PAST: The rationale for pharmacologic airway clearance
Pharmacologic airway clearance has long been incorporated into the management of bronchiectasis to reduce sputum burden, improve quality of life (QoL), and decrease pulmonary exacerbations. Much of this rationale was extrapolated from cystic fibrosis (CF), where impaired cystic fibrosis transmembrane conductance regulator (CFTR) function leads to dehydrated airway secretions and where osmotic agents and mucolytics have clear physiologic and clinical benefit. This CF-derived framework was subsequently adopted in noncystic fibrosis (non-CF) bronchiectasis, despite important differences in underlying pathophysiology.1
Expectorants and osmotic agents, including hypertonic saline (HS) and inhaled mannitol, enhance mucociliary clearance by increasing airway surface hydration. Mucolytics such as N-acetylcysteine (NAC), reduce mucus viscosity by disrupting disulfide bonds within mucin glycoproteins. In non-CF bronchiectasis, however, the evidence supporting these therapies has been modest, with small heterogenous trials showing variable effects on exacerbations and health-related QoL.2 Consequently, international guidelines, including those from the European Respiratory Society and British Thoracic Society, recommend pharmacologic mucoactives only selectively, acknowledging low certainty of evidence and emphasizing individualized use rather than routine prescription.1,3
PRESENT: Reassessing assumptions in light of contemporary evidence
A recent randomized controlled trial published in The New England Journal of Medicine evaluated hypertonic saline and carbocisteine as adjuncts to structured airway clearance therapy in non-CF bronchiectasis.4 Carbocisteine, a mucoactive not available in the United States, shares mechanistic similarities with NAC. Neither agent significantly reduced pulmonary exacerbation rates compared with standard care and key secondary outcomes, including health-related QoL, time to next exacerbation, antibiotic days, and lung function, were also not improved.4 Although, hypertonic saline demonstrated a numerically lower exacerbation rate (25% relative reduction in exacerbations), this did not reach statistical significance. Nonetheless, the observed signal may be clinically meaningful for selected patients and underscores the heterogeneity of treatment response.
These findings are clinically informative. In contrast to CF, preserved CFTR function in non-CF bronchiectasis permits rapid reabsorption of inhaled sodium and chloride, potentially limiting the sustained airway hydration achieved with osmotic therapies. The results therefore highlight a disconnect between physiologic plausibility and consistent patient-centered benefit at the population level.
FUTURE: Precision, de-escalation, and the central role of nonpharmacologic therapy
Rather than abandoning mucoactives entirely, current evidence supports a shift toward phenotype- and response-driven management. Ongoing early-phase investigations reflect this shift. The Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia (CLEAN-PCD) trial is evaluating idrevloride with or without hypertonic saline in primary ciliary dyskinesia, while the ARINA-1 (CLIMB) trial in the United Kingdom is exploring targeted mucus-modulating strategies. These efforts suggest a future focused on identifying biologically or clinically defined subgroups most likely to benefit from therapy.
In routine practice, reassessing chronic mucoactive use is reasonable. De-escalation in patients without clear symptomatic or exacerbation benefit may reduce treatment burden, cost, and regimen complexity—factors that influence adherence and QoL.
Importantly, this perspective does not contradict existing guidelines; rather, it operationalizes their conditional language by emphasizing measurable benefit over reflexive continuation. Nonpharmacologic airway clearance remains foundational therapy for all patients with non-CF bronchiectasis. Patient-directed techniques (huff coughing, active cycle of breathing, autogenic drainage, ELTGOL), device-assisted approaches (oscillatory positive expiratory pressure devices, high-frequency chest-wall oscillation), and exercise-based strategies such as pulmonary rehabilitation form the backbone of care.1 Optimizing adherence and technique in these modalities may yield greater real-world impact than routine pharmacologic escalation.
Viewed through a historical lens, airway clearance therapy in bronchiectasis has evolved from CF-derived rationale, through contemporary evidence-based reassessment, toward individualized precision care. The central question is no longer whether mucoactives work but for whom, under what circumstances, and at what cost in treatment burden—marking a shift from population-level intensification to patient-centered, outcome-driven therapy.
References
1. Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 2017;50(3):1700629. doi:10.1183/13993003.00629-2017
2. Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A. Mucoactive agents for bronchiectasis. Cochrane Database Syst Rev. 2014;(5):CD001289. doi:10.1002/14651858.CD001289.pub2
3. Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society guideline for bronchiectasis in adults. Thorax.2019;74(Suppl 1):1-69. doi:10.1136/thoraxjnl-2018-212463
4. Bradley JM, O’Neill B, McAuley DF, et al. Hypertonic saline or carbocisteine in bronchiectasis. N Engl J Med. 2025;393(16):1565-1577. doi:10.1056/NEJMoa2510095
