Despite recent advances in malaria control, Plasmodium falciparum continues to kill almost half a million persons annually, most of whom are children living in sub-Saharan Africa. Plasmodium falciparum is the most prevalent malaria parasite specie and the cause of the most severe form of disease and death. It accounted for 99.7% of all malaria cases in the World Health Organization (WHO) African Region in 2018. Children younger than 5 years of age and pregnant women are most at risk of malaria and death, accounting for 67% of the estimated 405,000 malaria deaths worldwide, with 94% of these in the African Region. Although there was an overall reduction in malaria deaths in 2018 compared with 2010, the malaria mortality reduction rate slowed since 2016 and this has malaria researchers questioning if current malaria treatment regimens are optimal and based on sound scientific evidence.~Severe malaria is a medical emergency which if not immediately treated results in 100% mortality. It is fundamental that plasma concentrations of a highly effective antimalarial drug are achieved as rapidly as possible. Artesunate is a water soluble hemisuccinate artemisinin derivative, available as sodium hemisuccinate salt for injection. Artesunate's excellent antimalarial property demonstrated by rapid parasite clearance, is enhanced by its high initial maximum concentration (Cmax) and rapid hydrolysis to its active metabolite dihydroartemisinin (DHA). Currently, the WHO recommends use of IV artesunate as first line treatment for severe malaria, administered for at least 24 hours, until the patient can tolerate oral medication and to complete treatment with a full course of an artemisinin combination therapy (ACT). Uganda adopted this policy for severe malaria treatment, however, parenteral artesunate is not widely available and effort to improve accessibility should be reinforced.~Current dosing regimens for IV artesunate are based on time to parasite clearance and not clinical endpoints related to physiologic changes that occur with parasitemia. Other measures of physiologic dysfunction can be used as study endpoints for a malaria treatment outcome analysis of current regimens for IV artesunate for severe malaria treatment. Improved dosing regimens will lead to fewer complications and likely fewer deaths. Such a strategy is needed to further reduce public health gains against malaria mortality that seem to have recently stalled.~For pediatric patients, IV artesunate dosing is weight-based to adjust for artesunate clearance and has been developed based on time to parasitemia clearance times, which may not completely reflect clinical cure. P. falciparum parasites are known for their capacity to infect red blood cells that then display variant surface antigens that adhere to endothelial vasculature in target organs. For this reason, measurement of parasite clearance in the peripheral blood may not reflect physiologic effects of severe malaria that result from end organ damage, whether through direct impairment of blood flow and decreased delivery of oxygen, a local inflammatory response directed against infected red blood cells attached to vascular endothelium, or rosetting of infected and uninfected red blood cells at the vasculature. Other measures of physiologic dysfunction when quantified alone or in an algorithmic fashion such as a score, may more accurately reflect successful treatment, including serum lactate, serum glucose, bicarbonate levels, Blantyre Coma Score (BCS), creatinine and hemoglobin. These measures, compared to the standard parasite clearance times from peripheral blood, may be more important to quantify and relate to pharmacologic dosing of antimalarial therapy.~Participants will receive the standard of care IV artesunate for initial treatment of severe malaria per WHO guidelines. Parenteral treatment will be administered for a minimum of 24 hours (irrespective of the patient's ability to tolerate oral medication earlier), after which patients will be evaluated clinically and assessed for ability for oral intake of antimalarials. Children who are able to transition to oral antimalarial therapy will initiate a 3-day course of artemisinin combination oral therapy per national guidelines. Biomarkers of physiologic dysfunction will be quantified at regular intervals and these biomarkers will be considered both independently and together as a weighted score (to be developed as an exploratory objective of this study) to relate to the pharmacokinetics (PK) of the active metabolite of IV artesunate, DHA and to efficacy markers that more accurately reflect clinical outcomes.
In this study, Ugandan children who are diagnosed with severe malaria will receive intravenous (IV) artesunate per World Health Organization (WHO) guidelines.