Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COV
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ORIGINAL PAPER
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 · Nader Yatim6,7 · Jeremy Boussier6,7 · Nicolas Gendron1,2 · Lina Khider8 · Jérôme Hadjadj7,9 · Guillaume Goudot8 · Benjamin Debuc10 · Philippe Juvin11 · Caroline Hauw‑Berlemont12 · Jean‑Loup Augy12 · Nicolas Peron12 · Emmanuel Messas4,13 · Benjamin Planquette1,14 · Olivier Sanchez1,14 · Bruno Charbit15 · Pascale Gaussem1,16 · Darragh Duffy6,7 · Benjamin Terrier17,18 · Tristan Mirault4,13 · Jean‑Luc Diehl1,19 Received: 4 May 2020 / Accepted: 21 May 2020 © Springer Nature B.V. 2020
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
Introduction SARS-CoV-2 infection can be paucisymptomatic or lead to the coronavirus disease-2019 (COVID-19), which has a very large pattern of disease severity, in particular in patients with cardiovascular comorbidities [1]. COVID-19 infection is associated with a coagulopathy characterized by an increase in procoagulant factors such as fibrinogen, together with a strong elevation of D-dimers that have been associated * David M. Smad
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