 95% CI 2·09-8·29, p<0·0001), male gender (4·20, 2·54-6·97, p<0·0001), plantation work (3·50, CI, 1·34-9·15, p=0·011), sleeping outside (3·61, 1·48-8·85, p=0·0049), travel (2·48, 1·45-4·23, p=0·0010), being aware of the presence of monkeys in the past 4 weeks (3·35, 1·91-5·88, p<0·0001), and having open eaves or gaps in walls (2·18, 1·33-3·59, p=0·0021) were independently associated with increased risk of symptomatic <i>P knowlesi</i> infection. Farming occupation (aOR 1·89, 95% CI 1·07-3·35, p=0·028), clearing vegetation (1·89, 1·11-3·22, p=0·020), and having long grass around the house (2·08, 1·25-3·46, p=0·0048) increased risk for <i>P knowlesi</i> infection but not other <i>Plasmodium</i> spp infection. G6PD deficiency seemed to be protective against <i>P knowlesi</i> (aOR 0·20, 95% CI 0·04-0·96, p=0·045), as did residual insecticide spraying of household walls (0·52, 0·31-0·87, p=0·014), with the presence of young sparse forest (0·35, 0·20-0·63, p=00040) and rice paddy around the house (0·16, 0·03-0·78, 0·023) also associated with decreased risk. Adult men working in agricultural areas were at highest risk of knowlesi malaria, although peri-domestic transmission also occurrs. Human behavioural factors associated with <i>P knowlesi</i> transmission could be targeted in future public health interventions. United Kingdom Medical Research Council, Natural Environment Research Council, Economic and Social Research Council, and Biotechnology and Biosciences Research Council.