Artesunate treatment of severe pediatric malaria: A review of parasite clearance kinetics and clinical implications

Severe malaria causes an estimated 1.24 million deaths every year, mostly in children in sub-Saharan Africa (1). Canadian pediatric infectious diseases practitioners may encounter life-threatening malaria among children emigrating from or returning from travel to the tropics. There were 195 reported cases of severe malaria in Canada between 2001 and 2012 (2), and the recent death of a malaria-infected adult in Alberta provided a reminder of the potential severity of the disease. Two large, multicentre, randomized controlled trials conclusively demonstrated a mortality benefit for the use of artesunate over quinine, the centuries-old standard, for children and adults with severe malaria (3,4). As a result, intravenous artesunate is now the treatment of choice for severe malaria, as reflected in guidelines from the WHO and the Canadian Committee to Advise on Tropical Medicine and Travel (5,6). Severe malaria in children most often manifests as either a single, or a combination of three clinical syndromes: severe malarial anemia, cerebral malaria and/or respiratory distress. In addition, patients with a high parasite density are at elevated risk for progression to severe disease and death. In travellers from low-transmission settings, such as Canada, the parasitemia threshold suggested for close monitoring, hospitalization and parenteral therapy is >2% (6). It should be emphasized that circulating parasites represent only a fraction of the sequestered parasite biomass in severe malaria, such that this threshold is imprecise. Artesunate is a water-soluble, semi-synthetic derivative of artemisinin, the active antimalarial component of the herb Artemisia annua (qinghaosu). Its use in clinical practice is expanding in malariaendemic areas of Africa and Asia, replacing quinine as the mainstay of severe malaria treatment (7). It is available across Canada, 24 h per day, through the Canadian Malaria Network and Health Canada’s Special Access Program (8). If, despite national efforts to ensure its accessibility, artesunate cannot be obtained in a timely manner for a patient with severe malaria, alternative agents (eg, atovaquone-proguanil or quinine) should be initiated pending arrival of artesunate. Although the weight of evidence and international consensus favour artesunate treatment, some countries continue to list quinidine or quinine for severe malaria as they await regulatory approval of artesunate (9,10). Clinicians consulting widely available online (9,11) or print (10,12) treatment guidelines for severe malaria may be puzzled by the United States (US) Centers for Disease Control and Prevention’s listing of quinidine as first-line therapy in the US, or quinine in the United Kingdom (Table 1). WHO-prequalified artesunate (Guilin Pharmaceutical, China) was used in major clinical trials with excellent efficacy (3); however, it has not yet obtained Health Canada, US Food and Drug Administration or European Union regulatory approval, creating a gap between the preferred evidence-based regimen and the regimen approved by regulatory authorities. High-quality artesunate from the Walter Reed Army Institute of Research (Maryland, USA) is, nonetheless, widely used in Canada and the US, made available to Canadians through the Canadian Malaria Network (2) and to US hospitals through a Food and Drug Administration-approved investigational new drug protocol (9). In addition to reducing mortality in patients with severe malaria, artesunate treatment also results in remarkably rapid parasite clearance. The kinetics of parasite elimination from the peripheral circulation under artesunate treatment are summarized in Table 2. Parasite clearance kinetics link the three themes discussed in the present article: postartemisinin-delayed hemolysis (PADH), a newly recognized adverse event and consequence of rapid parasite clearance; pharmacokinetics and dosing in young children who exhibit slower parasite clearance; and artesunate resistance, heralded by slow parasite clearance.