• Ignacio Melero, María Villalba-Esparza, Borja Recalde-Zamacona, Daniel Jiménez-Sánchez, Álvaro Teijeira, Alan Argueta, Laura García-Tobar, Laura Álvarez-Gigli, Cristina Sainz, David Garcia-Ros, Estefanía Toledo, Marta Abengozar-Muela, Mirian Fernández-Alonso, Mariano Rodríguez-Mateos, Gabriel Reina, Francisco Carmona-Torre, Jorge Augusto Quiroga, Jose L Del Pozo, Amy Cross, Álvaro López-Janeiro, David Hardisson, José I Echeveste, Maria D Lozano, Ling-Pei Ho, Paul Klenerman, Fadi Issa, Manuel F Landecho, and Carlos E de Andrea.
• Division of Immunology and Immunotherapy, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Navarra Institute for Health Research, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
• Chest. 2022 Nov 1; 162 (5): 100610161006-1016.

BackgroundExcessive inflammation is pathogenic in the pneumonitis associated with severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defense mechanism against bacteria, but have also been shown to mediate tissue damage in a number of diseases.Research QuestionCould NETs and their tissue-damaging properties inherent to neutrophil-associated functions play a role in the respiratory failure seen in patients with severe COVID-19, and how does this relate to the SARS-CoV-2 viral loads, IL-8 (CXCL8) chemokine expression, and cytotoxic T-lymphocyte infiltrates?Study Design And MethodsSixteen lung biopsy samples obtained immediately after death were analyzed methodically as exploratory and validation cohorts. NETs were analyzed quantitatively by multiplexed immunofluorescence and were correlated with local levels of IL-8 messenger RNA (mRNA) and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by reverse-transcriptase polymerase chain reaction and immunohistochemistry analysis.ResultsNETs were found in the lung interstitium and surrounding the bronchiolar epithelium with interindividual and spatial heterogeneity. NET density did not correlate with SARS-CoV-2 tissue viral load. NETs were associated with local IL-8 mRNA levels. NETs were also detected in pulmonary thrombi and in only one of eight liver tissues. NET focal presence correlated negatively with CD8+ T-cell infiltration in the lungs.InterpretationAbundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, but no correlation was found with viral loads. The strong association between NETs and IL-8 points to this chemokine as a potentially causative factor. The function of cytotoxic T-lymphocytes in the immune responses against SARS-CoV-2 may be interfered with by the presence of NETs.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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