Understanding and improving case management of severe febrile illness in highly malaria-endemic settings: an observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda
Authors: Signorell A , Hetzel M , Tshefu AK , Omoluabi E , Awor P , Lambiris M , Brunner N , Delvento G , Lee T , Okitawutshu J , Kalenga JC , Akano B , Ayodeji K , Okon C , Yusuff O , Athieno P , Kimera J , Tumukunde G , Angiro I , Buj V , Visser T , Napier H , Lengeler C , Burri C 
Published: July 2024

INTRODUCTION
In sub-Saharan Africa, over 400,000 children die annually from malaria and other preventable illnesses. Little is known about where these children die, from which causes, and under which circumstances. A better understanding of these factors is crucial to effectively address the remaining burden of preventable childhood diseases and mortality. Rectal artesunate (RAS) is a potentially life-saving pre-referral treatment for children with severe malaria. However, limited evidence is available regarding the operational feasibility of incorporating RAS into the continuum of care for severe malaria, and the unanticipated consequences, like inappropriate use as artemisinin monotherapy or treatment of uncomplicated malaria, this could have on overall case management.

METHODS
The Community Access to Rectal Artesunate for Malaria (CARAMAL) study accompanied the implementation of RAS as a pre-referral treatment in DRC, Nigeria and Uganda. 8,563 children aged <5 years with severe febrile illnesses were detected and enrolled at primary care level, and 6,348 at referral health facilities. The children were followed up during admission and after 28 days to assess healthcare-seeking patterns, RAS use and acceptance, anti-malarial treatment received at the various points of contact with the health system, and health outcomes at day 28.

ETHICS
This study was approved by the World Health Organization’s Research Ethics Review Committee; the University of Kinshasa School of Public Health Ethics Committee; the Health Research Ethics Committee of the Adamawa State Ministry of Health and the National Health Research Ethics Committee, Nigeria; the Research and Ethics Committee of the Makerere University School of Public Health and the Uganda National Council for Science and Technology; and CHAI’s Scientific and Ethical Review Committee.

RESULTS
Post-RAS introduction, RAS was administered to 88% of eligible patients in DRC, 52% in Nigeria, and 70% in Uganda. We followed up 93% of enrolled children (13,870/14,911) 28 days after enrolment at home to determine status and healthcare trajectory. After roll-out, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase in DRC (adjusted odds ratio, aOR: 0.48) and Uganda (aOR: 0.72). Postreferral treatment with parenteral artesunate was high (above 80%), but the administration of a full course of artemisinin-based combination therapy to complete treatment as per WHO guidelines was variable (from virtually zero in Nigeria to 65% in DRC). Hence, many children were in fact treated with artemisinin monotherapy. Case fatality rates (CFR) varied largely by country and place of initial presentation (range: 0.3% to 15%). RAS was associated with reduced likelihood of being dead or sick on day 28 only in Uganda (aOR: 0.61, p<0.05) where overall CFR was lowest. No protective effect was found in DRC and Nigeria. Most children were considered healthy on day 28, but over 60% had detectable malaria antigenaemia.

CONCLUSION
For RAS to be an effective pre-referral treatment for children with severe malaria in hard-to-reach locations, underlying health system factors need to be addressed to ensure a functional continuum of care.

CONFLICTS OF INTEREST
None declared