Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients

Abstract

Background: Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis.

Objectives: To explore endothelial damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening.

Methods: Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission.

Results: Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (p value at 0.009 and 0.003, respectively). Increase in SELE gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with p value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers.

Conclusion: Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.

Keywords: Angiogenesis; Angiopoietin-2; Biomarker; COVID-19; E-selectin; Endothelial.

Fig. 1

Correlations between plasma angiopoietin-2 and sE-selectin levels in COVID-19 patients. R for Kendall rank correlation coefficient

Fig. 2

E-selectin gene expression profile according to admission of patients in medical ward or ICU versus controls. ICU for intensive care unit; RNA for Ribonucleic Acid; Difference between groups evaluated with Kruskal–Wallis test

Fig. 3

Correlations between E-selectin and angiopoietin-2 and biological parameters of thrombo-inflammation. a–c correlations between sE-selectin and CRP, plasma creatinine and D-dimers. d–f: correlations between angiopoietin-2 and CRP, plasma creatinine and D-dimers. R for Kendall rank correlation coefficient

Fig. 4

ROC curve for angiopoietin-2 cut-off in direct ICU admission. Angiopoietin-2 level above 5000 pg/mL was identified using Youden index method as a potential criteria for COVID-19 transfer in ICU (AUC 77.12, 95% CI 62.4–91.9). AUC for area under the curve; CI for confidence interval; PPV for positive predictive value; NPV for negative predictive value. R for Kendall rank correlation coefficient; CRP for C-reactive protein