| dc.description.abstract | Background. Endothelial activation is involved in pathophysiology of severe malaria leading to blood-brain-barrier dysfunction (BBB), which could occur in the absence of neurologic signs, or may be associated with long-term neurocognitive impairment in children. Endothelial activation may also lead to parasite sequestration in the microvasculature leads to vascular congestion, tissue hypoxia and local inflammatory responses resulting in increased Angiopoietin-2 (Angpt-2) expression, and BBB dysfunction in cerebral malaria (CM) and other forms of severe malaria without neurological involvement such as severe malaria anaemia (SMA). Also, systemic tumour necrosis factor-α (TNF-α) may contribute to the pathogenesis of CM by promoting endothelial activation and parasite sequestration. APOE4, has been associated with worse cognition after traumatic brain injury, but better cognition after diarrheal disease. The relationship of APOE4 to mortality and cognition after severe malaria is not well understood.
Objective. The study’s main aim was to identify immunological and genetic risk factors associated with cognitive and neurological impairments in severe malaria in Ugandan children.
Methods. This prospective study was conducted at Mulago Hospital, Kampala, Uganda. Children ages 1.5 –12 years old were enrolled in the study from 2008–2015 to assess neurocognitive outcomes over 2 years of follow-up. CM was defined as coma (Blantyre Coma Score [BCS] ≤2 or Glasgow Coma Score [GCS] ≤8), Plasmodium falciparum on blood smear, and no other known cause of coma. SMA was defined as P. falciparum on blood smear and haemoglobin ≤5 g/dL. Children were managed according to the Ugandan Ministry of Health treatment guidelines at the time of the study. A reference group of age-matched community children (CC) with no active illness was recruited from the extended family or household compound of children with CM or SMA. Children underwent a medical history and physical examination at enrollment. Anthropometric z-scores were generated using age-appropriate WHO reference standards. Socioeconomic status (SES) was measured using a validated scoring system previously published. We evaluated the relationships between endothelial activation markers and using ELISAs, Luminex assay, APOE polymorphism RFLP PCR, malaria identifications were performed by microscopy, and neurocognitive tools calibrated for children between 1.5 years to 12 years old. Adjustment for multiple comparisons was conducted using the Benjamini-Hochberg Procedure of False Discovery Rate.
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Results. Children underwent neurocognitive evaluation at enrollment (CC) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed on admission samples. False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared to CC (p<0.0001 for all markers). Acute kidney injury (AKI) was independently associated with changes in VWF, sICAM-1, sE-Selectin, P-selectin, Angpt-2 (p<0.0001 for all). A log10 increase in Angpt-2 was associated with lower cognitive z scores across age groups (children <5, β -0.42, 95% CI, -0.69, -0.15, p=0.002; children ≥5, β -0.39, 95% CI, -0.67, -0.11, p=0.007) independent of disease severity (coma, number of seizures, AKI), and sociodemographic factors. In children with CM who had a lumbar puncture performed, Angpt-2 was associated with blood-brain-barrier dysfunction, and markers of neuro-inflammation and injury in the cerebrospinal fluid (TNFα, kynurenic acid, Tau. A greater proportion of children with CM or SMA were APOE4+ than CC (31%, 32%, and 24% respectively, P=0.02). APOE4+ children with CM had increased mortality (odds ratio, 2.28; 95% CI, 1.01, 5.11). However, APOE4 was associated with better long-term overall cognition in children <5 years old at baseline and in follow-up (β, 0.55; 95% CI, 0.04, 1.07, P=0.04); and better attention in children <5 years old at baseline but ≥5 years in follow-up (β 0.78; 95% CI, 0.26, 1.30, P=0.004). In contrast, APOE4+ was associated with worse attention in children ≥5 years old at CM episode (β, -0.90; 95% CI, –1.69, –0.10, P=0.03).
Conclusion. Overall, we found that elevated endothelial activation markers are associated with severe malaria, disease severity, and cognition over 2 years follow-up in Ugandan children. We found out that: Angpt-2 is a measure of disease severity and a risk factor for worse long-term cognition in children with severe malaria; Elevated admission Angpt-2 concentration in children with severe malaria is associated with worse outcomes in multiple neurocognitive domains. The relationship between Angpt-2 and worse cognition is evident in children < 5 years of age when affected by severe malaria and in selected domains in older years.; CSF TNF-α, but not plasma TNF-α correlated with key clinical outcomes in children with CM that include coma duration, acute and long-term neurologic deficits, and long-term cognitive impairment; and in children <5 years old, APOE4 is associated with higher risk of greater mortality in children with CM, but better long-term cognition in CM survivors. | en_US |
