Background Standard treatment for both uncomplicated and severe malaria is artemisinin derivatives. Delayed parasite clearance times preceded the appearance of artemisinin treatment failures in Southeast Asia. Most worldwide malaria cases are in sub-Saharan Africa (SSA), where clinically significant artemisinin resistance or treatment failure has not yet been detected. The recent emergence of a resistance-conferring genetic mutation in the Plasmodium falciparum parasite in Africa warrants continued monitoring throughout the continent. Methods An analysis was performed on data from a retrospective cohort study of Malawian children with cerebral malaria admitted between 2010 and 2019 to a public referral hospital, ascertaining parasite clearance times across years. Data were collected from patients treated for severe malaria with quinine or artesunate, an artemisinin derivative. Parasite density was determined at admission and every subsequent 6 h until parasitaemia was below 1000 parasites/µl.The mean parasite clearance time in all children admitted in any one year was compared to the parasite clearance time in 2014, the first year of artesunate use in Malawi. Results The median population parasite clearance time was slower from 2010 to 2013 (quinine-treated patients) compared to 2014, the first year of artesunate use in Malawi (30 h (95% CI: 30–30) vs 18 h (95% CI: 18–24)). After adjustment for admission parasite count, there was no statistically significant difference in the median population parasite clearance time when comparing 2014 with any subsequent year. Conclusion Malaria parasite clearance times in Malawian children with cerebral malaria remained constant between 2014 and 2019, arguing against evolving artemisinin resistance in parasites in this region.

Abstract.Artesunate therapy for severe malaria syndromes has been associated with post-treatment hemolysis and anemia. We defined post-malaria anemia as any decrease in hematocrit between the index hospitalization for severe malaria and 1 month after. We determined the incidence and severity of post-malaria anemia in Malawian children surviving cerebral malaria (CM) by analyzing hospital and follow-up data from a long-standing study of CM pathogenesis. Children enrolled before 2014 and treated with quinine (N = 258) were compared with those admitted in 2014 and after, and treated with artesunate (N = 235). The last hematocrit value obtained during hospitalization was compared with the 1-month post-hospitalization hematocrit value. The overall rate of a post-hospitalization decrease in hematocrit in children surviving CM was 5.3% (11 of 235 or 4.7% for quinine, 15 of 258 or 5.8% for artesunate; odds ratio, 3.23 [0.88, 18.38]); no patients with a decrease in hematocrit were symptomatic, and none required transfusion after hospitalization. Of the 26 children who had a decrease in hematocrit 1 month after hospitalization, 23.1% had evidence of a new malaria infection. When children treated with quinine and artesunate were combined, a higher hematocrit level on admission, lower quantitative histidine-rich protein level, and splenomegaly were associated independently with post-malaria anemia. In African survivors of CM, post-malaria anemia is rare, mild, and unassociated with the anti-malarial treatment received.

Background The location of Plasmodium falciparum within the body is determined by the life cycle of the parasite; young rings are in the peripheral blood, whereas mature parasites are sequestered in deep tissues. We can calculate a “ring ratio”, the proportion of parasites in the periphery to the total number of parasites in the body. Artesunate acts on all parasite life stages, whereas quinine is effective only on sequestered parasites. Children with cerebral malaria (CM) treated with artesunate clear parasites faster than those treated with quinine. In this study, we established the relationship between ring ratio and parasite clearance rate and used the ring ratio to determine if the benefit derived from artesunate treatment could be attributed to its broader effect on life cycle stages. Methods Ring ratios were calculated for 400 hospitalized children with CM in Blantyre, Malawi between 2010 and 2019 (quinine: 2010-2013, artesunate: 2014-2019). Results In both treatment groups, parasite clearance rates were positively associated with the ring ratios, with a stronger association in the artesunate era than the quinine era. In the quinine era an increase of one-unit log10 difference between parasitemia and plasma PfHRP2 (a proxy for ring ratio) resulted in a 0.27-unit increase in the parasite clearance rate, whereas in the artesunate era an equal increase resulted in a 0.41-unit increase (p = 0.04 for the difference). Conclusion This analysis provides in vivo evidence supporting the hypothesis that more rapid parasite clearance rates in artesunate recipients are due to its superiority over quinine in killing ring-stage parasites.

Background In severe malaria, artesunate decreases mortality compared to quinine. Artesunate’s introduction into clinical use in malaria-endemic areas revealed a unique adverse effect: severe hemolysis appearing several weeks after treatment completion. Though initial reports of post-artesunate hemolysis (PAH) were gathered from adult returning travelers, studies of African children revealed that PAH was less common in this semi-immune population. There are no published studies establishing the incidence and severity of PAH in several severe malarial syndromes in African children, including cerebral malaria (CM). We determined the incidence and severity of post-treatment hemolysis in Malawian children surviving CM by analyzing hospital and follow-up data from a long-standing study of CM pathogenesis. Methods Children aged 6 months to 14 years admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) with a clinical diagnosis of CM were enrolled in a retrospective cohort study. Children admitted before 2014 and treated with quinine (n=258) were compared to those admitted in 2014 and after and treated with artesunate (n=235). Hematocrit and parasite density were obtained at admission and every 6 hours until parasite clearance. The last hematocrit obtained during hospitalization was compared with the one-month post-hospitalization hematocrit value. Results The overall rate of a post-hospitalization decrease in hematocrit in children surviving CM was 5.3% (4.7% for quinine, 5.8% for artesunate, p value for difference= 0.582); no patients with a hematocrit decrease were symptomatic; none required transfusion. Of the 26 children with a decrease in hematocrit at one month after hospitalization, 23.1% had evidence of a new malaria infection. When children treated with quinine and artesunate were combined, a higher hematocrit on admission, lower quantitative histidine rich protein 2 level, and splenomegaly were independently associated with a post-treatment decrease in hematocrit. Conclusions In African survivors of CM, post-treatment hemolysis is rare, mild, and unassociated with the antimalarial treatment received.