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

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

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

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

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

Background: International guidelines recommend airway clearance management as one of the important pillars of bronchiectasis treatment. However, the extent to which airway clearance is used for people with bronchiectasis in Europe is unclear. The aim of the study was to identify the use of airway clearance management in patients with bronchiectasis across different countries and factors influencing airway clearance use., Methods: This was a prospective observational study using data from the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) Registry between January 2015 and April 2022. Prespecified options for airway clearance management were recorded, including airway clearance techniques, devices and use of mucoactive drugs., Results: 16 723 people with bronchiectasis from 28 countries were included in the study. The mean age was 67 years (interquartile range 57-74 years, range 18-100 years) and 61% were female. 72% of the participants reported daily sputum expectoration and 52% (95% CI 51-53%) of all participants reported using regular airway clearance management. Active cycle of breathing technique was used by 28% of the participants and airway clearance devices by 16% of participants. The frequency of airway clearance management and techniques used varied significantly between different countries. Participants who used airway clearance management had greater disease severity and worse symptoms, including a higher daily sputum volume, compared to those who did not use it regularly. Mucoactive drugs were also more likely to be used in participants with more severe disease. Access to specialist respiratory physiotherapy was low throughout Europe, but particularly low in Eastern Europe., Conclusions: Only a half of people with bronchiectasis in Europe use airway clearance management. Use of and access to devices, mucoactive drugs and specialist chest physiotherapy appears to be limited in many European countries., Competing Interests: Conflict of interest: B. Hererro-Cortina reports payment or honoraria for lectures, presentations, manuscript writing or educational events from SEPAR (Spanish Respiratory Society), and has a leadership or fiduciary role in SEPAR. S. Aliberti reports grants from Insmed Incorporated, Chiesi, Fisher and Paykel, and GSK; royalties or licences from McGraw Hill; consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MCD Italis Srl, Brahms, Physioassist SAS and GSK SpA; payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK SpA, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini; and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd and MSD Italia Srl. P.C. Goeminne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, GSK and Chiesi; support for attending meetings and/or travel from Chiesi; and participation on a data safety monitoring board or advisory board for Boehringer, GSK and Pfizer. E. Polverino reports grants from Grifols; consulting fees from Insmed, Bayer, Chiesi and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Chiesi, Grifols, GSK, Insmed, Menarini and Zambon; and support for attending meetings and/or travel from Insmed, Pfizer and Moderna. K. Dimakou reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Novartis, Boehringer Ingelheim, GSK, Norma Hellas, Chiesi, AstraZeneca and Zambon; support for attending meetings and/or travel from Novartis, Boehringer Ingelheim, GSK, Norma Hellas, Chiesi, AstraZeneca and Menarini, and participation on a data safety monitoring board or advisory board for Novartis, GSK and Chiesi. C.S. Haworth reports payment or honoraria for lectures, presentations, manuscript writing or educational events from 30 Technology, CSL Behring, Chisi, Insmed, Janssen, LifeArc, Meiji, Mylan, Pneumagen, Shionogi, Vertex and Zambon. M.R. Loebinger reports consulting fees from Armata, 30T, AstraZeneca, Parion, Insmed, Chiesi, Zambon, Electromed, Recode, AN2 and Boehringer Ingelheim; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed; and is ERS Infection Group Chair. A. De Soyza reports grants from AstraZeneca, Pfizer, GSK and Novartis; consulting fees from AstraZeneca, Insmed, GSK, Boehringer, 30T and Bayer; and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Pfizer, GSK and Novartis. M. Vendrell reports grants from Chiesi; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed and Publi Creation; support for attending meetings and/or travel from Zambon, Chiesi, Novartis, Behring and Gebro; participation on a data safety monitoring board or advisory board for Insmed; and receipt of equipment, materials, drugs, medical writing, gifts or services from Insmed and Novartis. P.R. Burgel reports grants from GSK and Vertex; consulting fees from AstraZeneca, Chiesi, GSK, Insmed, MSD, Vertex, Viatris and Zambon; and support for attending meetings and/or travel from AstraZeneca and Chiesi. S. Sutharsan reports grants from Vertex, Galapagos, Insmed, Proteostasis and Corbus; consulting fees from Insmed, Vertex Pharmaceuticals and Boehringer Ingelheim; and payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals, Boehringer Ingelheim and Insmed. S. Škrgat reports honoraria for educational events, invited lectures and presentations supported by Sanofi, AstraZeneca, Medis, Berlin-Chemie and Chiesi; and participation on a data safety monitoring board or advisory board for AstraZeneca. D. Stolz reports payment or honoraria for lectures, presentations, manuscript writing or educational events from CSL Behring, Berlin-Chemie, Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi and Sanofi; and participation on a data safety monitoring board or advisory board for GSK and CSL Behring. P. Kauppi reports support for attending meetings and/or travel from Nordic Respiratory Academy; participation on a data safety monitoring board or advisory board for Swedish Orphan Biovitrium; a leadership or fiduciary role for the Finnish Respiratory Society and Finnish Tuberculosis Foundation Grant Committee; and receipt of equipment, materials, drugs, medical writing, gifts or services from Theravance. A. Bossios reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi; and is Secretary of Assembly 5 (Airway diseases, asthma, COPD and chronic cough) of the ERS, Vice-chair of the Nordic Severe Asthma Network (NSAN)-NORDSTAR and a member of the Steering Committee of the ERS CRC for severe asthma (SHARP). I. Clifton reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca and GSK; and participation on a data safety monitoring board or advisory board for AstraZeneca, GSK and Infex Therapeutics. M.L. Crichton reports consulting fees from Boxer Capital LLC. P. Walker is Chair of the British Thoracic Society. D. Obradovic is President of the Serbian Society of Intensive Care Medicine. A. Amorim reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Zambon Group, and support for attending meetings and or/travel from Zambon Group, Boehringer Ingelheim and Novartis Farma. F. Blasi reports grants from AstraZeneca, Chiesi and Insmed; consulting fees from Menarini; and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Chiesi, GSK, Guidotti, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Viatris, Vertex and Zambon. M. Jankovic Makek reports consulting fees from Insmed, Biomerieux and MSD; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, MSD, Pfizer and Teva; and support for attending meetings and/or travel from MSD, Pfizer and Berlin-Chemie. M. Shteinberg reports consulting fees from GSK, Boehringer Ingelheim, Kamada and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis, Kamada and Sanofi; support for attending meetings and/or travel from Novartis, Actelion, Boehringer Ingelheim, GSK and Rafa; participation on a data safety monitoring board or advisory board for Bonus Therapeutics, Israel; leadership or fiduciary roles for EMBARC Management, Israel Pulmonology Society Board and the Israel Society for TB and Mycobacterial Diseases; receipt of equipment, materials, drugs, medical writing, gifts or services from Trudell Medical Int.; and is and Associate Editor of the American Journal of Respiratory and Critical Care Medicine. J.D. Chalmers reports grants from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GSK, Grifols, Insmed, LifeArc and Novartis; and consulting fees from AstraZeneca, Chiesi, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon. F.C. Ringshausen reports grants from German Center for Lung Research (DZL), German Center for Infection Research (DZIF), IMI (EU/EFPIA) and iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer and InfectoPharm; consulting fees from Parion, Grifols, Zambon, Insmed and Helmholtz-Zentrum für Infektionsforschung; payment or honoraria for lectures, presentations, manuscript writing or educational events from I!DE Werbeagentur GmbH, Interkongress GmbH, AstraZeneca, Insmed, Grifols and Universitätsklinikum Frankfurt am Main; payment for expert testimony from Social Court Cologne; support for attending meetings and/or travel from German Kartagener Syndrome and Primary Ciliary Dyskinesia Patient Advocacy Group Mukoviszidose e.V.; participation on a data safety monitoring board or advisory board for Insmed, Grifols and Shionogi; leadership or fiduciary roles as Coordinator of the ERN-LUNG Bronchiectasis Core Network, Chair of the German Bronchiectasis Registry PROGNOSIS, Member of the Steering Committee of the European Bronchiectasis Registry EMBARC, Member of the Steering Committee of the European Nontuberculous Mycobacterial Pulmonary Disease Registry EMBARC-NTM, Co-Speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD Patient Advocacy Group, Speaker of the Respiratory Infections and TB group of the German Respiratory Society, Speaker of the Cystic Fibrosis group of German Respiratory Society (DGP), principal investigator of the German Center for Lung Research, Member of the Protocol Review Committee of the PCD-CTN and Member of Physician Association of the German Cystic Fibrosis Patient Advocacy Group; and other financial or non-financial interests in AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes., Methods: We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up., Results: 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV 1 ), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22-1.38; p<0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44-1.67; p<0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52-2.39; p<0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29-1.56; p<0.0001), 1.98 (95% CI 1.77-2.21; p<0.0001) and 3.05 (95% CI 2.25-4.14; p<0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01-1.24; p=0.027), for each increment in sputum purulence., Conclusion: Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis., Competing Interests: Conflict of interest: S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher & Paykel and GlaxoSmithKline, royalties or licences from McGraw Hill, consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon SpA, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MCD Italia Srl, Brahms, PhysioAssist SAS and GlaxoSmithKline SpA, payment or honoraria for lectures, presentations, manuscript writing or educational events from GlaxoSmithKline SpA, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini, and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd and MSD Italia Srl. F.C. Ringshausen reports grants or contracts from the German Center for Lung Research (DZL), German Center for Infection Research (DZIF), IMI (EU/EFPIA), iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer and InfectoPharm, consulting fees from Parion, Grifols, Zambon, Insmed and Helmholtz-Zentrum für Infektionsforschung, payment or honoraria for lectures, presentations, manuscript writing or educational events from I!DE Werbeagentur GmbH, Interkongress GmbH, AstraZeneca, Insmed, Grifols and Universitätsklinikum Frankfurt am Main, payment for expert testimony from Social Court Cologne, support for attending meetings and/or travel from the German Kartagener Syndrome and Primary Ciliary Dyskinesia (PCD) Patient Advocacy Group Mukoviszidose eV, participation on a data safety monitoring board or advisory board for Insmed, Grifols and Shionogi, and leadership or fiduciary roles 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 Nontuberculous Mycobacterial Pulmonary Disease Registry EMBARC-NTM, Co-Speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD Patient Advocacy Group, Speaker of the Respiratory Infections and TB group of the German Respiratory Society (DGP), Speaker of the Cystic Fibrosis group of German Respiratory Society (DGP), PI of the German Center for Lung Research (DZL), Member of the Protocol Review Committee of the PCD-CTN, and Member of the Physician Association of the German Cystic Fibrosis Patient Advocacy Group; F.C. Ringshausen has other financial or non-financial interests with AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon. R. Dhar reports payment or honoraria for lectures, presentations, manuscript writing or educational events from LUPIN, CIPLA and Glenmark. C.S. Haworth reports payment or honoraria for lectures, presentations, manuscript writing or educational events from 30 Technology, CSL Behring, Chisi, Insmed, Janssen, LifeArc, Meiji, Mylan, Pneumagen, Shionogi, Vertex and Zambon. M.R. Loebinger reports consulting fees from Armata, 30T, AstraZeneca, Parion, Insmed, Chiesi, Zambon, Electromed, Recode, AN2 and Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, and a leadership or fiduciary role as ERS Infection Group Chair. K. Dimakou reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Novartis, Boehringer Ingelheim, GlaxoSmithKline, Norma Hellas, Chiesi, AstraZeneca and Zambon, support for attending meetings and/or travel from Novartis, Boehringer Ingelheim, GlaxoSmithKline, Norma Hellas, Chiesi, AstraZeneca and Menarini, and participation on a data safety monitoring board or advisory board for Novartis, GlaxoSmithKline and Chiesi. M.L. Crichton reports consulting fees from Boxer Capital LLC. A. De Soyza reports grants or contracts from AstraZeneca, Pfizer, GlaxoSmithKline and Novartis, consulting fees from AstraZeneca, Insmed, GlaxoSmithKline, Boehringer, 30T and Bayer, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Pfizer, GlaxoSmithKline and Novartis. M. Vendrell reports grants or contracts from Chiesi, payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed and Publi Creation, support for attending meetings and/or travel from Zambon, Chiesi, Novartis, Behring and Gebro, participation on a data safety monitoring board or advisory board for Insmed, and receipt of equipment, materials, drugs, medical writing, gifts or other services from Insmed and Novartis. P-R. Burgel reports grants or contracts from GlaxoSmithKline and Vertex, consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, MSD, Vertex, Viatris and Zambon, and support for attending meetings and/or travel from AstraZeneca and Chiesi. S. Skrgat reports honoraria for educational events, invited lectures and presentations supported by Sanofi, AstraZeneca, Medis, Berlin-Chemie and Chiesi, and participation on a data safety monitoring board or advisory board for AstraZeneca. A. de Roux reports consulting fees from Adboard Insmed, payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, AstraZeneca, GlaxoSmithKline, Berlin-Chemie and Boehringer Ingelheim, support for attending meetings and/or travel from AstraZeneca, and advisory board participation with Insmed. A. Bossios reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi, and leadership or fiduciary roles as Secretary of ERS Assembly 5 (Airway diseases, asthma, COPD and chronic cough), Vice-chair of the Nordic Severe Asthma Network (NSAN)-NORDSTAR and on the Steering Committee of ERS CRC Severe Asthma (SHARP). P. Kauppi reports support for attending meetings and/or travel from the Nordic Respiratory Academy, participation on a data safety monitoring board or advisory board for the Swedish Orphan Biovitrium, leadership or fiduciary roles for the Finnish Respiratory Society and Finnish Tuberculosis Foundation Grant Committee, and receipt of equipment, materials, drugs, medical writing, gifts or other services from Theravance. M. Murris reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Pfizer, payment for expert testimony from Vertex, support for attending meetings and/or travel from Zambon, and participation on a data safety monitoring board or advisory board for Zambon and Viatris. D. Obradovic reports a leadership or fiduciary role as president of the Serbian Society of Intensive Care Medicine. A. Amorim reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Zambon Group, and support for attending meetings and or/travel from Zambon Group, Boehringer Ingelheim and Novartis Farma. E. Van Braeckel reports grants or contracts from Insmed, Boehringer Ingelheim and Zambon. A. Shoemark reports consulting fees from Spirovant and Translate Bio, payment or honoraria for lectures, presentations, manuscript writing or educational events from Translate Bio, Ethris and Insmed, leadership or fiduciary roles in ERS CRCs (EMBARC, BEATPCD, AMR). M. Shteinberg reports consulting fees from GlaxoSmithKline, Boehringer Ingelheim, Kamada and Zambon, payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Teva, Novartis, Kamada and Sanofi, support for attending meetings and/or travel from Novartis, Actelion, Boehringer Ingelheim, GlaxoSmithKline and Rafa, participation on a data safety monitoring board or advisory board for Bonus Therapeutics, Israel, leadership or fiduciary roles in EMBARC, Israel Pulmonology Society, and Israel Society for TB and Mycobacterial Diseases, receipt of equipment, materials, drugs, medical writing, gifts or other services from Trudell Medical International, and is Associate Editor of the American Journal of Respiratory and Critical Care Medicine. P.C. Goeminne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, GlaxoSmithKline and Chiesi, support for attending meetings and/or travel from Chiesi, and participation on a data safety monitoring board or advisory board for Boehringer, GlaxoSmithKline and Pfizer. T. Welte reports grants from the German Ministry of Research and Education (BMBF), consulting fees and lecture honoraria from AstraZeneca, Chiesi, Grifols, GlaxoSmithKline, Insmed, MSD, Novartis, Pfizer and Sanofi, leadership roles for the German Center for Lung Research (DZL) – Board of Directors, Novartis Foundation – Board of Directors, Chairman of the Board of Trustees for CAPNETZ Foundation, German Lung Foundation, German Sepsis Foundation, and is Past President of the ERS, German Society of Pneumology and German Sepsis Society. F. Blasi reports grants or contracts from AstraZeneca, Chiesi, GlaxoSmithKline and Insmed, consulting fees from Menarini, GlaxoSmithKline and Om Pharma, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Viatris, Vertex and Zambon. E. Polverino reports grants or contracts from Grifols, consulting fees from Insmed, Bayer, Chiesi and Zambon, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Chiesi, Grifols, GlaxoSmithKline, Insmed, Menarini and Zambon, and support for attending meetings and/or travel from Insmed, Pfizer and Moderna. J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, LifeArc and Novartis, and consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon, and is Chief Editor of the European Respiratory Journal. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics., Methods: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively., Results: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL -1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus -IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response., Conclusion: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research., Competing Interests: Conflict of interest: R. Agarwal has received grants from Cipla Pharmaceuticals, India for conducting research in ABPA. D.W. Denning and family hold founder shares in F2G Ltd, a University of Manchester spin-out antifungal discovery company, and share options in TFF Pharma. He acts or has recently acted as a consultant to Pulmatrix, Pulmocide, Biosergen, TFF Pharmaceuticals, Rostra Therapeutics, Mucpharma PTY and Lifemine Therapeutics. In the last 3 years, he has been paid for talks on behalf of Mundipharma, Bio-Rad, Basilea, Gilead, Avir and Pfizer. He has been involved in multiple guideline groups, primarily focused on diagnostics and aspergillosis. D. Armstrong-James holds share options in Pulmocide Ltd. K. Asano is partially supported by a research grant on allergic disease and immunology from the Japan Agency for Medical Research and Development under grant number 22ek0410097. S.H. Chotirmall has served on advisory boards for CSL Behring, Pneumagen Ltd and Boehringer Ingelheim, on data monitoring boards for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University, and has received personal fees from AstraZeneca and Chiesi Farmaceutici, all unrelated to this work. H.J.F. Salzer has received honoraria for lectures or consulting fees from Ismed, GlaxoSmithKline, AstraZeneca, Advanz Pharma, MSD and Chiesi, all unrelated to this work. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell, and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon. C. Godet has received speaker fees and travel support from Pfizer and MSD, fees for board memberships from SOS Oxygène and Pulmatrix, and grant support from Ohre Pharma, Pfizer, MSD, SOS Oxygène, ISIS Medical, LVL Médical, Oxyvie, Vivisol, Elivie, CF Santé, Boehringer, Sandoz and AstraZeneca. M. Joest has received honoraria for lectures or grants from ALK-Abelló, AstraZeneca, Bencard, Berlin-Chemie, Boehringer Ingelheim, GlaxoSmithKline and HAL Allergy, all unrelated to this work. P. Nair reports grants and personal fees from AstraZeneca, Teva and Sanofi, personal fees from Equillium, Arrowhead Pharma and GlaxoSmithKline, and grants from Foresee and Cyclomedica, outside the submitted work. C.G. Baxter serves on strategic advisory board for Nob Hill Therapeutics Ltd. W.J. Calhoun is a member of the scientific advisory board of Pulmatrix, and that work is unrelated to this publication. O.A. Cornely reports grants from Cidara, F2G, Gilead, MSD, Mundipharma, Pfizer and Scynexis, consulting fees from AiCuris, Basilea, Cidara, Gilead, IQVIA, Matinas, Pfizer, PSI, Pulmocide and Scynexis, honoraria for lectures from Al-Jazeera, Gilead, Knight, MSD, Pfizer and Shionogi, and payment for expert testimony from Cidara. J.A. Douglass has received honoraria for educational presentations from AstraZeneca, GlaxoSmithKline, Novartis and CSL, has served on advisory boards for Sanofi-Aventis, Novartis, GlaxoSmithKline, AstraZeneca, Immunosis and CSL, and has undertaken contracted or investigator-initiated research on behalf of GlaxoSmithKline, Novartis, Immunosis, AstraZeneca, Sanofi-Aventis, Grifols, CSL, BioCryst and Equillium. R. Moss reports consulting fees from the Cystic Fibrosis Foundation, Astellas Pharma Inc., Nob Hill Therapeutics Inc., Pulmatrix, Mayne Pharma, Zambon Company SpA, Aridis Pharmaceuticals Inc., Regeneron Pharmaceuticals Inc. and 4D Molecular Therapeutics, royalties from UpToDate, Inc., and is a member of the board of directors for the Cystic Fibrosis Research Institute. D. Seidel received speaker fees from Pfizer, outside of the submitted work. R. Sprute has received speaker fees from Hikma and Pfizer, and travel support from Pfizer, all outside of the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: Neutrophils are important in the pathophysiology of coronavirus disease 2019 (COVID-19), but the molecular changes contributing to altered neutrophil phenotypes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We used quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes immediately following acute SARS-CoV-2 infection and during recovery., Methods: Prospective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May to December 2020). Patients were enrolled within 96 h of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID-19 acute lower respiratory tract infection (LRTI) and age-matched noninfected controls. Neutrophils were isolated from peripheral blood and analysed using mass spectrometry. COVID-19 severity and recovery were defined using the World Health Organization ordinal scale., Results: Neutrophil proteomes from 84 COVID-19 patients were compared to those from 91 LRTI and 42 control participants. 5800 neutrophil proteins were identified, with >1700 proteins significantly changed in neutrophils from COVID-19 patients compared to noninfected controls. Neutrophils from COVID-19 patients initially all demonstrated a strong interferon signature, but this signature rapidly declined in patients with severe disease. Severe disease was associated with increased abundance of proteins involved in metabolism, immunosuppression and pattern recognition, while delayed recovery from COVID-19 was associated with decreased granule components and reduced abundance of metabolic proteins, chemokine and leukotriene receptors, integrins and inhibitory receptors., Conclusions: SARS-CoV-2 infection results in the sustained presence of circulating neutrophils with distinct proteomes suggesting altered metabolic and immunosuppressive profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines., Competing Interests: Conflict of interest: H.R. Keir has received speaker fees from Insmed. A. Shoemark has received grant funding from AstraZeneca. A.J. Brenes has received support for attending meetings from the British Society for Proteome research. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell, and received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon. All other authors declare no conflicts of interest., (Copyright ©The authors 2024.)

Airway clearance techniques (ACTs) are part of the main management strategy for patients with bronchiectasis. Despite being a priority for patients, accessibility, implementation and reporting of ACTs are variable in clinical settings and research studies. This European Respiratory Society statement summarises current knowledge about ACTs in adults with bronchiectasis and makes recommendations to improve the future evidence base. A task force of 14 experts and two patient representatives (10 countries) determined the scope of this statement through consensus and defined six questions. The questions were answered based on systematic searches of the literature. The statement provides a comprehensive review of the physiological rationale for ACTs in adults with bronchiectasis, and the mechanisms of action along with the advantages and disadvantages of each ACT. Evidence on ACTs in clinical practice indicates that the most frequently used techniques are active cycle of breathing techniques, positive expiratory pressure devices and gravity-assisted drainage, although there is limited evidence on the type of ACTs used in specific countries. A review of 30 randomised trials for the effectiveness of ACTs shows that these interventions increase sputum clearance during or after treatment, reduce the impact of cough and the risk of exacerbations, and improve health-related quality of life. Furthermore, strategies for reducing the risk of bias in future studies are proposed. Finally, an exploration of patients' perceptions, barriers and enablers related to this treatment is also included to facilitate implementation and adherence to ACTs., Competing Interests: Conflict of interest: J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed, and received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis and Zambon. T. Tonia reports acting as the ERS Methodologist. The remaining authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Severe community-acquired pneumonia (sCAP) is associated with high morbidity and mortality, and while European and non-European guidelines are available for community-acquired pneumonia, there are no specific guidelines for sCAP., Materials and Methodology: The European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Latin American Thoracic Association (ALAT) launched a task force to develop the first international guidelines for sCAP. The panel comprised a total of 18 European and four non-European experts, as well as two methodologists. Eight clinical questions for sCAP diagnosis and treatment were chosen to be addressed. Systematic literature searches were performed in several databases. Meta-analyses were performed for evidence synthesis, whenever possible. The quality of evidence was assessed with GRADE (Grading of Recommendations, Assessment, Development and Evaluation). Evidence to Decision frameworks were used to decide on the direction and strength of recommendations., Results: Recommendations issued were related to diagnosis, antibiotics, organ support, biomarkers and co-adjuvant therapy. After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention and implications to health equity, recommendations were made for or against specific treatment interventions., Conclusions: In these international guidelines, ERS, ESICM, ESCMID and ALAT provide evidence-based clinical practice recommendations for diagnosis, empirical treatment and antibiotic therapy for sCAP, following the GRADE approach. Furthermore, current knowledge gaps have been highlighted and recommendations for future research have been made., Competing Interests: Conflict of interest: I. Martin-Loeches reports grants from GE, consulting fees from Gilead and MSD, lecture honoraria from MSD, Gilead and Mundipharma, and advisory board and lectures for Pfizer, MSD and Menarini, outside the submitted work. A. Torres reports consulting fees and lecture honoraria from Pfizer, Poliphor, MSD, Jansen and OM Pharma, and advisory board and lectures for Pfizer, MSD, Atriva, Jansen and Menarini, outside the submitted work. B. Nagavci serves as the ERS methodologist. S. Aliberti reports grants from Insmed Incorporated, Chiesi, and Fisher & Paykel, royalties from McGraw Hill, consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon, AstraZeneca UK Limited, CSL Behring GmbH, Grifols, Fondazione Charta, Boehringer Ingelheim, Chiesi, Zcube Srl, Menarini and MSD Italia Srl, lecture honoraria from GlaxoSmithKline Spa, and advisory board participation with Insmed Incorporated, Insmed Italy, AstraZeneca UK Limited and MSD Italia Srl, outside the submitted work. M. Antonelli reports grants from GE, consulting fees from Gilead, lecture honoraria from MSD, Chiesi, Fisher & Pickel, and Orphan, and a leadership role at ESICM, outside the submitted work. M. Bassetti reports research grants and/or advisor/consultant and/or speaker/chairman for Bayer, Biomerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Shionogi and ThermoFisher, outside the submitted work. L. Bos reports grants from the Dutch Lung Foundation (young investigator grant), the Dutch Lung Foundation and Health Holland (public–private partnership grant), Dutch Lung Foundation (Dirkje Postma Award), IMI COVID19 initiative and Amsterdam UMC fellowship, outside the submitted work. J. Chalmers reports research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed, and received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer and Zambon, outside the submitted work, and is chief editor of the ERJ. L. Derde reports grants from European Union's FP7 grant PREPARE (602525); EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, H2020 RECOVER grant agreement number 101003589, ZonMw grant ANAkinra voor de behandeling van CORonavirus infectious disease 2019 op de Intensive Care (ANACOR-IC) project number 10150062010003, lecture honoraria from Netherlands International Sepsis Symposium, travel support from ESICM, ISICEM, Weimar sepsis Update, European Respiratory Society, Critical Care Reviews, UPMC Pittsburgh, International Sepsis Forum and ANZICS/ACCCN ASM, and advisory board participation with Sepsis Canada International; REMAP-CAP has received drugs as part of the trial interventions; and the following leadership positions: chair, international trial steering committee, REMAP-CAP (2021–present), coordinating committee member, ECRAID (2021–present), member expert panel on COVID-19 therapeutics, European Commission (2021–present), member “Pandemic Preparedness Plan” committee, KNAW (2021–present), chair elect Education and Training Committee (2019–2021), chair Clinical Training Committee, ESICM (2019–2021), task force infectious threats, NVIC (chair 2019–2021), outside the submitted work. J. de Waele reports grants from Flanders Research Foundation and consulting fees from Pfizer and MSD, outside the submitted work. M. Kollef reports consulting fees from Merck, Pfizer and Shionogi, outside the submitted work. C. Luna reports grants as principal investigator in clinical trials, has participated on adjudication committee for diagnosis in clinical trials, has received honoraria for lectures on pulmonary infections, has received economical support for attending to the ERS and ATS meetings, and has participated on an advisory board for pneumococcal vaccines, outside the submitted work. R. Menendez reports lecture honoraria from, and participated on advisory boards for Pfizer, Advanz Pharma, Gilead Sciences and GSK, and travel support from Pfizer, Gilead and Advanz Pharma, outside the submitted work. M. Niederman reports grants from Shionogi, Merck and Bayer, consulting fees from Pfizer, Merck, Shionogi, Bayer, Nabriva and Thermo-Fisher, and participation on an advisory board for Fab'entec, outside the submitted work. D. Rigau formerly served as ERS methodologist. M. Schultz received grants from Zonmw (Netherlands Organisation For Health Research And Development) and financial support from Hamilton Medical AG, Switzerland, outside of this project. E. Weiss reports speaker and travel fees from MSD, Akcea Therapeutics and LFB, outside the submitted work. T. Welte reports grants from German Ministry of Research and Education, lecture honoraria from Advanz, Biotest, Thermo Fischer, MSD, Pfizer and Shionogi, outside the submitted work. R. Wunderink reports consultancy and lectures for bioMerieux, and consultancy for MSD, Shionogi, LaJolla, Venatorx, Vir and Microbiotx, and has acted as chairman, clinical evaluation committee for Pfizer, and as DSMB member for Vir, outside the submitted work. All other authors have nothing to disclose., (The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Identifying risk factors for poor outcomes can help with risk stratification and targeting of treatment. Risk factors for mortality and exacerbations have been identified in bronchiectasis but have been almost exclusively studied in European and North American populations. This study investigated the risk factors for poor outcome in a large population of bronchiectasis patients enrolled in India., Methods: The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India (EMBARC-India) registry is a prospective observational study of adults with computed tomography-confirmed bronchiectasis enrolled at 31 sites across India. Baseline characteristics of patients were used to investigate associations with key clinical outcomes: mortality, severe exacerbations requiring hospital admission, overall exacerbation frequency and decline in forced expiratory volume in 1 s., Results: 1018 patients with at least 12-month follow-up data were enrolled in the follow-up study. Frequent exacerbations (≥3 per year) at baseline were associated with an increased risk of mortality (hazard ratio (HR) 3.23, 95% CI 1.39-7.50), severe exacerbations (HR 2.71, 95% CI 1.92-3.83), future exacerbations (incidence rate ratio (IRR) 3.08, 95% CI 2.36-4.01) and lung function decline. Coexisting COPD, dyspnoea and current cigarette smoking were similarly associated with a worse outcome across all end-points studied. Additional predictors of mortality and severe exacerbations were increasing age and cardiovascular comorbidity. Infection with Gram-negative pathogens (predominantly Klebsiella pneumoniae ) was independently associated with increased mortality (HR 3.13, 95% CI 1.62-6.06), while Pseudomonas aeruginosa infection was associated with severe exacerbations (HR 1.41, 95% CI 1.01-1.97) and overall exacerbation rate (IRR 1.47, 95% CI 1.13-1.91)., Conclusions: This study identifies risk factors for morbidity and mortality among bronchiectasis patients in India. Identification of these risk factors may support treatment approaches optimised to an Asian setting., Competing Interests: Conflict of interest: M. Loebinger reports grants from AstraZeneca, Insmed and Grifols, outside the submitted work. F. Blasi reports grants from AstraZeneca, Bayer, Chiesi, GlaxoSmithKline, Menarini and Pfizer; consulting fees from Novartis, Pfizer, Zambon, Vertex, Viatris, AstraZeneca, Bayer, Chiesi, GlaxoSmithKline, Grifols, Guidotti, Insmed and Menarini, outside the submitted work. A. Shoemark reports grants from AstraZeneca, outside the submitted work. E. Polverino reports grants from Chiesi, Zambon, Shionogi, Teva, CSL Boehring, Insmed and Grifols, outside the submitted work. T. Welte reports grants from AstraZeneca and GlaxoSmithKline, outside the submitted work. M. Shteinberg reports grants from Trudell, GlaxoSmithKline, Novartis, Boehringer Ingelheim, AstraZeneca, Kamada, Vertex, Teva, Actelion and Rafa, outside the submitted work. S. Aliberti reports grants from Insmed, Chiesi and Fisher & Paykel; consulting fees from McGraw Hill, Insmed, Zambon, AstraZeneca, CSL Behring, Grifols, Fondazione Charta, Boehringer Ingelheim, Chiesi, Zcube, Menarini and GlaxoSmithKline, outside the submitted work. S. Limaye reports grants from Glenmark, supporting the present manuscript. J.D. Chalmers reports grants from AstraZeneca, Novartis, Boehringer Ingelheim, Insmed, GlaxoSmithKline and Gilead Sciences; consulting fees from AstraZeneca, Insmed, Boehringer Ingelheim, Janssen, Chiesi, Novartis, GlaxoSmithKline, Pfizer and Zambon, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis., Methods: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK., Results: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing., Conclusions: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management., Competing Interests: Conflict of interest: A. Shoemark has received grants from AstraZeneca. G. Wheway is currently employed by Illumina Inc. M.R. Loebinger has received consultancy or speaker fees from Insmed, AstraZeneca, Parion, Grifols and Armata. J.D. Chalmers has received grants or contracts from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Novartis and Insmed; and received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis and Zambon. J.S. Lucas reports grants from NHS England, NIHR and AIR Charity. H.M. Mitchison is a Trustee of Ciliopathy Alliance. A. De Soyza reports grants from AstraZeneca, GlaxoSmithKline and Pfizer; consulting fees and lecture honoraria from Gilead, GlaxoSmithKline, AstraZeneca, LifeArc and 30T; participation on advisory board at Bayer; receipt of equipment from GlaxoSmithKline. All other authors have nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Data describing cardiovascular outcomes in patients with coronavirus disease 2019 (COVID-19) and chronic kidney disease (CKD) are lacking. We compared cardiovascular outcomes of patients with and without COVID-19, stratified by CKD status., Methods: This retrospective, multi-regional data-linkage study utilised individual patient-level data from two Scottish cohorts. All patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Cohort 1 between 1 February 2020 and 31 March 2021 and in Cohort 2 between 28 February 2020 and 8 February 2021 were included., Results: Overall, 86 964 patients were tested for SARS-CoV-2. There were 36 904 patients (mean±sd age 61±21 years; 58.1% women; 15.9% CKD; 10.1% COVID-19 positive) in Cohort 1 and 50 060 patients (mean±sd age 63±20 years; 62.0% women; 16.4% CKD; 9.1% COVID-19 positive) in Cohort 2. In CKD patients, COVID-19 increased the risk of cardiovascular death by more than two-fold within 30 days (cause-specific hazard ratio (csHR) meta-estimate 2.34, 95% CI 1.83-2.99) and by 57% at the end of study follow-up (csHR meta-estimate 1.57, 95% CI 1.31-1.89). Similarly, the risk of all-cause death in COVID-19 positive versus negative CKD patients was greatest within 30 days (HR 4.53, 95% CI 3.97-5.16). Compared with patients without CKD, those with CKD had a higher risk of testing positive (11.5% versus 9.3%). Following a positive test, CKD patients had higher rates of cardiovascular death (11.1% versus 2.7%), cardiovascular complications and cardiovascular hospitalisations (7.1% versus 3.3%) than those without CKD., Conclusions: COVID-19 increases the risk of cardiovascular and all-cause death in CKD patients, especially in the short-term. CKD patients with COVID-19 are also at a disproportionate risk of cardiovascular complications than those without CKD., Competing Interests: Conflicts of interest: The authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QoL) and lung function are the most common end-points evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis., Methods: We evaluated treatment response in three randomised clinical trials that evaluated mucoactive therapy (inhaled mannitol), an oral anti-inflammatory/antibiotic (azithromycin) and an inhaled antibiotic (aztreonam). Treatment response was defined by an absence of exacerbations during follow-up, an improvement of QoL above the minimum clinically important difference and an improvement in forced expiratory volume in 1 s (FEV 1 ) of ≥100 mL from baseline., Results: Cumulatively the three trials included 984 patients. Changes in FEV 1 , QoL and exacerbations were heterogeneous in all trials analysed. Improvements in QoL were not correlated to changes in FEV 1 in the azithromycin and aztreonam trials (r= -0.17, p=0.1 and r=0.04, p=0.4, respectively) and weakly correlated in the mannitol trial (r=0.22, p<0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QoL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV 1 is not a responsive measure in bronchiectasis., Conclusions: Improvements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV 1 is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response, suggesting the need to develop biomarkers to identify responders., Competing Interests: Conflict of interest: O. Sibila has nothing to disclose. Conflict of interest: E. Laserna has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: L. Perea has nothing to disclose. Conflict of interest: D. Bilton has nothing to disclose. Conflict of interest: M.L. Crichton reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: A. De Soyza reports grants, travel support to attend international congresses and lecture fees from AstraZeneca, Bayer, Chiesi, Grifols, GlaxoSmithKline, Insmed, Pfizer, Novartis, Medimmune and Zambon, outside the submitted work. Conflict of interest: W.G. Boersma has nothing to disclose. Conflict of interest: J. Altenburg has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from GlaxoSmithKline, Grifols, Boehringer Ingelheim and Insmed, grants from AstraZeneca and Bayer Healthcare, personal fees from Aradigm, Pfizer and Napp, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Understanding the psychometric properties of health-related quality of life (HRQoL) questionnaires can help inform selection in clinical trials. Our objective was to assess the psychometric properties of HRQoL questionnaires in bronchiectasis using a systematic review and meta-analysis of the literature., Methods: A literature search was conducted. HRQoL questionnaires were assessed for psychometric properties (reliability, validity, minimal clinically important difference (MCID) and floor/ceiling effects). Meta-analyses assessed the associations of HRQoL with clinical measures and responsiveness of HRQoL in clinical trials., Results: 166 studies and 12 HRQoL questionnaires were included. The Bronchiectasis Health Questionnaire (BHQ), Leicester Cough Questionnaire (LCQ), Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) had good internal consistency in all domains reported (Cronbach's α≥0.7) across all studies, and the Quality of Life-Bronchiectasis (QOL-B), St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Disease Questionnaire (CRDQ) and Seattle Obstructive Lung Disease Questionnaire (SOLQ) had good internal consistency in all domains in the majority of (but not all) studies. BHQ, SGRQ, LCQ and CAT had good test-retest reliability in all domains reported (intraclass correlation coefficient ≥0.7) across all studies, and QOL-B, CRDQ and SOLQ had good test-retest reliability in all domains in the majority of (but not all) studies. HRQoL questionnaires were able to discriminate between demographics, important markers of clinical status, disease severity, exacerbations and bacteriology. For HRQoL responsiveness, there was a difference between the treatment and placebo effect., Conclusions: SGRQ was the most widely used HRQoL questionnaire in bronchiectasis studies and it had good psychometric properties; however, good psychometric data are emerging on the bronchiectasis-specific HRQoL questionnaires QOL-B and BHQ. Future studies should focus on the medium- to long-term test-retest reliability, responsiveness and MCID in these HRQoL questionnaires which show potential in bronchiectasis., Competing Interests: Conflict of interest: R.H. McLeese has nothing to disclose. Conflict of interest: A. Spinou is the developer of the Bronchiectasis Health Questionnaire, one of the questionnaires included in this review. Conflict of interest: Z. Alfahl has nothing to disclose. Conflict of interest: M. Tsagris has nothing to disclose. Conflict of interest: J.S. Elborn reports grants from IMI/European Commission Inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis (iABC), Novartis, Polyphor and Alexia, outside the submitted work. Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline and Novartis, personal fees from Chiesi, Zambon and Janssen, outside the submitted work. Conflict of interest: A. De Soyza reports other (meeting support) from AstraZeneca, nonfinancial support (in-kind research support) from Novartis, nonfinancial support (meeting support) from Forest labs, personal fees for lectures and advisory board work from Bayer, personal fees for advisory board work from Novartis, other (travel bursary) from Chiesi, Almirall and Boehringer Ingelheim, grants and personal fees for lectures and advisory board work from AstraZeneca, grants from Pfizer, outside the submitted work; has received medical education grant support for a UK bronchiectasis network from GlaxoSmithKline, Gilead, Chiesi and Forest labs; A. De Soyza's employing institution receives fees for his work as coordinating investigator in a phase III trial in bronchiectasis sponsored by Bayer. Conflict of interest: M.R. Loebinger reports personal fees from Insmed, AstraZeneca and Grifols, outside the submitted work. Conflict of interest: S.S. Birring reports grants and personal fees from Merck, personal fees from Bayer, Shionogi and Bellus, outside the submitted work; and has a patent BHQ pending, and a patent LCQ with royalties paid. Conflict of interest: K.C. Fragkos has nothing to disclose. Conflict of interest: R. Wilson has nothing to disclose. Conflict of interest: K. O'Neill has nothing to disclose. Conflict of interest: J.M. Bradley has nothing to disclose., (Copyright ©The authors 2021.)

There is increasing awareness of bronchiectasis in children and adolescents, a chronic pulmonary disorder associated with poor quality of life for the child/adolescent and their parents, recurrent exacerbations, and costs to the family and health systems. Optimal treatment improves clinical outcomes. Several national guidelines exist, but there are no international guidelines.The European Respiratory Society (ERS) Task Force for the management of paediatric bronchiectasis sought to identify evidence-based management (investigation and treatment) strategies. It used the ERS standardised methodology that included a systematic review of the literature and application of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to define the quality of the evidence and level of recommendations.A multidisciplinary team of specialists in paediatric and adult respiratory medicine, infectious disease, physiotherapy, primary care, nursing, radiology, immunology, methodology, patient advocacy and parents of children/adolescents with bronchiectasis considered the most relevant clinical questions (for both clinicians and patients) related to managing paediatric bronchiectasis. 14 key clinical questions (seven PICO (Patient, Intervention, Comparison, Outcome) and seven narrative) were generated. The outcomes for each PICO were decided by voting by the panel and parent/patient advisory group.This guideline addresses the definition, diagnostic approach and antibiotic treatment of exacerbations, pathogen eradication, long-term antibiotic therapy, asthma-type therapies (inhaled corticosteroids and bronchodilators), mucoactive drugs, airway clearance, investigation of underlying causes of bronchiectasis, disease monitoring, factors to consider before surgical treatment, and the reversibility and prevention of bronchiectasis in children/adolescents. Benchmarking quality of care for children/adolescents with bronchiectasis to improve clinical outcomes and evidence gaps for future research could be based on these recommendations., Competing Interests: Conflict of interest: A.B. Chang reports grants from the National Health and Medical Research Council, Australia; other fees to the institution from work relating to being an IDMC Member of an unlicensed vaccine (GlaxoSmithKline) and an advisory member of a study design for an unlicensed molecule for chronic cough (Merck) outside the submitted work. Conflict of interest: R. Fortescue has nothing to disclose. Conflict of interest: K. Grimwood reports grants from the National Health and Medical Research Council, Australia, during the conduct of the study. Conflict of interest: E. Alexopoulou has nothing to disclose. Conflict of interest: L. Bell has nothing to disclose. Conflict of interest: J. Boyd is an employee of the European Lung Foundation. Conflict of interest: A. Bush has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Insmed, personal fees from Chiesi, Novartis and Zambon, grants from Gilead Sciences, outside the submitted work. Conflict of interest: A.T. Hill has nothing to disclose. Conflict of interest: B. Karadag has nothing to disclose. Conflict of interest: F. Midulla has nothing to disclose. Conflict of interest: G.B. McCallum has nothing to disclose. Conflict of interest: Z. Powell has nothing to disclose. Conflict of interest: D. Snijders has nothing to disclose. Conflict of interest: W-J. Song has nothing to disclose. Conflict of interest: T. Tonia acts as a methodologist for the European Respiratory Society. Conflict of interest: C. Wilson has nothing to disclose. Conflict of interest: A. Zacharasiewicz has nothing to disclose. Conflict of interest: A. Kantar has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Bronchiectasis is a heterogenous disease with multiple underlying causes. The pathophysiology is poorly understood but neutrophilic inflammation and dysfunctional killing of pathogens is believed to be key. There are, however, no licensed therapies for bronchiectasis that directly target neutrophilic inflammation. In this review, we discuss our current understanding of neutrophil dysfunction and therapeutic targeting in bronchiectasis. Immunometabolic reprogramming, a process through which inflammation changes inflammatory cell behaviour by altering intracellular metabolic pathways, is increasingly recognised across multiple inflammatory and autoimmune diseases. Here, we show evidence that much of the neutrophil dysfunction observed in bronchiectasis is consistent with immunometabolic reprogramming. Previous attempts at developing therapies targeting neutrophils have focused on reducing neutrophil numbers, resulting in increased frequency of infections. New approaches are needed and we propose that targeting metabolism could theoretically reverse neutrophil dysfunction and dysregulated inflammation. As an exemplar, 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation has already been shown to reverse phagocytic dysfunction and neutrophil extracellular trap (NET) formation in models of pulmonary disease. AMPK modulates multiple metabolic pathways, including glycolysis which is critical for energy generation in neutrophils. AMPK activators can reverse metabolic reprogramming and are already in clinical use and/or development. We propose the need for a new immunomodulatory approach, rather than an anti-inflammatory approach, to enhance bacterial clearance and reduce bronchiectasis disease severity., Competing Interests: Conflict of interest: Y.H. Giam has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Insmed, personal fees from Chiesi, Novartis and Zambon, and grants from Gilead Sciences, outside of the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Existing quality-of-life and symptom tools used in bronchiectasis trials are either not disease specific or are complex and have not been consistently responsive. We developed a simple patient-reported visual analogue outcome measure, the Bronchiectasis Impact Measure (BIM), for use in clinical research, including clinical trials., Methods: Patients with bronchiectasis attending a tertiary referral clinic in the east of Scotland were invited to complete the BIM questionnaire and the quality-of-life bronchiectasis questionnaire at baseline with repeat questionnaires after 2 weeks and 6 months. We assessed internal consistency, test-retest reliability, construct validity and responsiveness by evaluating change during an acute exacerbation., Results: 173 patients were included. The eight domains (cough, sputum, breathlessness, tiredness, activity, general health, control, exacerbations) showed excellent internal consistency (Cronbach's α 0.93). The intraclass correlation coefficient demonstrated excellent reliability over a 2-week period: cough (0.79, 95% CI 0.70-0.85), sputum (0.86, 95% CI 0.80-0.90), dyspnoea (0.82, 95% CI 0.74-0.87), tiredness (0.88, 95% CI 0.82-0.91), activity (0.84, 95% CI 0.77-0.89), general health (0.81, 95% CI 0.74-0.87), control (0.83, 95% CI 0.75-0.88) and exacerbation (0.71, 95% CI 0.60-0.79). Domains correlated strongly with bronchiectasis severity and exacerbation history. Both distribution and patient-based methods estimated the minimal clinically important difference for each domain as 1.5 points on a 10-point scale. Statistically significant changes in all BIM domains were observed during an acute exacerbation., Conclusion: The BIM is a simple patient-reported outcome. This study validates the internal consistency, reliability, construct validity and response of the tool at acute exacerbation. Further validation of the tool is now required., Competing Interests: Conflict of interest: M.L. Crichton reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: E.K. Dudgeon has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Insmed, personal fees from Chiesi, Novartis and Zambon, grants from Gilead Sciences, outside the submitted work., (Copyright ©ERS 2021.)

Introduction: Hospitalised patients with coronavirus disease 2019 (COVID-19) as a result of SARS-CoV-2 infection have a high mortality rate and frequently require noninvasive respiratory support or invasive ventilation. Optimising and standardising management through evidence-based guidelines may improve quality of care and therefore patient outcomes., Methods: A task force from the European Respiratory Society and endorsed by the Chinese Thoracic Society identified priority interventions (pharmacological and non-pharmacological) for the initial version of this "living guideline" using the PICO (population, intervention, comparator, outcome) format. The GRADE approach was used for assessing the quality of evidence and strength of recommendations. Systematic literature reviews were performed, and data pooled by meta-analysis where possible. Evidence tables were presented and evidence to decision frameworks were used to formulate recommendations., Results: Based on the available evidence at the time of guideline development (20 February, 2021), the panel makes a strong recommendation in favour of the use of systemic corticosteroids in patients requiring supplementary oxygen or ventilatory support, and for the use of anticoagulation in hospitalised patients. The panel makes a conditional recommendation for interleukin (IL)-6 receptor antagonist monoclonal antibody treatment and high-flow nasal oxygen or continuous positive airway pressure in patients with hypoxaemic respiratory failure. The panel make strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir. Conditional recommendations are made against the use of azithromycin, hydroxychloroquine combined with azithromycin, colchicine, and remdesivir, in the latter case specifically in patients requiring invasive mechanical ventilation. No recommendation was made for remdesivir in patients requiring supplemental oxygen. Further recommendations for research are made., Conclusion: The evidence base for management of COVID-19 now supports strong recommendations in favour and against specific interventions. These guidelines will be regularly updated as further evidence becomes available., Competing Interests: Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Insmed, grants from Gilead Sciences, personal fees from Chiesi, Novartis and Zambon, outside the submitted work. Conflict of interest: M.L. Crichton reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: P.C. Goeminne reports personal fees for lectures from GSK and AstraZeneca, grants, personal fees for advisory board work and non-financial support for meeting attendance from Chiesi, outside the submitted work. Conflict of interest: B. Cao reports personal fees from F. Hoffmann-La Roche Ltd as a member of a steering committee, and grants from Peking Union Medical College Foundation, outside the submitted work. Conflict of interest: M. Humbert reports grants, personal fees and non-financial support from GlaxoSmithKline, personal fees from AstraZeneca, Novartis, Roche, Sanofi, Teva and Merck, grants and personal fees from Acceleron, Actelion and Bayer, outside the submitted work. Conflict of interest: M. Shteinberg reports grants, personal fees and non-financial support from GSK, grants and personal fees from Novartis, personal fees from Boehringer Ingelheim, AstraZeneca, Kamada, Vertex Pharmaceuticals, Teva and Zambon, non-financial support from Actelion and Rafa, outside the submitted work. Conflict of interest: K.M. Antoniou has nothing to disclose. Conflict of interest: C.S. Ulrik reports grants from Mundipharma, personal fees from AstraZeneca, GSK, Chiesi, Orion Pharma and TEVA, grants and personal fees from Boehringer Ingelheim, Sanofi Genzyme and Novartis, outside the submitted work. Conflict of interest: H. Parks has nothing to disclose. Conflict of interest: C. Wang has nothing to disclose. Conflict of interest: T. Vandendriessche has nothing to disclose. Conflict of interest: J. Qu has nothing to disclose. Conflict of interest: D. Stolz reports grants from AstraZeneca AG, Curetis AG and Boston Scientific, lecture fees from AstraZeneca AG, Novartis AG, GSK AG, Roche AG, Zambon, Pfizer, Schwabe Pharma AG and Vifor AG, outside the submitted work. Conflict of interest: C. Brightling has nothing to disclose. Conflict of interest: T. Welte reports grants from German Ministry of Health, German Ministry of Research and Education, DFG, WHO and EU, during the conduct of the study; personal fees for lectures and advisory board work from Roche, AstraZeneca, Boehringer, GSK and Novartis, outside the submitted work. Conflict of interest: S. Aliberti reports grants and personal fees for advisory board work from Bayer Healthcare, personal fees for lectures from Grifols and Menarini, personal fees for advisory board work from AstraZeneca and ZetaCube Srl, personal fees for advisory board work and lectures from Zambon and GlaxoSmithKline, grants and personal fees for advisory board work and lectures from Chiesi and INSMED, grants from Fisher & Paykel, outside the submitted work. Conflict of interest: A.K. Simonds has nothing to disclose. Conflict of interest: T. Tonia acts as ERS methodologist. Conflict of interest: N. Roche reports grants and personal fees from Boehringer Ingelheim, Novartis and Pfizer, personal fees from GSK, AstraZeneca, Chiesi, Sanofi and Zambon, outside the submitted work., (Copyright ©The authors 2021.)

Introduction: The chronic obstructive pulmonary disease (COPD) bacteriome associates with disease severity, exacerbations and mortality. While COPD patients are susceptible to fungal sensitisation, the role of the fungal mycobiome remains uncertain., Methods: We report the largest multicentre evaluation of the COPD airway mycobiome to date, including participants from Asia (Singapore and Malaysia) and the UK (Scotland) when stable (n=337) and during exacerbations (n=66) as well as nondiseased (healthy) controls (n=47). Longitudinal mycobiome analysis was performed during and following COPD exacerbations (n=34), and examined in terms of exacerbation frequency, 2-year mortality and occurrence of serum specific IgE (sIgE) against selected fungi., Results: A distinct mycobiome profile is observed in COPD compared with controls as evidenced by increased α-diversity (Shannon index; p<0.001). Significant airway mycobiome differences, including greater interfungal interaction (by co-occurrence), characterise very frequent COPD exacerbators (three or more exacerbations per year) (permutational multivariate ANOVA; adjusted p<0.001). Longitudinal analyses during exacerbations and following treatment with antibiotics and corticosteroids did not reveal any significant change in airway mycobiome profile. Unsupervised clustering resulted in two clinically distinct COPD groups: one with increased symptoms (COPD Assessment Test score) and Saccharomyces dominance, and another with very frequent exacerbations and higher mortality characterised by Aspergillus , Curvularia and Penicillium with a concomitant increase in serum sIgE levels against the same fungi. During acute exacerbations of COPD, lower fungal diversity associates with higher 2-year mortality., Conclusion: The airway mycobiome in COPD is characterised by specific fungal genera associated with exacerbations and increased mortality., Competing Interests: Conflict of interest: P.Y. Tiew has nothing to disclose. Conflict of interest: A.J. Dicker has nothing to disclose. Conflict of interest: H.R. Keir has nothing to disclose. Conflict of interest: M.E. Poh has nothing to disclose. Conflict of interest: S.L. Pang has nothing to disclose. Conflict of interest: M. Mac Aogáin has nothing to disclose. Conflict of interest: B.Q.Y. Chua has nothing to disclose. Conflict of interest: J.L. Tan has nothing to disclose. Conflict of interest: H. Xu has nothing to disclose. Conflict of interest: M.S. Koh has nothing to disclose. Conflict of interest: A. Tee has nothing to disclose. Conflict of interest: J.A. Abisheganaden has nothing to disclose. Conflict of interest: F.T. Chew reports personal fees for consultancy from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation and Olam International, outside the submitted work. Conflict of interest: B.E. Miller is an employee and shareholder of GlaxoSmithKline. Conflict of interest: R. Tal-Singer reports personal fees from Immunomet and VOCALIS Health, outside the submitted work; and is a former employee and current shareholder of GlaxoSmithKline. Conflict of interest: J.D. Chalmers reports grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Grifols and Insmed, grants from Gilead Sciences, personal fees from Chiesi, Napp, Novartis and Zambon, outside the submitted work. Conflict of interest: S.H. Chotirmall has nothing to disclose., (Copyright ©ERS 2021.)

The study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of tobramycin inhalation powder (TIP) on Pseudomonas aeruginosa sputum density in patients with bronchiectasis.This is a phase II, double-blind, randomised study in bronchiectasis patients aged ≥18 years with chronic P. aeruginosa infection. Patients were randomised 1:1:1 to either cohort A: three capsules of TIP once daily (84 mg); cohort B: five capsules once daily (140 mg) or cohort C: four capsules twice daily (224 mg). Within each cohort, patients were further randomised 2:2:1 either to TIP continuously, TIP cyclically (alternating 28 days of TIP and placebo) or placebo for 16 weeks, respectively and were followed up for 8 weeks.Overall, 107 patients were randomised to cohorts A (n=34), B (n=36) and C (n=37). All three TIP doses significantly reduced the P. aeruginosa sputum density from baseline to day 29 versus placebo in a dose-dependent manner (p≤0.0001, each). A smaller proportion of patients in the continuous-TIP (34.1%) and cyclical-TIP (35.7%) groups experienced pulmonary exacerbations versus placebo (47.6%) and also required fewer anti-pseudomonal antibiotics (38.6% on continuous TIP and 42.9% on cyclical TIP) versus placebo (57.1%) although not statistically significant. Pulmonary exacerbation of bronchiectasis was the most frequent (37.4%) adverse event. Overall, TIP was well tolerated, however, 23.4% of the patients discontinued the study drug due to adverse events.Continuous- and cyclical-TIP regimens with all three doses were safe and effective in reducing the P. aeruginosa sputum density in patients with bronchiectasis and chronic P. aeruginosa infection., Competing Interests: Conflict of interest: E. Polverino reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and personal fees from Bayer, Menarini, Grifols, Zambon, Pfizer, Chiesi, Teva, Shire, Insmed and Polyphor, and grants from Chiesi and Grifols, outside the submitted work. Conflict of interest: J.D. Chalmers reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants and personal fees from GSK, Boehringer-Ingelheim, AstraZeneca, Pfizer, Bayer Healthcare, Grifols, Napp, Aradigm corporation, and Insmed, outside the submitted work. Conflict of interest: H.A.W.M. Tiddens reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and personal fees from Vertex and Gilead, grants and personal fees from Novartis, and grants from Roche, Vertex, Chiesi and Vectura, outside the submitted work. Conflict of interest: H. Goossens reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study. Conflict of interest: M. Tunney reports grants from European Union IMI grant in collaboration with Novartis, during the conduct of the study; and grants from European Union, Novartis and Alaxia SAS, outside the submitted work. Conflict of interest: F.C. Ringhausen reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants, personal fees and non-financial support from Aposan, AstraZeneca, Bayer, Boehringer Ingelheim, Celtaxsys, Chiesi, Corbus, Grifols, InfectoPharm, Insmed, MSD, Novartis, PARI, Parion, Polyphor, Vertex and Zambon, outside the submitted work. Conflict of interest: A.T. Hill reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study. Conflict of interest: R. Pathan reports other from Novartis, outside the submitted work. Conflict of interest: G. Angyalosi reports other from Novartis, outside the submitted work. Conflict of interest: F. Blasi reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants and personal fees from AstraZeneca, Bayer, Grifols, Pfizer, Chiesi, GSK, Guidotti, Menarini, Novartis, Teva, Zambon and Insmed, outside the submitted work. Conflict of interest: S.J. Elborn reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants from Novartis, and personal fees from Vertex, Galapagos and Ionis, outside the submitted work. Conflict of interest: C.S. Haworth reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and grants and personal fees from Aradigm, Chiesi, Gilead, Grifols, GSK, Insmed, International Biophysics, Janssen, Mylan, Novartis, Teva, Vertex and Zambon, outside the submitted work. Conflict of interest: M.R. Loebinger reports grants from European Union IMI Grant (in collaboration with Novartis), during the conduct of the study; and personal fees from Bayer, Grifols, Astra Zeneca, Insmed and Polyphor, outside the submitted work., (Copyright ©ERS 2021.)

It is not known if inhaled antibiotics improve respiratory symptoms in patients with bronchiectasis. In the recent phase-3 ORBIT trials, 48 weeks' treatment with ARD-3150 (inhaled liposomal ciprofloxacin) did not significantly improve symptoms using the prespecified method of analysis comparing baseline symptoms to those after 48 weeks, when patients had been off treatment for 28 days. This method of analysis does not take account of possible improvements in symptoms while on active treatment.A post hoc analysis of two identical randomised trials of ARD-3150 (ORBIT-3 and -4) administered 28 days on and 28 days off in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. The quality-of-life bronchiectasis respiratory symptom scale (QOL-B-RSS), which has a one-week recall period, was administered every 28 days. We examined whether respiratory symptoms improved during on-treatment periods and the relationship of changes in QOL-B-RSS to changes in bacterial load using a mixed-model repeated measures approach.ARD-3150 treatment resulted in a significant improvement in respiratory symptoms during the on-treatment periods with concordant results between ORBIT-3 (estimate 1.4 points, se 0.49; p=0.004) and ORBIT-4 (estimate 1.1 point, se 0.41; p=0.006). The proportion of patients achieving a symptom improvement above the minimum clinically important difference was higher with ARD-3150 compared with placebo during on-treatment cycles (p=0.024). Changes in respiratory symptoms were correlated with changes in bacterial load in the treatment group (r=-0.89, p<0.0001). Individual estimates for decrements in the QOL-B RSS during exacerbation were -9.4 points (se 0.91) in ORBIT-3 and -10.8 points (0.74) in ORBIT-4 (both p<0.0001).Inhaled ARD-3150 resulted in significant improvements in respiratory symptoms during the on-treatment periods which were lost during off-treatment periods. These results supports the concept that reducing bacterial load can improve respiratory symptoms in patients with bronchiectasis., Competing Interests: Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, GlaxoSmithKline, Grifols, Insmed and Boehringer Ingelheim, personal fees from Chiesi, grants from Gilead, outside the submitted work. Conflict of interest: D. Cipolla has patents US 10,420,765, US 9,987,227, US 9,968,555, US 9,844,548, US 9,545,401, US 9,259,424, US 9,078,897, US 9,028,864, US 8,414,915, US 8,268,347, US 8,119,156, and US 8,071,127 issued. Conflict of interest: B. Thompson reports personal fees for consultancy from Aradigm, during the conduct of the study. Conflict of interest: A.M. Davis is an employee of Grifols. Conflict of interest: A. O'Donnell reports personal fees from Aradigm, during the conduct of the study. Conflict of interest: G. Tino has nothing to disclose. Conflict of interest: I. Gonda reports personal fees from Aradigm Corporation, during the conduct of the study; hold shares in Aradigm Corporation, outside the submitted work; and has two patents licensed with Aradigm Corporation. Conflict of interest: C. Haworth reports personal fees for research from Aradigm, personal fees for consultancy and lectures from Grifols, during the conduct of the study; personal fees for consultancy and lectures from Zambon/Profile, personal fees for consultancy from Chiesi, Gilead and GSK, grants and personal fees for consultancy and lectures from Insmed, grants from Novartis, grants and personal fees for lectures from TEVA, outside the submitted work. Conflict of interest: J. Froehlich is an employee of Aradigm., (Copyright ©ERS 2020.)

Introduction: Neutrophilic inflammation is a major driver of bronchiectasis pathophysiology, and neutrophil elastase activity is the most promising biomarker evaluated in sputum to date. How active neutrophil elastase correlates with the lung microbiome in bronchiectasis is still unexplored. We aimed to understand whether active neutrophil elastase is associated with low microbial diversity and distinct microbiome characteristics., Methods: An observational, cross-sectional study was conducted at the bronchiectasis programme of the Policlinico Hospital in Milan, Italy, where adults with bronchiectasis were enrolled between March 2017 and March 2019. Active neutrophil elastase was measured on sputum collected during stable state, microbiota analysed through 16S rRNA gene sequencing, molecular assessment of respiratory pathogens carried out through real-time PCR and clinical data collected., Results: Among 185 patients enrolled, decreasing α-diversity, evaluated through the Shannon entropy (ρ -0.37, p<0.00001) and Pielou's evenness (ρ -0.36, p<0.00001) and richness (ρ -0.33, p<0.00001), was significantly correlated with increasing elastase. A significant difference in median levels of Shannon entropy as detected between patients with neutrophil elastase ≥20 µg·mL -1 (median 3.82, interquartile range 2.20-4.96) versus neutrophil elastase <20 µg·mL -1 (4.88, 3.68-5.80; p<0.0001). A distinct microbiome was found in these two groups, mainly characterised by enrichment with Pseudomonas in the high-elastase group and with Streptococcus in the low-elastase group. Further confirmation of the association of Pseudomonas aeruginosa with elevated active neutrophil elastase was found based on standard culture and targeted real-time PCR., Conclusions: High levels of active neutrophil elastase are associated to low microbiome diversity and specifically to P. aeruginosa infection., Competing Interests: Conflict of interest: M. Oriano has nothing to disclose. Conflict of interest: A. Gramegna has nothing to disclose. Conflict of interest: L. Terranova has nothing to disclose. Conflict of interest: G. Sotgiu has nothing to disclose. Conflict of interest: I. Sulaiman has nothing to disclose. Conflict of interest: L. Ruggiero has nothing to disclose. Conflict of interest: L. Saderi has nothing to disclose. Conflict of interest: B. Wu has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from GlaxoSmithKline, Insmed, AstraZeneca and Boehringer Ingelheim, personal fees from Zambon, grants from Gilead and Grifols, outside the submitted work. Conflict of interest: L.N. Segal reports personal fees for consultancy from Beyond Air, grants from NIH, outside the submitted work. Conflict of interest: P. Marchisio has nothing to disclose. Conflict of interest: F. Blasi reports grants and personal fees from AstraZeneca, Chiesi, GSK, Insmed and Pfizer, grants from Bayer, personal fees from Guidotti, Grifols, Menarini, Mundipharma, Novartis and Zambon, outside the submitted work. Conflict of interest: S. Aliberti reports grants and personal fees from Bayer Healthcare, Aradigm Corporation, Grifols, Chiesi and INSMED, personal fees from AstraZeneca, Basilea, Zambon, Novartis, Raptor, Actavis UK Ltd and Horizon, outside the submitted work., (Copyright ©ERS 2020.)

By 21 May 2020, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) had caused more than 5 million cases of coronavirus 2019 (COVID-19) across more than 200 countries. Most countries with significant outbreaks have introduced social distancing or "lockdown" measures to reduce viral transmission. So the key question now is when, how and to what extent these measures can be lifted.Publicly available data on daily numbers of newly confirmed cases and mortality were used to fit regression models estimating trajectories, doubling times and the reproduction number (R 0 ) of the disease, before and under the control measures. These data ran up to 21 May 2020, and were sufficient for analysis in 89 countries.The estimates of R 0 before lockdown based on these data were broadly consistent with those previously published: between 2.0 and 3.7 in the countries with the largest number of cases available for analysis (USA, Italy, Spain, France and UK). There was little evidence to suggest that the restrictions had reduced R far below 1 in many places, with France having the most rapid reductions: R 0 0.76 (95% CI 0.72-0.82) based on cases, and 0.77 (95% CI 0.73-0.80) based on mortality.Intermittent lockdown has been proposed as a means of controlling the outbreak while allowing periods of increased freedom and economic activity. These data suggest that few countries could have even 1 week per month unrestricted without seeing resurgence of the epidemic. Similarly, restoring 20% of the activity that has been prevented by the lockdowns looks difficult to reconcile with preventing the resurgence of the disease in most countries., Competing Interests: Conflict of interest: M. Lonergan has nothing to disclose. Conflict of interest: J.D. Chalmers has received research grants from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Pfizer, Grifols, Bayer AG, Polyphor and Insmed; and received consultancy, congress travel or speaker fees from GlaxoSmithKline, Bayer Healthcare, Aradigm Corporation, Grifols, Pfizer, Boehringer Ingelheim, Napp and Insmed., (Copyright ©ERS 2020.)

Introduction: Inhaled antibiotics may improve symptom scores, but it is not known which specific symptoms improve with therapy. Item-level analysis of questionnaire data may allow us to identify which specific symptoms respond best to treatment., Methods: Post hoc analysis of the AIR-BX1 studies and two trials of inhaled aztreonam versus placebo in bronchiectasis. Individual items from the quality of life bronchiectasis (QOL-B) respiratory symptom scale, were extracted as representing severity of nine distinct symptoms. Generalised linear models were used to evaluate changes in symptoms with treatment versus placebo from baseline to end of first on-treatment cycle and mixed models were used to evaluate changes across the full 16-week trial., Results: Aztreonam improved cough (difference 0.22, 95% CI 0.08-0.37; p=0.002), sputum production (0.30, 95% CI 0.15-0.44; p<0.0001) and sputum colour (0.29, 95% CI 0.15-0.43; p<0.0001) versus placebo equating to a 20% improvement in cough and 25% improvement in sputum production and colour. Similar results were observed for cough, sputum production and sputum purulence across the trial duration (all p<0.05). Patients with higher sputum production and sputum colour scores had a greater response on the overall QOL-B (difference 4.82, 95% CI 1.12-8.53; p=0.011 for sputum production and 5.02, 95% CI 1.19-8.86; p=0.01 for sputum colour). In contrast, treating patients who had lower levels of bronchitic symptoms resulted in shorter time to next exacerbation (hazard ratio 1.83, 95% CI 1.02-3.28; p=0.042)., Conclusion: Baseline bronchitic symptoms predict response to inhaled aztreonam in bronchiectasis. More sensitive tools to measure bronchitic symptoms may be useful to better identify inhaled antibiotic responders and to evaluate patient response to treatment., Competing Interests: Conflict of interest: M.L. Crichton has nothing to disclose. Conflict of interest: M. Lonergan has nothing to disclose. Conflict of interest: A.F. Barker has nothing to disclose. Conflict of interest: O. Sibila has nothing to disclose. Conflict of interest: P. Goeminne has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants from Gilead, during the conduct of the study; grants and personal fees from AstraZeneca, GlaxoSmithKline, Grifols, Insmed and Boehringer Ingelheim, personal fees from Chiesi, grants from Gilead, outside the submitted work., (Copyright ©ERS 2020.)