Impact of seasonal malaria chemoprevention on hospital admissions and mortality in children under 5 years of age in Ouelessebougou, Mali.

BACKGROUND: Seasonal malaria chemoprevention is widely implemented in Sahel and sub-Sahel countries in Africa. Few studies have assessed the impact of the SMC on hospital admission and death when it is implemented in the health system. This retrospective study assessed the impact of seasonal malaria chemoprevention (SMC) on hospitalizations and deaths of children under 5 years of age during the second year of implementation of SMC in the health district of Ouelessebougou in Mali. METHODS: In February 2017, a survey was conducted to assess hospital admissions and deaths in children under 5 years of age in two health sub-districts where SMC was implemented in 2015 and two health sub-districts where SMC was not implemented. The survey reviewed deaths and hospitalizations of children under 5, in the four health sub-districts. The crude and specific incidence rates of hospitalizations and deaths were determined in both groups and expressed per 1000 children per year. A negative binomial regression model and a Cox model were used to estimate the relative risks of hospitalization and death after adjusting for confounders. The R software was used for data analysis. RESULTS: A total of 6638 children under 5 years of age were surveyed, 2759 children in the SMC intervention areas and 3879 children in the control areas. All causes mortality rate per 1000 person-years was 8.29 in the control areas compared to 3.63 in the intervention areas; age and gender adjusted mortality rate ratio 0.44 (95% CI 0.22-0.91), p = 0.027. The incidence rate of all causes hospital admissions was 19.60 per 1000 person-years in the intervention group compared to 33.45 per 1000 person-years in the control group, giving an incidence rate ratio (IRR) adjusted for age and gender of 0.61 (95% CI 0.44-0.84), p = 0.003. CONCLUSION: The implementation of SMC was associated with a substantial reduction in hospital admissions and all-cause mortality. Trial registration ClinicalTrials.gov NCT02646410.

Effect of Seasonal Malaria Chemoprevention on Immune Markers of Exhaustion and Regulation.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a novel strategy to reduce malaria infections in children. Infection with Plasmodium falciparum results in immune dysfunction characterized by elevated expression of markers associated with exhaustion, such as PD1 and LAG3, and regulatory CD4+FOXP3+ T cells. METHODS: In the current study, the impact of seasonal malaria chemoprevention on malaria-induced immune dysfunction, as measured by markers associated with exhaustion and regulatory T cells, was explored by flow cytometry. RESULTS: Children that received seasonal malaria chemoprevention had fewer malaria episodes and showed significantly lower fold changes in CD4+PD1+ and CD4+PD1+LAG3+ compared to those that did not receive SMC. Seasonal malaria chemoprevention had no observable effect on fold changes in CD8 T cells expressing PD1 or CD160. However, children receiving SMC showed greater increases in CD4+FOXP3+ T regulatory cells compared to children not receiving SMC. CONCLUSIONS: These results provide important insights into the dynamics of malaria-induced changes in the CD4 T-cell compartment of the immune system and suggest that the reduction of infections due to seasonal malaria chemoprevention may also prevent immune dysfunction. CLINICAL TRIALS REGISTRATION: NCT02504918.

Optimal mode for delivery of seasonal malaria chemoprevention in Ouelessebougou, Mali: A cluster randomized trial.

BACKGROUND: Seasonal malaria chemoprevention (SMC), the administration of complete therapeutic courses of antimalarials to children aged 3-59 months during the malaria transmission season, is a new strategy recommended by the World Health Organization (WHO) for malaria control in Sahelian countries such as Mali with seasonal transmission. The strategy is a highly cost-effective approach to reduce malaria burden in these areas. Despite the substantial benefits of SMC on malaria infection and disease, the optimal approach to deliver SMC remains to be determined. While fixed-point delivery (FPD) and non-directly observed treatment (NDOT) by community health workers are logistically attractive, these need to be evaluated and compared to other modes of delivery for maximal coverage. METHODS: To determine the optimal mode fixed-point (FPD) vs door-to-door delivery (DDD); directly observed treatment (DOT) vs. non- directly observed treatment (NDOT)), 31 villages in four health sub-districts were randomized to receive three rounds of SMC with Sulfadoxine-pyrimethamine plus Amodiaquine (SP+AQ) at monthly intervals using one of the following methods: FPD+DOT; FPD+NDOT; DDD+DOT; DDD+NDOT. The primary endpoint was SMC coverage assessed by cross-sectional survey of 2,035 children at the end of intervention period. RESULTS: Coverage defined as the proportion of children who received all three days of SMC treatment during the three monthly rounds based information collected by interview (primary endpoint) was significantly higher in children who received SMC using DDD 74% (95% CI 69% - 80%) compared to FPD 60% (95% CI 50% - 70%); p = 0.009. It was similar in children who received SMC using DOT or NDOT 65%, (95% CI 55% - 76%) versus 68% (95% CI 57% - 79%); p = 0.72. CONCLUSIONS: In summary, door-to-door delivery of SMC provides better coverage than FPD. Directly observed therapy, which requires more time and resources, did not improve coverage with SMC. TRIAL REGISTRATION: ClinicalTrials.gov NCT02646410.

Measuring the impact of seasonal malaria chemoprevention as part of routine malaria control in Kita, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a new strategy recommended by WHO in areas of highly seasonal transmission in March 2012. Although randomized controlled trials (RCTs) have shown SMC to be highly effective, evidence and experience from routine implementation of SMC are limited. METHODS: A non-randomized pragmatic trial with pre-post design was used, with one intervention district (Kita), where four rounds of SMC with sulfadoxine + amodiaquine (SP + AQ) took place in August-November 2014, and one comparison district (Bafoulabe). The primary aims were to evaluate SMC coverage and reductions in prevalence of malaria and anaemia when SMC is delivered through routine programmes using existing community health workers. Children aged 3-59 months from 15 selected localities per district, sampled with probability proportional to size, were surveyed and blood samples collected for malaria blood smears, haemoglobin (Hb) measurement, and molecular markers of drug resistance in two cross-sectional surveys, one before SMC (July 2014) and one after SMC (December 2014). Difference-in-differences regression models were used to assess and compare changes in malaria and anaemia in the intervention and comparison districts. Adherence and tolerability of SMC were assessed by cross-sectional surveys 4-7 days after each SMC round. Coverage of SMC was assessed in the post-SMC survey. RESULTS: During round 1, 84% of targeted children received at least the first SMC dose, but coverage declined to 67% by round 4. Across the four treatment rounds, 54% of children received four complete SMC courses. Prevalence of parasitaemia was similar in intervention and comparison districts prior to SMC (23.4 vs 29.5%, p = 0.34) as was the prevalence of malaria illness (2.4 vs 1.9%, p = 0.75). After SMC, parasitaemia prevalence fell to 18% in the intervention district and increased to 46% in the comparison district [difference-in-differences (DD) OR = 0.35; 95% CI 0.20-0.60]. Prevalence of malaria illness fell to a greater degree in the intervention district versus the comparison district (DD OR = 0.20; 95% CI 0.04-0.94) and the same for moderate anaemia (Hb < 8 g/dL) (DD OR = 0.26, 95% CI 0.11-0.65). The frequency of the quintuple mutation (dhfr N51I, C59R and S108N + dhps A437G and K540E) remained low (5%) before and after intervention in both districts. CONCLUSIONS: Routine implementation of SMC in Mali substantially reduced malaria and anaemia, with reductions of similar magnitude to those seen in previous RCTs. Improving coverage could further strengthen SMC impact. Trial registration clinical trial registration number NCT02894294.

Effect of seasonal malaria chemoprevention on the acquisition of antibodies to Plasmodium falciparum antigens in Ouelessebougou, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a new strategy to reduce malaria burden in young children in Sahelian countries. It consists of the administration of full treatment courses of sulfadoxine-pyrimethamine plus amodiaquine to children at monthly intervals during the malaria season. However, it is not clear if there is a cumulative effect of SMC over time on acquisition of antibodies to malaria antigens. METHODS: A cross-sectional serosurvey was carried out 1 month after the last dose of SMC in 2016. Children aged 3-4 years were randomly selected from areas where SMC was given for 1, 2 or 3 years during the malaria season. Children in the areas where SMC had been implemented for 1 year but who failed to receive SMC were used as comparison group. Antibody extracted from dry blood spots was used to measure IgG levels to CSP, MSP-142 and AMA1. RESULTS: The prevalence of antibodies to AMA-1 were high and similar in children who received SMC for 1, 2 or 3 years and also when compared to those who never received SMC (96.3 vs 97.5%, adjusted OR = 0.99, 95% CI 0.33-2.97, p = 0.99). The prevalence of antibodies to MSP-142 and to CSP were similar in children that received SMC for 1, 2 or 3 years, but were lower in these children compared to those who did not receive SMC (87.1 vs 91.2%, adjusted OR = 0.55, 95% CI 0.29-1.01, p = 0.05 for MSP-142; 79.8 vs 89.2%, adjusted OR = 0.52, 95% CI 0.30-0.90, p = 0.019 for CSP). CONCLUSIONS: SMC reduced seropositivity to MSP-142 and CSP, but the duration of SMC did not further reduce seropositivity. Exposure to SMC did not reduce the seropositivity to AMA1.