Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients

Crit Care. 2021 Feb 19;25(1):74. doi: 10.1186/s13054-021-03499-4.


Background: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS.

Methods: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.

Results: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001).

Conclusions: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.

Keywords: Acute respiratory distress syndrome; Angiopoietin-2; Biomarkers; COVID-19; Intercellular adhesion molecule-1; Receptor for advanced glycation end-products; Selectin; Vascular cell adhesion protein 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antigens, Neoplasm / analysis
  • Antigens, Neoplasm / blood
  • Area Under Curve
  • Biomarkers / analysis*
  • COVID-19 / blood
  • COVID-19 / prevention & control
  • Cohort Studies
  • E-Selectin / analysis
  • E-Selectin / blood
  • Female
  • Humans
  • Intensive Care Units / organization & administration
  • Intensive Care Units / statistics & numerical data
  • Intercellular Adhesion Molecule-1 / analysis
  • Intercellular Adhesion Molecule-1 / blood
  • Lung Injury / blood
  • Lung Injury / diagnosis*
  • Lung Injury / physiopathology
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinases / analysis
  • Mitogen-Activated Protein Kinases / blood
  • P-Selectin / analysis
  • P-Selectin / blood
  • Prospective Studies
  • ROC Curve
  • Respiration, Artificial / adverse effects*
  • Respiration, Artificial / standards
  • Respiration, Artificial / statistics & numerical data
  • Respiratory Distress Syndrome / blood
  • Respiratory Distress Syndrome / physiopathology
  • Versicans / analysis
  • Versicans / blood
  • Vesicular Transport Proteins / analysis
  • Vesicular Transport Proteins / blood


  • Antigens, Neoplasm
  • Biomarkers
  • E-Selectin
  • ICAM1 protein, human
  • P-Selectin
  • SELE protein, human
  • VCAN protein, human
  • VPS51 protein, human
  • Vesicular Transport Proteins
  • Intercellular Adhesion Molecule-1
  • Versicans
  • MOK protein, human
  • Mitogen-Activated Protein Kinases

Associated data