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Aim: Bronchiectasis (BE) is a disease defined by irreversible dilatation of the airway. Computed tomography (CT) plays an important role in the detection and quantification of BE. The aim of this study was three-fold: 1) to assess bronchus-artery (BA) dimensions using fully automated software in a cohort of BE disease patients; 2) to compare BA dimensions with semi-quantitative BEST-CT (Bronchiectasis Scoring Technique for CT) scores for BE and bronchial wall thickening; and 3) to explore the structure-function relationship between BA-method lumen dimensions and spirometry outcomes., Methods: Baseline CTs of BE patients who participated in a clinical trial were collected retrospectively. CTs were analysed manually with the BEST-CT scoring system and automatically using LungQ (v.2.1.0.1, Thirona, The Netherlands), which measures the following BA dimensions: diameters of bronchial outer wall (B out ), bronchial inner wall (B in ) and artery (A), and bronchial wall thickness (B wt ) and computes BA ratios (B out /A and B in /A) to assess bronchial widening. To assess bronchial wall thickness, we used the B wt /A ratio and the ratio between the bronchus wall area (B wa ) and the area defined by the outer airway (B oa ) (B wa /B oa )., Results: In total, 65 patients and 16 900 BA pairs were analysed by the automated BA method. The median (range) percentage of BA pairs defined as widened was 69 (55-84)% per CT using a cut-off value of 1.5 for B out /A, and 53 (42-65)% of bronchial wall were thickened using a cut-off value of 0.14 for B wt /A. BA dimensions were correlated with comparable outcomes for the BEST-CT scoring method with a correlation coefficient varying between 0.21 to 0.51. The major CT BA determinants of airflow obstruction were bronchial wall thickness (p=0.001) and a narrower bronchial inner diameter (p=0.003)., Conclusion: The automated BA method, which is an accurate and sensitive tool, demonstrates a stronger correlation between visual and automated assessment and lung function when using a higher cut-off value to define bronchiectasis., Competing Interests: Author contributions: A.L.P. Pieters contributed to the design of the work, data collection and drafted the manuscript up to the final version. Q. Lv contributed to the data collection, analyses and gave final approval for the manuscript. J.J. Meerburg contributed to the data collection for her previous studies. E-R. Andrinopoulou contributed to the analyses and gave final approval for the manuscript. H.A.W.M. Tiddens contributed to the design and analyses of the work and gave final approval for the manuscript. T. van der Veer, P. Ciet, J.D. Chalmers, M.R. Loebinger, C.S. Haworth and J.S. Elborn contributed to the design of the work and gave final approval for the manuscript. Conflict of interest: A.L.P. Pieters, Q. Lv, T. van der Veer, J.J. Meerburg, J.S. Elborn and E-R. Andrinopoulou declare no conflict of interest. Conflict of interest: P. Ciet has received grants or contract fees from NOW-Dutch Research Council and Horizon Pathfinder; and has received payment or honoraria for lectures, presentations etc. from Chiesi and Vertex, and travel support from the European Respiratory Society. He holds a leadership role as Chair of the Thoracic Group of the Cardiothoracic Taskforce of the European Society of Pediatric Radiology. Conflict of interest: J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell; has received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon; and is an associate editor of this journal. Conflict of interest: M.R. Loebinger has received consulting fees from Armata, 30T, AstraZeneca, Parion, Ismed, Chiesi, Zambon, Electromed, Recode and Boehringer Ingelheim; and has received payment or honoraria for lectures, presentations etc. from Chiesi, Insmed, Mylan and Zambon. Conflict of interest: C.S. Haworth has received consulting fees from 30 Technology, CSL Behring, Chiesi, Ismed, Janssen, LifeArc, Meiji, Mylan, Pneumagen, Shionogi, Vertex and Zambon; and has received payment or honoraria for lectures, presentations etc. from Chiesi, Ismed, Mylan and Zambon. Conflict of interest: H.A.W.M. Tiddens is professor emeritus at Erasmus MC and the CMO of Thirona; he has received consulting fees for Insmed, Chiesi and Boehringer, a provides paid courses for Vertex., (Copyright ©The authors 2024.)

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 [FEV 1 % 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 FEV 1 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., Competing Interests: Declaration of competing interest Z.A, G.E., D.G., K.O., K.F., A.H., M.C., T.G., C.J., J.B.: no conflict of interest. J.S.E.: reports grants from European Union IMI Grant (in collaboration with Novartis) and grants from Novartis, and personal fees from Vertex, Galapagos and Ionis, outside the submitted work. M.L.: reports funding from by the Innovative Medicines Initiative (IMI) and EFPIA companies under the European Commission funded project, iABC (grant 115721). Consulting fees from Armata, 30T, Astra Zeneca, Parion, Insmed, Chiesi, Zambon, Electromed, Recode, AN2, Boehringer Ingelheim and Mannkind. Payment or honoraria for lectures by Insmed and Unpaid ERS infection group chair. A.D.S.: received grants from AstraZeneca, Pfizer, GSK and Novartis for research into Bronchiectasis and consulting fees from AstraZeneca, Insmed, GSK, Boehringer, 30T and Bayer. J.C.: received funding from Astrazeneca, Boehringer Ingelheim, Chiesi, Glaxosmithkline, Insmed, Novartis, Gilead Sciences, Trudell, Genentech and consulting fees from Astrazeneca Boehringer Ingelheim, Chiesi, Glaxosmithkline, Insmed, Novartis, Pfizer, Zambon, Janssen, Antabio. J.H.: received funding from Astra Zeneca and consulting fees from Astra Zeneca and GSK. Payment for honorary lectures from Astra Zeneca, Boehringer Ingelheim, Chiesi, Sanofi, Takeda and equipment from Nonin. J.M.B.: received funding Northern Ireland Clinical Research Facility, Health and Social Care (Northern Ireland) and the National Institute for Health and Care Research. M.M.T: received funding from the European Union Innovative Medicines Initiative (Grant Agreement number 115721), Novartis, Spexis and Antabio., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There is increasing interest in the use of home-based monitoring in people with chronic lung diseases to improve access to care, support patient self-management, and facilitate the collection of information for clinical care and research. However, integration of home-based monitoring into clinical and research settings requires careful consideration of test performance and other attributes. There is no published guidance from professional respiratory societies to advance the science of home-based monitoring for chronic lung disease. Methods: An international multidisciplinary panel of 32 clinicians, researchers, patients, and caregivers developed a multidimensional framework for the evaluation of home-based monitoring in chronic lung disease developed through consensus using a modified Delphi survey. We also present an example of how the framework could be used to evaluate home-based monitoring using spirometry and pulse oximetry in adults with asthma, bronchiectasis/cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Results: The PANACEA framework includes seven domains (test P erformance, disease m ANA gement, C ost, patient E xperience, clinician E xperience, researcher E xperience, and A ccess) to assess the degree to which home-based monitoring assessments meet the conditions for clinical and research use in chronic lung disease. Knowledge gaps and recommendations for future research of home spirometry and pulse oximetry in asthma, bronchiectasis/CF, COPD, and ILD were identified. Conclusion: The development of the PANACEA framework allows standardized evaluation of home-based monitoring in chronic lung diseases to support clinical application and future research.

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis (BE). Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in BE, no drug that controls neutrophilic inflammation is licensed for the treatment of BE. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of neutrophil elastase) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in BE pathogenesis, and not just neutrophil elastase. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in BE and improve disease outcomes as a result. Clinical trials for CatC inhibitors in BE have reported positive Phase III results. In this narrative review, we discuss the role of high NSP activity in BE, and how this feature drives the associated morbidity and mortality seen in BE. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the BE lung, summarising clinical trial outcomes, and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in BE., (Copyright ©The authors 2024.)

Background: People hospitalised for coronavirus disease 2019 (COVID-19) have elevated incidence of diabetes. However, it is unclear whether this is due to shared risk factors, confounding or stress hyperglycaemia in response to acute illness., Methods: We analysed a multicentre prospective cohort study (PHOSP-COVID) of people ≥18 years discharged from NHS hospitals across the United Kingdom following COVID-19. Individuals were included if they attended at least one research visit with a HbA1c measurement within 14 months of discharge and had no history of diabetes at baseline. The primary outcome was new onset diabetes (any type), as defined by a first glycated haemoglobin (HbA1c) measurement ≥6.5% (≥48 mmol/mol). Follow-up was censored at the last HbA1c measurement. Age-standardised incidence rates and incidence rate ratios (adjusted for age, sex, ethnicity, length of hospital stay, body mass index, smoking, physical activity, deprivation, hypertension, hyperlipidaemia/hypercholesterolaemia, intensive therapy unit admission, invasive mechanical ventilation, corticosteroid use and C-reactive protein score) were calculated using Poisson regression. Incidence rates were compared with the control groups of published clinical trials in the United Kingdom by applying the same inclusion and exclusion criteria, where possible., Results: Incidence of diabetes was 91.4 per 1000 person-years and was higher in South Asian (incidence rate ratios [IRR] = 3.60; 1.77, 7.32; p < 0.001) and Black ethnic groups (IRR = 2.36; 1.07, 5.21; p = 0.03) compared with White ethnic groups. When restricted to similar characteristics, the incidence rates were similar to those in UK clinical trials data., Conclusion: Diabetes incidence following hospitalisation for COVID-19 is high, but it remains uncertain whether it is disproportionately higher than pre-pandemic levels., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Long COVID is a heterogeneous clinical syndrome characterised by a variety of reported symptoms and signs. Its clinical management is expected to differ significantly worldwide., Methods: A survey-based study investigating long COVID-related standard operating procedures (SOPs) has been conducted by the European Respiratory Society (ERS) END-COVID clinical research collaboration with the support of other international societies (ALAT, APSR, CHEST, ESCMID and PATS). A global analysis of the results is provided here, alongside sub-population analysis based on continents, national income levels, type of involved healthcare professional and inclusion or exclusion of paediatric patients., Findings: 1015 healthcare professionals from 110 different countries worldwide participated in this study, the majority of them being respiratory physicians (60.6%). A dedicated long COVID programme was present in 55.4% of the investigated institutions, with hospital admission during the acute infection being the main inclusion criteria to access them. Consistent differences in long COVID-related procedures were identified among centres, mainly regarding the multidisciplinary approach, the availability of telemedicine and psychological support, the type of requested exams and the total amount of visits in the centre., Interpretation: Long COVID management shows important differences related to geographical areas and national income levels. SOPs were significantly different when centres were managed by a pulmonologist or when paediatric patients were included., Competing Interests: Conflict of interest: M. Nigro has nothing to disclose. Conflict of interest: C. Valenzuela reports consulting fees from Boehringer Ingelheim, Hoffman-La Roche Ltd and BMS, and payment of honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Boehringer Ingelheim, in the past 36 months. Conflict of interest: F. Arancibia has nothing to disclose. Conflict of interest: M. Cohen is past president of ALAT. Conflict of interest: D.C.L. Lam is president of the APSR and FIRS. Conflict of interest: R.C. Maves reports clinical trial funding to his institution from AiCuris, Sound Pharmaceuticals and GeoVax; travel funding provided for committee work as a member of the American College of Chest Physicians (CHEST) Scientific Program Committee from CHEST, the Society of Critical Care Medicine (SCCM) Scientific Program Committee from the SCCM and the American Board of Internal Medicine (ABIM) Critical Care Medicine Approval Committee from the ABIM; honoraria paid to himself for clinical trial support as a medical monitor and data safety monitoring board member from LumaBridge, and for scientific advisory panel membership from Shionogi, all in the past 36 months; and a US patent on the candidate dengue vaccine unrelated to this study; and is chair of the CHEST Disaster Response and Global Health Section, and the CHEST Rapid Response Task Force, and a member of the CHEST Scientific Program Committee (all unpaid except for official travel funding as above); chair of the SCCM FCCS Crisis Management Committee, a member of the SCCM Congress Program Committee, Co-Vice Chair of the SCCM 2025 Critical Care Congress and Designated Co-Chair of the SCCM 2026 Critical Care Congress (all unpaid except for official travel funding as above); and a member of the ABIM Critical Care Medicine Approval Committee (travel funded plus honorarium for Board service). Conflict of interest: B. Rath reports European Union funding only; support for attending meetings and/or travel for MedScape and scientific societies only; patents not pertinent to this article; participation on a data safety monitoring or advisory board for GSK COVID-19 and influenza infant clinical trials, all in the past 36 months; and is on ISIRV, ESGREV, AAP and IPA vaccination-related steering committees. Conflict of interest: S.Q. Simpson is a board member of the American College of Chest Physicians and Chair of the Board of Directors of the Sepsis Alliance. Conflict of interest: Y. Song is a board member of the American College of Chest Physicians and Chair of the Board of Directors of the Sepsis Alliance. Conflict of interest: S. Tsiodras reports grants or contracts for the European Union (EU) projects EU-RESPONSE (funded by EU Horizon 2020), EU Prevent and EU Reverse, paid to his institution in the past 36 months. Conflict of interest: J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Chiesi, Gilead Sciences, Grifols, Genentech, GlaxoSmithKline, Insmed and Novartis; and consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Gilead Sciences, Grifols, Genentech, GlaxoSmithKline, Insmed, Novartis, Roche, Trudell, Zambon, Janssen and Pfizer, all in the past 36 months; and is an associate editor of this journal. Conflict of interest: S. Aliberti reports grants or contracts from Insmed Inc., Chiesi, Fisher and Paykel and GSK, paid to his institution; royalties or licences from McGraw Hill, paid to himself; consulting fees from Insmed Inc., Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MSD Italia S.r.l., Brahms, Physioassist SAS and GlaxoSmithKline Spa, paid to himself; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GlaxoSmithKline Spa, ThermoFisher Scientific, Insmed Italy, Insmed Ireland Ltd, Zambon and Fondazione Internazionale Menarini; and participation on a data safety monitoring or advisory board from Insmed Inc., Insmed Italy, AstraZeneca UK Ltd and MSD Italia S.r.l., all in the past 36 months., (Copyright ©The authors 2024.)

Objectives: Pseudomonas aeruginosa is the most common pathogen in the bronchiectasis lung, associated with worsened outcomes. P. aeruginosa genomic studies in this context have been limited to single-country, European studies. We aimed to determine strain diversity, adaptation mechanisms, and AMR features to better inform treatment., Methods: P. aeruginosa from 180 bronchiectasis patients in 15 countries, obtained prior to a phase 3, randomised clinical trial (ORBIT-3), were analysed by whole-genome sequencing. Phylogenetic groups and sequence types were determined, and between versus within patient genetic diversity compared using Analysis of Molecular Variance (AMOVA). The frequency of AMR-associated genes and mutations was also determined., Results: A total of 2854 P. aeruginosa isolates were analysed, predominantly belonging to phylogenetic group 1 (83%, n = 2359). Genetic diversity was far greater between than within patients, responsible for >99.9% of total diversity (AMOVA: phylogroup 1: df = 145, P < 0.01). Numerous pathways were under selection, some shared with CF (e.g., motility, iron acquisition), some unique to bronchiectasis (e.g., novel efflux pump PA1874). Multidrug resistance features were also frequent., Conclusions: We present a 10-fold increase in the availability of genomic data for P. aeruginosa in bronchiectasis, highlighting key distinctions with cystic fibrosis and potential targets for future treatments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bronchiectasis is understood to be the result of a complex interaction between infection, impaired mucociliary clearance, inflammation, and lung damage. Current therapeutic approaches to bronchiectasis are heavily focused on management of infection along with enhancing mucus clearance. Long-term antibiotics have had limited success in clinical trials, suggesting a need to re-evaluate the concept of bronchiectasis as an infective disorder. We invoke the example of asthma, for which treatment paradigms shifted away from targeting smooth muscle constriction, towards permanently suppressing airway inflammation, reducing risk and ultimately inducing remission with precision anti-inflammatory treatments. In this Review, we argue that bronchiectasis is primarily a chronic inflammatory disease, requiring early identification of at-risk individuals, and we introduce a novel concept of disease activity with important implications for clinical practice and future research. A new generation of novel anti-inflammatory treatments are under development and repurposing of anti-inflammatory agents from other diseases could revolutionise patient care., Competing Interests: Declaration of interests MS reports having received grant support (institutional) from GSK, Trudell Pharma, and the Tel Aviv League for Pulmonary Diseases; consulting fees (personal) from Astra Zeneca, Boehringer Ingelheim, Dexcel Pharma, GSK, Kamada, Synchrony Medical, Truemed, Vertex, and Zambon; travel grants (institutional) from Boehringer Ingelheim, Astra Zeneca, and Kamada; payment or honoraria from Astra Zeneca, Boehringer Ingelheim, Kamada, GSK, and Sanofi; participation on a data safety and monitoring board or advisory board for Bonus Biotherapeutics, Boehringer Ingelheim, Vertex, and Astra Zeneca; and is management board member for the Israeli Pulmonology Society, Israeli Society for Tuberculosis and Mycobacterial Diseases, and the associate editor for the American Journal of Respiratory and Critical Care Medicine. SHC reports consulting fees from CSL Behring, Boehringer Ingelheim, and Pneumagen, and payment for lectures from Astrazeneca and Chiesi; participation on DSMB for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University (Dammam, Saudi Arabia). JDC reports grants or contracts from Grifols; consulting fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxosmithkline, Grifols, Insmed, Janssen, Novartis, Pfizer, and Zambon; and leadership or fiduciary roles as Chair of European Respiratory Society Bronchiectasis Guideline Task Force, Chief Editor of European Respiratory Journal, and Chair of the European Multicentre Bronchiectasis Audit and Research Collaboration Clinical Research Collaboration. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Bronchiectasis is characterised by uncontrolled neutrophil serine protease (NSP) activity. Cathepsin C (CatC; dipeptidyl peptidase 1) activates NSPs during neutrophil maturation. CatC inhibitors can potentially reduce neutrophil-mediated lung damage. This Phase II, randomised, double-blind, placebo-controlled trial (AIRLEAF®; NCT05238675) evaluated efficacy, safety and optimal dosing of BI 1291583, a novel, reversible CatC inhibitor, in adults with bronchiectasis.In total, 322 participants were randomised (2:1:1:2) to receive one of three oral doses of BI 1291583 (1 mg/2.5 mg/5 mg) or placebo for 24 to 48 weeks. A multiple comparison procedure and modelling approach was used to demonstrate a non-flat dose-response curve based on the time to first pulmonary exacerbation up to Week 48. In addition, efficacy of individual BI 1291583 doses was evaluated based on the frequency of exacerbations, severe exacerbations (fatal or leading to hospitalisation and/or intravenous antibiotic administration), lung function and quality of life.A significant dose-dependent benefit of BI 1291583 over placebo was established based on time to first exacerbation (shape: Emax; adjusted p-value: 0.0448). Treatment with BI 1291583 5 mg and 2.5 mg numerically reduced the risk of an exacerbation compared with placebo (hazard ratios: 0.71 and 0.66, 95% CIs 0.48-1.05 and 0.40-1.08; both p>0.05). BI 1291583 2.5 mg showed numerically better efficacy compared with 5 mg across several endpoints; 1 mg was similar to placebo. The safety profile of BI 1291583 was similar to placebo.Treatment with BI 1291583 resulted in a reduction in the risk of experiencing an exacerbation in adults with bronchiectasis., (Copyright ©The authors 2024.)

Background: Serum anti-glycopeptidolipid (GPL) core immunoglobuin A (IgA) antibody test has been proposed as a diagnostic tool for Mycobacterium avium complex pulmonary diseases. Cross-reactivity with other non-tuberculous mycobacteria (NTM), including M. abscessus, indicates that it may have a role as a broader screening test for NTM pulmonary disease (NTM-PD). NTM-PD is believed to be underdiagnosed in patients with bronchiectasis., Research Question: Can the serum anti-GPL core IgA antibody test be used to screen for NTM-PD in bronchiectasis?, Study Design and Methods: Patients from the prospective European Bronchiectasis Registry (EMBARC-BRIDGE; NCT03791086) were enrolled. Patients from the United Kingdom, Italy, Spain, Belgium, the Netherlands, and Germany were included. A control cohort of patients without any underlying lung disease was also recruited. The levels of serum IgA antibodies against the GPL core were measured using an enzyme immunoassay kit, and receiver operating characteristics curve analysis was conducted to evaluate the accuracy of the antibody level in screening for NTM-PD., Results: 282 patients were enrolled (151 [53.6%] female, median age 68 years). Median (quartile 1-3) anti-GPL-core IgA antibody levels were 0.2 (0.1-0.3) U/mL in patients without NTM isolation and NTM-PD (n=238), 0.3 (0.2-0.4) U/mL in NTM isolation that were incompatible with the diagnosis of NTM-PD (n=18) and 1.5 (0.4-6.2) U/mL in NTM-PD (n=26) (P=0.0001). Antibody levels showed excellent accuracy in identifying patients with NTM-PD (area under the curve 0.886, 95% CI 0.800-0.973) in bronchiectasis cohort and also showed excellent discrimination of patients with NTM-PD from those with NTM isolation who did not meet the diagnostic criteria for NTM-PD (0.816, 95% CI 0.687-0.945)., Interpretation: The anti-GPL-core IgA antibody demonstrated excellent efficacy in screening for NTM-PD in a large bronchiectasis cohort., (Copyright © 2024. Published by Elsevier Inc.)

Background: Aspergillus species cause diverse clinical manifestations in bronchiectasis including allergic bronchopulmonary aspergillosis (ABPA), Aspergillus sensitization (AS), and raised IgG indicating exposure to or infection with Aspergillus., Research Question: What are the prevalence and clinical significance of Aspergillus-associated conditions in individuals with bronchiectasis?, Study Design and Methods: Patients with bronchiectasis enrolled into the European Bronchiectasis Registry from 2015 through 2022 with laboratory testing for Aspergillus lung disease (total IgE, IgE specific to Aspergillus or Aspergillus skin test, or IgG specific to Aspergillus and blood eosinophil counts) were included for analysis. Modified International Society for Human and Anima Mycology ABPA working group criteria (2021) were used to define ABPA., Results: Nine thousand nine hundred fifty-three patients were included. Six hundred eight patients (6.1%) were classified as having ABPA, 570 patients (5.7%) showed AS, 806 patients (8.1%) showed raised Aspergillus-specific IgG without AS, 184 patients (1.8%) showed both AS and had raised Aspergillus-specific IgG levels, and 619 patients (6.2%) demonstrated eosinophilic bronchiectasis (elevated eosinophil counts without evidence of Aspergillus lung disease). The remaining 72% showed negative Aspergillus serologic findings. Patients with ABPA, AS, or raised Aspergillus-specific IgG demonstrated more severe disease, with worse lung function and more frequent exacerbations at baseline. During long-term follow-up, patients with raised Aspergillus-specific IgG experienced higher exacerbation frequency and more severe exacerbations. AS was associated with increased exacerbations and hospitalizations only in patients not receiving inhaled corticosteroids (ICS)., Interpretation: Aspergillus lung disease is common in bronchiectasis. Raised IgG levels to Aspergillus are associated with significantly worse outcomes, whereas ABPA and AS are associated with severe disease and exacerbations with a risk that is attenuated by ICS use., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. P. reports support for attending meetings, travel, or both from the European Respiratory Society, Asthma + Lung UK, American Thoracic Society, and British Association for Lung Research (BALR). P. C. G. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed, GSK, and Chiesi; support for attending meetings, travel, or both from Chiesi; and participation on a data safety monitoring board or advisory board for Boehringer, GSK, and Pfizer. S. A. reports grants or contracts from any entity from Insmed Incorporated, Chiesi, Fisher and Paykel, and GSK; royalties or licences from McGraw Hill; consulting fees from Insmed, Inc, Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Ltd., AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MCD Italis SrL, Brahms, Physioassist SAS, and GlaxoSmithKline Spa; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GlaxoSmithKline Spa, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon, and Fondazione Internazionale Menarini; and participation on a data safety monitoring board or advisory board from Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd, and MSD Italia Srl. E. P. reports grants or contracts from any entity from Grifols; consulting fees from Insmed, Bayer, Chiesi, and Zambon; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Chiesi, Grifols, GlaxoSmithKline, Insmed, Menarini, and Zambon; and support for attending meetings, travel, or both from Insmed, Pfizer, and Moderna. M. L. C. reports consulting fees from Boxer Capital LLC. F. C. R. reports grants or contracts from any entity from German Center for Lung Research (DZL), German Center for Infection Research (DZIF), IMI (EU/EFPIA), and iABC Consortium (incl. Alaxia, Basilea, Novartis, and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer, InfectoPharm; consulting fees from Parion, Grifols, Zambon, Insmed, and Helmholtz-Zentrum für Infektionsforschung; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from I!DE Werbeagentur GmbH, Interkongress GmbH, AstraZeneca, Insmed, Grifols, and Universitätsklinikum Frankfurt am Main; payment for expert testimony from Social Court Cologne; support for attending meetings, travel, both from German Kartagener Syndrome and Primary Ciliary Dyskinesia Patient Advocacy Group Mukoviszidose e.V.; participation on a data safety monitoring board or advisory board for Insmed, Grifols, and Shionogi; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, as coordinator of the ERN-LUNG Bronchiectasis Core Network, chair of the German Bronchiectasis Registry PROGNOSIS, member of the steering committee of the European Bronchiectasis Registry EMBARC, member of the steering committee of the European Nontuberculous Mycobacterial Pulmonary Disease Registry EMBARC-NTM, cospeaker of the medical advisory board of the German Kartagener Syndrome and Primary Ciliary Dyskinesia Patient Advocacy Group, speaker of the respiratory infections and TB group of the German Respiratory Society, speaker of the cystic fibrosis group of German Respiratory Society (DGP), primary investigator of the German Center for Lung Research, member of the protocol review committee of the PCD-CTN, member of physician association of the German Cystic Fibrosis Patient Advocacy Group; and other financial or nonfinancial interests with AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex, and Zambon. R. D. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from LUPIN, CIPLA, and Glenmark. M. V. reports grants or contracts from any entity from Chiesi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed and Publi Creation; support for attending meetings, travel, or both from Zambon, Chiesi, Novartis, Behring, and Gebro; participation on a data safety monitoring board or advisory board for Insmed; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Insmed and Novartis. P.-R. B. reports grants or contracts from any entity from GSK and Vertex; consulting fees from AstraZeneca, Chiesi, GSK, Insmed, MSD, Vertex, Viatris, and Zambon; and support for attending meetings, travel, or both from AstraZeneca and Chiesi. C. S. H. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from 30 Technology, CSL Behring, Chiesi, Insmed, Janssen, LifeArc, Meiji, Mylan, Pneumagen, Shionogi, Vertex, and Zambon. A. D. reports grants or contracts from AstraZeneca, Pfizer, GSK, and Novartis; consulting fees from AstraZeneca, Insmed, GSK, Boehringer, 30T, and Bayer; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Pfizer, GSK, and Novartis. A. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Chiesi; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Head of Assembly 5 (airway diseases, asthma, COPD and chronic cough) of the European Respiratory Society, vice-chair of the Nordic Severe Asthma Network (NSAN)-NORDSTAR, and steering committee of European Respiratory Society CRC severe asthma, SHARP. J. R. reports payment or honoraria for lectures, presentations, speakers bureaus, or educational events from CSL Seqirus, Berlin-Chemie, GlaxoSmithKline, AstraZeneca, Chiesi, ThermoFisher, Boehringer Ingelheim, Pfizer, Shionogi, and INSMED; and participation on a data safety monitoring board or advisory board from GlaxoSmithKline, GILEAD, ThermoFischer, Shionogi, and INSMED. D. S. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CSL Behring, Berlin-Chemie, Menarini, Novartis, GlaxoSmithKline, AstraZeneca, Vifor, Merck, Chiesi, and Sanofi; and participation on a data safety monitoring board or advisory board from GlaxoSmithKline and CSL Behring. P. K. reports support for attending meetings, travel, or both from Nordic Respiratory Academy; participation on a data safety monitoring board or advisory board from Swedish Orphan Biovitrium; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, from Finnish Respiratory Society and Finnish Tuberculosis Foundation Grant Committee; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Theravance. A. A. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Zambon Group; and support for attending meetings, travel, or both from Zambon Group, Boehringer Ingelheim, and Novartis Farma. F. B. reports grants or contracts from any entity from AstraZeneca, Chiesi, and Insmed; consulting fees from Menarini; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Chiesi, GSK, Guidotti, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Viatris, Vertex, and Zambon. M. S. reports consulting fees from GKS, Boehringer Ingelheim, Kamada, and Zambon; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed, Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis, Kamada, and Sanofi; support for attending meetings, travel, or both from Novartis, Actelion, Boehringer Ingelheim, GSK, and Rafa; participation on a data safety monitoring board or advisory board for Bonus Therapeutics, Israel; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for EMBARC Management, Israel Pulmonology Society Board, and the Israel Society for TB and mycobacterial diseases; receipt of equipment, materials, drugs, medical writing, gifts, or other services from Trudell Medical International; and other financial or nonfinancial interests as the associate editor of American Journal of Respiratory Critical Care Medicine. K. D. 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, travel, or both 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. J. D. C. reports grants or contracts from any entity from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, LifeArc, and Novartis; and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio, and Zambon. M. R. L. reports consulting fees from Armata, 30T, AstraZeneca, Parion, Insmed, Chiesi, Zambon, Electromed, Recode, AN2, Mannkind, and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for the European Respiratory Society Infection Group (chair). None declared (J. D, A. G, M. M, O. S, M. v. d. E, A. T. H, R. W, O. M, R. M, A. T, T. W, W. B, J. S. E.)., (Copyright © 2024. Published by Elsevier Inc.)

Background: Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD., Methods: Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients., Results: We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1β levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability., Conclusions: These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients., (© 2024. The Author(s).)

Introduction: We aimed to explore how digital technology is currently used, could be used and how services could be improved in order to optimise bronchiectasis physiotherapy care., Methods: Online surveys were designed and distributed amongst people with bronchiectasis and physiotherapists in Northern Ireland. Responses to closed and open question formats were collected and analysed., Results: The survey was completed by 48 out of 100 physiotherapists (48%) between January 2020 and January 2021 and by 205 out of 398 people with bronchiectasis (52%) between October 2020 and October 2021. 56% of physiotherapists (27 out of 48) reporting using some type of digital technology to facilitate services, whereas 44% (21 out of 48) reported that they had never used a digital technology in this patient group. When physiotherapists were asked whether they would be likely to use certain remote and/or digital options to deliver follow-up care for airway clearance techniques, most (31-38 out of 48; 65-79%) indicated that they would. Regarding patient responses, most reported that they would use telephone consultation (145 out of 199, 73%) and a smaller proportion were likely to use video consultation (64 out of 199, 32%). The most commonly mentioned theme for improvement amongst patients was follow-ups, while improved access, quality of services and treatments were the most commonly mentioned amongst physiotherapists., Conclusion: Despite a large proportion of physiotherapists in this survey reporting no current use of digital technology in bronchiectasis physiotherapy care, there was significant interest and willingness to do so, amongst both physiotherapists and patients. This survey highlighted a range of care areas, specifically follow-up visits, where digital methods could be further explored., Competing Interests: Conflict of interest: K. O'Neill has nothing to disclose. Conflict of interest: B. O'Neil has nothing to disclose. Conflict of interest: R.H. McLeese has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Novartis and Insmed; and received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis and Zambon, in the past 36 months; and is an associate editor of this journal. Conflict of interest: J. Boyd is an employee of the European Lung Foundation. Conflict of interest: A. De Soyza reports grants or contracts from GlaxoSmithKline, AstraZeneca, Bayer, Gilead and Insmed, for work outside that presented in this article, with payment made to his institution; and a leadership or fiduciary role on the National Institute for Health Research HTA programme, in the past 36 months. Conflict of interest: P. McCallion has nothing to disclose. Conflict of interest: J.M. Bradley reports grants or contracts from Health and Social Care (Northern Ireland) and iABC (Polyphor and Alaxia), and using data analytics to design innovative clinical trials in respiratory disease, CLEAR, RECOVERY (RECOVERY-RS Respiratory Support), DIBS (Dual Bronchodilators in Bronchiectasis Study), ECFS-CTN, NI Clinical Research Facility, CLEAR 2, MARCH, Rejuvenating Rehab and PREPARE (Prehabilitation for Patients Awaiting Liver Transplantation), with all funding to her institution; and equipment for the Clear Trail study provided by Pari, in the past 36 months., (Copyright ©The authors 2024.)

Objectives: Allergic bronchopulmonary aspergillosis (ABPA) is a complex lung disease associated with significant morbidity. The ABPA Working Group (AWG) of the International Society for Human and Animal Mycology (ISHAM) revised their management guidelines in 2024, but there is currently no standardised tool to assess adherence to these recommendations., Methods: We extracted key recommendations from the updated 2024 ISHAM-AWG guidelines, focusing on critical areas: screening and diagnosis of ABPA, managing acute and treatment-dependent ABPA, and monitoring treatment response. Each item was assigned a score ranging from zero to three. We assigned negative scores to interventions not recommended by the guidelines., Results: We identified 38 items indicative of optimal clinical care for patients with ABPA. The score for screening asthmatics for ABPA was set at three points. For diagnosing ABPA, 16 items were included, with a score ranging from 12 to 16 points, depending on the specific components used (predisposing conditions, serum A. fumigatus-specific IgE and IgG, serum total IgE, blood eosinophil count and chest computed tomography). The management of acute ABPA comprised 11 items, with a maximum score of three points. For treatment-dependent ABPA, there were nine items (scores ranging from -3 to 6). Follow-up care comprised 10 items with a maximum score of 10-13 points, covering imaging, spirometry, testing serum total IgE levels and therapeutic drug monitoring., Conclusions: The EQUAL ABPA score has been developed as a comprehensive tool to quantify guideline adherence. Future studies will evaluate to which extent guideline adherence is associated with improved clinical outcomes for patients with ABPA., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Chronic lung infection with Pseudomonas aeruginosa is associated with increased exacerbations and mortality in people with bronchiectasis. The PROMIS-I and PROMIS-II trials investigated the efficacy and safety of 12-months of inhaled colistimethate sodium delivered via the I-neb., Methods: Two randomised, double-blind, placebo-controlled trials of twice per day colistimethate sodium versus placebo were conducted in patients with bronchiectasis with P aeruginosa and a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year in hospitals in Argentina, Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, the UK, and the USA. Randomisation was conducted through an interactive web response system and stratified by site and long term use of macrolides. Masking was achieved by providing colistimethate sodium and placebo in identical vials. After random assignment, study visits were scheduled for 1, 3, 6, 9, and 12 months (the end of the treatment period); and telephone calls were scheduled for 7 days after random assignment and 2 weeks after the end of treatment. The primary endpoint was the mean annual exacerbation rate. These trials are registered with EudraCT: number 2015-002743-33 (for PROMIS-I) and 2016-004558-13 (for PROMIS-II), and are now completed., Findings: 377 patients were randomly assigned in PROMIS-I (177 to colistimethate sodium and 200 to placebo; in the modified intention-to-treat population, 176 were in the colistimethate sodium group and 197 were in the placebo group) between June 6, 2017, and April 8, 2020. The annual exacerbation rate was 0·58 in the colistimethate sodium group versus 0·95 in the placebo group (rate ratio 0·61; 95% CI 0·46-0·82; p=0·0010). 287 patients were randomly assigned in PROMIS-II (152 were assigned to colistimethate sodium and 135 were assigned to placebo, in the modified intention-to-treat population), between Feb 12, 2018, and Oct 22, 2021. PROMIS-II was then prematurely terminated due to the effect of the COVID-19 pandemic. No significant difference was observed in the annual exacerbation rate between the colistimethate sodium and placebo groups (0·89 vs 0·89; rate ratio 1·00; 95% CI 0·75-1·35; p=0·98). No major safety issues were identified. The overall frequency of adverse events was 142 (81%) patients in the colistimethate sodium group versus 159 (81%) patients in the placebo group in PROMIS-I, and 123 (81%) patients versus 104 (77%) patients in PROMIS-II. There were no deaths related to study treatment., Interpretation: The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated., Funding: Zambon., Competing Interests: Declaration of interests CSH reports consultancy or speakers fees from 30 Technology, AstraZeneca, CSL Behring, Chiesi, Infex, Insmed, Janssen, Lifearc, Meiji, Mylan, Pneumagen, Shionogi, Vertex, and Zambon. MS reports research grants from Glaxosmithkline, Trudell, and Tel Aviv League for Lung Disease; consulting fees or speaker fees for Astrazeneca, Boehringer Ingelheim, Dexcel, Kamada, Rafa, Synchrony Medical, Trumed, Vertex, Zambon, and Sanofi Insmed; and data safety monitoring board participation for Bonus Biotherapeutics and Boehringer Ingelheim. KW reports research grants from Insmed, Paratek, Red Hill Biopharma, AN2, Spero, and Renovion; consulting fees from Insmed, Paratek, Red Hill Biopharma, AN2, Renovion, Spero, Zambon, and Janssen; and data safety monitoring board participation for Janssen and Red Hill Biopharma. AB declares research funding from Zambon; and contributed to UptoDate. FB reports research funding from Astrazeneca, Glaxosmithkline, Chiesi, and Insmed; and consulting fees or speakers fees from Astrazeneca, Chiesi, Glaxosmithkline, Menarini, Grifols, Insmed, Novartis, Pfizer, Sanofi, Vertex, Viatris, and Zambon. KD reports payments for consultancy or lectures from Boehringer Ingelheim, GSK, Menarini, Novartis, Norma Hellas, Chiesi, Astrazeneca, and Zambon. LCM reports a leadership role with Lung Foundation Australia; research grants from Boehringer Ingelheim, Astrazeneca, Zambon, Insmed, and Glaxosmithkline; and consultancy or speaker fees from Boehringer Ingelheim, Astrazeneca, Zambon, Insmed, Sequirius, and Glaxosmithkline. AEO reports research grants from Zambon, Insmed, Boehringer Ingelheim, Armata, and the US COPD foundation; consultancy or speaker fees from Insmed, Boehringer Ingelheim, Zambon, and Electromed; participation in a data safety monitoring board for Paraxel; and fees from Academic CME, Vindico Medical Education, Answers in CME, Peer Review Institute, CE, and RMEI. FCR reports grant from the German Centre for Lung Research, German Centre for Infection Research, EU Innovative Medicines Initiative, Mukoviszidose Institute, Novartis, Insmed, Grifols, Bayer, and InfectoPharm; consulting fees or lecture fees from Parion, Grifols, Zambon, Insmed, Helmholtz-Zentrum fur Infektionsforschung, Astrazeneca, Insmed, and Grifols; participation in data safety monitoring board for Insmed, Grifols, Shionogi, and Boehringer Ingelheim; provided expert testimony to the Social Court Cologne; received support to attend meetings from German Kartagener Syndrome and Primary Ciliary Dyskinesia Patient Advocacy Group and Mukoviszidose; was a coordinator of the ERN-LUNG Bronchiectasis Core Network; was the chair of the German Bronchiectasis Registry PROGNOSIS; was a member of the SteerCo of the European Bronchiectasis Registry EMBARC and SteerCo of the European Nontuberculous Mycobacterial Pulmonary Disease Registry EMBARC-NTM; was a co-speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD Patient Advocacy Group; was a speaker of the Respiratory Infections and TB group of the German Respiratory Society, the Cystic Fibrosis group of German Respiratory Society (DGP); was a principal investigator of the German Center for Lung Research, Member of the Protocol Review Committee of the PCD-CTN, Member of Physician Association of the German Cystic Fibrosis Patient Advocacy Group; and declares fees to institution from clinical trial work from AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, German Center for Lung Research/KKS Marburg, Insmed, Novartis, Parion, University of Dundee, Vertex, and Zambon. RMT reports research grants from Australian Institute of Infectious Diseases, Herston Infectious Diseases Institute, Metro South Health, and the Asia Pacific Society of Respirology Gallipoli Medical Research Foundation; an eductional grant from Insmed; support for attending a meeting from Beyond Air; and consulting fees from AN2 Therapeutics, Beyond Air, and Insmed. KJC reports consulting fees from Zambon. FP is an employee of Zambon. PC is an employee of Zambon; and reports an international patent application WO 23/012280 in the name of Zambon, designating PC as the inventor. JDC has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed, and Trudell; and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell, and Zambon. OS declares no competing interests., (Copyright © 2024 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.)

The ecological and evolutionary mechanisms of antimicrobial resistance (AMR) emergence within patients and how these vary across bacterial infections are poorly understood. Increasingly widespread use of pathogen genome sequencing in the clinic enables a deeper understanding of these processes. In this Review, we explore the clinical evidence to support four major mechanisms of within-patient AMR emergence in bacteria: spontaneous resistance mutations; in situ horizontal gene transfer of resistance genes; selection of pre-existing resistance; and immigration of resistant lineages. Within-patient AMR emergence occurs across a wide range of host niches and bacterial species, but the importance of each mechanism varies between bacterial species and infection sites within the body. We identify potential drivers of such differences and discuss how ecological and evolutionary analysis could be embedded within clinical trials of antimicrobials, which are powerful but underused tools for understanding why these mechanisms vary between pathogens, infections and individuals. Ultimately, improving understanding of how host niche, bacterial species and antibiotic mode of action combine to govern the ecological and evolutionary mechanism of AMR emergence in patients will enable more predictive and personalized diagnosis and antimicrobial therapies., (© 2024. Springer Nature Limited.)

Non-cystic fibrosis bronchiectasis is a long-term lung disease characterised by abnormal dilatation of the bronchi, with patients experiencing chronic productive cough and recurrent exacerbations. Currently, there are no licensed drugs for use in bronchiectasis while clinical trials have been conducted to either test new drugs or repurpose existing ones. These drugs target the underlying pathophysiology of bronchiectasis which is known to include infection, inflammation, mucus hypersecretion and retention. Most of the drugs used in daily clinical practice for bronchiectasis are off-label with no randomised trials exploring their safety. This review aims at exploring the safety profile of drugs frequently used in clinical practice to manage bronchiectasis, including antibiotics (e.g. macrolides, aminoglycosides, polymyxins, fluoroquinolones, aztreonam), mucoactive therapy (e.g. hypertonic saline, mannitol, DNase and carbocisteine), anti-inflammatory therapy (inhaled corticosteroids) and drugs currently in development for use in bronchiectasis (e.g. brensocatib, benralizumab and itepekimab)., (© The Author(s), 2024.)

Background: Despite advances in primary ciliary dyskinesia (PCD) research, many questions remain; diagnosis is complex and no disease-specific therapies exist. Using a mixed-methods approach, we aimed to identify priorities for clinical and epidemiological research and explore barriers to research., Methods: To obtain rich, relevant, diverse data, we performed in-depth semi-structured interviews with PCD specialists selected using purposive sampling. We transcribed, coded and analysed interview data using thematic analysis. Based on interview themes that we identified, we developed an anonymous survey and circulated it widely through the BEAT-PCD network., Results: We interviewed 28 participants from 15 countries across different disciplines and expertise levels. The main themes identified as priorities for PCD research were improving diagnosis; understanding prevalence and disease course; phenotypic variability; disease monitoring; treatment strategies; clinical trial end-points; and poorly researched areas. In total, 136 participants (49% paediatric pulmonologists) from 36 countries completed the survey. Most commonly reported barriers for research were low awareness about PCD and difficulties securing funding - in more than one-third of cases, participants reported undertaking predominantly unfunded research. Research questions ranked highest included priorities related to further improving diagnosis, treating PCD, managing upper and lower airway problems, and studying clinical variability and disease prognosis., Conclusion: We need to overcome barriers of limited funding and low awareness and promote collaborations between centres, disciplines, experts and patients to address identified PCD priorities effectively. Our results contribute to the ongoing efforts of guiding the use of existing limited research resources and setting up a roadmap for future research activities., Competing Interests: Conflict of interest: M. Goutaki reports grants from the Johanna Dürmüller-Bol Foundation outside the submitted work and is Co-Chair of the BEAT-PCD clinical research collaboration. Conflict of interest: Y.T. Lam is Work Package Co-Lead in clinical research collaboration BEAT-PCD funded by the European Respiratory Society. Conflict of interest: J.D. Chalmers reports grants from AstraZeneca, GlaxoSmithKline, Grifols, Gilead Sciences, Boehringer Ingelheim, Trudell, Insmed and Genentech; and consulting fees from AstraZeneca, GlaxoSmithKline, Grifols, Boehringer Ingelheim, Trudell, Insmed, Genentech, Pfizer, Antabio and Zambon, all outside the submitted work; and is an associate editor of this journal. Conflict of interest: J-F. Papon reports grants and consulting fees from Sanofi, GSK, Medtronic, AstraZeneca and ALK; lecture honoraria from Sanofi, GSK and Medtronic; and travel support from Sanofi and GSK, all outside the submitted work. Conflict of interest: J.S. Lucas reports grants from the Medical Research Council, Life Arc, NHS England, NIHR Southampton Biomedical Research Centre, AAIR charity, NIHR Research for Patient Benefit and Wessex Medical Research, outside the submitted work. Conflict of interest: All other authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge., Methods: Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium). HRQoL, assessed by the EuroQol-Five Dimensions-Five Levels utility index (EQ-5D-5L UI), pre-hospital and 1 year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient-reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias., Findings: Of the 1888 participants included in the primary analysis, 1149 received corticosteroids. There was no between-group difference in EQ-5D-5L UI at 1 year (mean difference 0.004, 95% CI -0.026-0.034). A similar reduction in EQ-5D-5L UI was seen at 1 year between corticosteroid exposed and nonexposed groups (mean±sd change -0.12±0.22 versus -0.11±0.22). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a cohort of 109 318 patients admitted to hospital with COVID-19, EQ-5D-5L UI at 1 year remained similar between the two groups., Interpretation: Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL 1 year after hospital discharge. Treatments to address the persistent reduction in HRQoL are urgently needed., Competing Interests: Conflict of interest: O.C. Leavy declares that their institute received joint funding from UKRI and NIHR (MR/V027859/1 and COV0319) to complete this work. A.B. Docherty declares that they were awarded funding from a Wellcome Clinical Research Career Development Fellowship (216606/Z/19/Z) to complete this work. A Sheikh declares that their institute was awarded grant funding from NIHR and UKRI to complete this work; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca's Thrombotic Thrombocytopenic Taskforce; and leadership or fiduciary roles for UK and Scottish Government COVID-19 advisory groups. C.E. Bolton declares that their institute received grant funding from NIHR/UKRI and NIHR to complete this work; and their institute received grant funding from Nottingham Hospitals Charity and University of Nottingham. G. Choudhury declares funding from GlaxoSmithKline and AstraZeneca; received honoraria for delivering talks from GSK, AZ, Chiesi and BI; participation on a Data Safety Monitoring Board or Advisory Board as Chair on the Act on COPD Programme for AZ in Scotland; and a leadership or fiduciary role as Chair for the Lothian Respiratory Managed Clinical Network. N.D. Bakerly declares they have received nonrestrictive educational grants from Chiesi, AZ and Teva for attending conferences; honoraria from Teva, AZ and GSK; support for attending meetings and/or travel from Chiesi and AZ; participation on a Data Safety Monitoring Board or Advisory Board for Teva; and receipt of equipment from Global Access Diagnostics (previously Mologic Inc). A. Shikotra declares that their institute was awarded joint funding from UKRI and the NIHR (MR/V027859/1 and COV0319) to complete this work. R. Aul declares lecture fees and support for attending a meeting from Boehringer Ingelheim. C. Echevarria declares a grant from GSK. J.R. Hurst declares funding from AstraZeneca; consulting fees from AstraZeneca and GSK; payment for lectures and presentations from AstraZeneca, Boehringer Ingelheim, Chiesi, Sanofi and Takeda; support for attending meetings and/or travel from AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca; and receipt of equipment from Nonin. M. Jones declares funding from the MRC to complete this work; funding from the MRC, British Lung Foundation and Boehringer Ingelheim; consulting fees from Skyhawk Therapeutics; and a leadership or fiduciary role in the AAIR Charity Scientific Committee. P. Pfeffer declares funding from NIHR. S. Rowland-Jones declares that their institute received funding from UKRI to complete this work; and their institute received funding from NIHR Sheffield Biomedical Research centre, Bill and Melinda Gates Foundation, UKRI (MRC) and EDCTP. D. Parekh declares funding from NIHR and MRC; and a leadership or fiduciary role for the Faculty of Intensive Care Medicine Board. A.A.R. Thompson declares that their institute was awarded a fellowship from the British Heart Foundation, and grant funding from Heart Research UK and the National Institute for Health and Care Research; payment for lectures and presentations from Janssen-Cilag Ltd; and support for attending meetings from Janssen-Cilag Ltd. M.J. Davies declares grant funding from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen; consulting fees from Eli Lilly, Boehringer Ingelheim, Novo Nordisk and Sanofi; payment for speaking for Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, AstraZeneca, Amgen, Napp Pharmaceuticals and Novartis; and is an advisory board member for Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, Lexicon, Pfizer, Medtronic and ShouTi Pharma Inc., and Zealand Pharma. A. De Soyza declares that their institute was awarded grant funding from AstraZeneca, Bayer, GSK, Chiesi, Novartis and Pfizer, outside the submitted manuscript; consulting fees from AstraZeneca, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed and Gilead; payment for lectures and presentations from AstraZeneca, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed, Gilead and 30T; participation on a Data Safety Monitoring Board or Advisory Board for Bayer; and receipt of drugs from GSK outside the submitted manuscript. S. Heller declares consulting fees from NovoNordisk; and participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly with payments made to their institution. J. Jacob declares funding from Gilead, Microsoft Research and GlaxoSmithKline; consulting fees from Boehringer Ingelheim, Roche, GlaxoSmithKline and NHSX; payment for lectures and presentations received from Boehringer Ingelheim, Roche, GlaxoSmithKline and Takeda; support for attending meetings and/or travel from Boehringer Ingelheim; patents planned, issued or pending (UK patent application number 2113765.8 and UK patent application number GB2211487.0); and participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim and Roche. R.G. Jenkins declares that their institute received funding from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX and Pliant; consulting fees from AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Veracyte, Resolution Therapeutics and Pliant; payment for lectures and presentations received from Boehringer Ingelheim, Chiesi, Roche, PatientMPower and AstraZeneca; payment for expert testimony from Pinsent Masons LLP; participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim, Galapagos and Vicore; and a leadership or fiduciary role for NuMedii and is president for Action for Pulmonary Fibrosis. W.D-C. Man declares that their institute received funding from National Institute for Health Research and NHS Accelerated Access Collaborative; and is Honorary President of the Association for Respiratory Technology and Physiology, and an associate editor of ERJ Open Research. G.P. McCann declares funding from NIHR (RP-2017-ST2-007) to complete this work; funding from the British Heart Foundation, Wellcome Trust and NIHR; and research support from Resonance Health, Circle CVi and Perspectum. S. Neubauer declares grant funding from Oxford NIHR Biomedical Research centre. P.J.M. Openshaw declares funding from UKRI-MRC/DHSC NIHR and UKRI-BEIS. M.J. Rowland declares support for attending meetings and/or travel from Novartis Pharmaceuticals; stock or stock options from Novartis Pharmaceuticals and Roche Pharmaceuticals; and is employed full time as a Senior Clinical Development Medical Director at Novartis Pharmaceuticals. J. Porter declares funding from Breathing Matters and UCL/H BRC (NIHR), and consulting fees from The Limbic. L.G. Heaney declares that their institute received funding from GSK, AstraZeneca and Roche/Genentech; payment for lectures received from AstraZeneca, Novartis, Roche/Genentech, Sanofi, Circassia, GlaxoSmithKline, Chiesi and Teva; support to travel to meetings from AstraZeneca and GSK; participation on a Data Safety Monitoring Board or Advisory Board for Novartis, Roche/Genentech, GSK, Teva and Celltrion; and funding from the NIHR (RfPB grant PB-PG-0317-20032). J.T. Scott declares funding from UKRI. M.G. Semple declares grant funding from National Institute of Health Research UK, Medical Research Council UK and Health Protection Research Unit in Emerging and Zoonotic Infections, and University of Liverpool to complete this work; participation on a Data Safety Monitoring Board or Advisory Board for Pfizer; leadership or fiduciary roles as Chair of Infectious Disease Scientific Advisory Board Integrum Scientific LLC and Director of MedEx Solutions Ltd; stock or stock options as minority owner of Integrum Scientific LLC and majority owner of MedEx Solutions Ltd; receipt of equipment, materials, drugs, medical writing, gifts or other services from Chiesi Farmaceutici SpA; and is a nonremunerated independent member of HMG UK Scientific Advisory Group for Emergencies (SAGE), COVID-19 Response (March 2020 to March 2022) and a nonremunerated independent member of HMG UK New Emerging Respiratory Virus Threats Advisory Group (NERVTAG) (2014 to July 2023). S.J. Singh declares grants or contracts from NIHR (programme grant (NIHR 202020), Wellcome Doctoral Training Programme, HTA Project Grant (NIHR 131015), NIHR DHSC/UKRI COVID-19 Rapid Response Initiative, NIHR Global Research Group (NIHR 17/63/20)), Actegy Limited and NIHR Senior Investigator; payment for presentations for GSK, Ministry of Justice, CIPLA, Sherbourne Gibbs; participation on NICE Expert Adviser Panel (long COVID), Wales Long COVID Advisory Board and NHS-E Long Covid Your Covid Recovery working group; and leadership or fiduciary roles as ATS Pulmonary Rehabilitation Assembly Chair, Clinical Lead RCP Pulmonary Rehabilitation Accreditation Scheme and Clinical Lead NACAP Audit for Pulmonary Rehabilitation. M. Toshner declares grant funding from the NIHR Cambridge BRC and NIHR HTA to complete this work; consulting fees from Janssen; support for attending meetings and/or travel from GSK and Janssen; and participation on a Data Safety Monitoring Board or Advisory Board for ComCov and FluCov. A. Horsley declares that their institute was awarded funding from UK Research and Innovation (MR/V027859/1), the National Institute of Health Research (NIHR) (COV0319) and NIHR Manchester BRC; and is Chair for the NIHR Translational Research Collaboration. M. Marks declares that their institute received joint funding from UKRI and NIHR to complete this work. K. Poinasamy declares funding from UKRI and NIHR to complete this work. A. Briggs declares consulting fees from Roche, Merck, Sanofi and GSK. J.K. Quint declares that their institute received funding from the Industrial Strategy Challenge Fund, the Medical Research Council, Health Data Research, GSK, BI, Asthma+Lung UK and AZ; and consulting fees from GlaxoSmithKline, Evidera, Chiesi, AstraZeneca and Insmed. J.D. Chalmers declares funding from AstraZeneca, Boehringer Ingelheim, Grifols, Gilead Sciences, Insmed, Genentech and GlaxoSmithKline; consulting fees from AstraZeneca, Boehringer Ingelheim, Grifols, Gilead Sciences, Insmed, Genentech, Glaxosmithkline, Antabio, Zambon and Trudell; and leadership or fiduciary roles as Chief Editor of the European Respiratory Journal and associate editor of ERJ Open Research, Chair of the British Thoracic Society Science and Research Committee, and Trustee of the British Thoracic Society. L.V. Wain declares funding from UK Research and Innovation (MR/V027859/1), GSK/Asthma+Lung UK (Professorship (C17-1)) and National Institute of Health Research (COV0319) to complete this work; funding from Orion Pharma, GSK, Genentech, AstraZeneca, Nordic Bioscience and Sysmex (OGT); consulting fees Galapagos, Boehringer Ingelheim and GSK; support for attending meetings and/or travel Genentech; participation on Advisory Board for Galapagos; leadership or fiduciary roles as an associate editor for the European Respiratory Journal, and Medical Research Council Board member and Deputy Chair. C.E. Brightling declares that their institute received grant funding from MRC/NIHR and NIHR to complete this work; their institute received grant funding from GSK, AZ, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma and Mologic; and consulting fees from GSK, AZ, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma, Mologic and Areteia. R.A. Evans declares funding from UKRI/MRC/NIHR to complete this work; funding from Wolfson Foundation and Genentech/Roche; consulting fees from AstraZeneca/Evidera; speaking fees from Boehringer and Moderna; support for attending meetings from Chiesi; and leadership or fiduciary roles as ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Secretary, and ATS Pulmonary Rehabilitation Assembly Chair. All other authors declare no conflicts of interest., (Copyright ©The authors 2024.)

Recent bronchiectasis studies from large-scale multinational, multicentre registries have demonstrated that the characteristics of the disease vary according to geographic region. However, most perspectives on bronchiectasis are dominated by data from Western countries. This review intends to provide an Asian perspective on the disease, focusing on the established registries in India, Korea and China. Asian patients with bronchiectasis are less likely to show female predominance and experience exacerbations, are more likely to be younger, have milder disease, and have fewer options for guideline-recommended treatment than those living in other global regions. Furthermore, Asian bronchiectasis patients demonstrate different comorbidities, microbiological profiles and unique endophenotypes, including post-tuberculosis and dry bronchiectasis. Notably, each Asian region reveals further geographic variations and inter-patient differences. Future studies are warranted to better characterise Asian patients with bronchiectasis., Competing Interests: Conflict of interest: H. Choi reports grant from the Basic Science Research Program of the Korean Ministry of Education (grant no. 2021R1I1A3052416); and consulting and lecture fees from Boryung Pharmaceutical Co., Ltd. and Kolon Pharma. J-F. Xu reports leadership or fiduciary roles in other boards, societies, committees, or advocacy groups (unpaid) with the Shanghai Medical Association, Chinese Thoracic Society, and Chinese Association of Chest Physicians. S.H. Chotirmall has served on advisory boards for CSL Behring, Pneumagen Ltd and Boehringer Ingelheim, on data monitoring boards for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University, and has received personal fees from AstraZeneca and Chiesi Farmaceutici, all unrelated to this work J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, LifeArc and Novartis; and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon. L.C. Morgan reports payment or honoraria for speakers’ bureau from Boehringer Ingelheim, AstraZeneca and Insmed, and educational events from GSK Pharmaceutical and AstraZeneca, all unrelated to this work. In addition, L.C. Morgan reports a leadership or fiduciary role in other boards, societies, committees, or advocacy groups (unpaid) as Chair of the Lung Foundation Australia. R. Dhar reports grants from GSK Pharmaceutical and Glenmark and Thorasis; and lecture fees from Cipla Ltd., Lupin Respira, Glenmark, Abbott, Sanofi and AstraZeneca., (Copyright ©The authors 2024.)

Chronic airway inflammation is a central feature in the pathogenesis of bronchiectasis (BE), which can be caused by cystic fibrosis (CFBE; hereafter referred to as CF lung disease) and non-CF-related conditions (NCFBE). Inflammation in both CF lung disease and NCFBE is predominantly driven by neutrophils, which release proinflammatory cytokines and granule proteins, including neutrophil serine proteases (NSPs). NSPs include neutrophil elastase, proteinase 3 and cathepsin G. An imbalance between NSPs and their antiproteases has been observed in people with CF lung disease and people with NCFBE. While the role of the protease/antiprotease imbalance is well established in both CF lung disease and NCFBE, effective therapies targeting NSPs are lacking. In recent years, the introduction of CF transmembrane conductance regulator (CFTR) modulator therapy has immensely improved outcomes in many people with CF (pwCF). Despite this, evidence suggests that airway inflammation persists, even in pwCF treated with CFTR modulator therapy. In this review, we summarise current data on neutrophilic inflammation in CF lung disease to assess whether neutrophilic inflammation and high, uncontrolled NSP levels play similar roles in CF lung disease and in NCFBE. We discuss similarities between the neutrophilic inflammatory profiles of people with CF lung disease and NCFBE, potentially supporting a similar therapeutic approach. Additionally, we present evidence suggesting that neutrophilic inflammation persists in pwCF treated with CFTR modulator therapy, at levels similar to those in people with NCFBE. Collectively, these findings highlight the ongoing need for new treatment strategies targeting neutrophilic inflammation in CF lung disease., Competing Interests: Conflict of interest: M.A. Mall has received research grants paid to their institution from the German Research Foundation (DFG), German Ministry for Education and Research (BMBF), German Innovation Fund and Vertex Pharmaceuticals; consultancy fees from Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals; speaker fees from Vertex Pharmaceuticals; and travel grants for participation in advisory boards for Boehringer Ingelheim and Vertex Pharmaceuticals. M.A. Mall is listed as inventor on an issued patent filed by the University of North Carolina at Chapel Hill, describing the Scnn1b-transgenic mouse. M.A. Mall also reports advisory board participation for Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals, and is a fellow of ERS. J.C. Davies has received research grants from the UK Cystic Fibrosis Trust, Cystic Fibrosis Foundation, Cystic Fibrosis Ireland, EPSRC and NIHR, has received fees for clinical trial leadership and/or advisory board participation and speaking roles from Abbvie, Algipharma, Arcturus, Boehringer Ingelheim, Eloxx, Enterprise Therapeutics, Genentech, LifeArc, Recode, Tavanta and Vertex Pharmaceuticals, and is the Deputy Editor for the Journal of Cystic Fibrosis. J.C. Davies acknowledges funding from the National Institute of Health and Care Research through the Imperial Biomedical Research Centre and a Senior Investigator Award and grant funding from the Cystic Fibrosis Trust. S.H. Donaldson reports grants from the Cystic Fibrosis Foundation and the NIH; clinical trial contracts from AstraZeneca, Calithera and Vertex Pharmaceuticals; consulting fees from Chiesi USA, Inc., Polarean and 501 Ventures; and travel grants from Enterprise Therapeutics and Gilead Sciences. S.H. Donaldson also reported advisory board participation for Boehringer Ingelheim and data and safety monitoring board participation for Abbvie. R. Jain reports research grants from the CF Foundation, consulting fees from Boehringer Ingelheim, Insmed and Recode, and payment of honoraria for participation in the Vertex Innovation Awards review committee from Vertex Pharmaceuticals. R. Jain also reports advisory/data and safety monitoring board participation for Armata. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Zambon, and has received consultancy fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed, Pfizer and Zambon. M. Shteinberg reports having received research grants paid to their institution from GlaxoSmithKline, Novartis and Trudell; travel grants from Actelion, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Rafa; speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Kamada, Novartis, Sanofi and Teva; and consultancy fees from Boehringer Ingelheim, GlaxoSmithKline, Kamada and Zambon. M. Shteinberg also reports data and safety monitoring board participation for Bonus Therapeutics, Israel and has unpaid roles in EMBARC, the Israel Pulmonology Society board and the Israel Society for TB and Mycobacterial Diseases., (Copyright ©The authors 2024.)

Background: The overall burden of bronchiectasis on patients and healthcare systems has not been comprehensively described. Here, we present the findings of a systematic literature review that assessed the clinical and socioeconomic burden of bronchiectasis with subanalyses by aetiology (PROSPERO registration: CRD42023404162)., Methods: Embase, MEDLINE and the Cochrane Library were searched for publications relating to bronchiectasis disease burden (December 2017-December 2022). Journal articles and congress abstracts reporting on observational studies, randomised controlled trials and registry studies were included. Editorials, narrative reviews and systematic literature reviews were included to identify primary studies. PRISMA guidelines were followed., Results: 1585 unique publications were identified, of which 587 full texts were screened and 149 were included. A further 189 citations were included from reference lists of editorials and reviews, resulting in 338 total publications. Commonly reported symptoms and complications included dyspnoea, cough, wheezing, sputum production, haemoptysis and exacerbations. Disease severity across several indices and increased mortality compared with the general population was reported. Bronchiectasis impacted quality of life across several patient-reported outcomes, with patients experiencing fatigue, anxiety and depression. Healthcare resource utilisation was considerable and substantial medical costs related to hospitalisations, treatments and emergency department and outpatient visits were accrued. Indirect costs included sick pay and lost income., Conclusions: Bronchiectasis causes significant clinical and socioeconomic burden. Disease-modifying therapies that reduce symptoms, improve quality of life and reduce both healthcare resource utilisation and overall costs are needed. Further systematic analyses of specific aetiologies and paediatric disease may provide more insight into unmet therapeutic needs., Competing Interests: Conflict of interest: The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell, and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon. M.A. Mall reports research grants paid to their institution from the German Research Foundation (DFG), German Ministry for Education and Research (BMBF), German Innovation Fund, Vertex Pharmaceuticals and Boehringer Ingelheim; consultancy fees from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals; speaker fees from Vertex Pharmaceuticals; and travel support from Boehringer Ingelheim and Vertex Pharmaceuticals. M.A. Mall also reports advisory board participation for AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals and is a fellow of ERS (unpaid). P.J. McShane is an advisory board member for Boehringer Ingelheim's Airleaf trial and Insmed's Aspen trial. P.J. McShane is also a principal investigator for clinical trials with the following pharmaceutical companies: Insmed: Aspen, 416; Boehringer Ingelheim: Airleaf; Paratek: oral omadacycline; AN2 Therapeutics: epetraborole; Renovian: ARINA-1; Redhill; Spero; and Armata. K.G. Nielsen reports advisory board membership for Boehringer Ingelheim. M. Shteinberg reports having received research grants from Novartis, Trudell Pharma and GlaxoSmithKline; travel grants from Novartis, Actelion, Boehringer Ingelheim, GlaxoSmithKline and Rafa; speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed, Teva, Novartis, Kamada and Sanofi; and advisory fees (including steering committee membership) from GlaxoSmithKline, Boehringer Ingelheim, Kamada, Syncrony Medical, Zambon and Vertex Pharmaceuticals. M. Shteinberg also reports data and safety monitoring board participation for Bonus Therapeutics, Israel and is an ERS Task Force member on bronchiectasis guideline development. S.D. Sullivan has participated in advisory boards for Boehringer Ingelheim and has research grants from Pfizer, Bayer and GlaxoSmithKline. S.H. Chotirmall is on advisory boards for CSL Behring, Boehringer Ingelheim and Pneumagen Ltd, served on a data and safety monitoring board for Inovio Pharmaceuticals Inc., and has received personal fees from AstraZeneca and Chiesi Farmaceutici., (Copyright ©The authors 2024.)

Background: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning., Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2-3 years, and whether symptoms at 2-3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2-3 years were associated with occupation change. People with lived experience were involved in the study., Findings: 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2-3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0·71 SD below the mean [IQR 0·16-1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2-3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2-3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35·0-48·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7·0-17·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2-3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6-31·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1·51 [95% CI 1·04-2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21-1·98] for every point increase in CCI-20)., Interpretation: Psychiatric and cognitive symptoms appear to increase over the first 2-3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19., Funding: National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research., Competing Interests: Declaration of interests AHa is co-director and owner of H2CD, and owner and director of Future Cognition, which support online studies and develop custom cognitive assessment software, respectively. PJHe is director and CEO of H2CD. JDC declares grants from AstraZeneca, Boehringer Ingelheim, Insmed, Novartis, Gilead Sciences, and Genentech; and consulting fees from AstraZeneca, Boehringer Ingelheim, Insmed, Novartis, Gilead Sciences, Chiesi, Zambon, and Genentech. L-PH declares grants to their institution from UK Research and Innovation (UKRI), Regenerative Medicine Platform, Celgene, British Lung Foundation, and Oxford Boehringer Ingleheim; the author is on the advisory board for the CATALYST trial and acts as chair of the Respiratory Translational Research Collaboration. AHo declares a grant to their institution from UKRI and the UK National Institute for Health Research (NIHR) to complete this work, funding from NIHR Manchester Clinical Research Facility to support study delivery, and personal funding from NIHR Manchester Biomedical Research Centre (BRC). AHo declares institutional payments to support grant-funded research from NIHR, UK Medical Research Council (MRC), Cystic Fibrosis Trust, Cystic Fibrosis Foundation, North West Lung Centre Charity, and Moulton Trust; consulting fees from Mylan Pharmaceuticals for advisory board participation; and payment from Vertex Pharmaceuticals for educational presentation, participation on a clinical trials advisory board, and writing of a review article. AHo's non-paid roles include chair of the Cystic Fibrosis Clinical Trials Accelerator Program, deputy chair of the NIHR Respiratory Translational Research Collaboration, and director of a university spin-out company (Mi-trial). BR declares payments from the British Heart Foundation Oxford Centre of Research Excellence, NIHR Oxford BRC, and UKRI for grants and contracts; and consulting fees from Axcella Therapeutics. ASh, ASi, and MM declare a grant to their institution from UKRI and NIHR to complete this work. ASh declares unremunerated participation on the AstraZeneca Thrombotic Thrombocytopenic Taskforce and Scottish and UK Governments COVID-19 advisory groups. LH-W declares a grant from NIHR unrelated to the submitted work; acting as independent chair of the NIHR Health Technology Assessment Committee for Colour COPD trial; and membership of the American Thoracic Society Pulmonary Rehabilitation Assembly Web and Planning Committees. NIL declares acting as director of research at the Intensive Care Society UK. CEB declares a grant to their institution from UKRI and NIHR to complete this work; the author reports grants from GSK, AstraZeneca, Sanofi, Boehringer Ingelheim, Chiesi, Novartis, Roche, Genentech, Mologic, and 4DPharma; and consultancy fees paid to their institution from GSK, AstraZeneca, Sanofi, Boehringer Ingelheim, Chiesi, Novartis, Roche, Genentech, Mologic, 4DPharma, and Teva. LVW declares research funding unrelated to the submitted work from GSK and Orion; consulting fees unrelated to the submitted work from Galapagos; a Wellcome Conference speaker honorarium; travel support from Genentech; advisory board participation for Galapagos; and an associate editor role for the European Respiratory Journal. RAE declares a grant to their institution from UKRI and NIHR to complete this work; the author declares speaker fees from Boehringer Ingelheim and unpaid roles as European Respiratory Society Assembly 01·02 Pulmonary Rehabilitation secretary and with the American Thoracic Society Pulmonary Rehabilitation Assembly programme committee. All other authors declare no competing interests., (Copyright © 2024 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.)

Continued improvements in the treatment of pulmonary infections have paradoxically resulted in a growing challenge of individuals with postinfectious pulmonary complications (PIPCs). PIPCs have been long recognized after tuberculosis, but recent experiences such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have underscored the importance of PIPCs following other lower respiratory tract infections. Independent of the causative pathogen, most available studies of pulmonary infections focus on short-term outcomes rather than long-term morbidity among survivors. In this document, we establish a conceptual scope for PIPCs with discussion of globally significant pulmonary pathogens and an examination of how these pathogens can damage different components of the lung, resulting in a spectrum of PIPCs. We also review potential mechanisms for the transition from acute infection to PIPC, including the interplay between pathogen-mediated injury and aberrant host responses, which together result in PIPCs. Finally, we identify cross-cutting research priorities for the field to facilitate future studies to establish the incidence of PIPCs, define common mechanisms, identify therapeutic strategies, and ultimately reduce the burden of morbidity in survivors of pulmonary infections.

Bronchiectasis has an increasing prevalence and substantial clinical and economic burden. Therefore, physicians should identify patients with bronchiectasis at high risk of disease progression to ensure optimal management in advance. The heterogeneity of bronchiectasis means it is unlikely that any single parameter could identify high-risk patients, therefore disease severity is usually assessed using validated composite tools, such as the Bronchiectasis Severity Index, FACED, and Bronchiectasis Aetiology Comorbidity Index, to predict long-term outcomes in bronchiectasis. Disease severity, however, implies an advanced process with lung destruction. Earlier intervention may prevent disease progression and improve outcomes. To identify patients at risk, rather than patients with established advanced disease, we need to shift our focus from disease severity to disease activity. Disease activity denotes the activation level of underlying pathophysiological processes and can be measured using clinical presentations and biomarkers. This review discusses a paradigm shift in bronchiectasis management, focusing on disease activity rather than severity, to prevent disease progression.

Background: Pulmonary embolism (PE) is a well-recognised complication of coronavirus disease 2019 (COVID-19) infection, and chronic thromboembolic pulmonary disease with and without pulmonary hypertension (CTEPD/CTEPH) are potential life-limiting consequences. At present the burden of CTEPD/CTEPH is unclear and optimal and cost-effective screening strategies yet to be established., Methods: We evaluated the CTEPD/CTEPH referral rate to the UK national multidisciplinary team (MDT) during the 2017-2022 period to establish the national incidence of CTEPD/CTEPH potentially attributable to COVID-19-associated PE with historical comparator years. All individual cases of suspected CTEPH were reviewed by the MDT for evidence of associated COVID-19. In a separate multicentre cohort, the risk of developing CTEPH following hospitalisation with COVID-19 was calculated using simple clinical parameters at a median of 5 months post-hospital discharge according to existing risk scores using symptoms, ECG and N-terminal pro-brain natriuretic peptide., Results: By the second year of the pandemic, CTEPH diagnoses had returned to the pre-pandemic baseline (23.1 versus 27.8 cases per month; p=0.252). Of 334 confirmed CTEPD/CTEPH cases, four (1.2%) patients were identified to have CTEPH potentially associated with COVID-19 PE, and a further three (0.9%) CTEPD without PH. Of 1094 patients (mean age 58 years, 60.4% male) hospitalised with COVID-19 screened across the UK, 11 (1.0%) were at high risk of CTEPH at follow-up, none of whom had a diagnosis of CTEPH made at the national MDT., Conclusion: A priori risk of developing CTEPH following COVID-19-related hospitalisation is low. Simple risk scoring is a potentially effective way of screening patients for further investigation., Competing Interests: Conflict of interest: J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell; received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon; and is Chief Editor of the European Respiratory Journal. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Rationale: The inflammasome is a key regulatory complex of the inflammatory response leading to interleukin-1β (IL-1β) release and activation. IL-1β amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1β in bronchiectasis has not been investigated., Objectives: To characterise the role of airway IL-1β in bronchiectasis, including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity., Methods: Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1β was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1β in the population (high versus low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air-liquid interface culture were used to study the effect of IL-1β on cilia function., Results: Patients with high sputum IL-1β had more severe disease, increased caspase-1 activity and an increased T-helper type 1, T-helper type 2 and neutrophil inflammatory response compared with patients with low IL-1β. The active-dominant form of IL-1β was associated with increased disease severity. High IL-1β was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1β treatment reduced the functionality of cilia and tight junctions of epithelial cells in vitro ., Conclusions: A subset of stable bronchiectasis patients show increased airway IL-1β, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction., Competing Interests: Conflict of interest: M. Shteinberg reports consulting fees from GSK, Boehringer Ingelheim, Kamada and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis, Kamada and Sanofi; support for attending meetings and/or travel from Novartis, Actelion, Boehringer Ingelheim, GSK and Rafa; participation on a data safety monitoring board or advisory board for Bonus Therapeutics, Israel; leadership roles for EMBARC Management, Israel Pulmonology Society Board, Israel Society for TB and Mycobacterial Diseases; receipt of equipment, materials, drugs, medical writing, gifts or other services from Trudell Medical Int; and is an associate editor of the American Journal of Respiratory and Critical Care Medicine. P.C. Goeminne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, GSK and Chiesi; support for attending meetings and/or travel from Chiesi; and participation on a data safety monitoring board or advisory board for Boehringer, GSK and Pfizer. E. Polverino reports grants or contracts from Grifols; consulting fees from Insmed, Bayer, Chiesi and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Chiesi, Grifols, GSK, Insmed, Menarini and Zambon; and support for attending meetings and/or travel from Insmed, Pfizer and Moderna. F. Blasi reports grants or contracts from AstraZeneca, Chiesi and Insmed; consulting fees from Menarini; and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Chiesi, GSK, Guidotti, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Viatris, Vertex and Zambon. S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher and Paykel and GSK; royalties or licences from McGraw Hill; consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MCD Italis SrL, Brahms, Physioassist SAS and GSK SpA; payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK SpA, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini; and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd and MSD Italia SrL. J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GSK, Grifols, Insmed, LifeArc and Novartis; and consulting fees from AstraZeneca, Chiesi, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon. A. Shoemark reports consulting fees from Spirovant and Translate Bio; payment or honoraria for lectures, presentations, manuscript writing or educational events from Translate Bio, Ethris and Insmed; and a leadership role in European Respiratory Society Clinical Research Collaborations (EMBARC, BEATPCD, AMR). The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Brensocatib is an investigational, oral, reversible inhibitor of dipeptidyl peptidase-1 shown to prolong time to first exacerbation in adults with bronchiectasis. Outlined here are the clinical trial design, and baseline characteristics and treatment patterns of adult patients enrolled in the phase 3 ASPEN trial (NCT04594369)., Methods: The ASPEN trial is a global study enrolling patients with a clinical history consistent with bronchiectasis (cough, chronic sputum production and/or recurrent respiratory infections), diagnosis confirmed radiologically and ≥2 exacerbations in the prior 12 months. It was designed to evaluate the impact of two brensocatib doses (10 mg and 25 mg) on exacerbation rate over a 52-week treatment period versus placebo. Comprehensive clinical data, including demographics, disease severity, lung function, Pseudomonas aeruginosa status and quality of life, were collected at baseline., Results: 1682 adults from 35 countries were randomised from December 2020 to March 2023. Mean age was 61.3 years and 64.7% were female. ∼70% had moderate-to-severe Bronchiectasis Severity Index (BSI) scores, 29.3% had ≥3 exacerbations in the prior 12 months and 35.7% were positive for P. aeruginosa . Mean BSI scores were highest in Australia/New Zealand (8.3) and lowest in Latin America (5.9). Overall, the most common aetiology was idiopathic (58.4%). In P. aeruginosa- positive versus P. aeruginosa- negative patients, lung function was lower, with greater long-term macrolide (21.5% versus 14.0%) and inhaled corticosteroid use (63.5% versus 53.9%). There was wide regional variation in long-term antibiotic use in patients with bronchiectasis and P. aeruginosa ., Discussion: ASPEN baseline characteristics and treatment profiles were representative of a global bronchiectasis population., Competing Interests: Conflict of interest: J.D. Chalmers reports receiving grants and personal fees from AstraZeneca, Boehringer Ingelheim, GSK, Zambon and Insmed Incorporated, a grant from Gilead, and personal fees from Novartis and Chiesi. Conflict of interest: He is an Associate Editor of this journal. P-R. Burgel reports grants from Vertex and GSK, outside the submitted work. P-R. Burgel also reports clinical trials: acting as main investigator and advisory activity for AstraZeneca, Chiesi, GSK, Insmed Incorporated, MSD, Viatris, Vertex and Zambon. P-R. Burgel reports substantial financial contributions to the budget of an institution he is responsible for from GSK, Vertex, Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose and Filière MUCO-CFTR. Conflict of interest: C.L. Daley reports grant support, advisory board fees and consulting fees from Insmed Incorporated; grant support from AN2 Therapeutics, Bugworks, Paratek Pharmaceuticals and Juvabis; advisory board work with AN2 Therapeutics, AstraZeneca, Cepheid, Hyfe, MannKind, Matinas Biopharma, NobHill, Spero Therapeutics and Zambon; consulting with Genentech and Pfizer; and data monitoring committee work with Otsuka Pharmaceutical, Eli Lilly and Company, and the Bill and Melinda Gates Foundation. Conflict of interest: A. De Soyza reports grants and fees from AstraZeneca, Boehringer Ingelheim, Bayer, Chiesi, Gilead Sciences, GSK, Insmed Incorporated and Zambon. Conflict of interest: C.S. Haworth reports receiving consultancy/speaker fees from 30 Technology, CSL Behring, Chiesi, Insmed Incorporated, Janssen, LifeArc, Meiji, Mylan, Novartis, Pneumagen, Shinogi, Teva, Vertex and Zambon. Conflict of interest: D. Mauger reports grants from NHLBI and drugs for NIH-funded clinical trials from Genentech, GSK, OM Pharma and Sanofi-Regeneron. Conflict of interest: Conflict of interest: K. Mange, A. Teper, C. Fernandez and D. Conroy are employees of and shareholders in Insmed Incorporated. Conflict of interest: M. Metersky reports receiving consulting fees from AN2 Therapeutics, Boehringer Ingelheim, Insmed Incorporated, Renovion, Tactile Inc. and Zambon. Conflict of interest: J.D. Chalmers, P-R. Burgel, C.L. Daley, A. De Soyza, C.S. Haworth, D. Mauger and M. Metersky served as members of the ASPEN trial steering committee. J.D. Chalmers, P-R. Burgel, C.L. Daley, A. De Soyza, C.S. Haworth and M. Metersky were investigators in the ASPEN trial., (Copyright ©The authors 2024.)

Background: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown., Methods: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease ( i.e. , asthma, COPD or bronchiectasis) were compared to the non-airways group., Results: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p<0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p<0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p<0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group., Conclusion: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge., Competing Interests: Conflict of interest: J.R. Hurst has received support to attend meetings, research grants, and personal payment and payment to his employer from pharmaceutical companies that make medicines to treat airways diseases. J.K. Quint reports grants from Industrial Strategy Challenge Fund, the Medical Research Council, Health Data Research, GlaxoSmithKline (GSK), Boehringer Ingelheim (BI), Asthma+Lung UK and AstraZeneca (AZ), and consulting fees from GSK, Evidera, Chiesi, AZ and Insmed outside the submitted work. P.E. Pfeffer reports grants from NIHR and GSK, Honoraria payments for lectures from AZ, GSK, Sanofi and Chiesi and travel fees from AZ, GSK, Sanofi outside the submitted work. N.J. Greening reports grants from GSK and BioAge, and personal fees and travel grants from Genentech, Roche, Chiesi, AZ, GSK, Pulmonx and Chiesi outside the submitted work. J.D. Chalmers is an associate editor of this journal. A. Horsley reports grants from UKRI, NIHR and NIHR Manchester BRC during the conduct of this study and unenumerated role as the chair of NIHR Translational Research Collaboration. A. Sheikh has served on AZ's thrombotic thrombocytopenic taskforce, and on a number of UK and Scottish Government COVID-19 advisory bodies; all these roles were unremunerated. B. Raman reports grant from BHF Oxford CRE and speaker fees from Axcella Therapeutics. R.A. Evans reports grants from UKRI/MRC, DHSC/NIHR, Wolfson Foundation and Genentec/Roche during the conduct of this study, travel and speaker fees from AZ/Evidera, Boehringer Ingelheim (BI), Moderna and Chiesi, and unremunerated leadership roles in ERS/ATS outside the submitted work. C.E. Brightling declares that their institute was awarded a grant from UKRI/NIHR to complete this work; the author reports grants from GSK, AZ, Sanofi, Regeneron, BI, Chiesi, Novartis, Roche, Genentech, Mologic and 4DPharma; and consultancy fees paid to their institution from GSK, AZ, Sanofi, BI, Chiesi, Novartis, Roche, Genentech, Mologic, 4DPharma and Areteia. A. De Soyza declares receiving personal consulting fees and travel grants from AZ, Bayer, GSK, Chiesi, Novartis, Pfizer, Insmed, Gilead and 30T outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2024.)

Respiratory viruses are a major trigger of exacerbations in chronic obstructive pulmonary disease (COPD). Airway neutrophilia is a hallmark feature of stable and exacerbated COPD but roles played by neutrophil extracellular traps (NETS) in driving disease pathogenesis are unclear. Here, using human studies of experimentally-induced and naturally-occurring exacerbations we identify that rhinovirus infection induces airway NET formation which is amplified in COPD and correlates with magnitude of inflammation and clinical exacerbation severity. We show that inhibiting NETosis protects mice from immunopathology in a model of virus-exacerbated COPD. NETs drive inflammation during exacerbations through release of double stranded DNA (dsDNA) and administration of DNAse in mice has similar protective effects. Thus, NETosis, through release of dsDNA, has a functional role in the pathogenesis of COPD exacerbations. These studies open up the potential for therapeutic targeting of NETs or dsDNA as a strategy for treating virus-exacerbated COPD., (© 2024. The Author(s).)

Bronchiectasis is a heterogeneous disease with multiple aetiologies and diverse clinical features. There is a general consensus that optimal treatment requires precision medicine approaches focused on specific treatable disease characteristics, known as treatable traits. Identifying subtypes of conditions with distinct underlying biology (endotypes) depends on the identification of biomarkers that are associated with disease features, prognosis or treatment response and which can be applied in clinical practice. Bronchiectasis is a disease characterised by inflammation, infection, structural lung damage and impaired mucociliary clearance. Increasingly there are available methods to measure each of these components of the disease, revealing heterogeneous inflammatory profiles, microbiota, radiology and mucus and epithelial biology in patients with bronchiectasis. Using emerging biomarkers and omics technologies to guide treatment in bronchiectasis is a promising field of research. Here we review the most recent data on biomarkers in bronchiectasis., Competing Interests: Conflict of interest: E. Johnson has nothing to disclose. M.B. Long reports travel support from the British Thoracic Society, Asthma+Lung UK and the American Thoracic Society, outside the submitted work. J.D. Chalmers reports grants from AstraZeneca, Genentech, Gilead Sciences, GlaxoSmithKline, Insmed, Grifols, Novartis and Boehringer Ingelheim; and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon, all outside the submitted work., (Copyright ©The authors 2024.)

Competing Interests: Conflict of interest: J.D. Chalmers reports grants or contracts from from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, LifeArc and Novartis; and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon. P.C. Goeminne reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Insmed, GSK and Chiesi; support for attending meetings and/or travel from Chiesi; and participation on a Data Safety Monitoring Board or Advisory Board with Boehringer Ingelheim, GSK and Pfizer. F.C. Ringshausen reports grants or contracts from the German Center for Lung Research (DZL), German Center for Infection Research (DZIF), IMI (EU/EFPIA) and iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer and InfectoPharm; consulting fees from Parion, Grifols, Zambon, Insmed and Helmholtz-Zentrum für Infektionsforschung; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from I!DE Werbeagentur GmbH, Interkongress GmbH, AstraZeneca, Insmed, Grifols, Universitätsklinikum Frankfurt am Main; payment for expert testimony from Social Court Cologne; support for attending meetings and/or travel from German Kartagener Syndrome and Primary Ciliary Dyskinesia Patient Advocacy Group Mukoviszidose e.V.; participation on a Data Safety Monitoring Board or Advisory Board with Insmed, Grifols and Shionogi; leadership or fiduciary roles in another board, society, committee or advocacy group (paid or unpaid) as Coordinator of the ERN-LUNG Bronchiectasis Core Network, Chair of the German Bronchiectasis Registry PROGNOSIS, Member of the Steering Committee of the European Bronchiectasis Registry EMBARC, Member of the Steering Committee of the European Nontuberculous Mycobacterial Pulmonary Disease Registry EMBARC-NTM, Co-Speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD Patient Advocacy Group, Speaker of the Respiratory Infections and TB group of the German Respiratory Society, Speaker of the Cystic Fibrosis group of German Respiratory Society (DGP), PI of the German Center for Lung Research, Member of the Protocol Review Committee of the PCD-CTN, Member of Physician Association of the German Cystic Fibrosis Patient Advocacy Group; and other financial or non-financial interests with AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon.

Bronchiectasis is a complex and heterogeneous inflammatory chronic respiratory disease with an unknown cause in around 30-40% of patients. The presence of airway infection together with chronic inflammation, airway mucociliary dysfunction and lung damage are key components of the vicious vortex model that better describes its pathophysiology. Although bronchiectasis research has significantly increased over the past years and different endotypes have been identified, there are still major gaps in the understanding of the pathophysiology. Genomic approaches may help to identify new endotypes, as has been shown in other chronic airway diseases, such as COPD.Different studies have started to work in this direction, and significant contributions to the understanding of the microbiome and proteome diversity have been made in bronchiectasis in recent years. However, the systematic application of omics approaches to identify new molecular insights into the pathophysiology of bronchiectasis (endotypes) is still limited compared with other respiratory diseases.Given the complexity and diversity of these technologies, this review describes the key components of the pathophysiology of bronchiectasis and how genomics can be applied to increase our knowledge, including the study of new techniques such as proteomics, metabolomics and epigenomics. Furthermore, we propose that the novel concept of trained innate immunity, which is driven by microbiome exposures leading to epigenetic modifications, can complement our current understanding of the vicious vortex. Finally, we discuss the challenges, opportunities and implications of genomics application in clinical practice for better patient stratification into new therapies., Competing Interests: Conflict of interest: L. Perea reports no conflicts of interest. R. Faner reports grants or contracts from AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Instituto de Salud Carlos III, European Research Council and Fondo Europeo de Desarrollo Regional (FEDER); lecture honoraria from AstraZeneca, Zambon and Chiesi; and consulting fees from AstraZeneca. J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, LifeArc and Novartis; and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon. O. Sibila reports no conflicts of interest., (Copyright ©The authors 2024.)

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NJS reports consulting fees and/or honoraria from Vertex, Chiesi, Gilead and Menarini. KDB reports consulting fees and/or honoraria from Vertex, ELoxx, Splisense and Arcturus. JGM reports honoraria from Vertex, Chiesi, Abbvie and Viatris. PGM reports consulting fees and/or honoraria from Vertex, AstraZenica, Limbic and MedEd. CS reports consulting fees and/or honoraria from Vertex, Chiesi, TFF and Pfizer. JC reports consulting fees for Astrazeneca, Boehringer Ingelheim, Grifols, Gilead sciences, Insmed, Genentech, Glaxosmithkline, Antabio, Zambon and Trudell. OCY reports consulting fees and honoraria from Vertex. DGD reports consulting fees and/or honoraria from Chiesi, Insmed and Vertex. DP reports payments for educational talks. DVD reports consulting fees for Arcturus, Arrevus, BiomX, Clarametyx, CFF, Enbiotix, Microbion, Pyros, Respirion and Zambon. ISG reports honoraria from Vertex. KWS, FB, VV, EDW, MW, EB, DD, PE, EG, GH, AK, DN, JAN, CR, IS, MDW report no personal fees/honoraria, (Copyright © 2024. Published by Elsevier B.V.)

Rationale: COPD and bronchiectasis are commonly reported together. Studies report varying impacts of co-diagnosis on outcomes, which may be related to different definitions of disease used across studies. Objectives: To investigate the prevalence of chronic obstructive pulmonary disease (COPD) associated with bronchiectasis and its relationship with clinical outcomes. We further investigated the impact of implementing the standardized ROSE criteria (radiological bronchiectasis [R], obstruction [FEV 1 /FVC ratio <0.7; O], symptoms [S], and exposure [⩾10 pack-years of smoking; E]), an objective definition of the association of bronchiectasis with COPD. Methods: Analysis of the EMBARC (European Bronchiectasis Registry), a prospective observational study of patients with computed tomography-confirmed bronchiectasis from 28 countries. The ROSE criteria were used to objectively define the association of bronchiectasis with COPD. Key outcomes during a maximum of 5 years of follow-up were exacerbations, hospitalization, and mortality. Measurements and Main Results: A total of 16,730 patients with bronchiectasis were included; 4,336 had a clinician-assigned codiagnosis of COPD, and these patients had more exacerbations, worse quality of life, and higher severity scores. We observed marked overdiagnosis of COPD: 22.2% of patients with a diagnosis of COPD did not have airflow obstruction and 31.9% did not have a history of ⩾10 pack-years of smoking. Therefore, 2,157 patients (55.4%) met the ROSE criteria for COPD. Compared with patients without COPD, patients who met the ROSE criteria had increased risks of exacerbations and exacerbations resulting in hospitalization during follow-up (incidence rate ratio, 1.25; 95% confidence interval, 1.15-1.35; vs. incidence rate ratio, 1.69; 95% confidence interval, 1.51-1.90, respectively). Conclusions: The label of COPD is often applied to patients with bronchiectasis who do not have objective evidence of airflow obstruction or a smoking history. Patients with a clinical label of COPD have worse clinical outcomes.

Aims: Brensocatib is a reversible inhibitor of dipeptidyl peptidase 1 (cathepsin C), in development to treat chronic non-cystic fibrosis bronchiectasis. The phase 2, randomized, placebo-controlled WILLOW trial (NCT03218917) was conducted to examine whether brensocatib reduced the incidence of pulmonary exacerbations. Brensocatib prolonged the time to the first exacerbation and led to fewer exacerbations than placebo. Because brensocatib potentially affects oral tissues due to its action on neutrophil-mediated inflammation, we analyzed periodontal outcomes in the trial participants., Materials and Methods: Patients with bronchiectasis were randomized 1:1:1 to receive once-daily oral brensocatib 10 or 25 mg or placebo. Periodontal status was monitored throughout the 24-week trial in a prespecified safety analysis. Periodontal pocket depth (PPD) at screening, week 8, and week 24 was evaluated. Gingival inflammation was evaluated by a combination of assessing bleeding upon probing and monitoring the Löe-Silness Gingival Index on 3 facial surfaces and the mid-lingual surface., Results: At week 24, mean ± SE PPD reductions were similar across treatment groups: -0.07 ± 0.007, -0.06 ± 0.007, and -0.15 ± 0.007 mm with brensocatib 10 mg, brensocatib 25 mg, and placebo, respectively. The distribution of changes in PPD and the number of patients with multiple increased PPD sites were similar across treatment groups at weeks 8 and 24. The frequencies of gingival index values were generally similar across treatment groups at each assessment. An increase in index values 0-1 and a decrease in index values 2-3 over time and at the end of the study were observed in all groups, indicating improved oral health., Conclusions: In patients with non-cystic fibrosis bronchiectasis, brensocatib 10 or 25 mg had an acceptable safety profile after 6 months' treatment, with no changes in periodontal status noted. Improvement in oral health at end of the study may be due to regular dental care during the trial and independent of brensocatib treatment., Knowledge Transfer Statement: The results of this study suggest that 24 weeks of treatment with brensocatib does not affect periodontal disease progression. This information can be used by clinicians when considering treatment approaches for bronchiectasis and suggests that the use of brensocatib will not be limited by periodontal disease risks. Nevertheless, routine dental/periodontal care should be provided to patients irrespective of brensocatib treatment., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.C. Gunsolley was a paid consultant (biostatistical and periodontal) for the WILLOW trial but received no compensation for the work on this manuscript. C. Fernandez is an employee of Insmed Incorporated. O. Sibila has received a grant from Zambon and personal or other fees from Bayer Healthcare, Insmed Incorporated, and Grifols. J.D. Chalmers has received grants and personal fees from AstraZeneca, Boehringer–Ingelheim, GSK, Zambon, and Insmed Incorporated; a grant from Gilead; and personal fees from Novartis and Chiesi. F.A. Scannapieco reports no conflicts of interest.

Rationale: Chest computed tomography (CT) scans are essential to diagnose and monitor bronchiectasis (BE). To date, few quantitative data are available about the nature and extent of structural lung abnormalities (SLAs) on CT scans of patients with BE. Objectives: To investigate SLAs on CT scans of patients with BE and the relationship of SLAs to clinical features using the EMBARC (European Multicenter Bronchiectasis Audit and Research Collaboration) registry. Methods: CT scans from patients with BE included in the EMBARC registry were analyzed using the validated Bronchiectasis Scoring Technique for CT (BEST-CT). The subscores of this instrument are expressed as percentages of total lung volume. The items scored are atelectasis/consolidation, BE with and without mucus plugging (MP), airway wall thickening, MP, ground-glass opacities, bullae, airways, and parenchyma. Four composite scores were calculated: total BE (i.e., BE with and without MP), total MP (i.e., BE with MP plus MP alone), total inflammatory changes (i.e., atelectasis/consolidation plus total MP plus ground-glass opacities), and total disease (i.e., all items but airways and parenchyma). Measurements and Main Results: CT scans of 524 patients with BE were analyzed. Mean subscores were 4.6 (range, 2.3-7.7) for total BE, 4.2 (1.2-8.1) for total MP, 8.3 (3.5-16.7) for total inflammatory changes, and 14.9 (9.1-25.9) for total disease. BE associated with primary ciliary dyskinesia was associated with more SLAs, whereas chronic obstructive pulmonary disease was associated with fewer SLAs. Lower FEV 1 , longer disease duration, Pseudomonas aeruginosa and nontuberculous mycobacterial infections, and severe exacerbations were all independently associated with worse SLAs. Conclusions: The type and extent of SLAs in patients with BE are highly heterogeneous. Strong relationships between radiological disease and clinical features suggest that CT analysis may be a useful tool for clinical phenotyping.

Background: Inhaled antibiotics are recommended conditionally by international bronchiectasis guidelines for the treatment of patients with bronchiectasis, but results of individual studies are inconsistent. A previous meta-analysis demonstrated promising results regarding the efficacy and safety of inhaled antibiotics in bronchiectasis. Subsequent publications have supplemented the existing body of evidence further in this area., Research Question: To what extent do inhaled antibiotics demonstrate both efficacy and safety as a treatment option for adults with bronchiectasis?, Study Design and Methods: Systematic review and meta-analysis of randomized controlled trials of inhaled antibiotics in adult patients with bronchiectasis. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for eligible studies. Studies were included if they enrolled adults with bronchiectasis diagnosed by CT imaging and had a treatment duration of at least 4 weeks. The primary end point was exacerbation frequency, with additional key efficacy end points including severe exacerbations, bacterial load, symptoms, quality of life, and FEV 1 . Data were pooled through random-effects meta-analysis., Results: Twenty studies involving 3,468 patients were included. Inhaled antibiotics were associated with reduced number of patients with exacerbations (risk ratio, 0.85; 95% CI, 0.75-0.96), a slight reduction in exacerbation frequency (rate ratio [RR], 0.78; 95% CI, 0.68-0.91), a probable reduction in the frequency of severe exacerbations (RR, 0.48; 95% CI, 0.31-0.74), and a likely slight increase in time to first exacerbation (hazard ratio, 0.80; 95% CI, 0.68-0.94). Inhaled antibiotics likely lead to a slight increase in the Quality of Life Questionnaire-Bronchiectasis respiratory symptom score (mean difference, 2.51; 95% CI, 0.44-4.31) and may reduce scores on the St. George Respiratory Questionnaire (mean difference, -3.13; 95% CI, -5.93 to -0.32). Bacterial load consistently was reduced, but FEV 1 was not changed with treatment. Evidence suggests little to no difference in adverse effects between groups (OR, 0.99; 95% CI, 0.75-1.30). Antibiotic-resistant organisms likely were increased by treatment., Interpretation: In this systematic review and meta-analysis, inhaled antibiotics resulted in a slight reduction in exacerbations, a probable reduction in severe exacerbations, and a likely slight improvement in symptoms and quality of life in adults with bronchiectasis., Trial Registry: International Prospective Register of Systematic Reviews; No.: CRD42023384694; URL: https://www.crd.york.ac.uk/prospero/., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: H. C. reports grants or contracts from the Korean Ministry of Education Basic Science Research Program [Grant 2021R1I1A3052416]; consulting fees from Boryung Pharmaceutical Co., Ltd.; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boryung Pharmaceutical Co., Ltd. C. S. H. reports consulting fees from 30 Technology, Aradigm, CSL Behring, Chiesi, Gilead, Grifols, GSK, Insmed, Janssen, LifeArc, Meiji, Mylan, Novartis, Pneumagen, Shionogi, Teva, Vertex, and Zambon (personal fees); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Chiesi, Insmed; and payment for expert testimony from Zambon. J. D. C. has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed, and Trudell and has received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell, and Zambon. None declared (R. C.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Bronchiectasis is characterized by acute exacerbations, but the biological mechanisms underlying these events are poorly characterized. Objectives: To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. Methods: A total of 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation before receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral, or both. Sputum inflammatory assessments included label-free liquid chromatography-tandem mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16 s rRNA sequencing was used to characterize the microbiome. Measurements and Main Results: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacterium was identified in 103 samples (86%), and a high bacterial load (total bacterial load > 10 7 copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients, with rhinovirus being the most common virus (31%). PCR testing was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, IL-1β, and CXCL8. These markers were particularly associated with bacterial and bacterial plus viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral, and eosinophilic events in both hypothesis-led and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating four subtypes of exacerbation. Conclusions: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses, and inflammatory dysregulation.

Rationale: Pseudomonas aeruginosa infection is associated with worse outcomes in bronchiectasis. Impaired neutrophil antimicrobial responses contribute to bacterial persistence. Gremubamab is a bivalent, bispecific monoclonal antibody targeting Psl exopolysaccharide and the type 3 secretion system component PcrV. Objectives: This study evaluated the efficacy of gremubamab to enhance killing of P. aeruginosa by neutrophils from patients with bronchiectasis and to prevent P. aeruginosa -associated cytotoxicity. Methods: P. aeruginosa isolates from a global bronchiectasis cohort ( n  = 100) underwent whole-genome sequencing to determine target prevalence. Functional activity of gremubamab against selected isolates was tested in vitro and in vivo . Patients with bronchiectasis ( n  = 11) and control subjects ( n  = 10) were enrolled, and the effect of gremubamab in peripheral blood neutrophil opsonophagocytic killing (OPK) assays against P. aeruginosa was evaluated. Serum antibody titers to Psl and PcrV were determined ( n  = 30; 19 chronic P. aeruginosa infection, 11 no known P. aeruginosa infection), as was the effect of gremubamab treatment in OPK and anti-cytotoxic activity assays. Measurements and Main Results: Psl and PcrV were conserved in isolates from chronically infected patients with bronchiectasis. Seventy-three of 100 isolates had a full psl locus, and 99 of 100 contained the pcrV gene, with 20 distinct full-length PcrV protein subtypes identified. PcrV subtypes were successfully bound by gremubamab and the monoclonal antibody-mediated potent protective activity against tested isolates. Gremubamab increased bronchiectasis patient neutrophil-mediated OPK (+34.6 ± 8.1%) and phagocytosis (+70.0 ± 48.8%), similar to effects observed in neutrophils from control subjects (OPK, +30.1 ± 7.6%). No evidence of competition between gremubamab and endogenous antibodies was found, with protection against P. aeruginosa -induced cytotoxicity and enhanced OPK demonstrated with and without addition of patient serum. Conclusions: Gremubamab enhanced bronchiectasis patient neutrophil phagocytosis and killing of P. aeruginosa and reduced virulence.

Rationale: Chronic infection and inflammation shapes the airway microbiome in bronchiectasis. Utilizing whole-genome shotgun metagenomics to analyze the airway resistome provides insight into interplay between microbes, resistance genes, and clinical outcomes. Objectives: To apply whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis to highlight a diverse pool of antimicrobial resistance genes: the "resistome," the clinical significance of which remains unclear. Methods: Individuals with bronchiectasis were prospectively recruited into cross-sectional and longitudinal cohorts ( n  = 280), including the international multicenter cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 (CAMEB 2) study ( n  = 251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing Pseudomonas aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing, and the bronchiectasis resistome was evaluated in association with clinical outcomes and underlying host microbiomes. Measurements and Main Results: The bronchiectasis resistome features a unique resistance gene profile and increased counts of aminoglycoside, bicyclomycin, phenicol, triclosan, and multidrug resistance genes. Longitudinally, it exhibits within-patient stability over time and during exacerbations despite between-patient heterogeneity. Proportional differences in baseline resistome profiles, including increased macrolide and multidrug resistance genes, associate with shorter intervals to the next exacerbation, whereas distinct resistome archetypes associate with frequent exacerbations, poorer lung function, geographic origin, and the host microbiome. Unsupervised analysis of resistome profiles identified two clinically relevant "resistotypes," RT1 and RT2, the latter characterized by poor clinical outcomes, increased multidrug resistance, and P. aeruginosa. Successful targeted eradication in P. aeruginosa -colonized individuals mediated reversion from RT2 to RT1, a more clinically favorable resistome profile demonstrating reduced resistance gene diversity. Conclusions: The bronchiectasis resistome associates with clinical outcomes, geographic origin, and the underlying host microbiome. Bronchiectasis resistotypes link to clinical disease and are modifiable through targeted antimicrobial therapy.

Formerly regarded as a rare disease, bronchiectasis is increasingly recognised. A renewed interest in this disease has led to significant progress in bronchiectasis research. Randomised clinical trials (RCTs) have demonstrated the benefits of airway clearance techniques, inhaled antibiotics and long-term macrolide therapy in bronchiectasis patients. However, the heterogeneity of bronchiectasis remains one of the most challenging aspects of management. Phenotypes and endotypes of bronchiectasis have been identified to help find "treatable traits" and partially overcome disease complexity. The goals of therapy for bronchiectasis are to reduce the symptom burden, improve quality of life, reduce exacerbations and prevent disease progression. We review the pharmacological and non-pharmacological treatments that can improve mucociliary clearance, reduce airway inflammation and tackle airway infection, the key pathophysiological features of bronchiectasis. There are also promising treatments in development for the management of bronchiectasis, including novel anti-inflammatory therapies. This review provides a critical update on the management of bronchiectasis focusing on treatable traits and recent RCTs., Competing Interests: Conflict of interest: H. Choi reports grants from the Basic Science Research Program of the Korean Ministry of Education (grant number 2021R1I1A3052416), and consulting and lecture fees from Boryung Pharmaceutical Co., Ltd and Kolon Pharma. P.J. McShane reports study funding (paid to institution) from Boehringer Ingelheim, Armata, Paratek, Renovian, Spero, AN2 Therapeutics and Insmed, and speaker fees from Insmed. S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher & Paykel and GlaxoSmithKline, royalties or licences from McGraw Hill, consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon SpA, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MSD Italia Srl, Brahms, Physioassist SAS and GlaxoSmithKline SpA, payment or honoraria for lectures, presentations, manuscript writing or educational events from GlaxoSmithKline SpA, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini, and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd and MSD Italia Srl. J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, LifeArc and Novartis, and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon., (Copyright ©The authors 2024.)

A rapid, quantitative serum S100A8/A9 (calprotectin) lateral flow test in combination with clinical status predicted outcomes in people hospitalised with COVID-19 and associated with a patient cluster driven by markers of neutrophil activation https://bit.ly/48e1BIv., Competing Interests: Conflict of interest: A.A.R. Thompson reports grants or contracts from British Heart Foundation, Heart Research UK, and National Institute for Health and Care Research, outside the submitted work; honoraria for lectures from Janssen-Cilag Ltd, outside the submitted work; and support received for travel and conference registration from Janssen-Cilag Ltd, outside the submitted work. Conflict of interest: A.M. Condliffe reports grants or contracts from NIHR and MRC, outside the submitted work. Conflict of interest: A. Shoemark reports grants or contracts from AstraZeneca, outside the submitted work; consulting fees from Spirovant and Translate Bio, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for Translate Bio, Ethris and Insmed, outside the submitted work; and involvement in European Respiratory Society Clinical Research Collaborations (EMBARC, BEATPCD and AMR), EMBARC3 is supported by project partners Armata, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Grifols, Insmed, Janssen, Lifearc, Novartis, and Zambon, disclosures made outside the submitted work. Conflict of interest: J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell, outside the submitted work; and consulting fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon, outside the submitted work; and is an associate editor of this journal. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)