Excessive neutrophil extracellular traps formation in sepsis induced acute respiratory distress syndrome: Role of citrullinated histone H3 as a surrogate biomarker and clinical implication Free

Background: Despite advancements in therapy, the management of sepsis-induced acute respiratory distress syndrome (ARDS) remains a significant challenge due to lack of appropriate indicators for diagnosing and monitoring. Excessive neutrophil extracellular traps (NETs) mediate inflammation, leading to sepsis severity and organ damage. Thus, citrullinated histone H3 (CitH3), a crucial mediator involved in NET formation mechanism and a byproduct of NETs, may be a novel biomarker reflecting NET burden in vivo and disease progression in sepsis-ARDS.

Method: A total of 40 endotracheal intubated patients with ARDS categorized as sepsis (n=28) and non-sepsis ARDS (n=12) were enrolled according to eligible criteria from the intensive care unit (ICU). The clinical outcomes (eg, 28-day mortality and 28-day ventilator-free days) were obtained prospectively. Paired blood and bronchoalveolar lavage (BAL) fluid samples were collected, and CitH3 concentrations were quantified using enzyme-linked immunosorbent assay (ELISA). Neutrophils were isolated by density gradient centrifugation for phenotypic analysis and assessment of NET formation using flow cytometry and immunofluorescence staining, respectively.

Result: CitH3 levels in both plasma and BAL fluid were significantly elevated in patients with sepsis-ARDS compared to controls and non-sepsis ARDS. Moreover, a strong positive correlation was observed between plasma and BAL CitH3 concentrations in the sepsis-induced ARDS group. Consistently, neutrophils from these patients exhibited an activated phenotype, as characterized by increased CD11b and decreased CD62L expression, and generated excessive NETs with elevated CitH3 detected in the culture supernatants ex vivo. For diagnostic performance, the area under the curve (AUC) in a receiver operating characteristic (ROC) curve for differentiating sepsis-ARDS from non-sepsis ARDS was 0.75 for plasma CitH3 and 0.80 for BAL CitH3. In terms of prognostic utility, the AUC for predicting 28-day mortality and ventilator-free days in sepsis-ARDS was 0.80 (log-rank test = 5.32) and 0.71 (log-rank test = 0.43), respectively. Notably, all the performances were improved when the CitH3 levels were combined with SOFA score. Additionally, CitH3 levels correlated with ARDS severity, as reflected by a decreased PaO₂/FiO₂ (P:F) ratio, increased SOFA scores, and elevated IL-6 concentrations.

Conclusion: CitH3 represents a promising in vivo biomarker for NET activity and may aid in the diagnosis and prognostication of sepsis-induced ARDS. Its correlation with disease severity suggests potential clinical utility. However, validation in larger patient cohorts is necessary to confirm its diagnostic and prognostic significance.

Disclosures: No relevant conflict of interest to declare.