Key Contributions by the Swiss Tropical and Public Health Institute Towards New and Better Drugs for Tropical Diseases.

Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine, coupled with deeply rooted partnerships with institutions in low- and middle-income countries (LMICs), the Swiss Tropical and Public Health Institute (Swiss TPH) has been a key contributor in many drug research and development consortia involving academia, pharma and product development partnerships. Our know-how of the maintenance of parasites and their life-cycles in the laboratory, plus our strong ties to research centres and disease control programme managers in LMICs with access to field sites and laboratories, have enabled systems for drug efficacy testing in vitro and in vivo, clinical research, and modelling to support the experimental approaches. Thus, Swiss TPH has made fundamental contributions towards the development of new drugs - and the better use of old drugs - for neglected tropical diseases and infectious diseases of poverty, such as Buruli ulcer, Chagas disease, food-borne trematodiasis (e.g. clonorchiasis, fascioliasis and opisthorchiasis), human African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, soil-transmitted helminthiasis and tuberculosis. In this article, we show case the success stories of molecules to which Swiss TPH has made a substantial contribution regarding their use as anti-infective compounds with the ultimate aim to improve people's health and well-being.

Assessing caregivers' perceptions of treatment-seeking for suspected severe malaria in the Democratic Republic of the Congo.

BACKGROUND: Malaria remains a major public health issue in the Democratic Republic of the Congo (DRC), accounting for 44% deaths among outpatient visits in children < 5 years of age, and 22% of facility deaths. Understanding determinants of caregivers' treatment-seeking patterns and decision-making is crucial in reducing the malaria burden. METHODS: In the frame of the Community Access to Rectal Artesunate for Malaria (CARAMAL) project, cross-sectional household surveys that randomly sampled villages and households were carried-out in three rural DRC health zones prior to the rollout of pre-referral Rectal Artesunate (RAS) and then 9 and 19 months after RAS rollout (post-RAS). Data were captured electronically through face-to-face interviews with the main caregivers of children < 5 years. Capillary blood samples of the children were tested for malaria and anaemia. The main study outcome was whether caregiver "sought treatment outside home" when the child had fever. Multilevel mixed effects logistic regression models using village as random effect and health zone as a fixed effect was performed to assess treatment-seeking predictors. RESULTS: 2439 household interviews were completed (pre-RAS 888 and post-RAS 1551), including 316 and 653 treatment-seeking interviews. Overall, 3499 children < 5 years were tested for malaria and anaemia (pre-RAS 1,315 and post-RAS 2184). Caregiver's recognition of severe malaria signs was poor, while knowledge of symptoms of uncomplicated malaria seemed high. Despite this, danger signs significantly increased the odds of seeking treatment (aOR = 2.12, 95%CI 1.03-4.38), the same was found for the "least poor" quintile (aOR = 3.01, 95%CI 1.03-8.82), as well as residents of Kingandu (aOR = 2.78, 95%CI 1.01-7.65). "Doing something at home" against fever negatively affected treatment-seeking in both study phases. RAS acceptance was high, at almost 100%. Malaria prevalence was higher post-RAS (45.2%) compared to pre-RAS (34.4%), p = 0.003, but anaemia, although high (≥ 75%), was similar in both study phases (p = 0.92). CONCLUSION: In remote communities with high malaria prevalence in the DRC, malaria remains a major problem. Improving the recognition of danger signs of severe disease and introducing pre-referral RAS may improve treatment-seeking and contribute to reducing malaria-related mortality among children-if quality of care can be guaranteed.

Starting at the community: Treatment-seeking pathways of children with suspected severe malaria in Uganda.

Community health workers (CHW) usually refer children with suspected severe malaria to the nearest public health facility or a designated public referral health facility (RHF). Caregivers do not always follow this recommendation. This study aimed at identifying post-referral treatment-seeking pathways that lead to appropriate antimalarial treatment for children less than five years with suspected severe malaria. An observational study in Uganda enrolled children below five years presenting to CHWs with signs of severe malaria. Children were followed up 28 days after enrolment to assess their condition and treatment-seeking history, including referral advice and provision of antimalarial treatment from visited providers. Of 2211 children included in the analysis, 96% visited a second provider after attending a CHW. The majority of CHWs recommended caregivers to take their child to a designated RHF (65%); however, only 59% followed this recommendation. Many children were brought to a private clinic (33%), even though CHWs rarely recommended this type of provider (3%). Children who were brought to a private clinic were more likely to receive an injection than children brought to a RHF (78% vs 51%, p<0.001) and more likely to receive the second or third-line injectable antimalarial (artemether: 22% vs. 2%, p<0.001, quinine: 12% vs. 3%, p<0.001). Children who only went to non-RHF providers were less likely to receive an artemisinin-based combination therapy (ACT) than children who attended a RHF (odds ratio [OR] = 0.64, 95% CI 0.51-0.79, p<0.001). Children who did not go to any provider after seeing a CHW were the least likely to receive an ACT (OR = 0.21, 95% CI 0.14-0.34, p<0.001). Health policies should recognise local treatment-seeking practices and ensure adequate quality of care at the various public and private sector providers where caregivers of children with suspected severe malaria actually seek care.

Spatio-temporal modelling of routine health facility data for malaria risk micro-stratification in mainland Tanzania.

As malaria transmission declines, the need to monitor the heterogeneity of malaria risk at finer scales becomes critical to guide community-based targeted interventions. Although routine health facility (HF) data can provide epidemiological evidence at high spatial and temporal resolution, its incomplete nature of information can result in lower administrative units without empirical data. To overcome geographic sparsity of data and its representativeness, geo-spatial models can leverage routine information to predict risk in un-represented areas as well as estimate uncertainty of predictions. Here, a Bayesian spatio-temporal model was applied on malaria test positivity rate (TPR) data for the period 2017-2019 to predict risks at the ward level, the lowest decision-making unit in mainland Tanzania. To quantify the associated uncertainty, the probability of malaria TPR exceeding programmatic threshold was estimated. Results showed a marked spatial heterogeneity in malaria TPR across wards. 17.7 million people resided in areas where malaria TPR was high (≥ 30; 90% certainty) in the North-West and South-East parts of Tanzania. Approximately 11.7 million people lived in areas where malaria TPR was very low (< 5%; 90% certainty). HF data can be used to identify different epidemiological strata and guide malaria interventions at micro-planning units in Tanzania. These data, however, are imperfect in many settings in Africa and often require application of geo-spatial modelling techniques for estimation.

Correction: Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study.

[This corrects the article DOI: 10.1371/journal.pmed.1004189.].

Pre-referral rectal artesunate is no "magic bullet" in weak health systems.

Severe malaria is a potentially fatal condition that requires urgent treatment. In a clinical trial, a sub-group of children treated with rectal artesunate (RAS) before being referred to a health facility had an increased chance of survival. We recently published in BMC Medicine results of the CARAMAL Project that did not find the same protective effect of pre-referral RAS implemented at scale under real-world conditions in three African countries. Instead, CARAMAL identified serious health system shortfalls that impacted the entire continuum of care, constraining the effectiveness of RAS. Correspondence to the article criticized the observational study design and the alleged interpretation and consequences of our findings.Here, we clarify that we do not dispute the life-saving potential of RAS, and discuss the methodological criticism. We acknowledge the potential for confounding in observational studies. Nevertheless, the totality of CARAMAL evidence is in full support of our conclusion that the conditions under which RAS can be beneficial were not met in our settings, as children often failed to complete referral and post-referral treatment was inadequate.The criticism did not appear to acknowledge the realities of highly malarious settings documented in detail in the CARAMAL project. Suggesting that trial-demonstrated efficacy is sufficient to warrant large-scale deployment of pre-referral RAS ignores the paramount importance of functioning health systems for its delivery, for completing post-referral treatment, and for achieving complete cure. Presenting RAS as a "magic bullet" distracts from the most urgent priority: fixing health systems so they can provide a functioning continuum of care and save the lives of sick children.The data underlying our publication is freely accessible on Zenodo.

Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study.

BACKGROUND: For a full treatment course of severe malaria, community-administered pre-referral rectal artesunate (RAS) should be completed by post-referral treatment consisting of an injectable antimalarial and oral artemisinin-based combination therapy (ACT). This study aimed to assess compliance with this treatment recommendation in children under 5 years. METHODS AND FINDINGS: This observational study accompanied the implementation of RAS in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Antimalarial treatment was assessed during admission in included referral health facilities (RHFs) in children under 5 with a diagnosis of severe malaria. Children were either referred from a community-based provider or directly attending the RHF. RHF data of 7,983 children was analysed for appropriateness of antimalarials; a subsample of 3,449 children was assessed additionally for dosage and method of ACT provision (treatment compliance). A parenteral antimalarial and an ACT were administered to 2.7% (28/1,051) of admitted children in Nigeria, 44.5% (1,211/2,724) in Uganda, and 50.3% (2,117/4,208) in DRC. Children receiving RAS from a community-based provider were more likely to be administered post-referral medication according to the guidelines in DRC (adjusted odds ratio (aOR) = 2.13, 95% CI 1.55 to 2.92, P < 0.001), but less likely in Uganda (aOR = 0.37, 95% CI 0.14 to 0.96, P = 0.04) adjusting for patient, provider, caregiver, and other contextual factors. While in DRC, inpatient ACT administration was common, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349). Study limitations include the unfeasibility to independently confirm the diagnosis of severe malaria due to the observational nature of the study. CONCLUSIONS: Directly observed treatment was often incomplete, bearing a high risk for partial parasite clearance and disease recrudescence. Parenteral artesunate not followed up with oral ACT constitutes an artemisinin monotherapy and may favour the selection of resistant parasites. In connection with the finding that pre-referral RAS had no beneficial effect on child survival in the 3 study countries, concerns about an effective continuum of care for children with severe malaria seem justified. Stricter compliance with the WHO severe malaria treatment guidelines is critical to effectively manage this disease and further reduce child mortality. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03568344).

Pre-referral rectal artesunate: no cure for unhealthy systems.

Pre-referral rectal artesunate suppositories can save the lives of children with severe malaria if patients receive adequate post-referral care. A multi-country randomised controlled trial reporting on the efficacy of rectal artesunate informed the current WHO guidelines. In October, 2022, we reported on the findings of the Community Access to Rectal Artesunate for Malaria (CARAMAL) project, a carefully monitored roll-out of quality-assured rectal artesunate into established community-based health-care systems in DR Congo, Nigeria, and Uganda. The aim of the project was to understand the challenges involved in the successful real-world implementation of pre-referral rectal artesunate and to inform subsequent scale-up in endemic countries. In our study, we found that children treated with pre-referral rectal artesunate in routine clinical practice did not have an increased chance of survival, most likely explained by shortfalls along the continuum of care. A substantial proportion of the more than 6200 severely ill children that were followed up 28 days after treatment initiation did not receive comprehensive severe malaria care, either due to an incomplete referral to a secondary facility, or due to incomplete post-referral treatment. The observational study design allowed for a realistic assessment of the obstacles involved in implementing pre-referral rectal artesunate in settings where malaria mortality remains high. Without improving the entire continuum of care, children will continue to die from severe malaria and promising interventions will fail to meet their full potential.

Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraints.

BACKGROUND: Rectal artesunate, an efficacious pre-referral treatment for severe malaria in children, was deployed at scale in Uganda, Nigeria, and DR Congo. In addition to distributing rectal artesunate, implementation required additional investments in crucial but neglected components in the care for severe malaria. We examined the real-world costs and constraints to rectal artesunate implementation. METHODS: We collected primary data on baseline health system constraints and subsequent rectal artesunate implementation expenditures. We calculated the equivalent annual cost of rectal artesunate implementation per child younger than 5 years at risk of severe malaria, from a health system perspective, separating neglected routine health system components from incremental costs of rectal artesunate introduction. FINDINGS: The largest baseline constraints were irregular health worker supervisions, inadequate referral facility worker training, and inadequate malaria commodity supplies. Health worker training and behaviour change campaigns were the largest startup costs, while supervision and supply chain management accounted for most annual routine costs. The equivalent annual costs of preparing the health system for managing severe malaria with rectal artesunate were US$2·63, $2·20, and $4·19 per child at risk and $322, $219, and $464 per child treated in Uganda, Nigeria, and DR Congo, respectively. Strengthening the neglected, routine health system components accounted for the majority of these costs at 71·5%, 65·4%, and 76·4% of per-child costs, respectively. Incremental rectal artesunate costs accounted for the minority remainder. INTERPRETATION: Although rectal artesunate has been touted as a cost-effective pre-referral treatment for severe malaria in children, its real-world potential is limited by weak and under-financed health system components. Scaling up rectal artesunate or other interventions relying on community health-care providers only makes sense alongside additional, essential health system investments sustained over the long term. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

The use of routine health facility data for micro-stratification of malaria risk in mainland Tanzania.

BACKGROUND: Current efforts to estimate the spatially diverse malaria burden in malaria-endemic countries largely involve the use of epidemiological modelling methods for describing temporal and spatial heterogeneity using sparse interpolated prevalence data from periodic cross-sectional surveys. However, more malaria-endemic countries are beginning to consider local routine data for this purpose. Nevertheless, routine information from health facilities (HFs) remains widely under-utilized despite improved data quality, including increased access to diagnostic testing and the adoption of the electronic District Health Information System (DHIS2). This paper describes the process undertaken in mainland Tanzania using routine data to develop a high-resolution, micro-stratification risk map to guide future malaria control efforts. METHODS: Combinations of various routine malariometric indicators collected from 7098 HFs were assembled across 3065 wards of mainland Tanzania for the period 2017-2019. The reported council-level prevalence classification in school children aged 5-16 years (PfPR5-16) was used as a benchmark to define four malaria risk groups. These groups were subsequently used to derive cut-offs for the routine indicators by minimizing misclassifications and maximizing overall agreement. The derived-cutoffs were converted into numbered scores and summed across the three indicators to allocate wards into their overall risk stratum. RESULTS: Of 3065 wards, 353 were assigned to the very low strata (10.5% of the total ward population), 717 to the low strata (28.6% of the population), 525 to the moderate strata (16.2% of the population), and 1470 to the high strata (39.8% of the population). The resulting micro-stratification revealed malaria risk heterogeneity within 80 councils and identified wards that would benefit from community-level focal interventions, such as community-case management, indoor residual spraying and larviciding. CONCLUSION: The micro-stratification approach employed is simple and pragmatic, with potential to be easily adopted by the malaria programme in Tanzania. It makes use of available routine data that are rich in spatial resolution and that can be readily accessed allowing for a stratification of malaria risk below the council level. Such a framework is optimal for supporting evidence-based, decentralized malaria control planning, thereby improving the effectiveness and allocation efficiency of malaria control interventions.

Acceptability of pre-referral rectal artesunate for severe malaria in children under 5 years by health workers and caregivers in the Democratic Republic of the Congo, Nigeria and Uganda.

BACKGROUND: For children below 6 years with suspected severe malaria attending a health care provider unable to provide parenteral malaria treatment, pre-referral rectal artesunate (RAS) is recommended by the World Health Organization to prevent death and disability. A number of African countries are in the process of rolling out quality-assured RAS for pre-referral treatment of severe malaria at community-level. The success of RAS depends, among other factors, on the acceptability of RAS in the communities where it is being rolled-out. Yet to date, there is limited literature on RAS acceptability. This study aimed to determine the acceptability of RAS by health care providers and child caregivers in communities where quality assured RAS was rolled out. This study was nested within the comprehensive multi-country observational research project Community Access to Rectal Artesunate for Malaria (CARAMAL), implemented in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Data from three different sources were analysed to understand RAS acceptability: interviews with health workers during three health care provider surveys (N = 341 community health workers and 467 primary health facility workers), with caregivers of children < 5 years of age during three household surveys (N = 9332 caregivers), and with caregivers of children < 5 years of age who were treated with RAS and enrolled in the CARAMAL Patient Surveillance System (N = 3645 caregivers). RESULTS: RAS acceptability was high among all interviewed stakeholders in the three countries. After the roll-out of RAS, 97-100% heath care providers in DRC, 98-100% in Nigeria and 93-100% in Uganda considered RAS as very good or good. Majority of caregivers whose children had received RAS for pre-referral management of severe malaria indicated that they would want to get the medication again, if their child had the same illness (99.8% of caregivers in DRC, 100% in Nigeria and 99.9% in Uganda). In three household surveys, 67-80% of caregivers whose children had not previously received RAS considered the medication as useful. CONCLUSION: RAS was well accepted by health workers and child caregivers in DRC, Nigeria and Uganda. Acceptability is unlikely to be an obstacle to the large-scale roll-out of RAS in the studied settings.

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study.

BACKGROUND: To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, accessing facilities offering parenteral antimalarials may be difficult. A randomised controlled trial found pre-referral treatment with rectal artesunate (RAS) to reduce deaths and disability in children who arrived at a referral facility with delay. This study examined the effectiveness of pre-referral RAS treatment implemented through routine procedures of established community-based health care systems. METHODS: An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children <5 years of age presenting to a community-based health provider with a positive malaria test and signs of severe malaria were enrolled and followed up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment. RESULTS: Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 13.8% (865/6286) of patients were sick on day 28. The CFR was higher after RAS roll-out in Nigeria (16.1 vs. 4.2%) and stable in DRC (6.7 vs. 6.6%) and Uganda (0.7 vs. 0.3%). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR=3.06, 95% CI 1.35-6.92 and aOR=2.16, 95% CI 1.11-4.21, respectively). Only in Uganda, RAS users were less likely to be dead or sick at follow-up (aOR=0.60, 95% CI 0.45-0.79). Post-referral parenteral antimalarials plus oral artemisinin-based combination therapy (ACT), a proxy for appropriate post-referral treatment, was protective. However, in referral health facilities, ACT was not consistently administered after parenteral treatment (DRC 68.4%, Nigeria 0%, Uganda 70.9%). CONCLUSIONS: Implemented at scale to the recommended target group, pre-referral RAS had no beneficial effect on child survival in three highly malaria-endemic settings. RAS is unlikely to reduce malaria deaths unless health system issues such as referral and quality of care at all levels are addressed. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov : NCT03568344.

Key factors predicting suspected severe malaria case management and health outcomes: an operational study in the Democratic Republic of the Congo.

BACKGROUND: Evidence suggests that pre-referral Rectal Artesunate (RAS) can be a life-saving intervention for severe malaria in remote settings in Africa. Recognition of danger signs indicative of severe malaria is critical for prompt and appropriate case management. METHODS: This was an observational study conducted in three Health Zones of the Democratic Republic of the Congo to determine the distribution of dangers signs for severe malaria and assess their impact on RAS use, referral completion, injectable treatment and ACT provision, and health outcomes including death. An individual-level analysis was carried out, using multilevel-mixed effects logistic regression models. Severely ill febrile children < 5 years seeking care from community-based healthcare providers were recruited into a patient surveillance system based on the presence of key danger signs. Clinical and case management data were collected comprehensively over a 28 days period. Treatment seeking was elicited and health outcomes assessed during 28 days home visits. RESULTS: Overall, 66.4% of patients had iCCM general danger signs. Age of 2-5 years and iCCM general danger signs predicted RAS use (aOR = 2.77, 95% CI 2.04-3.77). RAS administration positively affected referral completion (aOR = 0.63, 95% CI 0.44-0.92). After RAS rollout, 161 children died (case fatality ratio: 7.1%, 95% CI 6.1-8.2). RAS improved the health status of the children on Day 28 (aOR = 0.64, 95% CI 0.45-0.92) and there was a non-significant trend that mortality was higher in children not receiving RAS (aOR = 1.50, 95% CI 0.86-2.60). Full severe malaria treatment at the RHF including injectable anti-malarial and a course of ACT was highly protective against death (aOR = 0.26, 95% CI 0.09-0.79). CONCLUSIONS: The main findings point towards the fact that danger signs are reasonably well recognized by health provider at the primary care level, and that RAS could influence positively health outcomes of such severe disease episodes and death. Its effectiveness is hampered by the insufficient quality of care at RHF, especially the provision of a full course of ACT following parenteral treatment. These are simple but important findings that requires urgent action by the health system planners and implementers.

Care Seeking and Treatment of Febrile Children with and without Danger Signs of Severe Disease in Northern Uganda: Results from Three Household Surveys (2018-2020).

Identification, stabilization, and prompt referral of children with signs of severe febrile disease (danger signs) in rural communities are crucial for preventing complications and death from severe malaria, pneumonia, and diarrhea. We set out to determine the treatment-seeking practices and treatment patterns for children < 5 years of age with an acute febrile illness, with or without danger signs of severe disease, in a highly malaria-endemic area of northern Uganda. Three household surveys were conducted from November through December each year in 2018, 2019, and 2020. Overall, 30% of the children in the study were reported to have had a WHO-classified danger sign including convulsions, unconsciousness/unusually sleepy, inability to feed or drink, and vomiting everything. Only half of the children in this study sought care from a health provider. However, significantly more children with danger signs of severe disease sought and received treatment and diagnostics from a health provider, compared with those without danger signs (adjusted odds ratio: 1.6, 95% confidence interval: 1.2-2.0; P < 0.01). In the total population studied, care seeking in the public sector was 26% and similar to care seeking in the private sector (24%). Community health workers were used as the first source of care by 12% of the children. Approximately 38% of the children who were reported to have danger signs of severe disease requiring prompt referral and treatment did not seek care from a health provider. Understanding and addressing barriers to accessing healthcare could contribute to better treatment seeking practices.

A malaria-free China: global importance and key experience.

Malaria has a worldwide distribution and is the world's deadliest mosquito-borne disease. The goal of malaria elimination is also reflected in the United Nations Sustainable Development Goals and the Global Technical Strategy for Malaria 2016-2030 issued by the World Health Organization (WHO). China succeeded in its malaria elimination programme after being certified as malaria-free by the WHO on 30 June 2021. Therefore, we document some of the key lessons learnt in the course of the malaria elimination effort in China in this special volume, showing how different strategies made elimination feasible in different subregions of China with different epidemiological and socioeconomic characteristics, in order to present strong signals to other malaria-endemic countries that malaria elimination is feasible within one generation.

Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda.

INTRODUCTION: Children who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited. METHODS: An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways. RESULTS: Referral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79). CONCLUSIONS: The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral. TRIAL REGISTRSTION NUMBER: NCT03568344; ClinicalTrials.gov.

Sub-national tailoring of malaria interventions in Mainland Tanzania: simulation of the impact of strata-specific intervention combinations using modelling.

BACKGROUND: To accelerate progress against malaria in high burden countries, a strategic reorientation of resources at the sub-national level is needed. This paper describes how mathematical modelling was used in mainland Tanzania to support the strategic revision that followed the mid-term review of the 2015-2020 national malaria strategic plan (NMSP) and the epidemiological risk stratification at the council level in 2018. METHODS: Intervention mixes, selected by the National Malaria Control Programme, were simulated for each malaria risk strata per council. Intervention mixes included combinations of insecticide-treated bed nets (ITN), indoor residual spraying, larval source management, and intermittent preventive therapies for school children (IPTsc). Effective case management was either based on estimates from the malaria indicator survey in 2016 or set to a hypothetical target of 85%. A previously calibrated mathematical model in OpenMalaria was used to compare intervention impact predictions for prevalence and incidence between 2016 and 2020, or 2022. RESULTS: For each malaria risk stratum four to ten intervention mixes were explored. In the low-risk and urban strata, the scenario without a ITN mass campaign in 2019, predicted high increase in prevalence by 2020 and 2022, while in the very-low strata the target prevalence of less than 1% was maintained at low pre-intervention transmission intensity and high case management. In the moderate and high strata, IPTsc in addition to existing vector control was predicted to reduce the incidence by an additional 15% and prevalence by 22%. In the high-risk strata, all interventions together reached a maximum reduction of 76%, with around 70% of that reduction attributable to high case management and ITNs. Overall, the simulated revised NMSP was predicted to achieve a slightly lower prevalence in 2020 compared to the 2015-2020 NMSP (5.3% vs 6.3%). CONCLUSION: Modelling supported the choice of intervention per malaria risk strata by providing impact comparisons of various alternative intervention mixes to address specific questions relevant to the country. The use of a council-calibrated model, that reproduces local malaria trends, represents a useful tool for compiling available evidence into a single analytical platform, that complement other evidence, to aid national programmes with decision-making processes.

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.).

Feasibility, acceptability, and effectiveness of non-pharmaceutical interventions against infectious diseases among crisis-affected populations: a scoping review.

BACKGROUND: Non-pharmaceutical interventions (NPIs) are a crucial suite of measures to prevent and control infectious disease outbreaks. Despite being particularly important for crisis-affected populations and those living in informal settlements, who typically reside in overcrowded and resource limited settings with inadequate access to healthcare, guidance on NPI implementation rarely takes the specific needs of such populations into account. We therefore conducted a systematic scoping review of the published evidence to describe the landscape of research and identify evidence gaps concerning the acceptability, feasibility, and effectiveness of NPIs among crisis-affected populations and informal settlements. METHODS: We systematically reviewed peer-reviewed articles published between 1970 and 2020 to collate available evidence on the feasibility, acceptability, and effectiveness of NPIs in crisis-affected populations and informal settlements. We performed quality assessments of each study using a standardised questionnaire. We analysed the data to produce descriptive summaries according to a number of categories: date of publication; geographical region of intervention; typology of crisis, shelter, modes of transmission, NPI, research design; study design; and study quality. RESULTS: Our review included 158 studies published in 85 peer-reviewed articles. Most research used low quality study designs. The acceptability, feasibility, and effectiveness of NPIs was highly context dependent. In general, simple and cost-effective interventions such as community-level environmental cleaning and provision of water, sanitation and hygiene services, and distribution of items for personal protection such as insecticide-treated nets, were both highly feasible and acceptable. Logistical, financial, and human resource constraints affected both the implementation and sustainability of measures. Community engagement emerged as a strong factor contributing to the effectiveness of NPIs. Conversely, measures that involve potential restriction on personal liberty such as case isolation and patient care and burial restrictions were found to be less acceptable, despite apparent effectiveness. CONCLUSIONS: Overall, the evidence base was variable, with substantial knowledge gaps which varied between settings and pathogens. Based on the current landscape, robust evidence-based guidance is not possible, and a research agenda is urgently required that focusses on these specific vulnerable populations. Although implementation of NPIs presents unique practical challenges in these settings, it is critical that such an agenda is put in place, and that the lessons learned from historical and present experiences are documented to build a firm evidence base.

Community access to rectal artesunate for malaria (CARAMAL): A large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda.

The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s, allowing for rapid initiation of life-saving antimalarial treatment before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact. From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda (registered on ClinicalTrials.gov as NCT03568344). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. A number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed tracking of cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS. Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript does not intend to present key study results, but provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and costing of the RAS intervention.