Relationship between patient sex and anatomical sites of extrapulmonary tuberculosis in Mali.

Background: Contribution of host factors in mediating susceptibility to extrapulmonary tuberculosis is not well understood. Objective: To examine the influence of patient sex on anatomical localization of extrapulmonary tuberculosis. Methods: We conducted a retrospective cross-sectional study in Mali, West Africa. Hospital records of 1,304 suspected cases of extrapulmonary tuberculosis, available in TB Registry of a tertiary tuberculosis referral center from 2019 to 2021, were examined. Results: A total of 1,012 (77.6%) were confirmed to have extrapulmonary tuberculosis with a male to female ratio of 1.59:1. Four clinical forms of EPTB predominated, namely pleural (40.4%), osteoarticular (29.8%), lymph node (12.5%), and abdominal TB (10.3%). We found sex-based differences in anatomical localization of extrapulmonary tuberculosis, with males more likely than females to have pleural TB (OR: 1.51; 95% CI [1.16 to 1.98]). Conversely, being male was associated with 43% and 41% lower odds of having lymph node and abdominal TB, respectively (OR: 0.57 and 0.59). Conclusion: Anatomical sites of extrapulmonary tuberculosis differ by sex with pleural TB being associated with male sex while lymph node and abdominal TB are predominately associated with female sex. Future studies are warranted to understand the role of sex in mediating anatomical site preference of tuberculosis.

Effect of a fifth round of seasonal malaria chemoprevention in children aged 5-14 years in Dangassa, an area of long transmission in Mali.

Despite a significant reduction in the burden of malaria in children under five years-old, the efficient implementation of seasonal malaria chemoprevention (SMC) at large scale remains a major concern in areas with long malaria transmission. Low coverage rate in the unattainable areas during the rainy season, a shift in the risk of malaria to older children and the rebound in malaria incidence after stopping drug administration are mainly reported in these areas. These gaps represent a major challenge in the efficient implementation of SMC measures. An open randomized study was conducted to assess the effect of a fifth additional round to current regime of SMC in older children living in Dangassa, a rural malaria endemic area. Poisson regression Model was used to estimate the reduction in malaria incidence in the intervention group compared to the control group including age groups (5-9 and 10-14 years) and the use of long-lasting insecticidal nets (LLINs; Yes or No) with a threshold at 5%. Overall, a downward trend in participation rate was observed from August (94.3%) to November (87.2%). In November (round 4), the risk of malaria incidence was similar in both groups (IRR = 0.66, 95%CI [0.35-1.22]). In December (round 5), a decrease of 51% in malaria incidence was observed in intervention group compared to control group adjusted for age groups and the use of LLINs (IRR = 0.49, 95%CI [0.26-0.94]), of which 17% of reduction is attributable to the 5th round in the intervention group. An additional fifth round of SMC resulted in a significant reduction of malaria incidence in the intervention group. The number of SMC rounds could be adapted to the local condition of malaria transmission.

The West Africa ICEMR Partnerships for Guiding Policy to Improve the Malaria Prevention and Control.

The Mali National Malaria Control Program (NMCP) recently established a phased set of goals for eliminating malaria in Mali by 2030. Over the past decade, the scale-up of NMCP-led malaria control interventions has led to considerable progress, as evidenced by multiple malariometric indicators. The West Africa International Center of Excellence in Malaria Research (WA-ICEMR) is a multidisciplinary research program that works closely with the NMCP and its partners to address critical research needs for malaria control. This coordinated effort includes assessing the effectiveness of control interventions based on key malaria research topics, including immune status, parasite genetic diversity, insecticide and drug resistance, diagnostic accuracy, malaria vector populations and biting behaviors, and vectorial capacity. Several signature accomplishments of the WA-ICEMR include identifying changing malaria age demographic profiles, testing innovative approaches to improve control strategies, and providing regular reporting on drug and insecticide resistance status. The NMCP and WA-ICEMR partnership between the WA-ICEMR and the NMCP offers a comprehensive research platform that informs the design and implementation of malaria prevention and control research programs. These efforts build local expertise and capacity for the next generation of malaria researchers and guide local policy, which is crucial in sustaining efforts toward eliminating malaria in West Africa.

A Decade of Progress Accelerating Malaria Control in Mali: Evidence from the West Africa International Center of Excellence for Malaria Research.

This article highlights over a decade of signature achievements by the West Africa International Centers for Excellence in Malaria Research (WA-ICEMR) and its partners toward guiding malaria prevention and control strategies. Since 2010, the WA-ICEMR has performed longitudinal studies to monitor and assess malaria control interventions with respect to space-time patterns, vector transmission indicators, and drug resistance markers. These activities were facilitated and supported by the Mali National Malaria Control Program. Research activities included large-scale active and passive surveillance and expanded coverage of universal long-lasting insecticide-treated bed nets and seasonal malaria chemoprevention (SMC). The findings revealed substantial declines in malaria occurrence after the scale-up of control interventions in WA-ICEMR study sites. WA-ICEMR studies showed that SMC using sulfadoxine-pyrimethamine plus amodiaquine was highly effective in preventing malaria among children under 5 years of age. An alternative SMC regimen (dihydroartemisinin plus piperaquine) was shown to be potentially more effective and provided advantages for acceptability and compliance over the standard SMC regimen. Other findings discussed in this article include higher observed multiplicity of infection rates for malaria in historically high-endemic areas, continued antimalarial drug sensitivity to Plasmodium falciparum, high outdoor malaria transmission rates, and increased insecticide resistance over the past decade. The progress achieved by the WA-ICEMR and its partners highlights the critical need for maintaining current malaria control interventions while developing novel strategies to disrupt malaria transmission. Enhanced evaluation of these strategies through research partnerships is particularly needed in the wake of reported artemisinin resistance in Southeast Asia and East Africa.

Sex Differences in Active Pulmonary Tuberculosis Outcomes in Mali, West Africa.

Men and women often respond differently to infectious diseases and their treatments. Tuberculosis (TB) is a life-threatening communicable disease that affects more men than women globally. Whether male sex is an independent risk factor for unfavorable TB outcomes, however, has not been rigorously investigated in an African context, where individuals are likely exposed to different microbial and environmental factors. We analyzed data collected from a cohort study in Mali by focusing on newly diagnosed active pulmonary TB individuals who were treatment naive. We gathered baseline demographic, clinical, and microbiologic characteristics before treatment initiation and also at three time points during treatment. More males than females were affected with TB, as evidenced by a male-to-female ratio of 2.4:1. In addition, at baseline, males had a significantly higher bacterial count and shorter time to culture positivity as compared with females. Male sex was associated with lower smear negativity rate after 2 months of treatment also known as the intensive phase of treatment, but not at later time points. There was no relationship between patients' sex and mortality from any cause during treatment. This study suggests that sex-based differences in TB outcomes exist, with sex-specific effects on disease outcomes being more pronounced before treatment initiation and during the intensive phase of treatment rather than at later phases of treatment.

Trends in malaria epidemiological factors following the implementation of current control strategies in Dangassa, Mali.

BACKGROUND: Over the past decade, three strategies have reduced severe malaria cases and deaths in endemic regions of Africa, Asia and the Americas, specifically: (1) artemisinin-based combination therapy (ACT); (2) insecticide-treated bed nets (ITNs); and, (3) intermittent preventive treatment with sulfadoxine-pyrimethamine in pregnancy (IPTp). The rationale for this study was to examine communities in Dangassa, Mali where, in 2015, two additional control strategies were implemented: ITN universal coverage and seasonal malaria chemoprevention (SMC) among children under 5 years old. METHODS: This was a prospective study based on a rolling longitudinal cohort of 1401 subjects participating in bi-annual smear surveys for the prevalence of asymptomatic Plasmodium falciparum infection and continuous surveillance for the incidence of human disease (uncomplicated malaria), performed in the years from 2012 to 2020. Entomological collections were performed to examine the intensity of transmission based on pyrethroid spray catches, human landing catches and enzyme-linked immunosorbent assay (ELISA) testing for circumsporozoite antigen. RESULTS: A total of 1401 participants of all ages were enrolled in the study in 2012 after random sampling of households from the community census list. Prevalence of infection was extremely high in Dangassa, varying from 9.5 to 62.8% at the start of the rainy season and from 15.1 to 66.7% at the end of the rainy season. Likewise, the number of vectors per house, biting rates, sporozoites rates, and entomological inoculation rates (EIRs) were substantially greater in Dangassa. DISCUSSION: The findings for this study are consistent with the progressive implementation of effective malaria control strategies in Dangassa. At baseline (2012-2014), prevalence of P. falciparum was above 60% followed by a significant year-to-year decease starting in 2015. Incidence of uncomplicated infection was greater among children < 5 years old, while asymptomatic infection was more frequent among the 5-14 years old. A significant decrease in EIR was also observed from 2015 to 2020. Likewise, vector density, sporozoite rates, and EIRs decreased substantially during the study period. CONCLUSION: Efficient implementation of two main malaria prevention strategies in Dangassa substantially contribute to a reduction of both asymptomatic and symptomatic malaria from 2015 to 2020.

Predicting Malaria Transmission Dynamics in Dangassa, Mali: A Novel Approach Using Functional Generalized Additive Models.

Mali aims to reach the pre-elimination stage of malaria by the next decade. This study used functional regression models to predict the incidence of malaria as a function of past meteorological patterns to better prevent and to act proactively against impending malaria outbreaks. All data were collected over a five-year period (2012-2017) from 1400 persons who sought treatment at Dangassa's community health center. Rainfall, temperature, humidity, and wind speed variables were collected. Functional Generalized Spectral Additive Model (FGSAM), Functional Generalized Linear Model (FGLM), and Functional Generalized Kernel Additive Model (FGKAM) were used to predict malaria incidence as a function of the pattern of meteorological indicators over a continuum of the 18 weeks preceding the week of interest. Their respective outcomes were compared in terms of predictive abilities. The results showed that (1) the highest malaria incidence rate occurred in the village 10 to 12 weeks after we observed a pattern of air humidity levels >65%, combined with two or more consecutive rain episodes and a mean wind speed <1.8 m/s; (2) among the three models, the FGLM obtained the best results in terms of prediction; and (3) FGSAM was shown to be a good compromise between FGLM and FGKAM in terms of flexibility and simplicity. The models showed that some meteorological conditions may provide a basis for detection of future outbreaks of malaria. The models developed in this paper are useful for implementing preventive strategies using past meteorological and past malaria incidence.

Spatio-Temporal Dynamic of Malaria Incidence: A Comparison of Two Ecological Zones in Mali.

Malaria transmission largely depends on environmental, climatic, and hydrological conditions. In Mali, malaria epidemiological patterns are nested within three ecological zones. This study aimed at assessing the relationship between those conditions and the incidence of malaria in Dangassa and Koila, Mali. Malaria data was collected through passive case detection at community health facilities of each study site from June 2015 to January 2017. Climate and environmental data were obtained over the same time period from the Goddard Earth Sciences (Giovanni) platform and hydrological data from Mali hydraulic services. A generalized additive model was used to determine the lagged time between each principal component analysis derived component and the incidence of malaria cases, and also used to analyze the relationship between malaria and the lagged components in a multivariate approach. Malaria transmission patterns were bimodal at both sites, but peak and lull periods were longer lasting for Koila study site. Temperatures were associated with malaria incidence in both sites. In Dangassa, the wind speed (p = 0.005) and river heights (p = 0.010) contributed to increasing malaria incidence, in contrast to Koila, where it was humidity (p < 0.001) and vegetation (p = 0.004). The relationships between environmental factors and malaria incidence differed between the two settings, implying different malaria dynamics and adjustments in the conception and plan of interventions.

Effect of routine seasonal malaria chemoprevention on malaria trends in children under 5 years in Dangassa, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a new strategy to prevent malaria in children under 5 years old. It has been recommended by the World Health Organization since 2012 in malaria-endemic areas with seasonal transmission. This study aimed to assess the changes in malaria indicators through two consecutive years of SMC routine implementation in children under 5 years old in Dangassa, where malaria is endemic with a long and high transmission season. METHODS: From 2012 to 2016, a cohort study was conducted in Dangassa village. The study team based in the village followed all malaria clinical cases in children under 5 years old at the community health centre. During the study, SMC was routinely implemented in collaboration with the National Malaria Control Programme. The Cox regression model was used in order to compare malaria risk during the study. RESULTS: The Cox regression model showed a significant reduction in malaria clinical incidence, both in 2015 (HR = 0.27 (0.18-0.40), 95% CI) and in 2016 (HR = 0.23 (0.15-0.35), 95% CI) of SMC implementation compared to October 2013. Gametocyte and fever prevalence was lower between September and October during SMC implementation (2015 and 2016) compared to the same period before SMC implementation (2013-2014). A slight increase of malaria incidence was observed in December at the end of SMC implementation. CONCLUSION: SMC has significantly reduced both malaria incidence and gametocyte prevalence and improved haemoglobin levels in children under 5 years old after 2 years of routine implementation.

Clustering of asymptomatic Plasmodium falciparum infection and the effectiveness of targeted malaria control measures.

BACKGROUND: Because clustering of Plasmodium falciparum infection had been noted previously, the clustering of infection was examined at four field sites in West Africa: Dangassa and Dioro in Mali, Gambissara in The Gambia and Madina Fall in Senegal. METHODS: Clustering of infection was defined by the percent of persons with positive slides for asexual P. falciparum sleeping in a house which had been geopositioned. Data from each site were then tested for spatial, temporal and spatio-temporal clustering in relation to the prevalence of infection from smear surveys. RESULTS: These studies suggest that clustering of P. falciparum infection also affects the effectiveness of control interventions. For example, the clustering of infection in Madina Fall disappeared in 2014-2016 after vector control eliminated the only breeding site in 2013. In contrast, the temporal clustering of infection in Dioro (rainy season of 2014, dry season of 2015) was consistent with the loss of funding for Dioro in the second quarter of 2014 and disappeared when funds again became available in late 2015. The clustering of infection in rural (western) areas of Gambissara was consistent with known rural-urban differences in the prevalence of infection and with the thatched roofs, open eaves and mud walls of houses in rural Gambissara. In contrast, the most intense transmission was in Dangassa, where the only encouraging observation was a lower prevalence of infection in the dry season. Taken together, these results suggest: (a) the transmission of infection was stopped in Madina Fall by eliminating the only known breeding site, (b) the prevalence of infection was reduced in Dioro after financial support became available again for malaria control in the second half of 2015, (c) improvements in housing should improve malaria control by reducing the number of vectors in rural communities such as western Gambissara, and (d) beginning malaria control during the dry season may reduce transmission in hyperendemic areas such as Dangassa. CONCLUSIONS: From a conceptual perspective, testing for spatial, temporal and spatio-temporal clustering based on epidemiologic data permits the generation of hypotheses for the clustering observed and the testing of candidate interventions to confirm or refute those hypotheses.

Development of a data collection and management system in West Africa: challenges and sustainability.

BACKGROUND: Developing and sustaining a data collection and management system (DCMS) is difficult in malaria-endemic countries because of limitations in internet bandwidth, computer resources and numbers of trained personnel. The premise of this paper is that development of a DCMS in West Africa was a critically important outcome of the West African International Centers of Excellence for Malaria Research. The purposes of this paper are to make that information available to other investigators and to encourage the linkage of DCMSs to international research and Ministry of Health data systems and repositories. METHODS: We designed and implemented a DCMS to link study sites in Mali, Senegal and The Gambia. This system was based on case report forms for epidemiologic, entomologic, clinical and laboratory aspects of plasmodial infection and malarial disease for a longitudinal cohort study and included on-site training for Principal Investigators and Data Managers. Based on this experience, we propose guidelines for the design and sustainability of DCMSs in environments with limited resources and personnel. RESULTS: From 2012 to 2017, we performed biannual thick smear surveys for plasmodial infection, mosquito collections for anopheline biting rates and sporozoite rates and year-round passive case detection for malarial disease in four longitudinal cohorts with 7708 individuals and 918 households in Senegal, The Gambia and Mali. Major challenges included the development of uniform definitions and reporting, assessment of data entry error rates, unstable and limited internet access and software and technology maintenance. Strengths included entomologic collections linked to longitudinal cohort studies, on-site data centres and a cloud-based data repository. CONCLUSIONS: At a time when research on diseases of poverty in low and middle-income countries is a global priority, the resources available to ensure accurate data collection and the electronic availability of those data remain severely limited. Based on our experience, we suggest the development of a regional DCMS. This approach is more economical than separate data centres and has the potential to improve data quality by encouraging shared case definitions, data validation strategies and analytic approaches including the molecular analysis of treatment successes and failures.

West Africa International Centers of Excellence for Malaria Research: Drug Resistance Patterns to Artemether-Lumefantrine in Senegal, Mali, and The Gambia.

In 2006, artemether-lumefantrine (AL) became the first-line treatment of uncomplicated malaria in Senegal, Mali, and the Gambia. To monitor its efficacy, between August 2011 and November 2014, children with uncomplicated Plasmodium falciparum malaria were treated with AL and followed up for 42 days. A total of 463 subjects were enrolled in three sites (246 in Senegal, 97 in Mali, and 120 in Gambia). No early treatment failure was observed and malaria infection cleared in all patients by day 3. Polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) was 100% in Mali, and the Gambia, and 98.8% in Senegal. However, without PCR adjustment, ACPR was 89.4% overall; 91.5% in Mali, 98.8% in Senegal, and 64.3% in the Gambia (the lower value in the Gambia attributed to poor compliance of the full antimalarial course). However, pfmdr1 mutations were prevalent in Senegal and a decrease in parasite sensitivity to artesunate and lumefantrine (as measured by ex vivo drug assay) was observed at all sites. Recrudescent parasites did not show Kelch 13 (K13) mutations and AL remains highly efficacious in these west African sites.

Improving malaria control in West Africa: interruption of transmission as a paradigm shift.

With the paradigm shift from the reduction of morbidity and mortality to the interruption of transmission, the focus of malaria control broadens from symptomatic infections in children ≤5 years of age to include asymptomatic infections in older children and adults. In addition, as control efforts intensify and the number of interventions increases, there will be decreases in prevalence, incidence and transmission with additional decreases in morbidity and mortality. Expected secondary consequences of these changes include upward shifts in the peak ages for infection (parasitemia) and disease, increases in the ages for acquisition of antiparasite humoral and cellular immune responses and increases in false-negative blood smears and rapid diagnostic tests. Strategies to monitor these changes must include: (1) studies of the entire population (that are not restricted to children ≤5 or ≤10 years of age), (2) study sites in both cities and rural areas (because of increasing urbanization across sub-Saharan Africa) and (3) innovative strategies for surveillance as the prevalence of infection decreases and the frequency of false-negative smears and rapid diagnostic tests increases.

Sahel, savana, riverine and urban malaria in West Africa: Similar control policies with different outcomes.

The study sites for the West African ICEMR are in three countries (The Gambia, Senegal, Mali) and are located within 750 km of each other. In addition, the National Malaria Control Programmes of these countries have virtually identical policies: (1) Artemisinin Combination Therapies (ACTs) for the treatment of symptomatic Plasmodium falciparum infection, (2) Long-Lasting Insecticide-treated bed Nets (LLINs) to reduce the Entomololgic Inoculation Rate (EIR), and (3) sulfadoxine-pyrimethamine for the Intermittent Preventive Treatment of malaria during pregnancy (IPTp). However, the prevalence of P. falciparum malaria and the status of malaria control vary markedly across the four sites with differences in the duration of the transmission season (from 4-5 to 10-11 months), the intensity of transmission (with EIRs from unmeasurably low to 4-5 per person per month), multiplicity of infection (from a mean of 1.0 to means of 2-5) and the status of malaria control (from areas which have virtually no control to areas that are at the threshold of malaria elimination). The most important priority is the need to obtain comparable data on the population-based prevalence, incidence and transmission of malaria before new candidate interventions or combinations of interventions are introduced for malaria control.