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    • In Matthew Grigg and colleagues provide important insights

    2019-04-28

    In , Matthew Grigg and colleagues provide important insights into human activities that affect the risk of infection. This case-control study of infection was done in Sabah, Malaysia, which has had the highest recorded rates of infection globally. The study recruited 229 cases with infection over a 2 year pka kinase and 91 cases with infection due to other species. This study is the first published work of its kind and seeks to quantify the risk of infection for a wide range of potential risk factors, including demographics, medical history, work or school activities, sleeping or bathing patterns, travel activities, malaria prevention measures, travel history, interactions with monkeys, and features of the residences of participants. This study design and the wide range of risk factors assessed is a strength of this work and affords helpful insights into the risks most strongly associated with clinical episodes of . There are several findings from this study that are especially noteworthy. First, the study finds significant heterogeneity in co-transmission of and other species. The investigators found that infection was present widely throughout both districts of Kota Marudu and Kudat, whereas other species (ie, non- species) were largely confined to inland areas of Kota Marudu, with few cases on Kudat. This distribution suggests that current strategies are successfully targeting non- species and that residual cases are largely confined to remote regions, possibly those with lower coverage of control interventions. Grigg and colleagues also show that these strategies are having less impact on infections and that specific interventions need to be identified for successful elimination. It is important to note that the study design accounted for this geographic heterogeneity with regionally matched controls, enabling an assessment of specific risk factors. Second, the authors successfully identify several features of individuals with high-risk for disease. This includes a strong risk bias towards individuals over the age of 15 years (adjusted odds ratio [aOR] 4·16, 95% CI 2·09–8·29) and a strong bias towards men, who made up 76% (174 of 229 cases) of cases. Notably, the results showed that infection with other species was largely confined to individuals younger than 15 years but that men were also at higher risk. Similar findings were identified among the 19 cases and 1 subpatent infection described in a cross-sectional study in Indonesia. The study results also mirror gender-biased findings widely observed across southeast Asia for other species. These results show that interventions need to be strongly targeted towards men and that programmes centred on maternal and child health will be inadequate for malaria elimination, especially for . The observation that infection occurs in older individuals has several possible explanations that need further investigation. One possibility is that, in areas of co-transmission with other species, the acquisition of natural immunity to and early in life, is not providing substantial protection against infection. Further investigation is required to understand cross-protective immunity between these species, and the maintenance of natural immunity and memory responses over many years. The observation of higher risk in older individuals might also relate to occupational risk. The study identifies farming and palm oil plantation work as particularly high-risk occupations. Despite being quite different jobs, it is likely that there are many other shared risk factors, but these are not clearly disentangled in this study. A further subgroup analysis would be informative. Notably, the prevalence of G6PD deficiency was very low among cases compared with controls, and this was especially so for infections compared with other species. Significant uncertainty remains about the precise vectors, the plasticity of vector host-selection (ie, monkey human) and the exact location of vector exposure that results in human transmission of especially across different parts of Asia. In particular, uncertainty exists as to whether transmission is occurring predominately in the forest, farms at the forest-fringe, or villages, and the degree of transmission that is peri-domestic or domestic. Grigg and colleagues noted that having long grass around the house, and having open eaves or gaps in walls are associated with increased risk of . Similarly the use of indoor residual spraying, which was only implemented in 94 (41%) of the 229 cases, was associated with a significant reduction in risk. They also found that the use of bednets by 177 (78%) cases, seemed to have only a marginal effect on risk. These findings are generally supportive of those of Manin and colleagues who identified peri-domestic transmission as being a more greater problem than domestic transmission. Together these studies show that greater benefits might result from improving housing and cutting back peri-domestic vegetation than from intensifying indoor residual spraying and bednet distribution.