Time to Reconsider Mucoactive Agents for Airway Clearance
John Hansen-Flaschen, Gregory Tino
N Engl J Med Published September 28, 2025
DOI: 10.1056/NEJMe2512146
Bronchiectasis is characterized by multifocal airway dilatation and wall thickening observed on computed tomography of the chest and is commonly accompanied by persistent or recurrent infection of the airways.1 Bronchiectasis is a hallmark of cystic fibrosis and often overlaps with asthma and chronic obstructive pulmonary disease. Approximately 500,000 adults in the United States have bronchiectasis.
Professional-society guidelines2-4 emphasize two complementary strategies for treating symptomatic bronchiectasis: administration of antibiotic agents for exacerbations (selected on the basis of sputum-culture results) and techniques to augment clearance of purulent secretions from the airways. Airway clearance is considered to be important not only because retained secretions worsen symptoms but also because inflammatory mucus plaques may drive airway injury, leading to progressive airway dilation and wall thickening.5
Current practice varies considerably across centers, which reflects the limitations of existing research in defining best practices. Recommended airway-clearance routines are particularly diverse but usually include some combination of three interventions: inhalation or ingestion of a mucoactive agent, application of positive expiratory pressure or pulsatile agitation (or both) to the airways, and deliberate coughing, huffing, and slow, deep exhalations to clear the central airways.6
Inhalation of nebulized hypertonic saline is often recommended to loosen tenacious secretions.2–4,6,7 Other mucoactive agents are used mostly in Europe, notably N-acetylcysteine and carbocisteine (not available in the United States or Canada). Trials testing these agents have yielded mixed results, leaving unanswered questions as to which patients, if any, benefit from their use.8
The clinical trial now reported by Bradley et al.9 in the Journal sets new standards for experimental design and analysis of trials testing mucoactive therapy for bronchiectasis. In a two-by-two factorial, 52-week, open-label trial conducted at 20 centers in the United Kingdom, Bradley and colleagues randomly assigned 288 participants who had bronchiectasis unrelated to cystic fibrosis to receive standard care plus one of three mucoactive therapies — inhaled hypertonic saline, oral carbocisteine, or a combination of the two — or standard care alone. The primary outcome, the number of respiratory exacerbations over a 52-week period, was compared between hypertonic saline and no hypertonic saline and between carbocisteine and no carbocisteine. Multiple secondary outcomes, including measures of quality of life and lung function, were also assessed. No apparent between-group differences were observed in the number of exacerbations with the addition of either hypertonic saline or carbocisteine to standard care. Secondary outcomes also appeared to be similar regardless of the addition of either agent.
How should clinicians respond to this groundbreaking trial? The results shown convincingly that neither hypertonic saline nor carbocisteine should be prescribed routinely for continuous daily use across the broad spectrum of patients who have symptomatic bronchiectasis. However, we caution against abandoning airway mucoactive therapy altogether on the basis of this one trial.
Several considerations prompt such caution. First, mucoactive agents may favorably modify the rheologic characteristics of sputum but do not by themselves propel secretions proximally from distal to central airways where they can be cleared by expectoration. For best results, mucoactive agents should be administered before airway-clearance maneuvers are performed. The authors instructed trial participants to continue their preenrollment airway-clearance routines or taught them the active cycle of breathing technique. However, the authors could not objectively assess the quality, timing, or frequency of those maneuvers throughout the duration of the trial. Therapy may have failed in some participants because of suboptimal timing of or inadequate adherence to the airway-clearance protocol.
Second, although the trial enrolled participants who had disease that was at least moderately severe, those with the most advanced bronchiectasis were not assessed separately. The possibility remains that patients who have a greater chronic disease burden or are having an acute exacerbation may have a different response than the participants in this trial.
Third, orally administered carbocisteine is a mucolytic agent with unique pharmacokinetic features and mechanism of action.10 The disappointing response to this drug cannot be generalized to other mucoactive agents that have different effects on airway mucus.
The meticulously constructed and executed trial by Bradley et al. underscores unavoidable pragmatic limitations in clinical-trial design assessing airway-clearance techniques. A promising next step may be to assess whether these therapies effectively reopen distal airways narrowed or occluded by secretions. Recent advances in magnetic resonance imaging that uses hyperpolarized noble gas (3He and 129Xe) enable direct visualization of focal lung-ventilation defects caused by accumulation of secretions in distal airways. Pilot studies show amelioration of these ventilation defects after therapeutic interventions, including airway-clearance physiotherapy.11,12 With this screening approach, future clinical trials can be targeted to those interventions found to be the most effective in restoring distal lung ventilation in selected groups of patients.
Until further evidence is available, we recommend continuing to use airway clearance selectively for patients with bronchiectasis and chronic or acute chest congestion who are motivated to actively engage in their therapy. The choice of clearance method and use of an adjunctive mucoactive agent should be individualized on the basis of clinician assessment and patient-reported experience with airway clearance.
