Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature

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  • Jorge A Masso-Silva
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Alexander Moshensky
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Michael T Y Lam
    Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
  • Mazen F Odish
    Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
  • Arjun Patel
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Le Xu
    Department of Pediatrics, University of California, San Diego , La Jolla, California, USA
  • Emily Hansen
    Rady Children’s Hospital, San Diego, California, USA
  • Samantha Trescott
    Rady Children’s Hospital, San Diego, California, USA
  • Celina Nguyen
    Rady Children’s Hospital, San Diego, California, USA
  • Roy Kim
    Rady Children’s Hospital, San Diego, California, USA
  • Katherine Perofsky
    Rady Children’s Hospital, San Diego, California, USA
  • Samantha Perera
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Lauren Ma
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Josephine Pham
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Mark Rolfsen
    Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
  • Jarod Olay
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • John Shin
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Jennifer M Dan
    Division of Infectious Diseases and Global Public Heath, Department of Medicine, University of California, San Diego , La Jolla, California, USA
  • Robert K Abbott
    Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla , CA 92037, USA
  • Sydney Ramirez
    Division of Infectious Diseases and Global Public Heath, Department of Medicine, University of California, San Diego , La Jolla, California, USA
  • Thomas H Alexander
    Division of Head and Neck Surgery, Scripps Clinic , La Jolla, California, USA
  • Grace Y Lin
    Department of Pathology, University of California, San Diego , La Jolla, California, USA
  • Ana Lucia Fuentes
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Ira Advani
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Deepti Gunge
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
  • Victor Pretorius
    Division of Cardiovascular and Thoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California, USA
  • Atul Malhotra
    Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
  • Xin Sun
    Department of Pediatrics, University of California, San Diego , La Jolla, California, USA
  • Jason Duran
    Division of Cardiology, Department of Medicine, University of California, San Diego , La Jolla, California, USA
  • Mark Hepokoski
    Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA
  • Shane Crotty
    Division of Infectious Diseases and Global Public Heath, Department of Medicine, University of California, San Diego , La Jolla, California, USA
  • Nicole G Coufal
    Rady Children’s Hospital, San Diego, California, USA
  • Angela Meier
    Department of Anesthesiology, Division of Critical Care, University of California, San Diego , La Jolla, California, USA
  • Laura E Crotty Alexander
    Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA

説明

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1β, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P &lt; .0001). COVID-19 neutrophils had exaggerated oxidative burst (P &lt; .0001), NETosis (P &lt; .0001), and phagocytosis (P &lt; .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.</jats:p> </jats:sec>

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