Abstract: Neutrophilic airway inflammation is a key pathogenic driver of bronchiectasis, sustaining a vicious cycle of infection, mucus obstruction, recurrent exacerbations and progressive airway damage. The growing knowledge on the neutrophilic bronchiectasis endotype has led to increasing interest in host-directed approaches targeting neutrophilic mediators. Long-term macrolide therapy currently represents the reference anti-inflammatory treatment for patients with bronchiectasis at high risk of exacerbations and is supported by randomized controlled trials and extensive clinical experience. However, its use is limited by antimicrobial resistance, drug–to-drug interactions, safety concerns in selected populations and uncertainty regarding optimal dosing and duration. More recently, inhibition of Cathepsin C (CatC), an upstream regulator of neutrophil serine protease activation, has emerged as a novel therapeutic strategy aimed at reducing protease-driven airway injury. This manuscript presents a focused review of the literature that critically examines and compares long-term macrolides and CatC inhibitors with respect to their mechanisms of action, clinical evidence, safety profiles and potential roles within future treatment algorithms. We summarize data from Phase II and III trials of CatC inhibitors, particularly brensocatib, highlighting their effects on exacerbation risk, lung function trajectories and biomarkers of neutrophilic inflammation. We also discuss the limitations of the current evidence base, including restricted trial populations, limited long-term data and the lack of validated biomarkers to guide treatment selection in clinical practice. Finally, we discuss future perspectives for integrating these therapies into individualized, biomarker-informed management of bronchiectasis. Together, these developments support a shift towards more mechanism-based and personalized anti-inflammatory treatment strategies in bronchiectasis, in which treatment selection is guided by underlying inflammatory pathways. This review aims to translate current clinical evidence into practical considerations for patient selection and future therapeutic positioning, thereby helping bridge the gap between research and clinical implementation. Keywords: bronchiectasis, neutrophilic inflammation, cathepsin C, brensocatib, macrolides, DPP1 inhibitors, protease imbalance, host-directed therapy
Gramegna et al. (Wed,) studied this question.