ABSTRACT
Introduction: COVID-19 p atients o ften d evelop s ystemic i nflammation and hypercoagulability, leading to an increased thromboembolism risk and a poor evolution. The D-dimer level at the time of hospitalization predicts the risk of acute respiratory distress syndrome development, intensive care admission and death. Identifying additional biomarkers to assist physicians in risk stratification and decision-making processes is of upmost importance. Growth arrest-specific gene 6 (GAS6) is a vitamin K-dependent protein that plays a role in thrombosis, hemostasis, and inflammation and is a ligand for tyrosine kinase receptors AXL, MERTK & TYRO3 (TAM). AXL h as b een suggested to be a novel host receptor that promotes SARS-CoV-2 entry into human cells (Cell Research 2021, 31:126-140). Our goal was to determine if GAS6 and TAM receptors plasma level may be used as biomarker of disease severity in patients with COVID-19 and to assess if there is a correlation between GAS6 and D-dimer levels. Method(s): We enrolled a prospective observational single-center s tudy i ncluding 1 10 a dult p atients w ith P CR-confirmed SARS-CoV-2 infection from whom blood was collected at prespecified time points. Plasma concentrations of GAS6 and TAM receptors were determined by ELISA. Furthermore, coagulation parameters were measured in plasma. Result(s): The patient cohort was scored using the WHO Ordinal Scale for Clinical Improvement 2020 and divided into "mild COVID-19" (<=4) and "severe COVID-19" (>=5). Our data showed that plasma Gas6 level significantly increases with the severity of the COVID-19 disease (mild COVID-19: 10.72 +/- 1.33 ng/ml vs severe COVID-19: 18.70 +/- 1.05 ng/ml). Furthermore, we detected a significant increase in sAXL (mild COVID-19: 17.80 +/- 1.85 n g/ml v s s evere C OVID-19: 26.14 +/- 3.81 ng/ml) and sMERTK (mild COVID-19: 6.42 +/- 0.8 ng/ml vs severe COVID-19: 8.55 +/- 0.53 ng/ml) as well as an increase of sTyro3 by trend (mild COVID-19: 1.55 +/- 0.25 ng/ml vs severe COVID-19: 2.13 +/- 0.35 ng/ml) (Figure 1B). There was a positive correlation between increasing Gas6 levels and higher sAXL and sTYRO3 levels (Figure 1B). The WHO Ordinal Scale for Clinical Improvement 2020 positive correlated with sMERTK and D-Dimer levels. Conclusion(s): Gas6, sAXL, sMERTK, sTYRO3 might constitute valid biomarkers to help the clinician to tailor therapy in the assessment of COVID-19 severity in individual patients. (Figure Presented).
ABSTRACT
Background: B-cell depleting therapies increase COVID19 morbidity and mortality. For this specific population, evidencebased vaccination strategies are lacking. Here, we investigated humoral and cell mediated immune responses to SARS-CoV2 mRNA-based vaccines in patients receiving CD20-B-cell depleting agents for autoimmune disease, malignancy, or transplantation. Methods: Patients at the Bern University Hospital with a treatment history of anti-CD20 depleting agents (rituximab or ocrelizumab) were enrolled for analysis of humoral and cell-mediated immune responses (by IFN-g release assay) after completing vaccination against SARS-CoV2. Primary outcome was the the anti-spike antibody response in anti-CD20-treated patients (n = 96) in comparison to immunocompetent controls (n = 29). Results: Anti-spike IgG antibodies were detected in 49% of patients 1.79 months after the second vaccine dose (interquartile range, IQR: 1.16-2.48) compared to 100% of controls (p <0.001). SARS-CoV2 specific interferon-γ release was detected in 20% of patients and 75% of healthy controls (p <0.001). Only 11% of patients, but 75%of healthy controls showed positive reactions in both assays, respectively (p <0.001). Time since last anti-CD20 therapy (7.6 months), peripheral CD19+ (>27/μl), and CD4+ lymphocyte count (>653/μl) predicted humoral vaccine response (area under the curve [AUC]: 67% [CI 56-78], 67% [CI 55-80] and 66% [CI 54-79], (positive predictive value [PPV]: 0.78, 0.7 and 0.71). Conclusions: This study provides evidence for blunted humoral and cell-mediated immune responses elicited by SARS-CoV2 mRNA vaccines in patients with CD20-depleting treatment history. Lymphocyte subpopu-lation counts including CD4+ T helper cell counts are associated with vaccine response in this highly vulnerable population.