The five continuum of care criteria that should accompany rectal artesunate interventions: lessons learned from an implementation study in Malawi.

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.

Pre-referral intranasal artesunate powder for cerebral malaria: a proof-of-concept study.

BACKGROUND: Malaria still kills young children in rural endemic areas because early treatment is not available. Thus, the World Health Organization recommends the administration of artesunate suppositories as pre-referral treatment before transportation to the hospital in case of severe symptoms with an unavailable parenteral and oral treatment. However, negative cultural perception of the rectal route, and limited access to artesunate suppositories, could limit the use of artesunate suppositories. There is, therefore, a need for an alternative route for malaria pre-referral treatment. The aim of this study was to assess the potential of intranasal route for malaria pre-referral treatment. METHODS: The permeability of artesunate through human nasal mucosa was tested in vitro. The Transepithelial Electrical Resistance (TEER) of the nasal mucosa was followed during the permeation tests. Beside, regional deposition of artesunate powder was assessed with an unidose drug delivery device in each nostril of a nasal cast. Artesunate quantification was performed using Liquid Chromatography coupled to tandem Mass Spectrometry. RESULTS: The experimental model of human nasal mucosa was successfully implemented. Using this model, artesunate powder showed a much better passage rate through human nasal mucosa than solution (26.8 ± 6.6% versus 2.1 ± 0.3%). More than half (62.3%) of the artesunate dose sprayed in the nostrils of the nasal cast was recovered in the olfactory areas (44.7 ± 8.6%) and turbinates (17.6 ± 3.3%) allowing nose-to-brain and systemic drug diffusion, respectively. CONCLUSION: Artesunate powder showed a good permeation efficiency on human nasal mucosa. Moreover it can be efficiently sprayed in the nostrils using unidose device to reach the olfactory area leading to a fast nose-to-brain delivery as well as a systemic effect. Taken together, those results are part of the proof-of-concept for the use of intranasal artesunate as a malaria pre-referral treatment.

Readiness of the Kenyan public health sector to provide pre-referral care for severe paediatric malaria.

OBJECTIVE: To assess readiness among primary public health facilities in Kenya to provide pre-referral antimalarials for severe malaria. METHODS: Nine national surveys of randomly selected primary public health facilities undertaken bi-annually between 2017 and 2021 were analysed. The outcomes included the availability of pre-referral antimalarial drugs at the health facilities and health worker knowledge of recommended pre-referral treatment for severe malaria. RESULTS: A total of 1540 health workers from 1355 health facilities were interviewed. Injectable artesunate was available at 46%, injectable quinine at 7%, and artemether at 3% of the health facilities. None of the facilities had rectal artesunate suppositories in stock. A total of 960 (62%) health workers were trained on the use of injectable artesunate. 73% of the health workers who had ever referred a child with severe malaria were aware that artesunate was the recommended treatment, 49% said that intramuscular injection was the preferred route of administration, and 60% stated the correct dose. The overall knowledge level of the treatment policy was low at 21% and only slightly higher among trained than untrained health workers (24% vs 14%; p < 0.001) and those with access to guidelines versus those without access (29% vs 17%; p < 0.001). CONCLUSIONS: The readiness of primary health facilities and health workers to deliver appropriate pre-referral care to children with complicated malaria in Kenya is inadequate. Further investments are required to ensure (a) availability of nationally recommended pre-referral antimalarials; (b) appropriate training and supervision in their administration, and (c) monitoring of the entire referral process.

The preclinical discovery and development of rectal artesunate for the treatment of malaria in young children: a review of the evidence.

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.

Community understanding of the concept of pre-referral treatment and how this impacts on referral related decision-making following the provision of rectal artesunate: a qualitative study in western Uganda.

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.