Abstract
In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis - including in the lungs of patients with acute respiratory distress syndrome. We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.
Highlights
As of late May 2020, the coronavirus disease 2019 (COVID-19) pandemic has affected more than 5 million individuals from over 180 countries and has resulted in unprecedented health, social, and economic crises [1]
The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), manifesting with flu-like symptoms and a viral pneumonia that progresses to acute respiratory distress syndrome (ARDS) and even multiorgan failure in some individuals [2]
It has yet to be assessed whether neutrophil extracellular traps (NETs) contribute to the inflammatory storm that leads to respiratory failure in many patients with COVID-19, there is emerging evidence to implicate inflammatory cytokines, such as IL-1β and IL-6, in the COVID-19 milieu [18]
Summary
As of late May 2020, the coronavirus disease 2019 (COVID-19) pandemic has affected more than 5 million individuals from over 180 countries and has resulted in unprecedented health, social, and economic crises [1]. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), manifesting with flu-like symptoms and a viral pneumonia that progresses to acute respiratory distress syndrome (ARDS) and even multiorgan failure in some individuals [2]. Elevated levels of blood neutrophils are an early indicator of SARS-CoV-2 infection, predicting severe respiratory disease and worse outcomes [3, 4]. NETs are extracellular webs of DNA, histones, microbicidal proteins, and oxidant enzymes that are released by neutrophils to corral infections; when not properly regulated, NETs have the potential to initiate and propagate inflammation and thrombosis [12, 13]. NETs are intimately intertwined with both cytokines, and especially IL-1β, in many pulmonary and cardiovascular diseases [9, 19,20,21,22,23,24]
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