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Bronchoscopic lung volume reduction treatment with Zephyr one-way valves is an effective guideline-based treatment option for patients with severe emphysema and hyperinflation. However, in some cases the treatment response is less than anticipated or there might be a loss of initial treatment effect. Reasons for the lack of response can include incorrect assessment of collateral ventilation, improper valve placement, or patient related factors. Loss of initial benefit can be due to granulation tissue formation and subsequent valve dysfunction, or there may be side effects such as excessive coughing or infectious problems. Careful follow-up after treatment with valves is important and evaluation with a CT scan and/or bronchoscopy is helpful if there is no improvement after treatment or loss of initial benefit. This paper aims to describe the most important causes and provide a strategy of how to approach and manage these patients., Competing Interests: Declaration of competing interest PS declares consulting fees and educational fees. AV declares educational fees. GJC declares grants/contract, consulting fees, educational fees and participation on a DSMB. FJFH declares educational and consulting fees. DKH declares consulting fees and educational fees. AM declares consulting fees and educational fees. AC declares consulting fees and educational fees. MD declares consulting fees and support for attending meetings by GSK. JK declares consulting fees and educational fees. NS is a full-time employee of Pulmonx Corporation and declares stock options. DJS declares grants/contracts, consulting fees, educational fees and support for attending meetings. MP declares grants, consulting fees, educational fees, support for attending meetings and leadership or fiduciary roles. Regarding the consensus opinion meeting: PS, FJFH, RS, DH, RM, AM, RA, LK, AC, JK, DJS, and MP received travel and accommodation support and honoraria from Pulmonx. AV received an honorarium from Pulmonx. DEW, MD, GJC and TDK have no conflict., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, respiratory symptoms, inflammation of the airways, and systemic manifestations of the disease. Genetic susceptibility and environmental factors are important in the development of the disease, particularly exposure to cigarette smoke which is the most notable risk factor. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are the cause of cystic fibrosis (CF), which shares several pathophysiological pulmonary features with COPD, including airway obstruction, chronic airway inflammation and bacterial colonization; in addition, both diseases also present systemic defects leading to comorbidities such as pancreatic, gastrointestinal, and bone-related diseases. In patients with COPD, systemic CFTR dysfunction can be acquired by cigarette smoking, inflammation, and infection. This dysfunction is, on average, about half of that found in CF. Herein we review the literature focusing on acquired CFTR dysfunction and the potential role in the pathogenesis of comorbidities associated with COPD and chronic bronchitis., Competing Interests: Declaration of competing interest In the past 36 months, M. Miravitlles has received consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, CSL Behring, Inhibrx, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi and Grifols, speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, Cipla, Janssen, Kamada, Menarini, Takeda, Speciality Therapeutics, Zambon, CSL Behring, Grifols and Novartis, support for attending meetings/travel from Novartis, Boehringer Ingelheim and Menarini, research grants from Grifols, and has participated on a data safety monitoring board for Mereo. G.J. Criner has no declarations. M.A. Mall declares editorial support from Novartis Pharma AG since the initial planning of the work, and declares grants from German Ministry for Education and Research and the German Research Foundation, consulting fees from Abbvie, Antabio, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pieris Pharmaceuticals, Santhera, Sterna Biologicals and Vertex Paharmaceuticals, lecture fees from Arrowhead Pharmaceuticals, Boehringer Ingelheim and Vertex Pharmaceuticals, travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals, and personal fees for participation on advisory boards from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Pari and Abbvie; an elected unpaid member of the ECFS board. S.M. Rowe declares grant support for clinical trials conducted through university grants/contracts from Novartis, TranslateBio, Galapagos/Abbvie, Vertex Pharmaceuticals, research grant through University grants/contracts from Synedgen/Synspira, Eloxx, Ionis and AstraZeneca, consulting fees services on the design and conduct of clinical trials from Arcturus, Cystetic Medicines, Galapagos/Abbvie, Ionis, Novartis, Renovion, Synedgen/Synspira, Vertex Pharmaceuticals, support for travel to attend meetings from Vertex Pharmaceuticals; co-chair of the Next Generation Steering Committee with Vertex Pharmaceuticals, research product for investigator initiated research provided from Synedgen/Synspira and Renovion, consulting services on the design and conduct of clinical trials including stock options for Synedgen/Synspira and Renovion within the past 36 months; MTAs for investigator-initiated and externally funded research efforts from Ionis, Galapagos/Abbvie and Synedgen/Synspira, all in the past 36 months; and declares six patents. C.F. Vogelmeier declares institution grants from German Ministry of Education and Science (BMBF), AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Grifols and Novartis, consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini, Novartis and Nuvaira, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini and Novartis, in the past 36 months. B. Hederer was an employee of Novartis Pharma AG at the timing of writing this manuscript. M. Schoenberger is a full-time employee of Novartis Pharma AG and retains Novartis stock. P. Altman was an employee of Novartis Pharmaceutical Corporation at time of writing this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Most patients with chronic obstructive pulmonary disease (COPD) have at least one additional, clinically relevant chronic disease. Those with the most severe airflow obstruction will die from respiratory failure, but most patients with COPD die from non-respiratory disorders, particularly cardiovascular diseases and cancer. As many chronic diseases have shared risk factors (eg, ageing, smoking, pollution, inactivity, and poverty), we argue that a shift from the current paradigm in which COPD is considered as a single disease with comorbidities, to one in which COPD is considered as part of a multimorbid state-with co-occurring diseases potentially sharing pathobiological mechanisms-is needed to advance disease prevention, diagnosis, and management. The term syndemics is used to describe the co-occurrence of diseases with shared mechanisms and risk factors, a novel concept that we propose helps to explain the clustering of certain morbidities in patients diagnosed with COPD. A syndemics approach to understanding COPD could have important clinical implications, in which the complex disease presentations in these patients are addressed through proactive diagnosis, assessment of severity, and integrated management of the COPD multimorbid state, with a patient-centred rather than a single-disease approach., Competing Interests: Declaration of interests LMF declares consulting fees from Chiesi Farmaceutici; payment or honoraria for lectures, presentations, manuscript writing, or educational events from Novartis, Chiesi Farmaceutici, Chiesi Italia, GSK, AstraZeneca, and Alfasigma; and participation on a data safety monitoring board (DSMB) for Novartis and Chiesi, all outside of the submitted work. LMF was formerly a member of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). BRC declares consultancy fees from GSK, AstraZeneca, Menarini, Sanofi Aventis, and Axios; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Menarini, Chiesi, and Regeneron; support for attending meetings or travel from GSK and Sanofi Aventis; and participation on a DSMB or advisory board for GSK, AstraZeneca, AZ Therapeutics, Sanofi Aventis, and Vertex, all outside of the submitted work. BRC is a member of GOLD. AA declares grants for research projects from GSK, AstraZeneca, and Menarini; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Chiesi, Menarini, CIPLA, Zambon, and Sanofi Regeneron, all outside of the submitted work. AA holds the Chair of the Board of Directors of GOLD. GJC is member of GOLD. MTD declares grants paid to his institution from the US Department of Defense, American Lung Association, and National Institutes of Health; royalties from UpToDate; consulting fees from AstraZeneca, GSK, Novartis, Pulmonx, and Teva; and an unpaid role on the Board of Directors of the COPD Foundation, all outside of the submitted work. MD declares consulting fees from Sanofi Regeneron, outside of the submitted work. JKK declares grants paid to her institution from the American Thoracic Society Fellowship in Health Equity, Research Assistance for Primary Parents Award, COMMUNITY Center Investigator Development Core, Weill Cornell Medicine Dean's Diversity and Healthcare Disparity Research Award, and the National Institutes of Health (T32 HL134629); medical writing support from Novartis; medication samples delivered to her institution by Boehringer Ingelheim and GSK; and a donor gift to her institution from the Donna Redel Research Fund, all outside of the submitted work. LL declares fees to her institution from AstraZeneca for expert consultation, Chiesi for a lecture, and IPSA vzw, for lectures, outside of the submitted work. MM declares honoraria for lectures on COPD from AstraZeneca and GSK, outside of the submitted work. MMdO is a member of GOLD. SSS declares payments to his institution from Cipla for lectures, presentations, speakers bureaus, manuscript writing, or educational events. SSS has an unpaid leadership or fiduciary role with the Indian Chest Society, outside of the submitted work, and is a member of GOLD. DS declares grants to her institution from Curetis and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi; and participation on a DSMB or advisory board for CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi, all outside of the submitted work. LEGWV declares research grants to his institution from The Family Kamprad Foundation (20190024), the Swedish government and country council (ALF grant ALFGBG-824371), The Swedish Heart and Lung Foundation (20200150), and Svensk Lungmedicinsk Förening; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Boehringer, Novartis, Chiesi, Resmed, and Pulmonx, all outside of the submitted work. CFV declares grants to his institution from the German Ministry of Education and Science, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Grifols, and Novartis; consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, and Nuvaira; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, Roche, and Sanofi, all outside the submitted work. CFV holds the Chair of the Science Committee of GOLD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: We hypothesized that outcomes after 2 staged, contralateral single lung transplantation procedures (SSLTs) may be equivalent to those of double lung transplantation (DLT) by capitalizing on the known long-term survival advantages of DLT., Methods: Using the United Network for Organ Sharing data set (1987-2018), the largest national data set available, the outcomes of 278 SSLTs were retrospectively analyzed and compared with the outcomes of 21,121 standard DLTs., Results: During SSLT, the median interval between the 2 transplants was 960 days, and the indication for the second transplant was most often chronic lung allograft dysfunction (n = 148; 53.2%) or the same disease that necessitated the first transplant (n = 81; 29.1%). The patients who underwent SSLT were significantly older and had a higher baseline creatinine level than the patients who underwent DLT. Most posttransplantation short-term outcomes were equivalent between the second stage of SSLT and DLT, but renal insufficiency requiring hemodialysis was notably higher after SSLT. There were no differences in long-term survival. In multivariate analysis, baseline creatinine, O 2 support at rest, ventilator support at the time of the second transplantation, and posttransplantation renal insufficiency requiring dialysis were independent predictors of 1-year mortality after SSLT., Conclusions: Over a study period of 30 years, long-term survival after SSLT was comparable with survival after DLT. With further analysis of individual risk profiles, including the contributions of preoperative renal function and functional status, SSLT can be a valuable option for patients who would have undergone single lung transplantation to reap the long-term benefits of a second transplant., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features., Research Question: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?, Study Design and Methods: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV 1 (FEV 1 -BDR), change in FVC (FVC-BDR), and change in in FEV 1 , FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV 1 % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV 1 decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD)., Results: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV 1 -BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV 1 decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group., Interpretation: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease., (Published by Elsevier Inc.)

Background: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status., Methods: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed., Results: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers., Conclusions: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers., Clinical Trial Registration: GSK (CTT116855/NCT02164513)., Competing Interests: Declaration of competing interest DM and DAL are GSK employees and hold GSK stocks/shares. SB is a former GSK employee and holds GSK stocks/shares. GJC has received personal fees from Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Broncus Medical, Chiesi, CSA Medical, Eolo, Gala Therapeutics, GSK, Helios Medical, HGE Technologies, Merck, Medtronic, Mereo BioPharma, NGM Biopharmaceuticals, Novartis, Nuvaira, Olympus, Philips, Pulmonx, Respironics, Respivant Sciences, The Implementation Group and Verona. DMGH has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer and Sanofi, and non-financial support from Boehringer Ingelheim and GSK. MKH reports personal fees from Medscape and Integrity, as well as consulting fees from GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, Altesa Biopharma and United Therapeutics. She has received royalties from UpToDate, WW Norton and Penguin Random House. She has received payment or honoraria for consultancy from Cipla, Chiesi, AstraZeneca, Boehringer Ingelheim, GSK, Medscape and Integrity. She has served roles on boards or scientific committees for COPD foundation, ALA, Emerson School and GOLD, and has been a volunteer spokesperson for ALA and deputy editor of the ATS journal. She has received either in-kind research support or funds paid to the institution from the NIH, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation and the American Lung Association. She has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to the institution. She holds stock options from Meissa Vaccines and Altesa Biopharma. NAH is the Editor-in-Chief for Respiratory Medicine and was an investigator on the IMPACT study. He reports receiving personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Sanofi Genzyme, Novartis, Regeneron, Genentech, Sunovion, and Mylan for serving as an advisor or consultant. He also received research support from GSK, Boehringer Ingelheim and AstraZeneca. DH has received personal fees from GSK, Boehringer Ingelheim, AstraZeneca, Mylan, Novartis, and Sunovion. Research support from GSK, Boehringer Ingelheim and Mylan. He is a National Board of Directors member for the American Lung Association. PL has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi and GSK. FJM has received consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Gala, GSK, Novartis, Polarean, Pulmonx, Sanofi/Regeneron, Sunovion, Teva, Theravance/Viatris and Verona; grant support from AstraZeneca, Chiesi, GSK and Sanofi/Regeneron; payment or honoraria from UpToDate for participation in COPD CME activities; and participated in an event adjudication committee for MedTronic. FJM states that AstraZeneca, Boehringer Ingelheim and GSK are partners of the SPIROMICS program and partners in the NHLBI CAPTURE validation study; Novartis, Sanofi/Regeneron, Sunovion and Teva are partners of the SPIROMICS program; Theravance/Viatris are partners in the NHLBI CAPTURE validation study. TMS has received research grants from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, Compleware, Evidera (PPD), Forest Research Institute (now AstraZeneca), GSK, Novartis, Pearl Therapeutics, Proterix BioPharma, Oncocyte, Sanofi, Seer, Sunovion, Teva, Theravance BioPharma, Vapotherm, Verona Pharma, Restorbio and Westward, and personal fees from GSK, Sunovion, Theravance Biopharma and Vapotherm. DS has received consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GSK, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, and Verona. RAW has received personal fees from AstraZeneca, Boehringer Ingelheim, Contrafect, Roche-Genentech, Bristol Myers Squibb, Merck, Verona, Theravance, AbbVie, GSK, Chemerx, Kiniksa, Savara, Galderma, Kamada, Pulmonx, Kinevant, Vaxart, Polarean, Chiesi, 4D Pharma, Puretech, and grant support from AstraZeneca, Sanofi, Verona, Genentech, Boehringer Ingelheim and 4DX imaging. He has received payment for expert testimony from the United States Government and Genentech; and support for attending meetings and/or travel from AstraZeneca. Additionally, he has received editorial support from GSK, AstraZeneca, Boehringer Ingelheim and Merck Foundation; and has served on the Board of Directors/Medical and Scientific Advisory Committee for the COPD Foundation, and on a Scientific Advisory Board for the American Lung Association. RNvZS was an investigator on the IMPACT study and reports receiving personal fees from Aspen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GSK, MSD, Pfizer, Sanofi, Novartis and Roche. NB was an investigator on the IMPACT study and reports receiving consulting fees and serving as a participant in advisory boards for Kamada, AstraZeneca, Boehringer Ingelheim, GSK, Sanofi Genzyme and Novartis, as well as serving as a participant in advisory boards for Teva. He has also received lecture fees for Kamada, AstraZeneca, Boehringer Ingelheim, GSK and Sanofi Genzyme., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Unlike in other chronic lung diseases, criteria for lung transplant referral in sarcoidosis is not well-established. Waitlist mortality may offer clues in identifying clinical factors that warrant early referral. We aim to identify predictors for transplant waitlist mortality to improve referral criteria for patients with sarcoidosis., Methods: We conducted a retrospective analysis of 1034 sarcoidosis patients listed for lung transplantation from May 2005 to May 2019 in the Scientific Registry of Transplant Recipients (SRTR) database. All patients were listed after the establishment of the Lung Allocation Score (LAS). We compared patients who died on the transplant waitlist to those who survived to transplantation. Potential predictors of waitlist mortality were assessed utilizing univariate and multivariate analysis performed via logistic regression modeling., Results: Of 1034 candidates listed after LAS implementation, 704 were transplanted and 110 died on the waitlist. Significant predictors of waitlist mortality on multivariate analysis include female gender (OR 2.445; 95% CI 1.513-3.951; p = 0.0003) and severe pulmonary hypertension (OR 1.619; 95% CI 1.067-2.457; p = 0.0236). Taller minimum donor height (OR 0.606; 95% CI 0.379-0.969; p = 0.0365) and blood type B (OR 0.524; 95% CI 0.281-0.975 p = 0.0415) were associated with decreased likelihood of death on the waitlist., Conclusion: Among patients with sarcoidosis on the lung transplant waitlist, taller minimum donor height and blood type B were found to be protective factors against death on the waitlist. Female gender and severe pulmonary hypertension have a higher likelihood of death and earlier referral for transplantation in patients with these characteristics should be considered., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease with high mortality. Lung transplant remains a cornerstone of treatment despite the advent of antifibrotic therapy. In light of the increasing number of patients on antifibrotic therapy prior to lung transplantation it is paramount to demonstrate these medications do not augment postoperative complications following transplant., Research Question: Does antifibrotic therapy increase perioperative complications and mortality in lung transplant recipients?, Study Design and Methods: We conducted a retrospective chart review of all patients actively listed for lung transplant at Temple University Hospital from June 2014 to April 2017 with a listing diagnosis of IPF. Subjects who received treatment with antifibrotic therapy (either pirfenidone or nintedanib) up until the time of lung transplantation were compared to subjects not on therapy. Data was collected regarding baseline demographics, pulmonary function tests, IPF exacerbations, perioperative bleeding and cardiac events, and outcomes in the postoperative period., Results: A total of 94 subjects were included in the study: 42 subjects on antifibrotic therapy (28 pirfenidone, 14 nintedanib) and 52 subjects not on therapy in the pre-transplant period. Baseline characteristics were similar between study groups. Subjects treated with antifibrotic therapy pre-transplant were noted to have less FVC decline, fewer hospitalizations, and greater weight loss while on the transplant waiting list. No difference in post-transplant airway anastomosis complications, bleeding or mortality was observed between study groups., Interpretation: Subjects with IPF on antifibrotic therapy prior to lung transplantation had better preservation of lung function in the pre-transplant period, and similar outcomes in the postoperative period compared to those not on antifibrotic therapy before lung transplant., (Copyright © 2021. Published by Elsevier Ltd.)

This document summarizes the work of the COPD Technical Expert Panel working group. For patients with COPD, the most pressing current coverage barriers identified were onerous diagnostic requirements focused on oxygenation (rather than ventilation) and difficulty obtaining bilevel devices with backup rate capabilities. Because of these difficulties, many patients with COPD were instead sometimes prescribed home mechanical ventilators. Critical evidence supports changes to current policies, including randomized controlled trial evidence suggesting a mortality benefit from bilevel positive airway pressure with backup rate and updated clinical practice guidelines from the American Thoracic Society as well as the European Respiratory Society. To achieve optimal access to noninvasive ventilation for patients with COPD, we make the following key recommendations: (1) removal of the need for overnight oximetry testing; (2) the ability to initiate therapy using bilevel devices with backup rate capability; and (3) increased duration of time to meet adherence criteria (ie, a second 90-day trial period) in those patients actively engaged in their care. Clear guidelines based on medical necessity are also included for patients who require initiation of or switch to a home mechanical ventilator. Adoption of these proposed recommendations would result in the right device, for the right type of patient with COPD, at the right time. Finally, we emphasize the need for adequate clinical support during initiation and maintenance of home noninvasive ventilation in such patients., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Acute exacerbations negatively impact quality of life in patients with chronic obstructive pulmonary disease (COPD), but the impact of hospitalized exacerbations on quality of life is not clear. We hypothesized that patients with hospitalized exacerbations would benefit from hospitalization and experience improvement in general and disease-specific quality of life (as measured by the St. George's respiratory questionnaire (SGRQ) and the medical outcomes study 36-item short form health survey (SF-36)) compared to those without exacerbations, or with non-hospitalized acute exacerbations., Methods: 1219 COPD patients enrolled in either the simvastatin for the prevention of exacerbations in moderate-to severe COPD Trial (STATCOPE) or azithromycin for prevention of exacerbations of COPD trial (MACRO) were analyzed. Demographic information, spirometry, and symptom scores were noted at baseline. Exacerbation events and changes in quality of life scores were assessed over a mean of 538 days of follow-up., Results: Of patients studied, 25.6% were hospitalized, 44.0% had at least one outpatient exacerbation, and 30.4% had no exacerbation. Baseline SGRQ and SF-36 scores were severely impaired in all groups studied. Over time, SF-36 scores did not change significantly between groups. SGRQ symptom domain scores improved in other groups but did not improve in those hospitalized for a COPD exacerbation., Conclusions: At baseline, patients hospitalized for acute exacerbations of COPD had more impaired quality of life scores. Over time, SGRQ symptom domain scores improved in other groups but did not in those who were hospitalized. Other measurements of quality of life were not improved by hospitalization for COPD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Statins are widely used to lower lipids and reduce cardiovascular events. In vitro studies and small studies in patients with hyperlipidemias show statins inhibit tissue factor (TF) and blood coagulation mechanisms. We assessed the effects of simvastatin on TF and coagulation biomarkers in patients entered in STATCOPE, a multicenter, randomized, placebo-controlled trial of simvastatin (40 mg daily) versus placebo on exacerbation rates in patients with chronic obstructive pulmonary disease (COPD)., Methods: In 227 patients (114 simvastatin, 113 placebo; mean [± standard error of the mean] age 62 ± 0.53 years, 44.5% women) we measured (baseline, and 6 and 12 months): whole blood membrane TF-procoagulant activity (TF-PCA) and plasma factors VIIa, VII, VIII, fibrinogen, TF antigen, tissue factor pathway inhibitor (TFPI), thrombin-antithrombin complexes (TAT), and D-dimer. We excluded patients with diabetes, cardiovascular disease, and those taking or requiring a statin., Results: In the statin group, there was a small increase in TF-PCA (from 25.18 ± 1.08 to 30.36 ± 1.10 U/ml; p = .03) over 12 months; factors VIIa and VIII, fibrinogen, TAT, and D-dimer did not change. Plasma TFPI (from 52.4 ± 1.75 to 44.7 ± 1.78 ng/ml; p < .0001) and FVIIC (1.23 ± 0.04 to 1.15 ± 0.03 U/ml; p = .03) decreased and correlated with total cholesterol levels. No changes in biomarkers were observed with placebo., Conclusions: In contrast to previous studies on statins, in COPD patients without diabetes, cardiovascular disease, or requiring a statin treatment, simvastatin (40 mg per day) did not decrease TF or factors VIIa and VIII, fibrinogen, TAT, or D-dimer. The decreases in TFPI and factor VII reflect the decrease in serum lipids., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: In the Informing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler triple-therapy fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) reduced moderate/severe exacerbation rates vs FF/VI and UMEC/VI in patients with symptomatic COPD and a history of exacerbations, with a similar safety profile., Research Question: Are trial outcomes with single-inhaler triple-therapy FF/UMEC/VI vs FF/VI and UMEC/VI affected by age in patients with symptomatic COPD and a history of exacerbations?, Study Design and Methods: IMPACT was a phase III, double-blind, 52-week trial. Patients ≥ 40 years of age with symptomatic COPD and ≥ 1 moderate/severe exacerbation in the previous year were randomly assigned 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. End points assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough FEV 1 , proportion of St. George's Respiratory Questionnaire (SGRQ) responders (≥ 4 units decrease from baseline in SGRQ total score), and safety., Results: The intention-to-treat population comprised 10,355 patients; 4,724 (46%), 4,225 (41%), and 1,406 (14%) were ≤ 64, 65 to 74, and ≥ 75 years of age, respectively. FF/UMEC/VI reduced on-treatment moderate/severe exacerbation rates vs FF/VI (% reduction [95% CI]: ≤ 64 years, 8% [-1 to 16]; P = .070; 65-74 years, 22% [14-29]; P < .001; ≥ 75 years, 18% [3-31]; P = .021) and vs UMEC/VI (≤ 64 years, 16% [7-25]; P = .002; 65-74 years, 33% [25-41]; P < .001; ≥ 75 years, 24% [6-38]; P = .012), with greatest rate reduction seen in the 65 to 74 and ≥ 75 years subgroups. Post hoc analyses of CFB in trough FEV 1 and proportion of SGRQ responders at week 52 were significantly greater with FF/UMEC/VI than with FF/VI or UMEC/VI in all subgroups. No new safety signals were identified., Interpretation: FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status vs FF/VI and UMEC/VI irrespective of age for most end points, with a similar safety profile., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02164513; URL: www.clinicaltrials.govCTT116855., (Copyright © 2020. Published by Elsevier Inc.)

Coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality because of a lack of effective therapies. Therapeutic strategies under investigation target the overactive cytokine response with anti-cytokine or immunomodulators therapies. We present a unique case of severe cytokine storm resistant to multiple anti-cytokine therapies, but eventually responsive to etoposide. Thus, etoposide may have a role as salvage therapy in treatment of cytokine storm in COVID-19. To our knowledge, this is the first reported case of use of etoposide in COVID-19., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies., Research Question: What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)?, Study Design and Methods: Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis., Results: The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes., Interpretation: Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations., Research Question: To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD., Study Design and Methods: Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status., Results: The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001., Interpretation: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Black smokers have earlier development of lung disease as well as poorer sleep health than whites., Research Question: In a sample of black smokers, to what extent does sleep health modify the association between smoking level and functional exercise capacity?, Design and Methods: Cross-sectional data from 209 black smokers (≥ 1 cigarette in last month), aged 40 to 65 years with no evidence of sleep-disordered breathing (apnea-hypopnea index < 15) or severe COPD (FEV 1 > 50%), were used for the current study. Self-reported smoking rate, objectively measured sleep efficiency (SE), total sleep time (TST), and the 6-min walk test (6MWT) for functional exercise capacity were the key assessments., Results: The mean age was 54.8 years (SD, 5.96), and mean cigarettes smoked per day (cpd) was 8.71 (SD, 6.78). Mean SE was 69.9% (SD, 12.3%), and mean TST was 307.99 min (SD 92.2). In adjusted linear regression models of the 6MWT (meters), TST (slope estimate, -0.14; P = .14) and SE (slope estimate, -1.0; P = .19) were negatively associated with 6MWT. The smoking rate × SE interaction was highly significant (slope estimate, 0.18; P = .007) such that in individuals who smoked ≥ 10 cpd, every additional percentage of SE garnered an additional distance of 0.83 to 6.62 m. Similarly, the smoking rate × TST interaction was significant (slope estimate, 0.019; P = .03) such that in smokers who smoked ≥ 10 cpd, every additional minute of TST garnered an additional distance of 0.04 to 0.60 m., Interpretation: Higher SE and, to a lesser extent, longer TST, in black adults who smoke ≥ 10 cpd is associated with better 6MWT performance., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03534076; URL: www.clinicaltrials.gov., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear., Research Question: Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes?, Study Design and Methods: We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site., Results: The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66)., Interpretation: Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies., (Copyright © 2020 American College of Chest Physicians. All rights reserved.)

Background: The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations., Methods: Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient (< 20 ng/mL) vs not deficient (≥ 20 ng/mL). Outcomes of interest included % predicted FEV 1 (current and 1-year longitudinal decline) and COPD exacerbations (separately any and severe, occurring in prior year and first year of follow-up)., Results: Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV 1 (by 4.11%) at enrollment (95% CI, -6.90% to -1.34% predicted FEV 1 ; P = .004), 1.27% predicted greater rate of FEV 1 decline after 1 year (95% CI, -2.32% to -0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (-1.04% predicted; 95% CI, -1.96% to -0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04)., Conclusions: Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Benralizumab did not significantly reduce exacerbations compared with placebo in the phase 3 GALATHEA and TERRANOVA trials of benralizumab for patients with chronic obstructive pulmonary disease (COPD). We aimed to identify clinical and physiological characteristics of patients with COPD that could help to identify people who are likely to have the greatest treatment effect with benralizumab., Methods: We analysed individual study and pooled results from GALATHEA and TERRANOVA. At study enrolment, patients from GALATHEA and TERRANOVA were aged 40-85 years, had moderate to very severe airflow limitation, had elevated blood eosinophil counts, and at least two exacerbations or one severe exacerbation in the previous year despite dual inhaled therapy (inhaled corticosteroids plus long-acting β 2 -agonists or long-acting β 2 -agonists plus long-acting muscarinic antagonists) or triple inhaled therapy (inhaled corticosteroids plus long-acting β 2 -agonists plus long-acting muscarinic antagonists). We analysed data for 3910 patients who received benralizumab (30 mg or 100 mg subcutaneously every 8 weeks; first three doses every 4 weeks) or placebo with dual or triple therapy to identify factors consistently associated with annual exacerbation rate reduction. We evaluated the annual exacerbation rate for benralizumab versus placebo as the primary endpoint. GALATHEA and TERRANOVA are registered with ClinicalTrials.gov, NCT02138916 and NCT02155660, respectively., Findings: For 2665 patients with elevated blood eosinophil counts, treatment effect with benralizumab every 8 weeks at 100 mg, but not at 30 mg, occurred for patients with a history of more frequent exacerbations, poorer baseline lung function, or greater baseline lung function improvement with short-acting bronchodilators. Patients with baseline blood eosinophil counts of 220 cells per μL or greater with: three or more exacerbations in the previous year receiving benralizumab every 8 weeks versus placebo, had rate ratios (RRs) of 0·69 (95% CI 0·56-0·83) for 100 mg and 0·86 (0·71-1·04) for 30 mg; postbronchodilator FEV 1 of less than 40% had RRs of 0·76 (0·64-0·91) for 100 mg and 0·90 (0·76-1·06) for 30 mg; and postbronchodilator response of at least 15% had RRs of 0·67 (0·54-0·83) for 100 mg and 0·87 (0·71-1·07) for 30 mg. When combined factors were examined, patients with elevated baseline blood eosinophil counts, with three or more exacerbations in the previous year, and who were receiving triple therapy were identified as likely to benefit from benralizumab 100 mg every 8 weeks versus placebo (RR 0·70 [95% CI 0·56-0·88]). Benralizumab 30 mg every 8 weeks did not benefit patients meeting these criteria compared with placebo (RR 0·99 [95% CI 0·79-1·23])., Interpretation: Elevated blood eosinophil counts combined with clinical characteristics identified a subpopulation of patients with COPD who had reductions in exacerbations with benralizumab treatment. These hypothesis-generating analyses identified the potential efficacy of benralizumab 100 mg for this subpopulation. These findings require prospective evaluation in clinical trials., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale: Sarcoidosis progresses to end stage fibrotic lung disease in 10% of patients and may necessitate lung transplantation. Organ allocation is currently determined by the Lung Allocation Score (LAS), but its performance in a sarcoidosis population has not been evaluated., Objectives: To determine sarcoidosis-specific wait list mortality and identify predictive factors of death on the transplantation wait list., Methods: This was a single-center retrospective study of all sarcoidosis patients listed for lung transplant from March 2012 to February 2019. We compared patients who were transplanted to those who died awaiting organs. We collected baseline listing characteristics, physiologic testing, and outcomes data. Statistical analysis was performed by 2-tailed Student's t-test, Mann-Whitney U test, and Chi-Square analysis (where appropriate). Receiver-operating characteristic curves were constructed for variables reaching statistical significance., Results: Twenty eight sarcoidosis patients were included in analysis. Mortality among wait listed patients was 18%, which exceeded the mortality of COPD and IPF. LAS scores did not differ at initial listing (41 vs. 46, p = 0.35) or at transplant/death (41 vs. 41, p = 0.91); wait list times also did not statistically differ (307 days vs. 177 days, p = 0.19). We identified bilirubin (AUC = 0.92), DLCO (AUC = 0.84), FEV1/FVC at transplant/death (AUC = 0.85), and composite physiologic index (AUC = 0.86) as predictors of death on the transplant list. Pulmonary hypertension was not associated with death., Conclusion: Unexpected sudden death was common in our cohort and was associated with markers of advanced fibrotic disease, not pulmonary hypertension., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Chronic bronchitis (CB) increases risk of COPD exacerbations. We have shown that the St. George's Respiratory Questionnaire (SGRQ) CB definition identifies patients with a similar clinical phenotype as classically defined CB. Whether the SGRQ CB definition is a predictor of future COPD exacerbations is unknown., Methods: We analyzed 7,557 smokers with normal spirometry and Global Initiative for Chronic Obstructive Lung Disease stage 1-4 COPD in the Genetic Epidemiology of COPD study with longitudinal follow-up data on exacerbations. Subjects were divided into classic CB + or classic CB - , using the classic definition. In addition, subjects were divided into SGRQ CB + or SGRQ CB - . Exacerbation frequency and severe exacerbation frequency were determined in each group. Multivariable linear regressions were performed for exacerbation frequency with either classic CB or SGRQ CB and relevant covariates., Results: There were 1,434 classic CB + subjects and 2,290 SGRQ CB + subjects. The classic CB + group had a greater exacerbation frequency compared with the classic CB - group (0.69 ± 1.26 vs 0.36 ± 0.90 exacerbations per patient per year; P < .0001) and a greater severe exacerbation frequency (0.26 ± 0.74 vs 0.13 ± 0.46 severe exacerbations per patient per year; P < .0001). There were similar differences between the SGRQ CB + and SGRQ CB - groups. In multivariable analysis, both SGRQ CB and classic CB were independent predictors of exacerbation frequency, but SGRQ CB had a higher regression coefficient. In addition, SGRQ CB was an independent predictor of severe exacerbation frequency whereas classic CB was not., Conclusions: The SGRQ CB definition identified more subjects at risk for future exacerbations than the classic CB definition. SGRQ CB was at least a similar if not better predictor of future exacerbations than classic CB., (Copyright © 2019 American College of Chest Physicians. All rights reserved.)

Background: Previous studies have highlighted a relationship between reduction in rate of exacerbations with therapies containing inhaled corticosteroids (ICS) and baseline blood eosinophil count in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial showed that once-daily single-inhaler triple therapy significantly reduced exacerbations versus dual therapies. Blood eosinophil counts and smoking status could be important modifiers of treatment response to ICS. We aimed to model these relationships and their interactions, including outcomes other than exacerbations., Methods: IMPACT was a phase 3, randomised, double-blind, parallel-group, 52-week global study comparing once-daily single-inhaler triple therapy (fluticasone furoate-umeclidinium-vilanterol) with dual inhaled therapy (fluticasone furoate-vilanterol or umeclidinium-vilanterol). Eligible patients had moderate-to-very-severe COPD and at least one moderate or severe exacerbation in the previous year. We used fractional polynomials to model continuous blood eosinophil counts. We used negative binomial regression for numbers of moderate and severe exacerbations, severe exacerbations, and pneumonia. We modelled differences at week 52 in trough FEV 1 , St George's Respiratory Questionnaire (SGRQ) total score, and Transition Dyspnoea Index using repeated measurements mixed effect models. IMPACT was registered with ClinicalTrials.gov, number NCT02164513., Findings: The magnitude of benefit of regimens containing ICS (fluticasone furoate-umeclidinium-vilanterol n=4151 and fluticasone furoate-vilanterol n=4134) in reducing rates of moderate and severe exacerbations increased in proportion with blood eosinophil count, compared with a non-ICS dual long-acting bronchodilator (umeclidinium-vilanterol n=2070). The moderate and severe exacerbation rate ratio for triple therapy versus umeclidinium-vilanterol was 0·88 (95% CI 0·74 to 1·04) at blood eosinophil count less than 90 cells per μL and 0·56 (0·47 to 0·66) at counts of 310 cells per μL or more; the corresponding rate ratio for fluticasone furoate-vilanterol versus umeclidinium-vilanterol was 1·09 (0·91 to 1·29) and 0·56 (0·47 to 0·66), respectively. Similar results were observed for FEV 1 , Transition Dyspnoea Index, and SGRQ total score; however, the relationship with FEV 1 was less marked. At blood eosinophil counts less than 90 cells per μL and at counts of 310 cells per μL or more, the triple therapy versus umeclidinium-vilanterol treatment difference was 40 mL (95% CI 10 to 70) and 60 mL (20 to 100) for trough FEV 1 , -0·01 (-0·68 to 0·66) and 0·30 (-0·37 to 0·97) for Transition Dyspnoea Index score, and -0·01 (-1·81 to 1·78) and -2·78 (-4·64 to -0·92) for SGRQ total score, respectively. Smoking status modified the relationship between observed efficacy and blood eosinophil count for moderate or severe exacerbations, Transition Dyspnoea Index, and FEV 1 , with former smokers being more corticosteroid responsive at any eosinophil count than current smokers., Interpretation: This analysis of the IMPACT trial shows that assessment of blood eosinophil count and smoking status has the potential to optimise ICS use in clinical practice in patients with COPD and a history of exacerbations., Funding: GlaxoSmithKline., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test., Methods: We prospectively recruited 237 patients for this study from those enrolled in the Bronchial Sample Collection for a Novel Genomic Test (BRAVE) study in 29 US and European sites. Patients were undergoing evaluation for interstitial lung disease and had had samples obtained by clinically indicated surgical or transbronchial biopsy or cryobiopsy for pathology. Histopathological diagnoses were made by experienced pathologists. Available HRCT scans were reviewed centrally. Three to five transbronchial lung biopsy samples were collected from all patients specifically for this study, pooled by patient, and extracted for transcriptomic sequencing. After exclusions, diagnostic histopathology and RNA sequence data from 90 patients were used to train a machine learning algorithm (Envisia Genomic Classifier, Veracyte, San Francisco, CA, USA) to identify a usual interstitial pneumonia pattern. The primary study endpoint was validation of the classifier in 49 patients by comparison with diagnostic histopathology. To assess clinical utility, we compared the agreement and confidence level of diagnosis made by central multidisciplinary teams based on anonymised clinical information and radiology results plus either molecular classifier or histopathology results., Findings: The classifier identified usual interstitial pneumonia in transbronchial lung biopsy samples from 49 patients with 88% specificity (95% CI 70-98) and 70% sensitivity (47-87). Among 42 of these patients who had possible or inconsistent usual interstitial pneumonia on HRCT, the classifier showed 81% positive predictive value (95% CI 54-96) for underlying biopsy-proven usual interstitial pneumonia. In the clinical utility analysis, we found 86% agreement (95% CI 78-92) between clinical diagnoses using classifier results and those using histopathology data. Diagnostic confidence was improved by the molecular classifier results compared with histopathology results in 18 with IPF diagnoses (proportion of diagnoses that were confident or provisional with high confidence 89% vs 56%, p=0·0339) and in all 48 patients with non-diagnostic pathology or non-classifiable fibrosis histopathology (63% vs 42%, p=0·0412)., Interpretation: The molecular test provided an objective method to aid clinicians and multidisciplinary teams in ascertaining a diagnosis of IPF, particularly for patients without a clear radiological diagnosis, in samples that can be obtained by a less invasive method. Further prospective clinical validation and utility studies are planned., Funding: Veracyte., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The Lung Volume Reduction Coil Treatment in Patients With Emphysema (RENEW) trial reported improvements in quality of life, pulmonary function, and exercise performance following endobronchial coil treatment., Objectives: The purpose of this post hoc analysis was to identify baseline predictors, including quantitative CT measures, that identify patients most likely to significantly benefit from endobronchial coil therapy., Methods: Quantitative CT analysis by an independent radiology laboratory and a qualitative evaluation by five blinded experts of the baseline thoracic CT imaging were performed. Univariate and multivariate logistic regression analyses were performed to elucidate characteristics associated with clinical response., Results: In total, 125 patients underwent coil treatment and had evaluable 12-month follow-up results. Of these, 78 patients received treatment of lobes with the highest emphysematous destruction determined by quantitative CT analysis (quantitative visual match [QVM]+), and 47 received treatment in at least one lobe that was not the most destroyed (QVM-). From the 78 patients with QVM+ treatment, a subgroup of 50 patients (64%) was identified with baseline residual volume > 200% predicted, emphysema score > 20% low attenuation area, and absence of airway disease. In this subgroup, greater lobar residual volume reduction in the treated lobes was achieved, which was associated with significant mean ± SE improvement in FEV 1 (15.2 ± 3.1%), St. George's Respiratory Questionnaire (-12 ± 2 points), and residual volume (-0.57 ± 0.13 L)., Discussion: This post hoc analysis found that both significant hyperinflation (residual volume ≥ 200% predicted) and CT analysis are critical for patient selection and treatment planning for endobronchial coil therapy. Quantitative CT analysis is important to identify optimal lobar treatment and to exclude patients with insufficient emphysema (< 20% low attenuation area), whereas visual assessment identifies patients with signs of airway disease associated with worse outcomes., Trial Registry: ClinicalTrials.gov; No.: NCT01608490; URL: www.clinicaltrials.gov., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma., Methods: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV 1 /FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV 1 ., Results: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes., Conclusions: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD., (Copyright © 2019 American College of Chest Physicians. All rights reserved.)

Rationale: Characteristics associated with adherence to long-term oxygen therapy (LTOT) in COPD remain unclear., Objectives: To identify patient characteristics at the time of oxygen initiation associated with its adherence., Methods: We conducted a secondary analysis of data from 359 COPD participants assigned to oxygen in the Long-term Oxygen Treatment Trial. Participants were prescribed continuous (n = 214) or intermittent (n = 145) oxygen based on desaturation patterns at study entry. At the time of initial prescription, participants rated their perceived readiness, confidence, and importance to use oxygen on a 0-10 scale (0 = not at all, 10 = very much). During follow-up, they self-reported average hours per day of use (adherence). Adherence was averaged over short-term (0-30 days), medium-term (months 9-12), and long-term (month 13 to last follow-up) intervals. Multivariable logistic regression models explored characteristics associated with high adherence (≥16 h/day [continuous] or ≥8 h/day [intermittent]) during each time interval., Results: Participant readiness, confidence, and importance at the time of oxygen initiation were associated with high short- and medium-term adherence. For each unit increase in baseline readiness, the odds of high short-term adherence increased by 21% (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.05-1.40) and 94% (OR 1.94, 95% CI 1.45-2.59) in the continuous and intermittent groups, respectively. In both groups, high adherence in the medium-term was associated with high adherence in the long-term (continuous, OR 12.49, 95% CI 4.90-31.79; intermittent, OR 38.08, 95% CI 6.96-208.20)., Conclusions: Readiness, confidence, and importance to use LTOT at initiation, and early high adherence, are significantly associated with long-term oxygen adherence., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: N-acetylcysteine (NAC) 600 mg twice daily is a well-tolerated oral antioxidant mucolytic that reduces the risk of moderate to severe chronic obstructive pulmonary disease (COPD) exacerbations. PANTHEON was one of the largest studies to evaluate NAC in COPD. It recruited current, ex- and never-smokers, concomitantly treated with other medications, and used a symptom-based definition of COPD exacerbations rather than the conventional healthcare resource utilisation (HCU) criteria., Methods: This manuscript reports post-hoc analyses of the PANTHEON dataset investigating whether smoking status or use of concomitant medications influenced the efficacy of NAC in terms of reducing exacerbations, defined according to HCU., Results: Compared with placebo (N = 482), NAC (N = 482) reduced the rate of HCU events by 20% (p = 0.0027), with a larger effect in current/ex-smokers (23%; p < 0.01). In patients receiving NAC and long-acting inhaled bronchodilator(s) but no ICS, there was a 60% reduction in the rate of exacerbations compared to those receiving placebo, long-acting bronchodilator(s) and ICS (p < 0.0001)., Conclusions: Overall, these post-hoc hypothesis-generating analyses confirm that NAC reduces the rate of COPD exacerbations, particularly in patients with COPD who have a significant smoking history, and in those not treated with ICS. NAC may provide an alternative to ICS-containing combinations in these patient subgroups., Clinical Trial Registration: Chinese Clinical Trials Registry, ChiCTR-TRC-09000460., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has an expected median survival of 3 months. Lung transplantation is a potentially lifesaving therapy for AE-IPF. However, the current knowledge of transplantation outcomes during AE-IPF is limited to a few small retrospective studies, reporting only 1-year post-transplantation survival., Methods: Study population included patients with IPF consecutively listed for lung transplantation at a single institution between the years 2012 and 2016. We collected lung allocation score (LAS), hospitalization, and survival data. The primary outcome was survival among patients transplanted during stable IPF vs during AE-IPF., Results: Of 89 patients with IPF listed for lung transplantation, 52 were transplanted during stable IPF and 37 were hospitalized due to AE-IPF. Of these 37 patients, nine died before transplantation, and 28 were transplanted during AE-IPF. Fifty percent of patients transplanted during AE-IPF died in a mean follow-up of 1.6 ± 1.2 years compared with 12% of patients transplanted during stable IPF who died in a mean follow-up of 2.6 ± 1.2 years. The Kaplan-Meier survival curves post-transplantation after 1 and 3 years for patients who were transplanted during stable IPF were 94% and 90% vs 71% and 60% in patients who were transplanted during AE-IPF (P = .0001). LAS above 80 conferred a 3-year hazard ratio for mortality of 5.7 vs LAS lower than 80 (95% CI, 2.33-14.0; P < .0005)., Conclusions: Patients with IPF transplanted during AE-IPF had significantly worse short-term and long-term survival compared with patients transplanted during stable IPF. Patients with AE-IPF and very high LAS may not experience the survival advantage expected from lung transplantation., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: COPD is an age-related disease. The role of cellular senescence in COPD has not been fully elucidated. This study examined the relationship between telomere length of peripheral blood leukocytes and clinical outcomes, including health status, rate of exacerbations, and risk of mortality in individuals with COPD., Methods: Using quantitative polymerase chain reaction, we measured the absolute telomere length (aTL) of DNA extracted from blood samples of 576 participants with moderate-to-severe COPD treated with either azithromycin or placebo for 12 months in the Macrolide Azithromycin for Prevention of Exacerbations of COPD (MACRO) study. All participants were followed for approximately 13 months, during which time health status and exacerbations were carefully ascertained, and an additional 29 months for mortality. The rates of exacerbation and mortality were determined by dividing the aTL into two groups using the median value as the cutoff., Results: Participants with shorter telomere length had worse health status defined by higher St. George's Respiratory Questionnaire scores (β = -0.09, P = .034). In the placebo arm of the study, the rate of exacerbation (rate ratio, 1.50; 95% CI, 1.16-1.95; P = .002) and the risk of mortality (hazard ratio, 9.45; 95% CI, 2.85-31.36; P = .015) were significantly higher in the shorter telomere group than in the longer telomere group; these differences were not observed in the azithromycin arm (interaction P = .008 for exacerbation and interaction P = .017 for mortality) CONCLUSIONS: These data suggest that replicative senescence may help to predict poor outcomes in COPD. Shorter leukocyte telomere lengths may represent a clinically translatable biomarker for identifying individuals at increased risk of poor clinical outcomes in COPD., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

As seen in this CME online activity (available at http://journal.cme.chestnet.org/copd-hot-hmv), acute exacerbations of COPD are associated with significant levels of morbidity and mortality. Acute noninvasive ventilation has been demonstrated its clinical efficacy and cost-effectiveness in reducing intubation rate and mortality and in patients with acute decompensated hypercapnic exacerbations of COPD. However, those patients with evidence of chronic hypercapnic respiratory failure have worse long-term outcomes compared with patients who have only transient hypercapnia during the acute phase returning to eucapnia in the recovery stage. Indeed, there are limited options available to improve the clinical outcome in these COPD patients with persistent hypercapnia. The Home Oxygen Therapy-Home Mechanical Ventilation (HOT-HMV) trial investigated admission-free survival in patients with persistent hypercapnia following a life-threatening exacerbation requiring acute noninvasive ventilation. Phenotyping patients to ensure chronic hypercapnia enriched the trial population to identify those patients at highest risk of readmission or death following an exacerbation. The addition of home noninvasive ventilation to home oxygen therapy in patients with persistent hypercapnia led to improved admission-free survival. The noninvasive ventilation was titrated to overnight measures of transcutaneous CO 2 to achieve control of nocturnal hypoventilation, which improved daytime chronic respiratory failure. Home noninvasive ventilation is a complex intervention requiring a multidisciplinary team and long-term patient follow-up to maximize the clinical benefit to the patient., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

COPD is the third leading cause of death in the United States, with current rates of both morbidity and mortality persisting and contributing significantly to long-term disability. More than 11 million Americans are diagnosed with COPD, with an additional 13 million people estimated to be living with undiagnosed disease. For patients diagnosed with COPD, the turning point will be hospitalization. It is important, therefore, that new treatment techniques that manage the signs and symptoms of the COPD and impact the prevalence and severity of exacerbations, hospital admissions, quality of life, and activities of daily living, and innovative clinical management strategies that optimize hospital discharge planning, all show promise in improving outcomes for patients with COPD. In particular, readmissions following COPD hospitalization are associated with high morbidity, mortality, and costs of care, and therefore hospital readmissions are receiving close scrutiny as an opportunity to improve patient care. To this end, programs to assess the presence and severity of dyspnea, and secretion burden and clearance, through implementation of a telemedicine program, use of noninvasive ventilation or supplemental oxygen, and development of a comprehensive self-management program have all been found to be variously effective as elements of a posthospitalization treatment plan. In this series of multi-media presentations and roundtable discussions published in CHEST (available at http://journal.cme.chestnet.org/copd-advanced-patient), leading international faculties discuss some of these specific interventions in detail to provide clinicians with possible solutions to the challenges of managing their patients with advanced COPD., (Copyright © 2018. Published by Elsevier Inc.)

Background: Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time., Methods: In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post-bronchodilator FEV 1 . Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344., Findings: 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations., Interpretation: Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations., Funding: National Institutes of Health, and National Heart, Lung, and Blood Institute., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The burden of chronic obstructive pulmonary disease (COPD) in the USA continues to grow. Although progress has been made in the the development of diagnostics, therapeutics, and care guidelines, whether patients' quality of life is improved will ultimately depend on the actual implementation of care and an individual patient's access to that care. In this Commission, we summarise expert opinion from key stakeholders-patients, caregivers, and medical professionals, as well as representatives from health systems, insurance companies, and industry-to understand barriers to care delivery and propose potential solutions. Health care in the USA is delivered through a patchwork of provider networks, with a wide variation in access to care depending on a patient's insurance, geographical location, and socioeconomic status. Furthermore, Medicare's complicated coverage and reimbursement structure pose unique challenges for patients with chronic respiratory disease who might need access to several types of services. Throughout this Commission, recurring themes include poor guideline implementation among health-care providers and poor patient access to key treatments such as affordable maintenance drugs and pulmonary rehabilitation. Although much attention has recently been focused on the reduction of hospital readmissions for COPD exacerbations, health systems in the USA struggle to meet these goals, and methods to reduce readmissions have not been proven. There are no easy solutions, but engaging patients and innovative thinkers in the development of solutions is crucial. Financial incentives might be important in raising engagement of providers and health systems. Lowering co-pays for maintenance drugs could result in improved adherence and, ultimately, decreased overall health-care spending. Given the substantial geographical diversity, health systems will need to find their own solutions to improve care coordination and integration, until better data for interventions that are universally effective become available., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

As seen in this CME online activity (available at http://journal.cme.chestnet.org/home-niv-copd), COPD is a common and debilitating disease and is currently the third leading cause of death in the United States. The role of noninvasive ventilation (NIV) in the management of severe, hypercapnic COPD has been controversial. However, it was concluded that current data would support the following recommendations. Patients with COPD with a waking Paco2 > 50 to 52 mm Hg, an overnight Paco2 > 55 mm Hg, or both who are symptomatic and compliant with other therapies should be eligible for NIV. In addition, multiple previous hospital admissions for COPD exacerbation, requiring noninvasive/invasive mechanical ventilation, strongly suggest a need for chronic NIV. Patients with COPD with a BMI > 30 kg/m2 respond particularly well to this therapy. When the decision is made to start NIV, this treatment is probably best initiated during a short hospitalization, although this can be accomplished in the clinic, home, or sleep laboratory if well-trained clinicians are available. Newer modes of NIV such as volume-assured pressure support, particularly with autotitrating expiratory positive airway pressure (EPAP), may create the opportunity for home NIV initiation easier for less experienced physicians. Regardless of the mode selected, inspiratory pressures must be in the 20 to 25 cm H2O range to meaningfully increase tidal volume, reduce work of breathing, and, importantly, reduce waking arterial Paco2. EPAP is currently set at 4 to 5 cm H2O, although future technologies may allow this to be individualized to maximally reduce auto-positive end expiratory pressure. The NIV device should have a backup rate although it is controversial as to whether this should be set at a high (18-20 breaths/min) vs a low (8-10 breaths/min) rate. The proper use of NIV in appropriately chosen patients with COPD can improve quality of life and increase survival. Ongoing studies are assessing if the frequency of future hospitalizations can be reduced with NIV. Thus, NIV should be strongly considered in any patients with COPD meeting the criteria described here.

Background: COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations., Methods: In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion., Results: The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the patient with COPD., Conclusions: This guideline is unique because it provides an up-to-date, rigorous, evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations.

Background: Bronchodilator response has been noted in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response to β₂ agonists resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely to be far more common than is symptomatic bronchoconstriction with β₂ agonists, but no systematic studies have been done. We assessed the prevalence of paradoxical response in current and former smokers with and without COPD, and its radiological correlates and clinical implications., Methods: Non-Hispanic white and African-American patients (aged 45-80 years) from a large multicentre study COPDGene were classified into two groups on the basis of a paradoxical response, defined as at least a 12% and 200 mL reduction in forced expiratory volume in 1 sec (FEV₁) or forced vital capacity (FVC), or both, after administration of a shortacting β₂ agonist (180 μg salbutamol)., Findings: Patients were recruited from January, 2008, to June, 2011. 9986 (96%) of 10,364 patients enrolled in the COPDGene study were included in the analysis population (mean age 59·6 years [SD 9·0]). Paradoxical response was noted in 453 (5%) of 9986 patients and the frequency was similar in patients with COPD (198 [4%] of 4439) and smokers without airflow obstruction (255 [5%] of 5547). Compared with white patients, a paradoxical response was twice as common in African-American patients (227 [7%] of 3282 vs 226 [3%] of 6704; p<0·0001). In the multivariate analyses, African-American ethnic origin (adjusted odds ratio 1·89, 95% CI 1·50-2·39; p<0·0001), less emphysema (0·96, 0·92-0·99; p=0·023), and increased wall-area percentage of the segmental airways (1·04, 1·01-1·08; p=0·023) were independently associated with a paradoxical response. A paradoxical response was independently associated with worse dyspnoea (adjusted β for Modified Medical Research Council Dyspnoea Scale 0·12 [95% CI 0·00 to 0·24]; p=0·05), lower 6 min walk distance (-45·8 [-78·5 to -13·2]; p=0·006), higher Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index (0·31 [0·19 to 0·43]; p<0·0001), and a greater frequency of severe exacerbations (increased by a factor of 1·35, 1·00-1·81; p=0·048)., Interpretation: Paradoxical response to β₂ agonists is associated with respiratory morbidity and is more common in African-Americans. These findings might have implications for the use of β2agonists in some patients., Funding: National Institutes of Health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Dynamic hyperinflation (DH) after lung volume reduction surgery (LVRS) has not been well studied. It is not known if reductions in DH correlate with improvements in exercise performance post-LVRS., Methods: Forty-two upper-lobe predominant emphysema patients who underwent LVRS were analyzed. Inspiratory capacity was measured every 2 min during symptom-limited cardiopulmonary exercise test (CPET) and end-expiratory lung volumes (EELV) were calculated. The main measure of DH was EELV/TLC ratio matched at metabolic isotimes (based on the post-rehabilitation VCO2max)., Results: Patients had very severe airflow obstruction (FEV1 28.3 ± 7.0% predicted), were hyperinflated (TLC 125 ± 17% predicted) and gas trapped (RV 198 ± 39% predicted). Compared to the post-rehab baseline, dynamic hyperinflation (EELV/TLC) was significantly reduced after LVRS at 6, 12, 24, and 36 months. There were also increases in inspiratory reserve volume at matched isotimes after surgery. Patients adopted a slower, deeper breathing pattern during exercise after LVRS, which strongly correlated to reductions in DH. There were significant correlations between reductions in DH (EELV/TLC @50% VCO2max) and improvements in 6 min walk distance (Pearson r = -0.411, p = 0.02, n = 33) and maximal watts on CPET (Spearman r = -0.536, p = 0.001, n = 33) when comparing post-rehabilitation and 6 month post-LVRS values., Conclusion: Dynamic hyperinflation during exercise was reduced after LVRS (up to 3 years) and there was a strong association between alterations in breathing pattern and reduced DH after LVRS. This is the first study to demonstrate that reductions in DH correlated with improved exercise performance following LVRS., (Copyright © 2014 Elsevier Ltd. All rights reserved.)