Search

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.)

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.)

Introduction: Aspergillus sp. cause diverse clinical manifestations in bronchiectasis including Allergic bronchopulmonary aspergillosis (ABPA), Aspergillus sensitization (AS) and raised IgG indicating exposure or infection with Aspergillus., Research Question: What is the prevalence and clinical significance of Aspergillus-associated conditions in individuals with bronchiectasis?, Methods: Bronchiectasis patients enrolled into the EMBARC registry from 2015 to 2022 with laboratory testing for Aspergillus lung disease (total IgE, specific IgE to Aspergillus or Aspergillus skin test, IgG to Aspergillus and blood eosinophil counts) were included for analysis. Modified-ISHAM-ABPA working group criteria (2021) were used to define ABPA., Results: 9953 patients were included. 608 (6.1%) were classified as having ABPA, 570 (5.7%) showed Aspergillus sensitization, 806 (8.1%) had raised Aspergillus-specific IgG without sensitisation, 184 (1.8%) were both sensitised to Aspergillus and had raised Aspergillus-specific IgG and 619 (6.2%) had eosinophilic bronchiectasis (elevated eosinophil counts without evidence of Aspergillus lung disease). The remaining 72.0% had negative Aspergillus serology. Patients with ABPA, Aspergillus sensitization, and raised Aspergillus-specific IgG had more severe disease, with worse lung function and more frequent exacerbations at baseline. During long-term follow-up, patients with raised Aspergillus-specific IgG had higher exacerbation frequency and more severe exacerbations. Aspergillus sensitization associated with increased exacerbations and hospitalisations only in patients not receiving inhaled corticosteroids., Interpretation: Aspergillus lung disease is common in bronchiectasis. Raised IgG to Aspergillus is associated with significantly worse outcomes while ABPA and Aspergillus sensitization are associated with severe disease and exacerbations with a risk that is attenuated by inhaled corticosteroid use., (Copyright © 2024. Published by Elsevier Inc.)

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.)

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.)

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.)

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.)

Competing Interests: EDJ is supported by a Clinical Research Fellowship from the Scottish Government Chief Scientist Office. JDC is supported by the Asthma and Lung UK Chair of Respiratory Research.

Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: M. S. received grant support from GSK, Trudell Medical Int, consulting fees and/or honoraria from AstraZeneca, BI, Kamada, Sanofi, and Insmed. J. D. C. received grant support from AstraZeneca, Genentech, Gilead sciences, GSK, Grifols, Boehringer Ingelheim, Insmed, Novartis; consulting fees from AstraZeneca, Chiesi, GSK, Insmed, Novartis, Pfizer, Grifols, Boehringer Ingelheim, Janssen, Antabio, Zambon. None declared (O. S., N. S., R. F., A. J., N. O., P. S., J. U. S. J., M. C., P. M., C. N. M., W. S.).

Improving the treatment of non-cystic fibrosis bronchiectasis in children and adolescents requires high-quality research with outcomes that meet study objectives and are meaningful for patients and their parents and caregivers. In the absence of systematic reviews or agreement on the health outcomes that should be measured in paediatric bronchiectasis, we established an international, multidisciplinary panel of experts to develop a core outcome set (COS) that incorporates patient and parent perspectives. We undertook a systematic review from which a list of 21 outcomes was constructed; these outcomes were used to inform the development of separate surveys for ranking by parents and patients and by health-care professionals. 562 participants (201 parents and patients from 17 countries, 361 health-care professionals from 58 countries) completed the surveys. Following two consensus meetings, agreement was reached on a ten-item COS with five outcomes that were deemed to be essential: quality of life, symptoms, exacerbation frequency, non-scheduled health-care visits, and hospitalisations. Use of this international consensus-based COS will ensure that studies have consistent, patient-focused outcomes, facilitating research worldwide and, in turn, the development of evidence-based guidelines for improved clinical care and outcomes. Further research is needed to develop validated, accessible measurement instruments for several of the outcomes in this COS., Competing Interests: Declaration of interests ABC is a member of the independent data management committees for clinical trials for Moderna (COVID-19 vaccine), GSK (an unlicensed vaccine), and AstraZeneca (a monoclonal antibody); she also reports payments to her institution for consulting on study designs for Zambon and Boehringer Ingelheim, travel expenses from the European Respiratory Society and Boehringer Ingelheim, and personal fees for authorship of two UpToDate chapters, outside of the submitted work. AZ reports personal fees for lectures from AstraZeneca, Chiesi, Vertex Pharmaceuticals, and Sanofi, and travel fees from Vertex, outside of the submitted work. JDC reports personal consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Grifols, Pfizer, Jansen, Antabio, and Zambon, outside of the submitted work but related to bronchiectasis in adults; he also reports grants from AstraZeneca, Boehringer Ingelheim, Novartis, GSK, Gilead Sciences, Insmed, Grifols, and Genentech, outside of the submitted work but related to bronchiectasis in adults. MG reports personal consulting fees and honoraria for lectures and presentations and for advice on an adjudication board from Boehringer Ingelheim and for advice on study development from Roche, outside of the submitted work. JG reports unrestricted grants from OM Pharma and Mariomed Biotech, and receipt of wheeze-detection equipment without cost from OMRON; he also reports personal fees for advisory board membership from OM Pharma, GSK, and AstraZeneca, for his role as a chief investigator on an asthma study from AstraZeneca, for lectures from Sanofi, and for expert testimony for medical advice, outside of the submitted work. AM reports grants to his institution from Vertex. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Bronchiectasis, a previously neglected condition, now has renewed research interest. There are a few systematic reviews that have reported on the economic and societal burden of bronchiectasis in adults, but none have reported on children. We undertook this systematic review to estimate the economic burden of bronchiectasis in children and adults., Research Question: What is the health care resource utilization and economic burden of bronchiectasis in adults and children?, Study Design and Methods: We performed a systematic review identifying publications from Embase, PubMed, Web of Science, Cochrane (trials, reviews, and editorials), and EconLit about the economic burden and health care utilization in adults and children with bronchiectasis between January 1, 2001, and October 10, 2022. We used a narrative synthesis approach and estimated aggregate costs for several countries., Results: We identified 53 publications reporting on the economic burden and/or health care utilization of people with bronchiectasis. Total annual health care costs per adult patient ranged from 2021 $3,579 to $82,545 USD and were predominantly driven by hospitalization costs. Annual indirect costs including lost income because of illness (reported in only five studies) ranged from $1,311 to $2,898 USD. Total health care costs in children with bronchiectasis were $23,687 USD annually in the one study that estimated them. Additionally, one publication found that children with bronchiectasis missed 12 school days per year. We estimated aggregate annual health care costs for nine countries, ranging from $101.6 million per year in Singapore to $14.68 billion per year in the United States. We also estimated the aggregate cost of bronchiectasis in Australian children to be $17.77 million per year., Interpretation: This review highlights the substantial economic burden of bronchiectasis for patients and health systems. To our knowledge, it is the first systematic review to include the costs for children with bronchiectasis and their families. Future research to examine the economic impact of bronchiectasis in children and economically disadvantaged communities, and to further understand the indirect burden of bronchiectasis on individuals and the community, is needed., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. D. C. 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. A. B. C. reports multiple grants from NHMRC and other fees to the institution from work relating to IDMC membership of an unlicensed vaccine (GlaxoSmithKline), unlicensed monoclonal antibody for RSV (AstraZeneca), and a COVID-19 vaccine (Moderna), outside the submitted work; and fees to the institution from work relating to unlicensed therapies for bronchiectasis (inhaled antibiotics from Zambon and a molecule from Boehringer Ingelheim). P. C. G. has received grants from Chiesi, speaker fees from Insmed and GSK, and an advisory board fee from GlaxoSmithKline. None declared (J. M. R., V. G., S. K., N. K., F. H., J. M. M., S. M. M.)., (Copyright © 2023 American College of Chest Physicians. All rights reserved.)

Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea., Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107)., Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect., Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition., Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council., Competing Interests: Declaration of interests IDS declares a statistical editor honoraria role with Thorax. TP declares support from the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) to complete the work. ALH declares an editor-in-chief role for Computer Physics Communications. RA declares speaker fees and travel support from Boehringer Ingelheim. CEB declares their institute was awarded a grant from the UK Research and Innovation (UKRI)/NIHR and institutional support from NIHR Nottingham BRC to complete this work; the author reports grants from Nottingham Hospitals Charity and Nottingham University Hospitals Research and Innovation Department. TC declares support from the NIHR South London and Maudsley NHS Foundation Trust, King's College London BRC to complete the work; the author reports grants from Guy's and St Thomas' Charity, NIHR, and UKRI; the author has published self-help books on chronic fatigue for which she receives royalties; the author has received ad-hoc payments for workshops carried out in long-term conditions; the author declares travel and accommodation support; the author is part of the scientific committee of the British Association for Behavioural and Cognitive Psychotherapies (BABCP) and she is on the expert advisory panel for COVID-19 Rapid Guidelines. JDC declares grants from AstraZeneca, Novartis, Boehringer Ingelheim, Genentech, Gilead Sciences, Insmed, GlaxoSmithKline, and Grifols; the author reports consulting fees from AstraZeneca, Insmed, Boehringer Ingelheim, Janssen, Antabio, Chiesi, Novartis, Pfizer, Zambon, GlaxoSmithKline, and Grifols. GD declares support from the NIHR Imperial BRC, Royal Brompton and Harefield NGS Foundation Trust, Royal Brompton & Harefield Hospitals Charity, Imperial College Healthcare NHS Trust, and the Medical Research Council (MRC) to complete this work; the author reports grants from Genentech, AstraZeneca, British Lung Foundation (BLF) Early Cohort, GlaxoSmithKline, Novartis, Chiesi, and Boehringer Ingelheim; the author has a published chapter in a textbook for which he receives payment; the author declares a role in the advisory boards for AstraZeneca and Novartis and as honorarium as deputy editor of the American Journal of Respiratory and Critical Care Medicine (AJRCCM). L-PH declares grants from NIHR Oxford BRC. MGJ declares grants from the Royal Society, MRC, BLF, Boehringer Ingelheim, and the Asthma, Allergy and Inflammatory Research Charity. BR declares support from the British Heart Foundation (BHF) Oxford Centre of Research Excellence (CRE) to complete this work. SLR-J declares support for her institute from UKRI to complete the work; the author reports grants from UKRI, The European and Developing Countries Clinical Trials Partnership (EDCTP), MRC, Rosetrees Trust, and the Global Challenges Research Fund (GCRF); the author reports an honorarium for chapter contribution from the Federation of European Academies of Medicine; the author is Data and Safety Monitoring Board (DSMB) Chair for a Bexsero trial funded by Wellcome Trust; the author declares an editor role for AIDS journal. AVR declares support from NIHR Leicester BRC to complete the work. MS declares support for his institute from MRC/Department of Health and Social Care (DHSC) to complete the work. ASi declares support for her institute from UKRI/NIHR to complete the work. DGW declares an advanced Fellowship grant from NIHR; the author receives an honorarium from bioMérieux to present. TY declares support from the NIHR Leicester BRC to complete the work. RGJ declares grants from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX, Pliant; the author received consulting fees from AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Veracyte, Resolution Therapeutics, and Pliant; the author has received payments from Boehringer Ingelheim, Chiesi, Roche, patientMpower, and AstraZeneca; the author was paid for expert testimony by Pinsent Masons LLP; the author has participated on a DSMB for Boehringer Ingelheim, Galapagos, and Vicore; the author has held a leadership role at NuMedii and is President of Action for Pulmonary Fibrosis. SJS declares grants from NIHR, Wellcome Doctoral Training Programme (DTP), the Human Tissue Authority, NIHR DHSC/UKRI COVID-19 Rapid Response Initiative, NIHR Global Research Group, Actegy Limited, and as an NIHR Senior Investigator; the author has presented for GlaxoSmithKline, Ministry of Justice, CIPLA, and Sherbourne Gibbs; the author is on the National Institute for Health and Care Excellence (NICE) Expert Advisor Panel for Long COVID and was on the Wales Long COVID Advisory Board; the author is the American Thoracic Society (ATS) Pulmonary Rehabilitation Assembly Chair, Clinical Lead Royal Society of Physicians (RSP) Pulmonary Rehabilitation Accreditation Scheme, and Clinical Lead Nation Asthma and COPD Audit Programme (NACAP) for Pulmonary Rehabilitation. WD-CM declares grants for his institution from NIHR, National Health Service (NHS) Accelerated Access Collaborative, and BLF; the author is the honorary President of the Association for Respiratory Technology and Physiology but receives no payment. CEBr declares support from UKRI/DHSC and NIHR Leicester BRC to complete the work; the author reports grants from GlaxoSmithKline, AstraZeneca, Sanofi, CI, Chiesi, Novartis, Roche, Genentech, Mologic, and 4DPharma; the author received consulting fees paid to his institution from GlaxoSmithKline, AstraZeneca, Sanofi, BI, Chiesi, Novartis, Roche, Genentech, Mologic, 4DPharma, and TEVA. LVW declares support from UKRI, GlaxoSmithKline/Asthma + Lung UK, and NIHR to complete this work; the author receives grants from Orion Pharma, GlaxoSmithKline, Genentech, and AstraZeneca; the author received consulting fees paid to her institution from Galapagos and Boehringer Ingelheim; the author received support for attending a meeting from Genentech. JCP received consulting fees from Istesso and The Limbic; the author participated on a DSMB for Vicore. AART declares a fellowship grant from BHF and a grant from NIHR to his institution; the author received an honorarium for lectures from Janssen-Cilag Ltd; the author received support for attending meetings from Janssen-Cilag Ltd. AH declares support from UKRI, NIHR, and NIHR Manchester BRC to complete the work; the author is Chair NIHR Translational Research Collaboration (unpaid). PLM declares a grant for his institution from AstraZeneca; the author received consulting fees from Hoffmann-La Roche, Boehringer Ingelheim, AstraZeneca, Trevi, and Qureight; the author received speaker fees from Boehringer Ingelheim and Hoffmann-La Roche. RAE declares support from UKRI/MRC to complete the work; the author reports a grant from NIHR/Wolfson Foundation; the author received consulting fees from AstraZeneca for Long COVID; the author received a speaker fee from Boehringer Ingelheim for a lecture on Long COVID; the author received support to attend BTS conference virtually from Chiesi; the author is the European Respiratory Society Group 01.02 Pulmonary Rehabilitation Secretary (unpaid). JFB declares support to his institute from an MRC Transition Fellowship, Asthma + Lung UK, NIHR Manchester BRC, and UKRI; the author reports grants paid to his institution from the Small Business Research Initiative Home Spirometer and the National Institute of Academic Anaesthesia; the author has received support for attending meetings from TEVA and Therakos; the author is a committee member of the Royal Society of Medicine (RSM). All other authors declare no competing interests., (Copyright © 2023 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.)

Background: Bronchiectasis is a heterogeneous, neglected disease with few multicentre studies exploring the causes, severity, microbiology, and treatment of the disease across Europe. This aim of this study was to describe the clinical characteristics of bronchiectasis and compare between different European countries., Methods: EMBARC is an international clinical research network for bronchiectasis. We report on a multicentre, prospective, observational, non-interventional, cohort study (the EMBARC registry) conducted across 27 European countries and Israel. Comprehensive clinical data were collected from adult patients (aged ≥18 years) at baseline and annual follow-up visits using electronic case report form. Data from individual countries were grouped into four regions (the UK, northern and western Europe, southern Europe, and central and eastern Europe according to modified EU EuroVoc classification). Follow-up data were used to explore differences in exacerbation frequency between regions using a negative binomial regression model., Findings: Between Jan 12, 2015, and April 12, 2022, 16 963 individuals were enrolled. Median age was 67 years (IQR 57-74), 10 335 (60·9%) participants were female and 6628 (39·1%) were male. The most common cause of bronchiectasis in all 16 963 participants was post-infective disease in 3600 (21·2%); 6466 individuals (38·1%) were classified as idiopathic. Individuals with bronchiectasis experienced a median of two exacerbations (IQR 1-4) per year and 4483 (26·4%) patients had a hospitalisation for exacerbation in the previous year. When examining the percentage of all isolated bacteria, marked differences in microbiology were seen between countries, with a higher frequency of Pseudomonas aeruginosa and lower Haemophilus influenzae frequency in southern Europe, compared with higher H influenzae in the UK and northern and western Europe. Compared with other regions, patients in central and eastern Europe had more severe bronchiectasis measured by the Bronchiectasis Severity Index (51·3% vs 35·1% in the overall cohort) and more exacerbations leading to hospitalisations (57·9% vs 26·4% in the overall cohort). Overall, patients in central and eastern Europe had an increased frequency of exacerbations (adjusted rate ratio [RR] 1·12, 95% CI 1·01-1·25) and a higher frequency of exacerbations leading to hospitalisations (adjusted RR 1·71, 1·44-2·02) compared with patients in other regions. Treatment of bronchiectasis was highly heterogeneous between regions., Interpretation: Bronchiectasis shows important geographical variation in causes, microbiology, severity, and outcomes across Europe., Funding: European Union-European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative., Translations: For the Arabic, French, German, Greek, Hebrew, Irish, Russian and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests JC 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 (ERS) Bronchiectasis Guideline Task Force, Chief Editor of European Respiratory Journal, and Chair of EMBARC Clinical Research Collaboration. EP reports grants or contracts from Grifols; consulting fees from Bayer, Zambon, Pfizer, Chiesi, Shire, Shionogi, Insmed, Moderna, and Pfizer; payment for expert testimony from Chiesi; leadership or fiduciary roles as ERS Task Force for Bronchiectasis Guidelines, co-chair of EMBARC; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Zambon. FR reports grants or contracts from German Center for Lung Research (DZL), German Center for Infection Research (EU and European Federation of Pharmaceutical Industries and Associations [EFPIA]) and iABC Consortium (including Alaxia, Basilea, Novartis, and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer, and InfectoPharm, to the institution; consulting fees from Parion, Grifols, Zambon, Insmed, Helmholtz-Zentrum für Infektionsforschung; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from I!DE Werbeagentur, Interkongress, AstraZeneca, Insmed, Grifols, and Universitätsklinikum Frankfurt am Main; payment for expert testimony from Social Court Cologne, to the institution; support for attending meetings or travel from German Kartagener Syndrome and PCD PAG, and Mukoviszidose; 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 groups as Coordinator of the ERN-LUNG Bronchiectasis Core Network; Chair of the German Bronchiectasis Registry PROGNOSIS; Member of the SteerCo of the European Bronchiectasis Registry EMBARC; Member of the SteerCo of the European Non-tuberculous Mycobacterial registry EMBARC-NTM; Co-Speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD PAG; Speaker of the Respiratory Infections and tuberculosis group of the German Respiratory Society (DGP; Speaker of the Cystic Fibrosis group of DGP; Prinicipal Investigator for DZL; Member of the Protocol Review Committee of the PCD-CTN; Member of Physician Association of the German Cystic Fibrosis PAG; and fees for clinical trial participation paid to the institution from AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex, and Zambon. ADS reports grants or contracts from Bayer, Gilead, Pfizer, Astrazeneca, and Novartis, outside of the submitted work; consulting fees from Boehringer, Bayer, Gilead, Pfizer, GSK, and Astrazeneca, outside of the submitted work; support for attending meetings or travel from AstraZeneca, Chiesi, and GSK; and participation on a Data Safety Monitoring Board or Advisory Board for Bayer. MV reports participation in EMBARC registry; grants or contracts from Chiesi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Insmed and Publi creation; support for attending meetings or travel from Zambon, Chiesi, Novartis, Behring; 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. PRB reports grants or contracts from GSK and Vertex, to the institution; consulting fees from Insmed, Vertex, Viatris, and Zambon; and participation on a Data Safety Monitoring Board or Advisory Board for Insmed. CH reports grants or contracts from the National Institute for Health and Care Research (NIHR 2020, NIHR133876 Seven versus Fourteen Days Antibiotics for Patients with Bronchiectasis Requiring Intravenous Antibiotics to the institution and NIHR [2020–2023] Bronchodilators and corticosteroids in bronchiectasis) to the institution; consulting fees from 30 Technology, CSL Behring, Chiesi, Insmed, Janssen, LifeArc, Meiji, Mylan, Novartis, Pneumagen, Shionogi, and Zambon; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Zambon, Insmed, Chiesi, and 30 Technology. ML reports consulting fees from Armata, 30T, AstraZeneca, Parion, Insmed, Chiesi, Zambon, Electromed, Recode, AN2, and Savara; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed; and the ERS Infection Group chair role. KD reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Novartis, AstraZeneca, Boehringer Ingelheim, Chiesi, and Norma Hellas; and upport for attending meetings or travel from Novartis, AstraZeneca, Boehringer Ingelheim, Chiesi, Pfizer, Norma Hellas, and Menarini. MM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer; payment for expert testimony from Vertex; support for attending meetings or travel from Zambon; and participation on a Data Safety Monitoring Board or Advisory Board from Zambon, and Viatris. TW reports grants or contracts from German Ministry of Research and Education and consulting fees from AstraZeneca, GSK, and Insmed. FB reports grants or contracts from AstraZeneca, Chiesi, GSK, Insmed; consulting fees from GSK, Menarini, OM Pharma; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Chiesi, GSK, Grifols, Insmed, Menarini, Novartis, Ompharma, Pfizer, Sanofi, Vertex, Viatris, and Zambon. MS reports grants or contracts from GSK and Trudell pharma; consulting fees from AstraZeneca, Boehringer Ingelheim, Dexcel, Kamada, Synchrony Medical, Trumed, and Zambon; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, and Kamada; support for attending meetings or travel from Boehringer Ingelheim, AstraZeneca, and Kamada; participation on a Data Safety Monitoring Board or Advisory Board for Bonus Biotherapeutics, Boehringer Ingelheim, and AstraZeneca; leadership or fiduciary role in other board, society, committee, or advocacy group with Israeli Pulmonology Society, Israeli Society for Tuberculosis and Mycobacterial Diseases, and EMBARC as unpaid management board member and ERJ, Chest as unpaid Editorial board member; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Trudell Medical International. JSE reports grants or contracts from EU FP7 with Novartis and Polyphor; and consulting fees from Vertex. PG reports payment or honoraria for a lecture on bronchiectasis from GSK. SA reports grants or contracts from Insmed, Chiesi, Fisher & Paykel, to the institution; royalties or licenses with McGraw Hill; consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland, Zambon, AstraZeneca UK, AstraZeneca Pharmaceutical, CSL Behring, Grifols, Fondazione Charta, Boehringer Ingelheim, Chiesi Farmaceutici Spa, Zcube, MENARINI, MSD Italia, 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 for Insmed Incorporated, Insmed Italy, AstraZeneca UK, and MSD Italia. All other authors declare no competing interests., (Copyright © 2023 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.)

Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19., Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012., Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug., Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19., Funding: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial., Competing Interests: Declaration of interests JDC reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Gilead Sciences, Grifols, Insmed, Janssen, Novartis, and Zambon. CB reports grants from the UK National Institute for Health and Care Research Biomedical Research Centre during the conduct of the study; grants and personal fees from GSK, AstraZeneca, Chiesi, Boehringer-Ingelheim, Genentech, Roche, Sanofi, Regeneron, Merck, TEVA, Mologic, 4DPharma, and Novartis. AART reports grants and personal fees from British Heart Foundation and Actelion Pharmaceuticals. JU reports personal fees from Gilead Sciences and ViiV Healthcare and from Celltrion; and is supported by the UK Medical Research Council (MR/T023791/1). DPSD reports grants and personal fees from GSK, Vir Biotechnology, AstraZeneca, and Boehringer-Ingelheim. ASm has received non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune; and has done consultancy work with AstraZeneca and GSK. MP reports non-financial support for clinical trial work from AstraZeneca, GSK, Chiesi, and Oncimmune and consultancy work with AstraZeneca and GSK. All other authors report no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Nontuberculous mycobacterial (NTM) infections are difficult to diagnose and treat. Biomarkers to identify patients with active infection or at risk of disease progression would have clinical utility. Sputum is the most frequently used matrix for the diagnosis of NTM lung disease., Research Question: Can sputum proteomics be used to identify NTM-associated inflammatory profiles in sputum?, Study Design and Methods: Patients with NTM lung disease and a matched cohort of patients with COPD, bronchiectasis (BE), and cystic fibrosis (CF) without NTM lung disease were enrolled from two hospitals in the United Kingdom. Liquid chromatography-tandem mass spectrometry was used to identify proteomic biomarkers associated with underlying diagnosis (COPD, BE, and CF), the presence of NTM lung disease defined according to American Thoracic Society/Infectious Diseases Society of America criteria, and severity of NTM. A subset of patients receiving guideline-concordant NTM treatment were studied to identify protein changes associated with treatment response., Results: This study analyzed 95 sputum samples from 55 subjects (BE, n = 21; COPD, n = 19; CF, n = 15). Underlying disease and infection with Pseudomonas aeruginosa were the strongest drivers of sputum protein profiles. Comparing protein abundance in COPD, BE, and CF found that 12 proteins were upregulated in CF compared with COPD, including MPO, AZU1, CTSG, CAT, and RNASE3, with 21 proteins downregulated, including SCGB1A1, IGFBP2, SFTPB, GC, and CFD. Across CF, BE, and COPD, NTM infection (n = 15) was not associated with statistically significant differences in sputum protein profiles compared with those without NTM. Two proteins associated with iron chelation were significantly downregulated in severe NTM disease. NTM treatment was associated with heterogeneous changes in the sputum protein profile. Patients with NTM and a decrease in immune response proteins had a subjective symptomatic improvement., Interpretation: Sputum proteomics identified candidate biomarkers of NTM severity and treatment response. However, underlying lung disease and typical bacterial pathogens such as P aeruginosa are also key determinants of the sputum proteomic profile., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Bronchiectasis refers to both a clinical disease and a radiological appearance that has multiple causes and can be associated with a range of conditions. Disease heterogeneity and the absence of standardised definitions have hampered clinical trials of treatments for bronchiectasis and are important challenges in clinical practice. In view of the need for new therapies for non-cystic fibrosis bronchiectasis to reduce the disease burden, we established an international taskforce of experts to develop recommendations and definitions for clinically significant bronchiectasis in adults to facilitate the standardisation of terminology for clinical trials. Systematic reviews were used to inform discussions, and Delphi processes were used to achieve expert consensus. We prioritised criteria for the radiological diagnosis of bronchiectasis and suggest recommendations on the use and central reading of chest CT scans to confirm the presence of bronchiectasis for clinical trials. Furthermore, we developed a set of consensus statements concerning the definitions of clinical bronchiectasis and its specific signs and symptoms, as well as definitions for chronic bacterial infection and sustained culture conversion. The diagnosis of clinically significant bronchiectasis requires both clinical and radiological criteria, and these expert recommendations and proposals should help to optimise patient recruitment into clinical trials and allow reliable comparisons of treatment effects among different interventions for bronchiectasis. Our consensus proposals should also provide a framework for future research to further refine definitions and establish definitive guidance on the diagnosis of bronchiectasis., Competing Interests: Declaration of interests SA reports personal fees from AstraZeneca, Bayer Healthcare, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Zambon, and ZetaCube; and grants from Chiesi, Fisher & Paykel, and Insmed, outside of the submitted work. AFB reports personal fees from Wolters Kluwer and UpToDate, during the conduct of the study. FB reports personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Grifols, Guidotti, Insmed, Menarini, Novartis, Pfizer, Vertex, and Zambon; and grants from AstraZeneca, Bayer, Chiesi, GlaxoSmithKline, Menarini, and Pfizer, outside of the submitted work. JDC reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Insmed, Janssen, Novartis, and Zambon; and grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Science, Insmed, and Novartis, outside of the submitted work. MLC reports personal fees from AstraZeneca, outside of the submitted work. ADS reports grants and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Forest Labs, GlaxoSmithKline, Grifols, Insmed, Teva, and Zambon, outside of the submitted work. PCG reports personal fees from AstraZeneca and GlaxoSmithKline; and grants and non-financial support from Chiesi, outside of the submitted work. CSH reports personal fees from Aradigm, CSL Behring, GlaxoSmithKline, Grifols, Insmed, International Biophysics, Janssen, Meiji, Mylan, Novartis, Teva, and Zambon; and grants from Insmed, International Biophysics, and Teva, outside of the submitted work. MSM reports non-financial support from Boehringer Ingelheim, Insmed, and Zambon; and personal fees from Zambon, outside of the submitted work. MRL reports personal fees from AstraZeneca, Grifols, and Insmed, outside of the submitted work. AEO'D reports personal fees from Electromed, Insmed, and Zambon; and grants from AstraZeneca, Insmed, Janssen, and Zambon, outside of the submitted work. EP reports grants from Chiesi and Grifols; and personal fees from CSL Behring, Chiesi, Shionogi, Insmed, Shire, Teva, and Zambon, during the conduct of the study. FCR reports personal fees from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Celtaxsys, Chiesi, Corbus, Grifols, InfectoPharm, Insmed, Novartis, PARI, Parion, Polyphor, Vertex, and Zambon; grants from Bayer Healthcare, Grifols, InfectoPharm, Insmed, Novartis, and PARI; and non-financial support from PARI, outside of the submitted work. MS reports personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Kamada, Novartis, Teva, Vertex, and Zambon; grants from GlaxoSmithKline and Novartis; and non-financial support from Actelion, GlaxoSmithKline, and Rafa, outside of the submitted work. HT reports personal fees from Insmed, Novartis, Thirona, and Vertex; and grants from the Cystic Fibrosis Foundation, Insmed, and Novartis, outside of the submitted work. In addition, HT's institution, Erasmus MC, receives license fees for the chest CT image analysis PRAGMA-CF software developed by Thirona (Nijmegen, Netherlands) and by Resonance Health (Perth, Australia) and for the chest CT image analysis AA-method software co-developed by Erasmus MC and Thirona (Nijmegen, Netherlands). HT contributed to the development and validation of this software. GT reports grants from the US Bronchiectasis and non-tuberculous mycobacteria Research Registry (which is funded by the COPD Foundation); and personal fees from AstraZeneca and Cipla, outside of the submitted work. MV reports non-financial support from Chiesi, GlaxoSmithKline, Novartis, and Zambon; and personal fees from Insmed, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Inhaled antibiotics have been incorporated into contemporary European and British guidelines for bronchiectasis, yet no inhaled antibiotics have been approved in the United States or Europe for the treatment of bronchiectasis not related to cystic fibrosis. Pseudomonas aeruginosa infection is common in patients with bronchiectasis, contributing to a cycle of progressive inflammation, exacerbations, and airway remodelling., Objective: The aim of the current study was to identify and evaluate published studies of inhaled tobramycin solution or powder in patients with bronchiectasis and P. aeruginosa infection not associated with cystic fibrosis., Methods: A literature review was conducted utilising the PubMed and Cochrane databases. Studies published in the English language that reported safety and/or efficacy outcomes of inhaled tobramycin either alone or in combination with other antibiotics were included., Results: Seven clinical trials published between 1999 and 2021 were identified that met inclusion criteria. Inhaled tobramycin therapy was effective in reducing P. aeruginosa microbial density in the sputum of patients with bronchiectasis. Several studies demonstrated favourable impacts on hospitalisations, number and severity of exacerbations, and symptoms. Other studies were underpowered for these clinical outcomes or were exploratory in nature. Although tobramycin was generally well tolerated, some evidence of treatment-associated wheezing was reported., Conclusions: In patients with bronchiectasis and chronic P. aeruginosa infection, inhaled tobramycin was effective in reducing the density of bacteria in sputum, which may be associated with additional clinical benefits. Definitive phase 3 trials of inhaled tobramycin in patients with bronchiectasis are indicated to determine clinical efficacy and long-term safety., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Allergic bronchopulmonary aspergillosis (ABPA) is associated with frequent exacerbations and poor outcomes in chronic respiratory disease, but remains underdiagnosed. The role of fungal sensitization in bronchiectasis-COPD overlap (BCO) is unknown., Research Question: What is the occurrence and clinical relevance of Aspergillus sensitization and ABPA in BCO when compared with individuals with COPD or bronchiectasis without overlap?, Study Design: Prospective, observational, cross-sectional study., Methods: We prospectively recruited 280 patients during periods of clinical stability with bronchiectasis (n = 183), COPD (n = 50), and BCO (n = 47) from six hospitals across three countries (Singapore, Malaysia, and Scotland). We assessed sensitization responses (as specific IgE) to a panel of recombinant Aspergillus fumigatus allergens and the occurrence of ABPA in relationship to clinical outcomes., Results: Individuals with BCO show an increased frequency and clinical severity of ABPA compared with those with COPD and bronchiectasis without overlap. BCO-associated ABPA is associated with more severe disease, higher exacerbation rates, and lower lung function when compared with ABPA occurring in the absence of overlap. BCO with a severe bronchiectasis severity index (BSI; > 9) is associated significantly with the occurrence of ABPA that is unrelated to underlying COPD severity., Conclusions: BCO demonstrates a high frequency of ABPA that is associated with a severe BSI (> 9) and poor clinical outcomes. Clinicians should maintain a high index of suspicion for the potential development of ABPA in patients with BCO with high BSI., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Persistent ill health after acute COVID-19-referred to as long COVID, the post-acute COVID-19 syndrome, or the post-COVID-19 condition-has emerged as a major concern. We undertook an international consensus exercise to identify research priorities with the aim of understanding the long-term effects of acute COVID-19, with a focus on people with pre-existing airways disease and the occurrence of new-onset airways disease and associated symptoms. 202 international experts were invited to submit a minimum of three research ideas. After a two-phase internal review process, a final list of 98 research topics was scored by 48 experts. Patients with pre-existing or post-COVID-19 airways disease contributed to the exercise by weighting selected criteria. The highest-ranked research idea focused on investigation of the relationship between prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge in patients with and without pre-existing airways disease. High priority was also assigned to comparisons of the prevalence and severity of post-COVID-19 fatigue, sarcopenia, anxiety, depression, and risk of future cardiovascular complications in patients with and without pre-existing airways disease. Our approach has enabled development of a set of priorities that could inform future research studies and funding decisions. This prioritisation process could also be adapted to other, non-respiratory aspects of long COVID., Competing Interests: Declaration of interests CEB reports grants from the Post-hospitalisation COVID-19 study during the conduct of the study. JRH reports personal fees and non-financial support from pharmaceutical companies (AstraZeneca and GlaxoSmithKline) that make medicines to treat chronic obstructive pulmonary disease, outside the submitted work. JDC reports grants and personal fees from AstraZeneca and Boehringer Ingelheim, and personal fees from GlaxoSmithKline, Insmed, Novartis, Chiesi, and Zambon, outside the submitted work. PEP reports personal fees and non-financial support from AstraZeneca, and a grant and non-financial support from GlaxoSmithKline, outside the submitted work. AS reports grants from the Health Data Research UK BREATHE Hub, the Medical Research Council, and the National Institute for Health Research, during the conduct of the study. ADS has received medical education grant support for BRONCH-UK, a UK bronchiectasis network, from GlaxoSmithKline, Gilead, Chiesi, and Forest labs, and his institution receives fees for his work as coordinating investigator on a phase 3 trial in bronchiectasis sponsored by Bayer. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes., Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107)., Findings: We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9-6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40-59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity., Interpretation: We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care., Funding: UK Research and Innovation and National Institute for Health Research., Competing Interests: Declaration of interests JDC reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Insmed, personal fees from Chiesi, Zambon, Janssen, and Grifols, and grants from Gilead Sciences, outside the submitted work. TC reports grants from Guy's and St Thomas' Charity, fees from workshops, and fees from writing self-help books on fatigue, outside the submitted work. NE received a donation of SARS-CoV-2 lateral flow antigen test kits from Mologic, in relation to an unrelated COVID-19 project. Neither NE nor his institution have received any financial compensation and he has no financial relationship of any kind with Mologic. RAE reports grants from GlaxoSmithKline during the conduct of the study; and grants from the National Institute for Health Research (NIHR) and personal fees from GlaxoSmithKline, AstraZeneca, and Chiesi, outside the submitted work. AH reports personal fees from Vertex Pharmaceuticals, Mylan Healthcare, and the Cystic Fibrosis Foundation, and grants from JP Moulton Trust and NIHR, outside the submitted work. LGH reports receiving sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals, personal fees from Novartis, Hoffman la Roche/Genentech, Sanofi, Evelo Biosciences, GlaxoSmithKline, AstraZeneca, Teva, Theravance, and Circassia, and grants from Medimmune, Novartis UK, Roche/Genentech, GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, Medimmune, Aerocrine, and Vitalograph, outside the submitted work. NH reports that his research group has received unrestricted grants (managed by Guy's & St Thomas' Foundation Trust) from Philips and Resmed. Philips are contributing to the development of the MYOTRACE technology. SH reports personal fees and fees to institution for advisory boards and consultancy from Novo Nordisk, Eli Lilly, Zealand Pharma, and Sanofi Aventis, outside the submitted work. JJ reports personal fees from Boehringer Ingelheim, Roche, GlaxoSmithKline, and NHSX, outside the submitted work. RGJ reports personal fees and research funding from Biogen, personal fees from Galapagos, Heptares, Boehringer Ingelheim, Pliant, Roche/InterMune, MedImmune, PharmAkea, Bristol Myers Squibb, Chiesi, Roche/Promedior, Veracyte, and GlaxoSmithKline research funding from Galecto, collaborative award from RedX and Nordic Biosciences, and was an advisory board member for NuMedii, outside the submitted work. RGJ is supported by an NIHR Professorship (RP-2017-08-ST2-014) and is a trustee for Action for Pulmonary Fibrosis. GM reports grants from AstraZeneca, outside the submitted work. PJMO reports grants from the Medical Research Council (MRC), the EU, and NIHR, and personal fees from Pfizer, Nestle, and Janssen, outside the submitted work. PP reports a grant from NIHR, outside the submitted work. MRo reports a senior clinical fellowship as part of research training and a 1-year post working in Pharma Development Neurosciences with Roche Pharmaceuticals, outside the submitted work. ADS reports grants and personal fees from AstraZeneca, Bayer, Boehringer, Chiesi, Forest Laboratories, GlaxoSmithKline, Grifols, Insmed, MedImmune, Novartis, Pfizer, and 30T, outside the submitted work. MGS reports grants from NIHR, MRC, and the Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool, during the conduct of the study; and reports being a minority owner and chair of the infectious disease scientific advisory board for Integrum Scientific, outside the submitted work. AShe reports being a Member of the Scottish Government's Chief Medical Officer's COVID-19 Advisory Group. MT reports personal fees from Merck Sharp & Dohme and GlaxoSmithKline, and grants and personal fees from Bayer and Actelion, during the conduct of the study. LVW reports grants from GlaxoSmithKline and Orion, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 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.)

Background: Infection is a key component of bronchiectasis pathophysiology. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than does traditional culture methods. We aimed to evaluate the role of the microbiome in determining the risk of exacerbation and long-term outcomes, including all-cause mortality, in bronchiectasis., Methods: We did a prospective observational cohort study of patients with bronchiectasis from eastern Scotland. Patients were enrolled from Sept 11, 2012, to Dec 21, 2015, and followed until Jan 8, 2019, for long-term outcomes. Patients were included if they were aged 18 years or older, and had a high-resolution CT-confirmed diagnosis of bronchiectasis and clinical symptoms consistent with the disease. Sputum samples were obtained when patients were clinically stable. Repeat sputum samples were taken at stable and exacerbation visits during follow-up. The V3-V4 region of the bacterial 16S rRNA gene was sequenced using the Illumina MiSeq platform. The dominant bacterial genus in each sample was assigned on the basis of a previously published method. Microbiome characteristics were analysed for their association with measures of clinical disease severity and long-term outcomes using PERMANOVA, random forest, and survival analyses., Findings: Sequencing data were obtained from the sputum samples of 281 patients with bronchiectasis who were included in the stable baseline cohort. 49 (17%) of 281 patients provided more than one sample when clinically stable and were included in the longitudinal analysis. 64 (23%) patients provided both stable and exacerbation samples. In both stable bronchiectasis and during exacerbations, a sputum microbiome dominated by Proteobacteria and Firmicutes was observed. Individual patients' microbiome profiles were relatively stable over time, during exacerbations and at disease stability. Lower microbiome diversity, measured using the Shannon-Wiener diversity index, was associated with more severe bronchiectasis defined by the bronchiectasis severity index, lower FEV 1 , and more severe symptoms. Random forest analysis of baseline samples identified Pseudomonas, Enterobacteriaceae, and Stenotrophomonas as being associated with severe bronchiectasis (bronchiectasis severity index ≥9) and greater lung inflammation and Pseudomonas and Enterobacteriaceae with more frequent exacerbations. Patients in whom Pseudomonas was dominant (n=35) were at increased risk of all-cause mortality (hazard ratio 3·12, 95% CI 1·33-7·36; p=0·0091) and had more frequent exacerbations (incident rate ratio 1·69, 95% CI 1·07-2·67; p=0·024) during follow-up compared with patients with other dominant genera (n=246)., Interpretation: A reduction in microbiome diversity, particularly one associated with dominance of Pseudomonas, is associated with greater disease severity, higher frequency and severity of exacerbations, and higher risk of mortality. The microbiome might therefore identify subgroups of patients at increased risk of poor outcomes who could benefit from precision treatment strategies. Further research is required to identify the mechanisms of reduced microbiome diversity and to establish whether the microbiome can be therapeutically targeted., Funding: British Lung Foundation and European Respiratory Society EMBARC2 consortium., Competing Interests: Declaration of interests JDC reports research grants from AstraZeneca, Boehringer-Ingelheim, Chiesi, Gilead Sciences, GlaxoSmithKline, Insmed, Novartis, and Zambon. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because little is understood of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a method of host defence that has been implicated in multiple inflammatory diseases. We aimed to investigate the role of NETs in disease severity and treatment response in bronchiectasis., Methods: In this observational study, we did a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. First, we used liquid chromatography-tandem mass spectrometry to identify proteomic biomarkers associated with disease severity, defined using the bronchiectasis severity index, in patients with bronchiectasis (n=40) in Dundee, UK. Second, we validated these biomarkers in two cohorts of patients with bronchiectasis, the first comprising 175 patients from the TAYBRIDGE study in the UK and the second comprising 275 patients from the BRIDGE cohort study from centres in Italy, Spain, and UK, using an immunoassay to measure NETs. Third, we investigated whether pathogenic bacteria had a role in NET concentrations in patients with severe bronchiectasis. In a separate study, we enrolled patients with acute exacerbations of bronchiectasis (n=20) in Dundee, treated with intravenous antibiotics for 14 days and proteomics were used to identify proteins associated with treatment response. Findings from this cohort were validated in an independent cohort of patients who were admitted to the same hospital (n=20). Fourth, to assess the potential use of macrolides to reduce NETs in patients with bronchiectasis, we examined two studies of long-term macrolide treatment, one in patients with bronchiectasis (n=52 from the UK) in which patients were given 250 mg of azithromycin three times a week for a year, and a post-hoc analysis of the Australian AMAZES trial in patients with asthma (n=47) who were given 500 mg of azithromycin 3 times per week for a year., Findings: Sputum proteomics identified that NET-associated proteins were the most abundant and were the proteins most strongly associated with disease severity. This finding was validated in two observational cohorts, in which sputum NETs were associated with bronchiectasis severity index, quality of life, future risk of hospital admission, and mortality. In a subgroup of 20 patients with acute exacerbations, clinical response to intravenous antibiotic treatment was associated with successfully reducing NETs in sputum. Patients with Pseudomonas aeruginosa infection had a lessened proteomic and clinical response to intravenous antibiotic treatment compared with those without Pseudomonas infections, but responded to macrolide therapy. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma., Interpretation: We identified NETs as a key marker of disease severity and treatment response in bronchiectasis. These data support the concept of targeting neutrophilic inflammation with existing and novel therapies., Funding: Scottish Government, British Lung Foundation, and European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Clinical heterogeneity in bronchiectasis remains a challenge for improving the appropriate targeting of therapies and patient management. Antimicrobial peptides (AMPs) have been linked to disease severity and phenotype., Research Question: Can we identify clusters of patients based on the levels of AMPs, airway inflammation, tissue remodeling, and tissue damage to establish their relationship with disease severity and clinical outcomes?, Study Design and Methods: A prospective cohort of 128 stable patients with bronchiectasis were recruited across three centers in three different countries (Spain, Scotland, and Italy). A two-step cluster strategy was used to stratify patients according to levels of lactoferrin, lysozyme, LL-37, and secretory leukocyte protease inhibitor in sputum. Measurements of inflammation (IL-8, tumor growth factor β, and IL-6), tissue remodeling and damage (glycosaminoglycan, matrix metallopeptidase 9, neutrophil elastase, and total and bacterial DNA), and neutrophil chemotaxis were assessed., Results: Three clusters of patients were defined according to distinct airway profiles of AMPs. They represented groups of patients with gradually distinct airway infection and disease severity. Each cluster was associated with an airway profile of inflammation, tissue remodeling, and tissue damage. The relationships between soluble mediators also were distinct between clusters. This analysis allowed the identification of the cluster with the most deregulated local innate immune response. During follow-up, each cluster showed different risk of three or more exacerbations occurring (P = .03) and different times to first exacerbations (P = .03)., Interpretation: Bronchiectasis patients can be stratified in different clusters according to profiles of airway AMPs, inflammation, tissue remodeling, and tissue damage. The combination of these immunologic variables shows a relationship with disease severity and future risk of exacerbations., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop., (Copyright © 2020 American College of Chest Physicians. All rights reserved.)

In 2019, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) issued a substantial revision of the 2007 guideline on community-acquired pneumonia (CAP). Despite the fact that generalization of infectious disease guidelines is limited because of substantial geographic differences in microbiologic etiology and antimicrobial resistance, the ATS/IDSA guideline is frequently applied outside the United States. Therefore, this project aimed to give a perspective on the ATS/IDSA CAP recommendations related to the management of CAP outside the United States. For this, an expert panel composed of 14 international key opinion leaders in the field of CAP from 10 countries across five continents, who were not involved in producing the 2019 guideline, was asked to subjectively name the five most useful changes, the recommendation viewed most critically, and the recommendation that cannot be applied to their respective region. There was no formal consensus process, and the article reflects different opinions. Recommendations welcomed by most of the international pneumonia experts included the abandonment of the concept of "health-care-associated pneumonia," the more restrictive indication for empiric macrolide treatment in outpatients, the increased emphasis on microbiologic diagnostics, and addressing the use of corticosteroids. Main criticisms included the somewhat arbitrary choice of a 25% resistance threshold for outpatient macrolide monotherapy. Experts from areas with elevated mycobacterial prevalence particularly opposed the recommendation of fluoroquinolones, even as an alternative., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Chitinase activity is an important innate immune defence mechanism against infection that includes fungi. The 2 human chitinases: chitotriosidase (CHIT1) and acidic mammalian chitinase are associated to allergy, asthma, and COPD; however, their role in bronchiectasis and bronchiectasis-COPD overlap (BCO) is unknown., Research Question: What is the association between chitinase activity, airway fungi and clinical outcomes in bronchiectasis and bronchiectasis-COPD overlap?, Study Design and Methods: A prospective cohort of 463 individuals were recruited across five hospital sites in three countries (Singapore, Malaysia, and Scotland) including individuals who were not diseased (n = 35) and who had severe asthma (n = 54), COPD (n = 90), bronchiectasis (n = 241) and BCO (n = 43). Systemic chitinase levels were assessed for bronchiectasis and BCO and related to clinical outcomes, airway Aspergillus status, and underlying pulmonary mycobiome profiles., Results: Systemic chitinase activity is elevated significantly in bronchiectasis and BCO and exceed the activity in other airway diseases. CHIT1 activity strongly predicts bronchiectasis exacerbations and is associated with the presence of at least one Aspergillus species in the airway and frequent exacerbations (≥3 exacerbations/y). Subgroup analysis reveals an association between CHIT1 activity and the "frequent exacerbator" phenotype in South-East Asian patients whose airway mycobiome profiles indicate the presence of novel fungal taxa that include Macroventuria, Curvularia and Sarocladium. These taxa, enriched in frequently exacerbating South-East Asian patients with high CHIT1 may have potential roles in bronchiectasis exacerbations., Interpretation: Systemic CHIT1 activity may represent a useful clinical tool for the identification of fungal-driven "frequent exacerbators" with bronchiectasis in South-East Asian populations., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Objective assessment of symptoms in bronchiectasis is important for research and in clinical practice. The COPD Assessment Test (CAT) is a short, simple assessment tool widely used in COPD. The items included in the CAT are not specific to COPD and also reflect the dominant symptoms of bronchiectasis. We therefore performed a study to validate the CAT as an outcome measure in bronchiectasis., Methods: The CAT was administered to two cohorts of bronchiectasis patients along with other quality of life questionnaires. Patients underwent comprehensive clinical assessment. One cohort had repeated questionnaires collected before-and-after treatment of acute exacerbations. We analyzed convergent validity, repeatability, and responsiveness of the score and calculated the minimum clinically important difference (MCID) using a combination of distribution and anchor-based methods., Results: In both cohorts there were positive correlations between the CAT and the St. George's Respiratory Questionnaire (r = 0.90, P < .0001 and r = 0.87, P < .0001). There was an inverse relationship between CAT and Quality of Life - Bronchiectasis Respiratory Symptoms Scale (r = -0.75, P < .0001) and Leicester Cough Questionnaire score (r = -0.77, P < .0001). Patients with more severe disease, based on the bronchiectasis severity index, had significantly higher CAT scores. CAT also correlated with FEV 1 % predicted and 6-min walk distance (6MWD). CAT increased significantly at exacerbation and fell at recovery. The intraclass correlation coefficient for two measurements four-weeks apart while clinically stable was 0.88 (95% CI, 0.73-0.95, P < .0001). An MCID of 4 was most consistent., Conclusions: CAT is a valid, responsive symptom assessment tool in bronchiectasis. The MCID is estimated as 4 points., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: Non-cystic fibrosis bronchiectasis (NCFBE) with Pseudomonas aeruginosa has been associated with increased pulmonary exacerbation (PEx) and mortality risk. European Respiratory Society guidelines conditionally recommend inhaled antimicrobials for persons with NCFBE, P aeruginosa and three or more PEx/year. We report microbiological results of two randomized, 48-week placebo-controlled trials of ARD-3150 (inhaled liposomal ciprofloxacin) in individuals with NCFBE with P aeruginosa and PEx history [Lancet Respir Med 2019;7:213-26]., Methods: Respiratory secretions from 582 participants receiving up to six 28-day on/off treatment cycles were analysed for sputum P. aeruginosa, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Escherichia coli densities, P. aeruginosa susceptibilities to ciprofloxacin and nine other antimicrobials, and prevalence of other bacterial opportunists. Associations between PEx risk and sputum density, antimicrobial susceptibility and opportunist prevalence changes were studied., Results: Sputum P. aeruginosa density reductions from baseline after ARD-3150 treatments ranged from 1.77 (95% CI 2.13-1.40) versus 0.54 (95% CI 0.89-0.19) log 10  CFU/g for placebo (second period) to 2.07 (95% CI 2.45-1.69) versus 0.70 (95% CI 1.11-0.29) log 10  CFU/g for placebo (fourth period) with only modest correlation between density reduction magnitude and PEx benefit. ARD-3150 (but not placebo) treatment was associated with increased P. aeruginosa ciprofloxacin MIC but not emergence of other bacterial opportunists across the study; ciprofloxacin MIC 50 increased from 0.5 to 1 mg/L, MIC 90 increased from 4 to 16 mg/L. Other antimicrobial MIC were mostly unaffected., Conclusion: Microbiological changes over 48 weeks of ARD-3150 treatment appear modest. Ciprofloxacin susceptibility (but not other antimicrobial susceptibility) decreases were observed that did not appear to preclude PEx risk reduction benefit., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Although use of inhaled antibiotics is the standard of care in cystic fibrosis, there is insufficient evidence to support use of inhaled antibiotics in patients with bronchiectasis not due to cystic fibrosis. We aimed to assess the efficacy and safety of inhaled antibiotics for the long-term treatment of adults with bronchiectasis and chronic respiratory tract infections., Methods: We did a systematic review and meta-analysis of all randomised controlled trials of inhaled-antibiotic use in adult patients with bronchiectasis and chronic respiratory tract infections. Eligible publications were identified by searching MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov. Randomised controlled trials of inhaled antibiotics were included if the patients were adults with stable bronchiectasis diagnosed by CT or bronchography, the trials had treatment a duration of at least 4 weeks, and their outcomes met at least one of the endpoints of interest. Studies in cystic fibrosis were excluded. Efficacy endpoints assessed were bacterial load, bacterial eradication from sputum, frequency of exacerbations, time to first exacerbation, proportion of patients with at least one exacerbation, frequency of severe exacerbations, quality of life, change in FEV 1 , 6-min walk distance, mortality, adherence to treatment, and sputum volume; safety endpoints were adverse events and bacterial resistance in sputum. Each study was independently reviewed for methodological quality using the Cochrane risk of bias tool. Random-effects meta-analysis was used to pool individual studies. Heterogeneity was assessed using I 2 . The review is registered on PROSPERO, number CRD42019122892., Findings: 16 trials (n=2597 patients) were included for analysis. The mean reduction of colony forming units per g of sputum with inhaled antibiotics was -2·32 log units (95% CI -3·20 to -1·45; p<0·0001). Bacterial eradication was increased with inhaled antibiotic therapy (odds ratio [OR] 3·36, 1·63 to 6·91; p=0·0010). Inhaled antibiotics significantly reduced exacerbation frequency (rate ratio 0·81, 0·67 to 0·97; p=0·020). Time to first exacerbation was significantly prolonged with inhaled antibiotics (hazard ratio 0·83, 0·69 to 0·99; p=0·028). The proportion of patients with at least one exacerbation decreased (risk ratio 0·85, 0·74 to 0·97; p=0·015). There was a significant reduction in the frequency of severe exacerbations (rate ratio 0·43, 0·24 to 0·78; p=0·0050). The scores for neither the Quality of Life Bronchiectasis questionnaire nor St George's Respiratory Questionnaire improved above the minimal clinically important difference. The relative change in FEV 1 was a deterioration of 0·87% predicted value (-2·00 to 0·26%; p=0·13). Other efficacy endpoints were reported in only few studies or had few events. There was no difference in treatment-emergent adverse effects (OR 0·97, 0·67 to 1·40; p=0·85) or bronchospasm (0·99, 0·66 to 1·48; p=0·95). Emergence of bacterial resistance was evident at the end of the treatment period (risk ratio 1·91, 1·46 to 2·49; p<0·0001)., Interpretation: Inhaled antibiotics are well tolerated, reduce bacterial load, and achieve a small but statistically significant reduction in exacerbation frequency without clinically significant improvements in quality of life in patients with bronchiectasis and chronic respiratory tract infections., Funding: British Lung Foundation through the GSK/British Lung Foundation Chair of Respiratory Research and European Respiratory Society through the EMBARC2 consortium. EMBARC2 is supported by project partners Chiesi, Grifols, Insmed, Novartis, and Zambon., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Bronchiectasis guidelines recommend long-term macrolide treatment for patients with three or more exacerbations per year without Pseudomonas aeruginosa infection. Randomised controlled trials suggest that long-term macrolide treatment can prevent exacerbations in adult patients with bronchiectasis, but these individual studies have been too small to do meaningful subgroup analyses. We did a systematic review and individual patient data (IPD) meta-analysis to explore macrolide benefit in subpopulations, including those in which macrolide therapy is not currently recommended., Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, to identify double blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients with bronchiectasis. We applied no language restrictions. Randomised controlled trials were eligible if treatment was defined a priori as long term and had a primary or secondary outcome of bronchiectasis exacerbations. Studies in patients with cystic fibrosis bronchiectasis were excluded. The primary outcome of the meta-analysis was frequency of exacerbations requiring treatment with antibiotics. Secondary endpoints were time to first exacerbation, change in quality of life according to the St George's Respiratory Questionnaire (SGRQ), and change in FEV 1 . IPD meta-analysis was done using fixed effects models adjusting for age, sex, FEV 1 , and trial. We did prespecified subgroup analyses for each of the primary and secondary endpoints using one-step meta-analysis only. Subgroups were defined by age, sex, previous exacerbation frequency, smoking status, inhaled corticosteroid use at baseline, body-mass index at baseline, cause, C-reactive protein at baseline, baseline FEV 1 percentage of predicted, SGRQ total score, and Pseudomonas aeruginosa in sputum culture at baseline. The meta-analysis is registered with the PROSPERO international register of systematic reviews, number CRD42018102908., Findings: Of 234 identified studies, we included three randomised controlled trials, and IPD was obtained for 341 participants. Macrolide antibiotics reduced the frequency of exacerbations (adjusted incidence rate ratio [IRR] 0·49, 95% CI 0·36 to 0·66; p<0·0001). We also found that macrolide treatment improved the time to first exacerbation (adjusted hazard ratio 0·46, 0·34 to 0·61; p<0·0001) and was associated with improved quality of life measured by the SGRQ (mean improvement 2·93 points, 0·03 to 5·83; p=0·048). Macrolides were not associated with a significant improvement in FEV 1 (67 mL at 1 year, -22 to 112; p=0·14). Effect estimates in prespecified subgroup analyses revealed a reduced frequency of exacerbations in all prespecified subgroups, including a high level of benefit in patients with P aeruginosa infection (IRR 0·36, 0·18-0·72; p=0·0044) and in patients with one to two exacerbations per year (0·37, 0·16-0·88; p=0·025). Studies were rated as low risk of bias across all domains., Interpretation: Long-term macrolide treatment significantly reduces the frequency of exacerbations in patients with bronchiectasis, with similar benefits observed in all subgroups based on patient characteristics. This finding suggests that macrolides might be considered in patients in whom macrolides are not indicated according to the current guidelines, particularly if alternative approaches to reduce exacerbations have been unsuccessful. However, downsides of long-term macrolide treatment must also be taken into account., Funding: European Respiratory Society., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In patients with non-cystic fibrosis bronchiectasis, lung infection with Pseudomonas aeruginosa is associated with frequent pulmonary exacerbations and admission to hospital for treatment, reduced quality of life, and increased mortality. Although inhaled antibiotics are conditionally recommended for long-term management of non-cystic fibrosis bronchiectasis with frequent exacerbations, there is no approved therapy. We investigated the safety and efficacy of inhaled liposomal ciprofloxacin (ARD-3150) in two phase 3 trials., Methods: ORBIT-3 and ORBIT-4 were international, randomised, double-blind, placebo-controlled, phase 3 trials run concurrently in similar geographical regions. Eligible patients had non-cystic fibrosis bronchiectasis, had had at least two pulmonary exacerbations treated with antibiotics in the previous 12 months, and had a history of chronic P aeruginosa lung infection. Patients were randomly assigned (2:1) to receive either ARD-3150 or placebo. ARD-3150 (3 mL liposome encapsulated ciprofloxacin 135 mg and 3 mL free ciprofloxacin 54 mg) or 6 mL placebo (3 mL dilute empty liposomes mixed with 3 mL of saline) was self-administered once daily for six 56-day treatment cycles, for 48 weeks. The primary endpoint was time to first pulmonary exacerbation from the date of randomisation to week 48. We did primary and secondary efficacy, safety, and microbiology analyses on the full analysis population, which comprised all randomised patients who received at least one dose of study drug. ORBIT-3 and ORBIT-4 are registered with ClinicalTrials.gov, numbers NCT01515007 and NCT02104245, respectively., Findings: Between March 31, 2014, and Aug 19, 2015, we screened 514 patients in ORBIT-3 and 533 patients in ORBIT-4. The full analysis populations consisted of 278 patients in ORBIT-3 (183 patients received at least one dose of ARD-3150 and 95 received placebo) and 304 patients in ORBIT-4 (206 patients received at least one dose of ARD-3150 and 98 received placebo). In ORBIT-4, the median time to first pulmonary exacerbation was 230 days in the ARD-3150 group compared with 158 days in the placebo group, a statistically significant difference of 72 days (hazard ratio [HR] 0·72 [95% CI 0·53-0·97], p=0·032). In ORBIT-3, the median time to first pulmonary exacerbation was 214 days in the ARD-3150 group and 136 days in the placebo group, a non-statistically significant difference of 78 days (HR 0·99 [95% CI 0·71-1·38], p=0·97). In a pooled analysis of data from both ORBIT-3 and ORBIT-4, the median time to first pulmonary exacerbation was 222 days in the ARD-3150 group and 157 days in the placebo group, a non-statistically significant difference of 65 days (0·82 [0·65-1·02], p=0·074). The numbers of adverse events and serious adverse events were similar in both groups in ORBIT-3 and ORBIT-4., Interpretation: In patients with non-cystic fibrosis bronchiectasis and chronic P aeruginosa lung infection requiring antibiotic therapy in the preceding year, ARD-3150 led to a significantly longer median time to first pulmonary exacerbation compared with placebo in ORBIT-4, but not in ORBIT-3 or the pooled analysis. Inconsistency between the trials suggests further research is needed into the heterogeneity of non-cystic fibrosis bronchiectasis and optimal outcome measures for inhaled antibiotics., Funding: Aradigm Corporation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: International guidelines recommend simple spirometry for bronchiectasis patients. However, pulmonary pathophysiology of bronchiectasis is very complex and still poorly understood. Our objective was to characterize lung function in bronchiectasis and identify specific functional sub-groups., Methods: This was a multicenter, prospective, observational study enrolling consecutive adults with bronchiectasis during stable sate. Patients underwent body-plethysmography before and after acute bronchodilation testing, diffusing lung capacity (DLCO) with a 3-year follow up. Air trapping and hyperinflation were a residual volume (RV) > 120%predicted and a total lung capacity>120%predicted. Acute reversibility was: ΔFEV1 ≥12% and 200 mL from baseline (FEV1rev) and ΔRV ≥10% reduction from baseline (RVrev). Sensitivity analyses included different reversibility cutoffs and excluded patients with concomitant asthma or chronic obstructive pulmonary disease., Results: 187 patients were enrolled (median age: 68 years; 29.4% males). Pathophysiological abnormalities often overlapped and were distributed as follows: air trapping (70.2%), impaired DLCO (55.7%), airflow obstruction (41.1%), hyperinflation (15.7%) and restriction (8.0%). 9.7% of patients had normal lung function. RVrev (17.6%) was more frequent than FEV1rev (4.3%). Similar proportions were found after multiple sensitivity analyses. Compared with non-reversible patients, patients with RVrev had more severe obstruction (mean(SD) FEV1%pred: 83.0% (24.4) vs 68.9% (26.2); P = 0.02) and air trapping (RV%pred, 151.9% (26.6) vs 166.2% (39.9); P = 0.028)., Conclusions: Spirometry alone does not encompass the variety of pathophysiological characteristics in bronchiectasis. Air trapping and diffusion impairment, not airflow obstruction, represent the most common functional abnormalities. RVrev is related to worse lung function and might be considered in bronchiectasis' workup and for patients' functional stratification., (Copyright © 2018. Published by Elsevier Ltd.)

Introduction: Multiple Breath Washout (MBW) to measure Lung Clearance Index (LCI) is increasingly being used as a secondary endpoint in multicentre bronchiectasis studies. LCI data quality control or "over-reading" is resource intensive and the impact is unclear., Objectives: To assess the proportion of MBW tests deemed unacceptable with over-reading, and to assess the change in LCI (number of turnovers), LCI coefficient of variation (CV%) and tidal volume (VT) CV% results after over-reading., Methods: Data were analysed from 250 MBW tests (from 98 adult bronchiectasis patients) collected as part of the Bronch-UK Clinimetrics study in 5 UK centres. Each MBW test was over-read centrally using pre-defined criteria. MBW tests with <2 technically valid and repeatable trials were deemed unacceptable to include in analysis. In accepted tests, values for LCI, LCI CV% and VT CV% before and after over-reading, were compared., Results: Insufficient data was collected in 10/250 tests. With over-reading, 30/240 (12%) were deemed unacceptable to include in analysis. In those accepted tests, overall the change in LCI, LCI CV% and VT CV% with over-reading was not statistically significant. When MBW new sites were compared to MBW expert sites, the change in LCI with over-reading was significantly greater in MBW new sites (p = 0.047). Data suggests that over-reading could be important up to at least 12 months post initiation of MBW activity., Conclusion: MBW over-reading was important in this study as 12% of tests were considered unacceptable. Over-reading improved test result accuracy in sites new to MBW., (Copyright © 2018. Published by Elsevier Ltd.)

Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of bronchiectasis including observations related to the microbiome., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

European Respiratory Society guidelines for the management of adult bronchiectasis highlight the paucity of treatment options available for patients with this disorder. No treatments have been licensed by regulatory agencies worldwide, and most therapies used in clinical practice are based on very little evidence. Development of new treatments is needed urgently. We did a systematic review of scientific literature and clinical trial registries to identify agents in early-to-late clinical development for bronchiectasis in adults. In this Review, we discuss the mechanisms and potential roles of emerging therapies, including drugs that target airway and systemic inflammation, mucociliary clearance, and epithelial dysfunction. To ensure these treatments achieve success in randomised clinical trials-and therefore reach patients-we propose a reassessment of the current approach to bronchiectasis. Although understanding of the pathophysiology of bronchiectasis is at an early stage, we argue that bronchiectasis is a heterogeneous disease with many different biological mechanisms that drive disease progression (endotypes), and therefore the so-called treatable traits approach used in asthma and chronic obstructive pulmonary disease could be applied to bronchiectasis, with future trials targeted at the specific disease subgroups most likely to benefit., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Gastro-oesophageal reflux disease (GORD) is a common comorbidity in bronchiectasis, and is often associated with poorer outcomes. The cause and effect relationship between GORD and bronchiectasis has not yet been fully elucidated and a greater understanding of the pathophysiology of the interaction and potential therapies is required. This review explores the underlying pathophysiology of GORD, its clinical presentation, risk factors, commonly applied diagnostic tools, and a detailed synthesis of original articles evaluating the prevalence of GORD, its influence on disease severity and current management strategies within the context of bronchiectasis. The prevalence of GORD in bronchiectasis ranges from 26% to 75%. Patients with co-existing bronchiectasis and GORD were found to have an increased mortality and increased bronchiectasis severity, manifest by increased symptoms, exacerbations, hospitalisations, radiological extent and chronic infection, with reduced pulmonary function and quality of life. The pathogenic role of Helicobacter pylori infection in bronchiectasis, perhaps via aspiration of gastric contents, also warrants further investigation. Our index of suspicion for GORD should remain high across the spectrum of disease severity in bronchiectasis. Identifying GORD in bronchiectasis patients may have important therapeutic and prognostic implications, although clinical trial evidence that treatment targeted at GORD can improve outcomes in bronchiectasis is currently lacking., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: The goal of this study was to develop a simplified radiological score that could assess clinical disease severity in bronchiectasis., Methods: The Bronchiectasis Radiologically Indexed CT Score (BRICS) was devised based on a multivariable analysis of the Bhalla score and its ability in predicting clinical parameters of severity. The score was then externally validated in six centers in 302 patients., Results: A total of 184 high-resolution CT scans were scored for the validation cohort. In a multiple logistic regression model, disease severity markers significantly associated with the Bhalla score were percent predicted FEV 1 , sputum purulence, and exacerbations requiring hospital admission. Components of the Bhalla score that were significantly associated with the disease severity markers were bronchial dilatation and number of bronchopulmonary segments with emphysema. The BRICS was developed with these two parameters. The receiver operating-characteristic curve values for BRICS in the derivation cohort were 0.79 for percent predicted FEV 1 , 0.71 for sputum purulence, and 0.75 for hospital admissions per year; these values were 0.81, 0.70, and 0.70, respectively, in the validation cohort. Sputum free neutrophil elastase activity was significantly elevated in the group with emphysema on CT imaging., Conclusions: A simplified CT scoring system can be used as an adjunct to clinical parameters to predict disease severity in patients with idiopathic and postinfective bronchiectasis., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The burden of community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae (pneumococcus) among adults in Europe is poorly defined., Methods: Structured searches of PubMed were conducted to identify the incidence of pneumococcal CAP among adults across Europe., Results: The overall incidence rates for CAP was 68-7000 per 100,000 and the incidence in hospitalised CAP cases of all causes was 16-3581 per 100,000. In general the incidence of CAP increased consistently with age. Available data indicated higher burdens of pneumococcal CAP caused in groups with more comorbidities. Most cases of pneumococcal CAP (30%-78%) were caused by serotypes covered by PCV13 vaccine; the incidence of PCV13-related pneumonia decreased after the introduction of childhood vaccination., Conclusions: We observed a high burden adult pneumococcal CAP in Europe despite use of the 23-valent pneumococcal polysaccharide vaccine, particularly in elderly patients with comorbidities. CAP surveillance presented wide variations across Europe. Pneumococcal CAP has to be monitored very carefully due to the possible effect of current vaccination strategies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Rationale: Airway colonization by Potentially Pathogenic Microorganisms (PPM) in bronchiectasis is associated with worse clinical outcomes. The electronic nose is a non-invasive technology capable of distinguishing volatile organic compounds (VOC) in exhaled breath. We aim to explore if an electronic nose can reliably discriminate airway bacterial colonization in patients with bronchiectasis., Methods: Seventy-three clinically stable bronchiectasis patients were included. PPM presence was determined using sputum culture. Exhaled breath was collected in Tedlar bags and VOC breath-prints were detected by the electronic nose Cyranose 320 ® . Raw data was reduced to three factors with principal component analysis. Univariate ANOVA followed by post-hoc least significant difference test was performed with these factors. Patients were then classified using linear canonical discriminant analysis. Cross-validation accuracy values were defined by the percentage of correctly classified patients., Results: Forty-one (56%) patients were colonized with PPM. Pseudomonas aeruginosa (n = 27, 66%) and Haemophilus influenzae (n = 7, 17%) were the most common PPM. VOC breath-prints from colonized and non-colonized patients were significantly different (accuracy of 72%, AUROC 0.75, p < 0.001). VOC breath-prints from Pseudomonas aeruginosa colonized patients were significantly different from those of patients colonized with other PPM (accuracy of 89%, AUROC 0.97, p < 0.001) and non-colonized patients (accuracy 73%, AUROC 0.83, p = 0.007)., Conclusions: An electronic nose can accurately identify VOC breath-prints of clinically stable bronchiectasis patients with airway bacterial colonization, especially in those with Pseudomonas aeruginosa., (Copyright © 2018. Published by Elsevier Ltd.)