Circulating NET biomarkers as predictors of inflammatory storm escalation and critical illness in COVID-19

Background COVID-19 manifests with significant clinical heterogeneity, ranging from mild respiratory symptoms to ventilator-dependent acute respiratory distress syndrome (ARDS). C, formed by the release of decondensed chromatin to immobilize pathogens, have been implicated; however, their relationship with disease severity and the need for advanced respiratory support remains unclear. Methods Ninety-nine patients who were diagnosed with COVID-19 in 2022–2023 were recruited. The NETs were assessed in plasma by quantifying cell-free deoxyribonucleic acid (cfDNA), protein-DNA complexes, and citrullinated Histone H3 (CitH3). Predictions of severe illness were analyzed with receiver operating characteristic curves. Results Plasma levels of cfDNA, histone-DNA and Myeloperoxidase (MPO)-DNA, Neutrophil Elastase (NE)-DNA and CitH3 were significantly elevated in patients with COVID-19 and increased with disease severity. Moreover, patients requiring mechanical ventilation or high-flow oxygen therapy had significantly higher levels of cfDNA, Histone-DNA and CitH3. Correlation analysis showed that Histone-DNA and CitH3 exhibited significant positive correlation with Procalcitonin (PCT), respectively. Receiver operating characteristic (ROC) curve analysis indicated that CitH3 distinguished severe cases better than the absolute counts or percentage of leukocytes and neutrophil subsets, and superior to the traditional inflammatory indicators, such as C-reactive protein (CRP), and Interleukin (IL)−6. Histone-DNA and MPO-DNA are equal to or better than some clinical indicators in distinguishing disease severity. Conclusion These results highlight the important roles of NETs remnants in viral infections. The CitH3 in plasma represent early predictive biomarkers for the prognosis of COVID-19.