Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality

Angiopoietin-2 (Ang-2) is a key mediator of pulmonary vascular permeability. This study tested the association between plasma Ang-2 and mortality in pediatric acute respiratory distress syndrome (ARDS), with stratification for prior hematopoietic cellular transplantation (HCT), given the severe, yet poorly understood, ARDS phenotype of this subgroup. We enrolled 259 children <18 years of age with ARDS; 25 had prior HCT. Plasma Ang-2, von Willebrand Factor antigen (vWF), and vascular endothelial growth factor (VEGF) were measured on ARDS days 1 and 3 and correlated with patient outcomes. Day 1 and day 3 Ang-2 levels were associated with mortality independent of age, sex, race, and P/F ratio [odds ratio (OR) 3.7, 95% CI 1.1-11.5, P = 0.027; and OR 10.2, 95% confidence interval (CI) 2.2-46.5, P = 0.003, for each log(10) increase in Ang-2]. vWF was associated with mortality (P = 0.027), but VEGF was not. The association between day 1 Ang-2 and mortality was independent of levels of both vWF and VEGF (OR 3.6, 95% CI 1.1-12.1, P = 0.039, for each log10 increase in Ang-2). 45% of the cohort had a rising Ang-2 between ARDS day 1 and 3 (adjusted mortality OR 3.3, 95% CI 1.2-9.2, P = 0.026). HCT patients with a rising Ang-2 had 70% mortality compared with 13% mortality for those without (OR 16.3, 95% CI 1.3-197.8, P = 0.028). Elevated plasma levels of Ang-2 were associated with mortality independent of vWF and VEGF. A rising Ang-2 between days 1 and 3 was strongly associated with mortality, particularly in pediatric HCT patients, suggesting vulnerability to ongoing endothelial damage.