Circulating Neutrophil Extracellular Traps and Neutrophil Activation Are Increased in Proportion to Disease Severity in Human Malaria

[[[ Background: ]]] Neutrophil activation results in Plasmodium parasite killing in vitro, but neutrophil products including neutrophil extracellular traps (NETs) mediate host organ damage and may contribute to severe malaria. The role of NETs in the pathogenesis of severe malaria has not been examined. [[[ Methods: ]]] In Papua, Indonesia, we enrolled adults with symptomatic Plasmodium falciparum (n = 47 uncomplicated, n = 8 severe), Plasmodium vivax (n = 37), or Plasmodium malariae (n = 14) malaria; asymptomatic P falciparum (n = 19) or P vivax (n = 21) parasitemia; and healthy adults (n = 23) without parasitemia. Neutrophil activation and NETs were quantified by immunoassays and microscopy and correlated with parasite biomass and disease severity. [[[ Results: ]]] In patients with symptomatic malaria, neutrophil activation and NET counts were increased in all 3 Plasmodium species. In falciparum malaria, neutrophil activation and NET counts positively correlated with parasite biomass (Spearman rho = 0.41, P = .005 and r2 = 0.26, P = .002, respectively) and were significantly increased in severe disease. In contrast, NETs were inversely associated with parasitemia in adults with asymptomatic P falciparum infection (r2 = 0.24, P = .031) but not asymptomatic P vivax infection. [[[ Conclusions: ]]] Although NETs may inhibit parasite growth in asymptomatic P falciparum infection, neutrophil activation and NET release may contribute to pathogenesis in severe falciparum malaria. Agents with potential to attenuate these processes should be evaluated.