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The protein and molecular characteristics of variants of the alpha1-antitrypsin (AAT) gene are described, and available data on the genetic epidemiology of AAT deficiency are presented. [ABSTRACT FROM AUTHOR]

Background: The effect of dual systemic antibiotic therapy against Pseudomonas aeruginosa in patients with pre-existing lung disease is unknown. To assess whether dual systemic antibiotics against P. aeruginosa in outpatients with COPD, non-cystic fibrosis (non-CF) bronchiectasis, or asthma can improve outcomes., Methods: Multicenter, randomised, open-label trial conducted at seven respiratory outpatient clinics in Denmark. Outpatients with COPD, non-CF bronchiectasis, or asthma with a current P. aeruginosa-positive lower respiratory tract culture (clinical routine samples obtained based on symptoms of exacerbation not requiring hospitalisation), regardless of prior P. aeruginosa-status, no current need for hospitalisation, and at least two moderate or one hospitalisation-requiring exacerbation within the last year were eligible. Patients were assigned 1:1 to 14 days of dual systemic anti-pseudomonal antibiotics or no antibiotic treatment. Primary outcome was time to prednisolone or antibiotic-requiring exacerbation or death from day 20 to day 365., Results: The trial was stopped prematurely based in lack of recruitment during the COVID-19 pandemic, this decision was endorsed by the Data and Safety Monitoring Board. Forty-nine outpatients were included in the study. There was a reduction in risk of the primary outcome in the antibiotic group compared to the control group (HR 0.51 (95%CI 0.27-0.96), p = 0.037). The incidence of admissions with exacerbation within one year was 1.1 (95%CI 0.6-1.7) in the dual antibiotic group vs. 2.9 (95%CI 1.3-4.5) in the control group, p = 0.037., Conclusions: Use of dual systemic antibiotics for 14 days against P. aeruginosa in outpatients with chronic lung diseases and no judged need for hospitalisation, improved clinical outcomes markedly. The main limitation was the premature closure of the trial., Trial Registration: ClinicalTrials.gov, NCT03262142, registration date 2017-08-25., (© 2024. The Author(s).)

Background: Individuals with α 1 -antitrypsin deficiency have increased elastase activity resulting in continuous degradation of elastin and early onset of COPD. Increased elastase activity may also affect elastic properties of the heart, which may impact risk of heart failure. We tested the hypothesis that α 1 -antitrypsin deficiency is associated with increased risk of heart failure in two large populations., Methods: In a nationwide nested study of 2209 patients with α 1 -antitrypsin deficiency and 21 869 controls without α 1 -antitrypsin deficiency matched on age, sex and municipality, we recorded admissions and deaths due to heart failure during a median follow-up of 62 years. We also studied a population-based cohort of another 102 481 individuals from the Copenhagen General Population Study including 187 patients from the Danish α 1 -Antitrypsin Deficiency Registry, all with genetically confirmed α 1 -antitrypsin deficiency., Results: Individuals with versus without α 1 -antitrypsin deficiency had increased risk of heart failure hospitalisation in the nationwide cohort (adjusted hazard ratio 2.64, 95% CI 2.25-3.10) and in the population-based cohort (1.77, 95% CI 1.14-2.74). Nationwide, these hazard ratios were highest in those without myocardial infarction (3.24, 95% CI 2.70-3.90), without aortic valve stenosis (2.80, 95% CI 2.38-3.29), without hypertension (3.44, 95% CI 2.81-4.22), without atrial fibrillation (3.33, 95% CI 2.75-4.04) and without any of these four diseases (6.00, 95% CI 4.60-7.82). Hazard ratios for heart failure-specific mortality in individuals with versus without α 1 -antitrypsin deficiency were 2.28 (95% CI 1.57-3.32) in the nationwide cohort and 3.35 (95% CI 1.04-10.74) in the population-based cohort., Conclusion: Individuals with α 1 -antitrypsin deficiency have increased risk of heart failure hospitalisation and heart failure-specific mortality in the Danish population., Competing Interests: Conflict of interest: B.G. Nordestgaard has consultancies with Amarin, Akcea, Amgen, AstraZeneca, Denka Seiken, Kowa, Novartis, Novo Nordisk and Silence Therap. Conflict of interest: No conflicts of interest exist for S.V. Winther, E.M. Landt, N. Seersholm and M. Dahl., (Copyright ©The authors 2023.)

Background: Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma., Methods: This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20-365 from study allocation and (ii) days alive and without exacerbation within days 20-365 from the study allocation., Discussion: This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients., Trial Registration: ClinicalTrials.gov NCT03262142 . Registered on August 25, 2017., (© 2022. The Author(s).)

Objectives: It is unclear whether recurrent sputum culture with Pseudomonas aeruginosa from patients with chronic obstructive pulmonary disease (COPD) is caused by intermittent airway carriage by different P. aeruginosa lineages or persistent carriage by the same lineage, and whether lineages genetically adapt during carriage., Methods: Whole-genome sequencing was performed for P. aeruginosa isolates sampled longitudinally from sputum cultures in patients with COPD who were enrolled in an ongoing randomized controlled trial (clinicaltrials.gov: NCT03262142)., Results: A total of 153 P. aeruginosa isolates were sequenced for 23 patients during 365 days of follow-up. Recurrent presence of P. aeruginosa was seen in 19 patients (83%) and was caused by persistence of the same clonal lineage in all but one patient. We identified 38 genes mutated in parallel in two or more lineages, suggesting positive selection for adaptive mutations. Mutational enrichment analysis revealed genes important in antibiotic resistance and chronic infections to be more frequently mutated., Discussion: Recurrent P. aeruginosa was common and carried for a prolonged time after initial detection in the airways of patients with COPD. Recurrence was caused by persistence of the same clonal lineage and was associated with genetic adaptation. Trial data on possible clinical benefits of attempting antibiotic eradication of P. aeruginosa in COPD are warranted., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Increased elastase activity in α 1 -antitrypsin deficiency may affect elasticity of the arterial walls, and thereby blood pressure and susceptibility to cardiovascular disease. We hypothesized that severe α 1 -antitrypsin deficiency is associated with reduced blood pressure and susceptibility to cardiovascular disease., Methods: We genotyped 91,353 adults randomly selected from the Danish general population and 187 patients from the Danish α 1 -Antitrypsin Deficiency Registry and recorded baseline blood pressure, baseline plasma lipids and cardiovascular events during follow-up. 185 participants carried the ZZ genotype, 207 carried the SZ genotype and 91,148 carried the MM genotype., Results: α 1 -Antitrypsin deficiency was associated with decreases in blood pressure of up to 5 mmHg for systolic blood pressure and up to 2 mmHg for diastolic blood pressure, in ZZ vs SZ vs MM individuals (trend test, P's ≤ 0.01). Plasma triglycerides and remnant cholesterol were reduced in ZZ individuals compared with MM individuals (t-test, P's < 0.001). α 1 -Antitrypsin deficiency was associated with lower risk of myocardial infarction (trend test P = 0.03), but not with ischemic heart disease, ischemic cerebrovascular disease or hypertension (trend test, P's ≥ 0.59). However, when results for ischemic heart disease were summarized in meta-analysis with results from four previous studies, individuals with versus without α 1 -antitrypsin deficiency had an odds ratio for ischemic heart disease of 0.66 (95% CI:0.53-0.84)., Conclusions: Individuals with severe α 1 -antitrypsin deficiency have lower systolic and diastolic blood pressure, lower plasma triglycerides and remnant cholesterol, reduced risk of myocardial infarction, and a 34% reduced risk of ischemic heart disease., (© 2022. The Author(s).)

Background: Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD)., Methods: In an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9β SNPs., Results: The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9β, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9β and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, -1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively., Conclusions: In total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations., Competing Interests: The authors have declared that no competing interests exist.

Psychiatric side effects are well known from treatment with systemic corticosteroids. It is, however, unclear whether inhaled corticosteroids (ICS) have psychiatric side effects in patients with COPD. We conducted a nationwide cohort study in all Danish COPD outpatients who had respiratory medicine specialist-verified COPD, age ≥40 years, and no previous cancer. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder were assessed by Cox proportional hazards models. We observed a dose-dependent increase in the risk of antidepressant-use with ICS cumulated dose (HR 1.05, 95% CI 1.03-1.07, p = 0.0472 with low ICS exposure, HR 1.10, 95% CI 1.08-1.12, p < 0.0001 with medium exposure, HR 1.15, 95% CI 1.11-1.15, p < 0.0001 with high exposure) as compared to no ICS exposure. We found a discrete increased risk of admission to psychiatric hospitals in the medium and high dose group (HR 1.00, 95% CI 0.98-1.03, p = 0.77 with low ICS exposure, HR 1.07, 95% CI 1.05-1.10, p < 0.0001 with medium exposure, HR 1.13, 95% CI 1.10-1.15, p < 0.0001 with high exposure). The association persisted when stratifying for prior antidepressant use. Thus, exposure to ICS was associated with a small to moderate increase in antidepressant-use and psychiatric admissions.

Due to frequent exacerbations, many patients with chronic obstructive pulmonary disease (COPD) are exposed to oral corticosteroids (OCS), which may be thrombogenic. We evaluated the risk of hospitalisation with venous thromboembolism (VTE) and death in patients with acute exacerbation of COPD (AECOPD) treated with long and short OCS regimens. In this nationwide cohort study of 30,473 COPD outpatients treated for AECOPD, we compared the risk of VTE hospitalisation and all-cause mortality within 6 months in OCS dose of >250 mg vs. ≤250 mg. A multivariable Cox proportional hazard regression was used to estimate the risk. The incidence of VTE hospitalisations was 0.23%. A long OCS treatment course was associated with an increased risk of VTE compared to a short course (hazard ratio (HR) 1.69, [95% confidence interval (CI) 1.05 to 2.72], p < 0.031). A higher risk of all-cause mortality was seen in the group of COPD patients treated with a long OCS course (HR 1.71, [95% CI 1.63 to 1.79], p < 0.0001). The risk of reported VTE hospitalisation was higher among AECOPD patients treated with long courses of OCS, but the absolute risk was low, suggesting under-reporting of the condition.

Objectives: MTX is the most commonly recommended DMARD for first-line treatment of RA, however, it has been hypothesized to cause lung disease as an adverse effect. We investigated the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in persons with RA treated with MTX and other medications., Methods: From the Danish National Patient Register (NPR) and the DANBIO register for rheumatic diseases, we retrieved data on 30 512 persons with RA registered in 1997-2015. Information on ILD and respiratory failure was obtained from the NPR. Information on age and sex for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Registry. Associations between MTX and lung disease outcomes were analysed in Cox regression models with adjustment for age, calendar time, sex and other medications. Standardized incidence ratios (SIRs) of lung disease were calculated to compare the RA population with the general population., Results: There was no increased risk of lung disease with MTX treatment [one or more purchases compared with no purchases; HR 1.00 (95% CI 0.78, 1.27) for ILD and 0.54 (95% CI 0.43, 0.67) for respiratory failure] at the 5 year follow-up. The SIR was three to four times higher for ILD in MTX-treated persons with RA, but similar to the whole RA population compared with the background population., Conclusion: Persons with RA had an increased risk of ILD compared with the general population, but there was no further increased risk associated with MTX treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Depressive symptoms appear more often among patients with COPD and are associated with reduced disease control and increased mortality. Both smoking and COPD increase the risk of depressive symptoms. Whether smoking cessation among COPD patients affects the occurrence of depressive symptoms is unknown. We hypothesised that smoking cessation in patients with COPD leads to reduced use of antidepressants and fewer admissions to psychiatric hospitals with depression, anxiety or bipolar disorder., Methods: We conducted a nationwide retrospective case-control study, in patients from The Danish Register for COPD with spirometry-verified COPD, age ≥40 years, a history of smoking and absence of cancer. Consistent smokers were matched 1:1 with ex-smokers using a propensity score model. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder both descriptively was assessed by Cox proportional hazard models., Results: We included 21 184 patients. A total of 2011 consistent smokers collected antidepressant prescriptions compared with 1821 ex-smokers. Consistent smoking was associated with increased risk of filling prescription on antidepressants (HR 1.4, 95% CI 1.3-1.5, p<0.0001) and with increased risk of psychiatric hospital admission with either depression, anxiety or bipolar disorder (HR 2.0, 95% CI 1.6-2.5). The associations persisted after adjustment for former use of antidepressants., Conclusion: Consistent smoking among COPD patients was associated with increased use of antidepressants and admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder, compared to smoking cessation., Competing Interests: Conflict of interest: J.H. Vestergaard has nothing to disclose. Conflict of interest: P. Sivapalan reports nonfinancial support from Novartis and honoraria for lecturing from Boehringer Ingelheim outside the submitted work. Conflict of interest: R. Sørensen has nothing to disclose. Conflict of interest: J. Eklöf has nothing to disclose. Conflict of interest: I. Achir Alispahic has nothing to disclose. Conflict of interest: A. von Bülow has nothing to disclose. Conflict of interest: N. Seersholm has nothing to disclose. Conflict of interest: J-U.S. Jensen has nothing to disclose., (Copyright ©ERS 2020.)

Background: Long-term treatment with corticosteroids causes loss of bone density, but the effects of using short-term high-dose systemic-corticosteroid therapy to treat acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are unclear. Our aim was to determine whether high-dose corticosteroid therapy affected bone turnover markers (BTMs) to a greater extent compared to low-dose corticosteroid therapy., Methods: The CORTICO-COP trial (NCT02857842) showed that an eosinophil-guided corticosteroid intervention led to approximately 60% lower accumulated corticosteroid dose for hospitalized patients with AECOPD (low-dose group) compared with 5-day standard corticosteroid treatment (high-dose group). We compared the levels of BTMs C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) in 318 participants during AECOPD and at 1- and 3-month follow-up visits., Results: CTX decreased and P1NP increased significantly over time in both treatment groups. There were no significant differences between the groups at 1- or 3-months follow-up for P1NP. A significant drop in CTX was seen at 3 months (down Δ24% from the baseline, p = 0.017) for the high dose group., Conclusion: Short-term, high-dose systemic corticosteroid treatment caused a rapid suppression of biomarkers of bone resorption. Corticosteroids did not suppress biomarkers of bone formation, regardless of patients receiving low or high doses of corticosteroids. This therapy was, therefore, harmless in terms of bone safety, in our prospective series of COPD patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02857842 . Submitted August 2nd, 2016.

α 1 -Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α 1 -antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals., Competing Interests: Conflict of interest: G.N. McElvaney reports personal fees for advisory board work from CSL Behring and Vertex, grants and personal fees for advisory board work from Grifols, outside the submitted work. Conflict of interest: R.A. Sandhaus reports personal fees for advisory board work and reimbursement for travel from CSL Behring, during the conduct of the study; personal fees for advisory work from AstraZeneca, and is an unpaid advisory for Grifols, outside the submitted work. Conflict of interest: M. Miravitlles reports personal fees for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and Novartis, personal fees for consultancy from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols, grants from GlaxoSmithKline and Grifols, outside the submitted work. Conflict of interest: G.M. Turino has nothing to disclose. Conflict of interest: N. Seersholm has nothing to disclose. Conflict of interest: M. Wencker reports personal fees for consultancy from CSL Behring, during the conduct of the study. Conflict of interest: R.A. Stockley reports personal fees for advisory board work and lectures from AstraZeneca, personal fees for lectures from Nycomed, personal fees for advisory board work, lectures and meeting attendance from Boehringer Ingelheim and CSL Behring, personal fees for advisory board work from Shire, Chiesi, Polyphor, GlaxoSmithKline, Mereo BioPharma, Vertex Pharmaceuticals Inc. and Akari Therapeutics plc, outside the submitted work., (Copyright ©ERS 2020.)

Roflumilast is given as an add-on to inhalation medication in patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis. Animal experiments have documented deleterious effects of roflumilast in bacterial infections, but trials have not reported the risk of bacterial infections in patients. The objective of this study is to determine, among outpatients with severe COPD in a two-year follow-up period, the risk of hospitalization-requiring pneumonia, severe acute exacerbation in COPD (AECOPD-hosp), and death. Patients with COPD using roflumilast (roflumilast users) were compared to a propensity score-matched COPD control group not using roflumilast (non-roflumilast users). Roflumilast users had an increased 2-year risk of hospitalization-requiring pneumonia (HR 1.5, 95% CI 1.3 to 1.8, p- value < 0.0001) compared to controls, and of AECOPD-Hosp (hazard ratio(HR) 1.6, 95%, confidence interval (CI) 1.5 to 1.8, p- value < 0.0001) and. When adding an active comparator (theophylline) as a matching variable, the signal was largely unchanged. In conclusion, roflumilast was associated with an increased number of hospitalizations for pneumonia and for AECOPD. Since trials have not reported risks of bacterial complications and data regarding severe exacerbations in roflumilast users are sparse and diverging, these data are concerning. Trials focused on the risk of pneumonia, AECOPD, and other bacterial infections in roflumilast users are needed urgently., Competing Interests: P.S. reports personal fees from Boehringer Ingelheim outside the submitted work. All other authors declare no conflict of interest. The funders had no role in the design of the study; in the data collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Rationale and Objectives: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD., Study Design and Population: The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level <11 µM (50 mg·dL -1 ) and/or a proteinase inhibitor genotype ZZ, SZ or compound heterozygotes or homozygotes of other rare deficient variants. Assessments at baseline and during the yearly follow-up visits include lung function testing (spirometry, body plethysmography and diffusing capacity of the lung), exercise capacity, blood tests and questionnaires (symptoms, quality of life and physical activity). To ensure correct data collection, there will be designated investigator staff to document the data in the case report form. All data will be reviewed by the EARCO database manager., Summary: The EARCO Registry aims to understand the natural history and prognosis of AATD better with the goal to create and validate prognostic tools to support medical decision-making., Competing Interests: Conflict of interest: T. Greulich reports grants from CSL-Behring, Grifols and Kamda during the conduct of the study; personal fees for lectures and advisory boards from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK and Novartis, grants and personal fees for lectures and advisory boards from Grifols, and grants from the German Centre for Lung Research (DZL), outside the submitted work. Conflict of interest: A. Altraja reports travel support to attend the EARCO stakeholder board meeting on 17 June 2019 from EARCO during the conduct of the study; support for clinical trials and honoraria for advisory board meetings from CSL Behring, honoraria for lectures/chairmanships and advisory board meetings and travel support from Shire Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Chiesi (Norameda), GlaxoSmithKline, MSD, Novartis, Roche, Bayer and Actelion (Johnson & Johnson), research support from Pfizer, travel support from Teva, Sanofi and United Therapeutics (AOP Orphan), honoraria for lectures and travel support from Berlin-Chemie Menarini Group, and honoraria for lectures from Orion, outside the submitted work. Conflict of interest: M. Barrecheguren reports speaker fees from Menarini, Grifols, CSL Behring, Boehringer Ingelheim, Gebro Pharma and GlaxoSmithKline, and consulting fees from Novartis and GlaxoSmithKline, outside the submitted work. Conflict of interest: R. Bals reports grants and personal fees from AstraZeneca and Boehringer Ingelheim, personal fees from GlaxoSmithKline and Grifols, grants and personal fees from Novartis, personal fees from CSL Behring, grants from the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), Sander Stiftung, Schwiete Stiftung, Krebshilfe and Mukoviszidose e.V., outside the submitted work. Conflict of interest: J. Chlumsky reports personal fees for lectures and consultation from CSL Behring, and travel support from CSL Behring, outside the submitted work. Conflict of interest: J. Chorostowska-Wynimko reports grants, personal fees and nonfinancial support from Grifols, personal fees from Kamada, grants, personal fees and nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Pfizer, MSD and BMS, personal fees from GSK, Novartis amd Chiesi, personal fees and nonfinancial support from Roche, grants and personal fees from Boehringer Ingelheim, personal fees and nonfinancial support from Abbvie, grants, personal fees and nonfinancial support from CSL Behring, personal fees from Lekam, grants, personal fees and nonfinancial support from CelonPharma, and personal fees from Takeda, outside the submitted work. Conflict of interest: C. Clarenbach reports consulting fees and travel support from Vifor Pharma, and consulting or speaker fees from Boehringer, Novartis, GSK, AstraZeneca and Sanofi, outside the submitted work. Conflict of interest: L. Corda has nothing to disclose. Conflict of interest: A.G. Corsico has nothing to disclose. Conflict of interest: I. Ferrarotti has nothing to disclose. Conflict of interest: C. Esquinas has nothing to disclose. Conflict of interest: C. Gouder has nothing to disclose. Conflict of interest: A. Hećimović reports speaker fees from Roche, Boehringer Ingelheim, Novartis and MSD, outside the submitted work. Conflict of interest: A. Ilic has nothing to disclose. Conflict of interest: Y. Ivanov has nothing to disclose. Conflict of interest: S. Janciauskiene has nothing to disclose. Conflict of interest: W. Janssens reports receiving research grants and money for consultancy activities from Behring, AstraZeneca, Boerhinger Ingelheim, GSK, Chiesi, outside the submitted work. He is co-founder of ArtiQ, a spinoff company in healthcare. Conflict of interest: M. Kohler reports advisor fees from Novartis, Boehringer Ingelheim, AstraZeneca, GSK and Bayer, outside the submitted work. Conflict of interest: A. Krams reports personal fees and nonfinancial support from AstraZeneca, Berlin-Chemie/Menarini and Boehringer Ingelheim, personal fees from GlaxoSmithKline and Merck Serono, personal fees and nonfinancial support from Norameda (represents Chiesi in Baltic countries), personal fees from Novartis, and nonfinancial support from Mylan, outside the submitted work. Conflict of interest: B. Lara has nothing to disclose. Conflict of interest: R. Mahadeva reports personal fees from Chiesi, Astra Zeneca and Boehringer Ingelheim, and grants from Pfizer Open Air, outside the submitted work. Conflict of interest: G. McElvaney has sat on advisory boards for CSL Behring, Grifols, Vertex and Chiesi. Conflict of interest: J-F. Mornex reports nonfinancial support from ADAAT, grants, personal fees and nonfinancial support from LFB and CSL Behring, nonfinancial support from Grifols, personal fees and nonfinancial support from Polyphor, during the conduct of the study; personal fees and nonfinancial support from Actelion, GSK, Roche and Novartis, nonfinancial support from Bayer, personal fees and nonfinancial support from BMS, nonfinancial support from Pfizer and MSD, personal fees from Ellivie, and nonfinancial support from Boehringer, outside the submitted work. Conflict of interest: K. O'Hara reports nonfinancial support from ELF/ERS and Mereo BioPharma Group PLC, grants from CSL Behring, and also receives donations from individuals/companies as a result of fundraising activities; personal fees and nonfinancial support from NICE and nonfinancial support from Alpha-1 Global, outside the submitted work. Conflict of interest: D. Parr reports advisory board and consultancy fees from CSL Behring and Kamada, outside the submitted work. Conflict of interest: E. Piitulainen has nothing to disclose. Conflict of interest: K. Schmid-Scherzer has nothing to disclose. Conflict of interest: N. Seersholm has nothing to disclose. Conflict of interest: R.A. Stockley reports a grant for a small, investigator-lead project and personal fees for a trial steering board from CSL Behring; a lecture fee from GSK; advisory board fees from Vertex, inhbrix, Mereobiopharma and Novartis; and lecture fees from Grifols, during the conduct of the study. He acts in an advisory manner for several companies with an interest in α1-antitrypsin deficiency. Conflict of interest: J. Stolk has nothing to disclose. Conflict of interest: M. Sucena reports lecture fees and travel pay from Grifols and CSL Behring, outside the submitted work. Conflict of interest: H. Tanash has nothing to disclose. Conflict of interest: A. Turner reports grants and personal fees from CSL Behring; personal fees and nonfinancial support from Boehringer Ingelheim; nonfinancial support from GSK; grants, personal fees and nonfinancial support from AstraZeneca; grants, personal fees and nonfinancial support from Chiesi; grants from Grifols biotherapeutics, outside the submitted work. Conflict of interest: R. Ulmeanu has nothing to disclose. Conflict of interest: M. Wilkens reports that as chairman of the patient organisation Alpha1 Deutschland e.V., he does not receive personally any donations but his organisation receives money from public funds as well as from the pharmaceutical industry, including grants and travelling costs. Conflict of interest: A. Yorgancıoğlu reports grants from MSD, and personal fees from GSK, AstraZeneca, Abdi Ibrahim, Chiesi, Novartis and Sandoz, outside the submitted work. Conflict of interest: A. Zaharie has nothing to disclose. Conflict of interest: M. Miravitlles reports speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, AstraZeneca, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols, and research grants to his institution from GlaxoSmithKline and Grifols, outside the submitted work., (Copyright ©ERS 2020.)

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed.Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40-211 days) for AAT and 140 days (IQR 72-142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% versus 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group.We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes., Competing Interests: Conflict of interest: J. Stolk reports personal fees for consultancy from Kamada Ltd, during the conduct of the study, and grants from CSL Behring, outside the submitted work. Conflict of interest: N. Tov reports personal fees for consultancy from Kamada Ltd, during the conduct of the study, and is an employee of Kamada Ltd, outside the submitted work. Conflict of interest: K.R. Chapman reports personal fees for consultancy from Kamada Ltd, during the conduct of the study, and grants from CSL Behring and Grifols, outside the submitted work. Conflict of interest: P. Fernandez reports consultancy fees from Kamada Ltd, during the planning, design, conduct and reporting of the study. Conflict of interest: W. MacNee reports patient recruitment fees from Kamada Ltd, during the conduct of the study; and grants and personal fees from Pfizer and GlaxoSmithKline, and personal fees from Boehringer Ingelheim, AstraZeneca, Novartis, Zambon and Chiesi, outside the submitted work. Conflict of interest: N.S. Hopkinson has nothing to disclose. Conflict of interest: E. Piitulainen has nothing to disclose. Conflict of interest: N. Seersholm has nothing to disclose. Conflict of interest: C.F. Vogelmeier reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols and Novartis, and personal fees from CSL Behring, Chiesi, Menarini, Mundipharma, Teva and Cipla, outside the submitted work. Conflict of interest: R. Bals reports grants from Kamada Ltd, during the conduct of the study; and grants from BMBF, DFG, Schwiete Stiftung, Sander-Stiftung and Boehringer Ingelheim, and personal fees for advisory board work and travel to meetings from GlaxoSmithKline, CSL Behring, Boehringer Ingelheim, Grifols, AstraZeneca and Novartis, outside the submitted work. Conflict of interest: G. McElvaney reports personal fees for advisory board work from CSL Behring, grants and personal fees for advisory board work from Grifols, and grants from Chiesi, outside the submitted work. Conflict of interest: R.A. Stockley reports personal fees for advisory board membership from Kamada Ltd, during the conduct of the study; personal fees for advisory board membership and lectures from AstraZeneca, personal fees for advisory board membership from Medimmune, Almirall, Baxter, Chiesi and Polyphor, personal fees for lectures from Nycomed and Takeda, and personal fees for advisory board membership, lectures and travel to meetings from Boehringer Ingelheim and CSL Behring, outside the submitted work., (Copyright ©ERS 2019.)

Monitoring of tuberculosis (TB) treatment outcome is essential to ensure an effective TB control program. In this nationwide retrospective cohort study from Denmark we present TB treatment outcome rates and risk factors associated with an unfavourable outcome. All patients notified with pulmonary TB from 2009 through 2014 were included. Logistic regression analyses were used to identify risk factors for unfavourable outcome. In total, 1681 pulmonary TB cases were included. TB treatment success rates increased during the study period. In 2014, the treatment success rate reached 85% for new culture positive cases whereas 7% cases interrupted treatment. The mortality decreased during the study period from 12.3% to 4.1%. Several risk factors associated with unfavourable outcome were identified in a multivariable model: male (OR: 2.56), Greenlandic origin (OR: 1.80), abuse of alcohol (OR: 2.90), history of mental disorder (OR: 2.46), and anaemia at time of treatment initiation (OR: 1.92). In a TB low incidence setting such as the Danish, it is important to maintain focus on preventing an unfavourable TB outcome. Patient management and treatment can be optimized by taking into consideration risk factors such as those identified in the present study.

Background: Gelsolin is an actin-scavenger controlling the tissue damage from actin in the blood. Gelsolin levels in circulation drops when tissue damage and corresponding actin release is pronounced due to catabolic conditions. The purpose of this study was to determine if low plasma gelsolin independently predicts a reduced chance of weaning from ventilator-demanding respiratory failure in critically ill patients within 28 days from admission., Results: This cohort study included 746 critically ill patients with ventilator-demanding respiratory failure from the randomized clinical trial, "Procalcitonin And Survival Study (PASS)." Primary end point was successful weaning from mechanical ventilation within 28 days. We used multivariable Cox regression adjusted for age, sepsis, PaO2/FiO2 ratio and other known and suspected predictors of persistent respiratory failure. Follow-up was complete.For medical patients, baseline-gelsolin below the 25th percentile independently predicted a 40% lower chance of successful weaning within 28 days (HR 0.60, 95% CI 0.46-0.79, P = 0.0002); among surgical patients this end point was not predicted. Low gelsolin levels predicted chance of being "alive and out of intensive care at day 14" for both medical and surgical patients (HR 0.69, 95% CI 0.54-0.89, P = 0.004). Gelsolin levels did not predict 28 day mortality for surgical or medical patients., Conclusions: Low levels of serum gelsolin independently predict a decreased chance of successful weaning from ventilator within 28 days among medical intensive care patients. This finding has implications for identifying patients who need individualized intervention early in intensive care course to prevent unfavorable lung prognosis in acute respiratory failure., Trial Registration: This is a substudy to the PASS, Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.

Introduction: A large group of patients with chronic obstructive pulmonary disease (COPD) are exposed to an overload of oral corticosteroids (OCS) due to repeated exacerbations. This is associated with potential serious adverse effects. Therefore, we evaluated the impact of a recommended reduction of OCS duration in 2014 on the risk of pneumonia hospitalisation and all-cause mortality in patients with acute exacerbation of COPD (AECOPD)., Methods: This was a nationwide observational cohort study that was based on linked administrative registry data between 1 January 2010 and 31 October 2017. 10 152 outpatients with COPD (median age 70 years) treated with either a short (≤250 mg) or long course (>250 mg) of OCS for AECOPD were included in the study. Cox proportional hazards regression models were used to derive an estimation of multivariable adjusted HRs (aHRs) for pneumonia hospitalisation or all-cause mortality combined and pneumonia hospitalisation and all-cause mortality, separately., Results: The long course of OCS treatment for AECOPD was associated with an increased 1-year risk of pneumonia hospitalisation or all-cause mortality (aHR 1.3, 95% CI 1.1 to 1.4; p<0.0001), pneumonia hospitalisation (aHR 1.2, 95% CI 1.0 to 1.3; p=0.0110) and all-cause mortality (aHR 1.8, 95% CI 1.5 to 2.2; p<0.0001) as compared with the short course of OCS treatment. These results were confirmed in several sensitivity analyses., Conclusion: The change of recommendations from long courses to short courses of OCS for AECOPD in 2014 was strongly associated with a decrease in pneumonia admissions and all-cause mortality, in favour of short courses of OCS., Competing Interests: Competing interests: JV reports personal fees from GlaxoSmithKline, personal fees from Chiesi Pharmaceuticals, personal fees from Boehringer-Ingelheim, personal fees from Novartis, personal fees from AstraZeneca, outside the submitted work. TSI reports personal fees from AstraZeneca, outside the submitted work.

Background: Chest x-ray is central in screening and diagnosis of tuberculosis. However, sputum culture remains gold standard for diagnosis., Aim: To establish the rate of normal chest x-rays in tuberculosis patients found by spot sputum culture screening, and compare them to a group identified through passive case finding., Method: Chest x-rays from 39 culture-positive patients, identified by spot sputum culture screening in Copenhagen from 2012 to 2014, were included in the study (spot sputum culture group(SSC)). 39 normal chest x-rays from persons screened by mobile x-ray, and 39 chest x-rays from tuberculosis-patients identified through passive case finding(PCF) were anonymised and randomised. Two respiratory physicians and two radiologists assessed the chest x-rays., Results: The normal chest x-ray rate was higher in the non-tuberculosis control group (median = 32 (82.1%), range = 74.4% - 100%), compared to the SSC group (median = 7 (17.9%), range = 10.3% - 33.3%), and the PCF controls (median = 3(7.7%), range = 2.6% - 15.4%). In the SSC group 14 (35.9%) were categorized as normal by at least one study participant., Conclusion: A substantial minority of patients diagnosed with tuberculosis by spot sputum culture screening, and through passive case finding would not have been identified with chest x-ray alone, highlighting that a normal chest x-ray does not exclude pulmonary tuberculosis., (© 2019 The Authors. Published by Elsevier Ltd.)

Background: The most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects. Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, the aim of this study is to determine whether it is possible to reduce the use of systemic corticosteroids in AECOPD without influencing the outcome., Methods: This is an ongoing prospective multicenter randomized controlled open label trial comprising 320 patients with AECOPD recruited from four hospitals in Denmark. The patients are randomized 1:1 to either standard care or eosinophil-guided corticosteroid-sparing therapy where prednisolone is not administered if the daily blood sampling reveals an eosinophil level below 0.3 × 10 9 cells/L. The primary endpoint is length of hospital stay within 14 days after recruitment. The secondary endpoints are treatment failure, 30-day mortality rate, COPD related re-admission rate, change in FEV 1 , and a number of adverse effect measures obtained within 3 months after the index hospitalisation date related to corticosteroid usage., Discussion: This will be a very large RCT providing knowledge about the effectiveness of individualized biomarker-guided corticosteroid therapy in hospitalised patients with AECOPD., Trial Registration: Clinicaltrials.gov, NCT02857842 , 02-august-2016. Clinicaltrialregister.eu: Classification Code: 10,010,953, 02-marts-2016.

Rationale: As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening., Objectives: Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening., Methods: A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group)., Measurements and Main Results: Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group., Conclusions: No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).