Pre-referral rectal artesunate: no cure for unhealthy systems

Hetzel, Manuel W; Awor, Phyllis; Tshefu, Antoinette; Omoluabi, Elizabeth; Burri, Christian; Signorell, Aita; Lambiris, Mark; Visser, Theodoor; Cohen, Justin M.; Buj, Valentina; Lengeler, Christian

doi:10.1016/s1473-3099(22)00762-9

Cited by 7 publications

(8 citation statements)

References 28 publications

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“…Pre-referral RAS for children in hard-to-reach locations can only be an effective addition to a functioning continuum of care for severe malaria, if post-referral treatment is adequate [ 32 ]. While parenteral treatment was generally administered correctly and reliably, we found that the provision of ACTs to complete treatment was often not followed or left to the discretion of the caregiver for home treatment.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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).

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Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…This guidance has generated much debate. 18 – 21 Zambia’s health ministry began scaling up rectal artesunate in 26 additional districts in 2021, and interpreted the WHO guidance as a call to proactively monitor and strengthen the quality of severe malaria case management at health facilities.…”

Section: Discussionmentioning

confidence: 99%

Rectal artesunate for severe malaria, implementation research, Zambia

Green,

Quigley,

Kureya

et al. 2023

Bull World Health Organ

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Objective To determine whether the positive results of a single-district pilot project focused on rectal artesunate administration at the community level in Zambia could be replicated on a larger scale. Methods In partnership with government, in 10 rural districts during 2018–2021 we: (i) trained community health volunteers to administer rectal artesunate to children with suspected severe malaria and refer them to a health facility; (ii) supported communities to establish emergency transport, food banks and emergency savings to reduce referral delays; (iii) ensured adequate drug supplies; (iv) trained health workers to treat severe malaria with injectable artesunate; and (v) monitored severe malaria cases and associated deaths via surveys, health facility data and a community monitoring system. Results Intervention communities accessed quality-assured rectal artesunate from trained community health volunteers, and follow-on treatment for severe malaria from health workers. Based on formal data from the health management information system, reported deaths from severe malaria reduced significantly from 3.1% (22/699; 95% confidence interval, CI: 2.0–4.2) to 0.5% (2/365; 95% CI: 0.0–1.1) in two demonstration districts, and from 6.2% (14/225; 95% CI: 3.6–8.8) to 0.6% (2/321; 95% CI: 0.0–1.3) in eight scale-up districts. Conclusion Despite the effects of the coronavirus disease, our results confirmed that pre-referral rectal artesunate administered by community health volunteers can be an effective intervention for severe malaria among young children. Our results strengthen the case for wider expansion of the pre-referral treatment in Zambia and elsewhere when combined with supporting interventions.

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“…The tragedy of a child dying after having been diagnosed with severe malaria, but not being referred to a hospital for definitive treatment, must have affected adversely both the families and the health workers. The authors (and the WHO) suggested that RAS administration could have fatally reassured the caregivers, who were then less likely to take the child to the hospital [7]. But can we be sure that in children who died, the records on RAS administration were accurate?…”

Section: Was Ras Administration Reliably Recorded By Health Workers?mentioning

confidence: 99%

“…But the idea that these "real-world data" can provide information on the effectiveness of RAS is truly a myth [13]. In a follow-up viewpoint, the authors reinforce this misunderstanding: "controlled trials provide much less informative evidence of real-world effectiveness than observational studies do" [7]. This is fundamentally wrong.…”

Section: Why Causal Inference Was Not Possible From the Outsetmentioning

confidence: 99%

“…The largest double-blind randomised trial (Study 13) of RAS [5] did not meet statistical significance when assessed in all randomised patients, but suggested a substantial benefit in those children with severe falciparum malaria presenting after 6 h to the hospital (post hoc subgroup analysis). Development and deployment of RAS have gone very slowly, and now, as a direct result of the CARAMAL study, their deployment has been halted [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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The CARAMAL study could not assess the effectiveness of rectal artesunate in treating suspected severe malaria

Watson

Peto

White

2023

BMC Med

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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.

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Pre-referral rectal artesunate: no cure for unhealthy systems

Cited by 7 publications

References 28 publications

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

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

Rectal artesunate for severe malaria, implementation research, Zambia

The CARAMAL study could not assess the effectiveness of rectal artesunate in treating suspected severe malaria

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