Characteristics of the Western Province, Zambia, trial site for evaluation of attractive targeted sugar baits for malaria vector control.

BACKGROUND: The attractive targeted sugar bait (ATSB) is a novel malaria vector control tool designed to attract and kill mosquitoes using a sugar-based bait, laced with oral toxicant. Western Province, Zambia, was one of three countries selected for a series of phase III cluster randomized controlled trials of the Westham ATSB Sarabi version 1.2. The trial sites in Kenya, Mali, and Zambia were selected to represent a range of different ecologies and malaria transmission settings across sub-Saharan Africa. This case study describes the key characteristics of the ATSB Zambia trial site to allow for interpretation of the results relative to the Kenya and Mali sites. METHODS: This study site characterization incorporates data from the trial baseline epidemiological and mosquito sugar feeding surveys conducted in 2021, as well as relevant literature on the study area. RESULTS: CHARACTERIZATION OF THE TRIAL SITE: The trial site in Zambia was comprised of 70 trial-designed clusters in Kaoma, Nkeyema, and Luampa districts. Population settlements in the trial site were dispersed across a large geographic area with sparsely populated villages. The overall population density in the 70 study clusters was 65.7 people per square kilometre with a total site population of 122,023 people living in a geographic area that covered 1858 square kilometres. However, the study clusters were distributed over a total area of approximately 11,728 square kilometres. The region was tropical with intense and seasonal malaria transmission. An abundance of trees and other plants in the trial site were potential sources of sugar meals for malaria vectors. Fourteen Anopheles species were endemic in the site and Anopheles funestus was the dominant vector, likely accounting for around 95% of all Plasmodium falciparum malaria infections. Despite high coverage of indoor residual spraying and insecticide-treated nets, the baseline malaria prevalence during the peak malaria transmission season was 50% among people ages six months and older. CONCLUSION: Malaria transmission remains high in Western Province, Zambia, despite coverage with vector control tools. New strategies are needed to address the drivers of malaria transmission in this region and other malaria-endemic areas in sub-Saharan Africa.

Can Outreach Training and Supportive Supervision Improve Competency in Malaria Service Delivery? An Evaluation in Cameroon, Ghana, Niger, and Zambia.

Outreach Training and Supportive Supervision (OTSS) of malaria services at health facilities has been adopted by numerous malaria-endemic countries. The OTSS model is characterized by a hands-on method to enhance national guidelines and supervision tools, train supervisors, and perform supervision visits. An independent evaluation was conducted to evaluate the effectiveness of OTSS on health worker competence in the clinical management of malaria, parasitological diagnosis, and prevention of malaria in pregnancy. From 2018 to 2021, health facilities in Cameroon, Ghana, Niger, and Zambia received OTSS visits during which health workers were observed directly during patient consultations, and supervisors completed standardized checklists to assess their performance. Mixed-effects logistic regression models were developed to assess the impact of increasing OTSS visit number on a set of eight program-generated outcome indicators, including overall competency and requesting a confirmatory malaria test appropriately. Seven of eight outcome indicators showed evidence of beneficial effects of increased OTSS visits. Odds of health workers reaching competency thresholds for the malaria-in-pregnancy checklist increased by more than four times for each additional OTSS visit (odds ratio [OR], 4.62; 95% CI, 3.62-5.88). Each additional OTSS visit was associated with almost four times the odds of the health worker foregoing antimalarial prescriptions for patients who tested negative for malaria (OR, 3.80; 95% CI, 2.35-6.16). This evaluation provides evidence that successive OTSS visits result in meaningful improvements in indicators linked to quality case management of patients attending facilities for malaria diagnosis and treatment, as well as quality malaria prevention services received by women attending antenatal services.

Effectiveness of community case management of malaria on severe malaria and inpatient malaria deaths in Zambia: a dose-response study using routine health information system data.

BACKGROUND: Community case management of malaria (CCM) has been expanded in many settings, but there are limited data describing the impact of these services in routine implementation settings or at large scale. Zambia has intensively expanded CCM since 2013, whereby trained volunteer community health workers (CHW) use rapid diagnostic tests and artemether-lumefantrine to diagnose and treat uncomplicated malaria. METHODS: This retrospective, observational study explored associations between changing malaria service point (health facility or CHW) density per 1000 people and severe malaria admissions or malaria inpatient deaths by district and month in a dose-response approach, using existing routine and programmatic data. Negative binomial generalized linear mixed-effect models were used to assess the impact of increasing one additional malaria service point per 1000 population, and of achieving Zambia's interim target of 1 service point per 750 population. Access to insecticide-treated nets, indoor-residual spraying, and rainfall anomaly were included in models to reduce potential confounding. RESULTS: The study captured 310,855 malaria admissions and 7158 inpatient malaria deaths over 83 districts (seven provinces) from January 2015 to May 2020. Total CHWs increased from 43 to 4503 during the study period, while health facilities increased from 1263 to 1765. After accounting for covariates, an increase of one malaria service point per 1000 was associated with a 19% reduction in severe malaria admissions among children under five (incidence rate ratio [IRR] 0.81, 95% confidence interval [CI] 0.75-0.87, p < 0.001) and 23% reduction in malaria deaths among under-fives (IRR 0.77, 95% CI 0.66-0.91). After categorizing the exposure of population per malaria service point, there was evidence for an effect on malaria admissions and inpatient malaria deaths among children under five only when reaching the target of one malaria service point per 750 population. CONCLUSIONS: CCM is an effective strategy for preventing severe malaria and deaths in areas such as Zambia where malaria diagnosis and treatment access remains challenging. These results support the continued investment in CCM scale-up in similar settings, to improve access to malaria diagnosis and treatment.

Factors Associated With Human IgG Antibody Response to Anopheles albimanus Salivary Gland Extract, Artibonite Department, Haiti, 2017.

Serological data can provide estimates of human exposure to both malaria vector and parasite based on antibody responses. A multiplex bead-based assay was developed to simultaneously detect IgG to Anopheles albimanus salivary gland extract (SGE) and 23 Plasmodium falciparum antigens among 4185 participants enrolled in Artibonite department, Haiti in 2017. Logistic regression adjusted for participant- and site-level covariates and found children under 5 years and 6-15 years old had 3.7- and 5.4-fold increase in odds, respectively, of high anti-SGE IgG compared to participants >15 years. Seropositivity to P. falciparum CSP, Rh2_2030, and SEA-1 antigens was significantly associated with high IgG response against SGE, and participant enrolment at elevations under 200 m was associated with higher anti-SGE IgG levels. The ability to approximate population exposure to malaria vectors through SGE serology data is very dependent by age categories, and SGE antigens can be easily integrated into a multiplex serological assay.

The Immediate Effects of a Combined Mass Drug Administration and Indoor Residual Spraying Campaign to Accelerate Progress Toward Malaria Elimination in Grande-Anse, Haiti.

BACKGROUND: Haiti is planning targeted interventions to accelerate progress toward malaria elimination. In the most affected department (Grande-Anse), a combined mass drug administration (MDA) and indoor residual spraying (IRS) campaign was launched in October 2018. This study assessed the intervention's effectiveness in reducing Plasmodium falciparum prevalence. METHODS: An ecological quasi-experimental study was designed, using a pretest and posttest with a nonrandomized control group. Surveys were conducted in November 2017 in a panel of easy access groups (25 schools and 16 clinics) and were repeated 2-6 weeks after the campaign, in November 2018. Single-dose sulfadoxine-pyrimethamine and primaquine was used for MDA, and pirimiphos-methyl as insecticide for IRS. RESULTS: A total of 10 006 participants were recruited. Fifty-two percent of the population in the intervention area reported having received MDA. Prevalence diminished between 2017 and 2018 in both areas, but the reduction was significantly larger in the intervention area (ratio of adjusted risk ratios, 0.32 [95% confidence interval, .104-.998]). CONCLUSIONS: Despite a moderate coverage, the campaign was effective in reducing P. falciparum prevalence immediately after 1 round. Targeted MDA plus IRS is useful in preelimination settings to rapidly decrease the parasite reservoir, an encouraging step to accelerate progress toward malaria elimination.

Rapid Screening for Non-falciparum Malaria in Elimination Settings Using Multiplex Antigen and Antibody Detection: Post Hoc Identification of Plasmodium malariae in an Infant in Haiti.

Haiti is targeting malaria elimination by 2025. The Grand'Anse department in southwestern Haiti experiences one-third to half of all nationally reported Plasmodium falciparum cases. Although there are historical reports of Plasmodium vivax and Plasmodium malariae, today, non-falciparum infections would remain undetected because of extensive use of falciparum-specific histidine-rich protein 2 (HRP2) rapid diagnostic tests (RDT) at health facilities. A recent case-control study was conducted in Grand'Anse to identify risk factors for P. falciparum infection using HRP2-based RDTs (n = 1,107). Post hoc multiplex Plasmodium antigenemia and antibody (IgG) detection by multiplex bead assay revealed one blood sample positive for pan-Plasmodium aldolase, negative for P. falciparum HRP2, and positive for IgG antibodies to P. malariae. Based on this finding, we selected 52 samples with possible P. malariae infection using IgG and antigenemia data and confirmed infection status by species-specific PCR. We confirmed one P. malariae infection in a 6-month-old infant without travel history. Congenital P. malariae could not be excluded. However, our finding-in combination with historical reports of P. malariae-warrants further investigation into the presence and possible extent of non-falciparum malaria in Haiti. Furthermore, we showed the use of multiplex Plasmodium antigen and IgG detection in selecting samples of interest for subsequent PCR analysis, thereby reducing costs as opposed to testing all available samples by PCR. This is of specific use in low-transmission or eliminating settings where infections are rare.

Management of uncomplicated malaria among children under five years at public and private sector facilities in Mali.

BACKGROUND: Prompt and effective malaria diagnosis and treatment is a cornerstone of malaria control. Case management guidelines recommend confirmatory testing of suspected malaria cases, then prescription of specific drugs for uncomplicated malaria and for severe malaria. This study aims to describe case management practices for children aged 1-59 months seeking treatment with current or recent fever from public and private, rural and urban health providers in Mali. METHODS: Data were collected at sites in Sikasso Region and Bamako. Health workers recorded key information from the consultation including malaria diagnostic testing and result, their final diagnosis, and all drugs prescribed. Children with signs of severe diseases were ineligible. Consultations were not independently observed. Appropriate case management was defined as both 1) tested for malaria using rapid diagnostic test or microscopy, and 2) receiving artemisinin combination therapy (ACT) and no other antimalarials if test-positive, or receiving no antimalarials if test-negative. RESULTS: Of 1602 participating children, 23.7% were appropriately managed, ranging from 5.3% at public rural facilities to 48.4% at community health worker sites. The most common reason for 'inappropriate' management was lack of malaria diagnostic testing (50.4% of children). Among children with confirmed malaria, 50.8% received a non-ACT antimalarial (commonly artesunate injection or artemether), either alone or in combination with ACT. Of 215 test-negative children, 44.2% received an antimalarial drug, most commonly ACT. Prescription of multiple drugs was common: 21.7% of all children received more than one type of antimalarial, while 51.9% received an antibiotic and antimalarial. Inappropriate case management increased in children with increasing axillary temperatures and those seeking care over weekends. CONCLUSIONS: Multiple limitations in management of febrile children under five were identified, including inconsistent use of confirmatory testing and apparent use of severe malaria drugs for uncomplicated malaria. While we cannot confirm the reasons for these shortcomings, there is a need to address the high use of non-ACT antimalarials in this context; to minimize potential for drug resistance, reduce unnecessary expense, and preserve life-saving treatment for severe malaria cases. These findings highlight the challenge of managing febrile illness in young children in a high transmission setting.

Estimating malaria chemoprevention and vector control coverage using program and campaign data: A scoping review of current practices and opportunities.

BACKGROUND: Accurate estimation of intervention coverage is a vital component of malaria program monitoring and evaluation, both for process evaluation (how well program targets are achieved), and impact evaluation (whether intervention coverage had an impact on malaria burden). There is growing interest in maximizing the utility of program data to generate interim estimates of intervention coverage in the periods between large-scale cross-sectional surveys (the gold standard). As such, this study aimed to identify relevant concepts and themes that may guide future optimization of intervention coverage estimation using routinely collected data, or data collected during and following intervention campaigns, with a particular focus on strategies to define the denominator. METHODS: We conducted a scoping review of current practices to estimate malaria intervention coverage for insecticide-treated nets (ITNs); indoor residual spray (IRS); intermittent preventive treatment in pregnancy (IPTp); mass drug administration (MDA); and seasonal malaria chemoprevention (SMC) interventions; case management was excluded. Multiple databases were searched for relevant articles published from January 1, 2015 to June 1, 2018. Additionally, we identified and included other guidance relevant to estimating population denominators, with a focus on innovative techniques. RESULTS: While program data have the potential to provide intervention coverage data, there are still substantial challenges in selecting appropriate denominators. The review identified a lack of consistency in how coverage was defined and reported for each intervention type, with denominator estimation methods not clearly or consistently reported, and denominator estimates rarely triangulated with other data sources to present the feasible range of denominator values and consequently the range of likely coverage estimates. CONCLUSIONS: Though household survey-based estimates of intervention coverage remain the gold standard, efforts should be made to further standardize practices for generating interim measurements of intervention coverage from program data, and for estimating and reporting population denominators. This includes fully describing any projections or adjustments made to existing census or population data, exploring opportunities to validate available data by comparing with other sources, and explaining how the denominator has been restricted (or not) to reflect exclusion criteria.

Selection of Antibody Responses Associated With Plasmodium falciparum Infections in the Context of Malaria Elimination.

In our aim to eliminate malaria, more sensitive tools to detect residual transmission are quickly becoming essential. Antimalarial antibody responses persist in the blood after a malaria infection and provide a wider window to detect exposure to infection compared to parasite detection metrics. Here, we aimed to select antibody responses associated with recent and cumulative exposure to malaria using cross-sectional survey data from Haiti, an elimination setting. Using a multiplex bead assay, we generated data for antibody responses (immunoglobulin G) to 23 Plasmodium falciparum targets in 29,481 participants across three surveys. This included one community-based survey in which participants were enrolled during household visits and two sentinel group surveys in which participants were enrolled at schools and health facilities. First, we correlated continuous antibody responses with age (Spearman) to determine which showed strong age-related associations indicating accumulation over time with limited loss. AMA-1 and MSP-119 antibody levels showed the strongest correlation with age (0.47 and 0.43, p < 0.001) in the community-based survey, which was most representative of the underlying age structure of the population, thus seropositivity to either of these antibodies was considered representative of cumulative exposure to malaria. Next, in the absence of a gold standard for recent exposure, we included antibody responses to the remaining targets to predict highly sensitive rapid diagnostic test (hsRDT) status using receiver operating characteristic curves. For this, only data from the survey with the highest hsRDT prevalence was used (7.2%; 348/4,849). The performance of the top two antigens in the training dataset (two-thirds of the dataset; n = 3,204)-Etramp 5 ag 1 and GLURP-R0 (area-under-the-curve, AUC, 0.892 and 0.825, respectively)-was confirmed in the test dataset (remaining one-third of the dataset; n = 1,652, AUC 0.903 and 0.848, respectively). As no further improvement was seen by combining seropositivity to GLURP-R0 and Etramp 5 ag 1 (p = 0.266), seropositivity to Etramp 5 ag 1 alone was selected as representative of current or recent exposure to malaria. The validation of antibody responses associated with these exposure histories simplifies analyses and interpretation of antibody data and facilitates the application of results to evaluate programs.

Programmatic options for monitoring malaria in elimination settings: easy access group surveys to investigate Plasmodium falciparum epidemiology in two regions with differing endemicity in Haiti.

BACKGROUND: As in most eliminating countries, malaria transmission is highly focal in Haiti. More granular information, including identifying asymptomatic infections, is needed to inform programmatic efforts, monitor intervention effectiveness, and identify remaining foci. Easy access group (EAG) surveys can supplement routine surveillance with more granular information on malaria in a programmatically tractable way. This study assessed how and which type of venue for EAG surveys can improve understanding malaria epidemiology in two regions with different transmission profiles. METHODS: EAG surveys were conducted within the departments of Artibonite and Grand'Anse (Haiti), in regions with different levels of transmission intensity. Surveys were conducted in three venue types: primary schools, health facilities, and churches. The sampling approach varied accordingly. Individuals present at the venues at the time of the survey were eligible whether they presented malaria symptoms or not. The participants completed a questionnaire and were tested for Plasmodium falciparum by a highly sensitive rapid diagnostic test (hsRDT). Factors associated with hsRDT positivity were assessed by negative binomial random-effects regression models. RESULTS: Overall, 11,029 individuals were sampled across 39 venues in Artibonite and 41 in Grand'Anse. The targeted sample size per venue type (2100 in Artibonite and 2500 in Grand'Anse) was reached except for the churches in Artibonite, where some attendees left the venue before they could be approached or enrolled. Refusal rate and drop-out rate were < 1%. In total, 50/6003 (0.8%) and 355/5026 (7.1%) sampled individuals were hsRDT positive in Artibonite and Grand'Anse, respectively. Over half of all infections in both regions were identified at health facilities. Being male and having a current or reported fever in the previous 2 weeks were consistently identified with increased odds of being hsRDT positive. CONCLUSIONS: Surveys in churches were problematic because of logistical and recruitment issues. However, EAG surveys in health facilities and primary schools provided granular information about malaria burden within two departments in Haiti. The EAG surveys were able to identify residual foci of transmission that were missed by recent national surveys. Non-care seeking and/or asymptomatic malaria infections can be identified in this alternative surveillance tool, facilitating data-driven decision-making for improved targeting of interventions.

Risk Factors for Malaria Infection and Seropositivity in the Elimination Area of Grand'Anse, Haiti: A Case-Control Study among Febrile Individuals Seeking Treatment at Public Health Facilities.

The island of Hispaniola aims to eliminate malaria by 2025; however, there are limited data to describe epidemiologic risk factors for malaria in this setting. A prospective case-control study was conducted at four health facilities in southwest Haiti, aiming to describe factors influencing the risk of current and past malaria infection. Cases were defined as individuals attending facilities with current or recent fever and positive malaria rapid diagnostic test (RDT), while controls were those with current or recent fever and RDT negative. Serological markers of recent and cumulative exposure to Plasmodium were assessed using the multiplex bead assay from dried blood spots and used for alternate case definitions. Kuldorff's spatial scan statistic was used to identify local clusters of infection or exposure. Logistic regression models were used to assess potential risk factors for RDT positivity and recent exposure markers, including age-group, gender, and recruiting health facility as group-matching variables. A total of 192 cases (RDT positive) and 915 controls (RDT negative) were recruited. Consistent spatial clusters were identified for all three infection and exposure metrics, indicating temporal stability of malaria transmission at these sites. Risk factors included remoteness from health facilities and household construction, furthermore, insecticide-treated net ownership or use was associated with reduced odds of RDT positivity. These findings indicate the malaria risk in Grand'Anse is driven primarily by location. Travel, occupation, and other behavioral factors were not associated with malaria. These data can support the National Malaria Program to refine and target their intervention approaches, and to move toward elimination.

Evaluating malaria programmes in moderate- and low-transmission settings: practical ways to generate robust evidence.

BACKGROUND: Many countries have made substantial progress in scaling-up and sustaining malaria intervention coverage, leading to more focalized and heterogeneous transmission in many settings. Evaluation provides valuable information for programmes to understand if interventions have been implemented as planned and with quality, if the programme had the intended impact on malaria burden, and to guide programmatic decision-making. Low-, moderate-, and heterogeneous-transmission settings present unique evaluation challenges because of dynamic and targeted intervention strategies. This paper provides illustration of evaluation approaches and methodologies for these transmission settings, and suggests how to answer evaluation questions specific to the local context. METHODS: The Roll Back Malaria Monitoring and Evaluation Reference Group formed a task force in October 2017 to lead development of this framework. The task force includes representatives from National Malaria Programmes, funding agencies, and malaria research and implementing partners. The framework builds on existing guidance for process and outcome evaluations and impact evaluations specifically in high transmission settings. RESULTS: The theory of change describes how evaluation questions asked by national malaria programmes in different contexts influence evaluation design. The transmission setting, existing stratification, and data quality and availability are also key considerations. The framework is intended for adaption by countries to their local context, and use for evaluation at sub-national level. Confirmed malaria incidence is recommended as the primary impact indicator due to its sensitivity to detect changes in low-transmission settings. It is expected that process evaluations provide sufficient evidence for programme monitoring and improvement, while impact evaluations are needed following adoption of new mixes of interventions, operational strategies, tools or policies, particularly in contexts of changing malaria epidemiology. Impact evaluations in low-, moderate-, or heterogeneous-transmission settings will likely use plausibility designs, and methods highlighted by the framework include interrupted time series, district-level dose-response analyses, and constructed control methods. Triangulating multiple data sources and analyses is important to strengthen the plausibility argument. CONCLUSIONS: This framework provides a structure to assist national malaria programmes and partners to design evaluations in low-, moderate- or heterogeneous-transmission settings. Emphasizing a continuous cycle along the causal pathway linking process evaluation to impact evaluation and then programmatic decision-making, the framework provides practical guidance in evaluation design, analysis, and interpretation to ensure that the evaluation meets national malaria programme priority questions and guides decision-making at national and sub-national levels.

Quality control of multiplex antibody detection in samples from large-scale surveys: the example of malaria in Haiti.

Measuring antimalarial antibodies can estimate transmission in a population. To compare outputs, standardized laboratory testing is required. Here we describe the in-country establishment and quality control (QC) of a multiplex bead assay (MBA) for three sero-surveys in Haiti. Total IgG data against 21 antigens were collected for 32,758 participants. Titration curves of hyperimmune sera were included on assay plates, assay signals underwent 5-parameter regression, and inspection of the median and interquartile range (IQR) for the y-inflection point was used to determine assay precision. The medians and IQRs were similar for Surveys 1 and 2 for most antigens, while the IQRs increased for some antigens in Survey 3. Levey-Jennings charts for selected antigens provided a pass/fail criterion for each assay plate and, of 387 assay plates, 13 (3.4%) were repeated. Individual samples failed if IgG binding to the generic glutathione-S-transferase protein was observed, with 659 (2.0%) samples failing. An additional 455 (1.4%) observations failed due to low bead numbers (<20/analyte). The final dataset included 609,438 anti-malaria IgG data points from 32,099 participants; 96.6% of all potential data points if no QC failures had occurred. The MBA can be deployed with high-throughput data collection and low inter-plate variability while ensuring data quality.

Conventional and High-Sensitivity Malaria Rapid Diagnostic Test Performance in 2 Transmission Settings: Haiti 2017.

Accurate malaria diagnosis is foundational for control and elimination, and Haiti relies on histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs) identifying Plasmodium falciparum in clinical and community settings. In 2017, 1 household and 2 easy-access group surveys tested all participants (N = 32 506) by conventional and high-sensitivity RDTs. A subset of blood samples (n = 1154) was laboratory tested for HRP2 by bead-based immunoassay and for P. falciparum 18S rDNA by photo-induced electron transfer polymerase chain reaction. Both RDT types detected low concentrations of HRP2 with sensitivity estimates between 2.6 ng/mL and 14.6 ng/mL. Compared to the predicate HRP2 laboratory assay, RDT sensitivity ranged from 86.3% to 96.0% between tests and settings, and specificity from 90.0% to 99.6%. In the household survey, the high-sensitivity RDT provided a significantly higher number of positive tests, but this represented a very small proportion (<0.2%) of all participants. These data show that a high-sensitivity RDT may have limited utility in a malaria elimination setting like Haiti.

Use of Routine Health Information System Data to Evaluate Impact of Malaria Control Interventions in Zanzibar, Tanzania from 2000 to 2015.

BACKGROUND: Impact evaluations allow countries to assess public health gains achieved through malaria investments. This study uses routine health management information system (HMIS) data from Zanzibar to describe changes in confirmed malaria incidence and impact of case management and vector control interventions during 2000-2015. METHODS: HMIS data from 129 (82%) public outpatient facilities were analyzed using interrupted time series models to estimate the impact of artemisinin-based combination therapy (ACT), indoor residual spray, and long-lasting insecticidal nets. Evaluation periods were defined as pre-intervention (January 2000 to August 2003), ACT-only (September 2003 to December 2005) and ACT plus vector control (2006-2015). FINDINGS: After accounting for climate, seasonality, diagnostic testing rates, and outpatient attendance, average monthly incidence of confirmed malaria showed no trend over the pre-intervention period 2000-2003 (incidence rate ratio (IRR) 0.998, 95% CI 0.995-1.000). During the ACT-only period (2003-2005), the average monthly malaria incidence rate declined compared to the pre-intervention period, showing an overall declining trend during the ACT-only period (IRR 0.984, 95% CI 0.978-0.990). There was no intercept change at the start of the ACT-only period (IRR 1.081, 95% CI 0.968-1.208), but a drop in intercept was identified at the start of the ACT plus vector control period (IRR 0.683, 95% CI 0.597-0.780). During the ACT plus vector control period (2006-2015), the rate of decline in average monthly malaria incidence slowed compared to the ACT-only period, but the incidence rate continued to show an overall slight declining trend during 2006-2015 (IRR 0.993, 95% CI 0.992-0.994). INTERPRETATION: This study presents a rigorous approach to the use of HMIS data in evaluating the impact of malaria control interventions. Evidence is presented for a rapid decline in malaria incidence during the period of ACT roll out compared to pre-intervention, with a rapid drop in malaria incidence following introduction of vector control and a slower declining incidence trend thereafter.

Measuring malaria diagnosis and treatment coverage in population-based surveys: a recall validation study in Mali among caregivers of febrile children under 5 years.

BACKGROUND: Nationally-representative household surveys are the standard approach to monitor access to and treatment with artemisinin-based combination therapy (ACT) among children under 5 years (U5), however these indicators are dependent on caregivers' recall of the treatment received. METHODS: A prospective case-control study was performed in Mali to validate caregivers' recall of treatment received by U5s when seeking care for fever from rural and urban public health facilities, community health workers and urban private facilities. Clinician-recorded consultation details were the gold standard. Consenting caregivers were followed-up for interview at home within 2 weeks using standard questions from Demographic and Health Surveys and Malaria Indicator Surveys. RESULTS: Among 1602 caregivers, sensitivity of recalling that the child received a finger/heel prick was 91.5%, with specificity 85.7%. Caregivers' recall of a positive malaria test result had sensitivity 96.2% with specificity 59.7%. Irrespective of diagnostic test result, the sensitivity and specificity of caregivers' recalling a malaria diagnosis made by the health worker were 74.3% and 74.9%, respectively. Caregivers' recall of ACT being given had sensitivity of 43.2% and specificity 90.2%, while recall that any anti-malarial was given had sensitivity 59.0% and specificity 82.7%. Correcting caregivers' response of treatment received using a combination of a visual aid with photographs of common drugs for fever, prescription documents and retained packaging changed ACT recall sensitivity and specificity to 91.5% and 71.1%, respectively. CONCLUSIONS: These findings indicate that caregivers' responses during household surveys are valid when assessing if a child received a finger/heel prick during a consultation in the previous 2 weeks, and if the malaria test result was positive. Recall of ACT treatment received by U5s was poor when based on interview response only, but was substantially improved when incorporating visual aids, prescriptions and drug packaging review.

Methodological Considerations for Use of Routine Health Information System Data to Evaluate Malaria Program Impact in an Era of Declining Malaria Transmission.

Coverage of malaria control interventions is increasing dramatically across endemic countries. Evaluating the impact of malaria control programs and specific interventions on health indicators is essential to enable countries to select the most effective and appropriate combination of tools to accelerate progress or proceed toward malaria elimination. When key malaria interventions have been proven effective under controlled settings, further evaluations of the impact of the intervention using randomized approaches may not be appropriate or ethical. Alternatives to randomized controlled trials are therefore required for rigorous evaluation under conditions of routine program delivery. Routine health management information system (HMIS) data are a potentially rich source of data for impact evaluation, but have been underused in impact evaluation due to concerns over internal validity, completeness, and potential bias in estimates of program or intervention impact. A range of methodologies were identified that have been used for impact evaluations with malaria outcome indicators generated from HMIS data. Methods used to maximize internal validity of HMIS data are presented, together with recommendations on reducing bias in impact estimates. Interrupted time series and dose-response analyses are proposed as the strongest quasi-experimental impact evaluation designs for analysis of malaria outcome indicators from routine HMIS data. Interrupted time series analysis compares the outcome trend and level before and after the introduction of an intervention, set of interventions or program. The dose-response national platform approach explores associations between intervention coverage or program intensity and the outcome at a subnational (district or health facility catchment) level.

Reactive case-detection of malaria in Pailin Province, Western Cambodia: lessons from a year-long evaluation in a pre-elimination setting.

BACKGROUND: As momentum towards malaria elimination grows, strategies are being developed for scale-up in elimination settings. One prominent strategy, reactive case detection (RACD), involves screening and treating individuals living in close proximity to passively detected, or "index" cases. This study aims to use RACD to quantify Plasmodium parasitaemia in households of index cases, and identify risk factors for infection; these data could inform reactive screening approaches and identify target risk groups. METHODS: This study was conducted in the Western Cambodian province of Pailin between May 2013 and March 2014 among 440 households. Index participants/index cases (n = 270) and surrounding households (n = 110) were screened for Plasmodium infection with rapid diagnostic tests (RDT), microscopy and real-time polymerase chain reaction (PCR). Participants were interviewed to identify risk factors. A comparison group of 60 randomly-selected households was also screened, to compare infection levels of RACD and non-RACD households. In order to identify potential risk factors that would inform screening approaches and identify risk groups, multivariate logistic regression models were applied. RESULTS: Nine infections were identified in households of index cases (RACD approach) through RDT screening of 1898 individuals (seven Plasmodium vivax, two Plasmodium falciparum); seven were afebrile. Seventeen infections were identified through PCR screening of 1596 individuals (15 P. vivax, and 22 % P. falciparum/P. vivax mixed infections). In the control group, 25 P. falciparum infections were identified through PCR screening of 237 individuals, and no P. vivax was found. Plasmodium falciparum infection was associated with fever (p = 0.013), being a member of a control household (p ≤ 0.001), having a history of malaria infection (p = 0.041), and sleeping without a mosquito net (p = 0.011). Significant predictors of P. vivax infection, as diagnosed by PCR, were fever (p = 0.058, borderline significant) and history of malaria infection (p ≤ 0.001). CONCLUSION: This study found that RACD identified very few secondary infections when targeting index and neighbouring households for screening. The results suggest RACD is not appropriate, where exposure to malaria occurs away from the community, and there is a high level of treatment-seeking from the private sector. Piloting RACD in a range of transmission settings would help to identify the ideal environment for feasible and effective reactive screening methods.

The usefulness of school-based syndromic surveillance for detecting malaria epidemics: experiences from a pilot project in Ethiopia.

BACKGROUND: Syndromic surveillance is a supplementary approach to routine surveillance, using pre-diagnostic and non-clinical surrogate data to identify possible infectious disease outbreaks. To date, syndromic surveillance has primarily been used in high-income countries for diseases such as influenza--however, the approach may also be relevant to resource-poor settings. This study investigated the potential for monitoring school absenteeism and febrile illness, as part of a school-based surveillance system to identify localised malaria epidemics in Ethiopia. METHODS: Repeated cross-sectional school- and community-based surveys were conducted in six epidemic-prone districts in southern Ethiopia during the 2012 minor malaria transmission season to characterise prospective surrogate and syndromic indicators of malaria burden. Changes in these indicators over the transmission season were compared to standard indicators of malaria (clinical and confirmed cases) at proximal health facilities. Subsequently, two pilot surveillance systems were implemented, each at ten sites throughout the peak transmission season. Indicators piloted were school attendance recorded by teachers, or child-reported recent absenteeism from school and reported febrile illness. RESULTS: Lack of seasonal increase in malaria burden limited the ability to evaluate sensitivity of the piloted syndromic surveillance systems compared to existing surveillance at health facilities. Weekly absenteeism was easily calculated by school staff using existing attendance registers, while syndromic indicators were more challenging to collect weekly from schoolchildren. In this setting, enrolment of school-aged children was found to be low, at 54%. Non-enrolment was associated with low household wealth, lack of parental education, household size, and distance from school. CONCLUSIONS: School absenteeism is a plausible simple indicator of unusual health events within a community, such as malaria epidemics, but the sensitivity of an absenteeism-based surveillance system to detect epidemics could not be rigorously evaluated in this study. Further piloting during a demonstrated increase in malaria transmission within a community is recommended.

Novel Cross-Border Approaches to Optimise Identification of Asymptomatic and Artemisinin-Resistant Plasmodium Infection in Mobile Populations Crossing Cambodian Borders.

BACKGROUND: Human population movement across country borders presents a real challenge for malaria control and elimination efforts in Cambodia and its neighbouring countries. To quantify Plasmodium infection among the border-crossing population, including asymptomatic and artemisinin resistant (AR) parasites, three official border crossing points, one from each of Cambodia's borders with Thailand, Laos and Vietnam, were selected for sampling. METHODS AND FINDINGS: A total of 3206 participants (of 4110 approached) were recruited as they crossed the border, tested for malaria and interviewed. By real-time polymerase chain reaction (RT-PCR), 5.4% of all screened individuals were found to harbour Plasmodium parasites. The proportion was highest at the Laos border (11.5%). Overall there were 97 P. vivax (55.7%), 55 P. falciparum (31.6%), two P. malariae (1.1%) and 20 mixed infections (11.5%). Of identified infections, only 20% were febrile at the time of screening. Of the 24 P. falciparum samples where a further PCR was possible to assess AR, 15 (62.5%) had mutations in the K13 propeller domain gene, all from participants at the Laos border point. Malaria rapid diagnostic test (RDT) pLDH/HRP-2 identified a positivity rate of 3.2% overall and sensitivity compared to RT-PCR was very low (43.1%). Main individual risk factors for infection included sex, fever, being a forest-goer, poor knowledge of malaria prevention methods and previous malaria infection. Occupation, day of the week and time of crossing (morning vs. afternoon) also appeared to play an important role in predicting positive cases. CONCLUSIONS: This study offers a novel approach to identify asymptomatic infections and monitor AR parasite flow among mobile and migrant populations crossing the borders. Similar screening activities are recommended to identify other hot borders and characterise potential hot spots of AR. Targeted "customised" interventions and surveillance activities should be implemented in these sites to accelerate elimination efforts in the region.