Bayesian spatio-temporal distributed lag modeling for delayed climatic effects on sparse malaria incidence data

Background In many areas of the Greater Mekong Subregion (GMS), malaria endemic regions have shrunk to patches of predominantly low-transmission. With a regional goal of elimination by 2030, it is important to use appropriate methods to analyze and predict trends in incidence in these remaining transmission foci to inform planning efforts. Climatic variables have been associated with malaria incidence to varying degrees across the globe but the relationship is less clear in the GMS and standard methodologies may not be appropriate to account for the lag between climate and incidence and for locations with low numbers of cases. Methods In this study, a methodology was developed to estimate the spatio-temporal lag effect of climatic factors on malaria incidence in Thailand within a Bayesian framework. A simulation was conducted based on ground truth of lagged effect curves representing the delayed relation with sparse malaria cases as seen in our study population. A case study to estimate the delayed effect of environmental variables was used with malaria incidence at a fine geographic scale of sub-districts in a western province of Thailand. Results From the simulation study, the model assumptions which accommodated both delayed effects and excessive zeros appeared to have the best overall performance across evaluation metrics and scenarios. The case study demonstrated lagged climatic effect estimation of the proposed modeling with real data. The models appeared to be useful to estimate the shape of association with malaria incidence. Conclusions A new method to estimate the spatiotemporal effect of climate on malaria trends in low transmission settings is presented. The developed methodology has potential to improve understanding and estimation of past and future trends in malaria incidence. With further development, this could assist policy makers with decisions on how to more effectively distribute resources and plan strategies for malaria elimination

Limited polymorphism in the dihydrofolate reductase (dhfr) and dihydropteroate synthase genes (dhps) of Plasmodium knowlesi isolate from Thailand

Background: The 2022 malaria WHO reported around 4000 P. knowlesi infections in the South-East Asia region. In the same period, 72 positive cases were reported by the Department of Disease Control in Thailand, suggesting a persistent infection. Little is known about dihydrofolate reductase (pkdhfr) and dihydropteroate synthase (pkdhps), putative antimalarial resistance markers for P. knowlesi. The relevant amplification and sequencing protocol are presently unavailable. In this study, we developed a protocol for amplifying and evaluating pkdhps mutations. The haplotype pattern of pkdhfr–pkdhps in Thai isolates was analyzed, and the effects of these pkdhps mutations were predicted by using a computer program. Methods: Pkdhps were amplified and sequenced from 28 P. knowlesi samples collected in 2008 and 2020 from nine provinces across Thailand. Combining pkdhfr sequencing data from previous work with pkdhps data to analyze polymorphisms of pkdhfr and pkdhps haplotype. Protein modeling and molecular docking were constructed using two inhibitors, sulfadoxine and sulfamethoxazole, and further details were obtained through analyses of protein–ligand interactions by using the Genetic Optimisation for Ligand Docking program. A phylogenetic tree cluster analysis was reconstructed to compare the P. knowlesi Malaysia isolates. Results: Five nonsynonymous mutations in the pkdhps were detected outside the equivalence of the binding pocket sites to sulfadoxine and sulfamethoxazole, which are at N391S, E421G, I425R, A449S, and N517S. Based on the modeling and molecular docking analyses, the N391S and N517S mutations located close to the enzyme-binding pocket demonstrated a different docking score and protein–ligand interaction in loop 2 of the enzyme. These findings indicated that it was less likely to induce drug resistance. Of the four haplotypes of pkdhfr–pkdhps, the most common one is the R34L pkdhfr mutation and the pkdhps quadruple mutation (GRSS) at E421G, I425R, A449S, and N517S, which were observed in P. knowlesi in southern Thailand (53.57%). Based on the results of neighbor-joining analysis for pkdhfr and pkdhps, the samples isolated from eastern Thailand displayed a close relationship with Cambodia isolates, while southern Thailand isolates showed a long branch separated from the Malaysian isolates. Conclusions: A new PCR protocol amplification and evaluation of dihydropteroate synthase mutations in Knowlesi (pkdhps) has been developed. The most prevalent pkdhfr-pkdhps haplotypes (53.57%) in southern Thailand are R34L pkdhfr mutation and pkdhps quadruple mutation. Further investigation requires additional phenotypic data from clinical isolates, transgenic lines expressing mutant alleles, or recombinant proteins

Mapping malaria transmission foci in Northeast Thailand from 2011 to 2021: approaching elimination in a hypoendemic area

Background: Thailand is approaching local elimination of malaria in the eastern provinces. It has successfully reduced the number of cases over the past decade, but there are persistent transmission hot spots in and around forests. This study aimed to use data from the malaria surveillance system to describe the spatiotemporal trends of malaria in Northeast Thailand and fine-scale patterns in locally transmitted cases between 2011 and 2021. Methods: Case data was stratified based on likely location of infection and parasite species. Annual Parasite Index per 1000 population (API) was calculated for different categories. Time series decomposition was performed to identify trends and seasonal patterns. Statistically significant clusters of high (hot spots) and low (cold spots) API were identified using the Getis-Ord Gi* statistic. The stability of those hot spots and the absolute change in the proportion of API density from baseline were compared by case type. Results: The total number of confirmed cases experienced a non-linear decline by 96.6%, from 1061 in 2011 to 36 in 2021. There has been a decline in both Plasmodium vivax and Plasmodium falciparum case numbers, with only four confirmed P. falciparum cases over the last two years—a 98.89% drop from 180 in 2011. API was generally higher in Si Sa Ket province, which had peaks every 2–3 years. There was a large outbreak in Ubon Ratchathani in 2014–2016 which had a high proportion of P. falciparum reported. The proportion of cases classified increased over the study period, and the proportion of cases classed as indigenous to the village of residence increased from 0.2% to 33.3%. There were stable hot spots of indigenous and imported cases in the south of Si Sa Ket and southeast of Ubon Ratchathani. Plasmodium vivax hot spots were observed into recent years, while those of P. falciparum decreased to zero in Ubon in 2020 and emerged in the eastern part in 2021, the same year that P. falciparum hot spots in Si Sa Ket reached zero. Conclusions: There has been a large, non-linear decline in the number of malaria cases reported and an increasing proportion of cases are classed as indigenous to the patient’s village of residence. Stable hot spots of ongoing transmission in the forested border areas were identified, with transmission likely persisting because of remote location and high-risk forest-going behaviours. Future efforts should include cross-border collaboration and continued targeting of high-risk behaviours to reduce the risk of imported cases seeding local transmission

Expanding the roles of malaria post workers in Thailand: A qualitative study of stakeholder perspectives

In Thailand, since the 2000s, malaria post (MP) workers have been tasked with promptly detecting and treating all malaria cases to prevent onward transmission in the communities. Expanding their roles to provide health services beyond malaria has been proposed as a strategy to sustain their activities until elimination is reached. This article examines the perspectives of stakeholders on community-based malaria care to assess prospects for expanding the role of MPs. The study incorporated in-depth interviews (IDIs) and focus group discussions (FGDs). In forested communities and local health facilities in northeast Thailand bordering Lao PDR and Cambodia, where malaria transmission is low, IDIs were conducted with 13 MPs and 23 community members. An additional 14 policymakers and implementers across the health sector in Thailand were interviewed. The respondents highlighted how in these border areas population groups most at risk of malaria, namely forest goers and migrants, are reluctant to visit public health facilities. In these areas, MP workers are well integrated in their communities and remain relevant although the communities no longer see malaria as spriority. Common conditions such as dengue, diabetes, insect bites, diarrhea, mental illness and substance abuse, were identified as local health concerns needing potential add-on services from MP workers. Although challenges in terms of training, supervision, and financing were raised, opportunities included additional funds from local administrative offices to maintain and integrate malaria activities with other health programmes. Changes to the roles of MPs should be adapted to changing local needs, some of which were identified in this study, should avoid duplication and potential tensions with other local health programmes, and need to build on the capacity of the community and primary care system. These enabling factors are worthy of consideration by any malaria programmes looking into maintaining their village malaria workers in the Greater Mekong Subregion

Active Case Detection with Pooled Real-Time PCR to Eliminate Malaria in Trat Province, Thailand

We conducted contact tracing and high-risk group screening using pooled real-time polymerase chain reaction (PCR) to support malaria elimination in Thailand. PCR detected more Plasmodium infections than the local and expert microscopists. High-throughput pooling technique reduced costs and allowed prompt reporting of results

Forest malaria and prospects for anti-malarial chemoprophylaxis among forest goers: findings from a qualitative study in Thailand

Background: Across the Greater Mekong Subregion, malaria remains a dangerous infectious disease, particularly for people who visit forested areas where residual transmission continues. Because vector control measures offer incomplete protection to forest goers, chemoprophylaxis has been suggested as a potential supplementary measure for malaria prevention and control. To implement prophylaxis effectively, additional information is needed to understand forest goers’ activities and their willingness to use malaria prevention measures, including prophylaxis, and how it could be delivered in communities. Drawing on in-depth interviews with forest goers and stakeholders, this article examines the potential acceptability and implementation challenges of malaria prophylaxis for forest goers in northeast Thailand. Methods: In-depth interviews were conducted with forest goers (n = 11) and stakeholders (n = 16) including healthcare workers, community leaders, and policymakers. Interviews were audio-recorded, transcribed and coded using NVivo, employing an inductive and deductive approach, for thematic analysis. Results: Forest goers were well aware of their (elevated) malaria risk and reported seeking care for malaria from local health care providers. Forest goers and community members have a close relationship with the forest but are not a homogenous group: their place and time-at-risk varied according to their activities and length of stay in the forest. Among stakeholders, the choice and cost of anti-malarial prophylactic regimen—its efficacy, length and complexity, number of tablets, potential side effects, and long-term impact on users—were key considerations for its feasibility. They also expressed concern about adherence to the preventive therapy and potential difficulty treating malaria patients with the same regimen. Prophylaxis was considered a low priority in areas with perceived accessible health system and approaching malaria elimination. Conclusions: In the context of multi-drug resistance, there are several considerations for implementing malaria prophylaxis: the need to target forest goers who are at-risk with a clear period of exposure, to ensure continued use of vector control measures and adherence to prophylactic anti-malarials, and to adopt an evidence-based approach to determine an appropriate regimen. Beyond addressing current intervention challenges and managing malaria incidence in low-transmission setting, it is crucial to keep malaria services available and accessible at the village level especially in areas home to highly mobile populations

The contribution of active case detection to malaria elimination in Thailand

Introduction: Thailand’s malaria surveillance system complements passive case detection with active case detection (ACD), comprising proactive ACD (PACD) methods and reactive ACD (RACD) methods that target community members near index cases. However, it is unclear if these resource-intensive surveillance strategies continue to provide useful yield. This study aimed to document the evolution of the ACD programme and to assess the potential to optimise PACD and RACD. Methods: This study used routine data from all 6 292 302 patients tested for malaria from fiscal year 2015 (FY15) to FY21. To assess trends over time and geography, ACD yield was defined as the proportion of cases detected among total screenings. To investigate geographical variation in yield from FY17 to FY21, we used intercept-only generalised linear regression models (binomial distribution), allowing random intercepts at different geographical levels. A costing analysis gathered the incremental financial costs for one instance of ACD per focus. Results: Test positivity for ACD was low (0.08%) and declined over time (from 0.14% to 0.03%), compared with 3.81% for passive case detection (5.62%–1.93%). Whereas PACD and RACD contributed nearly equal proportions of confirmed cases in FY15, by FY21 PACD represented just 32.37% of ACD cases, with 0.01% test positivity. Each geography showed different yields. We provide a calculator for PACD costs, which vary widely. RACD costs an expected US$226 per case investigation survey (US$1.62 per person tested) or US$461 per mass blood survey (US$1.10 per person tested). Conclusion: ACD yield, particularly for PACD, is waning alongside incidence, offering an opportunity to optimise. PACD may remain useful only in specific microcontexts with sharper targeting and implementation. RACD could be narrowed by defining demographic-based screening criteria rather than geographical based. Ultimately, ACD can continue to contribute to Thailand’s malaria elimination programme but with more deliberate targeting to balance operational costs

Civilian-military malaria outbreak response in Thailand: an example of multi-stakeholder engagement for malaria elimination

Background In April 2017, the Thai Ministry of Public Health (MoPH) was alerted to a potential malaria outbreak among civilians and military personnel in Sisaket Province, a highly forested area bordering Cambodia. The objective of this study was to present findings from the joint civilian-military outbreak response. Methods A mixed-methods approach was used to assess risk factors among cases reported during the 2017 Sisaket malaria outbreak. Routine malaria surveillance data from January 2013 to March 2018 obtained from public and military medical reporting systems and key informant interviews (KIIs) (n = 72) were used to develop hypotheses about potential factors contributing to the outbreak. Joint civilian-military response activities included entomological surveys, mass screen and treat (MSAT) and vector control campaigns, and scale-up of the “1–3–7” reactive case detection approach among civilians alongside a pilot “1–3–7” study conducted by the Royal Thai Army (RTA). Results Between May–July 2017, the monthly number of MoPH-reported cases surpassed the epidemic threshold. Outbreak cases detected through the MoPH mainly consisted of Thai males (87%), working as rubber tappers (62%) or military/border police (15%), and Plasmodium vivax infections (73%). Compared to cases from the previous year (May–July 2016), outbreak cases were more likely to be rubber tappers (OR = 14.89 [95% CI: 5.79–38.29]; p \u3c 0.001) and infected with P. vivax (OR=2.32 [1.27–4.22]; p = 0.006). Themes from KIIs were congruent with findings from routine surveillance data. Though limited risk factor information was available from military cases, findings from RTA’s “1–3–7” study indicated transmission was likely occurring outside military bases. Data from entomological surveys and MSAT campaigns support this hypothesis, as vectors were mostly exophagic and parasite prevalence from MSAT campaigns was very low (range: 0-0.7% by PCR/microscopy). Conclusions In 2017, an outbreak of mainly P. vivax occurred in Sisaket Province, affecting mainly military and rubber tappers. Vector control use was limited to the home/military barracks, indicating that additional interventions were needed during high-risk forest travel periods. Importantly, this outbreak catalyzed joint civilian-military collaborations and integration of the RTA into the national malaria elimination strategy (NMES). The Sisaket outbreak response serves as an example of how civilian and military public health systems can collaborate to advance national malaria elimination goals in Southeast Asia and beyond

Civilian-military malaria outbreak response in Thailand: an example of multi-stakeholder engagement for malaria elimination.

BACKGROUND: In April 2017, the Thai Ministry of Public Health (MoPH) was alerted to a potential malaria outbreak among civilians and military personnel in Sisaket Province, a highly forested area bordering Cambodia. The objective of this study was to present findings from the joint civilian-military outbreak response. METHODS: A mixed-methods approach was used to assess risk factors among cases reported during the 2017 Sisaket malaria outbreak. Routine malaria surveillance data from January 2013 to March 2018 obtained from public and military medical reporting systems and key informant interviews (KIIs) (n = 72) were used to develop hypotheses about potential factors contributing to the outbreak. Joint civilian-military response activities included entomological surveys, mass screen and treat (MSAT) and vector control campaigns, and scale-up of the "1-3-7" reactive case detection approach among civilians alongside a pilot "1-3-7" study conducted by the Royal Thai Army (RTA). RESULTS: Between May-July 2017, the monthly number of MoPH-reported cases surpassed the epidemic threshold. Outbreak cases detected through the MoPH mainly consisted of Thai males (87%), working as rubber tappers (62%) or military/border police (15%), and Plasmodium vivax infections (73%). Compared to cases from the previous year (May-July 2016), outbreak cases were more likely to be rubber tappers (OR = 14.89 [95% CI: 5.79-38.29]; p < 0.001) and infected with P. vivax (OR=2.32 [1.27-4.22]; p = 0.006). Themes from KIIs were congruent with findings from routine surveillance data. Though limited risk factor information was available from military cases, findings from RTA's "1-3-7" study indicated transmission was likely occurring outside military bases. Data from entomological surveys and MSAT campaigns support this hypothesis, as vectors were mostly exophagic and parasite prevalence from MSAT campaigns was very low (range: 0-0.7% by PCR/microscopy). CONCLUSIONS: In 2017, an outbreak of mainly P. vivax occurred in Sisaket Province, affecting mainly military and rubber tappers. Vector control use was limited to the home/military barracks, indicating that additional interventions were needed during high-risk forest travel periods. Importantly, this outbreak catalyzed joint civilian-military collaborations and integration of the RTA into the national malaria elimination strategy (NMES). The Sisaket outbreak response serves as an example of how civilian and military public health systems can collaborate to advance national malaria elimination goals in Southeast Asia and beyond