Plasma surrogate markers of neutrophil extracellular traps correlate with disease severity in patients with moderate to severe acute respiratory distress syndrome

Abstract

Background: Although studies have evaluated the presence of cell-free DNA and neutrophil extracellular traps (NETs) in acute respiratory distress syndrome (ARDS), the kinetics of NET formation during the early ICU admission and whether plasma NET markers correlate with clinical outcomes in patients with moderate-to-severe hypoxemia remain unknown. We sought to determine whether serial plasma NET marker levels in study participants collected over 48 h post enrollment predict disease severity and mortality in non-COVID-19 ARDS patients. Methods: We obtained previously collected plasma samples (trial enrollment, 24 h, 48 h) from 200 randomly selected ARDS participants in the completed Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) Trial, as well as from 20 healthy control donors. We determined plasma levels of surrogate biomarkers for NETs using a cell-free DNA fluorescence assay and a plasma myeloperoxidase (MPO)-DNA complex ELISA. We correlated these surrogate biomarker levels with clinical outcomes from the ROSE trial study participants. Results: ROSE plasma samples demonstrated significantly higher NET levels compared to healthy donor controls. Individual study participant NET levels did not change over the forty-eight hours after trial enrollment. Higher levels of both surrogate markers correlated with fewer ventilator-free days, but only cell free-DNA correlated with mortality and higher illness severity scores. Conclusion: Surrogate markers for plasma NET levels measured in patients with moderate or severe ARDS correlate directly with adverse clinical outcomes and may serve as biomarkers for predicting severe disease. Further studies of surrogate biomarkers for NET formation in moderate-to-severe ARDS are warranted.