Resolvin E1-Chemerin receptor 1 axis is dysregulated in critical COVID-19 patients

Resolvin E1 (RvE1) and Resolvin D1 (RvD1) are key resolvins implicated in inflammation resolution of respiratory and infectious diseases. In contrast to cytokines, they have been scarcely explored in COVID-19 and their ability for discriminating COVID-19 severity and patient outcomes has not been compared with that of cytokines. Therefore, among a panel comprising cytokines (interleukin (IL)-1beta, IL-6, IL-10, tumor necrosis factor alpha, interferon gamma and granulocyte-macrophage colony-stimulating factor), RvD1 and RvE1 and their respective receptors (FPR2, Chemerin₁), we evaluated which mediators better distinguished COVID-19 severity, the need of mechanical ventilation and patient mortality. Blood was collected from 61 patients with "severe" (n = 27), "critical" (n = 17) and "critical on veno-venous extracorporeal membrane oxygenation (VV-ECMO)" (n = 17) COVID-19 at admission, days 3-4 and days 5-8, and from controls (n = 23) at a single time point. We measured cytokines by multiplex immunoassays, resolvins by enzyme-linked immunosorbent assays, and FPR2 and Chemerin₁ mRNA by real-time quantitative polymerase chain reaction. We obtained principal component analysis (PCA)/partial least squares discriminant analysis (PLS-DA) models significantly differentiating (P < 0.001): controls from each patient group; "severe" from all critical patients; patients without or with mechanical ventilation, and survivors from non-survivors. RvE1 consistently showed a variable importance in projection (VIP) score > 2.5 and a p(corr) >0.8, being the most relevant discriminating variable. Univariate and repeated measures multivariate analyses showed higher RvE1 in "critical on VV-ECMO", mechanically ventilated patients and non-survivors, while Chemerin₁ exhibited an opposite profile. RvE1 positively correlated with inflammation and partial pressure of CO₂, whereas Chemerin₁ correlated with lower inflammation, better respiratory function and lower hospital length of stay. We conclude that RvE1 was the mediator best distinguishing COVID-19 severity and that RvE1-Chemerin₁ axis is dysregulated in this disease.