Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.

A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum. We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.63; 95% CI:0.45-0.89; p = 0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p = 0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p = 0.022) epitope types. The association of symptomatic malaria with reduced hazard of homologous reinfection was strongest for rare epitope types. Symptomatic malaria provides more durable protection against reinfection with parasites bearing homologous epitope types. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.

Plasmodium vivax Prevalence in Semiarid Region of Northern Kenya, 2019.

In urban and rural areas of Turkana County, Kenya, we found that 2% of household members of patients with Plasmodium falciparum infections were infected with P. vivax. Enhanced surveillance of P. vivax and increased clinical resources are needed to inform control measures and identify and manage P. vivax infections.

Detection of Anopheles stephensi Mosquitoes by Molecular Surveillance, Kenya.

The Anopheles stephensi mosquito is an invasive malaria vector recently reported in Djibouti, Ethiopia, Sudan, Somalia, Nigeria, and Ghana. The World Health Organization has called on countries in Africa to increase surveillance efforts to detect and report this vector and institute appropriate and effective control mechanisms. In Kenya, the Division of National Malaria Program conducted entomological surveillance in counties at risk for An. stephensi mosquito invasion. In addition, the Kenya Medical Research Institute conducted molecular surveillance of all sampled Anopheles mosquitoes from other studies to identify An. stephensi mosquitoes. We report the detection and confirmation of An. stephensi mosquitoes in Marsabit and Turkana Counties by using endpoint PCR and morphological and sequence identification. We demonstrate the urgent need for intensified entomological surveillance in all areas at risk for An. stephensi mosquito invasion, to clarify its occurrence and distribution and develop tailored approaches to prevent further spread.

Adherence to national malaria treatment guidelines in private drug outlets: a cross-sectional survey in the malaria-endemic Kisumu County, Kenya.

BACKGROUND: Malaria prevalence in Kenya is 6%, with a three-fold higher prevalence in western Kenya. Adherence to malaria treatment guidelines improves care for suspected malaria cases and can reduce unnecessary anti-malarial use. Data on adherence to guidelines in retail drug outlets (DOs) is limited, yet approximately 50% of people with fever access treatment first in these outlets. This study assessed adherence to the national malaria treatment guidelines among DOs in a high transmission area of Western Kenya. METHODS: In a cross-sectional survey of DOs in Kisumu Central and Seme sub-counties in 2021, DO staff were interviewed using structured questionnaires to assess outlet characteristics (location, testing services), staff demographics (age, sex, training), and health system context (supervision, inspection). Mystery shoppers (research assistants disguised as clients) observed malaria management practices and recorded observations on a standardized tool. Adherence was defined as dispensing artemether-lumefantrine (AL) to patients with a confirmed positive test, accompanied by appropriate medication counseling. Logistic regression was used to test for association between adherence to guidelines and DO-related factors. RESULTS: None of the 70 DOs assessed had a copy of the guidelines, and 60 (85.7%) were in an urban setting. Staff adhered to the guidelines in 14 (20%) outlets. The odds of adherence were higher among staff who had a bachelor's degree {odds ratio (OR) 6.0, 95% confidence interval (95% CI) 1.66-21.74}, those trained on malaria rapid diagnostic test (RDT) {OR 4.4, 95% CI 1.29-15.04}, and those who asked about patient's symptoms {OR 3.6, 95% CI 1.08-12.25}. DOs that had higher odds of adherence included those with functional thermometers {OR 5.3, 95% CI 1.46-19.14}, those recently inspected (within three months) by Pharmacy and Poisons Board (PPB) {OR 9.4, 95% CI 2.55-34.67}, and those with all basic infrastructure {OR 3.9, 95% CI 1.01-15.00}. On logistic regression analysis, recent PPB inspection {adjusted OR (AOR) 4.6, 95% CI 1.03-20.77} and malaria RDT-trained staff (aOR 4.5, 95% CI 1.02-19.84) were independently associated with adherence. CONCLUSION: Most outlets didn't adhere to malaria guidelines. Regular interaction with regulatory bodies could improve adherence. Ministry of Health should enhance private sector engagement and train DOs on RDT use.

Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial.

BACKGROUND: Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. METHODS AND FINDINGS: We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. CONCLUSIONS: In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. TRIAL REGISTRATION: clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.

Experience and confidence in health technologies: evidence from malaria testing and treatment in Western Kenya.

BACKGROUND: Low adoption of effective health technologies increases illness morbidity and mortality worldwide. In the case of malaria, effective tools such as malaria rapid diagnostic tests (RDTs) and artemisinin-combination therapies (ACTs) are both under-used and used inappropriately. Individuals' confidence in RDTs and ACTs likely affects the uptake of these tools. METHODS: In a cohort of 36 households (280 individuals) in Western Kenya observed for 30 months starting in June 2017, we examined if experience with RDTs and ACTs changes people's beliefs about these technologies and how those beliefs affect treatment behavior. Household members requested a free RDT from the study team any time they suspected a malaria illness, and positive RDT results were treated with a free ACT. We conducted annual, monthly, and sick visit surveys to elicit beliefs about the accuracy of malaria RDT results and the effectiveness of ACTs. Beliefs were elicited on a 5-point Likert scale from "very unlikely" to "very likely." RESULTS: Over the study period, the percentage of survey respondents that said a hypothetical negative RDT result was "very likely" to be correct increased from approximately 55% to 75%. Controlling for initial beliefs, people who had been tested at least once with an RDT in the past year had 3.6 times higher odds (95% CI [1 1.718 7.679], P = 0.001) of saying a negative RDT was "very likely" to be correct. Confidence in testing was associated with treatment behavior: those who believed a negative RDT was "very likely" to be correct had 1.78 times higher odds (95% CI [1.079 2.934], P = 0.024) of adhering to a negative RDT result (by not taking ACTs) than those who were less certain about the accuracy of negative RDTs. Adherence to a negative test also affected subsequent beliefs: controlling for prior beliefs, those who had adhered to their previous test result had approximately twice the odds (OR = 2.19, 95% CI [1.661 2.904], P < 0.001) of saying that a hypothetical negative RDT was "very likely" to be correct compared to those who had not adhered. CONCLUSIONS: Our results suggest that greater experience with RDTs can not only increase people's confidence in their accuracy but also improve adherence to the test result.

Exposure to Diverse Plasmodium falciparum Genotypes Shapes the Risk of Symptomatic Malaria in Incident and Persistent Infections: A Longitudinal Molecular Epidemiologic Study in Kenya.

BACKGROUND: Repeated exposure to malaria infections could protect against symptomatic progression as people develop adaptive immunity to infections acquired over time. METHODS: We investigated how new, recurrent, and persistent Plasmodium falciparum infections were associated with the odds of developing symptomatic compared with asymptomatic malaria. Using a 14-month longitudinal cohort in Western Kenya, we used amplicon deep sequencing of 2 polymorphic genes (pfama1 and pfcsp) to assess overlap of parasite genotypes (represented by haplotypes) acquired within an individual's successive infections. We hypothesized infections with novel haplotypes would increase the odds of symptomatic malaria. RESULTS: After excluding initial infections, we observed 534 asymptomatic and 88 symptomatic infections across 186 people. We detected 109 pfcsp haplotypes, and each infection was classified as harboring novel, recurrent, or persistent haplotypes. Incident infections with only new haplotypes had higher odds of symptomatic malaria when compared with infections with only recurrent haplotypes [odds ratio (OR): 3.24; 95% confidence interval (CI), 1.20-8.78], but infections with both new and recurrent haplotypes (OR: 0.64; 95% CI: 0.15-2.65) did not. Assessing persistent infections, those with mixed (persistent with new or recurrent) haplotypes (OR: 0.77; 95% CI: 0.21-2.75) had no association with symptomatic malaria compared with infections with only persistent haplotypes. Results were similar for pfama1. CONCLUSIONS: These results confirm that incident infections with only novel haplotypes were associated with increased odds of symptomatic malaria compared with infections with only recurrent haplotypes but this relationship was not seen when haplotypes persisted over time in consecutive infections.

The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya.

BACKGROUND: Further reductions in malaria incidence as more countries approach malaria elimination require the identification and treatment of asymptomatic individuals who carry mosquito-infective Plasmodium gametocytes that are responsible for furthering malaria transmission. Assessing the relationship between total parasitaemia and gametocytaemia in field surveys can provide insight as to whether detection of low-density, asymptomatic Plasmodium falciparum infections with sensitive molecular methods can adequately detect the majority of infected individuals who are potentially capable of onward transmission. METHODS: In a cross-sectional survey of 1354 healthy children and adults in three communities in western Kenya across a gradient of malaria transmission (Ajigo, Webuye, and Kapsisywa-Kipsamoite), asymptomatic P. falciparum infections were screened by rapid diagnostic tests, blood smear, and quantitative PCR of dried blood spots targeting the varATS gene in genomic DNA. A multiplex quantitative reverse-transcriptase PCR assay targeting female and male gametocyte genes (pfs25, pfs230p), a gene with a transcriptional pattern restricted to asexual blood stages (piesp2), and human GAPDH was also developed to determine total parasite and gametocyte densities among parasitaemic individuals. RESULTS: The prevalence of varATS-detectable asymptomatic infections was greatest in Ajigo (42%), followed by Webuye (10%). Only two infections were detected in Kapsisywa. No infections were detected in Kipsamoite. Across all communities, children aged 11-15 years account for the greatest proportion total and sub-microscopic asymptomatic infections. In younger age groups, the majority of infections were detectable by microscopy, while 68% of asymptomatically infected adults (> 21 years old) had sub-microscopic parasitaemia. Piesp2-derived parasite densities correlated poorly with microscopy-determined parasite densities in patent infections relative to varATS-based detection. In general, both male and female gametocytaemia increased with increasing varATS-derived total parasitaemia. A substantial proportion (41.7%) of individuals with potential for onward transmission had qPCR-estimated parasite densities below the limit of microscopic detection, but above the detectable limit of varATS qPCR. CONCLUSIONS: This assessment of parasitaemia and gametocytaemia in three communities with different transmission intensities revealed evidence of a substantial sub-patent infectious reservoir among asymptomatic carriers of P. falciparum. Experimental studies are needed to definitively determine whether the low-density infections in communities such as Ajigo and Webuye contribute significantly to malaria transmission.

Mosquito Exposure and Malaria Morbidity: A Microlevel Analysis of Household Mosquito Populations and Malaria in a Population-Based Longitudinal Cohort in Western Kenya.

BACKGROUND: Malaria morbidity is highly overdispersed in the population. Fine-scale differences in mosquito exposure may partially explain this heterogeneity in individual malaria outcomes. METHODS: In 38 households we explored the effect of household-level mosquito exposure and individual insecticide-treated net (ITN) use on relative risk (RR) of confirmed malaria. We conducted monthly active surveillance (n = 254; 2624 person-months) and weekly mosquito collection (2092 household-days of collection), and used molecular techniques to confirm human blood feeding and exposure to infectious mosquitoes. RESULTS: Of 1494 female Anopheles (89.8% Anopheles gambiae sensu lato), 88.3% were fed, 51.9% had a human blood meal, and 9.2% were sporozoite infected. In total, 168 laboratory-confirmed malaria episodes were reported (incidence rate 0.064 episodes per person-month at risk; 95% confidence interval [CI], .055-.074). Malaria risk was directly associated with exposure to sporozoite-infected mosquitoes (RR, 1.24; 95% CI, 1.11-1.38). No direct effect was measured between ITN use and malaria morbidity; however, ITN use did moderate the effect of mosquito exposure on morbidity. CONCLUSIONS: Malaria risk increases linearly with vector density and feeding success for persons with low ITN use. In contrast, malaria risk among high ITN users is consistently low and insensitive to variation in mosquito exposure.

Improving rational use of ACTs through diagnosis-dependent subsidies: Evidence from a cluster-randomized controlled trial in western Kenya.

BACKGROUND: More than half of artemisinin combination therapies (ACTs) consumed globally are dispensed in the retail sector, where diagnostic testing is uncommon, leading to overconsumption and poor targeting. In many malaria-endemic countries, ACTs sold over the counter are available at heavily subsidized prices, further contributing to their misuse. Inappropriate use of ACTs can have serious implications for the spread of drug resistance and leads to poor outcomes for nonmalaria patients treated with incorrect drugs. We evaluated the public health impact of an innovative strategy that targets ACT subsidies to confirmed malaria cases by coupling free diagnostic testing with a diagnosis-dependent ACT subsidy. METHODS AND FINDINGS: We conducted a cluster-randomized controlled trial in 32 community clusters in western Kenya (population approximately 160,000). Eligible clusters had retail outlets selling ACTs and existing community health worker (CHW) programs and were randomly assigned 1:1 to control and intervention arms. In intervention areas, CHWs were available in their villages to perform malaria rapid diagnostic tests (RDTs) on demand for any individual >1 year of age experiencing a malaria-like illness. Malaria RDT-positive individuals received a voucher for a discount on a quality-assured ACT, redeemable at a participating retail medicine outlet. In control areas, CHWs offered a standard package of health education, prevention, and referral services. We conducted 4 population-based surveys-at baseline, 6 months, 12 months, and 18 months-of a random sample of households with fever in the last 4 weeks to evaluate predefined, individual-level outcomes. The primary outcome was uptake of malaria diagnostic testing at 12 months. The main secondary outcome was rational ACT use, defined as the proportion of ACTs used by test-positive individuals. Analyses followed the intention-to-treat principle using generalized estimating equations (GEEs) to account for clustering with prespecified adjustment for gender, age, education, and wealth. All descriptive statistics and regressions were weighted to account for sampling design. Between July 2015 and May 2017, 32,404 participants were tested for malaria, and 10,870 vouchers were issued. A total of 7,416 randomly selected participants with recent fever from all 32 clusters were surveyed. The majority of recent fevers were in children under 18 years (62.9%, n = 4,653). The gender of enrolled participants was balanced in children (49.8%, n = 2,318 boys versus 50.2%, n = 2,335 girls), but more adult women were enrolled than men (78.0%, n = 2,139 versus 22.0%, n = 604). At baseline, 67.6% (n = 1,362) of participants took an ACT for their illness, and 40.3% (n = 810) of all participants took an ACT purchased from a retail outlet. At 12 months, 50.5% (n = 454) in the intervention arm and 43.4% (n = 389) in the control arm had a malaria diagnostic test for their recent fever (adjusted risk difference [RD] = 9 percentage points [pp]; 95% CI 2-15 pp; p = 0.015; adjusted risk ratio [RR] = 1.20; 95% CI 1.05-1.38; p = 0.015). By 18 months, the ARR had increased to 1.25 (95% CI 1.09-1.44; p = 0.005). Rational use of ACTs in the intervention area increased from 41.7% (n = 279) at baseline to 59.6% (n = 403) and was 40% higher in the intervention arm at 18 months (ARR 1.40; 95% CI 1.19-1.64; p < 0.001). While intervention effects increased between 12 and 18 months, we were not able to estimate longer-term impact of the intervention and could not independently evaluate the effects of the free testing and the voucher on uptake of testing. CONCLUSIONS: Diagnosis-dependent ACT subsidies and community-based interventions that include the private sector can have an important impact on diagnostic testing and population-wide rational use of ACTs. Targeting of the ACT subsidy itself to those with a positive malaria diagnostic test may also improve sustainability and reduce the cost of retail-sector ACT subsidies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02461628.

Evaluation of malaria rapid diagnostic test (RDT) use by community health workers: a longitudinal study in western Kenya.

BACKGROUND: Malaria rapid diagnostic tests (RDTs) are a simple, point-of-care technology that can improve the diagnosis and subsequent treatment of malaria. They are an increasingly common diagnostic tool, but concerns remain about their use by community health workers (CHWs). These concerns regard the long-term trends relating to infection prevention measures, the interpretation of test results and adherence to treatment protocols. This study assessed whether CHWs maintained their competency at conducting RDTs over a 12-month timeframe, and if this competency varied with specific CHW characteristics. METHODS: From June to September, 2015, CHWs (n = 271) were trained to conduct RDTs using a 3-day validated curriculum and a baseline assessment was completed. Between June and August, 2016, CHWs (n = 105) were randomly selected and recruited for follow-up assessments using a 20-step checklist that classified steps as relating to safety, accuracy, and treatment; 103 CHWs participated in follow-up assessments. Poisson regressions were used to test for associations between error count data at follow-up and Poisson regression models fit using generalized estimating equations were used to compare data across time-points. RESULTS: At both baseline and follow-up observations, at least 80% of CHWs correctly completed 17 of the 20 steps. CHWs being 50 years of age or older was associated with increased total errors and safety errors at baseline and follow-up. At follow-up, prior experience conducting RDTs was associated with fewer errors. Performance, as it related to the correct completion of all checklist steps and safety steps, did not decline over the 12 months and performance of accuracy steps improved (mean error ratio: 0.51; 95% CI 0.40-0.63). Visual interpretation of RDT results yielded a CHW sensitivity of 92.0% and a specificity of 97.3% when compared to interpretation by the research team. None of the characteristics investigated was found to be significantly associated with RDT interpretation. CONCLUSIONS: With training, most CHWs performing RDTs maintain diagnostic testing competency over at least 12 months. CHWs generally perform RDTs safely and accurately interpret results. Younger age and prior experiences with RDTs were associated with better testing performance. Future research should investigate the mode by which CHW characteristics impact RDT procedures.

Multicenter Pivotal Clinical Trial of Urine Malaria Test for Rapid Diagnosis of Plasmodium falciparum Malaria.

The need to expand malaria diagnosis capabilities alongside policy requirements for mandatory testing before treatment motivates exploration of noninvasive rapid diagnostic tests (RDTs). We report the outcome of the first cross-sectional, single-blind clinical performance evaluation of a urine malaria test (UMT) for diagnosis of Plasmodium falciparum malaria in febrile patients. Matched urine and finger-prick blood samples from participants ≥2 years of age with fever (axillary temperature of ≥37.5°C) or with a history of fever in the preceding 48 h were tested with UMT and microscopy (as the gold standard). BinaxNOW (Pf and Pan versions) blood RDTs were done to assess relative performance. Urinalysis and rheumatoid factor (RF) tests were conducted to evaluate possible interference. Diagnostic performance characteristics were computed at 95% confidence intervals (CIs). Of 1,800 participants screened, 1,691 were enrolled; of these 566 (34%) were febrile, and 1,125 (66%) were afebrile. Among enrolled participants, 341 (20%) tested positive by microscopy, 419 (25%) were positive by UMT, 676 (40%) were positive by BinaxNOW Pf, and 368 (22%) were positive by BinaxNow Pan. UMT sensitivity among febrile patients (for whom the test was indicated) was 85%, and specificity was 84%. Among febrile children ≤5 years of age, UMT sensitivity was 93%, and specificity was 83%. The area under the receiver-operator characteristic curve (AUC) of UMT (0.84) was not significantly different from that of BinaxNOW Pf (0.86) or of BinaxNOW Pan (0.87), indicating that the tests do not differ in overall performance. Gender, seasons, and RF did not impact UMT performance. Leukocytes, hematuria, and urobilinogen concentrations in urine were associated with lower UMT specificities. UMT performance was comparable to that of the BinaxNOW Pf/Pan tests, making UMT a promising tool to expand malaria testing in public and private health care settings where there are challenges to blood-based malaria diagnosis testing.

Household beliefs about malaria testing and treatment in Western Kenya: the role of health worker adherence to malaria test results.

BACKGROUND: Although use of malaria diagnostic tests has increased in recent years, health workers often prescribe anti-malarial drugs to individuals who test negative for malaria. This study investigates how health worker adherence to malaria case management guidelines influences individuals' beliefs about whether their illness was malaria, and their confidence in the effectiveness of artemisinin-based combination therapy (ACT). METHODS: A survey was conducted with 2065 households in Western Kenya about a household member's treatment actions for a recent febrile illness. The survey also elicited the individual's (or their caregiver's) beliefs about the illness and about malaria testing and treatment. Logistic regressions were used to test the association between these beliefs and whether the health worker adhered to malaria testing and treatment guidelines. RESULTS: Of the 1070 individuals who visited a formal health facility during their illness, 82% were tested for malaria. ACT rates for malaria-positive and negative individuals were 89 and 49%, respectively. Overall, 65% of individuals/caregivers believed that the illness was "very likely" malaria. Individuals/caregivers had higher odds of saying that the illness was "very likely" malaria when the individual was treated with ACT, and this was the case both among individuals not tested for malaria [adjusted odds ratio (AOR) 3.42, 95% confidence interval (CI) [1.65 7.10], P = 0.001] and among individuals tested for malaria, regardless of their test result. In addition, 72% of ACT-takers said the drug was "very likely" effective in treating malaria. However, malaria-negative individuals who were treated with ACT had lower odds of saying that the drugs were "very likely" effective than ACT-takers who were not tested or who tested positive for malaria (AOR 0.29, 95% CI [0.13 0.63], P = 0.002). CONCLUSION: Individuals/caregivers were more likely to believe that the illness was malaria when the patient was treated with ACT, regardless of their test result. Moreover, malaria-negative individuals treated with ACT had lower confidence in the drug than other individuals who took ACT. These results suggest that ensuring health worker adherence to malaria case management guidelines will not only improve ACT targeting, but may also increase patient/caregivers' confidence in malaria testing and treatment.

A longitudinal cohort study of malaria exposure and changing serostatus in a malaria endemic area of rural Tanzania.

BACKGROUND: Measurements of anti-malarial antibodies are increasingly used as a proxy of transmission intensity. Most serological surveys are based on the use of cross-sectional data that, when age-stratified, approximates historical patterns of transmission within a population. Comparatively few studies leverage longitudinal data to explicitly relate individual infection events with subsequent antibody responses. METHODS: The occurrence of seroconversion and seroreversion events for two Plasmodium falciparum asexual stage antigens (MSP-1 and AMA-1) was examined using three annual measurements of 691 individuals from a cohort of individuals in a malaria-endemic area of rural east-central Tanzania. Mixed-effect logistic regression models were employed to determine factors associated with changes in serostatus over time. RESULTS: While the expected population-level relationship between seroprevalence and disease incidence was observed, on an individual level the relationship between individual infections and the antibody response was complex. MSP-1 antibody responses were more dynamic in response to the occurrence and resolution of infection events than AMA-1, while the latter was more correlated with consecutive infections. The MSP-1 antibody response to an observed infection seemed to decay faster over time than the corresponding AMA-1 response. Surprisingly, there was no evidence of an age effect on the occurrence of a conversion or reversion event. CONCLUSIONS: While the population-level results concur with previously published sero-epidemiological surveys, the individual-level results highlight the more complex relationship between detected infections and antibody dynamics than can be analysed using cross-sectional data. The longitudinal analysis of serological data may provide a powerful tool for teasing apart the complex relationship between infection events and the corresponding immune response, thereby improving the ability to rapidly assess the success or failure of malaria control programmes.

Use of malaria RDTs in various health contexts across sub-Saharan Africa: a systematic review.

BACKGROUND: The World Health Organization recommends parasitological confirmation of malaria prior to treatment. Malaria rapid diagnostic tests (RDTs) represent one diagnostic method that is used in a variety of contexts to overcome limitations of other diagnostic techniques. Malaria RDTs increase the availability and feasibility of accurate diagnosis and may result in improved quality of care. Though RDTs are used in a variety of contexts, no studies have compared how well or effectively RDTs are used across these contexts. This review assesses the diagnostic use of RDTs in four different contexts: health facilities, the community, drug shops and schools. METHODS: A comprehensive search of the Pubmed database was conducted to evaluate RDT execution, test accuracy, or adherence to test results in sub-Saharan Africa. Original RDT and Plasmodium falciparum focused studies conducted in formal health care facilities, drug shops, schools, or by CHWs between the year 2000 and December 2016 were included. Studies were excluded if they were conducted exclusively in a research laboratory setting, where staff from the study team conducted RDTs, or in settings outside of sub-Saharan Africa. RESULTS: The literature search identified 757 reports. A total of 52 studies were included in the analysis. Overall, RDTs were performed safely and effectively by community health workers provided they receive proper training. Analogous information was largely absent for formal health care workers. Tests were generally accurate across contexts, except for in drug shops where lower specificities were observed. Adherence to RDT results was higher among drug shop vendors and community health workers, while adherence was more variable among formal health care workers, most notably with negative test results. CONCLUSIONS: Malaria RDTs are generally used well, though compliance with test results is variable - especially in the formal health care sector. If low adherence rates are extrapolated, thousands of patients may be incorrectly diagnosed and receive inappropriate treatment resulting in a low quality of care and unnecessary drug use. Multidisciplinary research should continue to explore determinants of good RDT use, and seek to better understand how to support and sustain the correct use of this diagnostic tool.

Q Fever, Scrub Typhus, and Rickettsial Diseases in Children, Kenya, 2011-2012.

To increase knowledge of undifferentiated fevers in Kenya, we tested paired serum samples from febrile children in western Kenya for antibodies against pathogens increasingly recognized to cause febrile illness in Africa. Of patients assessed, 8.9%, 22.4%, 1.1%, and 3.6% had enhanced seroreactivity to Coxiella burnetii, spotted fever group rickettsiae, typhus group rickettsiae, and scrub typhus group orientiae, respectively.

Evaluating Spatial Interaction Models for Regional Mobility in Sub-Saharan Africa.

Simple spatial interaction models of human mobility based on physical laws have been used extensively in the social, biological, and physical sciences, and in the study of the human dynamics underlying the spread of disease. Recent analyses of commuting patterns and travel behavior in high-income countries have led to the suggestion that these models are highly generalizable, and as a result, gravity and radiation models have become standard tools for describing population mobility dynamics for infectious disease epidemiology. Communities in Sub-Saharan Africa may not conform to these models, however; physical accessibility, availability of transport, and cost of travel between locations may be variable and severely constrained compared to high-income settings, informal labor movements rather than regular commuting patterns are often the norm, and the rise of mega-cities across the continent has important implications for travel between rural and urban areas. Here, we first review how infectious disease frameworks incorporate human mobility on different spatial scales and use anonymous mobile phone data from nearly 15 million individuals to analyze the spatiotemporal dynamics of the Kenyan population. We find that gravity and radiation models fail in systematic ways to capture human mobility measured by mobile phones; both severely overestimate the spatial spread of travel and perform poorly in rural areas, but each exhibits different characteristic patterns of failure with respect to routes and volumes of travel. Thus, infectious disease frameworks that rely on spatial interaction models are likely to misrepresent population dynamics important for the spread of disease in many African populations.

Development and validation of a rapid assessment tool for malaria prevention.

BACKGROUND: Insecticide-treated bed nets (ITN) have been shown to be efficacious in reducing malaria morbidity and mortality in many regions. Unfortunately in some areas, malaria has persisted despite the scale up of ITNs. Recent reports indicate that human behaviour and mosquito behaviour are potential threats to the efficacy of ITNs. However, these concerns are likely highly heterogeneous even at very small scales. This study aimed at developing, testing and validating a rapid assessment tool to collect actionable information at local levels for a quick evaluation of potential barriers to malaria prevention. METHODS: The study was conducted at the Webuye Health and Demographic Surveillance Site in Bungoma East Sub-County, Kenya. Based on the findings from the case-control study, 12 primary surveillance components that encompass the major impediments to successful prevention were identified and used to develop a rapid assessment tool. Twenty community health volunteers were trained to identify patients with laboratory-confirmed malaria in six peripheral health facilities located within six sub locations and subsequently followed them up to their homes to conduct a rapid assessment. Sampling and analysis of the results of the survey are based on Lot Quality Assurance. RESULTS: The tool was able to detect local heterogeneity in bed net coverage, bed net use and larval site abundance in the six health facility catchment areas. Nearly all the catchment areas met the action threshold for incomplete household coverage (i.e. not all household members not using a net the previous night) except the peri-urban area. Although the threshold for nets not in good condition was set very high (≥50%), only two catchment areas failed to meet the action threshold. On the indicator for "Net not used every day last week", half of the areas failed, while for net ownership, only two areas met the action threshold. CONCLUSION: The rapid assessment tool was able to detect marked heterogeneity in key indicators for malaria prevention between patients attending health facilities, and can distinguish between priority areas for intervention. There is need to validate it for use in other contexts.

Using pay for performance incentives (P4P) to improve management of suspected malaria fevers in rural Kenya: a cluster randomized controlled trial.

BACKGROUND: Inappropriate treatment of non-malaria fevers with artemisinin-based combination therapies (ACTs) is a growing concern, particularly in light of emerging artemisinin resistance, but it is a behavior that has proven difficult to change. Pay for performance (P4P) programs have generated interest as a mechanism to improve health service delivery and accountability in resource-constrained health systems. However, there has been little experimental evidence to establish the effectiveness of P4P in developing countries. We tested a P4P strategy that emphasized parasitological diagnosis and appropriate treatment of suspected malaria, in particular reduction of unnecessary consumption of ACTs. METHODS: A random sample of 18 health centers was selected and received a refresher workshop on malaria case management. Pre-intervention baseline data was collected from August to September 2012. Facilities were subsequently randomized to either the comparison (n = 9) or intervention arm (n = 9). Between October 2012 and November 2013, facilities in the intervention arm received quarterly incentive payments based on seven performance indicators. Incentives were for use by facilities rather than as payments to individual providers. All non-pregnant patients older than 1 year of age who presented to a participating facility and received either a malaria test or artemether-lumefantrine (AL) were eligible to be included in the analysis. Our primary outcome was prescription of AL to patients with a negative malaria diagnostic test (n = 11,953). Our secondary outcomes were prescription of AL to patients with laboratory-confirmed malaria (n = 2,993) and prescription of AL to patients without a malaria diagnostic test (analyzed at the cluster level, n = 178 facility-months). RESULTS: In the final quarter of the intervention period, the proportion of malaria-negative patients in the intervention arm who received AL was lower than in the comparison arm (7.3% versus 10.9%). The improvement from baseline to quarter 4 in the intervention arm was nearly three times that of the comparison arm (ratio of adjusted odds ratios for baseline to quarter 4 = 0.36, 95% CI: 0.24-0.57). The rate of prescription of AL to patients without a test was five times lower in the intervention arm (adjusted incidence rate ratio = 0.18, 95% CI: 0.07-0.48). Prescription of AL to patients with confirmed infection was not significantly different between the groups over the study period. CONCLUSIONS: Facility-based incentives coupled with training may be more effective than training alone and could complement other quality improvement approaches. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (NCT01809873) on 11 March 2013.