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The parasite Plasmodium falciparum is the main cause of severe malaria (SM). Despite treatment with antimalarial drugs, more than 400,000 deaths are reported every year, mainly in African children. The diversity of clinical presentations associated with SM highlights important differences in disease pathogenesis that often require specific therapeutic options. The clinical heterogeneity of SM is largely unresolved. Here we report a network-based analysis of clinical phenotypes associated with SM in 2,915 Gambian children admitted to hospital with Plasmodium falciparum malaria. We used a network-based clustering method which revealed a strong correlation between disease heterogeneity and mortality. The analysis identified four distinct clusters of SM and respiratory distress that departed from the WHO definition. Patients in these clusters characteristically presented with liver enlargement and high concentrations of brain natriuretic peptide (BNP), giving support to the potential role of circulatory overload and/or right-sided heart failure as a mechanism of disease. The role of heart failure is controversial in SM and our work suggests that standard clinical management may not be appropriate. We find that our clustering can be a powerful data exploration tool to identify novel disease phenotypes and therapeutic options to reduce malaria-associated mortality.

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