To investigate the relationship between the angiopoietin-Tie-2 system, retinopathy and mortality in children with cerebral malaria (CM).
Case-control study of retinopathy positive versus retinopathy negative children with clinically defined CM.
Queen Elizabeth Central Hospital in Blantyre, Malawi.
155 children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ≤2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study.
Clinical and laboratory parameters were recorded at admission and fundoscopic exams were performed. Admission levels of angiopoietin-1, angiopoietin-2 and a soluble version of their cognate receptor (sTie-2) were measured by ELISA.
We show that angiopoietin-1 levels are decreased and angiopoietin-2 and sTie-2 levels are increased in children with CM who had retinopathy compared to those who did not. Angiopoietin-2 and sTie-2 were independent predictors of retinopathy (adjusted Odds ratio (95% CI): angiopoietin-2, 4.3 (1.3-14.6), p=0.019; sTie-2, 9.7 (2.1-45.8), p=0.004). Angiopoietin-2 and sTie-2 were positively correlated with the number of hemorrhages, the severity of retinal whitening and the extent of capillary whitening observed on fundoscopic exam (p<0.05 following adjustment for multiple comparisons). Angiopoietin-2 and sTie-2 levels were elevated in children with CM who subsequently died and Angiopoetin-2 was an independent predictor of death (adjusted Odds ratio: 3.9 (1.2-12.7), p=0.024). When combined with clinical parameters, Angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees.
These results provide insights into mechanisms of endothelial activation in CM and indicate that the angiopoietin-Tie-2 axis is associated with retinopathy and mortality in pediatric CM.
Keywords: cerebral malaria, retinopathy, mortality, biomarker, angiopoietin, sTie-2