ABSTRACT
BackgroundIncreased inflammation is a hallmark of COVID-19, with pulmonary and systemic inflammation identified in multiple cohorts of patients. Definitive cellular and molecular pathways driving severe forms of this disease remain uncertain. Neutrophils, the most numerous leukocytes in blood circulation, can contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in multiple neutrophil functions and circulating cytokine levels over time during COVID-19 may help define disease severity and guide care and decision making. MethodsBlood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil oxidative burst, neutrophil extracellular trap formation (NETosis), phagocytosis and cytokine levels were assessed ex vivo. Lung tissue was obtained immediately post-mortem for immunostaining. ResultsElevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified in COVID-19 plasma both at the first measurement and at multiple timepoints across hospitalization (p < 0.0001). Neutrophils had exaggerated oxidative burst (p < 0.0001), NETosis (p < 0.0001) and phagocytosis (p < 0.0001) relative to controls. Increased NETosis correlated with both leukocytosis and neutrophilia. Neutrophils and NETs were identified within airways and alveoli in the lung parenchyma of 40% of SARS-CoV-2 infected lungs. While elevations in IL-8 and ANC correlated to COVID-19 disease severity, plasma IL-8 levels alone correlated with death. ConclusionsCirculating neutrophils in COVID-19 exhibit an activated phenotype with increased oxidative burst, NETosis and phagocytosis. Readily accessible and dynamic, plasma IL-8 and circulating neutrophil function may be potential COVID-19 disease biomarkers.
ABSTRACT
OBJECTIVE: To determine whether circulating levels of osteopontin (OPN), osteoprotegerin (OPG), total soluble receptor activator of nuclear factor-kappa B ligand (total sRANKL), and high-sensitivity C-reactive protein (hsCRP) change in patients with rheumatoid arthritis (RA) during immunosuppressive therapy. METHODS: Twenty-five active RA patients were randomized to treatment with either etanercept alone or in combination with methotrexate (MTX). The treatment response after 16 weeks was assessed using the European League Against Rheumatism (EULAR) response criteria. Blood samples were taken before the start of and every fourth week during the study. OPN, OPG, and total sRANKL were measured by enzyme-linked immunosorbent assays (ELISAs) and hsCRP by highly sensitive turbidometry. RESULTS: At baseline, OPN and hsCRP were significantly (p<0.001) elevated compared to healthy persons. Compared to baseline only hsCRP levels decreased significantly (p<0.05 to p<0.001) in the EULAR responders through the study. OPN remained significantly (p<0.05) elevated at 16 weeks in patients with a low disease activity score (DAS< or =3.2). Total sRANKL increased significantly (p<0.05) from baseline to week 12. No statistically significant changes were observed in the non-responders. CONCLUSION: Active RA patients showed increased circulating levels of hsCRP and OPN, but only hsCRP decreased during etanercept therapy. Our findings suggest that OPN, OPG, total sRANKL, and hsCRP reflect different aspects of the inflammatory process in RA.
