Alterations in Systemic Extracellular Heme and Hemopexin Are Associated With Adverse Clinical Outcomes in Ugandan Children With Severe Malaria

[[[ Background: ]]] Malaria remains a major cause of global mortality. Extracellular heme, released during malaria-induced hemolysis, mediates a number of pathogenic processes associated with vascular and organ injury. Hemopexin (hpx) facilitates the degradation of extracellular heme. In this study, we explore the hypothesis that dysregulation of the heme-hpx axis is associated with disease severity, acute kidney injury (AKI), and outcome. [[[ Methods: ]]] Plasma levels of hemin and hpx (at admission, day 3, and day 14) were assessed in children with severe malaria in Jinja, Uganda. [[[ Results: ]]] The ratio of heme to hpx was higher at admission and decreased with recovery (median, 0.043 [interquartile range {IQR}, 0.007-0.239] on day 1, 0.024 [IQR, 0.005-0.126] on day 3, and 0.008 [IQR, 0.002-0.022] on day 14; P < .001). Ratios of heme to hpx at admission were higher in children with as compared to those without severe anemia (median, 0.124 [IQR, 0.024-0.431] vs 0.016 [IQR, 0.003-0.073]; P < .0001), children with as compared to those without respiratory distress (median, 0.063 [IQR, 0.017-0.413] vs 0.020 [IQR, 0.004-0.124]; P < .01), and children with as opposed to those without stage 3 AKI (median, 0.354 [IQR, 0.123-2.481] vs 0.037 [IQR, 0.005-0.172], P < .01). The heme to hpx ratio at admission was associated with 6-month mortality (median, 0.148 [IQR, 0.042-0.500] vs 0.039 [IQR, 0.007-0.172]; P = .012). [[[ Conclusions: ]]] The ratio of heme to hpx is associated with disease severity and adverse clinical outcomes in Ugandan children, and dysregulation of the heme axis may contribute to malaria pathogenesis.