Systemic Endothelial Activation Is Associated With Early Acute Respiratory Distress Syndrome in Children With Extrapulmonary Sepsis

Abstract

Objectives: Systemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome.

Design: Observational cohort.

Setting: Academic PICU.

Patients: Patients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19).

Interventions: None.

Measurements and main results: Endothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course.

Conclusions: Children with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

Figure 1.

Time 1 angiopoietin (Ang)-2 and Ang-2/Ang-1 ratio by group. Data are shown as boxplots with the horizontal line of each box representing the median, the ends of the box representing the 25th and 75th percentiles, and the whiskers representing the most extreme values within 1.5 times the interquartile range. Wilcoxon rank sum test was used to compare biomarkers between groups. *Significance defined as p value less than 0.0033 given multiple comparisons between controls versus all extrapulmonary sepsis. #Significance defined as p < 0.0033 given multiple comparisons between extrapulmonary sepsis with (w/) versus without (w/o) acute respiratory distress syndrome (ARDS).

Figure 2.

Receiver operating characteristic curves for Pediatric Risk of Mortality (PRISM)-3, selected time 1 (T1) biomarkers (angiopoietin [Ang]-2, Ang-2/Ang-1 ratio, von Willebrand factor [vWF], endocan), and the combination of PRISM-3 and T1 biomarkers to predict complicated course. Among patients with sepsis and after adjustment for age, cardiac, and gastrointestinal comorbidity, the area under the receiver operating characteristic curve (AUROC) for Ang-2 was 0.80 (95% CI, 0.72–0.89), for Ang-2/Ang-1 was 0.80 (95% CI, 0.71–0.89), for vWF was 0.81 (95% CI, 0.72–0.90), and for endocan was 0.81 (95% CI, 0.72–0.89) to predict complicated course. The AUROC for PRISM-3 alone (white) and the AUROC for the combination of PRISM-3 and any biomarker (gray) were not superior for prediction of complicated course compared with any biomarker alone (black).

Figure 3.

Odds of complicated course by time 1 (T1) biomarkers, stratified by acute respiratory distress syndrome (ARDS) status. Data are presented as adjusted odds ratio (OR) with 95% CIs for the association of T1 biomarkers with complicated course, stratified by ARDS status. A p value of less than or equal to 0.10 was defined a priori to indicate a significant difference in the odds of complicated course in sepsis patients with versus without ARDS. Ang = angiopoietin, CRP = C-reactive protein, ICAM = intracellular adhesion molecule, IL = interleukin, sFLT = soluble fms-like tyrosine kinase, Tie-2 = tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, VCAM = vascular adhesion molecule, VEGF = vascular endothelial growth factor, vWF = von Willebrand factor.