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

Savino Spadaro, Alberto Fogagnolo, Gianluca Campo, Ottavio Zucchetti, Marco Verri, Irene Ottaviani, Tanushree Tunstall, Salvatore Grasso, Valentina Scaramuzzo, Francesco Murgolo, Elisabetta Marangoni, Francesco Vieceli Dalla Sega, Francesca Fortini, Rita Pavasini, Paola Rizzo, Roberto Ferrari, Alberto Papi, Carlo Alberto Volta, Marco Contoli, Savino Spadaro, Alberto Fogagnolo, Gianluca Campo, Ottavio Zucchetti, Marco Verri, Irene Ottaviani, Tanushree Tunstall, Salvatore Grasso, Valentina Scaramuzzo, Francesco Murgolo, Elisabetta Marangoni, Francesco Vieceli Dalla Sega, Francesca Fortini, Rita Pavasini, Paola Rizzo, Roberto Ferrari, Alberto Papi, Carlo Alberto Volta, Marco Contoli

Abstract

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.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Box-and-whisker plot for comparison of the biomarkers in survivors (n = 20) and non-survivors COVID-19 (n = 11) patients at the inclusion of the study
Fig. 2
Fig. 2
Density distribution of six mediators; RAGE, ANG-2, ICAM-1, VCAM-1, P-Selectin, E-Selectin measured in serum samples collected at timepoint 1. The distribution is colored according to patient outcome, where red relates to patients who died, while blue denotes patients who recovered (survivors, n = 20). The horizontal axis represents the Log10 levels of mediators measured in pg/mL for RAGE and ANG-2 and in ng/mL for ICAM-1, VCAM-1, P-Selectin and E-Selectin. The vertical axis corresponds to the respective mediators. Figure generated using R statistical software, version 4.0.2

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