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Background: Guidelines aim to standardize and optimize diagnosis and management. We evaluated the quality of evidence supporting recommendations from different international adult guidelines on bronchiectasis, and classified with the GRADE system., Methods: Quality of eligible clinical practice guidelines was assessed for six domains using the AGREE II tool, with ≥ 80% rating as excellent., Results: Seven guidelines (283 recommendations) were analyzed, and four of them were considered "recommended for use" (three reported after 2017 as excellent). Overall, 144 (50.9%) recommendations were based on low-quality evidence, representing 81.5% in diagnosis and 36.2% in therapy. In contrast, 5/92 (5.4%) and 40/191 (20.9%) recommendations regarding diagnostic and treatment (respectively) were based on high-quality evidence. Quality agreement ratings were significantly (p< 0.05) higher for guidelines delivered after 2015, progressing from 27.7% to 58.3%, qualifying as excellent. Highest scores were documented in the domains of "scope and purpose" followed by "clarifying of presentation" and "editorial independence"., Conclusion: Updated guidelines reported after 2017 improved quality, although well-designed randomized clinical trials remain an unmet need. AGREE II quality assessment identified four guidelines qualified as recommended for use. Improvements are required in stakeholder involvement and applicability., (Copyright © 2022 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: The reported prevalence of immunodeficiencies in bronchiectasis patients is variable depending on the frequency and extent of immunological tests performed. European Respiratory Society guidelines recommend a minimum bundle of tests. Broadening the spectrum of immunological tests could increase the number of patients diagnosed with an immunodeficiency and those who could receive specific therapy. The primary objective of the present study was to assess the performance of different sets of immunological tests in diagnosing any, primary, secondary or treatable immunodeficiencies in adults with bronchiectasis., Methods: An observational, cross-sectional study was conducted at the Bronchiectasis Program of the Policlinico University Hospital in Milan, Italy, from September 2016 to June 2019. Adult outpatients with a clinical and radiological diagnosis of bronchiectasis underwent the same immunological screening during the first visit when clinically stable consisting of: complete blood count; immunoglobulin (Ig) subclass tests for IgA, IgG, IgM and IgG; total IgE; lymphocyte subsets; and HIV antibodies. The primary endpoint was the prevalence of patients with any immunodeficiencies using five different sets of immunological tests., Results: A total of 401 bronchiectasis patients underwent the immunological screening. A significantly different prevalence of bronchiectasis patients diagnosed with any, primary or secondary immunodeficiencies was found across different bundles. 44.6% of bronchiectasis patients had a diagnosis of immunodeficiency when IgG subclasses and lymphocyte subsets were added to the minimum bundle suggested by the guidelines., Conclusion: A four-fold increase in the diagnosis of immunodeficiencies can be found in adults with bronchiectasis when IgG subclasses and lymphocyte subsets are added to the bundle of tests recommended by guidelines., Competing Interests: Conflict of interest: S. Aliberti reports grants or contracts from Insmed, Chiesi and Fisher & Paykel; royalties or licences from McGraw Hill; consulting fees from Insmed, Zambon, AstraZeneca, CSL Behring GmbH, Grifols, Fondazione Charta, Boehringer Ingelheim, Chiesi, Zcube Srl and Menarini; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from GlaxoSmithKline, and for participation on a Data Safety Monitoring Board or Advisory Board for Insmed and AstraZeneca, all outside the submitted work. M. Mantero declares honoraria for educational events from GlaxoSmithKline and Boehringer Ingelheim, outside the present study. A. Stainer reports grants, speaker fees and travel support from AstraZeneca, Bayer, Chiesi, Forest Laboratories, GlaxoSmithKline, Insmed, Pfizer, Medimmune, Novartis and Zambon, outside the submitted work. E. Polverino reports grants or contracts from Grifols; consulting fees from Insmed, Chiesi and Zambon; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Insmed, GlaxoSmithKline, Teva, Boehringer Ingelheim, Chiesi and Zambon; support for attending meetings from Insmed and Teva, and for participation on a Data Safety Monitoring Board or Advisory Board from Insmed and Chiesi, all outside the submitted work. J.D. Chalmers reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Insmed, grants from Gilead Sciences, and personal fees from Chiesi, Novartis and Zambon, outside the submitted work. F. Blasi reports grants and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Pfizer and Insmed; grants from Bayer; and personal fees from Guidotti, Grifols, Menarini, Mundipharma, Novartis and Zambon, outside the submitted work. F. Amati, A. Gramegna, B. Vigone, M. Oriano, G. Sotgiu, E. Simonetta, L. Saderi, S. Tammaro and P. Marchisio report no conflict of interest., (Copyright ©The authors 2022.)

The previous issue of Clinics in Chest Medicine was published in 2012 and described the state of the art in the disease at that time. In the intervening years, bronchiectasis has experienced something of a renaissance, leaving behind the label of an "orphan disease." Major developments in the past 10 years including a deeper understanding of epidemiology include the development of international registries. An exponential increase in randomized clinical trials in bronchiectasis has strengthened the evidence base for treatments but much work remains to translate the increasing global interest in the disease into a better understanding of the condition and improved patient outcomes., Competing Interests: Disclosure Professor J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed, and Novartis. Consultancy and other fees from: AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, and Zambon., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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

Neutrophilic inflammation has a key role in the pathophysiology of multiple chronic lung diseases. The formation of neutrophil extracellular traps (NETs) has emerged as a key mechanism of disease in neutrophilic lung diseases including asthma, COPD, cystic fibrosis and, most recently, bronchiectasis. NETs are large, web-like structures composed of DNA and anti-microbial proteins that are able to bind pathogens, prevent microbial dissemination and degrade bacterial virulence factors. The release of excess concentrations of proteases, antimicrobial proteins, DNA and histones, however, also leads to tissue damage, impaired mucociliary clearance, impaired bacterial killing and increased inflammation. A number of studies have linked airway NET formation with greater disease severity, increased exacerbations and overall worse disease outcomes across the spectrum of airway diseases. Treating neutrophilic inflammation has been challenging in chronic lung disease because of the delicate balance between reducing inflammation and increasing the risk of infections through immunosuppression. Novel approaches to suppressing NET formation or the associated inflammation are in development and represent an important therapeutic target. This review will discuss the relationship between NETs and the pathophysiology of cystic fibrosis, asthma, COPD and bronchiectasis, and explore the current and future development of NET-targeting therapies., Competing Interests: Conflict of interest: H.R. Keir has nothing to disclose. Conflict of interest: J.D. Chalmers has received grants or contracts from AstraZeneca, Gilead Sciences, Boehringer Ingelheim, Novartis, Insmed and GlaxoSmithKline; consulting fees from AstraZeneca, Janssen, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Novartis, Insmed and Zambon; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Boehringer Ingelheim., (Copyright ©The authors 2022.)

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

Chronic lung diseases are the third leading cause of death worldwide and are increasing in prevalence over time. Although much of our traditional understanding of health and disease is derived from study of the male of the species - be it animal or human - there is increasing evidence that sex and gender contribute to differences in disease risk, prevalence, presentation, severity, treatment approach, response and outcomes. Chronic obstructive pulmonary disease, asthma and bronchiectasis represent the most prevalent and studied chronic lung diseases and have key sex- and gender-based differences which are critical to consider and incorporate into clinical and research approaches. Mechanistic differences present opportunities for therapeutic development whereas behavioural and clinical differences on the part of patients and providers present opportunities for greater education and understanding at multiple levels. In this review, we seek to summarise the sex- and gender-based differences in key chronic lung diseases and outline the clinical and research implications for stakeholders., Competing Interests: Conflict of interest: R. Somayaji has nothing to disclose. J.D. Chalmers has received research grants 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, outside the submitted work., (Copyright ©The authors 2022.)

Background: Bronchiectasis is a common but under-diagnosed chronic disorder characterised by permanent dilation of the airways arising from a cycle of recurrent infection and inflammation. Symptoms including chronic, persistent cough and productive phlegm are a significant burden for people with bronchiectasis, and the main aim of treatment is to reduce exacerbation frequency and improve quality of life. Prophylactic antibiotic therapy aims to break this infection cycle and is recommended by clinical guidelines for adults with three or more exacerbations a year, based on limited evidence. It is important to weigh the evidence for bacterial suppression against the prevention of antibiotic resistance and further evidence is required on the safety and efficacy of different regimens of intermittently administered antibiotic treatments for people with bronchiectasis., Objectives: To evaluate the safety and efficacy of intermittent prophylactic antibiotics in the treatment of adults and children with bronchiectasis., Search Methods: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted searches on 6 September 2021, with no restriction on language of publication., Selection Criteria: We included randomised controlled trials (RCTs) of at least three months' duration comparing an intermittent regime of prophylactic antibiotics with placebo, usual care or an alternate intermittent regimen. Intermittent prophylactic administration was defined as repeated courses of antibiotics with on-treatment and off-treatment intervals of at least 14 days' duration. We included adults and children with a clinical diagnosis of bronchiectasis confirmed by high resolution computed tomography (HRCT), plain film chest radiograph, or bronchography and a documented history of recurrent chest infections. We excluded studies where participants received high dose antibiotics immediately prior to enrolment or those with a diagnosis of cystic fibrosis, allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia, hypogammaglobulinaemia, sarcoidosis, or a primary diagnosis of COPD. Our primary outcomes were exacerbation frequency and serious adverse events. We did not exclude studies on the basis of review outcomes., Data Collection and Analysis: We analysed dichotomous data as odds ratios (ORs) or relative risk (RRs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures expected by Cochrane. We conducted GRADE assessments for the following primary outcomes: exacerbation frequency; serious adverse events and secondary outcomes: antibiotic resistance; hospital admissions; health-related quality of life., Main Results: We included eight RCTs, with interventions ranging from 16 to 48 weeks, involving 2180 adults. All evaluated one of three types of antibiotics over two to six cycles of 28 days on/off treatment: aminoglycosides, ß-lactams or fluoroquinolones. Two studies also included 12 cycles of 14 days on/off treatment with fluoroquinolones. Participants had a mean age of 63.6 years, 65% were women and approximately 85% Caucasian. Baseline FEV 1 ranged from 55.5% to 62.6% predicted. None of the studies included children. Generally, there was a low risk of bias in the included studies. Antibiotic versus placebo: cycle of 14 days on/off. Ciprofloxacin reduced the frequency of exacerbations compared to placebo (RR 0.75, 95% CI 0.61 to 0.93; I 2 = 65%; 2 studies, 469 participants; moderate-certainty evidence), with eight people (95% CI 6 to 28) needed to treat for an additional beneficial outcome. The intervention increased the risk of antibiotic resistance more than twofold (OR 2.14, 95% CI 1.36 to 3.35; I 2 = 0%; 2 studies, 624 participants; high-certainty evidence). Serious adverse events, lung function (FEV 1 ), health-related quality of life, and adverse effects did not differ between groups. Antibiotic versus placebo: cycle of 28 days on/off. Antibiotics did not reduce overall exacerbation frequency (RR 0.92, 95% CI 0.82 to 1.02; I 2 = 0%; 8 studies, 1695 participants; high-certainty evidence) but there were fewer severe exacerbations (OR 0.59, 95% CI 0.37 to 0.93; I 2 = 54%; 3 studies, 624 participants), though this should be interpreted with caution due to low event rates. The risk of antibiotic resistance was more than twofold higher based on a pooled analysis (OR 2.20, 95% CI 1.42 to 3.42; I 2 = 0%; 3 studies, 685 participants; high-certainty evidence) and consistent with unpooled data from four further studies. Serious adverse events, time to first exacerbation, duration of exacerbation, respiratory-related hospital admissions, lung function, health-related quality of life and adverse effects did not differ between study groups. Antibiotic versus usual care. We did not find any studies that compared intermittent antibiotic regimens with usual care. Cycle of 14 days on/off versus cycle of 28 days on/off. Exacerbation frequency did not differ between the two treatment regimens (RR 1.02, 95% CI 0.84 to 1.24; I 2 = 71%; 2 studies, 625 participants; moderate-certainty evidence) However, inconsistencies in the results from the two trials in this comparison indicate that the apparent aggregated similarities may not be reliable. There was no evidence of a difference in antibiotic resistance between groups (OR 1.00, 95% CI 0.68 to 1.48; I 2 = 60%; 2 studies, 624 participants; moderate-certainty evidence). Serious adverse events, adverse effects, lung function and health-related quality of life did not differ between the two antibiotic regimens., Authors' Conclusions: Overall, in adults who have frequent chest infections, long-term antibiotics given at 14-day on/off intervals slightly reduces the frequency of those infections and increases antibiotic resistance. Intermittent antibiotic regimens result in little to no difference in serious adverse events. The impact of intermittent antibiotic therapy on children with bronchiectasis is unknown due to an absence of evidence, and further research is needed to establish the potential risks and benefits., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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

Hospitalised patients with coronavirus disease 2019 (COVID-19) have a high mortality rate. There are an increasing number of published randomised controlled trials for anti-inflammatory, anti-viral and other treatments. The European Respiratory Society Living Guidelines for the Management of Hospitalised Adults with COVID-19 were published recently, providing recommendations on appropriate pharmacotherapy.Patient, Intervention, Comparator and Outcomes questions for key interventions were identified by an international panel and systematic reviews were conducted to identify randomised controlled trials meeting the inclusion criteria. The importance of end-points were rated, and mortality was identified as the key "critical" outcome for all interventions. Random-effects meta-analysis was used to pool studies and provide effect estimates for the impact of treatments on mortality.Corticosteroids, hydroxychloroquine, azithromycin, remdesivir, anti-interleukin (IL)-6 monoclonal antibodies, colchicine, lopinavir/ritonavir and interferon-β have been reviewed.Our results found further evidence in support of the use of corticosteroids, particularly dexamethasone, and anti-IL-6 receptor monoclonal antibody therapy. These data support the need to identify additional therapies with beneficial effects on mortality., Competing Interests: Conflict of interest: M.L. Crichton has nothing to disclose. Conflict of interest: P.C. Goeminne has nothing to disclose. Conflict of interest: K. Tuand has nothing to disclose. Conflict of interest: T. Vandendriessche has nothing to disclose. Conflict of interest: T. Tonia is an 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. 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., (Copyright ©The authors 2021.)

Macrolide antibiotics are well known for their antibacterial properties, but extensive research in the context of inflammatory lung disease has revealed that they also have powerful immunomodulatory properties. It has been demonstrated that these drugs are therapeutically beneficial in various lung diseases, with evidence they significantly reduce exacerbations in patients with COPD, asthma, bronchiectasis and cystic fibrosis. The efficacy demonstrated in patients infected with macrolide tolerant organisms such as Pseudomonas aeruginosa supports the concept that their efficacy is at least partly related to immunomodulatory rather than antibacterial effects. Inconsistent data and an incomplete understanding of their mechanisms of action hampers the use of macrolide antibiotics as immunomodulatory therapies. Macrolides recently demonstrated no clinically relevant immunomodulatory effects in the context of COVID-19 infection. This review provides an overview of macrolide antibiotics and discusses their immunomodulatory effects and mechanisms of action in the context of inflammatory lung disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Bronchiectasis, due to its highly heterogenous nature, requires an individualised approach to therapy. Patients experience symptoms and exacerbations driven by a combination of impaired mucociliary clearance, airway inflammation and airway infection. Treatment of bronchiectasis aims to enhance airway clearance and to address the underlying causes of inflammation and infection susceptibility. Bronchiectasis has multiple causes and so the pathophysiology leading to individual symptoms and exacerbations are different between individuals. Standardised investigations are recommended by international guidelines to identify the underlying causes of bronchiectasis. The process of identifying the underlying biology within an individual is called "endotyping" and is an emerging concept across chronic diseases. Endotypes that have a specific treatment are referred to as "treatable traits" and a treatable traits approach to managing patients with bronchiectasis in a holistic and evidence-based manner is the key to improved outcomes. Bronchiectasis is an area of intense research. Endotyping allows identification of subsets of patients to allow medicines to be tested differently in the future where trials, rather than trying to achieve a "one size fits all" solution, can test efficacy in subsets of patients where the treatment is most likely to be efficacious., Competing Interests: Conflict of interest: T. Pembridge has nothing to disclose. Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Insmed and Novartis, personal fees from Chiesi, Janssen, Grifols and Zambon, and grants from Gilead Sciences, outside the submitted work., (Copyright ©ERS 2021.)

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

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.)

Background: There is limited information regarding the effects of air pollutants, such as nitrogen oxides (NO x ), nitric oxide (NO 2 ), nitrous oxide (NO) and particulate matter with a diameter smaller than 10 μm (PM10), on acute limb ischaemia (ALI), a peripheral arterial disease (PAD) often with a poor clinical outcome. Patients and methods: We conducted an 18-year retrospective cohort study using routinely collected healthcare records from Ninewells Hospital, Dundee, and Perth Royal Infirmary, in Tayside, Scotland, UK from 2000 to 2017. ALI hospitalisation events and deaths were linked to daily NO x , NO 2 , NO and PM10 levels extracted from publicly available data over this same time period. Distributed lag models were used to estimate risk ratios for ALI hospitalisation and for ALI mortality, adjusting for temperature, humidity, day of the week, month and public holiday. Results: 5,608 hospital admissions in 2,697 patients were identified over the study period (mean age 71.2 years, ±11.1). NO x and NO were associated with an increase of ALI hospital admissions on days of exposure to pollutant (p=.018), while PM10 was associated with a cumulative (lag 0-9 days) increase (p=.027) of ALI hospital admissions in our study. There was no increase of ALI mortality associated with pollution levels. Conclusions: ALI hospital admissions were positively associated with ambient NO x and NO on day of high measured pollution levels and a cumulative effect was seen with PM10.

Deaths from air pollution in the UK are higher by a factor of 10 than from car crashes, 7 for drug-related deaths and 52 for murders, and yet awareness seems to be lacking in local government. We conducted an 18-year retrospective cohort study using routinely collected health care records from Ninewells Hospital, Dundee, and Perth Royal Infirmary, in Tayside, Scotland, UK, from 2000 to 2017. Hospitalisation events and deaths were linked to daily nitric oxides (NOX, NO, NO2), and particulate matter 10 (PM10) levels extracted from publicly available data over this same time period. Distributed lag models were used to estimate risk ratios for hospitalisation and mortality, adjusting for temperature, humidity, day of the week, month and public holiday. Nitric oxides and PM10 were associated with an increased risk of all hospital admissions and cardiovascular (CV) admissions on day of exposure to pollutant. This study shows a significant increase in all cause and CV hospital admissions, on high pollution days in Tayside, Scotland., (© 2021. The Author(s).)

Background: The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes., Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107)., Findings: We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9-6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40-59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity., Interpretation: We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care., Funding: UK Research and Innovation and National Institute for Health Research., Competing Interests: Declaration of interests JDC reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Insmed, personal fees from Chiesi, Zambon, Janssen, and Grifols, and grants from Gilead Sciences, outside the submitted work. TC reports grants from Guy's and St Thomas' Charity, fees from workshops, and fees from writing self-help books on fatigue, outside the submitted work. NE received a donation of SARS-CoV-2 lateral flow antigen test kits from Mologic, in relation to an unrelated COVID-19 project. Neither NE nor his institution have received any financial compensation and he has no financial relationship of any kind with Mologic. RAE reports grants from GlaxoSmithKline during the conduct of the study; and grants from the National Institute for Health Research (NIHR) and personal fees from GlaxoSmithKline, AstraZeneca, and Chiesi, outside the submitted work. AH reports personal fees from Vertex Pharmaceuticals, Mylan Healthcare, and the Cystic Fibrosis Foundation, and grants from JP Moulton Trust and NIHR, outside the submitted work. LGH reports receiving sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals, personal fees from Novartis, Hoffman la Roche/Genentech, Sanofi, Evelo Biosciences, GlaxoSmithKline, AstraZeneca, Teva, Theravance, and Circassia, and grants from Medimmune, Novartis UK, Roche/Genentech, GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, Medimmune, Aerocrine, and Vitalograph, outside the submitted work. NH reports that his research group has received unrestricted grants (managed by Guy's & St Thomas' Foundation Trust) from Philips and Resmed. Philips are contributing to the development of the MYOTRACE technology. SH reports personal fees and fees to institution for advisory boards and consultancy from Novo Nordisk, Eli Lilly, Zealand Pharma, and Sanofi Aventis, outside the submitted work. JJ reports personal fees from Boehringer Ingelheim, Roche, GlaxoSmithKline, and NHSX, outside the submitted work. RGJ reports personal fees and research funding from Biogen, personal fees from Galapagos, Heptares, Boehringer Ingelheim, Pliant, Roche/InterMune, MedImmune, PharmAkea, Bristol Myers Squibb, Chiesi, Roche/Promedior, Veracyte, and GlaxoSmithKline research funding from Galecto, collaborative award from RedX and Nordic Biosciences, and was an advisory board member for NuMedii, outside the submitted work. RGJ is supported by an NIHR Professorship (RP-2017-08-ST2-014) and is a trustee for Action for Pulmonary Fibrosis. GM reports grants from AstraZeneca, outside the submitted work. PJMO reports grants from the Medical Research Council (MRC), the EU, and NIHR, and personal fees from Pfizer, Nestle, and Janssen, outside the submitted work. PP reports a grant from NIHR, outside the submitted work. MRo reports a senior clinical fellowship as part of research training and a 1-year post working in Pharma Development Neurosciences with Roche Pharmaceuticals, outside the submitted work. ADS reports grants and personal fees from AstraZeneca, Bayer, Boehringer, Chiesi, Forest Laboratories, GlaxoSmithKline, Grifols, Insmed, MedImmune, Novartis, Pfizer, and 30T, outside the submitted work. MGS reports grants from NIHR, MRC, and the Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool, during the conduct of the study; and reports being a minority owner and chair of the infectious disease scientific advisory board for Integrum Scientific, outside the submitted work. AShe reports being a Member of the Scottish Government's Chief Medical Officer's COVID-19 Advisory Group. MT reports personal fees from Merck Sharp & Dohme and GlaxoSmithKline, and grants and personal fees from Bayer and Actelion, during the conduct of the study. LVW reports grants from GlaxoSmithKline and Orion, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Breath analysis is a burgeoning field, with interest in volatile organic compounds (VOCs) as a noninvasive diagnostic tool or an outcome measure, but no randomised controlled trials (RCTs) have yet evaluated this technology in a clinical trial longitudinally. In a pilot RCT, our exploratory objectives were feasibility of measuring VOCs via multiple techniques, assessing relationships between VOCs and Haemophilus colonisation and whether CXCR2 antagonism with danirixin altered lung microbiome composition in individuals with COPD., Method: 43 participants had VOCs and sputum biomarkers evaluated. VOCs and induced sputum were collected after 6 h of fasting at screening and at days 1, 7 and 14. VOCs were analysed via gas chromatography mass spectrometry (GC-MS), field asymmetric ion mobility spectrometry (FAIMS) and eNose. The primary outcome for these analyses was the relationship between VOCs and Haemophilus abundance determined by 16S rRNA sequencing., Results: A joint-effects model demonstrated a modest relationship between four exhaled VOCs and Haemophilus relative abundance (R 2 =0.55) measured only by GC-MS, but not as measured using gas chromtaography FAIMS or eNose. There was considerable variability in absolute quantities of individual VOCs longitudinally., Conclusions: VOC measurement in clinical trials to identify subsets of COPD is feasible, but assessment of new VOC technologies must include concurrent GC-MS validation. Further work to standardise collection of VOCs and measuring a background or "housekeeper" VOC is required to understand and normalise individual VOC quantities., Competing Interests: Conflict of interest: D. Mohan is a current employee and shareholder of Genentech/Roche. Conflict of interest: H.R. Keir has nothing to disclose. Conflict of interest: H. Richardson has nothing to disclose. Conflict of interest: D. Mayhew is a former employee of and shareholder in GSK. Conflict of interest: J. Boyer is a former employee of and shareholder in GSK. Conflict of interest: M.P. van der Schee is an employee of Owlstone Medical Ltd and holds options in the company. Conflict of interest: M.D. Allsworth is an employee of Owlstone Medical Ltd and holds options in the company. Conflict of interest: B.E. Miller is a former employee of and shareholder in GSK. Conflict of interest: R. Tal-Singer is a former employee of and shareholder in GSK, and has received personal fees from Immunomet, Vocalis Health and Ena Respiratory. Conflict of interest: J.D. Chalmers reports grants and personal fees from GSK during the conduct of the study; and research grants from Boehringer Ingelheim (BI), AstraZeneca (AZ), Gilead Sciences, Grifols and Insmed, and has received personal fees from BI, AZ, Chiesi, Grifols, Napp, Novartis, Insmed and Zambon., (Copyright ©The authors 2021.)

Chronic obstructive pulmonary disease (COPD) and bronchiectasis represent chronic airway diseases associated with significant morbidity and mortality. Bacteria and viruses are commonly implicated in acute exacerbations; however the significance of fungi in these airways remains poorly defined. While COPD and bronchiectasis remain recognized risk factors for the occurrence of Aspergillus-associated disease including chronic and invasive aspergillosis, underlying mechanisms that lead to the progression from colonization to invasive disease remain uncertain. Nonetheless, advances in molecular technologies have improved our detection, identification and understanding of resident fungi characterizing these airways. Mycobiome sequencing has revealed the complex varied and myriad profile of airway fungi in COPD and bronchiectasis, including their association with disease presentation, progression, and mortality. In this review, we outline the emerging evidence for the clinical importance of fungi in COPD and bronchiectasis, available diagnostic modalities, mycobiome sequencing approaches and association with clinical outcomes., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The Global Initiative for Chronic Obstructive Lung Disease 2021 Report recommends inhaled corticosteroid (ICS)-containing regimens as part of pharmacological treatment in patients with chronic obstructive lung disease (COPD) and frequent exacerbations, particularly with eosinophilic inflammation. However, real-world studies reveal overprescription of ICS in COPD, irrespective of disease presentation and inflammatory endotype, leading to increased risk of side effects, mainly respiratory infections. The optimal use of ICS in COPD therefore remains an area of intensive research, and additional biomarkers of benefit and risk are needed. Although the interplay between inflammation and infection in COPD is widely acknowledged, the role of the microbiome in shaping lower airway inflammation has only recently been explored. Next-generation sequencing has revealed that COPD disease progression and exacerbation frequency are associated with changes in the composition of the lung microbiome, and that the immunosuppressive effects of ICS can contribute to potentially deleterious airway microbiota changes by increasing bacterial load and the abundance of potentially pathogenic taxa such as Streptococcus and Haemophilus . Here, we explore the relationship between microbiome, inflammation, ICS use and disease phenotype. This relationship may inform the benefit:risk assessment of ICS use in patients with COPD and lead to more personalised pharmacological management.

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04-8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61-4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast., Competing Interests: “CM was supported by an AstraZeneca postdoctoral fellowship. SY, GL and AP are employees of AstraZeneca and may own stock or stock options. There are no patents, products in development or marketed products related to this manuscript to declare. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.”

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.)

Although it is of great importance for healthcare professionals to ensure that patients' needs and concerns are valued and that they feel confident in the quality of the care they receive, there have been few studies specifically addressing the opinions, experiences and needs of patients with bronchiectasis, and more importantly the emotional impact of the disease, diagnosis and treatment.  Using enterprise grade social listening tools, a comprehensive search around bronchiectasis was performed in five languages, on different social media platforms between January 2018 and December 2019 to obtain the perspectives of patients and caregivers from nine countries on symptoms, treatments and burden of the disease.  Over 27 000 mentions of bronchiectasis were identified on social media channels, 38.8% of which were posted by patients and caregivers. Approximately 1600 posts were found on bronchiectasis symptoms, out of which persistent cough, shortness of breath and mucus production (22%, 20% and 18%, respectively) were the most commonly discussed. The research revealed that existing diagnostic tests often delay diagnosis or provide inaccurate results, leading to multiple rounds of consults and substantial delays in treatment initiation and management of the disease. Misdiagnosis was common across different age groups, especially among patients without severe symptoms, and this was associated with an emotional burden of anger, confusion, frustration and anxiety.  Analysis of social media presents a new approach to derive insights on patients' experiences and emotions with bronchiectasis and has the potential to complement more traditional approaches to drive more patient-focused drug development., Competing Interests: Conflict of interest: I. Delestre-Levai was employed by and received salary from Chiesi Farmaceutici SpA. Conflict of interest: S. Aliberti reports personal fees from Bayer Healthcare, Grifols, AstraZeneca and Zambon, grants and personal fees from Chiesi and INSMED, personal fees from GlaxoSmithKline, Menarini and ZetaCube Srl, and grants from Fisher & Paykel, outside the submitted work; .Dr. Aliberti reports grants and personal fees from Bayer Healthcare, grants and personal fees from Aradigm Corporation, grants and personal fees from Grifols, personal fees from Astra Zeneca, personal fees from Basilea, personal fees from Zambon, personal fees from Novartis, personal fees from Raptor, grants and personal fees from Chiesi, personal fees from Actavis UK Ltd, personal fees from Horizon, grants and personal fees from INSMED, outside the submitted work. Conflict of interest: M. Almagro has nothing to disclose. Conflict of interest: C. Carnini is an employee of Chiesi Farmaceutici SpA. Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca and Boehringer Ingelheim, personal fees from Chiesi, grants and personal fees from GlaxoSmithKline, Insmed and Novartis, and personal fees from Zambon, outside the submitted work. Conflict of interest: S.C. George reports personal fees from Chiesi Farmaceutici SpA as part of commercial engagement during the conduct of the study; and personal fees from Chiesi Farmaceutici SpA outside the submitted work. S.C. George has disclosed that he is an employee of Decision Resources Group, part of Clarivate, which was employed by Chiesi Farmaceutici SpA to conduct this research. Conflict of interest: S. Shukla reports personal fees from Chiesi Farmaceutici SpA as part of commercial engagement during the conduct of the study; and personal fees from Chiesi Farmaceutici SpA outside the submitted work. S. Shukla has disclosed that she is an employee of Decision Resources Group, part of Clarivate, which was employed by Chiesi Farmaceutici SpA to conduct this research. Conflict of interest: A. Timothy has nothing to disclose. Conflict of interest: M.C. De Vuono reports personal fees from Chiesi Farmaceutici SpA outside the submitted work., (Copyright ©The authors 2021.)

Bronchiectasis is a complex, heterogeneous disorder defined by both a radiological abnormality of permanent bronchial dilatation and a clinical syndrome. There are multiple underlying causes including severe infections, mycobacterial disease, autoimmune conditions, hypersensitivity disorders, and genetic conditions. The pathophysiology of disease is understood in terms of interdependent concepts of chronic infection, inflammation, impaired mucociliary clearance, and structural lung damage. Neutrophilic inflammation is characteristic of the disease, with elevated levels of harmful proteases such as neutrophil elastase associated with worse outcomes. Recent data show that neutrophil extracellular trap formation may be the key mechanism leading to protease release and severe bronchiectasis. Despite the dominant of neutrophilic disease, eosinophilic subtypes are recognized and may require specific treatments. Neutrophilic inflammation is associated with elevated bacterial loads and chronic infection with organisms such as Pseudomonas aeruginosa . Loss of diversity of the normal lung microbiota and dominance of proteobacteria such as Pseudomonas and Haemophilus are features of severe bronchiectasis and link to poor outcomes. Ciliary dysfunction is also a key feature, exemplified by the rare genetic syndrome of primary ciliary dyskinesia. Mucus symptoms arise through goblet cell hyperplasia and metaplasia and reduced ciliary function through dyskinesia and loss of ciliated cells. The contribution of chronic inflammation, infection, and mucus obstruction leads to progressive structural lung damage. The heterogeneity of the disease is the most challenging aspect of management. An understanding of the pathophysiology of disease and their biomarkers can help to guide personalized medicine approaches utilizing the concept of "treatable traits.", Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: The author has received research grants or performed consultancy for Astrazeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Gilead Sciences, Grifols, Janssen, Novartis, and Zambon.

Rationale: Although platelets are considered key inflammatory mediators in respiratory diseases, their role in bronchiectasis has not been fully explored. Objectives: We hypothesized that thrombocytosis in stable state may be associated with bronchiectasis severity and worse clinical outcomes. Methods: Patients with bronchiectasis have been enrolled from 10 centers in Europe and Israel, with platelet count recorded during stable state. The primary outcome was 5-year all-cause mortality. Secondary outcomes included exacerbations, hospitalizations, and mortality at 1, 2, and 3-year follow-up. Analyses were conducted using logistic regression after adjustment for confounding variables. Results: Among the 1,771 patients (median age, 67 yr; 63.4% female) included, 136 (7.7%) had thrombocytosis. Patients with thrombocytosis had a significantly higher disease severity, worse quality of life, higher number of exacerbations and hospitalizations, and higher mortality rate at both 3-year (23 [22.8%] vs. 83 [8.5%], respectively; P  < 0.01) and 5-year (26 [35.1%] vs. 116 [15.9%], respectively; P  < 0.01) in comparison with those with normal platelet count. Thrombocytosis was significantly associated with hospitalizations because of severe exacerbations (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.20-2.79; P  = 0.01) after 1-year follow-up, as well as increased 3-year (OR, 3.06; 95% CI, 1.74-5.39; P  < 0.01) and 5-year (OR, 2.46; 95% CI, 1.39-4.37; P  < 0.01) mortality. Conclusions: Platelets represent a cheap and easy-to-evaluate biomarker, and the presence of thrombocytosis during stable state is associated with disease severity, hospitalizations because of exacerbations, poor quality of life, and mortality in adults with bronchiectasis.

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

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

Nontuberculous mycobacterial (NTM) pulmonary disease is a chronic respiratory infection associated with declining lung function, radiological deterioration and significantly increased morbidity and mortality. Patients often have underlying lung conditions, particularly bronchiectasis and COPD. NTM pulmonary disease is difficult to treat because mycobacteria can evade host defences and antimicrobial therapy through extracellular persistence in biofilms and sequestration into macrophages. Management of NTM pulmonary disease remains challenging and outcomes are often poor, partly due to limited penetration of antibiotics into intracellular spaces and biofilms. Efficient drug delivery to the site of infection is therefore a key objective of treatment, but there is high variability in lung penetration by antibiotics. Inhalation is the most direct route of delivery and has demonstrated increased efficacy of antibiotics like amikacin compared with systemic administration. Liposomes are small, artificial, enclosed spherical vesicles, in which drug molecules can be encapsulated to provide controlled release, with potentially improved pharmacokinetics and reduced toxicity. They are especially useful for drugs where penetration of cell membranes is essential. Inhaled delivery of liposomal drug solutions can therefore facilitate direct access to macrophages in the lung where the infecting NTM may reside. A range of liposomal drugs are currently being evaluated in respiratory diseases., Competing Interests: Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Conflict of interest: Boehringer Ingelheim, GlaxoSmithKline and Insmed; grants from Gilead Sciences and Grifols; and personal fees from Chiesi, Novartis and Zambon, outside the submitted work. Conflict of interest: J. van Ingen reports advisory board membership from Insmed, outside the submitted work. Conflict of interest: R. van der Laan is an employee of Insmed. Conflict of interest: J-L. Herrmann has nothing to disclose., (Copyright ©The authors 2021.)

The global burden of children and young people (CYP) with bronchiectasis is being recognised increasingly. They experience a poor quality of life and recurrent respiratory exacerbations requiring additional treatment, including hospitalisation. However, there are no published data on patient-driven clinical needs and/or research priorities for paediatric bronchiectasis. Parent/patient-driven views are required to understand the clinical needs and research priorities to inform changes that benefit CYP with bronchiectasis and reduce their disease burden. The European Lung Foundation and the European Respiratory Society Task Force for paediatric bronchiectasis created an international roadmap of clinical and research priorities to guide, and as an extension of, the clinical practice guideline. This roadmap was based on two global web-based surveys. The first survey (10 languages) was completed by 225 respondents (parents of CYP with bronchiectasis and adults with bronchiectasis diagnosed in childhood) from 21 countries. The parent/patient survey encompassed both clinical and research priorities. The second survey, completed by 258 health practitioners from 54 countries, was limited to research priorities. The two highest clinical needs expressed by parents/patients were: having an action management plan for flare-ups/exacerbations and access to physiotherapists. The two highest health practitioners' research priorities related to eradication of airway pathogens and optimal airway clearance techniques. Based on both surveys, the top 10 research priorities were derived, and unanimous consensus statements were formulated from these priorities. This document addresses parents'/patients' clinical and research priorities from both the parents'/patients' and clinicians' perspectives and will help guide research and clinical efforts to improve the lives of people with bronchiectasis., Competing Interests: Conflict of interest: A.B. Chang reports grants from the National Health and Medical Research Council, Australia; and other fees to her institution from work relating to being a IDMC Member of an unlicensed vaccine (GSK) and an advisory member of study design for unlicensed molecule for chronic cough (Merck) outside the submitted work. Conflict of interest: J. Boyd is an employee of the European Lung Foundation. Conflict of interest: L. Bell has nothing to disclose. Conflict of interest: V. Goyal has nothing to disclose. Conflict of interest: I.B. Masters has nothing to disclose. Conflict of interest: Z. Powell has nothing to disclose. Conflict of interest: C. Wilson has nothing to disclose. Conflict of interest: A. Zacharasiewicz reports financial compensation for participation in advisory boards for Vertex, Novartis, Chiesi, Gilead and AOP; and lecture fees from Hagleitner Hygiene, AstraZeneca and Heine und Löwenstein. Conflict of interest: E. Alexopoulou has nothing to disclose 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, and personal fees from Chiesi, Gilead Sciences, Novartis and Zambon, outside the submitted work. Conflict of interest: R. Fortescue has nothing to disclose. 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: D. Snijders has nothing to disclose. Conflict of interest: W-J. Song has nothing to disclose. Conflict of interest: T. Tonia reports acting as an ERS methodologist. Conflict of interest: K. Grimwood reports various project grants and a Centre of Research Excellence relating to bronchiectasis in children from the Australian National Health and Medical Research Council and the Australian Medical Research Future Fund during the conduct of the study. Conflict of interest: A. Kantar has nothing to disclose., (Copyright ©The authors 2021.)

Pneumonia causes a significant burden of disease worldwide. Although all populations are at risk of pneumonia, those at extremes of age and those with immunosuppressive disorders, underlying respiratory disease, and critical illness are particularly vulnerable. Although clinical practice guidelines addressing the management and treatment of pneumonia exist, few of the supporting studies focus on the crucial contributions of the host in pneumonia pathogenesis and recovery. Such essential considerations include the host risk factors that lead to susceptibility to lung infections; biomarkers reflecting the host response and the means to pursue host-directed pneumonia therapy; systemic effects of pneumonia on the host; and long-term health outcomes after pneumonia. To address these gaps, the Pneumonia Working Group of the Assembly on Pulmonary Infection and Tuberculosis led a workshop held at the American Thoracic Society meeting in May 2018 with overarching objectives to foster attention, stimulate research, and promote funding for short-term and long-term investigations into the host contributions to pneumonia. The workshop involved participants from various disciplines with expertise in lung infection, pneumonia, sepsis, immunocompromised patients, translational biology, data science, genomics, systems biology, and clinical trials. This workshop report summarizes the presentations and discussions and important recommendations for future clinical pneumonia studies. These recommendations include establishing consensus disease and outcome definitions, improved phenotyping, development of clinical study networks, standardized data and biospecimen collection and protocols, and development of innovative trial designs.

Adverse events are frequent in nontuberculous mycobacteria pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus, and gastrointestinal upset. These opinions can provide assistance in individual patient management decisions., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Healthcare workers (HCWs) are believed to be at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is not known to what extent the natural production of antibodies to SARS-CoV-2 is protective against re-infection., Methods: A prospective observational study of HCWs in Scotland (UK) from May to September 2020 was performed. The Siemens SARS-CoV-2 total antibody assay was used to establish seroprevalence in this cohort. Controls, matched for age and sex to the general local population, were studied for comparison. New infections (up to 2 December 2020) post antibody testing were recorded to determine whether the presence of SARS-CoV-2 antibodies protects against re-infection., Results: A total of 2063 health and social care workers were recruited for this study. At enrolment, 300 HCWs had a positive antibody test (14.5%). 11 out of 231 control sera tested positive (4.8%). HCWs therefore had an increased likelihood of a positive test (OR 3.4, 95% CI 1.85-6.16; p<0.0001). Dentists were most likely to test positive. 97.3% of patients who had previously tested positive for SARS-CoV-2 by reverse transcriptase (RT)-PCR had positive antibodies. 18.7% had an asymptomatic infection. There were 38 new infections with SARS-CoV-2 in HCWs who were previously antibody negative, and one symptomatic RT-PCR-positive re-infection. The presence of antibodies was therefore associated with an 85% reduced risk of re-infection with SARS-CoV-2 (hazard ratio 0.15, 95% CI 0.06-0.35; p=0.026)., Conclusion: HCWs were three times more likely to test positive for SARS-CoV-2 than the general population. Almost all infected individuals developed an antibody response, which was 85% effective in protecting against re-infection with SARS-CoV-2., Competing Interests: Conflict of interest: H. Abo-Leyah has nothing to disclose. Conflict of interest: S. Gallant has nothing to disclose. Conflict of interest: D. Cassidy has nothing to disclose. Conflict of interest: Y.H. Giam has nothing to disclose. Conflict of interest: J. Killick has nothing to disclose. Conflict of interest: B. Marshall has nothing to disclose. Conflict of interest: G. Hay has nothing to disclose. Conflict of interest: C. Snowdon has nothing to disclose. Conflict of interest: E.J. Hothersall has nothing to disclose. Conflict of interest: T. Pembridge has nothing to disclose. Conflict of interest: R. Strachan has nothing to disclose. Conflict of interest: N. Gallant has nothing to disclose. Conflict of interest: B.J. Parcell has nothing to disclose. Conflict of interest: J. George has nothing to disclose. Conflict of interest: E. Furrie 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, all outside the submitted work., (Copyright ©The authors 2021.)

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.)

Background: Poor treatment adherence in COPD patients is associated with poor clinical outcomes and increased healthcare burden. Personalized approaches for adherence management, supported with technology-based interventions, may offer benefits to patients and providers but are currently unproven in terms of clinical outcomes as opposed to adherence outcomes., Methods: Maximizing Adherence and Gaining New Information For Your COPD (MAGNIFY COPD study), a pragmatic cluster randomized trial, aims to evaluate the impact of an adherence technology package (interventional package), comprising an adherence review, ongoing provision of a dual bronchodilator but with an add-on inhaler sensor device and a connected mobile application. This will compare time to treatment failure and other clinical outcomes in patients identified at high risk of exacerbations with historic poor treatment adherence as measured by prescription collection to mono/dual therapy over one year (1312 patients) versus usual care. Treatment failure is defined as the first occurrence of one of the following: (1) moderate/severe COPD exacerbation, (2) prescription of triple therapy (inhaled corticosteroid/long-acting β 2 -agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]), (3) prescription of additional chronic therapy for COPD, or (4) respiratory-related death. Adherence, moderate/severe exacerbations, respiratory-related healthcare resource utilization and costs, and intervention package acceptance rate will also be assessed. Eligible primary care practices (N=176) participating in the Optimum Patient Care Quality Improvement Program will be randomized (1:1) to either adherence support cluster arm (suitable patients already receiving or initiated Ultibro ® Breezhaler ® [indacaterol/glycopyrronium] will be offered interventional package) or the control cluster arm (suitable patients continue to receive usual clinical care). Patients will be identified and outcomes collected from anonymized electronic medical records within the Optimum Patient Care Research Database. On study completion, electronic medical record data will be re-extracted to analyze outcomes in both study groups., Registration Number: ISRCTN10567920., Conclusion: MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring., Competing Interests: David Price has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Merck, Zentiva (Sanofi Generics), Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrolment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; personal fees from Airway Vista Secretariat, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L, Talos Health Solutions, WebMD Global LLC, outside the submitted work; and was an expert witness for GlaxoSmithKline. Rupert Jones declares grants from Astra Zeneca, GlaxoSmithKline and Novartis and personal fees for consultancy, speaker’s fees or travel support from Astra Zeneca, Boehringer Ingelheim, Glaxo Smith Kline, Novartis, Nutricia and OPRI. Victoria Carter is an employee of the study sponsor Observational & Pragmatic Research International Ltd (OPRI), the study sponsor, which has conducted paid research in respiratory disease on behalf of the following other organizations in the past 5 years: Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Sanofi, Takeda and Teva. Alan Kaplan received fee for advisory board or speakers bureau for Astra Zeneca, Boehringer Ingelheim, Covis, GSK, Merck Frosst, Pfizer, Purdue, Novartis, Sanofi, Teva, Trudel. David MG Halpin has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer and Sanofi, and non-financial support from Boehringer Ingelheim and Novartis. Anu Kemppinen and Allan Clark have nothing to disclose. Hilary Pinnock was paid an honorarium for writing an on-line piece on supported self-management for Teva website. She is involved with several professional or educational organisations which receive multi-company sponsorship. Job van Boven receives funding from the European Commission to Chair the European Network to Advance Best practices & technoLogy on medication adherencE (COST Action CA19132, ENABLE). His institution (Medication Adherence Expertise Center of the northern Netherlands, MAECON, University Medical Center Groningen, Groningen, the Netherlands) has received consultancy fees, speaking fees, and/or research grants from AstraZeneca, Boehringer Ingelheim, Chiesi, eLucid mHealth, Menarini, Novartis, Teva and Trudell Medical related to medication adherence but all unrelated to this study. Kai M. Beeh declares personal or institutional compensations from the following in the past 5 years: Kai Beeh is a full time employee of insaf Respiratory Research Institute. The institution has received compensation for services on advisory boards or consulting for AstraZeneca, Berlin Chemie, Boehringer, Chiesi, Cytos, GSK, Mundipharma, Novartis, Pohl Boskamp, Sanofi, Zentiva. The institution has received compensation for speaker activities in scientific meetings supported by AstraZeneca, Berlin Chemie, Boehringer, ERT, GSK, Novartis, Pfizer, Pohl Boskamp, Sanofi, Takeda. The institution has further received compensation for design and performance of clinical trials from AstraZeneca, Boehringer, GSK, Infinity, Mundipharma, Novartis, Parexel, Pearl Therapeutics, Pfizer, Revotar, Teva, Sterna, and Zentiva. Konstantinos Kostikas was an employee and shareholder of Novartis Pharma AG until October 31, 2018. He have received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Menarini, Novartis and Sanofi; his department has received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GSK, Menarini, Novartis and NuvoAir. Nicolas Roche reports research grants from Boehringer Ingelheim, Novartis, Pfizer and personal fees for consultancy, advisory boards, lectures and education, participation to steering committees from Boehringer Ingelheim, Novartis, Pfizer, Teva, GSK, AstraZeneca, Chiesi, Sanofi, Trudell, Zambon. James Chalmers reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Chiesi, grants and personal fees from Gilead Sciences, grants and personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from Zambon, from null, outside the submitted work; Dr. Chalmers reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim and Insmed, personal fees from Chiesi, grants and personal fees from Gilead Sciences, grants and personal fees from GlaxoSmithKline, grants and personal fees from Novartis, personal fees from Zambon, personal fees from Janssen, outside the submitted work. Omar Usmani reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Chiesi, grants and personal fees from GlaxoSmithKline, personal fees from Napp, personal fees from Mundi Pharma, personal fees from Sandoz, personal fees from Takeda, grants from Edmond pharma, personal fees from Cipla, personal fees from Covis, personal fees from Novartis, personal fees from Mereo BioPharma, personal fees from Orion, personal fees from Menarini, personal fees from Deva, personal fees from Roche, personal fees from, Trudel, personal fees from UCB outside the submitted work. Björn Holzhauer, Pascal Pfister, Hui Cao and Paul Mastoridis are employees of Novartis and holds stock in Novartis Pharma AG. The authors report no other conflicts of interest in this work., (© 2021 Price et al.)

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

Bronchiectasis has been a largely overlooked disease area in respiratory medicine. This is reflected by a shortage of large-scale studies and lack of approved therapies, in turn leading to a variation of treatment across centres. BronchUK (Bronchiectasis Observational Cohort and Biobank UK) is a multicentre, prospective, observational cohort study working collaboratively with the European Multicentre Bronchiectasis Audit and Research Collaboration project. The inclusion criteria for patients entering the study are a clinical history consistent with bronchiectasis and computed tomography demonstrating bronchiectasis. Main exclusion criteria are 1) patients unable to provide informed consent, 2) bronchiectasis due to known cystic fibrosis or where bronchiectasis is not the main or co-dominant respiratory disease, 3) age <18 years, and 4) prior lung transplantation for bronchiectasis. The study is aligned to standard UK National Health Service (NHS) practice with an aim to recruit a minimum of 1500 patients from across at least nine secondary care centres. Patient data collected at baseline includes demographics, aetiology testing, comorbidities, lung function, radiology, treatments, microbiology and quality of life. Patients are followed up annually for a maximum of 5 years and, where able, blood and/or sputa samples are collected and stored in a central biobank. BronchUK aims to collect robust longitudinal data that can be used for analysis into current NHS practice and patient outcomes, and to become an integral resource to better inform future interventional studies in bronchiectasis., Competing Interests: Conflict of interest: A. De Soyza has received grants or personal fees from AstraZeneca, Bayer, Chiesi, Grifols, GSK, Pfizer and Novartis. Conflict of interest: P. Mawson has nothing to disclose. Conflict of interest: A.T. Hill has nothing to disclose. Conflict of interest: J.S. Elborn reports acting as chief investigator on a phase I programme for Ionis; involvement in an Innovative Medicines Initiative inhaled antibiotics in bronchiectasis and cystic fibrosis programme with Novartis, Polphor and Alaxia for the European Commission; and support received from Vertex for other projects and travel support to attend the Australian CF conference, all during the conduct of the study. Conflict of interest: J.M. Bradley has nothing to disclose. Conflict of interest: C.S. Haworth reports personal fees from Aradigm related to the Orbit studies; advisory board fees from Chiesi and Gilead; personal fees from Grifols related to the Orbit studies; advisory board fees from GlaxoSmithKline; personal fees from Novartis related to the iBEST studies; advisory board and speaker fees from Vertex; personal fees related to the Promis studies and advisory board fees from Zambon; educational grants, speaker fees and advisory board fees from Insmed Incorporated; a research grant and advisory board fees from International Biophysics; educational grants and speaker fees from Teva; consultancy fees from Meiji; advisory board fees from Janssen; and speakers fees from Mylan, all outside the submitted work. Conflict of interest: R.A. Floto has nothing to disclose. Conflict of interest: R. Wilson has nothing to disclose. Conflict of interest: M.R. Loebinger reports advisory board and lecture fees from Insmed and Grifols, and advisory board fees from Bayer, Polyphor and AstraZeneca, outside the submitted work. Conflict of interest: M. Carroll has nothing to disclose. Conflict of interest: M. Crichton reports personal fees from AstraZeneca outside the submitted work. Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca and Boehringer Ingelheim, personal fees from Chiesi, grants and personal fees from GlaxoSmithKline, grants from Gilead Sciences, grants and personal fees from Insmed, and personal fees from Novartis and Zambon, outside the submitted work. Conflict of interest: A. Sullivan reports acting as a principal investigator for a multicentre Clinical Trial of Investigational Medicinal Product (CTIMP) sponsored by Novartis, and for a multicentre CTIMP sponsored by the University of Belfast with some medication/equipment provided by Pari Medical, both outside the submitted work. Conflict of interest: J. Brown has nothing to disclose. Conflict of interest: J.R. Hurst reports support to attend meetings, and payment to him and to his employer (University College London) for educational and advisory work from pharmaceutical companies that make medicines to treat respiratory diseases including bronchiectasis, outside the submitted work. Conflict of interest: J. Duckers has nothing to disclose. Conflict of interest: M. Kelly reports personal fees and nonfinancial support for presentations delivered locally from GlaxoSmithKline, and sponsorship to attend conferences from Bristol Myers Squibb and Napp, all outside the submitted work. Conflict of interest: J. Steer has nothing to disclose. Conflict of interest: T. Gatheral has nothing to disclose. Conflict of interest: P.P. Walker has nothing to disclose. Conflict of interest: C. Winstanley has nothing to disclose. Conflict of interest: A. McGuire has nothing to disclose. Conflict of interest: D. Denning and family hold founder shares in F2G Ltd, a University of Manchester spin-out antifungal discovery company. He acts or has recently acted as a consultant to Scynexis, Mayne, Pulmatrix, Pulmocide, Zambon, Biosergen and Fujifilm. In the last 3 years, he has been paid for talks on behalf of Hikma, Gilead and Pfizer. He is a longstanding member of the Infectious Disease Society of America Aspergillosis Guidelines group, the European Society for Clinical Microbiology and Infectious Diseases Aspergillosis Guidelines group, and the British Society for Medical Mycology Standards of Care committee. Conflict of interest: R. McNally reports that he is a coinvestigator on the MRC grant for the current study., (Copyright ©The authors 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.)

Pneumonia is a common acute respiratory infection that affects the alveoli and distal airways; it is a major health problem and associated with high morbidity and short-term and long-term mortality in all age groups worldwide. Pneumonia is broadly divided into community-acquired pneumonia or hospital-acquired pneumonia. A large variety of microorganisms can cause pneumonia, including bacteria, respiratory viruses and fungi, and there are great geographical variations in their prevalence. Pneumonia occurs more commonly in susceptible individuals, including children of <5 years of age and older adults with prior chronic conditions. Development of the disease largely depends on the host immune response, with pathogen characteristics having a less prominent role. Individuals with pneumonia often present with respiratory and systemic symptoms, and diagnosis is based on both clinical presentation and radiological findings. It is crucial to identify the causative pathogens, as delayed and inadequate antimicrobial therapy can lead to poor outcomes. New antibiotic and non-antibiotic therapies, in addition to rapid and accurate diagnostic tests that can detect pathogens and antibiotic resistance will improve the management of pneumonia.

Bronchiectasis, a progressive chronic airway disease, is characterized by microbial colonization and infection. We present an approach to the multi-biome that integrates bacterial, viral and fungal communities in bronchiectasis through weighted similarity network fusion ( https://integrative-microbiomics.ntu.edu.sg ). Patients at greatest risk of exacerbation have less complex microbial co-occurrence networks, reduced diversity and a higher degree of antagonistic interactions in their airway microbiome. Furthermore, longitudinal interactome dynamics reveals microbial antagonism during exacerbation, which resolves following treatment in an otherwise stable multi-biome. Assessment of the Pseudomonas interactome shows that interaction networks, rather than abundance alone, are associated with exacerbation risk, and that incorporation of microbial interaction data improves clinical prediction models. Shotgun metagenomic sequencing of an independent cohort validated the multi-biome interactions detected in targeted analysis and confirmed the association with exacerbation. Integrative microbiomics captures microbial interactions to determine exacerbation risk, which cannot be appreciated by the study of a single microbial group. Antibiotic strategies probably target the interaction networks rather than individual microbes, providing a fresh approach to the understanding of respiratory infection.

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.)