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

Jorge A. Masso-Silva, Alexander Moshensky, Michael T.Y. Lam, Mazen F. 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 K. Abbott, Sydney RamirezThomas H. Alexander, Grace Y. Lin, Ana Lucia Fuentes, Ira Advani, Deepti Gunge, Victor Pretorius, Atul Malhotra, Xin Sun, Jason Duran, Mark Hepokoski, Shane Crotty, Nicole G. Coufal, Angela Meier, Laura E. Crotty Alexander

Research output: Contribution to journalReview articlepeer-review

82 Scopus citations

Abstract

Background: 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. Methods: 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. Results: 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 < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)479-489
Number of pages11
JournalClinical Infectious Diseases
Volume74
Issue number3
DOIs
StatePublished - Feb 1 2022
Externally publishedYes

Keywords

  • COVID-19
  • NETosis
  • NETs
  • neutrophil

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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