In holoendemic Plasmodium falciparum transmission regions, malarial anemia is a leading cause of childhood morbidity and mortality. Identifying biomarkers of malaria disease severity is important for identifying at-risk groups and for improved understanding of the molecular pathways that influence clinical outcomes. We have previously shown that decreased cyclooxygenase (COX)-2-derived prostaglandin E-2 (PGE(2)) levels are associated with enhanced clinical severity in cerebral malaria, malarial anemia, and malaria during pregnancy. Since children with malaria often have increased incidence of additional infections, such as bacteremia and HIV-1, we extend our previous findings by investigating COX-2 and PGE(2) in children with falciparum malaria and co-infection with either bacteremia or HIV-1. Plasma bicyclo-PGE(2)/creatinine levels and peripheral blood COX-2 transcripts were significantly reduced in co-infected children relative to those with malaria mono-infection. Furthermore, suppression of circulating bicyclo-PGE(2) was significantly associated with reduced hemoglobin levels in both mono- and co-infected children with malaria, suggesting that bicyclo-PGE(2) may represent both a marker and mediator of malaria pathogenesis. (c) 2013 Elsevier Inc. All rights reserved.