Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients
By
Jorge A. Masso-Silva,
Alexander Moshensky,
Michael T. Y. Lam,
Mazen Odish,
Arjun Patel,
Le Xu,
Emily Hansen,
Samantha Trescott,
Celina Nguyen,
Roy Kim,
Katherine Perofsky,
Samantha Perera,
Lauren Ma,
Josephine Pham,
Mark Rolfsen,
Jarod Olay,
John Shin,
Jennifer M Dan,
Robert Abbott,
Sydney Ramirez,
Thomas H. Alexander,
Grace Y Lin,
Ana Lucia Fuentes,
Ira N. Advani,
Deepti Gunge,
Victor Pretorius,
Atul Malhotra,
Xin Sun,
Jason Duran,
Shane Crotty,
Nicole G Coufal,
Angela Meier,
Laura E Crotty-Alexander
Posted 15 Jan 2021
medRxiv DOI: 10.1101/2021.01.14.21249831
Background: Increased 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. Methods: Blood 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. Results: Elevations 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. Conclusions: Circulating 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.
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