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

David M. Smadja1,2 · Coralie L. Guerin1,3 · Richard Chocron4,5 et al…

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 COVID-19 · Angiogenesis · Endothelial · Biomarker · E-selectin · Angiopoietin-2

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