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Background: The emergence of the zoonotic monkey parasite Plasmodium knowlesi as the dominant cause of malaria in Malaysia has disrupted current national WHO elimination goals. Malaysia has free universal access to malaria care; however, out-of-pocket costs are unknown. This study estimated household costs of illness attributable to malaria due to P. knowlesi against other non-zoonotic Plasmodium species infections in Sabah, Malaysia., Methodology/principal Findings: Household costs were estimated from patient-level surveys collected from four hospitals between 2013 and 2016. Direct costs including medical and associated travel costs, and indirect costs due to lost productivity were included. One hundred and fifty-two malaria cases were enrolled: P. knowlesi (n=108), P. vivax (n=22), P. falciparum (n=16), and P. malariae (n=6). Costs were inflated to 2022 Malaysian Ringgits and reported in United States dollars (US$). Across all cases, the mean total costs were US$138 (SD=108), with productivity losses accounting for 58% of costs (US$80; SD=73). P. vivax had the highest mean total household cost at US$210, followed by P. knowlesi (US$127), P. falciparum (US$126), and P. malariae (US$105). Most patients (80%) experienced direct health costs above 10% of monthly income, with 58 (38%) patients experiencing health spending over 25% of monthly income, consistent with catastrophic health expenditure., Conclusions/significance: Despite Malaysia's free health-system care for malaria, patients and families face other related medical, travel, and indirect costs. Household out-of-pocket costs were driven by productivity losses; primarily attributed to infections in working-aged males in rural agricultural-based occupations. Costs for P. knowlesi were comparable to P. falciparum and lower than P. vivax. The higher P. vivax costs related to direct health facility costs for repeat monitoring visits given the liver-stage treatment required., Author Summary: Knowlesi malaria is due to infection with a parasite transmitted by mosquitos from monkeys to humans. Most people who are infected work or live near the forest. It is now the major type of malaria affecting humans in Malaysia. The recent increase of knowlesi malaria cases in humans has impacted individuals, families, and health systems in Southeast Asia. Although the region has made substantial progress towards eliminating human-only malaria species, knowlesi malaria threatens elimination targets as traditional control measures do not address the parasite reservoir in monkeys. The economic burden of illness due to knowlesi malaria has not previously been estimated or subsequently compared with other malaria species. We collected data on the cost of illness to households in Sabah, Malaysia, to estimate their related total economic burden. Medical costs and time off work and usual activities were substantial in patients with the four species of malaria diagnosed during the time of this study. This research highlights the financial burden which households face when seeking care for malaria in Malaysia, despite the free treatment provided by the government.

Background: Zoonotic P. knowlesi and P. cynomolgi symptomatic and asymptomatic infections occur across endemic areas of Southeast Asia. Most infections are low-parasitemia, with an unknown proportion below routine microscopy detection thresholds. Molecular surveillance tools optimizing the limit of detection (LOD) would allow more accurate estimates of zoonotic malaria prevalence., Methods: An established ultra-sensitive Plasmodium genus quantitative-PCR (qPCR) assay targeting the 18S rRNA gene underwent LOD evaluation with and without reverse transcription (RT) for P. knowlesi , P. cynomolgi and P. vivax using total nucleic acid preserved (DNA/RNA Shield ™ ) isolates and archived dried blood spots (DBS). LODs for selected P. knowlesi- specific assays, and reference P. vivax- and P. cynomolgi -specific assays were determined with RT. Assay specificities were assessed using clinical malaria samples and malaria-negative controls., Results: The use of reverse transcription improved Plasmodium species detection by up to 10,000-fold ( Plasmodium genus), 2759-fold ( P. knowlesi ), 1000-fold ( P. vivax ) and 10-fold ( P. cynomolgi ). The median LOD with RT for the Kamau et al. Plasmodium genus RT-qPCR assay was ≤0.0002 parasites/μL for P. knowlesi and 0.002 parasites/μL for both P. cynomolgi and P. vivax . The LODs with RT for P. knowlesi -specific PCRs were: Imwong et al. 18S rRNA (0.0007 parasites/μL); Divis et al. real-time 18S rRNA (0.0002 parasites/μL); Lubis et al. hemi-nested SICAvar (1.1 parasites/μL) and Lee et al. nested 18S rRNA (11 parasites/μL). The LOD for P. vivax- and P. cynomolgi- specific assays with RT were 0.02 and 0.20 parasites/μL respectively. For DBS P. knowlesi samples the median LOD for the Plasmodium genus qPCR with RT was 0.08, and without RT was 19.89 parasites/uL (249-fold change); no LOD improvement was demonstrated in DBS archived beyond 6 years. The Plasmodium genus and P. knowlesi -assays were 100% specific for Plasmodium species and P. knowlesi detection, respectively, from 190 clinical infections and 48 healthy controls. Reference P. vivax- specific primers demonstrated known cross-reactivity with P. cynomolgi ., Conclusion: Our findings support the use of an 18S rRNA Plasmodium genus qPCR and species-specific nested PCR protocol with RT for highly-sensitive surveillance of zoonotic and human Plasmodium species infections.