Neutrophil extracellular traps (NETs) as markers of disease severity in COVID-19

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 potential to propagate inflammation and microvascular thrombosis, including in the lungs of patients with acute respiratory distress syndrome. While elevated levels of blood neutrophils predict worse outcomes in COVID-19, the role of NETs has not been investigated. We now report that sera from patients with COVID-19 (n=50 patients, n=84 samples) have elevated levels of cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3); the latter two are highly 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. In summary, these data reveal high levels of NETs in many patients with COVID-19, where they may contribute to cytokine release and respiratory failure. 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.

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

“…Patient sera induce healthy control neutrophils to undergo NETosis. However, NETs may contribute to cytokine release and progression to respiratory failure (Zuo et al, 2020) and contribute to thrombosis via platelet-neutrophil interaction (Laridan et al, 2017).…”

Excessive Neutrophils and Neutrophil Extracellular Traps in COVID-19

“…Recently, two serum markers of neutrophil extracellular traps (NETs), myeloperoxidase (MPO)-DNA, and citrullinated histone H3 (Cit-H3) levels were found to be elevated in the serum of COVID-19 patients (10). This suggested that neutrophilia and excessive NETs may contribute to cytokine release and respiratory failure.…”

A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19)

“…GM-CSF will further activate CD14+/CD16+ inflammatory monocytes to produce a large amount of IL-6 and other inflammatory factors by a positive feedback effect [19,20]. In addition, high levels of neutrophil extracellular traps may also contribute to cytokine release [21]. Ultimately, uncontrolled inflammatory responses may lead to shock and tissue damage in the heart, liver and kidney, as well as respiratory failure or multiple organ failure, causing death in patients with severe COVID-19 [22,23] (Fig.…”