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BACKGROUND: Excessive 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 QUESTION: Could NETs and their tissue-damaging properties inherent to neutrophil-associated functions play a role in the respiratory failure seen in severe COVID-19 patients and how does this relate to the SARS-CoV-2 viral loads, IL-8 (CXCL8) chemokine expression, and cytotoxic T-lymphocytes infiltrates? STUDY DESIGN AND METHODS: Sixteen immediate post-mortem lung biopsies were methodically analyzed as exploratory and validation cohorts. NETs were quantitatively analyzed by multiplexed immunofluorescence and correlated with local levels of IL-8 mRNA and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by RT-PCR and immunohistochemistry. RESULTS: NETs 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 out of eight liver tissues. NET focal presence negatively correlated with CD8+ T-cell infiltration in the lungs. INTERPRETATION: Abundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, but no correlation is 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 the presence of NETs.

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Journal article



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COVID-19, Lungs, Neutrophil extracellular traps, Neutrophils, SARS-CoV-2