Individual-level Factors Associated with the Risk of Acquiring Human Malaria in Malaysia: a Case-control Study

Background: The emergence of human malaria due to the monkey parasite threatens elimination efforts in southeast Asia. Changes in land use are thought to be driving the rise in reported 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.

Methods: 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 cases and controls, and between and human-only spp malaria cases.

Findings: From Dec 5, 2012, to Jan 30, 2015, we screened 414 patients and subsequently enrolled 229 cases with malaria mono-infection and 91 cases with other spp infection. We enrolled 953 matched controls, including 683 matched to cases and 270 matched to non- 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 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 infection but not other spp infection. G6PD deficiency seemed to be protective against (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.

Interpretation: Adult men working in agricultural areas were at highest risk of knowlesi malaria, although peri-domestic transmission also occurrs. Human behavioural factors associated with transmission could be targeted in future public health interventions.

Funding: United Kingdom Medical Research Council, Natural Environment Research Council, Economic and Social Research Council, and Biotechnology and Biosciences Research Council.