The authors enrolled 382 patients at two hospitals in Uganda in a prospective observational study of severe sepsis. Because artemisinins improve survival in murine sepsis models, they performed a post hoc analysis of the association between the use of artemether-lumefantrine (A-L) and mortality in patients with or without malaria. In patients with negative malaria smears (N = 328 of 379), Kaplan-Meier curves revealed decreased combined inpatient and 30-day mortality among patients receiving A-L versus those who did not (20.6%, SE = 10.6 versus 48.8%, SE = 3.2; Log rank chi2 = 3.93, P = 0.048). The decrease in mortality associated with A-L was maintained in the most clinically ill patients determined by Karnofsky Performance Scores <or= 50 (16.7%, SE = 15.2 versus 58.3%, SE = 3.7; Log rank chi2 3.94, P = 0.041). Research into the properties of A-L is needed to improve treatment of sepsis without compromising malarial susceptibility.

For severe malarial syndromes such as cerebral malaria, adverse clinical outcomes are often mediated by the immune system rather than caused by the parasite directly. However, few therapeutic agents have been developed to modulate the host's immunopathological responses to infection. Here, the authors report that the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone modulated the host response to malaria by enhancing phagocytic clearance of malaria-parasitized erythrocytes and by decreasing inflammatory responses to infection via inhibition of Plasmodium falciparum glycosylphosphatidylinositol-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways. The authors found that, in the Plasmodium berghei strain ANKA experimental model of cerebral malaria, rosiglitazone modified the inflammatory response to malarial infection and improved the survival rate even when treatment was initiated as late as day 5 after infection. Further more, rosiglitazone reduced the parasitemia in a CD36-dependent manner in the Plasmodium chabaudi chabaudi hyperparasitemia model. These data suggest that PPARgamma agonists represent a novel class of host immunomodulatory drugs that may be useful for treatment of severe malaria syndromes.