Endothelial Activation, Acute Kidney Injury, and Cognitive Impairment in Pediatric Severe Malaria

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2020-09
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American English
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Wolters Kluwer
Abstract

Objectives: Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors.

Design: Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children.

Setting: Mulago National Referral Hospital in Kampala, Uganda.

Subjects: Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months.

Interventions: None.

Measurements and main results: Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log10 increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β -0.42, 95% CI, -0.69 to -0.15, p = 0.002; children ≥ 5, β -0.39, 95% CI, -0.67 to -0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau).

Conclusions: These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.

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Ouma BJ, Ssenkusu JM, Shabani E, et al. Endothelial Activation, Acute Kidney Injury, and Cognitive Impairment in Pediatric Severe Malaria. Crit Care Med. 2020;48(9):e734-e743. doi:10.1097/CCM.0000000000004469
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