Sputum Cathepsin G activity predicts exacerbations and hospitalizations in bronchiectasis

Background Bronchiectasis is a neutrophil-driven inflammatory chronic respiratory disease. While neutrophil elastase (NE) has been deeply investigated, other neutrophil serine proteases are less studied. The association between airway Cathepsin G (CatG) and clinical outcomes in bronchiectasis has not been described. Research question Is CatG sputum activity associated with clinical outcomes in bronchiectasis? Methods This international, multicenter, prospective cohort study enrolled bronchiectasis patients from three bronchiectasis programmes in Milan (Italy), Dundee (UK), and Barcelona (Spain). Participants were stratified into three groups based on sputum CatG activity measured using immunoassays. Data on clinical features, sputum characteristics, exacerbations, hospitalizations, and mortality were collected over a three-year follow-up period. Findings The median IQR activity of CatG in sputum was 45.1 1.3–128.8 ng·mL −1 . Patients with higher sputum CatG activity demonstrated significantly worse clinical outcomes in terms of disease severity (measured by the Bronchiectasis Severity Index, the E-FACED, the modified Reiff score, percentage predicted FEV1, and the prevalence of chronic bacterial infections, particularly Pseudomonas aeruginosa ) and disease activity (daily produced sputum volume and quality of life scores). Additionally, high CatG activity was linked to more frequent exacerbations during the 3-year follow-up (IRR 1.62; 95% CI: 1.26–2.02) and a greater risk of hospitalization due to severe exacerbations (IRR 2.32; 95% CI: 1.03–5.21). A strong correlation was found between sputum CatG and NE activities. Interpretation Sputum CatG activity relates to disease severity, disease activity, and prognosis in bronchiectasis. High CatG levels are associated with more severe clinical outcomes and could serve as a target for future therapeutic interventions, including DPP1 inhibitors.