Mucoactive agents in bronchiectasis: a systematic review and meta-analysis

Clinical Snapshot

Key Findings

• P Value: Exacerbations: p=0.22 (NS); FEV1% predicted: p=0.03

• Effect Size: Exacerbations: MD -0.40/patient/year; FEV1% predicted: MD +3.23% (9 studies, n=767); no significant differences for other spirometry, quality of life, or adverse events

• Primary Outcome: Annualised exacerbation incidence: pooled mean difference -0.40 exacerbations per patient per year (7 RCTs, n=1259); not statistically significant

• Nnt Or Sensitivity: NNT not calculable from reported data; FEV1 improvement of 3.23% is below the commonly accepted MCID of 5-12% for bronchiectasis populations, and is based on very low certainty evidence with I²=69.9%

• Confidence Interval: Exacerbations: 95% CI -1.04 to 0.24; FEV1% predicted: 95% CI 0.31 to 6.15

Clinical Application

Multiple agents reviewed are widely available and low-cost (e.g., carbocisteine, N-acetylcysteine, hypertonic saline). However, the absence of evidence of benefit from this review means prescribing decisions should be individualised and based on patient-specific factors including sputum characteristics, exacerbation history, and tolerability. Ongoing monitoring of clinical response is essential. Carbocisteine is not currently listed on the PBS for bronchiectasis. Hypertonic saline (3% and 7%) is used in Australian respiratory practice and can be prescribed off-label. N-acetylcysteine is available OTC and on PBS for other indications. Mannitol dry powder inhaler (Bronchitol) received TGA approval for CF but not for non-CF bronchiectasis. RACGP and Thoracic Society of Australia and New Zealand (TSANZ) guidelines do not currently recommend routine mucoactive therapy for non-CF bronchiectasis, a position supported by this review's findings. Australian clinicians should note that the ERS 2017 bronchiectasis guidelines similarly lack strong recommendations for mucoactive agents, and this updated meta-analysis reinforces clinical equipoise. Participation in or referral to clinical trials of specific agents (e.g., hypertonic saline, inhaled mannitol) should be encouraged where available. Adults with non-cystic fibrosis bronchiectasis in whom mucoactive therapy is being considered, particularly those with frequent exacerbations, impaired mucociliary clearance, or significant sputum burden

Abstract

BACKGROUND: Mucoactive agents aim to improve mucociliary clearance in bronchiectasis, disrupting the cycle of impaired clearance, infection and inflammation. Registry data show 28% of patients use these agents, but prescribing varies due to limited evidence. We aimed to update evidence on mucoactive agents' effects in adults with bronchiectasis. METHODS: We conducted a systematic review and meta-analysis, searching Medline, Embase, CENTRAL and trial registries to 1 October 2025. Eligible studies included adults with bronchiectasis, evaluating any mucoactive agent versus placebo or control. Cystic fibrosis and paediatric studies were excluded. The primary outcome was exacerbation frequency; secondary outcomes included lung function, quality of life and adverse events. FINDINGS: From 1512 records, 24 studies (20 randomised, four observational: n=7051) evaluated eight mucoactive agents (ambroxol, bromhexine, carbocisteine, erdosteine, hypertonic saline, mannitol, N-acetylcysteine, rhDNase). Most trials had high or some risk of bias. Seven randomised studies (n=1259) reported exacerbations; pooled analysis did not demonstrate a statistically significant difference in annualised exacerbation incidence (mean difference -0.40 per patient per year, 95% CI -1.04-0.24; p=0.22; I2=91%; very low certainty). Nine studies (n=767) reported percent predicted forced expiratory volume in 1 s (FEV1 % pred), showing a small mean increase of 3.23% (95% CI 0.31-6.15; p=0.03; I2=69.9%; very low certainty). Pooled analyses did not demonstrate significant differences for other spirometry measures, quality of life or adverse events. INTERPRETATION: Pooled evidence did not show a reduction in exacerbations and FEV1 % pred improvements were small. Evidence certainty was low/very low, meaning overall clinical benefit remains uncertain, highlighting the need for targeted trials of specific agents and subgroups.

References

1. 1.McCullough, B., Busby, J., O'Neill, B., Connolly, B., McLeese, R. H., Linden, D., McAuley, D. F., Elborn, J. S., De Soyza, A., Chalmers, J. D., Clarke, M., & Bradley, J. M. (2026). Mucoactive agents in bronchiectasis: a systematic review and meta-analysis. European Respiratory Review, 35. https://doi.org/10.1183/16000617.0014-2026