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.

IntroductionChildren 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.MethodsAn 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.ResultsReferral 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).ConclusionsThe 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 numberNCT03568344; ClinicalTrials.gov.

Background To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, higher-level facilities offering parenteral antimalarials are often difficult to access. A randomised controlled trial found pre-referral rectal artesunate (RAS) to reduce death and disability in children who delay arriving at a referral facility. This study examined the effectiveness of pre-referral RAS treatment in established community-based health care systems. Methods An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo, Nigeria and Uganda. Children < 5 years presenting to a community-based health provider with a positive malaria test and signs of severe malaria were 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. Findings 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; 865/6286 patients were sick at follow-up. In all countries, the CFR was higher after RAS-roll-out (6.7 vs. 6.6% in DRC, 16.1 vs. 4.2% in Nigeria, 0.7 vs. 0.3% in Uganda). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR = 3.31, 95% CI 1.43-7.65 and aOR = 2.42, 95% CI 1.25-4.70, respectively). In Uganda, RAS users were less likely to be dead or sick at follow-up (aOR = 0.61, 95% CI 0.46-0.80). Post-referral parenteral antimalarials were protective in all countries; however, the effect of ACT administration was inconsistent. Interpretation RAS pre-referral treatment had no beneficial effect on child survival in three highly malaria endemic settings. RAS is unlikely to reduce malaria deaths unless health system shortfalls such as referral and post-referral treatment are addressed.

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.

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. RAS allows the 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 to-date: (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 Nigeria, Uganda and the Democratic Republic of the Congo (DRC). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. In order to achieve this, a number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed to track 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 provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and cost-effectiveness of the RAS intervention.

BackgroundAppropriate clinical management of severe malaria is critical to avert morbidity and death. Recommended treatment consists of an injectable antimalarial followed by a full course of oral artemisinin-based combination therapy (ACT). Children who cannot access prompt parenteral treatment should be administered a single dose of rectal artesunate (RAS) and promptly referred to an appropriate facility for further care. This study aimed to assess compliance with the treatment recommendation in children under 5 years diagnosed with severe malaria and admitted to referral facilities in 3 high-burden sub-Saharan African countries.Methods and FindingsThis study accompanied the implementation of RAS as a pre-referral treatment in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children under 5 who were admitted at a referral health facility (RHF) with a diagnosis of severe malaria were included. Type and dosage of antimalarial treatment at RHFs was assessed for children referred from a community-based provider and those directly attending the RHF. We used multivariable regression models to assess factors associated with administration of compliant treatment.RHF data of 7,983 children was analysed for compliance with regards to antimalarials, a subsample of 3,449 children was assessed in more detail for schedule and dosage compliance and method of ACT provision. Overall, 42.0% (3,356/7,983) of admitted children were administered full treatment consisting of a parenteral antimalarial and an ACT, with large variation among study countries (2.7% in Nigeria, 44.5% in Uganda and 50.3% in DRC). Children receiving RAS from a community-based provider were more likely to be administered compliant post-referral medication at RHFs in DRC (adjusted odds ratio (aOR)=2.19, 95% CI 1.60-2.99), but less likely in Uganda (aOR = 0.43, 95% CI 0.19-0.96). Use of injectable antimalarials was very high in all three countries (99.2% (1,344/1,355) in Uganda, 98.1% (413/421) in Nigeria and 94.4% (1,580/1,673) in DRC), with most children receiving the recommended minimum of three doses (99.0% (1,331/1,344) in Uganda, 95.5% (1,509/1,580) in DRC and 92.0% (380/413) in Nigeria). Rather than being administered in the RHF, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349), while this was rarely done in DRC (0.8%, 14/1,669) where inpatient administration was more common.ConclusionsDirectly observed treatment with both a parenteral antimalarial and an ACT was rare and variable between countries, bearing a high risk for incomplete parasite clearance and disease recrudescence. Parenteral artesunate not followed up with a full course of oral ACT constitutes an artemisinin monotherapy and may favour the selection or development of resistant parasites. Stricter health worker compliance with the WHO severe malaria treatment guidelines is therefore needed to effectively manage this disease and further reduce child mortality.

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).

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.