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Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.

  • Author(s): Masso-Silva, Jorge A
  • Moshensky, Alexander
  • Lam, Michael TY
  • Odish, Mazen
  • Patel, Arjun
  • Xu, Le
  • Hansen, Emily
  • Trescott, Samantha
  • Nguyen, Celina
  • Kim, Roy
  • Perofsky, Katherine
  • Perera, Samantha
  • Ma, Lauren
  • Pham, Josephine
  • Rolfsen, Mark
  • Olay, Jarod
  • Shin, John
  • Dan, Jennifer M
  • Abbott, Robert
  • Ramirez, Sydney
  • Alexander, Thomas H
  • Lin, Grace Y
  • Fuentes, Ana Lucia
  • Advani, Ira
  • Gunge, Deepti
  • Pretorius, Victor
  • Malhotra, Atul
  • Sun, Xin
  • Duran, Jason
  • Hepokoski, Mark
  • Crotty, Shane
  • Coufal, Nicole G
  • Meier, Angela
  • Alexander, Laura E Crotty
  • et al.


Increased inflammation has been well defined in 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 (ARDS), 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.


Blood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.


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 both at first measurement and across hospitalization (p<0.0001). COVID neutrophils had exaggerated oxidative burst (p<0.0001), NETosis (p<0.0001) and phagocytosis (p<0.0001) 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 SARS-CoV-2 infected lungs available for examination (2 out of 5). While elevations in IL-8 and ANC correlated with disease severity, plasma IL-8 levels alone correlated with death.


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 shows that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

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