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Abstract 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

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. [ABSTRACT FROM AUTHOR]

Abstract Background Rectal artesunate (RAS) is a World Health Organization (WHO) recommended intervention that can save lives of children 6 years and younger suffering from severe malaria and living in remote areas. Access to RAS and a referral system that ensures continuity of care remains a challenge in low resource countries, raising concerns around the value of this intervention. The objective of this study was to inform RAS programming, using practical tools to enhance severe malaria continuum of care when encountered at community level. Methods A single country two-arm-controlled study was conducted in Malawi, where pre-referral interventions are provided by community health workers (CHWs). The study populations consisted of 9 and 14 village health clinics (VHCs) respectively, including all households with children 5 years and younger. CHWs in the intervention arm were trained using a field-tested toolkit and the community had access to information, education, and communication (IEC) mounted throughout the zone. The community in the control arm had access to routine care only. Both study arms were provided with a dedicated referral booklet for danger signs, as a standard of care. Results The study identified five continuum of care criteria (5 CoC Framework) to reinforce RAS programming: (1) care transitions emerged as to be dependent on a strong cue to action and proximity to an operational VHC with a resident CHWs; (2) consistency of supplies assured the population of the VHC’s functionality for severe danger signs management; (3) comprehensiveness care ensured correct assessment and dosing; (4) connectivity of care between all tiers using the referral slip was feasible and perceived positively by caregivers and CHWs and (5) communication between providers from different points of care. Compliance was high throughout but optimized when administered by a sensitized CHW. Over 93% experienced a rapid improvement in the status of their child post RAS. Conclusion RAS cannot operate within a vacuum. The impact of this lifesaving intervention can be easily lost, unless administered as part of a system-based approach. Taken together, the 5CC Framework, identified in this study, provides a structure for future RAS practice guidelines. Trial registration number and date of registration PACTR201906720882512- June 20, 2019.

Abstract CARAMAL was a large observational study which recorded mortality in children with suspected severe malaria before and after the roll-out of rectal artesunate in Nigeria, Uganda and the Democratic Republic of the Congo. The results of CARAMAL have had a huge impact on public health policy leading to a World Health Organization moratorium on the roll-out of rectal artesunate. The conclusion reported in the abstract uses strong causal language, stating that “pre-referral RAS [rectal artesunate suppositories] had no beneficial effect on child survival”. We argue that this causal interpretation of the study results is not justified. Data from the CARAMAL study inform chiefly on the strengths and weaknesses of referral systems in these three countries and do not inform reliably as to the beneficial effect of providing access to a known life-saving treatment.

Abstract 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.

Abstract 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

Abstract 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

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. [ABSTRACT FROM AUTHOR]

CARAMAL was a large observational study which recorded mortality in children with suspected severe malaria before and after the roll-out of rectal artesunate in Nigeria, Uganda and the Democratic Republic of the Congo. The results of CARAMAL have had a huge impact on public health policy leading to a World Health Organization moratorium on the roll-out of rectal artesunate. The conclusion reported in the abstract uses strong causal language, stating that "pre-referral RAS [rectal artesunate suppositories] had no beneficial effect on child survival". We argue that this causal interpretation of the study results is not justified. Data from the CARAMAL study inform chiefly on the strengths and weaknesses of referral systems in these three countries and do not inform reliably as to the beneficial effect of providing access to a known life-saving treatment. [ABSTRACT FROM AUTHOR]

Background: Rectal artesunate (RAS) is a World Health Organization (WHO) recommended intervention that can save lives of children 6 years and younger suffering from severe malaria and living in remote areas. Access to RAS and a referral system that ensures continuity of care remains a challenge in low resource countries, raising concerns around the value of this intervention. The objective of this study was to inform RAS programming, using practical tools to enhance severe malaria continuum of care when encountered at community level. Methods: A single country two-arm-controlled study was conducted in Malawi, where pre-referral interventions are provided by community health workers (CHWs). The study populations consisted of 9 and 14 village health clinics (VHCs) respectively, including all households with children 5 years and younger. CHWs in the intervention arm were trained using a field-tested toolkit and the community had access to information, education, and communication (IEC) mounted throughout the zone. The community in the control arm had access to routine care only. Both study arms were provided with a dedicated referral booklet for danger signs, as a standard of care. Results: The study identified five continuum of care criteria (5 CoC Framework) to reinforce RAS programming: (1) care transitions emerged as to be dependent on a strong cue to action and proximity to an operational VHC with a resident CHWs; (2) consistency of supplies assured the population of the VHC's functionality for severe danger signs management; (3) comprehensiveness care ensured correct assessment and dosing; (4) connectivity of care between all tiers using the referral slip was feasible and perceived positively by caregivers and CHWs and (5) communication between providers from different points of care. Compliance was high throughout but optimized when administered by a sensitized CHW. Over 93% experienced a rapid improvement in the status of their child post RAS. Conclusion: RAS cannot operate within a vacuum. The impact of this lifesaving intervention can be easily lost, unless administered as part of a system-based approach. Taken together, the 5CC Framework, identified in this study, provides a structure for future RAS practice guidelines. Trial registration number and date of registration PACTR201906720882512- June 20, 2019. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background The Democratic Republic of the Congo adopted the strategy of using, at the community level, a dose of rectal artesunate as a pre-referral treatment for severe malaria amongst children under 5 years who could not quickly reach a health care facility and take oral medication. However, the adherence to referral advice after the integration of this strategy and the acceptability of the strategy were unknown. Methods To assess adherence by the mothers/caretakers of children under 5 years to referral advice provided by the community health workers after pre-referral treatment of severe malaria with rectal artesunate, the authors conducted a noninferiority community trial with a pre- and post-intervention design in 63 (pre-intervention) and 51 (post-intervention) community care sites in 4 provinces (Kasaï-Oriental, Kasaï-Central, Lomami, Lualaba) from August 2014 through June 2016. The pre- and post-intervention surveys targets 387 mothers of children under 5 years and 63 community health workers and 346 mothers and 41 community health workers, respectively. A 15% margin was considered for noninferiority analyses due to the expected decrease in adherence to referral advice after the introduction of the new intervention. Results The mothers acknowledged that the rectal route was often used (60.7%), and medicines given rectally were considered more effective (63.6%) and easy to administer (69.7%). The acceptability of pre-referral rectal artesunate was relatively high: 79.4% (95% CI 75.4–83.3) among mothers, 90.3% (95% CI 82.3–96.8) among community health workers, and 97.8% (95% CI 93.3–100) among nurses. Adherence to referral advice at post-intervention [84.3% (95% CI 80.6–88.1)] was non-inferior to pre-intervention adherence [94.1% (95% CI 91.7–96.4)]. Conclusions The integration of pre-referral rectal artesunate for severe malaria into the community care site in the DR Congo is feasible and acceptable. It positively affected adherence to referral advice. However, more health education is needed for parents of children under 5 years and community health workers.

Artemisinin-based combination therapies (ACTs) were introduced as the standard of care for uncomplicated malaria in Africa almost two decades ago. Recent studies in East Africa have reported a gradual increase in kelch13 ( k13 ) mutant parasites associated with reduced artesunate efficacy. As part of the Community Access to Rectal Artesunate for Malaria project, we collected blood samples from 697 children with signs of severe malaria in northern Uganda between 2018 and 2020, before and after the introduction of rectal artesunate (RAS) in 2019. K13 polymorphisms were assessed, and parasite editing and phenotyping were performed to assess the impact of mutations on parasite resistance. Whole-genome sequencing was performed, and haplotype networks were constructed to determine the geographic origin of k13 mutations. Of the 697 children, 540 were positive for Plasmodium falciparum malaria by PCR and were treated with either RAS or injectable artesunate monotherapy followed in most cases by ACT. The most common k13 mutation was C469Y (6.7%), which was detected more frequently in samples collected after RAS introduction. Genome editing confirmed reduced in vitro susceptibility to artemisinin in C469Y-harboring parasites compared to wild-type controls ( P < 0.001). The haplotypic network showed that flanking regions of the C469Y mutation shared the same African genetic background, suggesting a single and indigenous origin of the mutation. Our data provide evidence of selection for the artemisinin-resistant C469Y mutation. The realistic threat of multiresistant parasites emerging in Africa should encourage careful monitoring of the efficacy of artemisinin derivatives and strict adherence to ACT treatment regimens., Competing Interests: The authors declare no conflict of interest.

Abstract Background Community health workers (CHWs) were trained to identify children with malaria who could not take oral medication, treat them with rectal artesunate (RA) and refer them to the closest healthcare facility to complete management. However, many children with such symptoms did not seek CHWs’ care. The hypothesis was that the cost of referral to a health facility was a deterrent. The goal of this study was to compare the out-of-pocket costs and time to seek treatment for children who sought CHW care (and received RA) versus those who did not. Methods Children with symptoms of severe malaria receiving RA at CHWs and children with comparable disease symptoms who did not go to a CHW were identified and their parents were interviewed. Household out-of-pocket costs per illness episode and speed of treatment were evaluated and compared between RA-treated children vs. non-RA treated children and by central nervous symptoms (CNS: repeated convulsions, altered consciousness or coma). Results Among children with CNS symptoms, costs of RA-treated children were similar to those of non-RA treated children ($5.83 vs. $4.65; p = 0.52), despite higher transport costs ($2.74 vs. $0.91; p

Abstract Background Successful pre-referral treatment with rectal artesunate (RA) for suspected severe malaria requires operational linkages between community health workers (CHWs) and referral facilities, acceptance of pre-referral treatment and adherence to referral practices by CHWs and caregivers. This qualitative study investigated how community understanding of the concept of ‘pre-referral treatment’ is used in referral related decision-making following provision of RA in Uganda. Methods Narrative interviews were conducted with 30 caregivers of children under five who received RA within the previous three months and the 30 associated CHWs who provided the treatment. Nineteen focus group discussions incorporating vignettes from the interviews were held with further caregivers, and 12 with CHWs and women representatives. Twenty traditional healers were targeted for semi-structured interview. Thematic analysis followed a ‘meaning-based’ approach. Results CHWs were aware of essential information to be given to caregivers on prescribing RA as indicated by the job aid, specifically urgency for referral, yet there was insufficient emphasis on RA not being a full treatment for severe malaria. Information shared by the CHW appeared to be influenced by the perceived urgency with which the CHW needed to act and the time of day or night the child was seen. Seven of the 32 caregivers did not complete referral post RA administration. Caregivers seemed more likely to adhere to referral advice if they perceived their child’s condition to be severe. Previous caregiver experience and CHW comparisons with Artemisinin-based Combination Therapy (ACT) as a treatment for uncomplicated malaria appeared to raise misperceptions that RA is a complete treatment for severe malaria, thus reducing likelihood to complete referral. CHW implication, or caregiver interpretation, of the need to monitor the child, and some prescription of ACT post RA administration, also confused the need for referral. Both CHWs and caregivers requested further information about the role of RA. Conclusions CHW advice should emphasise RA as providing temporary relief prior to facility-based treatment, the importance of referral whether or not a change is seen in the child’s condition, and the dangers of not completing referral. Social behaviour change communication, training and support supervision activities could help promote these messages.

Background: The Democratic Republic of the Congo adopted the strategy of using, at the community level, a dose of rectal artesunate as a pre-referral treatment for severe malaria amongst children under 5 years who could not quickly reach a health care facility and take oral medication. However, the adherence to referral advice after the integration of this strategy and the acceptability of the strategy were unknown. Methods: To assess adherence by the mothers/caretakers of children under 5 years to referral advice provided by the community health workers after pre-referral treatment of severe malaria with rectal artesunate, the authors conducted a noninferiority community trial with a pre- and post-intervention design in 63 (pre-intervention) and 51 (post-intervention) community care sites in 4 provinces (Kasaï-Oriental, Kasaï-Central, Lomami, Lualaba) from August 2014 through June 2016. The pre- and post-intervention surveys targets 387 mothers of children under 5 years and 63 community health workers and 346 mothers and 41 community health workers, respectively. A 15% margin was considered for noninferiority analyses due to the expected decrease in adherence to referral advice after the introduction of the new intervention. Results: The mothers acknowledged that the rectal route was often used (60.7%), and medicines given rectally were considered more effective (63.6%) and easy to administer (69.7%). The acceptability of pre-referral rectal artesunate was relatively high: 79.4% (95% CI 75.4–83.3) among mothers, 90.3% (95% CI 82.3–96.8) among community health workers, and 97.8% (95% CI 93.3–100) among nurses. Adherence to referral advice at post-intervention [84.3% (95% CI 80.6–88.1)] was non-inferior to pre-intervention adherence [94.1% (95% CI 91.7–96.4)]. Conclusions: The integration of pre-referral rectal artesunate for severe malaria into the community care site in the DR Congo is feasible and acceptable. It positively affected adherence to referral advice. However, more health education is needed for parents of children under 5 years and community health workers. [ABSTRACT FROM AUTHOR]

Introduction: Plasmodium falciparum , the deadliest malaria parasite, kills hundreds of thousands of people per year, mainly young children in Sub-Saharan Africa. Artesunate suppositories are recommended as pre-referral malaria treatment in remote endemic areas for severely ill children to prevent progression of the disease and to provide extra time for patients until the definitive severe malaria treatment can be administered., Areas Covered: The authors provide an overview of the discovery of artesunate and its different formulations focusing on rectal administration, summarizing key studies concerning the pharmacokinetic, pharmacodynamic, safety, tolerability and efficacy of rectal artesunate leading to WHO recommendation and market authorization in Africa. In addition, studies on acceptance and adherence to rectal artesunate administration and the post-launch status are also covered., Expert Opinion: Efforts by ministries of health in malaria endemic countries together with international health organizations should establish and enforce guidelines to ensure the correct use of artesunate suppositories only as pre-referral medication in presumed severe malaria cases to minimize the risk of abuse as a monotherapy for treatment of uncomplicated malaria. The priority is to not jeopardize the efficacy of artesunate and to prevent resistance development against this valuable drug class in Africa.

Background: Community health workers (CHWs) were trained to identify children with malaria who could not take oral medication, treat them with rectal artesunate (RA) and refer them to the closest healthcare facility to complete management. However, many children with such symptoms did not seek CHWs' care. The hypothesis was that the cost of referral to a health facility was a deterrent. The goal of this study was to compare the out-of-pocket costs and time to seek treatment for children who sought CHW care (and received RA) versus those who did not. Methods: Children with symptoms of severe malaria receiving RA at CHWs and children with comparable disease symptoms who did not go to a CHW were identified and their parents were interviewed. Household out-of-pocket costs per illness episode and speed of treatment were evaluated and compared between RA-treated children vs. non-RA treated children and by central nervous symptoms (CNS: repeated convulsions, altered consciousness or coma). Results: Among children with CNS symptoms, costs of RA-treated children were similar to those of non-RA treated children ($5.83 vs. $4.65; p = 0.52), despite higher transport costs ($2.74 vs. $0.91; p < 0.0001). However, among children without CNS symptoms, costs of RA-treated children were higher than the costs of non-RA treated children with similar symptoms ($5.62 vs. $2.59; p = 0.0001), and the main driver of the cost difference was transport. After illness onset, CNS children reached CHWs for RA an average of 9.0 h vs. 16.1 h for non-RA treated children reaching first treatment [difference 7.1 h (95% CI − 1.8 to 16.1), p = 0.11]. For non-CNS patients the average time to CHW-delivered RA treatment was 12.2 h vs. 20.1 h for those reaching first treatment [difference 7.9 h (95% CI 0.2–15.6), p = 0.04]. More non-RA treated children developed CNS symptoms before arrival at the health centre but the difference was not statistically significant (6% vs. 4%; p = 0.58). Conclusions: Community health worker-delivered RA does not affect the total out-of-pocket costs when used in children with CNS symptoms, but is associated with higher total out-of-pocket costs when used in children with less severe symptoms. RA-treated children sought treatment more quickly. [ABSTRACT FROM AUTHOR]

Background: Successful pre-referral treatment with rectal artesunate (RA) for suspected severe malaria requires operational linkages between community health workers (CHWs) and referral facilities, acceptance of pre-referral treatment and adherence to referral practices by CHWs and caregivers. This qualitative study investigated how community understanding of the concept of 'pre-referral treatment' is used in referral related decision-making following provision of RA in Uganda.Methods: Narrative interviews were conducted with 30 caregivers of children under five who received RA within the previous three months and the 30 associated CHWs who provided the treatment. Nineteen focus group discussions incorporating vignettes from the interviews were held with further caregivers, and 12 with CHWs and women representatives. Twenty traditional healers were targeted for semi-structured interview. Thematic analysis followed a 'meaning-based' approach.Results: CHWs were aware of essential information to be given to caregivers on prescribing RA as indicated by the job aid, specifically urgency for referral, yet there was insufficient emphasis on RA not being a full treatment for severe malaria. Information shared by the CHW appeared to be influenced by the perceived urgency with which the CHW needed to act and the time of day or night the child was seen. Seven of the 32 caregivers did not complete referral post RA administration. Caregivers seemed more likely to adhere to referral advice if they perceived their child's condition to be severe. Previous caregiver experience and CHW comparisons with Artemisinin-based Combination Therapy (ACT) as a treatment for uncomplicated malaria appeared to raise misperceptions that RA is a complete treatment for severe malaria, thus reducing likelihood to complete referral. CHW implication, or caregiver interpretation, of the need to monitor the child, and some prescription of ACT post RA administration, also confused the need for referral. Both CHWs and caregivers requested further information about the role of RA.Conclusions: CHW advice should emphasise RA as providing temporary relief prior to facility-based treatment, the importance of referral whether or not a change is seen in the child's condition, and the dangers of not completing referral. Social behaviour change communication, training and support supervision activities could help promote these messages. [ABSTRACT FROM AUTHOR]

Background:  Use of community health workers (CHWs) to increase access to diagnosis and treatment of malaria is recommended by the World Health Organization. The present article reports on training and performance of CHWs in applying these recommendations., Methods:  Two hundred seventy-nine CHWs were trained for 3-5 days in Burkina Faso, Nigeria, and Uganda, and 19 were certified to diagnose and treat only uncomplicated malaria and 235 to diagnose and treat both uncomplicated and severe malaria. Almost 1 year after training, 220 CHWs were assessed using standard checklists using facility staff responses as the reference standard., Results:  Training models were slightly different in the 3 countries, but the same topics were covered. The main challenges noticed were the low level of education in rural areas and the involvement of health staff in the supervision process. Overall performance was 98% (with 99% in taking history, 95% in measuring temperature, 85% for measuring respiratory rates, 98% for diagnosis, 98% for classification, and 99% for prescribing treatment). Young, single, new CHWs performed better than their older, married, more experienced counterparts., Conclusions:  Training CHWs for community-based diagnosis and treatment of uncomplicated and severe malaria is possible with basic and refresher training and close supervision of CHWs' performance., Clinical Trials Registration:  ISRCTRS13858170., (© 2016 World Health Organization; licensee Oxford Journals.)

Background:  Children aged <5 years were enrolled in a large study in 3 countries of sub-Saharan Africa because they had danger signs preventing them from being able to take oral medications. We examined compliance and factors associated with compliance with referral advice for those who were treated with rectal artesunate., Methods:  Patient demographic data, speed of accessing treatment after danger signs were recognized, clinical symptoms, malaria microscopy, treatment-seeking behavior, and compliance with referral advice were obtained from case record forms of 179 children treated with prereferral rectal artesunate in a multicountry study. We held focus group discussions and key informant interviews with parents, community health workers (CHWs), and facility staff to understand the factors that deterred or facilitated compliance with referral advice., Results:  There was a very high level of compliance (90%) among patients treated with prereferral rectal artesunate. Age, symptoms at baseline (prostration, impaired consciousness, convulsions, coma), and malaria status were not related to referral compliance in the analysis., Conclusions:  Teaching CHWs to diagnose and treat young children with prereferral rectal artesunate is feasible in remote communities of Africa, and high compliance with referral advice can be achieved., (© 2016 World Health Organization; licensee Oxford Journals.)

Background:  If malaria patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate prior to hospital referral can prevent death and disability. The goal is to reduce death from malaria by having rectal artesunate treatment available and used. How best to do this remains unknown., Methods:  Villages remote from a health facility were randomized to different community-based treatment providers trained to provide rectal artesunate in Ghana, Guinea-Bissau, Tanzania, and Uganda. Prereferral rectal artesunate treatment was provided in 272 villages: 109 through community-based health workers (CHWs), 112 via trained mothers (MUMs), 25 via trained traditional healers (THs), and 26 through trained community-chosen personnel (COMs); episodes eligible for rectal artesunate were established through regular household surveys of febrile illnesses recording symptoms eligible for prereferral treatment. Differences in treatment coverage with rectal artesunate in children aged <5 years in MUM vs CHW (standard-of-care) villages were assessed using the odds ratio (OR); the predictive probability of treatment was derived from a logistic regression analysis, adjusting for heterogeneity between clusters (villages) using random effects., Results:  Over 19 months, 54 013 children had 102 504 febrile episodes, of which 32% (31 817 episodes) had symptoms eligible for prereferral therapy; 14% (4460) children received treatment. Episodes with altered consciousness, coma, or convulsions constituted 36.6% of all episodes in treated children. The overall OR of treatment between MUM vs CHW villages, adjusting for country, was 1.84 (95% confidence interval [CI], 1.20-2.83; P = .005). Adjusting for heterogeneity, this translated into a 1.67 higher average probability of a child being treated in MUM vs CHW villages. Referral compliance was 81% and significantly higher with CHWs vs MUMs: 87% vs 82% (risk ratio [RR], 1.1 [95% CI, 1.0-1.1]; P < .0001). There were more deaths in the TH cluster than elsewhere (RR, 2.7 [95% CI, 1.4-5.6]; P = .0040)., Conclusions:  Prereferral episodes were almost one-third of all febrile episodes. More than one-third of patients treated had convulsions, altered consciousness, or coma. Mothers were effective in treating patients, and achieved higher coverage than other providers. Treatment access was low., Clinical Trials Registration:  ISRCTN58046240., (© 2016 World Health Organization; licensee Oxford Journals.)