OBJECTIVES:Eosinophilic bronchiectasis is defined by a blood eosinophil count (BEC) ≥300 cells/µL, but blood eosinophils imperfectly reflect airway eosinophilic inflammation. Here, we investigated the relationship between eosinophilic airway inflammation, blood eosinophils and clinical severity in bronchiectasis and explored the phenotype associated with eosinophilic bronchiectasis. METHODS:Sputum from 180 patients with stable CT-confirmed bronchiectasis was utilised to investigate airway levels of eosinophil proteins (eosinophil peroxidase (EPX), eosinophil derived-neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein (MBP) and Galectin-10 (Gal-10)) using a novel stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. To profile eosinophilic bronchiectasis, a nested analysis of patients with BEC <150 cells/µL (n=52) and ≥300 cells/µL (n=49) was conducted. RESULTS:Sputum concentrations of Gal-10, ECP and EDN were weakly but significantly associated with radiological severity, FEV1 and sputum culture positivity for Pseudomonas aeruginosa. Airway eosinophil protein concentrations did not associate with exacerbation frequency. Total eosinophil protein concentration moderately correlated with BECs (r=0.33 95% CI 0.14 to 0.49, p=0.0007). Nested analysis revealed increased sputum PCR-positivity for P. aeruginosa (26.7% vs 7.7%, p=0.033) and an increased frequency of patients showing signs of Aspergillus sensitisation (defined as Aspergillus-specific IgE titres >0.35 kUA/L, 24.5% vs 3.8%) in eosinophilic bronchiectasis. Sputum inflammatory biomarkers and clinical parameters did not differ between groups. CONCLUSIONS:LC-MS/MS can detect eosinophilic inflammation within bronchiectasis sputum. Weak associations between elevated airway eosinophil proteins, bronchiectasis severity and P. aeruginosa infection were observed. Direct measurement of eosinophilic airway inflammation provides additional information in addition to BECs. Eosinophilic bronchiectasis associated with P. aeruginosa infection and Aspergillus sensitisation.

BACKGROUND:Dipeptidyl peptidase-1 (DPP1) inhibitors prevent the activation of neutrophil serine proteases and reduce exacerbations in people with bronchiectasis. We previously identified a novel effect of DPP1 inhibitors in reducing the neutrophil pseudoenzyme azurocidin-1 (AZU1). The aim of this study was to investigate the role of AZU1 in the pathophysiology of bronchiectasis. METHODS:Sputum AZU1 concentrations were analysed in multiple cohorts. These consisted of two observational cohorts of patients with bronchiectasis (EMBARC BRIDGE cohort 1 and cohort 2) and a cohort of patients with chronic obstructive pulmonary disease (COPD; TARDIS COPD cohort) to correlate AZU1 with disease severity and exacerbations. A rhinovirus challenge study was used to investigate AZU1 concentrations during experimental exacerbation in COPD, people who smoke, and controls. A post-hoc analysis of the phase 2 WILLOW trial of brensocatib versus placebo was used to assess the effect of DPP1 inhibition on airway AZU1. FINDINGS:Higher AZU1 sputum concentration was associated with increased bronchiectasis disease severity index (p<0·0001), decreased percentage predicted forced expiratory volume in 1 second (r=-0·4662, p<0·001), and increased exacerbation frequency (p<0·0019; EMBARC cohort 1, n=197). AZU1 was associated with radiological severity (Reiff score), symptoms (quality of life bronchiectasis respiratory symptom score), and bacterial infection (sputum microbiology and 16S microbiome alpha diversity; highest levels of AZU1 were found in airway samples with Pseudomonas aeruginosa; p<0·0001; EMBARC cohort 2, n=144). Bronchiectasis patients with bacterial and viral exacerbations had increased concentrations of AZU1 (p=0·0003; n=96). These findings were extended to COPD, in which AZU1 was related to COPD severity (COPD cohort, n=101), and in patients with COPD challenged with rhinovirus A16, AZU1 was increased at day 9 post-challenge (p<0·001; n=9). In-vitro AZU1 impaired ciliary function and epithelial integrity, suggesting a mechanism by which AZU1 drives disease pathogenesis. In a post-hoc analysis of the WILLOW trial, AZU1 was the most downregulated protein with brensocatib treatment (brensocatib 10 mg, n=71; brensocatib 25 mg, n=73; and placebo, n=71). Over 24 weeks, AZU1 was significantly reduced by DPP1 inhibition (p<0·0001). INTERPRETATION:AZU1 was identified as a novel marker of disease severity in bronchiectasis, associated with bacterial infection and exacerbation, and targeted by DPP1 inhibition. FUNDING:EMBARC3 and Insmed.

RATIONALE:The frequent exacerbator phenotype was previously defined using a threshold of  ≥3 exacerbations per year in bronchiectasis. However, the contribution of each prior exacerbation to future risk as well as the influence of severe exacerbations and different etiologies and regions remain poorly understood. OBJECTIVES:To quantify the risk associated with each prior exacerbation of bronchiectasis in predicting future exacerbations and severe exacerbations, and to determine whether this association varies across different etiologies and geographic regions. METHODS:We analyzed data from the European Bronchiectasis Registry (EMBARC), including 30 countries across Europe and Asia. The association between baseline exacerbation history and future exacerbations was tested using negative binomial regression over up to 5 years of follow-up. Severe exacerbations were defined as those requiring hospitalization. MEASUREMENTS AND MAIN RESULTS:A total of 19 324 patients with bronchiectasis were included. Each prior exacerbation was associated with an increased risk of exacerbations and severe exacerbations. Incidence rate ratio (IRR) for future exacerbations was 1.45 (95% CI 1.34-1.58, P < .001) for 1 exacerbation; 1.84 (95% CI 1.69-1.99, P < .001) for 2 exacerbations; 2.50 (95% CI 2.29-2.73, P < .001) for 3 exacerbations; and 3.56 (95% CI 3.32-3.82, P < .001) for patients with 4 or more prior exacerbations. Additionally, 1 prior severe exacerbation was associated with increased risk of exacerbation (IRR = 1.52, 95% CI 1.45-1.60, P < .001) and strongly associated with future severe exacerbations (IRR = 3.96, 95% CI 3.71-4.22, P < .001). The frequent exacerbator phenotype was consistent across different etiologies and geographic regions. CONCLUSIONS:The frequent exacerbator phenotype is highly consistent across patient subgroups and regions. Each prior exacerbation is associated with a progressively higher risk, with no definitive threshold-defining high risk.

Background Neutrophilic airway inflammation is associated with disease severity and exacerbation frequency in bronchiectasis. Neutrophil protease inhibition significantly reduced exacerbation rates in phase II and III trials in bronchiectasis, highlighting this disease feature as an important therapeutic target. Additional neutrophil targeting therapeutics are needed to reduce the burden of the disease. Herein, we describe the protocol for the AIR-NET trial, the first randomised, open-label, multifactorial, multicentre, adaptive platform trial for people with bronchiectasis, run via the EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) network, to investigate the safety and efficacy of several repurposed anti-inflammatory treatments. Methods and analysis Participants with bronchiectasis confirmed by computed tomography, daily sputum production and evidence of active airway neutrophilic inflammation (based on a positive lateral flow test for neutrophil elastase (NE) activity), across 10 sites in the UK, will be randomised to one of several repurposed drugs with published evidence of effects on neutrophilic inflammation and acceptable safety profile (oral dose: disulfiram 400 mg once daily; dipyridamole 200 mg twice daily; doxycycline 100 mg once daily; n=42 per arm) or usual care, according to arm-specific eligibility criteria, and treated for 28 days. New arms will be added to the trial through an adaptive design. The primary end-point is change from baseline in sputum NE activity (a validated biomarker and surrogate of exacerbation risk) at day 28. Key secondary endpoints include time-to-first exacerbation, quality of life questionnaires, neutrophil function and safety. Summary AIR-NET will establish a multi-centre network with integrated clinical and translational capabilities for the investigation of therapies in bronchiectasis aiming to identify key anti-inflammatory mechanisms and effective re-purposed treatments.

Background Mucoactives such as hypertonic saline (HTS) and carbocisteine are widely used in the treatment of bronchiectasis, though there is insufficient evidence to support their use. The aim of this mechanistic sub-study, embedded within the CLEAR trial, was to characterise the properties of sputum from patients with bronchiectasis and to assess whether treatment with HTS and/or carbocisteine altered these properties. Methods In CLEAR, patients were randomised to receive HTS, carbocisteine, HTS plus carbocisteine or standard care, and sputum samples were collected at randomisation (baseline) and at 2 and 8 weeks post-randomisation. Sputum viscoelasticity was determined by rotational plate rheometry. Biomarkers were quantified by ELISA and microbiome composition was assessed by next-generation sequencing. The primary outcome was differences in sputum viscoelasticity between groups at 2 weeks following the commencement of treatment. Results Sputum viscoelastic properties were not reduced by 2 or 8 weeks of treatment with HTS and/or carbocisteine (n=6–15 per group). Sputum biomarker levels and bacterial community composition were similar across groups at 2 or 8 weeks. At baseline, viscoelasticity (crossover point σc) was positively correlated with IL-8 (r=0.49, p=0.012) and greater relative bacterial dominance (r=0.35, p=0.041). Conclusions These data do not support the use of HTS or carbocisteine to alter sputum viscoelasticity, inflammatory marker levels or bacterial community composition in patients with bronchiectasis.

Background: Primary ciliary dyskinesia is an inherited cause of bronchiectasis. Little is known about disease course and outcomes in adults compared to other bronchiectasis aetiologies. Methods: Data were analysed from four prospective international bronchiectasis registries (EMBARC- Europe, BRR -USA, CanBE-NTM -Canada and ABR -Australia). Comparisons of disease severity and outcomes were made between people with PCD and bronchiectasis of other causes. Follow up data for exacerbations and severe exacerbations were assessed using negative binomial regression adjusted for confounders. Cox proportional hazards regression was used to investigate the association between PCD diagnosis and new infection with Pseudomonas aeruginosa and mortality. A nested biomarker study was conducted in European patients (EMBARC-BRIDGE). Results: 836/24601 (3.3%) adults with bronchiectasis had a diagnosis of PCD. Compared to other aetiologies, patients with PCD were significantly younger at baseline (median age (IQR) 41 (29-58) vs 68 (59-75), with lower FEV1% predicted (67.8 (IQR 47.2-85.4) vs 76.7 (IQR 57.4-94.4)) and were more frequently infected with P. aeruginosa (40.7% vs 18.2%), Haemophilus influenzae (23.3 vs 14.6) and other pathogens. In the nested mechanistic study Adults with PCD had significantly higher levels of airway neutrophilic inflammation (NE, PR3, AZU1, OLFM4). Bronchiectasis was bilateral and predominantly in the middle and lower lobes.In long-term follow-up, Adults with PCD were at higher risk of exacerbations and severe exacerbations even after adjustment for confounders (age, sex, lung function, COPD, asthma, NTM diagnosis, P. aeruginosa infection, MRC dyspnoea score, medications, country/region) Incidence Rate Ratio (IRR) 1.32 (95% CI 1.13-1.53) and IRR 1.66(1.35-2.06) respectively. Patients with PCD were at markedly increased risk of new P.aeruginosa infection. Mortality risk was not increased. Conclusion: Adults with Adults with PCD are a very high risk endotype of bronchiectasis with an increased risk of exacerbations, severe exacerbations and new P. aeruginosa infection. Funding: EMBARC is supported by the European Respiratory Society through the Clinical Research Collaboration programme. EMBARC4 is supported by project partners Astrazeneca, Alarmin Therapeutics, Boehringer Ingelheim, Centauri therapeutics, Chiesi, CSL Behring, Glaxosmithkline, Grifols, Insmed, Lifearc, Roche, UCB Therapeutics, Verona Pharma, Zambon. BEAT-PCD is supported by the European Respiratory Society. JDC and AS are supported by GSK/Asthma and Lung UK Chair of Respiratory Research. Declaration of Interest: A Shoemark reports support for the present manuscript from the European Respiratory Society through the EMBARC3 consortium, which is supported by project partners Armata, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Grifols, Insmed, Janssen, Lifearc, Novartis, and Zambon; grants or contracts from AstraZeneca and Lifearc; consulting fees from Spirovant, Translate Bio, and ReCode Therapeutics; payment or honoraria from Translate Bio, Ethris, and Insmed; and unpaid involvement in European Respiratory Society Clinical Research Collaborations (EMBARC, BEATPCD, and AMR Lung). F C Ringshausen reports grants or contracts to institution from the German Center for Lung Research (DZL), German Center for Infection Research (DZIF), IMI (EU/EFPIA), iABC Consortium (including Alaxia, Basilea, Novartis, and Polyphor), Mukoviszidose Institute, Novartis, and Insmed Germany; consulting fees from Parion Sciences, Boehringer Ingelheim, Insmed, and Chiesi; payment or honoraria from I!DE Werbeagentur GmbH, Insmed, Grifols, University Hospital Hamburg, AstraZeneca, Clinigo GmbH, and Sanofi; participation on Data Safety Monitoring or Advisory Boards for Insmed, Boehringer Ingelheim, Parion Sciences, and Chiesi; roles as co-chair of the German Bronchiectasis Registry PROGNOSIS, member of the Steering Committee of the European Bronchiectasis Registry EMBARC, and PI of the German Center for Lung Research; and fees for clinical trial participation paid to institution from AstraZeneca, Boehringer Ingelheim, Insmed, Novartis, Parion Sciences, Recode, Ruhr University-Bochum, University of Dundee, UMC Utrecht, and Vertex. M R Loebinger reports consulting fees from 30 Technology, AstraZeneca, Insmed, Chiesi, ReCode, Boehringer Ingelheim, Ethris, Mannkind, AN2 Therapeutics, MucPharm, and Galapagos; payment or honoraria from Insmed; support for attending the BTS winter meeting from Insmed; and participation on a Data Safety Monitoring or Advisory Board for Sanofi. M Crisafulli reports sponsorship of the Australian Bronchiectasis Registry (ABR) paid to Lung Foundation Australia from Insmed Incorporated, Boehringer Ingelheim, GSK, Zambon, and AstraZeneca. A E Brunton reports a role as an employee of the Bronchiectasis and NTM Association, which sponsors the BRR. E Polverino reports consulting fees from Insmed, Grifols, Pari, and CSL Behring; payment or honoraria from Insmed, Pari, Grifols, and CSL Behring; and participation on a Data Safety Monitoring or Advisory Board for Insmed. R Ewen reports payment or honoraria from Boehringer Ingelheim Pharma GmbH & Co. KG and support for attending meetings and/or travel from Boehringer Ingelheim Pharma GmbH & Co. KG and Chiesi GmbH. A De Soyza reports grants and contracts to institution from GSK, 30 Technology, and Sanofi; consulting fees from 30 Technology, Insmed, AstraZeneca, and Sanofi; and payment or honoraria from AstraZeneca, Bayer, GSK, Insmed, Zambon, Sanofi, Fisher & Paykel, and Inogen. M Vendrell reports payment or honoraria to institution from Insmed and Teva; support for attending meetings and/or travel from Pari, Grifols, Chiesi, Insmed, and Gebro; participation on a Data Safety Monitoring or Advisory Board for Insmed; and a role as President of the Catalan Respiratory Society SOCAP involving Chiesi, Astra, Bial, Sanofi, Vivisol, Pfizer, Pari, Resmed, Boehringuer, Faes, and Menarini. P R Burgel reports grants or contracts to institution from Vaincre la Mucoviscidose; consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, MSD, Vertex, and Viatris; and support for attending meetings and/or travel paid to institution from AstraZeneca, Chiesi, and Zambon. C S Haworth reports grants or contracts to institution from AstraZeneca; consulting fees from 30 Technology, AstraZeneca, BiomX, Boehringer Ingelheim, Chiesi, Clarametyx, Infex, Insmed, LifeArc, Pneumagen, Revagenix, Sanofi, Vertex, and Zambon; payment or honoraria from Chiesi, Insmed, Vertex, and Zambon; payment for expert testimony from Zambon; and a role as an ECFS Board member. K Dimakou reports payment or honoraria to institution from Novartis, Boehringer Ingelheim, GSK, Norma Hellas, Chiesi, AstraZeneca, and Zambon; support for attending meetings and/or travel from Novartis, Boehringer Ingelheim, GSK, Norma Hellas, Chiesi, AstraZeneca, and Menarini; and participation on a Data Safety Monitoring or Advisory Board for Novartis, GSK, and Chiesi. F Blasi reports grants from AstraZeneca, Chiesi, and Insmed; consulting fees from Menarini; and personal fees for lectures and advisory boards from AstraZeneca, Chiesi, Boehringer Ingelheim, GSK, Grifols, Insmed, Menarini, MSD, OM Pharma, Pfizer, Sanofi, Vertex, and Zambon. J Altenburg reports consulting fees from Insmed; payment or honoraria from Takeda Nederland, Insmed, and Chiesi; and participation on a Data Safety Monitoring or Advisory Board for Insmed. M Shteinberg reports grants or contracts from the Tel Aviv League for Lung Disease and G. Baum Foundation; consulting fees from AstraZeneca, Boehringer Ingelheim, Dexcel, Insmed, Kamada, Synchrony Medical, Trumed, and Zambon; payment or honoraria from AstraZeneca, Boehringer Ingelheim, CSL Behring, GSK, Kamada, Sanofi, and Insmed; support for attending meetings and/or travel from Boehringer Ingelheim Israel, AstraZeneca Israel, Kamada, Rafa, and GSK Israel; participation on a Data Safety Monitoring or Advisory Board for Bonus Biotherapeutics, Boehringer Ingelheim, AstraZeneca, Insmed, and GSK; and roles as Associate Editor for AJRCCM, Treasurer for the Israeli Society for Tuberculosis and Mycobacterial Diseases, management board member for EMBARC, editorial board member for ERJ, and ERS taskforce member for bronchiectasis guidelines and transitioning in bronchiectasis. P C Goeminne reports consulting fees from AstraZeneca and Boehringer Ingelheim; payment or honoraria from AstraZeneca, Insmed, and RMEI; support for attending meetings and/or travel from AstraZeneca and Chiesi; participation on a Data Safety Monitoring or Advisory Board for Boehringer Ingelheim; and an unpaid board member role for the Belgian Respiratory Society. R Dhar reports payment or honoraria from Cipla, GSK, Glenmark, AstraZeneca, Zuventus, Sanofi, and Lupin; and participation on a Data Safety Monitoring or Advisory Board for Glenmark, Lupin, Sun Pharma, and Cipla. S Aliberti reports grants or contracts to institution from GSK; consulting fees from Insmed Incorporated, Insmed Netherlands BV, Insmed Germany GmbH, Physioassist SAS, Boehringer Ingelheim Italia SpA, Boehringer Ingelheim International GmbH, Thermo Fisher Scientific, Zambon Italia Srl, Sanofi Srl, Providens DOO, Pfizer Srl, Limare LLC, GSK SpA, Chiesi Farmaceutici SpA, and Vertex Pharmaceuticals (Europe) Limited; and participation on a Data Safety Monitoring or Advisory Board for GSK SpA, Boehringer Ingelheim Italia SpA, Moderna Italy Srl, Zambon SpA, Chiesi Farmaceutici SpA, Insmed Incorporated, Insmed Netherlands BV, AN2 Therapeutics Inc, Modernatx, and Boehringer Ingelheim International GmbH. C S Thornton reports grants or contracts from CIHR, Alberta Innovates Health Solutions, NFRF, CHEST Foundation, CFI JELF, Cystic Fibrosis Canada, and the Cystic Fibrosis Foundation; consulting fees from Boehringer Ingelheim and Clarametyx; support for attending meetings and/or travel from the Cystic Fibrosis Foundation; and participation on a Data Safety Monitoring or Advisory Board for the AirNET Trial (investigator-initiated trial). L Morgan reports consulting fees from GSK, Boehringer Ingelheim, Insmed, Chiesi, and AstraZeneca; payment or honoraria from Boehringer Ingelheim, Insmed, Sanofi, GSK, and AstraZeneca; participation on a Data Safety Monitoring or Advisory Board for AstraZeneca, Chiesi, GSK, and Boehringer Ingelheim; honorary roles as CI of the Australian Bronchiectasis Registry and Chair of Lung Foundation Australia; and fees for clinical trial participation paid to institution from AstraZeneca, Boehringer Ingelheim, Insmed, Parion, and Mannkind. M L Metersky reports grants or contracts from Insmed, Armata, and Sanofi; payment or honoraria from Insmed, Boehringer Ingelheim, and UCB; participation on a Data Safety Monitoring or Advisory Board for Verona, Renovion, and AN2; and a leadership or fiduciary role for the Bronchiectasis & NTM Association. J D Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, Gilead, Grifols, Insmed, and Trudell; and consulting fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Insmed, Janssen, Novartis, Pfizer, and Zambon. P J McShane, M B Long, R C Hull, M Frohlich, E D Johnson, E Cant, M Smith, J Jarand, and L Burr have no conflicts of interest to report.

BACKGROUND:Bronchiectasis and diabetes commonly coexist and are associated with immune dysfunction and increased susceptibility to infection. Although diabetes is associated with worse prognosis in cystic fibrosis-related bronchiectasis, data are scarce for its impact on non-cystic fibrosis bronchiectasis. This study aimed to characterise the impact of diabetes on clinical outcomes and microbial and inflammatory profiles in patients with bronchiectasis. METHODS:This analysis comprised data from the European Bronchiectasis Registry (EMBARC), Respiratory Research Network of India (EMBARC-India), Chinese Bronchiectasis Registry (BE-China), and Australian Bronchiectasis Registry (ABR); 30 263 patients with CT-confirmed bronchiectasis in 33 countries were included in the analysis: 16 963 from EMBARC (Jan 12, 2015, to April 12, 2022), 2361 from EMBARC-India plus additional Asian countries (June 1, 2015, to Sept 1, 2017), 10 324 from BE-China (Jan 10, 2020, to March 31, 2024), and 615 from the ABR (March 7, 2016, to Sept 11, 2018). Clinical data were compared between patients with and without diabetes. Long-term outcome data were available in EMBARC and EMBARC-India. Microbiome and inflammatory profiles were characterised in a sub-cohort of EMBARC patients by sputum 16S rRNA sequencing (n=433) and serum Olink (n=479). FINDINGS:2487 (8·2%) of 30 263 patients with bronchiectasis had diabetes. Patients with diabetes had a higher prevalence of comorbidities than those without diabetes, including cardiovascular disorders (53·5% vs 21·8%, p<0·0001), asthma (27·5% vs 21·0%, p<0·0001), and chronic obstructive pulmonary disease (34·3% vs 19·0%, p<0·0001). Patients with diabetes had more severe disease than those without diabetes, with higher Bronchiectasis Severity Index scores (8 [IQR 5-12] vs 7 [4-10], p<0·0001) and UK Medical Research Council (MRC) dyspnoea scores (p<0·0001) and more hospital admissions in the previous year (p<0·0001). After adjustment for confounders, outcomes were significantly worse in patients with diabetes than in those without diabetes, including more frequent exacerbations (incidence rate ratio [IRR] 1·18 [95% CI 1·09-1·28], p<0·0001), hospital admissions (IRR 1·57 [1·40-1·76], p<0·0001), and higher 5-year mortality (hazard ratio 1·80 [1·53-2·12], p<0·0001). The sputum microbiome was significantly altered in patients with diabetes compared to those without diabetes, with increased isolation of Enterobacteriaceae (p<0·0001), Moraxella catarrhalis (p=0·0035), and Haemophilus influenzae (p=0·046). In serum, Gal-4 and GDF-15, established biomarkers of disease severity and cardiovascular risk in diabetes, were significantly increased in patients with diabetes (Gal-4, p<0·0001; GDF-15, p=0·0019). INTERPRETATION:Patients with diabetes and bronchiectasis are a high-risk population with more severe disease, worse outcomes, increased comorbidities, and increased risk of infections compared with patients without diabetes. These findings support inclusion of diabetes as a risk factor in individualised risk assessments for bronchiectasis. FUNDING:European Respiratory Society, Armata, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Grifols, Insmed, Janssen, Lifearc, Roche, Verona Pharma, Zambon, National Natural Science Foundation of China, Innovation Program of the Shanghai Municipal Education Commission, Program of the Shanghai Municipal Science and Technology Commission, Program of the Shanghai Shenkang Development Center, EU/European Federation of Pharmaceutical Industries and Associations, Innovative Medicines Initiative, and Inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis Consortium.

Introduction:Chronic rhinosinusitis (CRS) is a common comorbidity in bronchiectasis. Previous studies suggested that bronchiectasis with CRS is associated with elevated type 2 biomarkers, representing an "eosinophilic bronchiectasis" phenotype. However, whether the association with type 2 inflammation exists in rare aetiologies of bronchiectasis such as primary ciliary dyskinesia (PCD) or immune deficiency is unknown. Our aim was to explore the prevalence of CRS with and without nasal polyposis (CRSwNP and CRSnNP), their impact on bronchiectasis outcomes, and their association with type 2 inflammatory biomarkers in patients with bronchiectasis of various aetiologies. Methods:Using data from the EMBARC bronchiectasis registry, we classified patients with bronchiectasis as having no CRS, CRSnNP or CRSwNP. Regression models were used to test the effect of CRS on symptom scores and long-term outcomes. Multivariate models were created for elevated "type 2 biomarkers", defined as elevated blood eosinophil count or total IgE. Results:Among 16 640 people with bronchiectasis, 2703 (20.9%) had CRSnNP and 1223 (7.3%) had CRSwNP. CRSwNP and CRSnNP were associated with worse symptoms and more frequent exacerbations, but lower hospitalisations and mortality. Type 2 biomarkers were elevated in people with comorbid CRSwNP in idiopathic bronchiectasis, but not in bronchiectasis secondary to PCD or immune deficiency. In multivariable analysis, CRSwNP was independently associated with elevated type 2 biomarkers. Conclusions:CRS and nasal polyposis are common comorbidities in bronchiectasis, associated with worse symptoms and exacerbations. Elevated type 2 biomarkers are associated with CRS, but this finding is dependent on the aetiology of bronchiectasis.

BACKGROUND:Our objective is to document major healthcare resource use and associated costs in the care of patients with bronchiectasis, with a particular focus on the costs incurred by exacerbations. METHODS:We use a unique dataset from the Bronchiectasis Observational Cohort and Biobank UK. The study includes a baseline cohort of 1119 patients with a primary diagnosis of bronchiectasis, followed for up to five years. Data were extracted and linked to centrally held National Health Service (NHS) resource use data. RESULTS:The average age of the cohort was 64 years and 62% were female. The most common bronchiectasis aetiology was idiopathic or post-infectious. Across follow-ups, exacerbations became less frequent: the proportion of patients with no events increased for all settings, while recurrent (≥2) events declined markedly and single-event categories remained largely stable. Exacerbations were predominantly managed in primary care settings. Based on exacerbation frequency and type and applying 2024/2025 NHS reference costs, the estimated total healthcare exacerbation costs for the study population ranged from £2 million to £3.2 million. Disaggregated estimates for the highest cost scenario include: general practitioner (GP)-only exacerbations (n=2824 events; £479 945), emergency department-managed exacerbations (n=311; £260 126) and inpatient-managed exacerbations (n=680; £2 428 291). The average estimated cost per patient over the full period was £1943. This corresponds to a weighted annual average of £495 per patient (including patients with no exacerbations), with most costs attributable to inpatient-managed exacerbations. Specifically, the average cost was £2980 for individuals with one or more exacerbations, £4865 for those with two or more and £5875 for those with three or more. CONCLUSIONS:The findings highlight the economic burden of bronchiectasis exacerbations and demonstrate that targeted management strategies to reduce exacerbation rates should increase health benefits and substantially reduce healthcare costs associated with bronchiectasis.

Primary ciliary dyskinesia (PCD) is a genetically and clinically diverse disorder characterised by loss of normal ciliary function leading to chronic oto-sino pulmonary disease, situs abnormalities and subfertility in men and women. There is limited evidence to support robust guidelines on the management of children and adults with PCD; however, there is a clear clinical need to establish a framework of care for the follow-up of these patients. The European Respiratory Society (ERS) has published consensus statements on diagnostic and treatment approaches in children with PCD, and the BEAT-PCD (Better Experimental Approaches to Treat PCD) network provides guidance on infection prevention and control. This is a national consensus statement to outline a set of standards for the provision of specialist care for children and adults with PCD living in England. A national PCD expert panel made up of specialists working in both paediatric and adult UK highly specialist management services, was established to create a consensus statement on the minimum standards of care for PCD. Using a modified Delphi process, consensus to a statement required at least 80% agreement within the PCD expert panel group. Patient organisation representatives were involved in reviewing the statement and have produced an accompanying layperson summary. We present a consensus statement on 15 standards covering provision of pulmonary, ear, nose and throat, and fertility care, screening for situs abnormalities and transition from paediatric to adult care services. It is targeted at clinicians and allied health professionals managing paediatric and adult patients with PCD, patient organisations and patients and their families.

Background:Culture-independent molecular techniques could potentially be used to measure microbiological efficacy in response to antibiotic treatment and improve understanding of the role of the airway microbiota in determining response in patients with chronic respiratory disease. Methods:Using molecular methods, we analysed changes in the sputum microbiota in samples from 107 participants with bronchiectasis recruited to the iBEST-1 study, and defined community endotypes based on response to tobramycin inhalation powder (TIP) treatment. The relationship between microbiota metrics in these endotypes and clinical and inflammatory biomarkers were also determined. Results:There was a significant reduction in Pseudomonas aeruginosa density, measured by quantitative polymerase chain reaction (qPCR), between Days 1 and 29 for participants in the TIP treatment (n=63; p<0.0001) but not placebo (n=20; p>0.05) group. Based on decrease in P. aeruginosa density (oprL copies·mL-1) over 28 days, two clusters of participants receiving TIP were observed and stratified as either responders (≥2Log10; n=26) or non-responders (<2Log10; n=37). In responders, a shift to a microbial community structure less dominated (p=0.018) by a pathogen was apparent and associated with a greater improvement in inflammatory and fewer participant exacerbations in the following 6 months (27% versus 49%; p=0.117) when compared to non-responders. Lung function was higher at Day 1 in responders (median=64.6% predicted) than non-responders (μ̃median=50.3% predicted) and independently predicted response to treatment with TIP (p=0.013). Conclusions:qPCR may be a useful, culture-independent microbiological efficacy end-point in clinical trials. Using qPCR, participants with bronchiectasis were stratified into endotpyes which predicted response to antimicrobial treatment, potentially allowing for a more personalised approach to therapy.

BACKGROUND:Bronchiectasis guidelines are inconsistent with regard to the effectiveness of mucoactive agents, and their use varies geographically. Large trials are needed to assess safety and effectiveness. METHODS:For this open-label, randomized, two-by-two factorial trial at 20 sites in the United Kingdom, we enrolled participants with non-cystic fibrosis bronchiectasis who had frequent pulmonary exacerbations and daily sputum production. Current smokers and persons who had recently received mucoactive treatments were excluded. All participants received standard care and were also assigned either to one of three mucoactive-drug groups - hypertonic saline (the hypertonic-saline group), hypertonic saline and carbocisteine (the combination group), or carbocisteine (the carbocisteine group) - or to standard care alone. The comparisons were between hypertonic saline and no hypertonic saline and between carbocisteine and no carbocisteine, with each category consisting of two groups. The primary outcome was the number of pulmonary exacerbations over a 52-week period. Key secondary outcomes were scores on disease-specific health-related quality-of-life assessments, time to next pulmonary exacerbation, and safety. RESULTS:A total of 288 participants underwent randomization. No treatment interactions were found. The mean number of adjudicated fully qualifying pulmonary exacerbations over the 52-week period was 0.76 (95% confidence interval [CI], 0.58 to 0.95) with hypertonic saline as compared with 0.98 (95% CI, 0.78 to 1.19) with no hypertonic saline (adjusted between-group difference in the means, -0.25 [95% CI, -0.57 to 0.07; P = 0.12]) and 0.86 (95% CI, 0.66 to 1.06) with carbocisteine as compared with 0.90 (95% CI, 0.70 to 1.09) with no carbocisteine (adjusted between-group difference in the means, -0.04 [95% CI, -0.36 to 0.28; P = 0.81]). Secondary outcomes and the incidence of adverse events, including serious adverse events, were similar across the groups. CONCLUSIONS:In participants with bronchiectasis, neither hypertonic saline nor carbocisteine significantly reduced the mean incidence of pulmonary exacerbations over a period of 52 weeks. (Funded by the National Institute for Health and Care Research Health Technology Assessment Programme and others; ISRCTN Registry number, ISRCTN89040295.).

Introduction Bronchiectasis is a chronic inflammatory airway disease. Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces pulmonary inflammation by preventing the activation of neutrophil serine proteases. In the phase II WILLOW trial, brensocatib prolonged time to first exacerbation in patients with bronchiectasis. In this post hoc analysis we compare clinical outcomes in patients from WILLOW according to baseline disease characteristics. Methods Adults with bronchiectasis treated with brensocatib (10 or 25 mg) or placebo once daily were analysed by baseline Bronchiectasis Severity Index (BSI) score (≤4 (mild), 5–8 (moderate), or ≥9 (severe)), exacerbation history (2 or ≥3 in the previous year), blood eosinophil count (<300 cells per µL or ≥300 cells per µL), long-term macrolide use (≥6 months; no or yes) and Pseudomonas aeruginosa culture at screening (negative or positive). End-points were time to first exacerbation, annualised exacerbation rate, change in lung function from baseline, and safety. All patients who received brensocatib were pooled and compared with placebo. Results Treatment with brensocatib versus placebo was associated with a longer time to first exacerbation (hazard ratio (95% confidence interval), BSI: ≤4, 0.28 (0.08–0.96); 5–8, 0.75 (0.35–1.60); ≥9, 0.61 (0.35–1.04); prior exacerbations: 2, 0.56 (0.34–0.90); ≥3, 0.71 (0.32–1.59); blood eosinophils per µL: <300, 0.66 (0.42–1.06); ≥300, 0.49 (0.20–1.20); long-term macrolide use: no, 0.60 (0.38–0.94); yes, 0.60 (0.25–1.45); P. aeruginosa culture: negative, 0.54 (0.32–0.92); positive, 0.68 (0.37–1.27)). Safety results were similar across subgroups. Discussion Patients treated with brensocatib had a numerically longer time to first exacerbation and reduced annualised rate of exacerbation versus placebo across all key baseline disease characteristics.

Background and Objective This study explored the relationship between total bacterial density, airway microbiota composition and clinical parameters in bronchiectasis. We determined changes with time during clinical stability and following antibiotic treatment of a pulmonary exacerbation. Methods We conducted a multicentre longitudinal cohort study of UK participants with CT confirmed bronchiectasis. Sputum samples and clinical parameters [FEV1% predicted, lung clearance index, C-reactive protein, white cell count and Quality of Life] were collected when participants were clinically stable and pre/post-antibiotic treatment of an exacerbation. Total bacterial density and microbiota community composition was measured by quantitative polymerase chain reaction and sequencing of the V4 region of bacterial 16S rRNA, respectively. Results Among 105 participants at baseline, 65 (62%) were female with a mean age of 65 years and FEV1 at 69% predicted. In participants who remained clinically stable (n=15), no significant changes were observed in bacterial density, microbiota diversity, richness, evenness, and dominance (p=0.30, 0.45, 0.54, 0.23 and 0.43; respectively) across four time points over a 1-year period. Similarly, for participants with paired pre/post-antibiotic treatment samples (n=19), no significant changes were observed (p=0.30, 0.46, 0.44, 0.71 and 0.58; respectively). However, considerable fluctuation in community composition between samples was apparent for most patients. Total bacterial density and microbiota composition did not correlate with clinical parameters at baseline (n=75). Conclusions Stability in bacterial density and microbiota diversity, richness, evenness and dominance was observed over time at a population level but considerable fluctuation was apparent in samples from individual patients.