A marker of human neutrophil elastase mediated club cell secretory protein-16 degradation (CC16-HNE) is associated with mortality and pulmonary hypertension in idiopathic pulmonary fibrosis

<bold>Background:</bold> Idiopathic pulmonary fibrosis (IPF) is a fast-progressing disease with poor survival. IPF is characterized by epithelial injury, fibrosis, and an aberrant immune response. Club cells are essential for lung homeostasis by repairing the injured epithelial layer and secreting anti-inflammatory club cell secretory protein-16 (CC16). Additionally, activated neutrophils can release human neutrophil elastase (HNE) as part of an inflammation response. We investigated if serum measurements of CC16 degradation by HNE (CC16-HNE) was related to IPF mortality and pulmonary hypertension (PH) comorbidity. <bold>Methods:</bold> Serum CC16-HNE was assessed at baseline in 99 prevalent IPF subjects by the neoepitope-specific ELISA nordicCC16-HNE^TM along with pulmonary function and PH. Mortality was registered over five years. IPF subjects were dichotomized into low vs high baseline serum CC16-HNE at the median and analysed by Kaplan-Meier for survival association. Serum CC16-HNE was compared for IPF subjects with (n=13) or without (n=86) PH by a linear regression model adjusting for age and sex. <bold>Results:</bold> Low baseline serum CC16-HNE was associated with increased risk of mortality in IPF (HR 1.79 [95% CI 1.03-3.13]; p=0.04). Lower levels were observed in IPF subjects with PH (mean 58.4 [95%CI 45.4-75.2] ng/mL) than those without PH (mean 87.7 [95%CI 77.5-99.1] ng/mL; p=0.004). <bold>Conclusions:</bold> Low serum CC16-HNE at baseline was associated with increased risk of mortality and PH comorbidity in IPF. Thus, CC16 degradation by HNE is relevant and could serve as a prognostic biomarker for IPF and PH comorbidity diagnosis.