Plasma Amino Acid Concentrations in Children With Severe Malaria Are Associated With Mortality and Worse Long-term Kidney and Cognitive Outcomes.

BACKGROUND: Global changes in amino acid levels have been described in severe malaria (SM), but the relationship between amino acids and long-term outcomes in SM has not been evaluated. METHODS: We measured enrollment plasma concentrations of 20 amino acids using high-performance liquid chromatography in 500 Ugandan children aged 18 months to 12 years, including 122 community children and 378 children with SM. The Kidney Disease: Improving Global Outcomes criteria were used to define acute kidney injury (AKI) at enrollment and chronic kidney disease (CKD) at 1-year follow-up. Cognition was assessed over 2 years of follow-up. RESULTS: Compared to laboratory-defined, age-specific reference ranges, there were deficiencies in sulfur-containing amino acids (methionine, cysteine) in both community children and children with SM. Among children with SM, global changes in amino acid concentrations were observed in the context of metabolic complications including acidosis and AKI. Increases in threonine, leucine, and valine were associated with in-hospital mortality, while increases in methionine, tyrosine, lysine, and phenylalanine were associated with postdischarge mortality and CKD. Increases in glycine and asparagine were associated with worse attention in children <5 years of age. CONCLUSIONS: Among children with SM, unique amino acid profiles are associated with mortality, CKD, and worse attention.

Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia.

Importance: Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. Objective: To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. Design, Setting, and Participants: This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. Exposure: CM or SMA. Main Outcomes and Measures: Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. Results: A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (ß = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (ß = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (ß = -1.39; 95% CI, -2.18 to -0.60; P = .001). Conclusions and Relevance: In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.

Decreased parasite burden and altered host response in children with sickle cell anemia and severe anemia with malaria.

Plasmodium falciparum malaria causes morbidity and mortality in African children with sickle cell anemia (SCA), but comparisons of host responses to P falciparum between children with SCA (homozygous sickle cell disease/hemoglobin SS [HbSS]) and normal hemoglobin genotype/hemoglobin AA (HbAA) are limited. We assessed parasite biomass and plasma markers of inflammation and endothelial activation in children with HbAA (n = 208) or HbSS (n = 22) who presented with severe anemia and P falciparum parasitemia to Mulago Hospital in Kampala, Uganda. Genotyping was performed at study completion. No child had known SCA at enrollment. Children with HbSS did not differ from children with HbAA in peripheral parasite density, but had significantly lower sequestered parasite biomass. Children with HbSS had greater leukocytosis but significantly lower concentrations of several plasma inflammatory cytokines, including tumor necrosis factor α (TNF-α). In contrast, children with HbSS had threefold greater concentrations of angiopoietin-2 (Angpt-2), a marker of endothelial dysregulation associated with mortality in severe malaria. Lower TNF-α concentrations were associated with increased risk of postdischarge mortality or readmission, whereas higher Angpt-2 concentrations were associated with increased risk of recurrent clinical malaria. Children with SCA have decreased parasite sequestration and inflammation but increased endothelial dysregulation during severe anemia with P falciparum parasitemia, which may ameliorate acute infectious complications but predispose to harmful long-term sequelae.

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

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, ß -0.42, 95% CI, -0.69 to -0.15, p = 0.002; children ≥ 5, ß -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.