Impact of Oxidative Stress on Risk of Death and Readmission in African Children With Severe Malaria: A Prospective Observational Study

Abstract

Background: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality.

Methods: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed.

Results: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment.

Conclusions: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA.

Clinical trials registration: NCT01093989.

Keywords: Plasmodium falciparum; cerebral malaria; child; heme oxygenase-1; malaria; malondialdehyde; oxidative stress; severe malarial anemia; superoxide dismutase.

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Flow diagram of patient enrollment, treatment randomization, and mortality. Abbreviations: D, delayed iron therapy; I, immediate iron therapy; LTFU, lost to follow-up; ZPP, zinc protoporphyrin.

Figure 2.

Baseline measurements of select plasma oxidative stress biomarkers in children with cerebral malaria (CM) or severe malarial anemia (SMA) compared with community children (CC). Shown are plasma malondialdehyde concentration (A), heme oxygenase-1 concentration (B), and superoxide dismutase activity (C) in children with CM or SMA compared with CC. Circles represent plasma biomarker values in individual children. Boxes show median and interquartile range; bars show minimum and maximum values. Statistical comparisons were performed with the Kruskal–Wallis rank test, and post hoc analysis used Dunn test for pairwise comparisons using the Benjamini–Hochberg approach. *P < .02; **P < .001. Abbreviations: CC, community children; CM, cerebral malaria; HO-1, heme oxygenase-1; MDA, malondialdehyde; SMA, severe malarial anemia; SOD, superoxide dismutase.