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

doi:10.1093/cid/ciab437

Review

. 2022 Feb 11;74(3):479-489.

doi: 10.1093/cid/ciab437.

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^{1

2}, Alexander Moshensky^{1

2}, Michael T Y Lam^{2

3}, Mazen F Odish², Arjun Patel^{1

2}, Le Xu⁴, Emily Hansen^{5

4}, Samantha Trescott^{5

4}, Celina Nguyen^{5

4}, Roy Kim^{5

4}, Katherine Perofsky^{5

4}, Samantha Perera^{1

2}, Lauren Ma^{1

2}, Josephine Pham^{1

2}, Mark Rolfsen², Jarod Olay^{1

2}, John Shin^{1

2}, Jennifer M Dan^{6

7}, Robert K Abbott^{8

9}, Sydney Ramirez^{6

7}, Thomas H Alexander¹⁰, Grace Y Lin¹¹, Ana Lucia Fuentes^{1

2}, Ira Advani^{1

2}, Deepti Gunge^{1

2}, Victor Pretorius¹², Atul Malhotra², Xin Sun⁴, Jason Duran¹³, Mark Hepokoski², Shane Crotty^{6

7}, Nicole G Coufal^{5

4}, Angela Meier¹⁴, Laura E Crotty Alexander^{1

2}

Affiliations

¹ Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA.
² Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
³ The Salk Institute, La Jolla, California, USA.
⁴ Department of Pediatrics, University of California, San Diego , La Jolla, California, USA.
⁵ Rady Children's Hospital, San Diego, California, USA.
⁶ Division of Infectious Diseases and Global Public Heath, Department of Medicine, University of California, San Diego , La Jolla, California, USA.
⁷ La Jolla Institute for Immunology, La Jolla, California, USA.
⁸ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla , CA 92037, USA.
⁹ Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla , CA 92037, USA.
¹⁰ Division of Head and Neck Surgery, Scripps Clinic , La Jolla, California, USA.
¹¹ Department of Pathology, University of California, San Diego , La Jolla, California, USA.
¹² Division of Cardiovascular and Thoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California, USA.
¹³ Division of Cardiology, Department of Medicine, University of California, San Diego , La Jolla, California, USA.
¹⁴ Department of Anesthesiology, Division of Critical Care, University of California, San Diego , La Jolla, California, USA.

PMID: 33988226
PMCID: PMC8241438
DOI: 10.1093/cid/ciab437

Review

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 et al. Clin Infect Dis. 2022.

. 2022 Feb 11;74(3):479-489.

doi: 10.1093/cid/ciab437.

Authors

Affiliations

¹ Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California, USA.
² Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
³ The Salk Institute, La Jolla, California, USA.
⁴ Department of Pediatrics, University of California, San Diego , La Jolla, California, USA.
⁵ Rady Children's Hospital, San Diego, California, USA.
⁶ Division of Infectious Diseases and Global Public Heath, Department of Medicine, University of California, San Diego , La Jolla, California, USA.
⁷ La Jolla Institute for Immunology, La Jolla, California, USA.
⁸ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla , CA 92037, USA.
⁹ Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla , CA 92037, USA.
¹⁰ Division of Head and Neck Surgery, Scripps Clinic , La Jolla, California, USA.
¹¹ Department of Pathology, University of California, San Diego , La Jolla, California, USA.
¹² Division of Cardiovascular and Thoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California, USA.
¹³ Division of Cardiology, Department of Medicine, University of California, San Diego , La Jolla, California, USA.
¹⁴ Department of Anesthesiology, Division of Critical Care, University of California, San Diego , La Jolla, California, USA.

PMID: 33988226
PMCID: PMC8241438
DOI: 10.1093/cid/ciab437

Erratum in

Correction to: Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 Patients: A Case Series and Review of the Literature.
Masso-Silva JA, Moshensky A, Lam MTY, Odish M, Patel A, Xu L, Hansen E, Trescott S, Nguyen C, Kim R, Perofsky K, Perera S, Ma L, Pham J, Rolfsen M, Olay J, Shin J, Dan JM, Abbott R, Ramirez S, Alexander TH, Lin GY, Fuentes AL, Advani I, Gunge D, Pretorius V, Malhotra A, Sun X, Duran J, Hepokoski M, Crotty S, Coufal NG, Meier A, Crotty Alexander LE. Masso-Silva JA, et al. Clin Infect Dis. 2022 May 30;74(10):1889-1890. doi: 10.1093/cid/ciac216. Clin Infect Dis. 2022. PMID: 35416961 Free PMC article. No abstract available.

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.

Keywords: COVID-19; NETosis; NETs; neutrophil.

Published by Oxford University Press for the Infectious Diseases Society of America 2021.

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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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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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