Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria

Abstract

Objective To investigate the relationship between the angiopoietin-Tie-2 system, retinopathy and mortality in children with cerebral malaria (CM). Design Case-control study of retinopathy positive versus retinopathy negative children with clinically defined CM. Setting Queen Elizabeth Central Hospital in Blantyre, Malawi. Subjects 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. Measurements 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. Main results 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. Conclusions 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.

miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

“…There are limitations to this study. Although the Ang-1 plasma levels are consistent with other murine and human studies of cerebral malaria, the Ang-2 plasma levels are higher than in human studies (22,45,58), The Ang-2 ELISA is a new (but validated) assay, and there are less published data; however, the levels observed in our uninfected mice are in agreement with the manufacturer's expected ranges for plasma, and our group consistently obtained the same range of plasma Ang-2 levels. Although suppress the IFN-γ receptor (51).…”

Association of angiopoietin-2 and Ki-67 expression with vascular density and sunitinib response in metastatic renal cell carcinoma

“…Alternatively, Ang2 expressed by metastatic nodules, or by the host vasculature as a more general response to disease, might contribute to the determined serum Ang2. Indeed, elevated circulating Ang2 levels have been reported to predict for poor prognosis in numerous noncancerous diseases, such as sepsis and malaria [16,[42][43][44]. In these diseases, the activated endothelial cells of the normal vessels likely secrete Ang2 [45].…”

Pediatric Cerebral Malaria: A Scourge of Africa

“…Specific markers of endothelial cell activation, such as Ang-2, have been associated with poor outcome [80]. Production of nitric oxide by endothelial cells has multiple effects, including vasorelaxation, inhibition of platelet aggregation and downregulation of endothelial adhesion molecules, all of which could lead to protection against CM.…”