Abstract
AbstractThis study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.
Highlights
Pneumonia associated with SARS-CoV-2 is a life-threatening condition characterized by diffuse alveolar damage, with the formation of hyaline membranes and interstitial thickening
These aspects are shared with acute respiratory distress syndrome (ARDS), a highly fatal condition that is associated in many cases with severe virus- and sepsis-associated pneumonia
3-day angiopoietin-2 course and older age (HR, 2.991; 95% CI, 1.052-8.500; P 5 .040) were independent risk factors for in-hospital mortality by multivariate analysis
Summary
Pneumonia associated with SARS-CoV-2 is a life-threatening condition characterized by diffuse alveolar damage, with the formation of hyaline membranes and interstitial thickening. Histologic autopsy data from the severe acute respiratory syndrome epidemic in 2003 showed varying degrees of exudative- and proliferative-phase acute lung injury, as indicated by the presence of edema, inflammatory infiltrates, pneumocyte hyperplasia, and fibrinous exudates. Apart from the expected pathologic findings, the authors reported severe endothelial injury associated with the intracellular presence of the virus, with intravascular fibrin deposition, edema, and red blood cell extravasation in areas of diffuse acute alveolar damage.[2] These aspects are shared with acute respiratory distress syndrome (ARDS), a highly fatal condition that is associated in many cases with severe virus- and sepsis-associated pneumonia
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