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.

Acute respiratory tract infections represent a significant burden in primary care, with antibiotics often prescribed unnecessarily. This contributes to the escalating threat of antimicrobial resistance (AMR) by increasing the burden of infectious diseases and mortality risk. This is a report from a joint European Society of Clinical Microbiology and Infectious Diseases/European Respiratory Society research seminar held in November 2023 to discuss the role of in vitro diagnostic tests to combat AMR in community-acquired respiratory tract infections. We review the diagnostic tools available and in development, and the challenges related to their assessment, implementation in clinical settings and their overall impact on AMR.

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.

Antimicrobial resistance is a significant threat to healthcare worldwide. The appropriate use of antimicrobials could decrease the excess morbidity of respiratory infections and contribute to reducing the emergence of multidrug resistance. For this purpose, the European Union has funded the VALUE-Dx project to assess the value of rapid diagnostic tests in combatting antimicrobial resistance by optimizing antibiotic use in community-acquired lower respiratory tract infections (CA-LRTI). In this context, the current statement aims to review the literature and current practice regarding the role of rapid diagnostic tests in managing CA-LRTI for antibiotic stewardship purpose and combatting antimicrobial resistance. In particular, this paper evaluates the accuracy of rapid diagnostic tests for the aetiological diagnosis of CA-LRTI, the usefulness of biomarkers and clinical algorithms in the management of CA-LRTI, the differences in aetiology according to the diagnostic protocol and tests applied for CA-LRTI after the introduction of rapid diagnostic tests for a complete microbiological investigation and, finally, the role of rapid diagnostic tests in antibiotic stewardship protocols in improving clinical outcomes.

Background Bronchiectasis is a complex disease with geographical variability in its presentation and management. Despite the growing contribution of international registries, real-world data on the Italian bronchiectasis population remain limited. The objective of the present study was to describe the demographic, clinical, microbiological, functional and treatment characteristics of Italian patients with bronchiectasis and to compare them with those of patients from other Southern European countries. Methods This was a secondary analysis of adults from 18 Italian centres included in the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) registry, with comparisons made to patients in Spain, Greece, Portugal, Turkey, Israel and Malta (Southern European countries). Demographics, comorbidities, exacerbation history, spirometry, microbiology and treatment patterns were evaluated. Results Among 1657 Italian patients, the majority were female (70.5%) with a median age of 65 years, with high rates of idiopathic bronchiectasis (55.4%) and preserved lung function. Compared with other Southern European countries (n=2638), Italian patients had lower disease severity (median Bronchiectasis Severity Index: 6 versus 7; p<0.001), less frequent isolation of Pseudomonas aeruginosa, and lower prevalence of daily sputum production and purulence, despite identical quality of life (median Quality of Life Questionnaire-Bronchiectasis Respiratory Symptom Score: 70.4 in both groups). Treatment patterns differed, with lower use of inhaled antibiotics (1.1% versus 13.1%) and macrolides (6.0% versus 14.3%), but more widespread use of airway clearance (48.4% versus 35.9%) among patients from Italy versus other Southern European countries. Conclusions These findings may reflect earlier referral, diagnostic preferences or structural differences in care delivery in Italy compared with other Southern European countries. This work lays the foundation for tailored national strategies and future longitudinal studies. The largest bronchiectasis cohort ever studied in Italy reveals unique clinical traits and highlights key differences from other Southern European countries, and provides real-world data to shape better care models and guide future research.

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: 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:Clinical trials assessing the management of pneumonia use heterogeneous outcomes, often lacking patient relevance or standardisation. We developed two core outcome sets (COSs) for future clinical trials evaluating interventions in community-acquired pneumonia (CAP) and nosocomial pneumonia (hospital-acquired pneumonia and ventilator-associated pneumonia) to improve the consistency and comparability of evidence. METHODS:A multistage, multistakeholder process was undertaken, comprising 1) a systematic review of previously used outcomes conducted by our team, 2) qualitative interviews with patients and 3) a two-round online Delphi survey involving 289 participants (patients, relatives and healthcare professionals) from 58 countries. This diverse sample ensured a broad representation of clinical and patient perspectives. Final outcomes were agreed upon through structured voting in two virtual consensus meetings in April 2025. RESULTS:The final COS for CAP includes: treatment success/failure, all-cause mortality, serious adverse events, readmissions (admission for community-based trials), duration of symptoms and time to clinical stability (for hospitalised patients). The nosocomial pneumonia COS includes: treatment success/failure, all-cause mortality, serious adverse events, readmission and need for ventilatory support. The panel suggested measuring mortality at 30 days from study enrolment and readmission at 30 days post-discharge. CONCLUSIONS:These COSs, developed by a European Respiratory Society Task Force, provide a standardised framework for outcome selection in pneumonia trials and were informed by broad stakeholder input, including patients. Their use is expected to improve the relevance, quality and comparability of future research in pneumonia.

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 Limited evidence exists to guide Elexacaftor-Tezacaftor-Ivacaftor (ETI) use in adults with cystic fibrosis (awCF) and preserved lung function (ppFEV1 >90%). To address the resulting variability in prescribing practices, we conducted a European survey among a group of adult CF centres aiming at identifying factors influencing ETI initiation decisions in adults with preserved lung function. Methods Between April and June 2024, we invited 25 ECFS prescribers from 25 adult CF centres to participate in a web-based survey to explore factors influencing ETI initiation in adults with CF and ppFEV₁ >90%. The survey questionnaire collected data on centre characteristics, prescribing ETI attitudes, and the impact of specific clinical variables on ETI prescription decision in this subgroup. Results Twenty-three CF specialists (92%) responded. Most specialists (69.6%) favoured early treatment initiation in all eligible patients. A key factors influencing ETI initiation decisions was the presence of respiratory symptoms. In adults with preserved lung function, however, microbiological and imaging features emerged as the most influential factors driving treatment decision. While patient willingness and symptoms strongly encouraged ETI use, factors like age over 50, a history of mental health issues, and pregnancy desire resulted in conflicting prescribing attitudes among centers. Conclusions Although several disease markers more consistently support the decision to initiate ETI in individuals with preserved lung function, the absence of clear clinical guidance contributes to heterogeneous prescribing practices across centres. This highlights the need for longitudinal studies to clarify the long-term outcomes of ETI in this population.

Antimicrobial resistance is a significant threat to healthcare worldwide. The appropriate use of antimicrobials could decrease the excess morbidity of respiratory infections and contribute to reducing the emergence of multidrug resistance. For this purpose, the European Union has funded the VALUE-Dx project to assess the value of rapid diagnostic tests in combatting antimicrobial resistance by optimising antibiotic use in community-acquired lower respiratory tract infections (CA-LRTI). In this context, the current statement aims to review the literature and current practice regarding the role of rapid diagnostic tests in managing CA-LRTI for antibiotic stewardship purpose and combatting antimicrobial resistance. In particular, the present paper evaluates the accuracy of rapid diagnostic tests for the aetiological diagnosis of CA-LRTI, the usefulness of biomarkers and clinical algorithms in the management of CA-LRTI, the differences in aetiology according to the diagnostic protocol and tests applied for CA-LRTI after the introduction of rapid diagnostic tests for a complete microbiological investigation and, finally, the role of rapid diagnostic tests in antibiotic stewardship protocols in improving clinical outcomes.

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.