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

Abstract

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).

Fig 1. Details of analysis dataset and definitions of antimalarial treatment compliance.

Of the 14,911 children enrolled in the CARAMAL study (either by a community-based provider or at the RHF), 7,983 underwent treatment at a RHF and were included in the analysis (2,257 enrolled during the RAS pre-implementation period (pre-RAS), 5,726 enrolled after RAS was rolled out (post-RAS)). A total of 1,600 received pre-referral RAS during the post-RAS phase, 4,126 did not. Medication appropriateness was assessed for the full dataset (highlighted in light grey), treatment compliance was analysed for the post-implementation subsample (shown with blue background). ACT, artemisinin-based combination therapy; CRF, case report form; DRC, Democratic Republic of the Congo; RAS, rectal artesunate; RHF, referral health facility. ¹ Enrolled in CARAMAL study by community-based provider or directly enrolled at RHF. ² Followed up after admission to RHF. ³ Post-RAS subsample with more detailed treatment data.

Fig 2. Appropriateness of antimalarial medication provided to children diagnosed with severe malaria before and after the implementation of RAS, by country and by RAS implementation period (%).

Treatment of admitted children referred by a community-based provider or directly attending an RHF was assessed before and after the roll-out of RAS (pre vs. post). Proportion of children administered at least 1 dose of an injectable antimalarial (artesunate, artemether, or quinine; white bars) and at least 1 dose of an injectable antimalarial and an in-hospital ACT consisting of either ALU or ASAQ (blue bars). ACT, artemisinin-based combination therapy; ALU, artemether-lumefantrine; AM, antimalarial; ASAQ, artesunate-amodiaquine; DRC, Democratic Republic of the Congo; RAS, rectal artesunate.

Fig 3. Antimalarial treatment compliance for children diagnosed with severe malaria after the implementation of RAS, by country and by enrolling provider (%).

Antimalarial treatment administered in-hospital or prescribed at discharge to children referred by a CHW or PHC (C) or directly attending an RHF (R). (A) Administration of at least 3 doses of an injectable antimalarial (artesunate, artemether, or quinine). (B) Administration of at least 3 doses of an injectable antimalarial and in-hospital follow-on ACT (light blue bars) or in-hospital administered/at discharge prescribed/dispensed follow-on ACT (dark blue bars). Data collection period: Uganda and DRC: April 2019–July 2020, Nigeria: May 2019–July 2020. ACT, artemisinin-based combination therapy; AM, antimalarial; DRC, Democratic Republic of the Congo; RAS, Rectal Artesunate; RHF, Referral Health Facility.