Mass Azithromycin Distribution to Prevent Child Mortality in Burkina Faso: The CHAT Randomized Clinical Trial.

Importance: Repeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions. Objective: To evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention. Design, Setting, and Participants: This cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities. Interventions: Communities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023. Main Outcomes and Measures: The primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census. Results: A total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1% (16.0%) of the censused children received the scheduled study drug in the azithromycin group and 89.8% (17.1%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95% CI, 0.67-1.02; P = .07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95% CI, 0.57-0.94) in those aged 24 to 59 months. Conclusions and Relevance: Mortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03676764.

Intestinal Injury Biomarkers Predict Mortality in Pediatric Severe Malaria.

Severe malaria (SM) increases the risk of invasive bacterial infection, and there is evidence to suggest increased gastrointestinal permeability. Studies have shown sequestration of infected erythrocytes in intestinal microvasculature, and in vivo studies of rectal mucosa have demonstrated disruption of microvascular blood flow. However, the extent of intestinal injury in pediatric malaria is not well characterized. In this study, two serum biomarkers of intestinal injury, trefoil factor 3 (TFF3) and intestinal fatty acid binding protein (I-FABP), were analyzed in 598 children with SM and 120 healthy community children (CC), 6 months to 4 years of age. Serum was collected at enrollment and 1 month for laboratory studies, and participants were monitored for 12 months. Intestinal injury biomarkers were significantly elevated in children with SM, with 18.1% having levels of TFF3 and/or I-FABP greater than the 99th percentile of CC levels. TFF3 levels continued to be elevated at 1 month, while I-FABP levels were comparable to CC levels. Both markers predicted in-hospital mortality {odds ratio (OR) (95% confidence interval [CI]), 4.4 (2.7, 7.3) and 2.3 (1.7, 3.1)} for a natural log increase in TFF3 and I-FABP, respectively. TFF3 was also associated with postdischarge mortality (OR, 2.43 [95% CI, 1.1, 4.8]). Intestinal injury was associated with acute kidney injury (AKI), acidosis (P < 0.001 for both), and angiopoietin 2, a maker of endothelial activation. In conclusion, intestinal injury is common in pediatric severe malaria and is associated with an increased mortality. It is strongly associated with AKI, acidosis, and endothelial activation. IMPORTANCE In children with severe malaria, intestinal injury is a common complication associated with increased mortality. Intestinal injury is associated with acute kidney injury, acidosis, and endothelial activation. Interventions promoting intestinal regeneration and repair represent novel approaches to improve outcomes.

Activation of cGAS-STING by Lethal Malaria N67C Dictates Immunity and Mortality through Induction of CD11b+ Ly6Chi Proinflammatory Monocytes.

Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) play critical roles in the innate immunity against infectious diseases and are required to link pathogen DNA sensing to immune responses. However, the mechanisms by which cGAS-STING-induced cytokines suppress the adaptive immune response against malaria infections remain poorly understood. Here, cGAS-STING signaling is identified to play a detrimental role in regulating anti-malaria immunity. cGAS or STING deficiency in mice markedly prolongs mouse survival during lethal malaria Plasmodium yoelii nigeriensis N67C infections by reducing late interleukin (IL)-6 production. Mechanistically, cGAS/STING recruits myeloid differentiation factor 88 (MyD88) and specifically induces the p38-dependent signaling pathway for late IL-6 production, which, in turn, expands CD11b+ Ly6Chi proinflammatory monocytes to inhibit immunity. Moreover, the blockage or ablation of the cGAS-STING-MyD88-p38-IL-6 signaling axis or the depletion of CD11b+ Ly6Chi proinflammatory monocytes provides mice a significant survival benefit during N67C and other lethal malaria-strain infections. Taken together, these findings identify a previously unrecognized detrimental role of cGAS-STING-MyD88-p38 axis in infectious diseases through triggering the late IL-6 production and proinflammatory monocyte expansion and provide insight into how targeting the DNA sensing pathway, dysregulated cytokines, and proinflammatory monocytes enhances immunity against infection.

Mosquito Net Use in Early Childhood and Survival to Adulthood in Tanzania.

BACKGROUND: It has been hypothesized that in high-transmission settings, malaria control in early childhood (<5 years of age) might delay the acquisition of functional immunity and shift child deaths from younger to older ages. METHODS: We used data from a 22-year prospective cohort study in rural southern Tanzania to estimate the association between early-life use of treated nets and survival to adulthood. All the children born between January 1, 1998, and August 30, 2000, in the study area were invited to enroll in a longitudinal study from 1998 through 2003. Adult survival outcomes were verified in 2019 through community outreach and mobile telephones. We used Cox proportional-hazards models to estimate the association between the use of treated nets in early childhood and survival to adulthood, adjusting for potential confounders. RESULTS: A total of 6706 children were enrolled. In 2019, we verified information on the vital status of 5983 participants (89%). According to reports of early-life community outreach visits, approximately one quarter of children never slept under a treated net, one half slept under a treated net some of the time, and the remaining quarter always slept under a treated net. Participants who were reported to have used treated nets at half the early-life visits or more had a hazard ratio for death of 0.57 (95% confidence interval [CI], 0.45 to 0.72) as compared with those who were reported to have used treated nets at less than half the visits. The corresponding hazard ratio between 5 years of age and adulthood was 0.93 (95% CI, 0.58 to 1.49). CONCLUSIONS: In this long-term study of early-life malaria control in a high-transmission setting, the survival benefit from early-life use of treated nets persisted to adulthood. (Funded by the Eckenstein-Geigy Professorship and others.).

Effect of biannual azithromycin distribution on antibody responses to malaria, bacterial, and protozoan pathogens in Niger.

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.

Child, maternal, and adult mortality in Sierra Leone: nationally representative mortality survey 2018-20.

BACKGROUND: Sierra Leone's child and maternal mortality rates are among the highest in the world. However, little is known about the causes of premature mortality in the country. To rectify this, the Ministry of Health and Sanitation of Sierra Leone launched the Sierra Leone Sample Registration System (SL-SRS) of births and deaths. Here, we report cause-specific mortality from the first SL-SRS round, representing deaths from 2018 to 2020. METHODS: The Countrywide Mortality Surveillance for Action platform established the SL-SRS, which involved conducting electronic verbal autopsies in 678 randomly selected villages and urban blocks throughout the country. 61 surveyors, in teams of four or five, enrolled people and ascertained deaths of individuals younger than 70 years in 2019-20, capturing verbal autopsies on deaths from 2018 to 2020. Centrally, two trained physicians independently assigned causes of death according to the International Classification of Diseases (tenth edition). SL-SRS death proportions were applied to 5-year mortality averages from the UN World Population Prospects (2019) to derive cause-specific death totals and risks of death nationally and in four Sierra Leone regions, with comparisons made with the Western region where Freetown, the capital, is located. We compared SL-SRS results with the cause-specific mortality estimates for Sierra Leone in the 2019 WHO Global Health Estimates. FINDINGS: Between Sept 1, 2019, and Dec 15, 2020, we enrolled 343 000 people and ascertained 8374 deaths of individuals younger than 70 years. Malaria was the leading cause of death in children and adults, nationally and in each region, representing 22% of deaths under age 70 years in 2020. Other infectious diseases accounted for an additional 16% of deaths. Overall maternal mortality ratio was 510 deaths per 100 000 livebirths (95% CI 483-538), and neonatal mortality rate was 31·1 deaths per 1000 livebirths (95% CI 30·4-31·8), both among the highest rates in the world. Haemorrhage was the major cause of maternal mortality and birth asphyxia or trauma was the major cause of neonatal mortality. Excess deaths were not detected in the months of 2020 corresponding to the peak of the COVID-19 pandemic. Half of the deaths occurred in rural areas and at home. If the Northern, Eastern, and Southern regions of Sierra Leone had the lower death rates observed in the Western region, about 20 000 deaths (just over a quarter of national total deaths in people younger than 70 years) would have been avoided. WHO model-based data vastly underestimated malaria deaths and some specific causes of injury deaths, and substantially overestimated maternal mortality. INTERPRETATION: Over 60% of individuals in Sierra Leone die prematurely, before age 70 years, most from preventable or treatable causes. Nationally representative mortality surveys such as the SL-SRS are of high value in providing reliable cause-of-death information to set public health priorities and target interventions in low-income countries. FUNDING: Bill & Melinda Gates Foundation, Canadian Institutes of Health Research, Queen Elizabeth Scholarship Program.

Clinical aspects and outcomes of patients with malaria at Chris Hani Baragwanath Academic Hospital,Johannesburg, South Africa.

BACKGROUND: South Africa (SA) is currently experiencing a significant increase in malaria cases despite having shifted focus from malaria control towards malaria elimination. The clinical features of malaria are nonspecific, but their relative frequency on presentation are not well described. HIV and malaria are both independently associated with high mortality in sub-Saharan Africa. There are important interactions between HIV and malaria. OBJECTIVES: To describe the population characteristics of patients with malaria at Chris Hani Baragwanath Academic Hospital, Johannesburg, SA, clinical and biochemical features of severity, the proportion of patients with HIV infection, management and outcomes. METHODS: A prospective observational study was conducted whereby patients with a confirmed laboratory diagnosis of malaria were identified, approached and consented for study inclusion over the time period January 2017 - January 2018. Clinical and biochemical data were collected at the time of consent and later analysed. RESULTS: The mean (standard deviation) age was 35.7 (12.98) years, and 72 (70.6%) of the 102 patients were male. Peak admissions for malaria were in January, with 58 patients (56.9%) admitted during January 2017 and 2018. All malaria cases were imported, with 74.5% associated with travel to Mozambique. The majority of the patients (61.8%) were expatriates living in SA. The most common presenting symptoms were chills (95.1%), weakness (94.1%), fever (91.2%), headache (90.2%) and lethargy (88.2%). The most common clinical signs were dehydration (31.4%), prostration (19.6%) and jaundice (13.7%). Among the 40 patients (39.2%) who had severe malaria, prostration was the most common feature of severity (19.6%), 8 (7.8%) were admitted to an intensive care unit, and 6 (5.9%) required haemodialysis. The median (interquartile range) duration of hospital stay was 5 (3 -6) (range 2 - 35) days. HIV status was known in 83 patients (81.4%), of whom 32 (38.6%) were HIV-positive. Malaria prophylaxis had been taken by only 8 patients. The all-cause mortality rate was 4.9%, and mortality attributable to malaria 3.9%. CONCLUSIONS: There was a high proportion of complicated malaria cases, particularly in January. The majority of patients were young expatriate males with a history of travel to southern Mozambique or Limpopo Province, with very few taking malaria prophylaxis. Most clinical signs and symptoms were constitutional and nonspecific. A large number of patients were found to be HIV-positive, and most were newly diagnosed. Mortality was high, at around five times the national average, and may have been an underestimate.

Cost-effectiveness analysis of integrated community case management delivery models utilizing drug sellers and community health workers for treatment of under-five febrile cases of malaria, pneumonia, diarrhoea in rural Uganda.

BACKGROUND: Malaria, pneumonia and diarrhoea continue to be the leading causes of death in children under the age of five years (U5) in Uganda. To combat these febrile illnesses, integrated community case management (iCCM) delivery models utilizing community health workers (CHWs) or drug sellers have been implemented. The purpose of this study is to compare the cost-effectiveness of delivering iCCM interventions via drug sellers versus CHWs in rural Uganda. METHODS: This study was a cost-effectiveness analysis to compare the iCCM delivery model utilizing drug sellers against the model using CHWs. The effect measure was the number of appropriately treated U5 children, and data on effectiveness came from a quasi-experimental study in Southwestern Uganda and the inSCALE cross-sectional household survey in eight districts of mid-Western Uganda. The iCCM interventions were costed using the micro-costing (ingredients) approach, with costs expressed in US dollars. Cost and effect data were linked together using a decision tree model and analysed using the Amua modelling software. RESULTS: The costs per 100 treated U5 children were US$591.20 and US$298.42 for the iCCM trained-drug seller and iCCM trained-CHW models, respectively, with 30 and 21 appropriately treated children in the iCCM trained-drug seller and iCCM trained-CHW models. When the drug seller arm (intervention) was compared to the CHW arm (control), an incremental effect of 9 per 100 appropriately treated U5 children was observed, as well as an incremental cost of US$292.78 per 100 appropriately treated children, resulting in an incremental cost-effectiveness ratio (ICER) of US$33.86 per appropriately treated U5 patient. CONCLUSION: Since both models were cost-effective compared to the do-nothing option, the iCCM trained-drug seller model could complement the iCCM trained-CHW intervention as a strategy to increase access to quality treatment.

Causes of death after biannual azithromycin treatment: A community-level randomized clinical trial.

The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children <6 months who received azithromycin merit further investigation in high-mortality settings. Trial registration: NCT02048007.

Public health-relevant consequences of the COVID-19 pandemic on malaria in sub-Saharan Africa: a scoping review.

BACKGROUND: The COVID-19 pandemic has resulted in unprecedented challenges to health systems worldwide, including the control of non-COVID-19 diseases. Malaria cases and deaths may increase due to the direct and indirect effects of the pandemic in malaria-endemic countries, particularly in sub-Saharan Africa (SSA). This scoping review aims to summarize information on public health-relevant effects of the COVID-19 pandemic on the malaria situation in SSA. METHODS: Review of publications and manuscripts on preprint servers, in peer-reviewed journals and in grey literature documents from 1 December, 2019 to 9 June, 2021. A structured search was conducted on different databases using predefined eligibility criteria for the selection of articles. RESULTS: A total of 51 papers have been included in the analysis. Modelling papers have predicted a significant increase in malaria cases and malaria deaths in SSA due to the effects of the COVID-19 pandemic. Many papers provided potential explanations for expected COVID-19 effects on the malaria burden; these ranged from relevant diagnostical and clinical aspects to reduced access to health care services, impaired availability of curative and preventive commodities and medications, and effects on malaria prevention campaigns. Compared to previous years, fewer country reports provided data on the actual number of malaria cases and deaths in 2020, with mixed results. While highly endemic countries reported evidence of decreased malaria cases in health facilities, low endemic countries reported overall higher numbers of malaria cases and deaths in 2020. CONCLUSIONS: The findings from this review provide evidence for a significant but diverse impact of the COVID-19 pandemic on malaria in SSA. There is the need to further investigate the public health consequences of the COVID-19 pandemic on the malaria burden. Protocol registered on Open Science Framework: https://doi.org/10.17605/OSF.IO/STQ9D.

Associating the scale-up of insecticide-treated nets and use with the decline in all-cause child mortality in the Democratic Republic of Congo from 2005 to 2014.

BACKGROUND: To reduce the malaria burden and improve the socioeconomic status of its citizens, the Democratic Republic of Congo scaled up key malaria control interventions, especially insecticide-treated nets (ITNs), between 2005 and 2014. Since then, the effects of these interventions on malaria mortality and morbidity have not been assessed. This study aimed to measure the impact of the National Malaria Control Programme's efforts and to inform future control strategies. METHODS: The authors used data from the Demographic and Health Surveys 2007 and 2013-2014 to assess trends in all-cause childhood mortality (ACCM) against trends in coverage of malaria interventions at national and subnational levels. The authors used the plausibility argument to assess the impact of the malaria control interventions and used Kaplan-Meier survival probability and Cox proportional hazard models to examine the effect of ITN ownership on child survival. Contextual factor trends affecting child survival were also considered. RESULTS: Countrywide, household ownership of at least one ITN increased, from 9% in 2007 to 70% in 2013-2014. All provinces experienced similar increases, with some greater than the national level. ITN use increased between 2007 and 2013-2014 among children under five (6% to 55%). Severe anaemia (haemoglobin concentration < 8 g/dl) prevalence among children aged 6-59 months significantly decreased, from 11% (95% confidence interval [CI] 9-13%) in 2007 to 6% (95% CI 5-7%) in 2013-2014. During the same period, ACCM declined, from 148 (95% CI 132-163) to 104 (95% CI 97-112) deaths per 1000 live births. The decline in ACCM was greater among children aged 6-23 months (relative reduction of 36%), compared to children aged 24-59 months (relative reduction of 12%). Cox regression indicated that household ownership of at least one ITN reduced the risk of mortality by 24% among children under five (risk ratio = 0.76, 95% CI 0.64-0.90). Contextual factor analysis revealed marginal improvements in socioeconomic indicators and other health interventions. CONCLUSIONS: Given the patterns of the coverage of malaria control interventions, patterns in ACCM by province, and marginal improvements in contextual factors, the authors conclude that the malaria control interventions have plausibly contributed to the decrease in ACCM in the Democratic Republic of Congo from 2005 to 2014.

Malaria incidence and mortality in Zimbabwe during the COVID-19 pandemic: analysis of routine surveillance data.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has posed a unique challenge to health care systems globally. To curb COVID-19 transmission, mitigation measures such as travel restrictions, border closures, curfews, lockdowns, and social distancing have been implemented. However, these measures may directly and indirectly affect the delivery and utilization of essential health services, including malaria services. The suspension of indoor residual spraying (IRS) and insecticide-treated net (ITN) distribution, shortages of malaria commodities, and reduced demand for health services have hindered the continued delivery of malaria services. The overall goal of this analysis was to describe the trends in malaria incidence and mortality in Zimbabwe prior to and during the pandemic to understand the consequences of COVID-19-related changes in the delivery and utilization of malaria services. METHODS: Monthly data on the number of malaria cases and deaths by district for the period January 2017 to June 2020 were obtained from the national health management information system (HMIS). District-level population data were obtained from the 2012 Census. Malaria incidence per 1000 population and malaria deaths per 100,000 population were calculated for 2017, 2018, 2019, and 2020 and mapped to describe the spatial and temporal variation of malaria at the district level. RESULTS: Compared to the same period in 2017, 2018 and 2019, there was an excess of over 30,000 malaria cases from January to June 2020. The number of malaria deaths recorded in January to June 2020 exceeded the annual totals for 2018 and 2019. District level maps indicated that areas outside high malaria burden provinces experienced higher than expected malaria incidence and mortality, suggesting potential outbreaks. CONCLUSIONS: The observed surge in malaria cases and deaths in January to June 2020 coincided with the onset of COVID-19 in Zimbabwe. While further research is needed to explore possible explanations for the observed trends, prioritizing the continuity of essential malaria services amid the COVID-19 pandemic remains crucial.

World Malaria Day 2021: Commemorating 15 Years of Contribution by the United States President's Malaria Initiative.

World Malaria Day 2021 coincides with the 15th anniversary of the United States President's Malaria Initiative (PMI) and follows the first anniversary of the declaration of the coronavirus disease (COVID-19) pandemic. From 2006 to the present, the PMI has led to considerable country-managed progress in malaria prevention, care, and treatment in 24 of the highest-burden countries in sub-Saharan Africa and three countries in the Southeast Asia Greater Mekong subregion. Furthermore, it has contributed to a 29% reduction in malaria cases and a 60% reduction in the death rates in sub-Saharan Africa. In this context of progress, substantial heterogeneity persists within and between countries, such that malaria control programs can seek subnational elimination in some populations but others still experience substantial malaria disease and death. During the COVID-19 pandemic, most malaria programs have shown resilience in delivering prevention campaigns, but many experienced important disruptions in their care and treatment of malaria illness. Confronting the COVID-19 pandemic and building on the progress against malaria will require fortitude, including strengthening the quality and ensuring the safety and resiliency of the existing programs, extending services to those currently not reached, and supporting the people and partners closest to those in need.