What is the optimal dose of N-acetylcysteine in adult patients with bronchiectasis?—data from the RIBRON registry

Introduction

By definition, bronchiectasis can no longer be regarded as a mere radiological finding; it must be accompanied by a compatible clinical presentation—most commonly chronic cough with excessive sputum production, often mucopurulent or purulent in nature, and a history of exacerbations throughout the disease course (1).

Two of the key factors that clearly influence the progression of bronchiectasis are the degree of airway inflammation and the presence of chronic infection by pathogenic microorganisms, particularly Pseudomonas aeruginosa (PA) (2). Consequently, both pharmacological and non-pharmacological treatments—regardless of the strength of supporting evidence—are aimed at controlling key aspects of the disease: alleviating symptoms such as cough and dyspnea, reducing inflammation (e.g., with anti-inflammatory agents), controlling infection (e.g., through various routes of antibiotic administration), and managing mucus hypersecretion (e.g., through respiratory physiotherapy, mucolytics, and expectorants) (3-5). Both the degree of airway inflammation and the presence of chronic infection by pathogenic microorganisms, particularly PA, have been associated with worse clinical outcomes, including an increased frequency and severity of exacerbations and, in some cases, higher mortality (6-8). This approach is reflected in current national and international bronchiectasis management guidelines (3-5).

Mucus hypersecretion, in particular, is a critical therapeutic target. Its presence has been linked to a higher number and severity of exacerbations, reduced quality of life, and increased isolation of pathogenic organisms (9,10). From a pharmacological perspective, treatment with hypertonic saline at concentrations of at least 5–6% has demonstrated clinical efficacy (11). However, among commercially available mucolytics, none have shown sufficient scientific evidence to warrant prioritization within the therapeutic algorithm. Nevertheless, global registry data consistently report that N-acetylcysteine (N-AC) is the most frequently used mucolytic (12-17). This molecule not only exerts mucolytic effects but also possesses antioxidant and even antimicrobial properties, depending on the dosage, and is considered highly safe even at elevated doses (18-20).

A recent meta-analysis in patients with chronic obstructive pulmonary disease (COPD) demonstrated that daily doses of 600–1,200 mg of N-AC reduced both sputum volume and exacerbation rates (21). In bronchiectasis—a condition inherently defined by excessive bronchial secretions—a recent study showed similar outcomes, including reductions in exacerbation frequency, hospitalizations, sputum volume and purulence, and PA isolation. However, the majority of patients in this study received 600 mg/day of N-AC for at least 3 months. A small, unadjusted subgroup analysis suggested that a higher dose of 1,200 mg/day might lead to an additional 11% reduction in exacerbation rates, though no further improvements were observed in other parameters compared to the 600 mg/day dose. These findings, however, must be interpreted with caution due to the lack of adjustment for potential confounding variables (22).

The primary aim of the present study is to specifically evaluate the efficacy of 1,200 mg/day of N-AC compared to 600 mg/day in patients with bronchiectasis. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1159/rc).

Methods

Study design

This study is based on data from the Spanish Bronchiectasis Registry (RIBRON) (12-14), collected between February 2015 and December 2019. This registry comprises a historical (retrospective) cohort of 2,630 patients aged over 18 years, followed for a median of 7 years, from 43 centers across Spain. The diagnosis of bronchiectasis was confirmed both by high-resolution computed tomography and by a clinical presentation consistent with this diagnosis. Data regarding all pharmacological treatments, including dose and administration during both acute and stable phases, were collected at the initiation and termination of each treatment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the registry’s affiliated ethics committee (Hospital Josep Trueta, Girona, approval No. 001-2012), and all participants provided written informed consent at their respective centers.

Patients

From the 2,630 patients, those who met the following two inclusion criteria were selected: (I) complete clinical, pulmonary function, etiological, laboratory, and treatment data, all obtained during a stable phase of the disease (with no exacerbations at least four weeks prior to the measurement of the variables); and (II) use of N-AC, either at a dose of 600 mg (n=252) or 1,200 mg (n=116), for a minimum of 2 years without interruption of the treatment following the baseline variable measurements described above. No patient received more than 1,200 mg/day of N-AC.

The main exclusion criterion was a diagnosis of cystic fibrosis (CF).

Variables

The primary outcome was the adjusted between-group difference in the within-group changes in exacerbation rates at the end of the 2-year study, comparing patients who received 600 versus 1,200 mg/day of N-AC, initiated during a clinically stable phase. Throughout this period, patients consistently maintained the same N-AC dosage without interruptions.

Variables analyzed (all during the stable phase of bronchiectasis) included: general (age and gender), and anthropometric baseline data, body mass index (BMI)]; habits (smoke); bronchiectasis etiology (COPD, asthma, post-infectious and idiopathic); comorbidities (quantified using the Charlson Comorbidity Index); pulmonary function [forced expiratory volume in 1 second (FEV₁)%, predicted]; treatments (use of inhaled corticosteroids, macrolides, physiotherapy, long-acting β₂ adrenergic (LABA) and hypertonis saline at 7% (HS7%)]; clinical [dyspnea measured by modified Medical Research Council (mMRC) and daily sputum quantity, usual sputum purulence], baseline exacerbations and hospitalizations [analytical (C-reactive protein, fibrinogen and platelets), radiological (number of pulmonary lobes affected), microbiological findings (chronic bronchial infection by PA and other potentially pathogenic microorganisms)]; and severity scores [FACED (acronym of FEV₁, age, colonization, extension and dyspnea)] (7), E-FACED (exacerbations-FACED) (8), and Bronchiectasis Severity Index (BSI) (6).

Exacerbations were defined (per 2015 registry standards) as a worsening of typical bronchiectasis symptoms—cough, dyspnea, hemoptysis, increased sputum volume or purulence, chest pain, or wheezing—lasting more than 24 hours and requiring antibiotic therapy. Exacerbations were classified as mild-to-moderate if managed with oral antibiotics, and severe if hospitalization or intravenous antibiotic therapy (in hospital or at home) was required (23).

Statistical analysis

Quantitative data were expressed as mean ± standard deviation or median (interquartile range), depending on the distribution assessed using the Kolmogorov-Smirnov test. Qualitative variables were expressed as percentages. Correlations between quantitative variables were evaluated using Pearson’s or Spearman’s correlation coefficients, depending on distribution.

Given that the primary endpoint was the adjusted intergroup difference in intragroup changes, and assuming an alpha error of 0.05, a beta error of 0.20, no dropouts, and a predefined 27% reduction based on prior data, a minimum of 101 patients per group was required.

Patients were categorized into two groups (Figure 1): those receiving 600 mg/day and those receiving 1,200 mg/day of N-AC with 2 years of follow-up data during a clinically stable phase.

Figure 1 Flowchart of the study design, including the prescription, dosage, and duration of N-AC administration, alongside the timeline of the study period for both groups, and the variables analyzed for comparative purposes. N-AC, N-acetylcysteine; PA, Pseudomonas aeruginosa.

To account for baseline imbalances and minimize confounding between treatment groups, PSM approach was applied. The two groups consisted of patients receiving 1,200 mg/day of N-AC (n=116) and those receiving 600 mg/day of N-AC (n=252).

Propensity scores were estimated using a multivariable logistic regression model, with treatment group (1,200 vs. 600 mg of N-AC) as the dependent variable and the aforementioned baseline variables as independent predictors. Matching was performed using the nearest-neighbor method without replacement, in a variable ratio (1:n) to maximize the sample size while maintaining balance. A caliper width was not applied.

Following matching, a total of 104 patients from the 1,200 mg/day N-AC group were successfully matched to 219 patients from the 600 mg/day N-AC group, forming a matched analytical cohort of 323 patients. Balance diagnostics were conducted by examining standardized mean differences (SMDs) for all covariates included in the propensity model. An SMD threshold of <0.1 was considered indicative of adequate covariate balance between groups.

Following the application of PSM, the baseline difference along with the 95% confidence interval (95% CI) was calculated for both the 600 mg and 1,200 mg groups. This matched cohort was used for all subsequent outcome analyses to reduce bias and emulate the conditions of a randomized controlled comparison. Given the relatively small sample size in both groups following the application of PSM, standardized differences were calculated for all variables included in the matching process, as well as for all post-matching covariates. The cutoff points considered were as follows: less than 0.1 indicating good balance; between 0.1 and 0.2 representing an acceptable threshold (although requiring further review); and greater than 0.2 suggesting a significant imbalance. The standardized differences were conducted using the MatchIt package in R.

The between-group difference in baseline values was then computed based on the within-group differences, resulting in the intergroup difference of the intragroup changes. This value was further adjusted for covariates (fully adjusted; see footnote of Table 1). A Poisson test was used to assess both intra- and intergroup adjusted differences.

Even after PSM, results were additionally adjusted for clinically relevant baseline variables as identified by the investigators: sex, age, baseline FEV₁, presence of COPD or asthma, Charlson Comorbidity Index, use of bronchodilators, inhaled corticosteroids, inhaled antibiotics or macrolides, dyspnea, and the extent of bronchiectasis (i.e., number of pulmonary lobes affected).

To facilitate interpretation by the reader, these values were also calculated as the percentage improvement in the 1,200 mg group compared to the 600 mg group with respect to the main variables (mild-to-moderate exacerbations, hospitalizations, and total exacerbations). For all comparisons, a P value <0.05 was considered statistically significant

All statistical analyses were performed using SPSS version 20 (SPSS Inc.) and the PSM was conducted using the MatchIt package in R. A P value <0.05 was considered statistically significant.

Results

This observational study analyzed historical cohorts. Of the 2,630 initially enrolled patients, 169 were excluded due to a diagnosis of CF. Thus, 2,461 patients were included. Of these, 252 patients (68.5%) received 600 mg/day and 116 patients (31.5%) received 1,200 mg/day during at least 2 years since their inclusion in the study to the end of the study without interruption of the treatment. After applying PSM, 219 patients remained in the 600 mg/day group and 104 in the 1,200 mg/day group for final comparative analysis.

As shown in Table 1, patients receiving 1,200 mg/day of N-AC initially had higher baseline severity: more total exacerbations, more hospitalizations, greater sputum volume, higher rates of PA isolation, and increased use of certain treatments compared to those receiving 600 mg/day. After applying PSM, the groups were adequately balanced for these key baseline characteristics.

In all cases, both for the variables balanced through the use of PSM and those included as covariates in the adjusted analysis, the standardized differences were below 0.1.

Effect on exacerbations and hospitalizations

As shown in Table 2, baseline annual rates of exacerbations, hospitalizations, and total exacerbations were 1.38±1.4, 0.58±1.5, and 1.96±2.4, respectively, in the 600 mg/day group; and 1.26±1.6, 0.53±1.4, and 1.89±2.1, respectively, in the 1,200 mg/day group.

After full adjustment for confounders (including those not matched in the PSM), the 1,200 mg/day group demonstrated a significant intragroup-intergroup reduction in: exacerbation rate: −0.16 exacerbations/year (95% CI: −0.09 to −0.25; P=0.01); Hospitalizations: −0.07 hospitalizations/year (95% CI: −0.05 to −0.20; P=0.03) and Total exacerbation rate: −0.20/year (95% CI: −0.12 to −0.32; P=0.002), respectively.

These correspond to relative reductions of 48.6%, 29.9%, and 54.1%, respectively, for the 1,200 mg/day group compared to the 600 mg/day group. Despite the use of PSM, results were further adjusted for clinically relevant variables not fully matched (see footnote of Table 2).

Effect on sputum volume and purulence

As shown in Figure 2, patients receiving 1,200 mg/day of N-AC showed a significant reduction in both sputum purulence and daily sputum volume compared with the 600 mg/day group. Specifically: the proportion of patients with mucopurulent sputum decreased by 8.5% (P=0.041), and the proportion of patients expectorating >20 cc/day decreased by 24.3% (P=0.001).

Figure 2 Impact of N-acetylcysteine on the degree of purulence and sputum volume.

Effect on chronic bronchial infection by PA

As illustrated in Figure 3, following PSM, 22.4% of patients in the 600 mg/day group and 27.4% in the 1,200 mg/day group presented with chronic bronchial infection due to PA. Over the study period, the prevalence of PA isolation decreased by 4.1% in the 600 mg/day group and by 5.0% in the 1,200 mg/day group. The absolute intergroup difference in reduction was –0.9%, which did not reach statistical significance (P=NS).

Figure 3 Effect of N-acetylcysteine on bronchial infection caused by PA. PA, Pseudomonas aeruginosa.

Discussion

According to the results of this real-life study based on national bronchiectasis guidelines and data from the RIBRON, the use of 1,200 mg/day of N-AC for at least 6 months is both statistically and clinically superior to 600 mg/day. Patients receiving the higher dose experienced a significantly greater reduction in the rates of mild-to-moderate exacerbations, hospitalizations, and total exacerbations. Additionally, there was a statistically significant decrease in total sputum volume and a trend toward reduced sputum purulence. However, no significant differences were observed between groups regarding the prevalence of PA isolation.

Despite being the most widely used mucolytic globally (12-17), the scientific evidence supporting the use of N-AC in bronchiectasis remains limited (24,25). Nonetheless, both national and international guidelines recommend its use in patients with copious bronchial secretions (3-5). A recent meta-analysis in patients with pre-COPD or chronic bronchitis (not necessarily with bronchiectasis) showed that N-AC at doses of 600–1,200 mg/day for at least 6 months reduced exacerbation incidence by 19% and significantly improved symptoms such as cough, sputum production, and dyspnea (21).

Evidence specific to bronchiectasis is scarcer. A randomized controlled trial (RCT) by Jayaram et al. (24)., conducted with only 8 patients per arm, offers limited conclusions, although it did demonstrate the safety of doses as high as 2400 mg/day. More robust, albeit still limited, evidence comes from the RCT by Qi et al. (25), where 1,200 mg/day of N-AC reduced the incidence of exacerbations in the N-AC group was compare with the control group (1.31 vs. 1.98 exacerbations per patient-year; risk ratio, 0.41; 95% CI: 0.17–0.66; P=0.001 alongside improvements in quality of life [ COPD Assessment Test (CAT) score] and sputum quantity but not in the time to first exacerbation. However, that study had several limitations, including lack of a placebo group, questionable diagnostic criteria [based only on high-resolution computed tomography (HRCT) findings, including traction and asymptomatic bronchiectasis], treatment-naïve patients, and a single-center design without external validation.

By using a real-life study model and leveraging the RIBRON registry—which includes over 2,600 clinically and radiologically confirmed bronchiectasis patients followed for a median of 7 years—our findings support the effectiveness of N-AC at 600 mg/day over at least 6 months. This dose was associated with an approximately 30% reduction in exacerbation rate, a 17% decrease in hospitalizations, a 60% reduction in sputum volume, a 5% decline in purulent sputum, and a 12% decrease in PA isolation. A prior (underpowered and unadjusted) subgroup analysis of patients on 1,200 mg/day suggested an additional 11% reduction in total exacerbation rate (22).

In the present study, the 1,200 mg/day dose of N-AC was associated with a 48.6% greater reduction in exacerbation rate, 29.9% greater reduction in hospitalizations, and 54.1% reduction in total exacerbations compared to 600 mg/day. Furthermore, a 24.3% greater reduction in sputum volume was observed, with no significant adverse events reported in either dosage group. These findings (the multiple effects of N-AC) suggest that the use of N-AC in patients with bronchiectasis could be considered at a higher step in the therapeutic algorithm for bronchiectasis, alongside inhaled antibiotics, macrolides, or hypertonic saline, in order to promote expectoration.

Strengths and limitations

A major strength of this study lies in its real-world design, focusing on well-defined bronchiectasis (excluding traction and dry bronchiectasis) treated in accordance with national guidelines using both pharmacologic and non-pharmacologic approaches. The sample size was sufficient, even after applying PSM, allowing for robust statistical comparisons between groups with comparable baseline characteristics.

The most important limitation is the non-randomized design. Although PSM was used to minimize bias and approximate causal inference, unmeasured confounders may still have influenced the results. Additionally, bronchiectasis characteristics vary widely across regions and populations, so these findings should be confirmed in other patient cohorts worldwide—preferably through well-designed RCTs based on the most recent international definition of bronchiectasis. Finally, the majority of patients prescribed N-AC are those who have previously received other treatments, such as antibiotics (typically inhaled), macrolides, and hypertonic saline.

Conclusions

In conclusion, N-AC at a dose of 1,200 mg/day is safe and more clinically effective than 600 mg/day in reducing annual exacerbation and hospitalization rates, as well as sputum volume, in patients with bronchiectasis. These findings have important clinical implications and support 1,200 mg/day as the optimal dose of N-AC for patients in whom mucolytic therapy is indicated within the bronchiectasis therapeutic algorithm.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (James D. Chalmers and Wei-Jie Guan) for the series “Frontiers in Bronchiectasis Management: Translational Science and Practice” published in Journal of Thoracic Disease. The article has undergone external peer review.

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1159/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1159/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1159/prf

Funding: This study was financed by ZAMBON SA, without participation in any part of the study or interpretation of the results.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1159/coif). The series “Frontiers in Bronchiectasis Management: Translational Science and Practice” was commissioned by the editorial office without any funding or sponsorship. The authors report that this study was financed by ZAMBON SA for translation. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the registry’s affiliated ethics committee (Hospital Josep Trueta, Girona, approval No. 001-2012), and all participants provided written informed consent at their respective centers.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Aliberti S, Goeminne PC, O'Donnell AE, et al. Criteria and definitions for the radiological and clinical diagnosis of bronchiectasis in adults for use in clinical trials: international consensus recommendations. Lancet Respir Med 2022;10:298-306. [Crossref] [PubMed]
2. Fuschillo S, De Felice A, Balzano G. Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms. Eur Respir J 2008;31:396-406. [Crossref] [PubMed]
3. Martínez-García MÁ, Máiz L, Olveira C, et al. Spanish Guidelines on Treatment of Bronchiectasis in Adults. Arch Bronconeumol (Engl Ed) 2018;54:88-98. [Crossref] [PubMed]
4. Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J 2017;50:1700629. [Crossref] [PubMed]
5. Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax 2019;74:1-69. [Crossref] [PubMed]
6. Chalmers JD, Goeminne P, Aliberti S, et al. The bronchiectasis severity index. An international derivation and validation study. Am J Respir Crit Care Med 2014;189:576-85. [Crossref] [PubMed]
7. Martínez-García MÁ, de Gracia J, Vendrell Relat M, et al. Multidimensional approach to non-cystic fibrosis bronchiectasis: the FACED score. Eur Respir J 2014;43:1357-67. [Crossref] [PubMed]
8. Martinez-Garcia MA, Athanazio RA, Girón R, et al. Predicting high risk of exacerbations in bronchiectasis: the E-FACED score. Int J Chron Obstruct Pulmon Dis 2017;12:275-84. [Crossref] [PubMed]
9. Ramsey KA, Chen ACH, Radicioni G, et al. Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis. Am J Respir Crit Care Med 2020;201:661-70. [Crossref] [PubMed]
10. Murray MP, Pentland JL, Turnbull K, et al. Sputum colour: a useful clinical tool in non-cystic fibrosis bronchiectasis. Eur Respir J 2009;34:361-4. [Crossref] [PubMed]
11. Máiz Carro L, Martínez-García MA. Nebulized hypertonic saline in noncystic fibrosis bronchiectasis: a comprehensive review. Ther Adv Respir Dis 2019;13:1753466619866102. [Crossref] [PubMed]
12. Martinez-García MA, Villa C, Dobarganes Y, et al. RIBRON: The spanish Online Bronchiectasis Registry. Characterization of the First 1912 Patients. Arch Bronconeumol (Engl Ed) 2021;57:28-35. [Crossref] [PubMed]
13. Çakır Edis E, Çilli A, Kızılırmak D, et al. Bronchiectasis in Türkiye: Data from a Multicenter Registry (Turkish Adult Bronchiectasis Database). Balkan Med J 2024;41:206-12. [Crossref] [PubMed]
14. Lee H, Choi H, Sim YS, et al. KMBARC registry: protocol for a multicentre observational cohort study on non-cystic fibrosis bronchiectasis in Korea. BMJ Open 2020;10:e034090. [Crossref] [PubMed]
15. Chalmers JD, Polverino E, Crichton ML, et al. Bronchiectasis in Europe: data on disease characteristics from the European Bronchiectasis registry (EMBARC). Lancet Respir Med 2023;11:637-49.
16. Xu JF, Zheng HZ, Lu HW, et al. Baseline characteristics of patients in the Chinese Bronchiectasis Registry (BE-China): a multicentre prospective cohort study. Lancet Respir Med 2025;13:166-76. [Crossref] [PubMed]
17. Dhar R, Singh S, Talwar D, et al. Clinical outcomes of bronchiectasis in India: data from the EMBARC/Respiratory Research Network of India registry. Eur Respir J 2023;61:2200611. [Crossref] [PubMed]
18. Cazzola M, Calzetta L, Page C, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev 2015;24:451-61. [Crossref] [PubMed]
19. Guerini M, Condrò G, Friuli V, et al. N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A Review. Pharmaceuticals (Basel) 2022;15:217. [Crossref] [PubMed]
20. Santus P, Signorello JC, Danzo F, et al. Anti-Inflammatory and Anti-Oxidant Properties of N-Acetylcysteine: A Fresh Perspective. J Clin Med 2024;13:4127. [Crossref] [PubMed]
21. Papi A, Alfano F, Bigoni T, et al. N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses. Arch Bronconeumol 2024;60:269-78. [Crossref] [PubMed]
22. Oscullo G, Méndez R, Olveira C, et al. Effect of N-Acetylcysteine on Bronchiectasis in a Real-life Study. Data From the Spanish RIBRON Registry. Arch Bronconeumol 2025;61:196-202. [Crossref] [PubMed]
23. Martínez-García MÁ, Máiz L, Olveira C, et al. Spanish Guidelines on the Evaluation and Diagnosis of Bronchiectasis in Adults. Arch Bronconeumol (Engl Ed) 2018;54:79-87. [Crossref] [PubMed]
24. Jayaram L, King PT, Hunt J, et al. Evaluation of high dose N- Acetylcysteine on airway inflammation and quality of life outcomes in adults with bronchiectasis: A randomised placebo-controlled pilot study. Pulm Pharmacol Ther 2024;84:102283. [Crossref] [PubMed]
25. Qi Q, Ailiyaer Y, Liu R, et al. Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial. Respir Res 2019;20:73. [Crossref] [PubMed]