Plasma Soluble Intercellular Adhesion Molecule-1 Has a Central Role in Biomarker Network Analysis and Is Associated With Poor Outcomes in Two Distinct Pediatric Cohorts of Acute Respiratory Distress Syndrome and Acute Respiratory Failure

Abstract

Objectives: Intercellular adhesion molecule-1 (ICAM-1) is a glycoprotein expressed on immune, endothelial, and epithelial cells. In the setting of inflammation, it becomes upregulated and spliced into a soluble form (soluble ICAM-1 [sICAM-1]). This study examined the association of sICAM-1 with clinical outcomes in two large pediatric cohorts with acute respiratory distress syndrome (ARDS) and acute respiratory failure (ARF) and examined the relationships between sICAM-1 and other protein biomarkers utilizing network analysis to contextualize its role in ARDS pathophysiology.

Design: Secondary analysis of prospective cohort studies.

Setting: Multicenter PICUs.

Patients or subjects: Critically ill children with ARDS (Pediatric Acute Lung Injury [PALI], 2008-2014) and ARF (Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial [CAF-PINT], 2012-2016).

Interventions: None.

Measurements and main results: sICAM-1 levels were measured from plasma collected within 72 hours of diagnosis. The primary outcome was in-hospital mortality, and secondary outcomes included multiple organ dysfunction and ventilator-free days. We constructed a biomarker correlation-based network that included sICAM-1 and 32 plasma biomarkers reflective of inflammation, endothelial and epithelial injury, and extracellular matrix degradation. Key biomarkers with centrality metrics in the top 10% (≥ 90th percentile) were defined as critical hubs within the network. The study included 214 children from PALI and 251 from CAF-PINT. In-hospital mortality was 18% and 14%, respectively. Baseline median oxygenation index ratios were 10 (interquartile range [IQR], 5.6-19.7) and 8.5 (IQR, 3.5-17.7). Higher plasma sICAM-1 was associated with in-hospital mortality, multiple organ dysfunction, and fewer ventilator-free days in each of the two cohorts (all p < 0.05). Tissue inhibitor of metalloproteinase-1 (composite centrality, 0.99), tumor necrosis factor receptor-1 (0.83), sICAM-1 (0.74), and interleukin-8 (0.74) were identified as network hubs.

Conclusions: Elevated sICAM-1 levels were associated with poor outcomes in two separate cohorts of ARDS and ARF patients. Network analysis revealed sICAM-1 as a central hub, characterized by high centrality metrics. These findings underscore the multifaceted role of sICAM-1 in leukocyte transmigration, inflammation, and endothelial dysfunction and highlight its critical role in ARDS pathophysiology.

Keywords: acute respiratory distress syndrome; acute respiratory failure; inflammation; network analysis; pediatric acute respiratory distress syndrome; soluble intercellular adhesion molecule.

Figure 1.

Correlation heat map of 33 biomarkers in Pediatric Acute Lung Injury cohort. Ang-2 = angiopoietin-2, A1AT = α-1 antitrypsin, A2MB = α-2 macroglobulin, BDNF = brain-derived neurotrophic factor, B2MB = β-2 microglobulin, C3 = complement component 3, CRP = C-reactive protein, etoxan = eosinophil chemotactic protein, EPCR = endothelial protein C-receptor, fibrino = fibrinogen, MCP = monocyte chemotactic protein, IL-6 = interleukin-6, IL-8 = interleukin-8, IL-10 = interleukin-10, IL-18 = interleukin-18, MIP-1 β = macrophage inflammatory protein-1β, MMP-9 = matrix metalloproteinases-9, MMP-3 = matrix metalloproteinases-3, RAGE = soluble receptor of advanced glycation end-products, SCF = stem cell factor, sICAM = soluble intercellular adhesion molecule-1, SPD = surfactant protein-D, TIMP-1 = tissue inhibitor of metalloproteinase-1, TM = thrombomodulin, TNFR-1 = tumor necrosis factor receptor-1, TSP = T-cell specific protein, VCAM-1 = vascular cell adhesion molecule-1, VDBP = vitamin-D protein, VEGF = vascular endothelial growth factor, vWF = von Willebrand factor.

Figure 2.

Force-directed graph: The biomarker correlation network was visualized using Cytoscape (33). Edges (i.e., correlations) are weighted based on the absolute value of the Spearman coefficient between connected nodes (i.e., biomarkers), with edge color indicating a positive (black) or negative (red dotted) correlation. Node color represents communities identified using the fast-greedy algorithm, weighted by the absolute value of the Spearman coefficient. Node size reflects the composite centrality metric. The layout was determined using the prefuse force-directed algorithm, based on the normalized value of edge weights. Soluble intercellular adhesion molecule-1 (sICAM-1) is highlighted with a bold edge. Ang-2 = angiopoietin-2, A1AT = α-1 antitrypsin, A2MB = α-2 macroglobulin, BDNF = brain-derived neurotrophic factor, B2MB = β-2 microglobulin, CRP = c-reactive protein, C3 = complement component 3, etoxan = eosinophil chemotactic protein, EPCR = endothelial protein C-receptor, IL-6 = interleukin-6, IL-8 = interleukin-8, IL-10 = interleukin-10, IL-18 = interleukin-18, RAGE = soluble receptor of advanced glycation end-products, MCP = monocyte chemotactic protein, MIP-1β = macrophage inflammatory protein-1β, MMP-3 = matrix metalloproteinases-3, MMP-9 = matrix metalloproteinases-9, SCF = stem cell factor, SPD = surfactant protein-D, TIMP-1 = tissue inhibitor of metalloproteinase-1, TM = thrombomodulin, TNFR-1 = tumor necrosis factor receptor-1, TSP = T-cell specific protein, VCAM-1 = vascular cell adhesion molecule-1, VEGF = vascular endothelial growth factor, vWF = von Willebrand factor.