Symptoms, risk of future exacerbations, and response to long-term macrolide treatment in bronchiectasis: an observational study
- PMID: 40885209
- DOI: 10.1016/S2213-2600(25)00160-2
Symptoms, risk of future exacerbations, and response to long-term macrolide treatment in bronchiectasis: an observational study
Abstract
Background: Previous studies have suggested that daily symptoms are a marker of bronchiectasis disease activity and could therefore identify patients at increased risk of exacerbation. However, international bronchiectasis guidelines recommend long-term macrolide treatment only in patients with three or more exacerbations per year. We aimed to investigate if symptoms independently predict future exacerbations and therefore identify additional responders to long-term macrolide treatment.
Methods: We used data from the EMBARC registry, a multicentre international bronchiectasis database. Baseline symptoms were evaluated with the quality-of-life bronchiectasis questionnaire respiratory symptoms score (QoL-B-RSS), followed-up for at least 1 year, and were related to the future risk of exacerbations. We subsequently conducted a post-hoc pooled analysis of three randomised controlled trials of macrolides (ie, BLESS, BAT, and EMBRACE) in 341 participants with bronchiectasis to determine if baseline symptoms were associated with response to long-term macrolide treatment, using a negative binomial regression model.
Findings: 9466 patients from the 19 324 patients included in the EMBARC registry had available QoL-B-RSS assessment at baseline and 1-year follow-up. The median age was 68 years (IQR 58-74), 5763 (60·9%) were female, and 3703 (39·1%) were male. The median Bronchiectasis Severity Index score was 7 (4-10) and Pseudomonas aeruginosa was present in the sputum of 2041 (21·6%) patients within 12-months of baseline. Previous exacerbations (rate ratio (RR) for every additional exacerbation 1·11, 95% CI 1·10-1·12; p<0·0001) and symptoms (RR for every 10 points lower QoL-B-RSS 1·10, 1·09-1·11; p<0·0001) were identified as independent risk factors for future exacerbations. The number of exacerbations during 1-year of follow-up was similar between patients with three or more exacerbations at baseline and average symptom scores (QoL-B-RSS 60-70; RR 1·58, 95% CI 1·48-1·69) and the group with no previous exacerbations but high symptom scores (RR 1·55, 1·41-1·70). The same pattern was observed in the post-hoc analysis of randomised controlled trials, both in the macrolide and placebo groups. The number-needed-to-treat to prevent exacerbations with long-term macrolide therapy was similar for patients selected based on frequent exacerbations (1·45, 95% CI 1·08-2·24) and in those with few previous exacerbations, but high symptom scores 1·43 (1·06-2·18).
Interpretation: Our results suggest that symptoms are an independent risk factor for future exacerbations in bronchiectasis. Patients who are highly symptomatic derive a similar benefit from macrolide treatment as patients with a high baseline exacerbation frequency.
Funding: EU, European Federation of Pharmaceutical Industries and the Associations Innovative Medicines Initiative Inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis Consortium, European Respiratory Society.
Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of interests EP reports grants or contracts from Grifols; consulting fees from Insmed, Pari, Electromed, Grifols, and Chiesi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed, Pari, Electromed, Grifols, Chiesi, and GSK; support for attending meetings and/or travel from Insmed; and participation on a Data Safety Monitoring Board or Advisory Board from Insmed. FCR reports grants or contracts from the German Center for Lung Research, the German Center for Infection Research (EU and European Federation of Pharmaceutical Industries and Associations), the iABC Consortium (including Alaxia, Basilea, Novartis, and Polyphor), the Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer, and InfectoPharm, to their institution; consulting fees from Parion Sciences, Boehringer Ingelheim, Insmed, and Chiesi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from I!DE Werbeagentur GmbH, Insmed, Grifols, Universitätsklinikum Frankfurt am Main, University Hospital Hamburg, AstraZeneca, and Sanofi; participation on a Data Safety Monitoring Board or Advisory Board for Insmed, Boehringer Ingelheim, Parion Sciences, and Chiesi; a leadership or fiduciary roles in other board, society, committee, or advocacy groups as a former coordinator of the ERN-LUNG Bronchiectasis Core Network, co-chair of the German Bronchiectasis Registry PROGNOSIS, a member of the SteerCo of the European Bronchiectasis Registry EMBARC, and principal investigator of the German Center for Lung Research; and fees for clinical trial participation paid to their institution from AstraZeneca, Boehringer Ingelheim, Insmed, Novartis, Parion Sciences, Recode, Ruhr University-Bochum, the University of Dundee, and Vertex. MV reports consulting fees from Chiesi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed and Teva; support for attending meetings and/or travel from Pari, Chiesi, and Zambon; and participation on a Data Safety Monitoring Board or Advisory Board from Insmed. P-RB reports grants or contracts from GSK and Vertex to their institution and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Chiesi, GSK, Insmed, MSD, Pfizer, Vertex, Viatris, and Zambon. CSH reports consulting fees from 30 Technology, Chiesi, Infex, Insmed, LifeArc, Pneumagen, Vertex, and Zambon; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Chiesi, Insmed, Vertex, and Zambon; and payment for expert testimony from Zambon. MRL reports consulting fees from Armata, 30 Technology, AstraZeneca, Parion Sciences, Insmed, Chiesi, Zambon, Electromed, Recode, Boehringer Ingelheim, Ethris, Mannkind, and AN2 Therapeutics and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed. HC reports grants or contracts from the Korean Ministry of Education Basic Science Research Program (number 2021R1I1A3052416) and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boryung Pharmaceutical, Kolon Pharma, and Abbott. SHC reports consulting fees from CSL Behring, Boehringer Ingelheim, and Pneumagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca and Chiesi; and participation on a Data Safety Monitoring Board or Advisory Board from Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University. JRH reports grants or contracts from AstraZeneca; consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Takeda; and support for attending meetings and/or travel from AstraZeneca. KD reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, Boehringer Ingelheim, GSK, NORMA Hellas, Chiesi, AstraZeneca, and Zambon; support for attending meetings or travel from Novartis, Boehringer Ingelheim, GSK, NORMA Hellas, Chiesi, AstraZeneca, and Menarini; and participation on a Data Safety Monitoring Board or Advisory Board from Novartis, GSK, and Chiesi. AB reports grants or contracts from AstraZeneca outside of the submitted work; honoraria and lecture fees from Chiesi, GSK, and AstraZeneca paid to their institution, outside of the submitted work; leadership or fiduciary roles in other board, society, committee, or advocacy groups as paid or unpaid Head of Assembly 5 (Airway diseases, asthma, COPD, and chronic cough), the European Respiratory Society, co-chair of the Nordic severe asthma network, and a member of the steering committee of SHARP, European Respiratory Society's severe asthma Clinical Research Collaboration; and a member of the steering committee of the Swedish National Airway Register. FB reports grants or contracts from AstraZeneca, GSK, and Insmed; consulting fees from Menarini, OM Pharma, and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Chiesi, GSK, Grifols, Insmed, Menarini, OM Pharma, Pfizer, Sanofi, Vertex, Viatris, and Zambon. MS reports grants or contracts from GSK, Trudell pharma, and the Tel Aviv league for lung diseases; consulting fees from AstraZeneca, Boehringer Ingelheim, Dexcel, Kamada, Synchrony Medical, Trumed, Vertex, and Zambon; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, Insmed, and Kamada; support for attending meetings or travel from Boehringer Ingelheim, AstraZeneca, Rafa, GSK Israel, and Kamada; participation on a Data Safety Monitoring Board or Advisory Board for Bonus Biotherapeutics, Boehringer Ingelheim, and AstraZeneca; leadership or fiduciary roles in other board, society, committee, or advocacy groups with AJRCCM Associate Editor, the Israeli Pulmonology Society, the Israeli Society for Tuberculosis and Mycobacterial Diseases, and EMBARC as an unpaid management board member and European Respiratory Journal, Chest as an unpaid Editorial board member; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Trudell Medical International. PCG reports payment or honoraria for a lecture on bronchiectasis from Insmed; support for attending meetings and/or travel from AstraZeneca and Chiesi; and participation on a Data Safety Monitoring Board or Advisory Board from Boehringer Ingelheim, AstraZeneca, and Merck. LT reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda and Insmed. JDC reports grants or contracts from Grifols; consulting fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Grifols, Insmed, Janssen, Novartis, Pfizer, and Zambon; and leadership or fiduciary roles as Chair of the European Respiratory Society Bronchiectasis Guideline Task Force, Chief Editor of European Respiratory Journal, and Chair of EMBARC Clinical Research Collaboration. NK could not be reached to declare any competing interests. All other authors declare no competing interests.
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