Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children &lt;5 years of age

Hetzel, Manuel W; Okitawutshu, Jean; Tshefu, Antoinette; Omoluabi, Elizabeth; Awor, Phyllis; Signorell, Aita; Brunner, Nina C.; Kalenga, Jean-Claude; Akano, Babatunde; Ayodeji, Kazeem; Okon, Charles; Yusuf, Ocheche; Athieno, Proscovia; Kimera, Joseph; Tumukunde, Gloria; Angiro, Irene; Delvento, Giulia; Lee, Tristan; Lambiris, Mark; Kwiatkowski, Marek; Cereghetti, Nadja; Visser, Theodoor; Napier, Harriet G.; Cohen, Justin M.; Buj, Valentina; Burri, Christian; Lengeler, Christian

doi:10.1101/2021.09.24.21263966

Cited by 12 publications

(30 citation statements)

References 20 publications

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“…Two critical aspects of the continuum of care for severe malaria cases, namely referral completion and post-referral treatment, have been described in other manuscripts (Signorell et al, manuscript in preparation, (12)). But neither seem to provide an explanation of the difference in CFR between the two groups of patients (11).…”

Section: Introductionmentioning

confidence: 89%

“…This research was conducted as part of the CARAMAL project that accompanied the roll-out of pre-referral RAS into existing iCCM and IMCI systems. The complete methods are detailed elsewhere (Lengeler et al, manuscript in preparation, (11)). This analysis includes children with suspected severe malaria enrolled by community-based providers (CORPs or PHCs) in Nigeria.…”

Section: Methodsmentioning

confidence: 99%

“…In an observational study, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project investigated the health impact of introducing RAS in remote populations in the Democratic Republic of the Congo, Nigeria, and Uganda (11). In Nigeria, the study did not find a positive health effect of introducing pre-referral RAS in three Local Government Areas (LGA) of Adamawa State.…”

Section: Introductionmentioning

confidence: 99%

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Treatment-seeking for children with suspected severe malaria attending community health workers and primary health centres in Adamawa State, Nigeria

Lee

Omoluabi²,

Ayodeji³

et al. 2021

Preprint

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BackgroundThe Community Access to Rectal Artesunate for Malaria project investigated the feasibility of introducing pre-referral rectal artesunate into existing community-based health services. In that study, the case fatality rate of children visiting primary health centres (PHCs) was 19% compared to 6% in children first visiting community health workers, locally called Community Oriented Resource Persons (CORPs). As case management practices did not fully explain this finding, this publication investigates other reasons underlying the observed difference in case fatality.MethodsThe observational study enrolled 589 children under the age of five years with fever and danger signs indicative of severe malaria attending CORPs and PHCs in Adamawa State, Nigeria, between June 2018 and July 2020. After 28 days, follow-up visits were conducted with caregivers to understand background characteristics, severity of symptoms, home treatment administration, and treatment seeking practices during the child’s illness. These factors were compared between children visiting CORPs versus those visiting PHCs as their first health provider.ResultsChildren visiting PHCs were more likely to display danger signs indicative of central nervous system involvement (90% vs. 74%, p < 0.01) and have four or more danger signs (50% vs. 39%, p = 0.02). The delay between illness onset and visiting the community-based provider did not differ between children attending a CORP and children attending a PHC. PHC attendances more often lived in urban areas (16% vs 4%, p=0.01) and travelled farther to their first health provider, which was usually a community-based provider. Although practicing home treatment was common, especially among children attending PHCs (42% vs 33%, p=0.04), almost none of the children were given an antimalarial. PHCs were visited for their professionalism and experience while CORPs were visited for their low cost and because caregivers personally knew and trusted the provider.ConclusionsOur comparison of children with suspected severe malaria seeking care from two kinds of community-based health care providers in Nigeria suggest that illness severity may be the primary driver behind the observed difference in case fatality rate.

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Section: Introductionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment-seeking for children with suspected severe malaria attending community health workers and primary health centres in Adamawa State, Nigeria

Lee

Omoluabi²,

Ayodeji³

et al. 2021

Preprint

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“…In DRC, the CFR was substantially higher in community enrolments: 7.3% [95% CI 6.3-8.5], than in RHF enrolments: 1.9% [95% CI 1.4-2.6]. A detailed analysis of the CFR, a pre-post RAS impact analysis, as well as an individual risk factor analysis for mortality and severe disease are presented in a forthcoming publication [25]. The difference in case definitions between severe febrile illness under iCCM and the classic WHO definition of severe malaria are shown in Table 3.…”

Section: Overall Case Fatality Rates (Cfr)mentioning

confidence: 99%

“…A number of companion papers will present specific results on RAS impact [25], the referral process and its problems [26], post-referral care [Signorell et al manuscript in preparation] and the cost-effectiveness of RAS [Lambiris et al, submitted]. In addition, a number of country-specific publications will document in more detail the specifics of RAS implementation and impact in each project country.…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

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

Lengeler

Burri

Awor

et al. 2021

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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.

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

Brunner

Omoluabi²,

Awor

et al. 2021

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Background: Children who receive pre-referral 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. In this study, we investigated the relationship between RAS implementation and administration and referral completion. Methods and Findings: 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 five 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, treatments received, and their health outcome. In total, 8,365 children were enrolled, 77% of whom fulfilled all inclusion criteria and had a known referral completion status. Referral completion was 67% (1,408/2,104) in DRC, 48% (287/600) in Nigeria and 58% (2,170/3,745) 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 odds ratio [aOR] = 0.48, 95% CI 0.30-0.77 and aOR = 0.72, 95% CI 0.58-0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared to RAS non-users in the post-roll-out phase (aOR = 0.18, 95% CI 0.05-0.71). 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 1.17-2.79). 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 pre-referral 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.

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Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children <5 years of age

Cited by 12 publications

References 20 publications

Treatment-seeking for children with suspected severe malaria attending community health workers and primary health centres in Adamawa State, Nigeria

Treatment-seeking for children with suspected severe malaria attending community health workers and primary health centres in Adamawa State, Nigeria

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

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

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